TOXICOLOGICAL PROFILE FOR 

DICHLOROBENZENES 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry
 

August 2006 
DICHLOROBENZENES ii 

DISCLAIMER 

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

Agency for Toxic Substances and Disease Registry. 
DICHLOROBENZENES iii 

UPDATE STATEMENT 

A Toxicological Profile for dichlorobenzenes, Draft for Public Comment was released in September 

2004. 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 
DICHLOROBENZENES iv 

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DICHLOROBENZENES 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 was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Julie Louise Gerberding, M.D., M.P.H. 

Administrator 

Agency for Toxic Substances and 

Disease Registry
 
DICHLOROBENZENES vi 

*Legislative Background 

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 November 17, 1997 (62 FR 61332). For prior 

versions of the list of substances, see Federal Register notices dated April 29, 1996 (61 FR 18744); 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); and February 

28, 1994 (59 FR 9486). Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR 

to prepare a toxicological profile for each substance on the list. 
 

DICHLOROBENZENES vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

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

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

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

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

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

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

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

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

the general health effects observed following exposure. 

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

and assesses the significance of toxicity data to human health. 

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

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

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

reported in this section. 

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

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

following exposure. 

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

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 

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

Section 3.7 Children’s Susceptibility 

Section 6.6 Exposures of Children 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-888-42-ATSDR or (404) 498-0110 Fax: (770) 488-4178 

E-mail: atsdric@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 
DICHLOROBENZENES viii 

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

Toxicity; and numerous chemical-specific case studies. 

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, 55 West Seegers Road, Arlington Heights, 

IL 60005 • Phone: 847-818-1800 • FAX: 847-818-9266. 
DICHLOROBENZENES ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Malcolm Williams, DVM, Ph.D. 

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

Stephen Bosch, B.S. 

Daniel Plewak, B.S. 

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 Research Implementation 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. 
DICHLOROBENZENES x 

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DICHLOROBENZENES xi 

PEER REVIEW 

A peer review panel was assembled for 1,2-, 1,3-, and 1,4-dichlorobenzenes. The panel consisted of the 

following members: 

1. Dr. Olen Brown, Emeritus Research Professor, University of Missouri, 527 North Cedar Lake 

Drive West, Columbia, Missouri; 

2. Dr. Robert Michaels, President, RAM TRAC Corporation, 3100 Rosendale Road, Schenectady, 

New York; and 

3.	 Dr. Clint Skinner, President, Skinner Associates, 3985 Shooting Star Road, Creston, California. 

These experts collectively have knowledge of dichlorobenzenes’ 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. 
DICHLOROBENZENES xii 

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DICHLOROBENZENES xiii 

CONTENTS 

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

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

FOREWORD ...............................................................................................................................................iv 

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

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

PEER REVIEW ............................................................................................................................................x 

CONTENTS................................................................................................................................................xii 

LIST OF FIGURES ...................................................................................................................................xvi 

LIST OF TABLES...................................................................................................................................xviii 

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

1.1 WHAT ARE DICHLOROBENZENES? ....................................................................................1 

1.2 WHAT HAPPENS TO DICHLOROBENZENES WHEN THEY ENTER THE

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

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

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

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

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

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO

 DICHLOROBENZENES? ..........................................................................................................7 

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

 TO DICHLOROBENZENES? ....................................................................................................8 

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 

DICHLOROBENZENES IN THE UNITED STATES.............................................................11 

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

2.3 MINIMAL RISK LEVELS (MRLs) .........................................................................................21 

3. HEALTH EFFECTS..............................................................................................................................53 

3.1 INTRODUCTION.....................................................................................................................53 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................53 

3.2.1 Inhalation Exposure ..............................................................................................................54 

3.2.1.1 Death ............................................................................................................................77 

3.2.1.2 Systemic Effects...........................................................................................................78 

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................95 

3.2.1.4 Neurological Effects.....................................................................................................96 

3.2.1.5 Reproductive Effects....................................................................................................97 

3.2.1.6 Developmental Effects .................................................................................................99 

3.2.1.7 Cancer.........................................................................................................................100 

3.2.2 Oral Exposure......................................................................................................................101 

3.2.2.1 Death ..........................................................................................................................102 

3.2.2.2 Systemic Effects.........................................................................................................152 
 

 

 

DICHLOROBENZENES xiv 

3.2.2.3 Immunological and Lymphoreticular Effects.............................................................182 

3.2.2.4 Neurological Effects...................................................................................................183 

3.2.2.5 Reproductive Effects..................................................................................................185 

3.2.2.6 Developmental Effects ...............................................................................................187 

3.2.2.7 Cancer.........................................................................................................................190 

3.2.3 Dermal Exposure.................................................................................................................193 

3.2.3.1 Death ..........................................................................................................................193 

3.2.3.2 Systemic Effects.........................................................................................................194 

3.2.3.3 Immunological and Lymphoreticular Effects.............................................................195 

3.2.3.4 Neurological Effects...................................................................................................195 

3.2.3.5 Reproductive Effects..................................................................................................195 

3.2.3.6 Developmental Effects ...............................................................................................195 

3.2.3.7 Cancer.........................................................................................................................195 

3.3 GENOTOXICITY ...................................................................................................................195 

3.4 TOXICOKINETICS................................................................................................................202 

3.4.1 Absorption...........................................................................................................................203 

3.4.1.1 Inhalation Exposure....................................................................................................203 

3.4.1.2 Oral Exposure.............................................................................................................204 

3.4.1.3 Dermal Exposure ........................................................................................................206 

3.4.2 Distribution .........................................................................................................................207 

3.4.3 Metabolism..........................................................................................................................210 

3.4.4 Elimination and Excretion...................................................................................................215 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ...........216 

3.5 MECHANISMS OF ACTION ................................................................................................222 

3.5.1 Pharmacokinetic Mechanisms.............................................................................................222 

3.5.2 Mechanisms of Toxicity......................................................................................................223 

3.5.3 Animal-to-Human Extrapolations.......................................................................................225 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................226 

3.7 CHILDREN’S SUSCEPTIBILITY.........................................................................................228 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................231 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Dichlorobenzenes..........................232 

3.8.2 Biomarkers Used to Characterize Effects Caused by Dichlorobenzenes............................233 

3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................234 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.............................................235 

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................236 

3.11.1 Reducing Peak Absorption Following Exposure ............................................................237 

3.11.2 Reducing Body Burden...................................................................................................237 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects .........................................238 

3.12 ADEQUACY OF THE DATABASE......................................................................................239 

3.12.1 Existing Information on Health Effects of Dichlorobenzenes........................................239 

3.12.2 Identification of Data Needs ...........................................................................................243 

3.12.3 Ongoing Studies..............................................................................................................254 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................255 

4.1 CHEMICAL IDENTITY.........................................................................................................255 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................255 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................263 

5.1 PRODUCTION .......................................................................................................................263 

5.2 IMPORT/EXPORT .................................................................................................................265 

5.3 USE..........................................................................................................................................269 
DICHLOROBENZENES xv 

5.4 DISPOSAL..............................................................................................................................270 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................271 

6.1 OVERVIEW............................................................................................................................271 

6.2 RELEASES TO THE ENVIRONMENT................................................................................275 

6.2.1 Air .......................................................................................................................................278 

6.2.2 Water...................................................................................................................................281 

6.2.3 Soil ......................................................................................................................................283 

6.3 ENVIRONMENTAL FATE....................................................................................................284
 

6.3.1 Transport and Partitioning...................................................................................................284 

6.3.2 Transformation and Degradation ........................................................................................289 

6.3.2.1 Air...............................................................................................................................289 

6.3.2.2 Water ..........................................................................................................................289 

6.3.2.3 Sediment and Soil.......................................................................................................291 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................294 

6.4.1 Air .......................................................................................................................................294 

6.4.2 Water...................................................................................................................................302 

6.4.3 Sediment and Soil ...............................................................................................................307 

6.4.4 Other Environmental Media................................................................................................310 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................311 

6.6 EXPOSURES OF CHILDREN...............................................................................................316 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................321 

6.8 ADEQUACY OF THE DATABASE......................................................................................322 

6.8.1 Identification of Data Needs ...............................................................................................322 

6.8.2 Ongoing Studies..................................................................................................................325 

7. ANALYTICAL METHODS ...............................................................................................................327 

7.1 BIOLOGICAL MATERIALS.................................................................................................327 

7.2 ENVIRONMENTAL SAMPLES............................................................................................331 

7.3 ADEQUACY OF THE DATABASE......................................................................................335 

7.3.1 Identification of Data Needs ...............................................................................................336 

7.3.2 Ongoing Studies..................................................................................................................337 

8. REGULATIONS AND ADVISORIES ...............................................................................................338 

9. REFERENCES .................................................................................................................................... 346 

10. GLOSSARY ......................................................................................................................................397 

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 
DICHLOROBENZENES xvi 

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DICHLOROBENZENES xvii 

LIST OF FIGURES 

3-1. Levels of Significant Exposure to 1,2-Dichlorobenzene—Inhalation................................................ 61 

3-2. Levels of Significant Exposure to 1,4-Dichlorobenzene—Inhalation................................................ 73 

3-3. Levels of Significant Exposure to 1,2-Dichlorobenzene—Oral....................................................... 114 

3-4. Levels of Significant Exposure to 1,3-Dichlorobenzene—Oral....................................................... 123 

3-5. Levels of Significant Exposure to 1,4-Dichlorobenzene—Oral....................................................... 145 

3-6. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance....................................................................................................218 

3-7. Existing Information on Health Effects of 1,2-Dichlorobenzene .....................................................240 

3-8. Existing Information on Health Effects of 1,3-Dichlorobenzene .....................................................241 

3-9. Existing Information on Health Effects of 1,4-Dichlorobenzene .....................................................242 

6-1. Frequency of NPL Sites with 1,2-Dichlorobenzene Contamination ................................................272 

6-2. Frequency of NPL Sites with 1,3-Dichlorobenzene Contamination ................................................273 

6-3. Frequency of NPL Sites with 1,4-Dichlorobenzene Contamination ................................................274 

6-4. The Decomposition of 1,4-Dichlorobenzene in Air .........................................................................290 

6-5. The Decomposition of 1,4-Dichlorobenzene in Soil and Water.......................................................292 
DICHLOROBENZENES xviii 

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DICHLOROBENZENES xix 

LIST OF TABLES 

3-1. Levels of Significant Exposure to 1,2-Dichlorobenzene—Inhalation................................................ 55 

3-2. Levels of Significant Exposure to 1,4-Dichlorobenzene—Inhalation................................................ 63 

3-3. Levels of Significant Exposure to 1,2-Dichlorobenzene—Oral....................................................... 103 

3-4. Levels of Significant Exposure to 1,3-Dichlorobenzene—Oral....................................................... 119 

3-5. Levels of Significant Exposure to 1,4-Dichlorobenzene—Oral....................................................... 125 

3-6. Genotoxicity of Dichlorobenzenes In Vivo.......................................................................................196 

3-7. Genotoxicity of Dichlorobenzenes In Vitro......................................................................................197 

3-8. Tissue Concentrations (nmol/g tissue) of Radioactivity in Male Wistar Rats at Four Time 

Points after Oral Administration of 10 mg/kg 14C-Labeled 1,2-Dichlorobenzene in Corn Oil........208 

3-9. Parameters in PBPK Models for 1,2-Dichlorobenzene ....................................................................220 

4-1. Chemical Identity of 1,2-, 1,3-, and 1,4-Dichlorobenzene ...............................................................256 

4-2. Physical and Chemical Properties of 1,2-, 1,3-, and 1,4-Dichlorobenzene ......................................259 

5-1. Influence of Catalysts on the Ratio 1,4-:1,2-Dichlorobenzene.........................................................264 

5-2. Facilities that Produce, Process, or Use 1,2-Dichlorobenzene .........................................................266 

5-3. Facilities that Produce, Process, or Use 1,3-Dichlorobenzene .........................................................267 

5-4. Facilities that Produce, Process, or Use 1,4-Dichlorobenzene .........................................................268 

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

1,2-Dichlorobenzene ........................................................................................................................276 

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

1,3-Dichlorobenzene ........................................................................................................................277 

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

1,4-Dichlorobenzene ........................................................................................................................279 

6-4. Comparison of Bioconcentration Factors (BCFs) for Various Chlorinated Benzenes in Fish .........287 

6-5. Levels of 1,4-Dichlorobenzene in Indoor Air...................................................................................295 

6-6. Levels of 1,4-Dichlorobenzene in Outdoor Air................................................................................300 
DICHLOROBENZENES xx 

6-7. Levels of 1,4-Dichlorobenzene Detected in Workplace Air.............................................................301 

6-8. Levels of 1,2-Dichlorobenzene in Outdoor Air................................................................................303 

6-9. Levels of 1,3-Dichlorobenzene in Outdoor Air................................................................................304 

6-10. Concentrations of 1,4-Dichlorobenzene in Blood Samples............................................................314 

6-11. Dichlorobenzene Concentrations (μg/kg) in Human Placentas from Five Slovak Regions...........317 

7-1. Analytical Methods for Determining Dichlorobenzenes in Biological Materials ............................328 

7-2. Analytical Methods for Determining Dichlorobenzenes in Environmental Samples.......................332 

8-1. Regulations and Guidelines Applicable to Dichlorobenzenes..........................................................342 
DICHLOROBENZENES 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about dichlorobenzenes (DCBs) and the effects of 

exposure to them. 

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. 1,2-, 1,3-, and 1,4-Dichlorobenzene have been identified in 

at least 281, 175, and 330, respectively, of the 1,662 current or former NPL sites. Although the 

total number of NPL sites evaluated for these substances is not known, the possibility exists that 

the number of sites at which dichlorobenzenes are 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 these substances 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 dichlorobenzenes, 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 them. 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 ARE DICHLOROBENZENES? 

Each of the three types of DCBs (i.e., 1,2-DCB, 1,3-DCB, and 1,4-DCB) contains two chlorine 

atoms connected to one benzene molecule. 1,2-DCB is a colorless to pale yellow liquid used to 

make herbicides. 1,3-DCB is a colorless liquid used to make herbicides, insecticides, medicine, 

and dyes. 1,4-DCB, the most important of the three chemicals, is a colorless to white solid. It 
DICHLOROBENZENES 2 

1. PUBLIC HEALTH STATEMENT 

smells like mothballs and it is one of two chemicals commonly used to make mothballs. 

1,4-DCB also is used to make deodorant blocks used in garbage cans and restrooms, and to help 

control odors in animal-holding facilities. 1,4-DCB has been used as an insecticide on fruit and 

as an agent to control mold and mildew growth on tobacco seeds, leather, and some fabrics. 

Recently, using 1,4-DCB to make resins has become very important. 

When a package of 1,4-DCB is opened, it ‘sublimates’, that is, it slowly changes from a solid 

into a vapor, and enters the atmosphere. The vapor acts as a deodorizer and insect killer. Most 

of the 1,2-, 1,3-, and 1,4-DCB released into the environment is present as a vapor. DCBs can 

burn, but they do not burn easily. Most people begin to smell 1,4-DCB when it is in the air at a 

concentration of 0.18 parts per million (ppm) and 0.011 ppm in water. 

DCBs do not occur naturally; chemical companies produce them to make products for home use 

and other chemicals such as herbicides and plastics. More information about the properties and 

uses of 1,2-, 1,3-, and 1,4-DCB is provided in Chapters 4 and 5. 

1.2 WHAT HAPPENS TO DICHLOROBENZENES WHEN THEY ENTER THE 

ENVIRONMENT? 

Most of the 1,4-DCB enters the environment when it is used in mothballs and in toilet-deodorizer 

blocks. Some 1,4-DCB is released to the air by factories that make or use it, and only a little is 

released to soil and water. Very little 1,4-DCB enters the environment from hazardous waste 

sites. Some 1,2- and 1,3-DCBs are released into the environment when used to make herbicides 

and when people use products that contain these chemicals. Companies that make 1,4-DCB also 

make unwanted amounts of 1,2-DCB during the process. 1,2-DCB is released to the 

environment when companies dispose of these unwanted supplies. 

Because DCBs do not dissolve easily in water, the small amounts that enter water quickly 

evaporate into the air. If they are released to groundwater, they may be transported through the 

ground to surface water. Sometimes, DCBs bind to soil and sediment. DCBs in soil usually are 
DICHLOROBENZENES 3 

1. PUBLIC HEALTH STATEMENT 

not easily broken down by soil organisms. Evidence suggests that plants and fish absorb DCBs. 

1,4-DCB has been detected at concentrations of up to 470 parts per billion (ppb) in fish. 

More information about DCBs in the environment is provided in Chapters 5 and 6. 

1.3 HOW MIGHT I BE EXPOSED TO DICHLOROBENZENES? 

Humans are exposed to 1,4-DCB mainly by breathing vapors from 1,4-DCB products used in the 

home, such as mothballs and toilet-deodorizer blocks. Reported levels of 1,4-DCB in some 

homes and public restrooms have ranged from 0.291 to 272 parts of 1,4-DCB per billion parts 

(ppb) of air. 1,2- and 1,3-DCB are not found frequently in the air of homes and buildings 

because, unlike 1,4-DCB, these chemicals are not used in household products. Outdoor levels of 

1,4-DCB range from 0.01 to 1 ppb and are much lower than levels in homes and buildings. 

Levels in the air around hazardous waste sites are low and range from 0.01 to 4.2 ppb. Outdoor 

air levels generally range from 0.01 to 0.1 ppb for 1,2-DCB and from 0.001 to 0.1 ppb for 

1,3-DCB. 

DCBs have been found in samples of drinking water from surface water sources. 1,4-DCB was 

found in 13% of surface water samples collected during a national survey. These samples 

contained about 0.008–154 ppb of 1,4-DCB. DCBs also have been found in drinking water from 

wells but at low concentrations. DCBs are found only infrequently in soil, but they have been 

detected in soil around hazardous waste sites in the United States. 

DCBs have been detected in beef, pork, chicken, eggs, baked goods, soft drinks, butter, peanut 

butter, fruits, vegetables, and fish. However, the levels of DCBs in foods are generally low. 

The average daily adult intake of 1,4-DCB is about 35 micrograms (μg), which comes mainly 

from breathing 1,4-DCB vapors released from products in homes and businesses. The average 

daily adult respiratory exposure of the other DCBs is about 1.8 μg for 1,2-DCB and about 0.8 μg 

for 1,3-DCB. 
DICHLOROBENZENES 4 

1. PUBLIC HEALTH STATEMENT 

Individuals can be occupationally exposed to DCBs in workplace air at much higher levels than 

the general public is exposed. Levels measured in the air of factories that make or process 

1,4-DCB products have ranged from 5.6 to 748 ppm of air. In addition, people who live or work 

near industrial facilities or hazardous waste sites that have high levels of DCBs may have greater 

exposure to these compounds due to emissions from the facilities and waste sites. People who 

work or live in buildings where air fresheners, toilet block deodorants, or moth balls containing 

1,4-DCB are used also are expected to have a higher exposure to this compound, which could 

occur from skin contact as well as by breathing. 

More information on how you could be exposed to DCBs is given in Chapter 6. 

1.4 HOW CAN DICHLOROBENZENES ENTER AND LEAVE MY BODY? 

The main way DCBs enter your body is through the lungs when you breathe in DCB vapors 

released in the workplace or in the home from use of products that contain it. When you breathe 

in these chemicals for a few hours, it is likely that some of the DCBs that have entered your body 

will get into your bloodstream. 

DCBs also can get into your body if you drink water or eat certain foods that contain them, such 

as meat, chicken, eggs, or fish. Most of the DCBs that enter your body from food and water will 

get into your bloodstream. It is not likely that DCBs will enter your body through the skin if you 

touch products that contain them. 

1,4-DCB used in the home could be accidentally swallowed, especially by young children. This 

possibility exists because household products that contain 1,4-DCB, particularly some kinds of 

mothballs and deodorant blocks, might be freely available in closets or bathrooms. 

Most of the DCB that enters your body (perhaps more than 95%) leaves through the urine in less 

than a week. Small amounts (perhaps 1–2%) leave your body in the feces and in the air you 

breathe out. Tiny amounts remain in your fat and might stay there for a long time. 
DICHLOROBENZENES 5 

1. PUBLIC HEALTH STATEMENT 

Most of the DCBs that enter your body are changed into other chemicals, mainly 

dichlorophenols. It is not known if these breakdown products are more or less harmful than the 

DCBs themselves. 

More information about how DCBs enter and leave the body is found in Chapter 3. 

1.5 HOW CAN DICHLOROBENZENES 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. 

Most of the information on health effects of DCBs is from studies of 1,2- and 1,4-DCB. Very 

little is known about the health effects of 1,3-DCB, especially in humans, but they are likely to 

be similar to those of the other DCBs. 

Inhaling the vapor or dusts of 1,2-DCB and 1,4-DCB at very high concentrations could be very 

irritating to your eyes and nose and cause burning and tearing of the eyes, coughing, difficult 

breathing, and an upset stomach. These concentrations could occur in workplaces, but are much 

higher than you would be exposed to in the home. 1,4-DCB is the only DCB that is commonly 

used in household products (mainly mothballs and toilet-deodorizer blocks). Scientists have no 

clear evidence that the moderate use of common household products containing 1,4 DCB will 

cause any problems to your health. A recent study reports limited evidence suggesting that 

inhalation exposure to 1,4-DCB may result in decreases in lung function. Some people reported 
DICHLOROBENZENES 6 

1. PUBLIC HEALTH STATEMENT 

health problems, such as dizziness, headaches, and liver problems, from very high levels of 

1,4-DCB in the home. However, these people used very high amounts of 1,4-DCB products and 

continued to use the products for months or even years, even though they felt ill. People who ate 

1,4-DCB products regularly for long periods (months to years) because of its sweet taste 

developed skin blotches and problems with red blood cells, such as anemia (iron-poor blood). 

Little information is available about the effects of skin contact with DCBs. 1,4-DCB might 

cause a burning feeling in your skin if you hold mothballs or toilet-deodorizer blocks against 

your skin for a long time. 

Breathing or eating any of the DCBs caused harmful effects in the liver of laboratory animals. 

Animal studies also found that 1,2-DCB and 1,4-DCB caused effects in the kidneys and blood, 

and that 1,3-DCB caused thyroid and pituitary effects. There is no clear evidence that 1,2-DCB 

and 1,4-DCB impair reproduction or fetal development in animals at levels below those that also 

cause serious health effects in the mother, although there is an indication that 1,4-DCB can affect 

development of the nervous system after birth. 

Lifetime exposure to 1,4-DCB by breathing or eating induced liver cancer in mice. 1,2-DCB 

was not carcinogenic in laboratory animals, and 1,3-DCB has not been tested for its potential to 

cause cancer. The animal studies suggest that 1,4-DCB could play a role in the development of 

cancer in humans, but we do not definitely know this. The U.S. Department of Health and 

Human Services (DHHS) has determined that 1,4-DCB might be a human carcinogen. The 

International Agency for Research on Cancer (IARC) determined that 1,4-DCB is possibly 

carcinogenic to humans. Both IARC and the EPA concluded that 1,2-DCB and 1,3-DCB are not 

classifiable as to human carcinogenicity. 

More information about how DCBs can affect your health is given in Chapter 3. 

1.6 HOW CAN DICHLOROBENZENES AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 
DICHLOROBENZENES 7 

1. PUBLIC HEALTH STATEMENT 

Children are exposed to DCBs in many of the same ways adults are. It is possible that mothballs 

and toilet bowl deodorant blocks containing 1,4-DCB could be played with or accidentally 

swallowed, especially by young children. Because children tend to be curious about unknown 

powders and liquids, and because these products might be easily accessible in cabinets, closets, 

or bathrooms, children could be at a higher risk of exposure to 1,4-DCB than adults. 

Children who are exposed to DCBs are likely to exhibit the same effects as adults, although this 

is not known for certain. Thus, all health problems of DCBs observed in adults are of potential 

concern in children. 

Children can also be exposed to DCBs prenatally, because all three isomers have been detected 

in placenta samples, as well as through breast feeding. There is no reliable evidence suggesting 

that DCBs cause birth defects, although animal data raise concern for effects of 1,4-DCB on 

postnatal development of the nervous system. 

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

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

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

department to investigate. 

You and your children could be exposed to 1,4-DCB in your home if you use consumer products 

that contain 1,4-DCB, such as some toilet bowl cleaners and mothballs. Exposure of children to 

1,4-DCB can be minimized by discouraging them from playing with, swallowing, or having skin 

contact with treated products. These items should be stored out of reach of young children and 

kept in their original containers to prevent accidental poisonings. Keep your Poison Control 

Center’s number by the phone. 
DICHLOROBENZENES 8 

1. PUBLIC HEALTH STATEMENT 

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

EXPOSED TO DICHLOROBENZENES? 

Several tests can be used to show if you have been exposed to DCBs. The most commonly used 

tests measure their dichlorophenol breakdown products in urine and blood. These tests require 

special equipment that is not routinely available in a doctor's office, but they can be performed in 

a special laboratory. 

The presence of the dichlorophenol breakdown products in the urine indicates a person has been 

exposed to DCBs within the previous day or two. For example, detection of 2,5-dichlorophenol 

in urine is commonly used to determine worker exposure to 1,4-DCB in industrial settings. 

Another test measures levels of DCBs in your blood, but this is used less often. Neither of these 

tests can be used to show how high the level of DCB exposure was or to predict whether harmful 

health effects will follow. 

More information about how 1,4-DCB can be measured in exposed people is presented 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 
DICHLOROBENZENES 9 

1. PUBLIC HEALTH STATEMENT 

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 dichlorobenzenes include the following: 

The federal government has taken a number of steps to protect people from excessive exposure 

to DCBs. EPA has listed 1,2-, 1,3-, and 1,4-DCB as hazardous wastes and subjects them to 

hazardous waste regulations. EPA has set maximum levels of 600 micrograms (μg) of 1,2-DCB 

and 75 μg of 1,4-DCB per liter of drinking water. 1,4-DCB is a pesticide registered with EPA, 

and its manufacturers must provide certain kinds of information to EPA for it to be registered for 

use as a pesticide. OSHA has set maximum levels of 50 ppm for 1,2-DCB and 75 ppm for 

1,4-DCB in workplace air for an 8-hour day, 40-hour workweek. 

More information about federal and state regulations regarding DCBs is presented 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 
 

 

 

 

 

 

 

DICHLOROBENZENES 10 

1. PUBLIC HEALTH STATEMENT 

and technical assistance number at 1-888-42ATSDR (1-888-422-8737), by e-mail at 

atsdric@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/ 
DICHLOROBENZENES 11 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO DICHLOROBENZENES IN 

THE UNITED STATES 

Dichlorobenzenes (DCBs) are chlorinated aromatic compounds that have three isomeric forms. 1,2-DCB 

is a colorless to pale yellow liquid used primarily as a precursor for 3,4-dichloroaniline herbicides. 

1,3-DCB is a colorless liquid used in the production of various herbicides, insecticides, pharmaceuticals, 

and dyes. 1,4-DCB, the most commercially important dichlorobenzene isomer, is a volatile colorless to 

white crystalline material with a mothball-like, penetrating odor. It is used as a deodorant for restrooms, 

for moth control, and in the production of polyphenylene sulfide (PPS) resin. 

DCBs are not known to occur naturally in the environment. The primary sources of 1,4-DCB of 

industrial or commercial origin in the environment are releases from space deodorants and moth 

repellants into the atmosphere. 1,4-DCB might also be released into water through waste water streams 

and landfill leachate and to soil through sewage sludge application, disposal of industrial waste, and 

atmospheric deposition. 1,2- and 1,3-DCBs are expected to be released to the environment during their 

use in herbicide production or during the use of other products containing these isomers. 1,2-DCB is 

produced in large quantities as a by-product during the production of 1,4-DCB and can be released into 

the environment during the disposal of unused supplies. 

1,2-, 1,3-, and 1,4-DCB have similar physical and chemical properties, and consequently are expected to 

have similar environmental fates. DCBs will exist predominantly in the vapor-phase in the atmosphere. 

They are degraded in the atmosphere by reaction with hydroxyl radicals, with atmospheric lifetimes 

(theoretically calculated) of about 1 month. The detection of these chemicals in rainwater suggests that 

atmospheric removal via washout is possible. Depending on soil type, DCBs are expected to be 

moderately mobile in soil and to volatilize from surface water and soil surfaces to the atmosphere. 

Volatilization, sorption, biodegradation, and bioaccumulation are likely to be competing processes, with 

the dominant fate being determined by local environmental conditions. 

DCB concentrations in soil, water, and food are generally low in comparison to concentrations in air, 

indicating that exposure of the general population to DCBs is predominantly by inhalation. Individuals 

are more likely to be exposed to 1,4-DCB than to the other isomers due to the widespread use of the 
DICHLOROBENZENES 12 

2. RELEVANCE TO PUBLIC HEALTH 

1,4-isomer in deodorant and moth repellent products. Measured DCB concentrations in ambient outdoor 

air generally range from 0.01 to 0.1 ppb for 1,2-DCB, from 0.001 to 0.1 ppb for 1,3-DCB, and from 

0.01 to 1 ppb for 1,4-DCB. The average daily adult intakes of 1,2-, 1,3-, and 1,4-DCB from ambient air 

have been estimated to be about 1.8, 0.8, and 35 μg/day, respectively. The heavy use of products 

containing 1,4-DCB in homes and other buildings has resulted in higher concentrations of this substance 

in indoor air compared to concentrations in outdoor air. Measured 1,4-DCB concentrations in indoor air 

generally range from 0.1 ppb to 100 ppb. Indoor inhalation exposure to 1,2- or 1,3-DCB is not expected 

to be important since these substances are not used in household and consumer products to the extent of 

1,4-DCB. 1,2- and 1,4-DCB have been detected in adipose tissue at concentrations ranging from <0.1 to 

38 ppb and from 0.2 to 500 ppb, respectively. 1,4-DCB has been detected in blood samples at 

concentrations ranging from below 0.04 to 45 ppb, while measured 1,2-DCB concentrations in blood are 

below 3 ppb. 

Children can be exposed to DCBs prenatally, as indicated by the detection of all three isomers in placenta 

samples, as well as through breast feeding. 1,2-DCB concentrations measured in whole human milk 

range from 3 to 29 ppb. 1,3- and 1,4-DCB were detected together in whole human milk with mean and 

maximum concentrations of 6 and 75 ppb, respectively. These isomers were detected in milkfat samples 

at a mean concentration of 161 ppb and a maximum concentration of 4,180 ppb. 1,2-, 1,3-, and 1,4-DCB 

measured separately in whole human milk samples had concentrations of 9, <5, and 25 ppb, respectively, 

while the milk fat of these samples contained 230 ppb of 1,2-DCB and 640 ppb of 1,4-DCB. Children 

and adults are perhaps at equal risk for exposure to 1,4-DCB since there is no evidence to indicate that 

children are likely to be exposed to lower amounts of 1,4-DCB from everyday living. While actual 

exposure reports are limited to a small number of case reports, available evidence suggests that children 

may be exposed to 1,4-DCB if they eat or play with moth balls or toilet deodorizers. 

2.2 SUMMARY OF HEALTH EFFECTS 

1,2-Dichlorobenzene. 1,2-DCB is quickly and extensively absorbed through both the gastrointestinal 

tract and the respiratory tract; studies measuring the absorption of 1,2-DCB following dermal exposure 

are not available. Following absorption, 1,2-DCB is distributed throughout the body, but tends to be 

found in greatest levels in the fat, kidney, and liver. 1,2-DCB is initially metabolized by cytochrome 

P-450 enzymes, specifically P4502E1, to an active epoxide followed by hydrolysis to 2,3-dichlorophenol 

or 3,4-dichlorophenol. The dichlorophenols may be further oxidized or, more often, be conjugated to 

glutathione, sulfate, or to form the glucuronide; conjugation occurs extensively, with virtually no 
 

 

 

DICHLOROBENZENES 13 

2. RELEVANCE TO PUBLIC HEALTH 

unconjugated metabolites reported in the available studies. Metabolism is believed to occur mainly in the 

liver, but may occur at lower levels in other tissues, such as the kidney or lung. Elimination of 1,2-DCB 

from the body is rapid, with the majority of a single dose being removed within the first 75 hours 

postexposure; elimination occurs primarily in the urine as metabolites. 

Information on health effects of 1,2-DCB in humans is essentially limited to observations of respiratory 

tract and eye irritation in workers chronically exposed to the vapor. The potential for inhaled 1,2-DCB to 

cause respiratory tract effects is also shown by the induction of nasal olfactory lesions in an acuteduration study in mice. This effect occurred at concentrations similar to or below the lowest exposure 

levels that caused systemic effects in rats, mice, and guinea pigs in other acute and intermediate-duration 

inhalation studies. No intermediate-duration studies examined the nasal cavity, indicating that a critical 

effect for longer-term inhalation exposures cannot be identified. The liver is the primary systemic target 

of toxicity in animals exposed to 1,2-DCB. Acute-, intermediate,- and chronic-duration inhalation and 

oral studies clearly identify the liver as a sensitive target of oral exposure, inducing increases in liver 

weight at low levels of exposure and histological changes such as cloudy swelling and centrilobular 

degeneration and necrosis at higher levels in rats and mice. 

Data on the possible effects of 1,2-DCB on reproductive or developmental end points in humans are not 

available. Studies by both the oral and inhalation routes of exposure failed to find effects of 1,2-DCB on 

histology of reproductive organs or indices of reproduction in rats and mice. Similarly, limited available 

data suggest that inhalation and oral exposure to 1,2-DCB do not significantly affect prenatal 

development in rats or rabbits. 

Data on the possible carcinogenic effects of 1,2-DCB in humans are not available. Exposure to 1,2-DCB 

by the oral route has not been shown to cause an increase in tumor formation following lifetime exposure 

in rats or mice. The potential carcinogenic effects of 1,2-DCB by other routes of exposure have not been 

evaluated. EPA determined that 1,2-DCB is not classifiable as to human carcinogenicity and categorized 

it in cancer weight-of-evidence Group D. The International Agency for Research on Cancer (IARC) 

similarly determined that 1,2-DCB is not classifiable as to carcinogenicity to humans (Group 3). 

A more detailed discussion of the hepatic and respiratory effects associated with 1,2-DCB exposure 

follows. The reader is referred to Section 2.2, Discussion of Health Effects by Route of Exposure, for 

additional information on these and other health effects. 
DICHLOROBENZENES 14 

2. RELEVANCE TO PUBLIC HEALTH 

Hepatic Effects. Data on the hepatic effects of 1,2-DCB in exposed humans are not available for any 

exposure route. The liver is the primary target in animals orally exposed to 1,2-DCB, generally resulting 

in centrilobular damage in acute- and subchronic-duration studies. A single exposure to 1,500 mg/kg in 

rats caused lethal central necrosis. In rats exposed to 455 mg/kg/day for 15 days, severe liver damage, 

characterized by intense necrosis and fatty changes and porphyria, were reported. Similarly, rats exposed 

to 300 mg/kg/day for 10 days showed hepatic necrosis of slight severity and increased serum alanine 

aminotransferase (ALT). However, an acute (14-day) study by the National Toxicology Program showed 

no hepatic effects in male or female rats given doses as high as 500 or 1,000 mg/kg/day for 

14 consecutive days. The inconsistency between these findings might be due to a small number of 

animals in the14-day study and a low incidence and severity of lesions in the 10-day study. Centrilobular 

liver effects similar to those reported in the acute studies were found in several intermediate-duration 

studies in rats and mice, occurring in rats exposed to 188 mg/kg/day for 138 doses, rats exposed to 

400 mg/kg/day for 90 days, rats exposed to 250 mg/kg/day or greater for 13 weeks, and mice exposed to 

250 mg/kg/day for 13 weeks. A chronic study in rats and mice found no nonneoplastic liver effects in 

either sex of either species, even at exposures up to 120 mg/kg/day, suggesting that the nonneoplastic 

hepatic effects of 1,2-DCB may have a threshold, which might fall between 120 and 188 mg/kg/day. 

Respiratory Tract Effects. Periodic industrial hygiene surveys and medical examinations were 

conducted in a plant where an unreported number of men were exposed to 1,2-DCB at an average level of 

15 ppm (range, 1–44 ppm) for an unreported duration; no nasal or eye irritation was attributable to 

exposure. Additionally, the study author noted that the researchers detected 1,2-DCB odor at a 

concentration of 50 ppm without eye or nasal irritation during repeated vapor inhalation experiments on 

animals. An earlier source reported that occupational exposure to 100 ppm of 1,2-DCB caused irritation 

of the eyes and respiratory passages of exposed humans. Data on the effects of 1,2-DCB on the 

respiratory tract in humans following oral or dermal exposure are not available. 

In male mice exposed to 1,2-DCB in mean concentrations of 0, 64, or 163 ppm for 6 hours/day, 

5 days/week for 4, 9, or 14 days, histopathologic lesions were observed in the olfactory epithelium of the 

nasal cavity at ≥64 ppm. The olfactory epithelial lesions were graded as very severe following the 4-day 

exposure and moderate after the 14 day exposure, indicating to the study authors that repair may occur 

despite continued exposure. The more severe cases were characterized by a complete loss of olfactory 

epithelium, which left only partially denuded basement membrane. No histological alterations were 

observed in the respiratory epithelium of the nasal cavity, or in the trachea or lungs. No effects on 
 

 

DICHLOROBENZENES 15 

2. RELEVANCE TO PUBLIC HEALTH 

respiratory tract tissues were reported in intermediate- or chronic-duration inhalation studies in animals; 

however, in most cases, evaluation of nasal tissues was not conducted. 

1,3-Dichlorobenzene. Data on the absorption of 1,3-DCB in humans and animals are not available for 

any route of exposure; however, absorption of the compound can be inferred from studies that have 

detected 1,3-DCB or metabolites in the breast milk, blood, and fat of humans and in the bile and urine of 

exposed animals. Distribution is believed to be similar to the other DCB isomers, but data demonstrating 

this are not currently available. Similar to the other DCB isomers, 1,3-DCB is initially metabolized by 

cytochrome P 450 enzymes, followed by extensive conjugation, primarily to glutathione. 1,3-DCB is 

eliminated mainly in the urine, similar to the other DCB isomers. 

Studies on the toxic effects of 1,3-DCB in humans are not available. No studies evaluating the toxicity of 

1,3-DCB following dermal or inhalation exposure in animals were located. Information on the oral 

toxicity of 1,3-DCB in animals is available from one 90-day systemic toxicity study and one 

developmental toxicity study. The intermediate-duration study found effects in the thyroid, pituitary, and 

liver of rats, with thyroid lesions occurring at dose levels lower than those inducing pituitary and liver 

effects. The information on the developmental toxicity study of 1,3-DCB is from a gavage study reported 

without details as an abstract, which reported no treatment-related effects on prenatal development in rats. 

Reproductive function and carcinogenicity have not been evaluated in humans or animals exposed to 

1,3-DCB. EPA determined that 1,3-DCB is not classifiable as to human carcinogenicity and categorized 

it in cancer weight-of-evidence Group D. IARC similarly determined that 1,3-DCB is not classifiable as 

to carcinogenicity to humans (Group 3). 

A more detailed discussion of the endocrine and hepatic effects associated with 1,3-DCB exposure 

follows. The reader is referred to Section 2.2, Discussion of Health Effects by Route of Exposure, for 

additional information on these and other health effects. 

Endocrine Effects. In a 90-day study in rats given 0, 9, 37, 147, or 588 mg/kg/day, the most sensitive 

reported effects were on the pituitary and thyroid glands. Histologically, depletion of colloid density in 

the thyroid, characterized by decreased follicular size with scant colloid and follicles lined by cells that 

were cuboidal to columnar, was increased in a dose-related manner in males exposed to ≥9 mg/kg/day, 

and in females exposed to ≥37 mg/kg/day. The pituitary glands of males exposed to 1,3-DCB showed 

cytoplasmic vacuolization of the pars distalis in all exposed groups, but the incidence was statistically 

significant only in animals exposed to ≥147 mg/kg/day. Increases in serum cholesterol in males at 
DICHLOROBENZENES 16 

2. RELEVANCE TO PUBLIC HEALTH 

≥9 mg/kg/day and females at ≥37 mg/kg/day, and serum calcium in both sexes at ≥37 mg/kg/day were 

also believed by the authors to be related to effects on endocrine end points, possibly reflecting a 

disruption of hormonal feedback mechanisms, or target organ effects on the pituitary, hypothalamus, 

and/or other endocrine organs. 

Hepatic Effects. In male and female rats exposed by gavage to up to 735 mg/kg/day for 10 days, 

hepatic effects included significantly increased relative liver weight in males at ≥147 mg/kg/day and 

females at ≥368 mg/kg/day, and altered histopathology at ≥368 mg/kg/day in both sexes. The main 

hepatic histological change was dose-related centrolobular hepatocellular degeneration, characterized by 

varying degrees of cytoplasmic vacuolization and swelling with intact membranes. Other hepatic 

alterations included hepatocellular necrosis that was sporadically noted in animals exposed to 

≥147 mg/kg/day; this change was usually minimal to mild, and tended to increase in incidence and 

severity in males in a dose-related manner. In a 90-day study of 1,3-DCB toxicity, rats of both sexes were 

exposed by gavage to up to 588 mg/kg/day. Relative liver weights were increased in both sexes at 

≥147 mg/kg/day. Dose-related increases in histological lesions, including inflammation, hepatocellular 

alterations, and hepatocellular necrosis were reported at doses of ≥147 mg/kg/day. Other statistically 

significant liver-associated effects included significantly increased serum aspartate aminotransferase 

(AST) levels (90–100% higher than controls) in males at ≥9 mg/kg/day and females at ≥37 mg/kg/day, 

but whether these changes were due to an effect on the liver or an endocrine effect is not clear. Serum 

lactate dehydrogenase (LDH) levels were also reduced in males at ≥9 mg/kg/day, but the biological 

significance of a decrease in liver enzymes is unclear. 

1,4-Dichlorobenzene. Following inhalation or oral exposure, absorption of 1,4-DCB is rapid and 

complete. Data on the absorption of 1,4-DCB following dermal exposure are not available; however, 

absorption is believed to be very low, based on a very high (>6 g/kg) dermal LD50 for 1,4-DCB in rats, 

and on a lack of systemic effects in humans who held solid 1,4-DCB in their hands. Similar to the other 

dichlorobenzene isomers, 1,4-DCB is distributed throughout the body, but tends to be found in greatest 

levels in fat, liver, and kidney. Metabolism of 1,4-DCB is similar to that of 1,2-DCB, with an initial 

oxidation to an epoxide, followed by hydrolysis to 2,5-dichlorophenol. Extensive phase II metabolism 

occurs subsequently, with eliminated metabolites found mainly as the sulfate, glucuronide, or mercapturic 

acid. 1,4-DCB is eliminated almost exclusively in the urine, primarily as conjugates of 2,5-dichlorophenol. 
DICHLOROBENZENES 17 

2. RELEVANCE TO PUBLIC HEALTH 

Information on the health effects of 1,4-DCB in humans is available from limited observations in exposed 

workers and case reports. Workers who were chronically exposed to 1,4-DCB vapor experienced 

irritation of the nose and eyes and case reports of people who inhaled or ingested 1,4-DCB suggest that 

the liver, nervous system, and hematopoietic system are systemic targets in humans. The available 

limited information on these systemic effects in humans is consistent with findings in animals exposed to 

1,4-DCB. 

The acute, intermediate,- and chronic-duration toxicity of 1,4-DCB in animals has been evaluated in a 

number of studies, predominantly in rats and mice. The respiratory tract is a target of inhaled 1,4-DCB as 

shown by histopathological changes in the lungs of acutely exposed rats and guinea pigs and nasal 

olfactory epithelium of chronically exposed rats and mice. Liver and kidney effects are the best studied 

and most consistently observed effects of inhalation and oral exposure. There is a general pattern in 

which increased liver weight and hepatocellular hypertrophy are predominant effects at exposure levels 

below those inducing more serious histopathological changes in the liver (e.g., congestion, fatty 

degeneration, focal necrosis) and clinical signs of toxicity in the respiratory tract (e.g., nose and eye 

irritation following inhalation exposure) and nervous system (e.g., tremors and salivation). Exposure of 

male rats to 1,4-DCB, but not female rats or either sex of other species, causes development of renal 

lesions that have been shown to be the result of interaction with the protein α2μ-globulin, a mechanism 

specific to male rats and not relevant to humans. There are a few reports of effects on the hematologic 

system, adrenal gland, and thyroid, but these occurred at inhalation or oral exposure levels similar to or 

higher than those causing liver and kidney effects. Chronic inhalation exposure to 1,4-DCB induced 

nasal olfactory epithelial lesions in rats at concentrations below those causing liver effects. 

Data on the effects of 1,4-DCB on reproductive end points in humans are not available. Oral or inhalation 

exposure to 1,4-DCB has not been demonstrated to produce treatment-related adverse changes in 

reproductive tissue histology or on reproductive end points in animals. Two-generation inhalation and 

oral studies in rats found that 1,4-DCB did not affect reproductive performance but induced postnatal 

toxicity in F1 and F2 offspring, including reductions in survival on day 4, body weight gain, and 

neurobehavioral performance at doses similar to or lower than those inducing liver effects in 

intermediate-duration systemic toxicity studies. No teratogenic effects were induced in rats by inhalation 

or oral exposure to 1,4-DCB, although indications of fetotoxicity (e.g., extra ribs) occurred at levels that 

were maternally toxic. 
DICHLOROBENZENES 18 

2. RELEVANCE TO PUBLIC HEALTH 

1,4-DCB is carcinogenic in animals following chronic inhalation and oral exposure. Inhalation and oral 

lifetime studies found liver tumors in male and female mice but not in rats of either sex. Chronic oral 

exposure also induced renal tubular cell adenocarcinomas in male rats, but these appear to be associated 

with male rat-specific α2μ-globulin nephropathy and not relevant to carcinogenicity in humans. IARC 

determined that 1,4-DCB is possibly carcinogenic to humans (Group 2B). The Department of Health and 

Human Services (DHHS) concluded that 1,4-DCB is reasonably anticipated to be a human carcinogen. 

A more detailed discussion of the hepatic, respiratory, developmental, and carcinogenic effects associated 

with 1,4-DCB exposure follows. The reader is referred to Section 2.2, Discussion of Health Effects by 

Route of Exposure, for additional information on these effects and other health effects. 

Hepatic Effects. In two human fatalities believed to be caused by 1,4-DCB inhalation, the subjects 

died of massive hepatic necrosis; the exposure concentrations are not known. A 3 year-old child who had 

been playing with crystals containing 1,4-DCB for 4–5 days was jaundiced with pale mucous membranes, 

indicative of liver damage. 

Many animal studies by both the oral and inhalation routes have confirmed the liver as a sensitive target 

for 1,4-DCB toxicity. Inhaled exposure concentrations of 158–211 ppm, at exposure durations from 

2 weeks to 7 months, resulted in increased liver weights, cloudy swelling of the liver, and, at higher 

exposure levels, centrilobular hypercellular hypertrophy and necrosis. Exposure to 270 ppm for 13 weeks 

caused increased liver weight in rats and mice and hepatocellular hypertrophy and increased serum 

enzymes in mice. Exposure to 538 ppm for 10 weeks, and throughout mating and gestation for females, 

resulted in hepatocellular hypertrophy and increased liver weights in both the parental (F0) generation and 

the F1 generation offspring. In chronic inhalation studies in rats and mice, no effects were seen in either 

sex of either species at 75 ppm, but at 300 ppm, histological changes in the lung were seen in male mice, 

but not in female mice or in either sex of rats. Acute oral studies have demonstrated hepatic effects 

(increased liver weight) at concentrations as low as 300 mg/kg in rats, with higher concentrations 

resulting in increased liver cell proliferation and vacuolated and/or basophilic cytoplasm of centrilobular 

cells. Similar hepatic effects occurred in mice orally exposed to 300 mg/kg/day for 1 week. In rats 

exposed to 1,4-DCB for 13 weeks, increased relative liver weight was seen at ≥75 mg/kg/day, with 

centrilobular hypertrophy present at 300 mg/kg/day (Lake et al. 1997), and necrosis reported at 

1,200 mg/kg/day (NTP 1987); oral studies in mice have reported similar effects (NTP 1987). A study of 

1,4-DCB in male and female Beagle dogs found that oral exposure to 50 or 75 mg/kg/day caused 

increased serum levels of liver enzymes, increased liver weights, hepatocellular hypertrophy, pigment 
DICHLOROBENZENES 19 

2. RELEVANCE TO PUBLIC HEALTH 

deposition, and hepatic portal inflammation after 6–12 months. In the only chronic-duration (2-year) oral 

study of 1,4-DCB toxicity, no effects were seen in either sex of rats exposed to up to 300 mg/kg/day, 

while both sexes of mice showed significant, dose-related increases in hepatocellular degeneration, 

starting at 300 mg/kg/day. 

Respiratory Tract Effects. A case of pulmonary granulomatosis was reported to have occurred in a 

53-year-old woman who for 12–15 years had been inhaling 1,4-DCB crystals that were scattered on a 

weekly basis on the carpets and furniture of her home. A lung biopsy revealed the presence of 1,4-DCB 

crystals with the surrounding lung parenchyma being distorted by fibrosis, thickening of the alveolar 

walls, and marked infiltrates of lymphocytes and mononuclear phagocytes. These effects are most likely 

related to the physical interaction of 1,4-DCB crystals (or any crystals when inhaled) with lung tissue, 

rather than to chemical toxicity. A health survey of 58 men occupationally exposed to 1,4-DCB for 

8 hours/day, 5 days/week for 8 months to 25 years (average, 4.75 years) found the odor to be faint at 15– 

30 ppm and strong at 30–60 ppm, with painful irritation of the nose and eyes usually occurring at 

concentrations ranging from 80 to 160 ppm. At levels >160 ppm, the air was considered not breathable 

for unacclimated persons. 

An evaluation of 953 adult participants in the Third National Health and Nutrition Examination Survey of 

the general U.S. population found statistically significant inverse associations between blood levels of 

1,4-DCB and two measures of pulmonary function. When compared with subjects in the lowest decile of 

1,4-DCB blood concentration (0.10 ppb), subjects in the highest decile (>4.40 ppb) had decrements of 

-153 mL in forced expiratory volume in 1 second (FEV1) and -346 mL/second in maximum midexpiratory flow rate (MMEFR). There were no significant associations with forced vital capacity (FVC) 

or peak expiratory flow rate (PEFR). Although it is unclear whether the observed decrements in FEV1 

and MMEFR are biologically meaningful, and other studies investigating effects of 1,4-DCB on lung 

function are not available, the findings suggest that exposure to 1,4-DCB may possibly contribute to 

decreases in lung function. 

Pulmonary effects (interstitial edema, congestion, and alveolar hemorrhage) were observed in rats and 

guinea pigs following intermittent exposure to 175 ppm of 1,4-DCB for 16 days. The experimental 

design and report of this study have a number of deficiencies, such that the observations provide only 

qualitative evidence of exposure-related acute respiratory effects. Support for the respiratory tract as a 

target for inhaled 1,4-DCB in animals is provided by the induction of nasal lesions in rats and mice 

chronically exposed to 1,4-DCB for 6 hours/day, 5 days/week for 2 years. An increased incidence of 
DICHLOROBENZENES 20 

2. RELEVANCE TO PUBLIC HEALTH 

histological changes of the nasal olfactory epithelium occurred in female rats exposed to 75 or 300 ppm, 

and male rats and female mice exposed to 300 ppm. In rats treated with 1,200 or 1,500 mg/kg/day or 

greater by gavage for 13 weeks, epithelial necrosis of the nasal turbinates was reported; similar effects 

were not seen in mice exposed by gavage to up to 1,800 mg/kg/day, or in rats or mice exposed by gavage 

for 2 years to up to 600 mg/kg/day. 

Developmental Effects. A 21-year-old woman who had eaten 1–2 blocks of 1,4-DCB toilet 

freshener per week for the first 38 weeks of pregnancy gave birth to an apparently normal child. In a 

2-generation study of the effects of inhaled 1,4-DCB on reproduction and development, the number of 

pups that died during the perinatal period was increased, and the body weights at postnatal day 0 and 

28 were significantly decreased, in animals exposed to 538 ppm; exposures to 66 or 211 ppm had no 

effect on developmental end points. In rabbits exposed to 300 ppm, but not those exposed to 800 ppm, 

there was a significant increase in the number of resorptions and the percentages of resorbed 

implantations per litter; the fact that the effect did not occur in the rabbits exposed to the higher exposure 

level suggests that it was not treatment-related. A 2-generation oral study in rats found toxicity in the 

offspring at doses ≥90 mg/kg/day; effects included reduced birth weight in F1 pups, increased mortality 

on postnatal day 4 in F1 and F2 pups, clinical manifestations of dry and scaly skin (until approximately 

postnatal day 7) in F1 and F2 pups, and reduced neurobehavioral performance (draw-up reflex evaluated at 

weaning) in F2 pups. No exposure-related changes occurred at 30 mg/kg/day. Other evaluations of 

developmental effects of 1,4-DCB following oral exposure have been negative. 

Cancer. Data on the carcinogenic effects of 1,4-DCB in humans are not available. 1,4-DCB has been 

shown to be carcinogenic in chronic animal studies by both the inhalation and oral routes. Following 

lifetime inhalation exposure, a dose-related increase in hepatocellular adenomas and carcinomas was 

observed in mice of both sexes, whereas incidences of liver or other tumors were not increased in rats. 

Following lifetime oral exposure, hepatic tumors (hepatocellular adenomas and carcinomas and 

histiocytic sarcomas) were increased in mice of both sexes, but not in either sex of rats. The oral bioassay 

also found that the male rats exposed to 1,4-DCB developed renal tubular cell adenocarcinomas, but these 

are believed to be the result of interaction with α2μ-globulin, a renal protein not present in humans. Data 

on the possible carcinogenic effects of 1,4-DCB following dermal exposure are not available. 
DICHLOROBENZENES 21 

2. RELEVANCE TO PUBLIC HEALTH 

2.3 MINIMAL RISK LEVELS (MRLs) 

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

dichlorobenzenes. 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 1994k), 

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

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

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

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

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

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

1,2-Dichlorobenzene 

Acute-Duration Exposure. No MRL was derived for acute-duration inhalation exposure to 

1,2-DCB due to insufficient data. No information was located regarding the acute inhalation toxicity of 

1,2-DCB in humans. The nasal cavity was a target of acute inhalation in animals as shown by a study in 

which male mice were exposed to 64 or 163 ppm of 1,2-DCB for 6 hours/day, 5 days/week for 4, 9, or 

14 days (Zissu 1995). Histological examinations of the upper and lower respiratory tracts found that 

nasal olfactory epithelial lesions occurred at both levels of exposure. The nasal lesions were graded as 

very severe following the 4 day exposure and moderate after the 14 day exposure, suggesting to the study 

authors that some tissue repair might have occurred despite continued exposure. The more severe cases 

were characterized by a complete loss of olfactory epithelium, which left only the partially denuded 

basement membrane. No histological alterations were observed in the respiratory epithelium of the nasal 

cavity, or in the trachea or lungs. Nonrespiratory tissues were not evaluated in this study. 
DICHLOROBENZENES 22 

2. RELEVANCE TO PUBLIC HEALTH 

Acute systemic effects of inhaled 1,2-DCB include histopathology in the liver (marked centrilobular 

necrosis) and kidneys (cloudy swelling of tubular epithelium) of rats exposed to 977 ppm for 1 hour 

(Hollingsworth et al. 1958), but not to 539 ppm for 3 or 6.5 hours (Hollingsworth et al. 1958) or 322 ppm 

for 6 hours/day for 10 days (DuPont 1982). Maternal body weight gain was decreased in rats and rabbits 

that were exposed to 100, 200, or 400 ppm of 1,2-DCB for 6 hours/day on days 6–15 (rats) or 6– 

18 (rabbits) of gestation (Hayes et al. 1985). No prenatal developmental toxicity was observed in the 

rabbits, although skeletal variations (delayed ossification of cervical vertebral centra) occurred in fetuses 

of rats at 400 ppm, indicating that developmental effects occurred in rats at concentrations that also 

caused maternal toxicity. Based on these findings, a lowest-observed-adverse-effect level (LOAEL) of 

100 ppm for systemic toxicity and 400 ppm for developmental toxicity are identified. 

The nasal histopathology findings in mice show that the upper respiratory tract is a sensitive target for 

acute inhalation exposure to 1,2-DCB, as serious olfactory lesions occurred at exposure concentrations 

below those that caused systemic or developmental effects in rats and rabbits. The 64 ppm LOAEL for 

severe nasal olfactory lesions precludes derivation of an acute inhalation MRL for 1,2-DCB because: 

(1) a no-observed-adverse-effect level (NOAEL) for nasal lesions was not determined, (2) no other 

animal studies tested exposure levels below 100 ppm or evaluated the nasal cavity, and (3) it is not 

ATSDR’s practice to derive MRLs based on serious LOAELs. 

Intermediate-Duration Exposure. No intermediate-duration inhalation MRL was derived for 

1,2-DCB due to insufficient data. Information on the toxicity of intermediate-duration inhalation 

exposures to 1,2-DCB is limited to the findings of a multispecies intermediate study (Hollingsworth et al. 

1958) and a 2-generation reproduction study in rats (Bio/dynamics 1989). In the intermediate study, rats 

and guinea pigs were exposed to 49 or 93 ppm for 7 hours/day, 5 days/week for 6–7 months 

(Hollingsworth et al. 1958). Mice were similarly exposed to 49 ppm only, and rabbits and monkeys were 

similarly exposed to 93 ppm only, although the rabbit and monkey data are compromised by small 

numbers of animals (two rabbits/sex and two female monkeys). No compound-related histopathological 

or other changes occurred in any of the animals exposed to 49 ppm. The only remarkable findings at 

93 ppm were statistically significant decreases in final body weight (8.9% less than controls) in male rats 

and absolute spleen weight (20% less than controls) in male guinea pigs, indicating that the NOAEL and 

LOAEL for systemic effects are 49 and 93 ppm, respectively. In the reproductive toxicity study, male 

and female rats were exposed to 50, 150, or 394 ppm of 1,2-DCB for 6 hours/day, 7 days/week for 

10 weeks before mating and subsequently through the F1 generation (Bio/dynamics 1989). α2μ-Globulin­
 

 

DICHLOROBENZENES 23 

2. RELEVANCE TO PUBLIC HEALTH 

related renal changes were found in adult males of both generations at all levels of exposure, but these 

effects are specific to male rats and are not relevant to humans. Decreased body weight gain, increased 

absolute and relative liver weights, and centrilobular hepatocyte hypertrophy occurred in adult rats of 

both sexes and generations at ≥150 ppm, indicating that the NOAEL and LOAEL for systemic effects are 

50 and 150 ppm. There were no effects on reproduction in either generation, indicating that the NOAEL 

for reproductive toxicity is 394 ppm. As discussed in the acute inhalation MRL section, a NOAEL of 

200 ppm and a LOAEL of 400 ppm were found for developmental toxicity (skeletal variations) in rats 

(Hayes et al. 1985). 

As discussed above, NOAELs of 49–50 ppm and LOAELs of 93–150 ppm are identified for systemic 

effects in intermediate-duration inhalation studies of 1,2-DCB in rats and guinea pigs (Bio/dynamics 

1989; Hollingsworth et al. 1958). Neither of these studies evaluated possible effects in the nasal cavity, a 

known sensitive target of 1,2-DCB based on acute data. As indicated in the acute inhalation MRL 

section, 64 ppm was a serious LOAEL for nasal olfactory lesions in rats intermittently exposed to 

1,2-DCB for 4–14 days (Zissu 1995). Derivation of an intermediate-duration MRL for 1,2-DCB is 

precluded because the 64 ppm serious LOAEL for acute exposure is lower than the available 

intermediate-duration LOAELs for systemic and developmental effects. 

Chronic-Duration Exposure. No MRL was derived for chronic-duration inhalation exposure to 

1,2-DCB due to insufficient data. The available information consists of two limited human reports. 

Workers who were exposed to concentrations of 1,2-DCB ranging from 1 to 44 ppm (average 15 ppm) for 

unreported durations did not experience eye or nasal irritation, or show any changes in standard blood and 

urine indices, as determined by periodic occupational health examinations (Hollingsworth et al. 1958). 

1,2-DCB also did not cause eye or nasal irritation in workers exposed to approximately 50 ppm 

(researchers exposed during the conduct of inhalation studies in animals), although the odor was 

perceptible at this level (Hollingsworth et al. 1958). Occupational exposure to higher concentrations of 

100 ppm 1,2-DCB was reported to be irritating to the eyes and respiratory passages (Elkins 1950). The 

lack of adequate exposure-response data and any additional information in these reports, as well as a lack 

of chronic toxicity data in animals, precludes derivation of a chronic inhalation MRL. 

1,3-Dichlorobenzene 

No MRLs were derived for inhalation exposure to 1,3-DCB due to a lack of acute-, intermediate-, and 

chronic-duration inhalation studies. 
DICHLOROBENZENES 24 

2. RELEVANCE TO PUBLIC HEALTH 

1,4-Dichlorobenzene 

Acute-Duration Exposure. 

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

1,4-DCB. 

A limited amount of information is available on the toxicity of inhaled 1,4-DCB in humans. Case reports 

of people who inhaled 1,4-DCB provide indications that the liver and nervous system are systemic targets 

of inhalation toxicity in humans, but are limited by lack of adequate quantitative exposure information 

and/or verification that 1,4-DCB was the only factor associated with the effects (Cotter 1953; Miyai et al. 

1988; Reygagne et al. 1992). 

Observations in workers who were occupationally exposed to 1,4-DCB for 8 hours/day, 5 days/week for 

an average of 4.75 years (range from 8 months to 25 years) provide information relevant to acute 

inhalation exposures. The odor was found to be faint at 15–30 ppm and strong at 30–60 ppm. Painful 

irritation of the eyes and nose was usually experienced at 50–80 ppm, although the irritation threshold 

was higher (80–160 ppm) in workers acclimated to exposure. Concentrations above 160 ppm caused 

severe irritation and were considered intolerable to people not adapted to it. The odor and irritation 

effects are considered to be good acute warning properties that are expected prevent excessive exposures, 

although the industrial experience indicates that it is possible for people to become sufficiently acclimated 

to tolerate high concentrations of the vapor (Hollingsworth et al. 1956). Periodic occupational health 

examinations showed no cataracts or any other lens changes in the eyes, or effects on clinical indices (red 

blood cell count, total and differential white blood cell counts, hemoglobin, hematocrit, mean corpuscular 

volume, blood urea nitrogen, sedimentation rate, or urinalysis) attributable to exposure. 

Information on effects of acute-duration inhalation exposure to 1,4-DCB in animals is available from 

short-term systemic toxicity studies in rats and guinea pigs (Hollingsworth et al. 1956), a male 

reproduction study rats (Anderson and Hodge 1976), and developmental toxicity studies in rats and 

rabbits (Hayes et al. 1985; Hodge et al. 1977). In the systemic toxicity study, five rats of each sex and 

five guinea pigs of each sex were exposed to 173 ppm of 1,4-DCB for 7 hours/day, 5 days/week for 

16 days (Hollingsworth et al. 1956). Mild histological effects of interstitial edema, congestion, and 

alveolar hemorrhage were observed in the lungs of male rats and female guinea pigs. The experimental 

design and report of this study have a number of deficiencies, such that reported observations provide 
DICHLOROBENZENES 25 

2. RELEVANCE TO PUBLIC HEALTH 

only qualitative evidence of exposure-related respiratory effects. In the reproduction study (a dominant 

lethal test), a NOAEL of 450 ppm was identified for reproductive performance in male mice that were 

exposed for 6 hours/day for 5 days prior to weekly mating with unexposed females for 8 weeks 

(Anderson and Hodge 1976). No maternal or developmental toxicity occurred in rats that were exposed 

to 75–500 ppm for 6 hours/day on days 6–15 of gestation (Hodge et al. 1977), indicating that the highest 

NOAEL for reproductive effects in rats is 500 ppm. A developmental study in which rabbits were 

exposed to 100–800 ppm for 6 hours/day on gestation days 6–18 found evidence of fetotoxicity (a minor 

variation of the circulatory system) only at 800 ppm, which was also maternally toxic as shown by body 

weight loss early in gestation (Hayes et al. 1985), indicating that 800 ppm is a LOAEL for maternal and 

developmental effects in rabbits. 

The lung is the target of concern for inhaled 1,4-DCB in rats and guinea pigs acutely exposed to 173 ppm 

(Hollingsworth et al. 1956) because the only effects observed in the acute reproductive and 

developmental studies were indications of maternal and fetotoxicity in rabbits at a much higher levels of 

800 ppm (Hayes et al. 1985). Support for the respiratory tract as a sensitive target for 1,4-DCB vapor in 

animals is provided by the induction of nasal lesions in rats intermittently exposed to levels as low as 

75 ppm for 104 weeks in the study used to derive the chronic inhalation MRL for 1,4-DCB (Aiso et al. 

2005b; Japan Bioassay Research Center 1995). Additionally, the animal data are consistent with the 

human experience indicating that occupational exposure to 1,4-DCB causes painful nose and eye irritation 

in the range of 50–160 ppm (Hollingsworth et al. 1956). The current Threshold Limit Value-Time 

Weighted Average (TLV-TWA) for 1,4-DCB of 10 ppm, which is intended to minimize the potential for 

eye irritation in exposed workers (ACGIH 2001), is largely based on the human findings of 

Hollingsworth et al. (1956). 

As discussed above, eye and nose irritation are critical effects of acute and longer-term inhalation 

exposures to 1,4-DCB in humans. Because odor detection is a warning property expected to prevent 

irritation caused by 1,4 DCB (Hollingsworth et al. 1956), the highest level at which an odor was detected 

that was simultaneously without irritant effects, 30 ppm, was designated a minimal LOAEL for irritation 

for the purposes of derivation of the MRL; the 15 ppm level was therefore designated a NOAEL for 

irritant effects. Using the NOAEL of 15 ppm for eye and nose irritation in humans, and applying a total 

uncertainty factor of 10 (for individual variability), an MRL of 2 ppm was derived for acute inhalation 

exposure to 1,4-DCB. 
DICHLOROBENZENES 26 

2. RELEVANCE TO PUBLIC HEALTH 

Intermediate-Duration Exposure. 

•	 An MRL of 0.2 ppm has been derived for intermediate-duration (15–364 days) inhalation 

exposure to 1,4-DCB. 

A limited amount of information is available on the intermediate-duration toxicity of inhaled 1,4-DCB in 

humans. Case reports of people who inhaled 1,4-DCB over periods of months provide indications that 

the liver and nervous system are systemic targets of inhalation toxicity in humans, but are limited by lack 

of adequate quantitative exposure information and/or verification that 1,4-DCB was the only factor 

associated with the effects (Cotter 1953; Miyai et al. 1988; Reygagne et al. 1992). 

Information on effects of intermediate-duration inhalation exposure to 1,4-DCB in animals is available 

from 4–7-month toxicity studies in rats, mice, guinea pigs, rabbits, and monkeys (Hollingsworth et al. 

1956), a 13-week toxicity study in rats and mice (Aiso et al. 2005a), and a 2-generation reproductive/ 

developmental toxicity study in rats (Tyl and Neeper-Bradley 1989). These studies show that hepatic 

effects increase in severity with increasing level of exposure, ranging from increased liver weight at low 

levels to degenerative and necrotic changes at higher concentrations, and identify the liver as the most 

sensitive target of intermediate-duration inhalation of 1,4-DCB. The lowest reliable hepatic effect levels 

are identified in the 13-week and 2-generation studies, as discussed below. 

In the 13-week study, groups of 10 male and 10 female F344 rats and 10 male and 10 female BDF1 mice 

were chamber-exposed to 1,4-DCB vapor (>99.9% pure) at concentrations of 0, 25, 55, 120, 270, or 

600 ppm for 6 hours/day, 5 days/week for 13 weeks (Aiso et al. 2005a). End points evaluated during the 

study included clinical signs (daily) and body weight and food consumption (weekly). End points 

evaluated at the end of the 13-week exposure period included hematology (red blood cells [RBC], 

hemoglobin [Hb], Hematocrit [Hct], mean corpuscular volume [MCV], mean corpuscular hemogloblin 

[MCH]), blood biochemistry (total protein, albumin, total cholesterol, triglyceride, phospholipid, AST, 

ALT, alkaline phosphatase, blood urea nitrogen [BUN], creatine), organ weights, and histopathology. 

The histological examinations were comprehensive and included the nasal cavity, in accordance with 

OECD test guidelines for a 90-day inhalation study (Aiso 2005; OECD 1981). 

There were no exposure-related effects on survival, clinical signs, or body weight gain in the rats (Aiso et 

al. 2005a). Hematological changes suggestive of microcytic anemia occurred in male rats, including 

significantly decreased RBC count and hemoglobin concentration at ≥120 ppm, hematocrit at ≥270 ppm, 
 

 

 

DICHLOROBENZENES 27 

2. RELEVANCE TO PUBLIC HEALTH 

and MCV and MCH at 600 ppm. Serum biochemical changes included significant increases in total 

protein in both sexes at 600 ppm, albumin in females at ≥270 ppm and males at 600 ppm, and total 

cholesterol and phospholipid in males at ≥270 ppm and females at 600 ppm, and significant decreases in 

triglycerides in males at 600 ppm, AST in both sexes at 600 ppm, and ALT and AP in males at ≥270 ppm. 

The biological significance of decreases in serum levels of liver enzymes is unclear. Organ weight 

changes included >10% increases in absolute and relative weights of liver in males at ≥270 ppm and 

females at 600 ppm, kidneys in males at ≥270 ppm, and spleen in males at 600 ppm. Histological effects 

included significantly increased incidences of centrilobular hepatocellular hypertrophy in the liver in male 

rats at 600 ppm and kidney lesions indicative of α2μ-globulin nephropathy in male rats at ≥270 ppm. 

There were no histopathological changes in hematopoietic tissues, suggesting that the anemia in the male 

rats was secondary to α2μ-globulin nephropathy-related effects on erythropoietin synthesis in the renal 

tubules. 

There were no exposure-related effects on survival, clinical signs, or body weight gain in the mice (Aiso 

et al. 2005a). Organ weight changes in the mice included >10% increases in liver weight in males at 

≥270 ppm (relative) and 600 ppm (absolute) and females at 600 ppm (absolute and relative); relative liver 

weights were 9.7, 9.7, 10.1, 23.9, and 62.6% higher than controls in the low- to high-dose males. There 

were no significant hematological changes in either sex. Serum ALT levels were significantly increased 

in males at ≥270 ppm (18.2, 9.1, 18.2, 54.5 and 164% higher than controls in the low- to high-dose 

groups). Other serum biochemical changes included significant increases in ALT in females at 600 ppm, 

AST in males at 600 ppm, and total cholesterol and total protein in both sexes at 600 ppm. Histological 

examinations showed significantly increased incidences of centrilobular hepatocellular hypertrophy in 

male mice at ≥270 ppm and female mice at 600 ppm; incidences in the control to high dose males were 

0/10, 0/10, 0/10, 0/10, 10/10, and 10/10. Affected hepatocytes were characterized by cell enlargement, 

varying nuclear size and shape, and coarse chromatin and inclusion bodies in the nucleus; the severity of 

these lesions was rated as slight at 270 ppm (males) and moderate at 600 ppm (both sexes). The moderate 

hepatocellular hypertrophy in the 600 ppm male mice was accompanied by single cell necrosis (1/10) and 

focal liver necrosis (2/10). 

The lowest effect level in the 13-week study (Aiso et al. 2005a) study is 270 ppm based on the kidney and 

hematological effects in male rats and liver effects in rats and mice. The kidney and hematological 

effects are consistent with α2μ-globulin nephropathy, which is specific to male rats and not relevant to 

humans. The mice were more sensitive to the liver effects of 1,4-DCB than the rats because the only 

hepatic change in the 270 ppm rats was increased liver weight, whereas hepatocellular hypertrophy and 
 

 

DICHLOROBENZENES 28 

2. RELEVANCE TO PUBLIC HEALTH 

increased serum ALT occurred in addition to increased liver weight in the 270 ppm mice. Additionally, 

at the next highest tested level of 600 ppm, the mice had nuclear changes and evidence of necrosis in the 

hypertrophic hepatocytes, and increased serum AST as well as ALT, whereas none of these indicators of 

hepatocellular damage occurred in the rats. Based on increased relative liver weight (>10%) in both 

species and histological and serum enzyme changes in the mice, this study identified a NOAEL of 

120 ppm and a LOAEL of 270 ppm for hepatic effects. 

In the two-generation study, groups of 28 Sprague-Dawley rats of each sex were exposed to actual mean 

1,4-DCB concentrations of 0, 66, 211, and 538 ppm (Tyl and Neeper-Bradley 1989). Additional groups 

of 10 females were similarly exposed for 10 weeks in a satellite study. The animals in the main study 

were paired within groups for a 3 week mating period to produce the F1 generation. Main study males 

that did not successfully mate in the first 10 days of the mating period were paired with the satellite 

females for 10 days. Main study females that did not successfully mate during the first 10 days of the 

mating period were paired with proven males for the remaining 11 days of the mating period. Exposures 

of the main study F0 females were continued throughout the mating period and the first 19 days of 

gestation, discontinued from gestation day 20 through postnatal day 4, and then resumed until sacrifice at 

weaning on postnatal day 28. Exposures of the satellite F0 females were continued through mating until 

sacrifice on gestation day 15. Exposures of the F0 males continued until sacrificed at the end of the study 

and satellite mating periods. Groups of 28 F1 weanlings/sex and satellite groups of 10 F1 female 

weanlings were exposed for 11 weeks and mated as described above to produce the F2 generation. 

Additionally, 20 F1 weanlings/sex from the control and high exposure groups served as recovery animals 

that were observed without exposure for 5 weeks prior to sacrifice. Complete necropsies were performed 

on all F0 and F1 adult (parental) animals, F1 recovery animals, F1 weanlings not used in the rest of the 

study, and F2 weanlings, and histology was evaluated in the F0 and F1 parental animals. Histological 

examinations were conducted on the liver and kidneys in all groups and on selected other tissues 

(pituitary, vagina, uterus, ovaries, testes, epididymides, seminal vesicles, prostate, and tissues with gross 

lesions) in the control and high-exposure groups. The kidney evaluation included examination for the 

presence of α2μ-globulin droplets. Additional end points evaluated in the parental generations included 

clinical observations, mortality, body weight, and food consumption. Mating and fertility indices were 

determined for F0 and F1 males and females, and gestational, live birth, postnatal survival (4, 7, 14, 21, 

and 28 days), and lactation indices were determined for the F1 and F2 litters. 

No effects on reproductive parameters in either generation were reported, although systemic toxicity 

occurred at all dose levels in F0 and F1 adult rats (Tyl and Neeper-Bradley 1989). Hyaline droplet 
DICHLOROBENZENES 29 

2. RELEVANCE TO PUBLIC HEALTH 

nephropathy was found in F0 and F1 adult males at ≥66 ppm. Manifestations of this male rat-specific 

renal syndrome included α2μ-globulin accumulation and increased kidney weights at ≥66 ppm, and other 

characteristic histological changes at 538 ppm. Body weights and weight gains were significantly 

reduced in F0 and F1 adult males and F1 adult females during the pre-breed exposure periods at 538 ppm. 

Absolute liver weights were increased in F0 males by 6, 16, and 38% in the 66, 211, and 538 ppm groups, 

respectively; the differences were statistically significantly different from control in the 211 and 538 ppm 

groups. In F0 females, absolute liver weights were increased by 9 and 31% at 211 and 538 ppm, 

respectively, but statistical significance was achieved only at 538 ppm. Similar changes were seen in 

relative liver weights of the F0 generation, with respective increases of 5, 14, and 52% in the 66, 211, and 

538 ppm males and 4, 9, and 31% in the 66, 211, and 538 ppm females; all groups of treated males, and 

the 211 and 538 ppm female groups, were statistically significantly different from controls. Relative liver 

weights were also significantly increased in F1 adult males at ≥211 ppm and in F1 adult females at 

538 ppm. Hepatocellular hypertrophy was observed in the livers of F0 and F1 males and females at 

538 ppm; no hepatic histological changes were induced at the lower exposure concentrations. Other 

effects also occurred in the F0 and F1 males and females at 538 ppm, indicating that there was a consistent 

pattern of adult toxicity at the high exposure level, including reduced food consumption and increased 

incidences of clinical signs (e.g., tremors, unkempt appearance, urine stains, salivation, and nasal and 

ocular discharges); these effects only sporadically occurred at 211 ppm. Other effects at 538 ppm 

included reduced gestational and lactational body weight gain, and postnatal toxicity, as evidenced by 

increased number of stillborn pups, reduced pup body weight, and reduced postnatal survival in F1 and/or 

F2 litters. This study identified: (1) a NOAEL of 66 ppm and LOAEL of 211 ppm for increased (>10% 

above controls) relative liver weight in adult rats, and (2) a serious LOAEL of 538 ppm for systemic 

toxicity (central nervous system and other clinical signs) in adult rats and developmental toxicity 

(increased stillbirths and perinatal mortality) in their offspring (Tyl and Neeper-Bradley 1989). The 

identification of increased liver weight as a critical effect of 1,4-DCB toxicity is supported by findings of 

increased liver weight and serum liver enzyme levels and histopathologic liver lesions following repeated 

oral exposure (Naylor and Stout 1996). 

Benchmark dose (BMD) analysis of the male rat serum ALT data (Aiso et al. 2005a) was conducted using 

all appropriate continuous-variable models in the EPA Benchmark Dose Software (Version 1.3.2) and a 

benchmark response (BMR) of 1 standard deviation change from the control mean. None of the models 

provided an adequate fit to the variance, precluding the use of this data set for selecting a point of 

departure for deriving an MRL. Available continuous-variable models were also fit to the Tyl and 

Neeper-Bradley (1989) data for changes in liver weight in male rats using a BMR of 1 standard deviation. 
 

 

 

 

 

DICHLOROBENZENES 30 

2. RELEVANCE TO PUBLIC HEALTH 

The 2-degree polynomial model was the best fitting model, predicting a benchmark concentration 

(BMC1sd) and BMCL1sd (lower 95% confidence limit on the BMC1sd) of 120 and 92 ppm, respectively. A 

summary of the predicted BMCs and BMCL for both end points, as well as details of the BMD modeling, 

are presented in Appendix A. 

Using the BMCL1sd of 92 ppm for increased liver weight in male rats and EPA (1994k) inhalation 

reference concentration (RfC) methodology to determine the MRL, the BMCL1sd of 92 ppm was durationadjusted for intermittent exposure, as follows: 

BMCL1sd ADJ = (BMCL1sd) (hours/24 hours) (days/7 days) 

= (92 ppm) (6 hours/24 hours) (7 days/7 days) 

= 23 ppm 

1,4-DCB exhibited the effects outside of the respiratory tract and consequently is treated as a 

category 3 gas for purposes of calculating the MRL. The human equivalent concentration (HEC) for 

extrarespiratory effects produced by a category 3 gas is calculated by multiplying the duration-adjusted 

BMCL1sd (BMCL1sd ADJ, see below) by the ratio of blood:gas partition coefficients (Hb/g) in animals and 

humans (EPA 1994k). Hb/g values were not available for 1,4-DCB in rats and humans. Using a default 

value of 1 for the ratio of partition coefficients, the BMCL1sd HEC becomes 23 ppm: 

BMCL1sd HEC	 = (BMCL1sd ADJ) x [(Hb/g)RAT / (Hb/g)HUMAN],
 

= 23 ppm x [1] = 23 ppm
 

The BMCL1sd HEC was divided by a total uncertainty factor of 100 to derive the MRL. This uncertainty 

factor is comprised of component factors of 10 for interspecies extrapolation, and 10 for human 

variability. Although the rat exposure concentration was adjusted to a HEC, an uncertainty factor of 

10 was still applied, because HEC calculation was based on an assumption of equivalent blood-gas 

partition coefficients, and not on actual data. Dividing the 23 ppm BMCL1sd HEC for increased liver weight 

in male rats by an uncertainty factor of 100 (10 for interspecies extrapolation and 10 for human 

variability) yields an MRL of 0.2 ppm for intermediate-duration inhalation exposure to 1,4-DCB. 

Chronic-Duration Exposure. 

•	 An MRL of 0.01 ppm has been derived for chronic-duration (≥365 days) inhalation exposure to 

1,4-DCB. 
DICHLOROBENZENES 31 

2. RELEVANCE TO PUBLIC HEALTH 

A limited amount of information is available on the long-term toxicity of inhaled 1,4-DCB in humans. 

Periodic occupational health examinations of workers who were exposed to 1,4-DCB for an average of 

4.75 years (range, 8 months to 25 years) showed no changes in standard blood and urine indices 

(Hollingsworth et al. 1956). The odor was found to be faint at 15–30 ppm and strong at 30–60 ppm. 

Painful irritation of the eyes and nose was usually experienced at 50–80 ppm, although the irritation 

threshold was higher (80–160 ppm) in workers acclimated to exposure. Concentrations above 160 ppm 

caused severe irritation and were considered intolerable to people not adapted to it. Occasional 

examination of the eyes showed no cataracts or any other lens changes. The odor and irritation properties 

are considered to be fairly good warning properties that should prevent excessive exposures, although the 

industrial experience indicates that it is possible for people to become sufficiently acclimated to tolerate 

high concentrations of the vapor (Hollingsworth et al. 1956). The data from this study are inadequate for 

chronic MRL derivation due to poor characterization of long-term exposure levels, insufficient 

investigation of systemic health end points, and reporting and other study deficiencies. Although the 

available occupational data are insufficient for chronic MRL derivation, the nose and eye irritation 

findings in humans are consistent with nasal effects observed in chronically exposed animals, as 

discussed below. 

Information on the chronic inhalation toxicity of 1,4-DCB in animals is available from two studies in rats 

and mice (Aiso et al. 2005b; Japan Bioassay Research Center 1995; Riley et al. 1980a, 1980b). In the 

Riley et al. (1980a, 1980b) studies, rats of both sexes and female mice were exposed to 75 or 500 ppm of 

1,4-DCB for 5 hours/day, 5 days/week for up to 76 weeks (rats) or 57 weeks (mice), followed by 

32 weeks (rats) or 18–19 weeks (mice) without exposure. There were no exposure-related 

histopathological changes in the nasal cavity or other tissues in either species. Liver and kidney weights 

were increased in rats of both sexes at 500 ppm, but the toxicological significance is questionable due to 

the negative histopathology findings and the lack of related clinical chemistry effects. Evaluation of the 

mouse data is limited by reporting insufficiencies in the available summary of the study. 

In the other chronic study (Aiso et al. 2005b; Japan Bioassay Research Center 1995), groups of 50 male 

and female F344/DuCrj rats and 50 male and female Crj:BDF1 mice were exposed to 1,4-DCB in target 

concentrations of 0, 20, 75, or 300 ppm for 6 hours/day, 5 days/week for 104 weeks. Study end points 

included clinical signs and mortality, body weight (weekly for the first 13 weeks, and subsequently every 

4 weeks), and hematology, blood biochemistry, and urinalysis indices (evaluated at end of study). 

Selected organ weight measurements (liver, kidneys, heart, lungs, spleen, adrenal, brain, testis, and ovary) 

and comprehensive gross pathology and histology evaluations were performed on all animals at the end of 
DICHLOROBENZENES 32 

2. RELEVANCE TO PUBLIC HEALTH 

the study or at time of unscheduled death. No interim pathology examinations were performed. As 

summarized below, this study identifies a NOAEL of 20 ppm and a LOAEL of 75 ppm for dose-related 

eosinophilic changes in the olfactory epithelium in female rats. 

For the rats, the actual mean chamber concentrations were 0, 19.8, 74.8, or 298.4 ppm over the duration 

of the study (Aiso et al. 2005b; Japan Bioassay Research Center 1995). The number of rats surviving to 

scheduled termination was significantly (p<0.05) reduced at 300 ppm in males. Survival in the male rats 

was noticeably lower than controls beginning at approximately study week 80, and overall survival at 0, 

20, 75, and 300 ppm was 66% (33/50), 68% (34/50), 58% (29/50), and 36% (18/50), respectively. There 

were no exposure-related decreases in survival in the female rats, or effects on growth or food 

consumption in either sex. Changes in various hematological and blood biochemical indices (mean cell 

volume, total cholesterol, phospholipids, blood urea nitrogen, creatinine, and calcium in males; total 

protein, total bilirubin, blood urea nitrogen, and potassium in females) occurred at 300 ppm, but a lack of 

numerical data and statistical analysis precludes interpretations of significance for these end points. 

Absolute and relative liver weights in both sexes and kidney weights in males were significantly 

increased at 300 ppm. Additional findings included histopathological changes in the kidneys and nasal 

epithelia. The kidney lesions occurred only in male rats at 300 ppm and included significantly increased 

incidences of mineralization of the renal papilla and in hyperplasia of the urothelium. The nasal lesions 

mainly included increased incidences of eosinophilic changes (globules) in the olfactory epithelium 

(moderate or greater severity) in males at 300 ppm and females at ≥75 ppm. Incidences of this lesion at 0, 

20, 75, and 300 ppm were 1/50, 2/50, 2/50, and 7/50 in males, and 28/50, 29/50, 39/50, and 47/50 in 

females. The increases were statistically significant (p≤0.05, Fisher's Exact Test performed by ATSDR) 

at ≥75 ppm in females and 300 ppm in males, and there was a trend of increasing response with 

increasing dose in both sexes (Cochran-Armitage test, performed by ATSDR). Other nasal lesions that 

were significantly increased at 300 ppm were eosinophilic globules in the respiratory epithelium (11/50, 

10/50, 14/50, 38/50) and respiratory metaplasia in the nasal gland (5/50, 4/50, 4/50, 33/50) in females at 

300 ppm. Kidney lesions were increased only in male rats at 300 ppm and included significantly 

increased incidences of mineralization of the renal papilla (0/50, 1/50, 0/50, 41/50) and in hyperplasia of 

the urothelium (7/50, 8/50, 13/50, 32/50). 

For the mice, the actual mean chamber concentrations were 0, 19.9, 74.8, or 298.3 ppm over the duration 

of the study. Survival was significantly reduced in male mice at 300 ppm (due to an increase in liver 

tumor deaths), but comparable to controls in the females. Terminal body weight was significantly 

reduced at 300 ppm in males (11.5% less than controls, beginning at study week 80). Changes in various 
DICHLOROBENZENES 33 

2. RELEVANCE TO PUBLIC HEALTH 

hematological and blood biochemical indices (total cholesterol, serum glutamic oxaloacetic transaminase 

[SGOT], serum glutamic pyruvic transaminase [SGPT], lactic dehydrogenase [LDH], and alkaline 

phosphatase [AP] in both sexes; platelet numbers, total protein, albumin, total cholesterol, blood urea 

nitrogen, and calcium in females) occurred at 300 ppm (Japan Bioassay Research Center 1995), but a lack 

of reported numerical data and results of statistical analysis precludes interpretation of these end points. 

Absolute and relative liver and kidney weights in both sexes were significantly increased at 300 ppm. 

Additional findings included histopathological changes in the nasal cavity, liver, and testes. The nasal 

lesions included significantly increased incidences of respiratory metaplasia in the nasal gland (moderate 

severity) in males at 75 ppm (9/49, 12/49, 18/50, 11/49) and olfactory epithelium (slight severity) in 

males at 75 ppm (23/49, 30/49, 37/50, 22/49) and females at 300 ppm (7/50, 6/50, 2/49, 20/50); the 

effects in the males were not dose-related (i.e., incidences were increased at 75 ppm but not at 300 ppm). 

The incidence of centrilobular hepatocellular hypertrophy was significantly increased in male mice at 

300 ppm (0/49, 0/49, 0/50, 34/49). Incidences of liver tumors were also increased at 300 ppm; these 

included hepatocellular carcinoma in males (12/49, 17/49, 16/50, 38/49) and females (2/50, 4/50, 2/49, 

41/50), hepatocellular adenoma in females (2/50, 10/50, 6/49, 20/50), hepatoblastoma in males (0/49, 

2/49, 0/50, 8/49) and females (0/50, 0/50, 0/49, 6/50), and histiocytic sarcoma in males (0/49, 3/49, 1/50, 

6/49). Testicular mineralization was significantly increased in males at ≥75 ppm (27/49, 35/49, 42/50, 

41/49) (Japan Bioassay Research Center 1995). The testicular mineralization was not considered to be a 

toxicologically significant effect (Aiso 2006) because (1) no signs of testicular toxicity were observed in 

mice exposed for 13 weeks (Aiso et al. 2005a), and (2) it was confined to the testicular capsules and 

testicular blood vessels and not observed in the testicular parenchyma, indicating that it is a finding 

commonly observed in aged mice independent of exposure to 1,4-DCB (Aiso 2006). 

The results of this study indicate that moderate or severe eosinophilic changes in the nasal olfactory 

epithelium in female rats is the most sensitive toxic effect in the most sensitive species and sex. The 

NOAEL and LOAEL for these nasal lesions are 19.8 and 74.8 ppm, respectively. To derive a point of 

departure for MRL derivation, BMD analysis was conducted using the incidences of the nasal lesions 

(moderate or greater severity) in the female rats. Data for other end points were not modeled because the 

effects occurred at higher concentrations (nasal lesions and hepatocellular hypertrophy in mice, kidney 

lesions in rats) or were not toxicologically significant (testicular mineralization in mice). All 

dichotomous models in the Benchmark Dose Software (version 1.3.2) were fit to the female rat nasal 

lesion incidence data. All models provided adequate fits to the data, and the quantal linear model 

provided the best fit to the data. Using a BMR level of 10% extra risk above the control incidence, the 

quantal linear model resulted in a benchmark concentration (BMC10) of 14.08 ppm and lower 95% 
 

 

 

 

 

 

 

 

DICHLOROBENZENES 34 

2. RELEVANCE TO PUBLIC HEALTH 

confidence limit (BMCL10) of 9.51 ppm. A summary of the predicted BMCs and BMCLs, as well as 

details of the BMD modeling, are presented in Appendix A. 

Using the BMCL10 value of 9.51 ppm for increased incidences of nasal lesions in female rats and EPA 

(1994k) inhalation RfC methodology to determine the MRL, the BMCL10 was duration-adjusted for 

intermittent exposure, as follows: 

BMCL10 ADJ = (BMCL10) (hours/24 hours) (days/7 days) 

= (9.51 ppm) (6 hours/24 hours) (5 days/7 days) 

= 1.70 ppm 

For the nasal olfactory epithelium changes in female rats, 1,4-DCB was treated as a category 1 gas with 

effects in the extrathoracic region for purposes of calculating the HEC. Using EPA (1988, 1994b) 

reference values, the regional gas deposition ratio was calculated as follows (EPA 1994a): 

RGDRET = [(VE/SAET)A/(VE/SAET)H] 

= (0.24 m3

/day/15cm2)/(20 m3/day/200cm2) 

= 0.16 

 where: RGDRET = regional gas deposition ratio in the extrathoracic region 

VE = minute volume in rats (VE)A or humans (VE)H 

 SAET = extrathoracic surface area in rats (SAET)A or humans (SAET)H 

The HEC was calculated by multiplying the rat BMCL10 ADJ by the RGDRET to yield a BMCL10 HEC of 

0.27 ppm, as follows: 

BMCL10 HEC = BMCL10 ADJ x RGDRET

 = 1.70 ppm x 0.16 

= 0.27 ppm 

The BMCL10 HEC of 0.27 ppm for nasal effects in rats was divided by a total uncertainty factor of 30 to 

calculate the MRL. This uncertainty factor is comprised of component factors of 3 for interspecies 

extrapolation and 10 for human variability. A 3-fold uncertainty factor was used instead of a default 

10-fold factor to extrapolate from rats to humans, because the dosimetry adjustment (i.e., calculation of 

the human equivalent exposure for time and concentration [NOAELHEC]) addresses one of the two areas 

of uncertainty encompassed in an interspecies extrapolation factor. The dosimetric adjustment addresses 

the pharmacokinetic component of the extrapolation factor, but the pharmaco-dynamic area of uncertainty 

remains as a partial factor for interspecies uncertainty. Dividing the 0.27 ppm NOAEL10 HEC by the 

uncertainty factor of 30 yields an MRL of 0.01 ppm for chronic-duration inhalation exposure to 1,4-DCB. 
DICHLOROBENZENES 35 

2. RELEVANCE TO PUBLIC HEALTH 

Oral MRLs 

1,2-Dichlorobenzene 

Acute-Duration Exposure. 

•	 An MRL of 0.7 mg/kg/day has been derived for acute-duration (≤14 days) oral exposure to 

1,2-DCB. 

Information on effects of acute oral exposure to sublethal doses of 1,2-DCB consists of findings in three 

systemic toxicity studies in rats and mice and one developmental toxicity study in rats (NTP 1985; 

Rimington and Ziegler 1963; Robinson et al. 1991; Ruddick et al. 1983). These studies administered the 

compound by gavage and collectively identify the liver as the most sensitive target. Severe liver damage, 

characterized by intense necrosis and fatty changes as well as porphyria, occurred in rats administered 

455 mg/kg/day for 15 consecutive days (Rimington and Ziegler 1963). Rats that were exposed to 

300 mg/kg/day for 10 consecutive days had hepatic effects that included necrosis and increased serum 

ALT (Robinson et al. 1991). Hepatocellular degeneration and necrosis occurred in mice that were 

exposed to 250 or 500 mg/kg/day for 14 consecutive days (NTP 1985). The 15-day rat and 14-day mouse 

studies are limited by small numbers of animals (3–5 per dose) and lack of a NOAEL due a single dose 

level (Rimington and Ziegler 1963) or lack of histopathology evaluations at doses lower than the LOAEL 

(NTP 1985). The 10-day study (Robinson et al. 1991) is the most appropriate basis for MRL derivation 

because it is well designed, included four dose levels, and provides dose-response data for several hepatic 

end points. 

In the Robinson et al. (1991) study, groups of 10 male and 10 female Sprague-Dawley rats were treated 

with 1,2-DCB in corn oil by gavage at doses of 0, 37.5, 75, 150, or 300 mg/kg/day for 10 consecutive 

days. The doses were selected on the basis of a reported rat oral LD50 of 500 mg/kg. End points 

evaluated during the study included clinical signs, body weight, and food and water consumption. 

Evaluations at the end of the exposure period included hematology (five indices), serum chemistry 

(nine indices including aspartate AST, ALT, LDH, cholesterol, blood urea nitrogen, and creatinine), and 

selected organ weights (brain, liver, spleen, lungs, thymus, kidneys, adrenal glands, heart, and testes or 

ovaries). Histological examinations were performed on various tissues including liver, kidneys, urinary 

bladder, heart, skin, muscle, bone, respiratory tract (nasal cavity with turbinates, lungs), nervous system 
 

 

DICHLOROBENZENES 36 

2. RELEVANCE TO PUBLIC HEALTH 

(brain, sciatic nerve), immunological (spleen, thymus, lymph nodes), gastrointestinal (duodenum, ileum, 

jejunum, salivary gland, colon, cecum, rectum), endocrine (adrenal glands, pancreas), and reproductive 

(testes, seminal vesicles, prostate, ovaries) in the high-dose and control groups. Target organs identified 

in the high-dose group were also histologically evaluated at the lower dose levels. 

No clinical signs or effects on survival were observed (Robinson et al. 1991). Body weight gain was 

significantly reduced in the male rats at 300 mg/kg/day (final body weights were 10.9% lower than 

controls), but not in females, and there were no exposure-related changes in food consumption in either 

sex. Statistically significant changes in organ weights predominantly occurred at 300 mg/kg/day, 

including significantly decreased absolute spleen weight in both sexes and decreased absolute heart, 

kidney, thymus, and testes weights in males. Liver weight (absolute and relative) was significantly 

increased in females at ≥150 mg/kg/day and males at 300 mg/kg/day; compared to controls in the low- to 

high-dose females, absolute liver weights were 1.8, 9.0, 20.5, and 29.0% increased and relative liver 

weights were 6.8, 7.6, 21.7, and 34.5% increased. Clinical chemistry findings included significantly 

increased serum ALT in both sexes at 300 mg/kg/day and serum phosphorus in females at 

≥150 mg/kg/day. Serum cholesterol was significantly increased in females at ≥37.5 mg/kg/day, but the 

toxicological significance is unclear because the values were similar at all dose levels and showed no 

dose-response. Histopathological findings were limited to the liver and included necrosis that was slight 

in severity and significantly (p=0.04) increased in males at 300 mg/kg/day (4/10 compared to 0/10 in 

controls); incidences in the other dose groups were not reported, although the study authors indicated that 

target organs in the high-dose groups were histologically evaluated at the lower dose levels. Incidences 

of other hepatic lesions were not significantly increased, but included inflammation (characterized by 

lymphocyte and macrophage infiltrates) and degeneration of hepatocytes (characterized by varying 

degrees of fibrillar or vacuolated cytoplasm and swelling with intact cell membranes). This study 

identified a NOAEL of 75 mg/kg/day and a LOAEL of 150 mg/kg/day for increased liver weight (>10%) 

in female rats, as well as a LOAEL of 300 mg/kg/day for liver necrosis in male rats. 

To derive a point of departure for MRL derivation, BMD dose analysis was conducted using the rat 

absolute liver weight data. The liver lesion data were not subjected to BMD analysis because incidences 

of liver necrosis were only reported for control and high-dose rats. Serum liver enzyme (ALT, AST, 

LDH) data were not subjected to BMD analysis because a statistically significant increase was noted only 

for serum ALT in the high-dose group of male rats and the magnitude of the increase (50% higher than 

the control serum ALT level) is not considered to be adverse. All continuous variable models in the EPA 

Benchmark Dose Software (Version 1.3.2) were fit to the absolute liver weight data from male and female 
 

 

DICHLOROBENZENES 37 

2. RELEVANCE TO PUBLIC HEALTH 

rats. One standard deviation increase from the control mean value was selected as the BMR in the 

absence of a biological rationale for using an alternative BMR. A summary of the predicted BMDs and 

BMDLs, as well as details of the BMD modeling, are presented in Appendix A. The linear model was 

determined to the best-fitting model for the liver weight data in male rats (provided a BMD1sd of 

249.04 mg/kg/day and a BMDL1sd of 158.55 mg/kg/day) and female rats (provided a BMD1sd of 

84.67 mg/kg/day and a BMDL1sd of 67.73 mg/kg/day). Among the best-fitting model results, the lowest 

BMDL1sd of 67.73 mg/kg/day was selected as the point of departure for deriving the MRL. The BMDL1sd 

of 67.73 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolation from animals to 

humans and 10 for human variability) to derive an MRL of 0.7 mg/kg/day for acute-duration oral 

exposure to 1,2-DCB. 

Intermediate-Duration Exposure. 

•	 An MRL of 0.6 mg/kg/day has been derived for intermediate-duration (15–364 days) oral 

exposure to 1,2-DCB. 

Information on effects of intermediate-duration oral exposure to 1,2-DCB is available from three 

intermediate studies in rats and mice identifying the liver as the most sensitive target of toxicity 

(Hollingsworth et al. 1958; NTP 1985; Robinson et al. 1991). Incidences of degenerative liver lesions 

were significantly increased in rats exposed to 250–500 mg/kg/day for ≥13 weeks (Hollingsworth et al. 

1958; NTP 1985; Robinson et al. 1991) and mice exposed to 250 mg/kg/day for 13 weeks (NTP 1985). 

Necrotic lesions occurred in several rats at 125 mg/kg/day (1/10 males, 3/10 females), but the increase 

was not statistically significant (NTP 1985). Other hepatic findings in rats exposed to lower doses (125– 

188 mg/kg/day for ≥13 weeks) included increases in relative liver weight and serum levels of ALT, 

cholesterol, serum protein, and decreases in serum triglycerides. Increased serum ALT is an inconsistent 

finding because it was induced in rats exposed to ≥100 mg/kg/day for 90 days (Robinson et al. 1991), but 

not in rats exposed to ≥125 mg/kg/day for 13 weeks (NTP 1985). Additionally, the increase in serum 

ALT was not dose-related and serum levels of other liver-associated enzymes were not increased in either 

the Robinson et al. (1991) study (AST, LDH, and AP) or the NTP (1985) study (AP and GGTP). The 

lowest LOAEL is 125 mg/kg/day, which is a minimal LOAEL for increased liver weight in rats in the 

NTP (1985) study. 

In the NTP (1985) study, groups of 10 male and 10 female F344 rats and 10 male and 10 female 

B6C3F1 mice were administered 1,2-DCB in doses of 0, 30, 60, 125, 250, or 500 mg/kg/day for 
DICHLOROBENZENES 38 

2. RELEVANCE TO PUBLIC HEALTH 

5 days/week for 13 weeks. Histology examinations of the liver were limited to the control and three 

highest dose groups. Degenerative lesions were significantly (p≤0.05) increased in both species at 

≥250 mg/kg/day. Changes in the rats included necrosis of individual hepatocytes at ≥250 mg/kg/day and 

centrilobular degeneration at 500 mg/kg/day; total incidences of these lesions at 0, 125, 250, and 

500 mg/kg/day were 0/10, 1/10, 4/9, and 8/10 in males, and 0/10, 3/10, 5/10, and 7/8 in females. Relative 

liver weights were significantly increased at 125, 250, and 500 mg/kg/day in the males (8, 17, and 45% 

higher than controls) and females (8, 15, and 30%); increased relative liver weights were not seen at 

lower doses in either sex. There were no increases in serum levels of liver enzymes [ALT, AP, or GGPT] 

at any dose in either sex. Serum cholesterol was significantly increased in males at ≥30 mg/kg/day (50.0, 

17.6, 26.5, 70.6, and 109% higher than controls in the low to high dose groups; not significant at 

60 mg/kg/day) and females at ≥125 mg/kg/day (12.2, 12.2, 32.6, 26.5, and 51.0%). Although increases in 

serum cholesterol were observed at doses as low as 30 mg/kg/day, the toxicological significance is 

unclear because there was no clear dose-response unless the increase at 30 mg/kg/day is considered to be 

outlying. Urinary concentrations of uroporphyrin and coproporphyrin were 3–5 times higher than 

controls in the 500 mg/kg/day males and females, but this increase was not considered indicative of 

porphyria because total porphyrin concentration in the liver was not altered at any dose level and no 

pigmentation indicative of porphyria was observed by ultraviolet light at necropsy. The 60 and 

125 mg/kg/day doses are the NOAEL and LOAEL, respectively, for hepatic effects in rats based on the 

increases in liver weight in both sexes. 

In the mice, no compound-related histopathological changes were observed in either sex at 0 and 

125 mg/kg/day or in females at 250 mg/kg/day. Lesions that were significantly increased included 

necrosis of individual hepatocytes, hepatocellular degeneration and/or pigment deposition in 4/10 males 

at 250 mg/kg/day, and centrilobular necrosis, necrosis of individual hepatocytes, and/or hepatocellular 

degeneration in 9/10 males and 9/10 females at 500 mg/kg/day. Relative liver weights were significantly 

increased at 500 mg/kg/day in both sexes, but there were no exposure-related changes in serum levels of 

ALT, AP, or GGPT in either sex at any dose (no other clinical chemistry indices were examined in the 

mice). Based on the liver lesion data, the NOAEL and LOAEL in mice are 125 and 250 mg/kg/day, 

respectively. 

To derive a point of departure for MRL derivation, BMD analysis was conducted using liver lesion and 

liver weight data from the NTP (1985) study. Dichotomous models available in the EPA Benchmark 

Dose Software (Version 1.3.2) were fit to data for incidences of liver lesions (single cell necrosis, 

centrilobular necrosis, and/or hepatocellular degeneration) in male and female rats (combined) and male 
 

 

 

DICHLOROBENZENES 39 

2. RELEVANCE TO PUBLIC HEALTH 

mice. Because there were no apparent differences in sensitivity to 1,2-DCB among the male and female 

rats, the liver lesion data were combined to increase the statistical power for BMD analysis. For each data 

set, BMDs and their lower 95% confidence limits (BMDLs) were calculated using a BMR of 10% extra 

risk. All available models provided adequate fit to liver lesion data for male and female rats combined. 

The best-fitting model was the quantal quadratic model, which provided a BMD10 of 108.71 mg/kg/day 

and a BMDL10 of 92.08 mg/kg/day. The log-probit model was determined to be the best-fitting model for 

the male mouse incidence data and provided a BMD10 of 176.05 mg/kg/day and BMDL10 of 

114.58 mg/kg/day. Continuous variable models in the EPA Benchmark Dose Software were fit to the 

relative liver weight data for male and female rats using a BMR of 1 standard deviation from the control 

mean. Adequate fits were not obtained for the male rat liver weight data, but the linear model was the 

best-fitting model for the female data, resulting in a BMD1sd of 108.15 mg/kg/day and a BMDL1sd of 

89.27 mg/kg/day. A summary of the predicted BMDs and BMDLs for both end points, as well as details 

of the BMD modeling, are presented in Appendix A. 

The BMDL1sd of 89.27 mg/kg/day from the best-fitting modeling results of the female rat relative liver 

weight data is lower than the BMDL10 of 92.08 mg/kg/day from the best-fitting modeling results of liver 

lesion incidences in the male and female rats combined and the BMDL10 of 114.58 mg/kg/day from the 

best-fitting model results of liver lesion incidences in the male mice. Therefore, the BMDL1sd of 

89.27 mg/kg/day for increased relative liver weight in the female rats was selected as the point of 

departure for the MRL. The BMDL1sd of 89.27 mg/kg/day was adjusted for intermittent experimental 

exposure (5 days/7 days) to give a duration-adjusted BMDL1sd of 63.76 mg/kg/day, and divided by an 

uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability) to derive an 

intermediate-duration oral MRL of 0.6 mg/kg/day for 1,2-DCB. 

Chronic-Duration Exposure. 

•	 An MRL of 0.3 mg/kg/day has been derived for chronic-duration (≥365 days) oral exposure to 

1,2-DCB. 

One chronic oral toxicity study of 1,2-DCB is available. In this study groups of F344/N rats 

(50/sex/group) and B6C3F1 mice (50/sex/group) were administered 1,2-DCB in corn oil by gavage in 

doses of 0, 60, or 120 mg/kg/day for 5 days/week for 103 weeks (NTP 1985). Evaluations included 

clinical signs, body weight, and necropsy and histology on all animals. Organ weight and clinical 

chemistry indices were not assessed. The only exposure-related effect in either species was a 
DICHLOROBENZENES 40 

2. RELEVANCE TO PUBLIC HEALTH 

significantly increased incidence of renal tubular regeneration in the male mice. This lesion showed a 

dose-related trend, and was statistically significantly elevated in high-dose animals, but not in low-dose 

animals. The NOAEL for the lesion was therefore 60 mg/kg/day, and the LOAEL was 120 mg/kg/day. 

To derive a point of departure for MRL derivation, BMD analysis was conducted using the kidney lesion 

incidence data. All dichotomous models in the Benchmark Dose Software (version 1.3.2) were fit to the 

male mouse incidence data for renal tubule regeneration. A 10% extra risk above the control incidence 

was selected as the BMR in the absence of a biological rationale for using an alternative BMR. A 

summary of the predicted BMDs and BMDLs, as well as details of the BMD modeling, are presented in 

Appendix A. The logistic model was the best-fitting model, resulting in a BMD10 of 62.96 mg/kg/day and 

a BMDL10 of 43.04 mg/kg/day. The BMDL10 43.04 mg/kg/day was adjusted for intermittent 

experimental exposure (5 days/7 days) to give a duration-adjusted BMDL10 of 30.74 mg/kg/day, and 

divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human 

variability) to derive a chronic-duration oral MRL of 0.3 mg/kg/day for 1,2-DCB. 

1,3-Dichlorobenzene 

Acute-Duration Exposure. 

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

1,3-DCB. 

The acute oral database for 1,3-DCB consists of one short-term toxicity study in which groups of 10 male 

and 10 female Sprague Dawley rats were administered gavage doses of 0, 37, 147, 368, or 735 mg/kg/day 

in corn oil for 10 consecutive days (McCauley et al. 1995). End points evaluated during the study 

included clinical signs, survival, body weight, and food and water consumption. At the end of the study, 

blood was collected for hematology and serum chemistry analyses (erythrocytes, leukocytes, hemoglobin, 

hematocrit, mean corpuscular volume, glucose, BUN, creatinine, AP, AST, ALT, cholesterol, LDH, and 

calcium levels), and selected organs were weighed (brain, liver, spleen, lungs with lower half of trachea, 

thymus, kidneys, adrenal glands, heart, and gonads). Gross pathology was evaluated in all animals, and 

comprehensive histological examinations were performed in the high dose and control groups; histology 

in the lower dose groups was limited to the liver. Inflammatory and degenerative lesions were graded on 

a relative scale from one to four depending on the severity (minimal, mild, moderate, or marked). 
DICHLOROBENZENES 41 

2. RELEVANCE TO PUBLIC HEALTH 

No compound-related deaths or overt clinical signs were observed (McCauley et al. 1995). Body weight 

was significantly reduced in both sexes at 735 mg/kg/day (20 and 13% lower than controls in males and 

females, respectively). Food consumption was significantly decreased at 735 mg/kg/day in males (12%, 

normalized by body weight), and water consumption was significantly increased (8–13%) in females at 

≥735 mg/kg/day. The hematological evaluation showed 8% decreased MCV in females at 

735 mg/kg/day. The clinical chemistry analyses showed statistically significant changes in several 

indices, but serum cholesterol was the only end point that had values that exceeded the reference range. 

Serum cholesterol was significantly increased in females at 368 and 735 mg/kg/day (94 and 63% higher 

than controls, respectively), as well as in males at 368 and 735 mg/kg/day (79 and 84% higher than 

controls, respectively). Relative liver weight was significantly increased in males at ≥147 mg/kg/day and 

females at ≥368 mg/kg/day; increases in the males were 9.1, 31.3, 50.63, and 32.5% higher than controls 

in the low- to high-dose groups. Other significant changes in relative organ weight included decreased 

spleen weight in females at ≥368 mg/kg/day and males at 735 mg/kg/day, decreased thymus weight in 

both sexes at 735 mg/kg/day, and decreased testes weight in males at 735 mg/kg/day. Absolute organ 

weights were not reported. Histological changes primarily occurred in the liver, particularly centrilobular 

hepatocellular degeneration at ≥368 mg/kg/day. This lesion was characterized by varying degrees of 

cytoplasmic vacuolization and swelling with intact membranes, and occurred in the 368 and 

735 mg/kg/day groups in 2/10 and 9/10 males, respectively, and 6/10 and 10/10 females, respectively; 

incidences in the other groups were not reported but are presumed to be 0/10. Other hepatic alterations 

included hepatocellular necrosis that was sporadically noted in the 147, 368, and 735 mg/kg/day groups. 

This change was usually minimal to mild, and was reported to increase in incidence and severity in the 

males in a dose-related manner; however, incidences were not reported. The only other reported 

histological change was atrophy of the thymus, characterized by loss of normal differentiation between 

medulla and cortex. The thymic atrophy was observed in 2/10 males (both marked in severity) and 

2/9 females (both mild in severity) at 735 mg/kg/day; this change was not observed in controls, and the 

other dosed groups were not examined. The 147 mg/kg/day dose is the LOAEL (minimal) for liver 

effects based on the >10% increase in relative liver weight in male rats. The NOAEL for increased liver 

weight is 37 mg/kg/day. 

To derive a point of departure for MRL derivation, BMD analysis was conducted using liver effects data 

from the McCauley et al. (1995) study. The liver effects data modeled included incidences of 

hepatocellular degeneration, absolute liver weights and mean serum cholesterol levels. All dichotomous 

variable models available in the EPA Benchmark Dose Software (Version 1.3.2) were fit to the incidence 

data for hepatocellular degeneration in male and female rats using a BMR of 10% extra risk. All 
DICHLOROBENZENES 42 

2. RELEVANCE TO PUBLIC HEALTH 

continuous variable models in the BMD software were fit to the mean absolute liver weight data and 

mean serum cholesterol level data in male and female rats using a BMR of 1 standard deviation increase 

above the control mean. A summary of the predicted BMDs and BMDLs for all end points, as well as 

details of the BMD modeling, are presented in Appendix A. The best-fitting models resulted in a 

BMDL10 of 207.86 mg/kg/day for hepatocellular degeneration in male rats (log-probit model), a 

BMDL10 of 159.37 mg/kg/day for hepatocellular degeneration in female rats (log-probit model), and a 

BMDL1sd of 36.32 mg/kg/day for absolute liver weight changes in female rats (2-degree polynomial 

model). The lowest BMDL1sd of 36.32 mg/kg/day was selected as the most conservative point of 

departure for deriving an MRL. The BMDL1sd of 36.32 mg/kg/day was divided by an uncertainty factor 

of 100 (10 for animal to human extrapolation and 10 for human variability) to derive an acute-duration 

oral MRL of 0.4 mg/kg/day for 1,3-DCB. 

Intermediate-Duration Exposure. 

•	 An MRL of 0.02 mg/kg/day has been derived for intermediate-duration (15–364 days) oral 

exposure to 1,3-DCB. 

The database for intermediate-duration oral exposure to 1,3-DCB consists of one intermediate toxicity 

study in which groups of 10 male and 10 female Sprague Dawley rats were administered gavage doses of 

0, 9, 37, 147, or 588 mg/kg/day in corn oil for 90 consecutive days (McCauley et al. 1995). End points 

evaluated during the study included clinical signs and mortality, body weight, and food and water 

consumption. At end of the exposure period, blood was collected for hematology and serum chemistry 

analyses (erythrocytes, leukocytes, hemoglobin, hematocrit, mean corpuscular volume, glucose, BUN, 

creatinine, AP, AST, ALT, cholesterol, LDH, and calcium levels), selected organs were weighed (brain, 

liver, spleen, lungs with lower half of trachea, thymus, kidneys, adrenal glands, heart, and gonads), and 

gross pathology was assessed. Histological examinations were performed on all tissues that were 

examined grossly in all high-dose rats and in one-half of control rats, as well as in the liver, thyroid, and 

pituitary glands from all animals in the 9, 37, and 147 mg/kg/day dose groups. Inflammatory and 

degenerative lesions were graded on a relative scale from one to four depending on the severity (minimal, 

mild, moderate, or marked). 

No compound-related deaths or overt clinical signs were observed (McCauley et al. 1995). Body weight 

was reduced in both sexes at 588 mg/kg/day (24 and 10% lower than controls in males and females, 

respectively). The decreased weight gain was progressive throughout the exposure period and occurred 
DICHLOROBENZENES 43 

2. RELEVANCE TO PUBLIC HEALTH 

despite increased food and water consumption in the same groups. Other effects included increased 

relative kidney weight in males at ≥147 mg/kg/day and females at 588 mg/kg/day, but there were no renal 

histopathological changes in any of the exposed animals. Hematological alterations consisted of 

significant increases in leukocyte levels in males at 147 mg/kg/day and females at 588 mg/kg/day, and in 

erythrocyte levels in males at 588 mg/kg/day. As discussed below, histopathology and serum chemistry 

findings indicated that the thyroid, pituitary, and liver were the most sensitive targets of toxicity. 

Thyroid effects included significantly (p≤0.05) increased incidences of reduced colloidal density in 

follicles that exceeded normal variability in male rats at ≥9 mg/kg/day and female rats at ≥37 mg/kg/day 

(control to high dose group incidences of 2/10, 8/10, 10/10, 8/9, and 8/8 in males, and 1/10, 5/10, 8/10, 

8/10, and 8/9 in females) (McCauley et al. 1995). Depletion of colloid density in the thyroid was 

characterized by decreased follicular size with scant colloid and follicles lined by cells that were cuboidal 

to columnar. The severity of the colloid density depletion generally ranged from mild to moderate, 

increased with dose level, and was greater in males than females. Incidences of male rats with thyroid 

colloidal density depletion of moderate or marked severity were significantly increased at 

≥147 mg/kg/day (0/10, 0/10, 2/10, 5/9, and 6/8). 

Pituitary effects included significantly (p≤0.05) increased incidences of cytoplasmic vacuolization in the 

pars distalis in male rats at ≥147 mg/kg/day (2/10, 6/10, 6/10, 10/10, and 7/7). The vacuoles were 

variably sized, irregularly shaped, and often poorly defined, and the severity of the lesions (i.e., number of 

cells containing vacuoles) ranged from minimal to mild and generally increased with increasing dose 

level. Incidences of male rats with pituitary cytoplasmic vacuolization of moderate or marked severity 

were significantly increased at 588 mg/kg/day (1/10, 0/10, 2/10, 3/9, and 7/7). The pituitary lesion was 

reported to be similar to "castration cells" found in gonadectomized rats and considered to be an indicator 

of gonadal deficiency. No compound-related pituitary lesions were observed in female rats. Serum 

cholesterol was significantly increased in males at ≥9 mg/kg/day and in females at ≥37 mg/kg/day in a 

dose-related manner, and serum calcium was significantly increased in both sexes at ≥37 mg/kg/day. The 

investigators suggested that these serum chemistry changes might reflect a disruption of hormonal 

feedback mechanisms, or target organ effects on the pituitary, hypothalamus, and/or other endocrine 

organs. 

Hepatic effects occurred in both sexes at 147 and 588 mg/kg/day, including significantly increased 

relative liver weight and incidences of liver lesions (McCauley et al. 1995). Absolute organ weights were 

not reported. Liver lesions were characterized by inflammation, hepatocellular alterations (eosinophilic 
DICHLOROBENZENES 44 

2. RELEVANCE TO PUBLIC HEALTH 

homogeneous inclusions), and hepatocellular necrosis. Liver lesions that were significantly (p≤0.05) 

increased included hepatocellular cytoplasmic alterations of minimal to mild severity in males at 

≥147 mg/kg/day (1/10, 2/10, 1/10, 6/10, and 7/9) and females at 588 mg/kg/day (0/10, 2/10, 0/10, 1/10, 

and 7/9), and necrotic hepatocyte foci of minimal severity at 588 mg/kg/day in both males (1/10, 2/10, 

1/10, 2/10, and 5/9) and females (0/10, 0/10, 0/10, 3/10, and 5/9). Other statistically significant liverassociated effects included significantly increased serum AST levels (90–100% higher than controls) in 

males at ≥9 mg/kg/day and females at ≥37 mg/kg/day. Serum cholesterol levels were significantly 

increased in males at ≥9 mg/kg/day and females at ≥37 mg/kg/day, but might be pituitary-related, as 

indicated above. Serum LDH levels were reduced in males at ≥9 mg/kg/day and BUN levels were 

reduced in both sexes at 588 mg/kg/day, but the biological significance of decreases in these indices is 

unclear. 

To derive a point of departure for MRL derivation, BMD analysis was conducted using data for thyroid 

and pituitary lesion incidences and serum AST and cholesterol levels. Continuous variable models in the 

EPA Benchmark Dose Software (Version 1.3.2) were fit to serum AST levels in the male rats and the 

serum cholesterol levels in the male and female rats using a one standard deviation change from the 

control mean as the BMR. Dichotomous variable models in the BMD software were fit to the incidence 

data for thyroid lesions (reduced follicular colloidal density) and pituitary lesions (cytoplasmic 

vacuolation in the pars distalis) in the male rats. A summary of the predicted BMDs and BMDLs for all 

of the end points, as well as details of the BMD modeling, are presented in Appendix A. None of the 

models provided an adequate fit for the serum AST, serum cholesterol, or thyroid lesion data. For the 

pituitary lesion incidence data, all of the models provided adequate fit. The probit model provided the 

best fit, but nearly identical fits were provided by three other models (gamma, quantal-linear, and 

Weibull). Because the BMD10 of 4.08 mg/kg/day and associated BMDL10 of 2.10 mg/kg/day from the 

gamma, quantal-linear, and Weibull models are lower than those from the probit model (BMD10 = 

7.79 mg/kg/day; BMDL10 = 4.46 mg/kg/day), a conservative health protective approach was taken and the 

lower BMDL10 of 2.10 mg/kg/day was selected as the point of departure for deriving the MRL. The 

BMDL10 of 2.1 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolation from animals 

to humans and 10 for human variability) to derive an MRL of 0.02 mg/kg/day for intermediate-duration 

oral exposure to 1,3-DCB. 
DICHLOROBENZENES 45 

2. RELEVANCE TO PUBLIC HEALTH 

Chronic-Duration Exposure. 

No MRL was derived for chronic-duration oral exposure to 1,3-DCB due to a lack of chronic oral studies. 

1,4-Dichlorobenzene 

Acute-Duration Exposure. No acute-duration oral MRL was derived for 1,4-DCB due to insufficient 

data. Information on effects of non-lethal acute-duration oral exposures to 1,4-DCB is essentially limited 

to hepatic and renal changes of unclear toxicological significance observed in studies designed to 

elucidate mechanisms of liver and kidney toxicity in rats and mice. Acute liver damage, as assessed by 

histopathology and serum enzyme/biochemical indicators following gavage exposure, was not induced by 

high levels of 1,4-DCB in rat given single doses of ≤2790 mg/kg (Allis et al. 1992), rats and mice given 

single doses of ≤1,200 mg/kg/day (Eldridge et al. 1992), or rats and mice administered ≤300 and 

≤600 mg/kg/day, respectively, 5 days/week for 1 week (Lake et al. 1997). Porphyria, manifested as 

increased porphyrin levels in liver and urine and suggestive of hepatic damage, was reported in rats that 

were orally exposed to 770 mg/kg/day for 5 days (Rimington and Ziegler 1963). Although there was no 

clear evidence of liver injury in acute studies, similar dose levels of 1,4-DCB are toxic following 

intermediate- and chronic-duration exposures. 

Increased hepatocelluar proliferation, as measured by increased incorporation of bromodeoxyridine 

(BrdU) or [3H] thymidine into DNA-synthesizing liver cells, has been demonstrated in rats and mice at 

doses ≥150 mg/kg/day in a number of single dose and short-term oral studies that found no histological or 

other indications of overt liver damage (Eldridge et al. 1990, 1992; Hasmall et al. 1997; Lake et al. 1997; 

Sherman et al. 1998; Umemura et al. 1992, 1996). The induction of liver cell proliferation in the absence 

of manifest hepatoxicity suggests that the proliferation is a response to mitogenic stimulation rather than 

compensatory regeneration to cytotoxicity. Cellular proliferation and other changes have also been 

demonstrated in the kidney tubular epithelia of male rats, but not in female rats or mice of either sex, 

following short-term oral exposures to doses ≥150 mg/kg/day (Eldridge et al. 1992; Lake et al. 1997; 

Sherman et al. 1998; Umemura et al. 1992). The renal effects are consistent with the induction of 

α2μ-globulin nephropathy in male rats by similar doses of 1,4-DCB in other acute oral studies 

(Charbonneau et al. 1989b; Dietrich and Swenberg 1991; Saito et al. 1996), but are not relevant to 

humans. Induction of hepatic microsomal xenobiotic metabolizing enzymes appears to be the most 

sensitive effect of acute/short-term exposure to 1,4-DCB (Elovaara 1998). For example, oral exposure to 

doses as low as 20 mg/kg/day for 14 days increased the activities of glucuronyl transferase, benzpyrene 
DICHLOROBENZENES 46 

2. RELEVANCE TO PUBLIC HEALTH 

hydroxylase, and enzymes involved in the detoxification of O-ethyl-O-nitrophenyl phenylphosphorothionate (EPN) in rats (Carlson and Tardiff 1976). Induction of hepatic microsomal enzymes is not 

necessarily adverse, but does indicate that the liver is sensitive to relatively low doses of 1,4-DCB. 

The toxicological significance of the hepatic microsomal enzyme changes is unclear and the information 

on other liver effects is insufficient to identify a reliable NOAEL or LOAEL for acute/short-term oral 

exposure to 1,4-DCB. The lack of adequate data on the threshold of adverse effects precludes derivation 

of an MRL for acute duration oral exposure. 

Intermediate-Duration Exposure. 

•	 An MRL of 0.07 mg/kg/day has been derived for intermediate-duration (15–364 days) oral 

exposure to 1,4-DCB. 

Information on the systemic toxicity of intermediate-duration oral exposure to 1,4-DCB is available from 

a number of studies conducted in rodents, mainly rats and mice, as well as one study in dogs. Liver and 

kidney effects are the most consistently observed, best characterized, and most sensitive findings in these 

studies. The lowest observed adverse effect level is for liver toxicity in dogs, although reproductive and 

developmental studies in rats indicate that offspring are particularly sensitive to 1,4-DCB toxicity during 

the postnatal preweaning period. 

Hepatic effects induced by intermediate-duration oral exposures to 1,4-DCB ranged from increased liver 

weight and hepatocyte enlargement to hepatocellular degeneration, lesions, necrosis, and tumors in rats, 

mice, rabbits, and dogs. Increases in serum levels of enzymes and alterations in other end points (e.g., 

serum cholesterol and triglycerides) indicative of hepatocellular damage or liver dysfunction have also 

been induced. Increased liver weight is the most sensitive hepatic end point in intermediate-duration 

studies in rats, observed at doses as low as 150 mg/kg/day for 4–13 weeks and 188 mg/kg/day for 

192 days (Hollingsworth et al. 1956; Lake et al. 1997; Umemura et al. 1998). There was no indication of 

early liver damage in rats exposed to 150 mg/kg/day for 4 weeks using an immunohistochemical marker 

of centrilobular hepatocyte injury (Umemura et al. 1998), and increases in liver porphyrins in rats 

exposed to 50–200 mg/kg/day for 120 days were not considered to be toxicologically significant (Carlson 

1977). Hepatocellular hypertrophy and decreased serum triglycerides occurred in rats exposed to 

≥300 mg/kg/day for 13 weeks (Lake et al. 1997; NTP 1987). Higher dose levels of 1,4-DCB induced 

degenerative liver lesions in rats exposed to 376 mg/kg/day for 192 days (slight cirrhosis and focal 
 

 

DICHLOROBENZENES 47 

2. RELEVANCE TO PUBLIC HEALTH 

necrosis) (Hollingsworth et al. 1956) or 1,200 mg/kg/day for 13 weeks (hepatocyte degeneration and 

necrosis) (NTP 1987). In mice, hepatocellular degeneration was induced at doses ≥600 mg/kg/day for 

13 weeks (NTP 1987), and rabbits had cloudy swelling and minimal focal necrosis in the liver after 

exposure to 500 mg/kg/day for 367 days (Hollingsworth et al. 1956). Dogs are more sensitive to hepatic 

effects of intermediate-duration 1,4-DCB exposure than the other species because serum enzyme levels 

were increased following exposure to doses as low as 50 mg/kg/day for 6 months (Naylor and Stout 

1996). 

Renal changes, including hyaline droplet accumulation, increased kidney weights, and tubular lesions, are 

characteristically observed effects of subchronic and chronic oral exposure to 1,4-DCB in male rats at 

doses ≥75 mg/kg/day (Bomhard et al. 1988; Lake et al. 1997; NTP 1987). These findings are not 

considered for MRL derivation because there is a scientific consensus that they are related to the 

α2μ-globulin nephropathy syndrome, which is specific to male rats and not relevant to humans. 

Subchronic studies in female rats found increased kidney weight, but no indications of nephrotoxic action 

(i.e., no histopathology or effects on urinary indices of renal function), following exposure to 

≥188 mg/kg/day for 192 days or 600 mg/kg/day for 13 weeks (Bomhard et al. 1988; Hollingsworth et al. 

1956). 

Developmental toxicity studies provide no indications that 1,4-DCB is teratogenic in rats at oral doses as 

high as 1,000 mg/kg/day during gestation, although fetotoxicity occurred at maternally toxic levels 

≥500 mg/kg/day (Giavini et al. 1986; Ruddick et al. 1983). Decreased maternal weight gain and 

increased incidences of extra ribs, a skeletal variation attributable to the maternal toxicity, occurred in rats 

at gestational dose levels ≥500 mg/kg/day, but not at 250 mg/kg/day (Giavini et al. 1986). In a twogeneration study, reproductive and developmental toxicity were evaluated in male and female rats that 

were orally exposed to 30, 90, or 270 mg/kg/day of 1,4-DCB (Bornatowicz et al. 1994). No effects on 

mating and fertility indices were observed at any level, although toxicity occurred in the offspring at 

doses ≥90 mg/kg/day. Effects at ≥90 mg/kg/day included reduced birth weight in F1 pups and increased 

total number of deaths from birth to postnatal day 4 in F1 and F2 pups, clinical manifestations of dry and 

scaly skin (until approximately postnatal day 7) and tail constriction with occasional partial tail loss 

(during postnatal days 4–21) in F1 and F2 pups, reduced neurobehavioral performance (draw-up reflex 

evaluated at weaning) in F2 pups, and increased relative liver weight in adult F1 males. No exposurerelated changes were found at 30 mg/kg/day, indicating that this is the NOAEL for reproductive and 

developmental toxicity in rats. 
 

 

 

DICHLOROBENZENES 48 

2. RELEVANCE TO PUBLIC HEALTH 

As discussed above, liver, kidney, and perinatal developmental toxicity are main effects of concern for 

intermediate-duration oral exposure to 1,4-DCB in animals. The dog is the most sensitive tested species, 

as liver effects were induced by exposure to doses as low as 50 mg/kg/day for 6 months (Naylor and Stout 

1996), which are below subchronic LOAELs of approximately 150–200 mg/kg/day for liver and kidney 

effects in rats and mice. The two-generation study in rats demonstrates that oral exposure to 1,4-DCB can 

cause perinatal developmental toxicity, including reduced birth weight and neonatal survival in F1 and 

F2 pups, at doses ≥90 mg/kg/day (Bornatowicz et al. 1994). Although this finding indicates that perinatal 

developmental toxicity is an additional sensitive end point for 1,4-DCB exposure, the lower 50 mg/kg/day 

LOAEL for liver effects in dogs (Naylor and Stout 1996) is a more appropriate basis for MRL derivation. 

In the dog study, groups of five male and five female beagles were orally administered 1,4-DCB by 

capsule in dose levels of 0, 10, 50, or 75 mg/kg/day on 5 days/week for 1 year (Naylor and Stout 1996). 

Complete details on the experimental design and results of the study are provided in the section on the 

chronic oral MRL for 1,4-DCB. As summarized below, 6-month interim liver enzyme findings are 

consistent with liver enzyme, liver weight, and histopathological changes observed at 1 year. Hepatic end 

points evaluated at 6 months were limited to clinical chemistry indices, including serum ALT, AST, 

GGTP, and AP, whereas the 1-year end-of-study evaluations included liver weight and histology in 

addition to clinical chemistry. Effects on serum enzymes included statistically significantly increased AP 

in males at 50 mg/kg/day after 6 and 12 months, females at 50 mg/kg/day after 6 and 12 months, and 

females at 75 mg/kg/day after 6 and 12 months. Serum AP levels were not statistically significantly 

increased in the 75 mg/kg/day males at months 6 or 12, but only three animals were evaluated in this dose 

group. As detailed in the chronic MRL summary, the increases in serum AP were similar in magnitude 

after 6 and 12 months, ranging from 330 to 761% higher than control values. Other clinical chemistry 

findings included significantly increased serum ALT (75 mg/kg/day females at month 12) and GGTP 

(75 mg/kg/day females at months 6 and 12), and significantly decreased albumin (50 and 75 mg/kg/day in 

males at months 6 and 12, and 75 mg/kg/day in females at month 6). Absolute and relative liver weights 

were significantly increased in both sexes at 50 and 75 mg/kg/day (except absolute liver weight in 

50 mg/kg/day males). Hepatic lesions included hepatocellular hypertrophy (diffuse or multifocal in all 

males and females at 50 and 75 mg/kg/day, and one female at 10 mg/kg/day), hepatocellular pigment 

deposition (two males and one female each at 50 and 75 mg/kg/day), bile duct/ductule hyperplasia (one 

male and one female at 75 mg/kg/day), and hepatic portal inflammation (periportal accumulation of 

neutrophils in one male at 50 mg/kg/day and two males at 75 mg/kg/day). The 50 mg/kg/day dose is a 

intermediate-duration LOAEL based on the increases in serum AP at 6 months. This serum enzyme 

change is a sufficient indication of intermediate-duration hepatotoxicity because the increases were 
 

 

DICHLOROBENZENES 49 

2. RELEVANCE TO PUBLIC HEALTH 

similar in magnitude to those observed after 1 year and associated with increased liver weight and liver 

lesions; the latter effects likely developed earlier in the study but could not be detected due to the lack of 

organ weight and histology examinations before 1 year. 

To derive a point of departure for MRL derivation, BMD analysis was conducted using the Naylor and 

Stout (1996) data for changes in serum AP levels in female dogs. Mean serum AP levels in the female 

dogs exhibited a dose-response relationship and were significantly increased in the 50 and 75 mg/kg/day 

groups. Although significantly increased mean serum AP levels were noted in the 50 mg/kg/day male 

dogs, the increase was not significant in the 75 mg/kg/day males; only three males in this dose group were 

available for the assessment of serum AP levels. Therefore, the male serum AP data were not modeled. 

Continuous variable models in the EPA Benchmark Dose Software (Version 1.3.2) were fit to serum AP 

data in the female dogs using a one standard deviation change from the control mean as the BMR. A 

summary of the predicted BMDs and BMDLs, as well as details of the BMD modeling, are presented in 

Appendix A. The best fit was provided by the polynomial model, which resulted in a BMD1sd of 

12.48 mg/kg/day and a BMDL1sd of 9.97 mg/kg/day. The BMDL1sd of 9.97 mg/kg/day was adjusted for 

intermittent experimental exposure (5 days/7 days) to give a duration-adjusted BMDL1sd of 7 mg/kg/day, 

and divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human 

variability) to derive an intermediate-duration oral MRL of 0.07 mg/kg/day for 1,4-DCB. 

Chronic-Duration Exposure. 

•	 An MRL of 0.07 mg/kg/day has been derived for chronic-duration (365 days or more) oral 

exposure to 1,4-DCB. 

Information on the chronic oral effects of 1,4-DCB is available from one study each in rats, mice, rabbits, 

and dogs. Observed effects included nephropathy in rats (including tubular degeneration and atrophy in 

females) exposed to ≥150 mg/kg/day on 5 days/week for 103 weeks (NTP 1987), hepatocellular 

degeneration and nephropathy in mice exposed to ≥300 mg/kg/day on 5 days/week for 103 weeks (NTP 

1987), and cloudy swelling and minimal focal necrosis in rabbits exposed to 500 mg/kg/day in 263 doses 

in 367 days (Hollingsworth et al. 1956). The lowest chronic LOAEL in these studies was 150 mg/kg/day 

for kidney effects in female rats (NTP 1987). Liver and kidney effects were induced in dogs at doses 

below the LOAELs in the other species. As summarized below, doses as low as 50 mg/kg/day for 1 year 

were hepatotoxic in dogs (Naylor and Stout 1996). 
 

 

 

DICHLOROBENZENES 50 

2. RELEVANCE TO PUBLIC HEALTH 

In the dog study, groups of five male and five female beagles were orally administered 1,4-DCB by 

capsule in dose levels of 0, 10, 50, or 75 mg/kg/day for 1 year (Naylor and Stout 1996). Based on the 

summarized design of a 4-week dose range-finding study, it is presumed that dosing was 5 days/week. 

The 75 mg/kg/day dose is a time-weighted average level reflecting dose decreases at the beginning of the 

study in response to unexpected severe toxicity. An initial high dose of 150 mg/kg/day was adjusted to 

100 mg/kg/day for males during week 3, and a further decrease to 75 mg/kg/day was made for both sexes 

at the beginning of week 6. Both high-dose males and females were untreated during weeks 4 and 5 to 

allow for recovery. End points evaluated throughout the study included clinical observations (daily), 

body weight (weekly), and food consumption (weekly). Ophthalmoscopic examinations were performed 

prior to study start and just prior to study completion. Hematology (11 indices, including activated partial 

thromboplastin time), clinical chemistry (18 indices, including ALT, AST, GGTP, AP, and creatinine 

phosphokinase), and urinalysis (10 indices) were performed at month 6 and study completion (month 12). 

Organ weights, gross pathology, and histology were evaluated at month 12. 

Mortality occurred the first 25 days of the study before dose reduction; exposure to 150 mg/kg/day caused 

one male dog to be sacrificed in extremis on day 12, one male death on day 25, and one female death on 

day 24 (Naylor and Stout 1996). A control male died on day 83, but all other dogs survived to the end of 

the study. Treatment-related clinical signs were primarily limited to severely affected high-dose dogs and 

the control male that died; these included hypoactivity, dehydration, decreased defecation, blood-like 

fecal color, emesis, emaciation, and/or pale oral mucosa. There were no significant group differences in 

mean body weight at the end of the study. Body weight gain was significantly reduced during the first 

month of the study, but recovered following dose reduction and adjustment of food availability. A mild 

anemia was observed at month 6 (significantly reduced red blood cells in females and HCT in males) at 

75 mg/kg/day, but it resolved by the end of the study. The mild anemia correlated with histologic 

findings of bone marrow erythroid hyperplasia in females, and splenic excessive hematopoiesis and 

megakaryocyte proliferation in both sexes, indicating a compensatory response to the earlier anemia. 

Hepatic effects occurred at ≥50 mg/kg/day in both sexes as shown by changes in liver enzymes, increased 

liver weight, and histopathology. Effects on serum enzyme levels included significantly increased AP in 

males at 50 mg/kg/day at months 6 and 12 (731 and 620% higher than controls, respectively), females at 

50 mg/kg/day at months 6 and 12 (525 and 330% higher), and females at 75 mg/kg/day at months 6 and 

12 months (761 and 680% higher). Serum AP was also increased in males at 75 mg/kg/day after 6 and 

12 months, but the changes were not statistically significant, possibly due to a reduced group size of 

3 males at 75 mg/kg/day. Other clinical chemistry findings included significantly increased ALT in 

females at 75 mg/kg/day at month 12 (253% higher than controls), increased GGTP in females at 
DICHLOROBENZENES 51 

2. RELEVANCE TO PUBLIC HEALTH 

75 mg/kg/day at months 6 and 12 (131 and 161% higher), and decreased albumin in males at 50 and 

75 mg/kg/day at month 6 (16 and 18% lower than controls) and females at 75 mg/kg/day at month 6 (19% 

lower). Absolute and relative liver weights were significantly increased (40–70% higher than controls) in 

both sexes at 50 and 75 mg/kg/day (except absolute liver weight in 50 mg/kg/day males). Hepatocellular 

hypertrophy (diffuse or multifocal) occurred in all males and females at 50 and 75 mg/kg/day and in one 

female at 10 mg/kg/day. The study authors (Naylor and Stout 1996) considered the hepatocellular 

hypertrophy (multifocal) in the single 10 mg/kg/day female dog to be an adaptive response to a xenobiotic 

agent rather than a direct treatment related effect. Other liver lesions considered to be treatment-related 

included hepatocellular pigment deposition (two males and one female each at 50 and 75 mg/kg/day), bile 

duct/ductule hyperplasia (one male and one female at 75 mg/kg/day), and hepatic portal inflammation 

(periportal accumulation of neutrophils in one male at 50 mg/kg/day and two males at 75 mg/kg/day). 

Kidney effects included collecting duct epithelial vacuolation in one male at 75 mg/kg/day and at all dose 

levels in females (one each at 10 and 50 mg/kg/day and two at 75 mg/kg/day). The renal lesion was 

considered to be a possible effect of treatment at ≥50 mg/kg/day, because it was accompanied by 

increased relative kidney weight in females at ≥50 mg/kg/day and grossly observed renal discoloration in 

two females at 75 mg/kg/day. The highest chronic NOAEL and lowest LOAEL are 10 and 50 mg/kg/day, 

respectively, based on the hepatic effects in dogs (increased liver weight, changes in liver enzymes, and 

histopathology). 

To derive a point of departure for MRL derivation, BMD analysis was performed on the serum AP level 

and relative liver weight data for the female dogs. The incidences of hepatocellular hypertrophy in the 

females (0/5, 1/5, 5/5, and 5/5 at 0, 10, 50, and 75 mg/kg/day) and males (0/5, 0/5, 5/5, and 5/5) are 

inappropriate for BMD modeling due to actual or effective responses of 0% in the control and low dose 

groups and 100% in the higher dose groups. The response in the low-dose female dog is effectively 0% 

because the authors implied that the hypertrophy in this single animal was not a hepatotoxic response. 

The incidences of the other dog liver lesions were not subjected to BMD analysis due to the low numbers 

of responders and group sizes. Continuous variable models in the EPA Benchmark Dose Software 

(Version 1.3.2) were fit to serum AP and relative liver weight data in the female dogs using a one 

standard deviation change from the control mean as the BMR. A summary of the predicted BMDs and 

BMDLs, as well as details of the BMD modeling, are presented in Appendix A. The relative liver weight 

data were judged to be unsuitable for BMD analysis due to inadequate modeling of variance. The best fit 

for the serum AP data was provided by the polynomial model, which resulted in a BMD1sd of 

15.40 mg/kg/day and a BMDL1sd of 12.32 mg/kg/day. The BMDL1sd of 12.32 mg/kg/day was rounded to 

one significant figure (10 mg/kg/day), adjusted for intermittent experimental exposure (5 days/7 days) to 
DICHLOROBENZENES 52 

2. RELEVANCE TO PUBLIC HEALTH 

give a duration-adjusted BMDL1sd of 7 mg/kg/day, and divided by an uncertainty factor of 100 (10 for 

animal to human extrapolation and 10 for human variability) to derive a chronic-duration oral MRL of 

0.07 mg/kg/day for 1,4-DCB. 
DICHLOROBENZENES 53 

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 dichlorobenzenes. 

It contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 
DICHLOROBENZENES 54 

3. HEALTH EFFECTS 

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. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of 

dichlorobenzenes are indicated in Tables 3-1 and 3-5 and Figures 3-1 and 3-5. 

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 

Descriptive data are available from reports of humans exposed to 1,2- and 1,4-DCB by inhalation (and 

possibly dermal contact). It is important to note that the case studies discussed in this section should be 

interpreted with caution since they reflect incidents in which individuals have reportedly been exposed to 

1,2- and 1,4-DCB, and they assume that there has been no other exposure to potentially toxic or infectious 

agents. There is usually little or no verification of these assumptions, and often no estimate of the level of 

exposure which may have occurred. With only rare exceptions, case studies in general are not 

scientifically equivalent to carefully designed epidemiological studies or to adequately controlled and 

monitored laboratory experiments. Thus, the case studies described below should be considered only as 

providing supplementary evidence that 1,2- and 1,4-DCB may cause the reported human effects. The 

highest NOAEL and all reliable LOAEL values after inhalation exposure to 1,2- and 1,4-DCB are 

recorded in Tables 3-1 and 3-2, respectively, and plotted in Figures 3-1 and 3-2, respectively. No LSE 

tables or figures were generated for 1,3-DCB due to a lack of inhalation data. 
2122

1532

2123

1236

2125

29

2097

322322

322

2082

100

2022

977977

Table 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

ACUTE EXPOSURE Death 

1 Rat 6 hr 1532 M (14-day LC50) Bonnet et al. 1982 (Sprague- 1,2-dichlorobenzene Dawley) 

2 Mouse 6 hr 1236 (14-day LC50) Bonnet et al. 1982 (Sprague- 1,2-dichlorobenzene Dawley) 

Systemic 

3 Rat 4 hr Hemato 29 M Brondeau et al. 1990

(Sprague- 1,2-dichlorobenzene Dawley) 

4 Rat 10 d Hepatic 322 DuPont 1982 6 hr/d (NS) 1,2-dichlorobenzene 

Renal 322 Bd Wt 322 (slight body weight loss) 

5 Rat 10 d Bd Wt 100 F (reduced maternal body Hayes et al. 1985 Gd 6-18 (Fischer- 344) 6 hr/d weight gain throughout 1,2-dichlorobenzene gestation) 

6 Rat 0.5 hr Hepatic 977 M (marked central lobular Hollingsworth et al. 1958 (albino) (NS) necrosis) 1,2-dichlorobenzene 

Renal 977 M (cloudy swelling of

tubular epithelium)

DICHLOROBENZENES

3. HEALTH EFFECTS

55
2023

977977

2024

539539

2025

539539

2026

64

2079

100

2081

400

Table 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

7 Rat 1 hr Hepatic 977 M (marked central lobular Hollingsworth et al. 1958 (albino) (NS) necrosis) 1,2-dichlorobenzene 

Renal 977 M (cloudy swelling of

tubular epithelium)

8 Rat 3 hr Hepatic 539 M Hollingsworth et al. 1958 (albino) (NS) 1,2-dichlorobenzene 

Renal 539 M 

9 Rat 6.5 hr Hepatic 539 M Hollingsworth et al. 1958 (albino) (NS) 1,2-dichlorobenzene 

Renal 539 M 

10 Mouse 4-14 d Resp 64 M (moderate to severe Zissu 1995 5 d/wk 

6 hr/d nasal olfactory epithelial 1,2-dichlorobenzene lesions) (NS) 

11 Rabbit 13 d Bd Wt 100 F (slight maternal body Hayes et al. 1985 Gd 6-18 (New weight loss on Gd 6-8 1,2-dichlorobenzene 6 hr/d Zealand) followed by recovery) 

Reproductive 

12 Rat 10 d 400 F Hayes et al. 1985 Gd 6-18 (Fischer- 344) 6 hr/d 1,2-dichlorobenzene 

DICHLOROBENZENES

3. HEALTH EFFECTS

56
2078

400

2080

200

400

2077

400

2119

50

150

50

150

Table 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

13 Rabbit 13 d 400 F Hayes et al. 1985 Gd 6-18 (New 6 hr/d 1,2-dichlorobenzene Zealand) 

Developmental 

14 Rat 10 d 200 F 400 F (delayed ossification of Hayes et al. 1985 Gd 6-18 (Fischer- 344) cervical vertebral centra) 6 hr/d 1,2-dichlorobenzene 

15 Rabbit 13 d 400 F Hayes et al. 1985 Gd 6-18 (New 6 hr/d 1,2-dichlorobenzene Zealand) 

INTERMEDIATE EXPOSURE Systemic 

16 Rat 2 generations Hepatic 50 150 (centrilobular Bio/dynamics 1989 7 hr/d (CD) 6 d/wk hepatocellular 1,2-dichlorobenzene hypertrophy in F0 and F1 

adults) 

Bd Wt 50 150 (reduced body weight

gain in F0 and F1 adults)

DICHLOROBENZENES

3. HEALTH EFFECTS

57
2010

9393939349

93

2019

49494949

2012

9393939393

Table 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

17 Rat 6-7 mo Resp 93 M Hollingsworth et al. 1958 5 d/wk (albino) 7 hr/d 1,2-dichlorobenzene 

(NS) 

Cardio 93 MHepatic 93 MRenal 93 MBd Wt 49 M 93 M (9.3% reduced body

weight gain) 

18 Mouse 6.5 mo Resp 49 F Hollingsworth et al. 1958 5 d/wk (NS) 7 hr/d 1,2-dichlorobenzene 

(NS) 

Hepatic 49 FRenal 49 FBd Wt 49 F

Gn Pig 6-7 mo 19 Resp 93 Hollingsworth et al. 1958 5 d/wk (NS) 7 hr/d 1,2-dichlorobenzene 

(NS) 

Cardio 93Hepatic 93Renal 93Bd Wt 93

DICHLOROBENZENES

3. HEALTH EFFECTS

58
2021

939393939393

2017

93

2013

93

2118

394

2011

93

Table 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

Rabbit 6-7 mo 20 Resp 93 Hollingsworth et al. 1958 5 d/wk (albino) 7 hr/d 1,2-dichlorobenzene 

(NS) 

Cardio 93Hemato 93Hepatic 93Renal 93Bd Wt 93

Immuno/ Lymphoret 

21 Rat 6-7 mo 93 Hollingsworth et al. 1958 5 d/wk (albino) 7 hr/d 1,2-dichlorobenzene 

(NS) 

22 Gn Pig 6-7 mo 93 M (20% reduced absolute Hollingsworth et al. 1958 5 d/wk (NS) 7 hr/d spleen weight) 1,2-dichlorobenzene 

(NS) 

Reproductive 

23 Rat 2 generations 394 Bio/dynamics 1989 7 hr/d (CD) 6 d/wk 1,2-dichlorobenzene 

24 Rat 6-7 mo 93 M Hollingsworth et al. 1958 5 d/wk (albino) 7 hr/d 1,2-dichlorobenzene 

(NS) 

DICHLOROBENZENES

3. HEALTH EFFECTS

59
2015

93

25 

Table 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

Gn Pig 6-7 mo 93 M Hollingsworth et al. 1958 5 d/wk (albino) 7 hr/d 1,2-dichlorobenzene 

(NS) 

a The number corresponds to entries in Figure 3-1. Bd Wt = body weight; Cardio = cardiovascular; d = day(s); F = Female; Gd = gestational day; Gn pig = guinea pig; Hemato = hematological; hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LC50 = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; ppm = parts per million; Resp = respiratory; wk = week(s) 

DICHLOROBENZENES

3. HEALTH EFFECTS

60
Death 

Respiratory Hematological Hepatic Renal Body Weight Reproductive 

Figure 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation
	

Acute (≤14 days)
	

Systemic 

ppm 

10000 

1r
	

2m
	

1000
	 6r 7r 6r 7r 

8r 9r 8r 9r 

12r 13h 

4r 4r 4r 

100 5r 11h 

10m 

3r 

10 

DICHLOROBENZENES

3. HEALTH EFFECTS

61

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
Respiratory 

Cardiovascular Hematological Hepatic Renal Body Weight Immuno/

1000 

Figure 3-1 Levels of Significant Exposure to 1,2-dichlorobenzene - Inhalation (Continu

Intermediate (15-364 days)
	

Systemic
	

ppm 

16r 16r 

100 19g 17r 20h 19g 17r 20h 20h 19g 17r 20h 19g 17r 20h 19g 17r 20h 22g 21r 

16r 16r 18m 18m 18m 18m 17r 

10 

DICHLOROBENZENES

3. HEALTH EFFECTS

62

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
2136

15

30 50

500

508508508508508

502

300

800

501

500

503

800

3

508

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

ACUTE EXPOSURE Systemic 

1 Human 4.75 yr b Resp 15 M 30 M (minimal nose and eye 50 M (painful irritation of nose Hollingsworth et al. 1956 5 d/wk irritation) and eyes) 1,4-dichlorobenzene 8 hr/d

(occup)

2 Rat 10 d Resp 508 F Hodge et al. 1977 Gd 6-15 (Alderley- 6 hr/d 1,4-dichlorobenzene Park) 

Cardio 508 F Hepatic 508 F Renal 508 F Bd Wt 508 F 

3 Rabbit 13 d Bd Wt 300 F 800 F (slight maternal body Hayes et al. 1985 Gd 6-18 (New 6 hr/d weight loss on Gd 6-8 1,4-dichlorobenzene Zealand) followed by recovery) 

Reproductive 

4 Rat 10 d 500 F Hodge et al. 1977 Gd 6-15 (Alderley- 6 hr/d 1,4-dichlorobenzene Park) 

5 Rabbit 13 d 800 F Hayes et al. 1985 Gd 6-18 (New 6 hr/d 1,4-dichlorobenzene Zealand) 

Developmental 

6 Rat 10 d 508 F Hodge et al. 1977 Gd 6-15 (Alderley- 6 hr/d 1,4-dichlorobenzene Park) 

DICHLOROBENZENES

3. HEALTH EFFECTS

63
11

300

800

6

798

7

798

9

798

2129

600120

270

600

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

7 Rabbit 13 d 300 F 800 F (increased incidence of Hayes et al. 1985 Gd 6-18 (New retroesophageal right 1,4-dichlorobenzene 6 hr/d Zealand) subclavian artery) 

INTERMEDIATE EXPOSURE Death 

8 Rat 9-12 wk 798 (2/19 males and 2/15 Hollingsworth et al. 1956 5 d/wk (NS) 8 hr/d females died) 1,4-dichlorobenzene 

9 Gn Pig 4-4.5 wk 798 M (2/16 died) Hollingsworth et al. 1956 5 d/wk (NS) 8 hr/d 1,4-dichlorobenzene 

10 Rabbit 12 wk 798 (3 males and 1 female Hollingsworth et al. 1956 5 d/wk (NS) 8 hr/d died) 1,4-dichlorobenzene 

Systemic 

11 Rat 13 wk Resp 600 Aiso et al. 2005a 5 d/wk (Fischer- 344) 6 hr/d 1,4-dichlorobenzene 

Hepatic 120 M 270 M (increased liver weight,

serum cholesterol, andserum phospholipids)

Bd Wt 600 

DICHLOROBENZENES

3. HEALTH EFFECTS

64
16

798

173

173

173

798

173798

173

798

17

9696

158

96

158

341

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

12 Rat 2-12 wk Resp 798 F 173 M (slight interstitial edema, Hollingsworth et al. 1956 5 d/wk (NS) 7 or 8 hr/d alveolar hemorrhage) 1,4-dichlorobenzene 

Cardio 173 Hepatic 173 F (slight liver congestion 798 (cloudy swelling and 

and granular central necrosis) degeneration) 

Renal 173 (increased relative kidney

weight)

Ocular 798 (eye irritation) 

Bd Wt 173 798 (unquantitated weight

loss)

13 Rat 5.1-7.1 mo Hemato 96 Hollingsworth et al. 1956 5 d/wk (NS) 7 hr/d 1,4-dichlorobenzene 

Hepatic 96 158 (increased relative liver

weight; cloudy swelling ordegeneration ofparenchyma)

Renal 96 158 M (increased relative kidney

weight)

Bd Wt 341 

DICHLOROBENZENES

3. HEALTH EFFECTS

65
2001

211 53866211

211538

538211

538

66211

211538

211

538

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/

Duration/

a Frequency Key to Species NOAEL (Route) Figure (Strain) System (ppm) 

14 Rat 2 generations Resp 211 (SpragueDawley) 

c

Hepatic 66 M 

211 F 

Renal 538 F Ocular 211 

d

Bd Wt 66 M 

211 F 

Other 211 

LOAEL 

Reference Less Serious Serious 

(ppm) (ppm) Chemical Form Comments 

538 Tyl and Neeper-Bradley 1989 

1,4-dichlorobenzene 

d

211 M (increased liver weight) 538 F 538 (encrustation of 

periocular region; lacrimation) 

d

211 M (decreased body weight 

in the male F0 group and in the F1 male and females in the 5-week recovery study) 

538 F 538 (decreased grooming; 

unkempt appearance; decreased food consumption) 

DICHLOROBENZENES

3. HEALTH EFFECTS

66
2128

600600120

270

600600

19

158961589615896

20

96

158 341

34196

158

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

15 Mouse 13 wk Resp 600 Aiso et al. 2005a 5 d/wk BDF1 

6 hr/d 1,4-dichlorobenzene

Hemato 600 Hepatic 120 M 270 M (increased relative liver

weight and serum ALT)

Renal 600 Bd Wt 600 

16 Mouse 5.1-7.1 mo Hepatic 158 M Hollingsworth et al. 1956 5 d/wk (NS) 7 hr/d d 1,4-dichlorobenzene 96 F 

Renal 158 M 

d

96 F 

Bd Wt 158 M 

d

96 F 

17 Gn Pig 5.1-7.1 mo Hepatic 96 158 F (increased relative liver 341 (focal necrosis, slight Hollingsworth et al. 1956 5 d/wk (NS) 7 hr/d weight) cirrhosis in males) 1,4-dichlorobenzene 

Renal 341 Bd Wt 96 158 (slight depression in final

body weight)

DICHLOROBENZENES

3. HEALTH EFFECTS

67
21

173

798173

798

798173 798173

798

23

173

798

173

798

798

798

173

798

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

18 Gn Pig 2-4.5 wk Resp 173 F (alveolar hemorrhage Hollingsworth et al. 1956 5 d/wk (NS) 7 or 8 hr/d and edema) 1,4-dichlorobenzene 

Cardio 798 Hepatic 173 798 (cloudy swelling in the 

liver and central necrosis) 

Renal 798 Ocular 173 798 (eye irritation) Bd Wt 173 798 (body weight loss, not

quantified)

19 Rabbit 2-12 wk Resp 173 F (lung congestion and 798 (emphysema in 2/8) Hollingsworth et al. 1956 5 d/wk (NS) 7 or 8 hr/d interstitial edema) 1,4-dichlorobenzene 

Hepatic 173 798 (cloudy swelling in the 

liver and central necrosis) 

Renal 798 Ocular 798 (eye irritation; reversible

nonspecific eye changes)

Bd Wt 173 798 (decreased body weight

gain, not quantitated)

DICHLOROBENZENES

3. HEALTH EFFECTS

68
2121

50

29

798

2002

211

538

30

798

31

798

504

158

505

173

2003

538

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

Immuno/ Lymphoret 

20 Gn Pig 12 wk 50 M Suzuki et al. 1991

(Hartley) 1,4-dichlorobenzene 

Neurological 

21 Rat 9-12 wk 798 (tremors, weakness, Hollingsworth et al. 1956 5 d/wk (NS) 8 hr/d unconsciousness) 1,4-dichlorobenzene 

22 Rat 2 generations 211 538 (tremors and other signs Tyl and Neeper-Bradley 1989 

of neurotoxity in F0 and 1,4-dichlorobenzene F1 adults) 

23 Gn Pig 4-4.5 wk 798 (tremors, weakness, Hollingsworth et al. 1956 5 d/wk (NS) unconsciousness) 8 hr/d 1,4-dichlorobenzene 

24 Rabbit 12 wk 798 (tremors, weakness, Hollingsworth et al. 1956 5 d/wk (NS) 8 hr/d unconsciousness) 1,4-dichlorobenzene 

Reproductive 

25 Rat 5.1-7.1 mo 158 M Hollingsworth et al. 1956 5 d/wk (NS) 7 hr/d 1,4-dichlorobenzene 

26 Rat 16 d 173 M Hollingsworth et al. 1956 5 d/wk (NS) 7 hr/d 1,4-dichlorobenzene 

27 Rat 2 generations 538 Tyl and Neeper-Bradley 1989 (Sprague- 1,4-dichlorobenzene Dawley) 

DICHLOROBENZENES

3. HEALTH EFFECTS

69
506

173

507

158

2004

93211

538

2110

300

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

28 Gn Pig 16 d 173 M Hollingsworth et al. 1956 5 d/wk (NS) 7 hr/d 1,4-dichlorobenzene 

29 Gn Pig 5.1-7.1 mo 158 M Hollingsworth et al. 1956 5 d/wk (NS) 7 hr/d 1,4-dichlorobenzene 

Developmental 

30 Rat 2 generations 93 538 (increased stillbirths and Tyl and Neeper-Bradley 1989 (Sprague- reduced postnatal 1,4-dichlorobenzene Dawley) 211 survival in F1 and F2 

pups) 

CHRONIC EXPOSURE Death 

31 Rat 104 wk 300 M (30% reduced survival) Aiso et al. 2005b 5 d/wk (Fischer- 344) 6 hr/d 1,4-dichlorobenzene 

chamber 

DICHLOROBENZENES

3. HEALTH EFFECTS

70
2111

7520

30075

75

300

300

2114

75

300

75300

300

75

300

2117

300

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

Systemic 

Rat 104 wk 32 Resp 75 M 300 M (eosinophilic changes in Aiso et al. 2005b 5 d/wk (Fischer- 344) 6 hr/d e olfactory epithelium) 1,4-dichlorobenzene 20 F

d chamber 75 F (eosinophilic changes in 

nasal olfactory epithelium) 

Renal 75 M 300 M (mineralization of renal

papilla, urothelialhyperplasia)

Bd Wt 300 

33 Mouse 104 wk Resp 75 F 300 F (metaplasia in nasal Aiso et al. 2005b 5 d/wk Crj:BDF1 olfactory epithelium) 6 hr/d 1,4-dichlorobenzene 

chamber 

d

Hepatic 75 M 300 M (centrilobular

hepatocellular

300 F hypertrophy)

Bd Wt 75 300 (reduced terminal body

weight)

Reproductive 

34 Rat 104 wk 300 Aiso et al. 2005b 5 d/wk (Fischer- 344) 6 hr/d 1,4-dichlorobenzene 

chamber 

DICHLOROBENZENES

3. HEALTH EFFECTS

71
2115

300

2116

30030010

Table 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 

35 Mouse 104 wk 300 Aiso et al. 2005b 5 d/wk Crj:BDF1 6 hr/d 1,4-dichlorobenzene 

chamber 

Cancer 

36 Mouse 104 wk 300 M (CEL: hepatocellular Aiso et al. 2005b 5 d/wk Crj:BDF1 6 hr/d carcinoma, hepatic 1,4-dichlorobenzene histiocytic sarcoma) chamber 

300 F (CEL: bronchoalveolar 

adenoma and carcinoma) 

10 F (CEL: hepatocellular 

adenoma and carcinoma) 

a The number corresponds to entries in Figure 3-2. b Used to derive an acute-duration inhalation minimal risk level (MRL) of 2 ppm. The MRL was obtained by dividing the NOAEL by an uncertainty factor of 10 (for human variability). c Study result used to derive an intermediate-duration inhalation Minimal Risk Level (MRL) of 0.2 ppm for 1,4-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on liver weight to select a point of departure, which was adjusted for intermittent exposure and converted to a Human Equivalent Concentration (HEC), then divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). d 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 of effect for the most sensitive gender are presented. e Study result used to derive a chronic-duration inhalation Minimal Risk Level (MRL) of 0.01 ppm for 1,4-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on incidences of nasal lesions to select a point of departure, which was adjusted for intermittent exposure and converted to a Human Equivalent Concentration, then divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans using a dosimetric adjustment and 10 for human variability). 

ALT = alamine aminotransferase; Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); F = Female; Gastro = gastrointestinal; Gd = gestational day; 

Gn pig = guinea pig; Hemato = hematological; hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; occup = occupational; Resp = respiratory; wk = week(s); yr = year(s) 

DICHLOROBENZENES

3. HEALTH EFFECTS

72
Respiratory 

Cardiovascular Hepatic Renal Body Weight Reproductive Developmental 

Figure 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation
	

Acute (≤14 days)
	

Systemic 

ppm 

1000 

3h 5h 7h 

2r 2r 2r 2r 2r 6r 

3h 

4r 

7h 

100 

1
	

1
	

1 

10 

1 

DICHLOROBENZENES

3. HEALTH EFFECTS

73

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
Death 

Respiratory Cardiovascular Hematological Hepatic Renal 

Figure 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (Continu

Intermediate (15-364 days) 

Systemic 

ppm 

1000 

9g 8r 10h 12r 19h 18g 18g 12r 19h 18g 19h 18g 

15m 11r 15m 15m 14r 14r 

17g 17g 

15m 11r 

14r 14r 14r 

18g 12r 19h 12r 18g 12r 19h 12r 18g 17g 13r 13r 

15m 11r 

100 13r 17g 16m 13r 16m 13r 

14r 

10 

1 

DICHLOROBENZENES

0.1 

3. HEALTH EFFECTS

74

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
Other 

Immuno/Lymphor Neurological Reproductive DevelopmBody Weight 

1000 

Figure 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation (Continu

Intermediate (15-364 days) 

Systemic
	

ppm 

18g 17g 

100 17g 16m 

10 

1 

0.1 

18g 12r 19h 23g 21r 24h 

15m 11r 14r 22r 27r 30r 

13r 

14r 14r 22r 30r 

12r 19h 28g 26r 29g 25r 

30r 

14r 

20g 

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

DICHLOROBENZENES

3. HEALTH EFFECTS

75
Death 

Respiratory Hepatic Renal Body Weight Reproductive Cancer * 

 

 

Figure 3-2 Levels of Significant Exposure to 1,4-dichlorobenzene - Inhalation
	

Chronic (≥365 days)
	

Systemic 

33m
	 33m
	 32r
	 33m
	 32r
	 34r
	 36m
	 36m
	

33m 

32r 

32r 32r 33m 32r 33m 35m 

35m 

36m 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

response and do not imply the existence of a threshold for the cancer endpoint. 

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

ppm 

1000 

31r 

100 

10 

1 

0.1 

0.01 

DICHLOROBENZENES

3. HEALTH EFFECTS

76
DICHLOROBENZENES 77 

3. HEALTH EFFECTS 

3.2.1.1 Death 

1,2-Dichlorobenzene. No studies were located regarding death in humans following inhalation exposure 

to 1,2-DCB. 

Inhalation LC50 values of 1,532 and 1,236 ppm were determined for rats and mice, respectively, that were 

exposed to 1,2-DCB for 6 hours and observed for the following 14 days (Bonnet et al. 1982). No 

mortality was observed in rats that were exposed to 1,2-DCB in concentrations of 977 ppm for 0.5–1 hour 

or 539 ppm for 3 hours (Hollingsworth et al. 1958). 

1,3-Dichlorobenzene. No studies were located regarding death in humans or animals following 

inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. Only one report of human death attributed to 1,4-DCB inhalation exposure has 

been located in the literature. A 60-year-old man and his wife died within months of each other due to 

acute yellow atrophy of the liver (also known as massive hepatic necrosis or fulminant hepatitis; 

diagnosis was not verified histologically) (Cotter 1953). Their home had been "saturated" with 1,4-DCB 

moth ball vapor for a period of about 3–4 months, but no air measurements were available. Clinical 

symptoms included severe headache, diarrhea, numbness, clumsiness, slurred speech, weight loss 

(50 pounds in 3 months in the case of the husband), and jaundice. The wife died within a year of the 

initial exposure; however, it was not clear if 1,4-DCB was the primary cause of death. This case study 

did not address whether these individuals consumed excessive amounts of alcohol or had previous 

medical problems, such as a chronic liver infection. 

Several studies were located regarding death in animals after inhalation exposure to 1,4-DCB. In an 

acute-duration study, two of six male CD-1 mice exposed to 1,4-DCB at an air concentration of 640 ppm, 

6 hours/day for 5 days died on the fifth day; no deaths were reported at an exposure level of 320 ppm 

(Anderson and Hodge 1976). 

Mortality data were also reported in intermediate-duration studies using rats, guinea pigs, and rabbits. In 

studies performed by Hollingsworth et al. (1956), rats, guinea pigs, and rabbits were exposed to 1,4-DCB 

vapors for 9–12 weeks at an air concentration of 798 ppm, 8 hours/day, 5 days/week. In that study, 4 of 

34 rats, 2 of 23 guinea pigs, and 4 of 16 rabbits died during the study period. The exact number of 

exposures that resulted in death was not specified. 
DICHLOROBENZENES 78 

3. HEALTH EFFECTS 

In a chronic-duration study, there was no evidence of a treatment effect on mortality in Wistar rats 

exposed to 1,4-DCB at concentrations up to 490–499 ppm for 5 hours/day, 5 days/week for 76 weeks 

(Riley et al. 1980a). 

Another chronic study found that survival was significantly reduced in male rats (F344/DuCrj) that were 

exposed 300 ppm 1,4-DCB for 6 hours/day, 5 days/week for 104 weeks (Aiso et al. 2005b; Japan 

Bioassay Research Center 1995). Survival in the male rats was noticeably lower than controls beginning 

at approximately study week 80, and terminal survival in the 0, 20, 75, and 300 ppm groups of the study 

were 66% (33/50), 68% (34/50), 58% (29/50), and 36% (18/50), respectively. There were no effects on 

survival in similarly exposed female rats. Male mice (Crj:BDF1) that were similarly exposed to the same 

levels of 1,4-DCB had slightly reduced survival at all levels of exposure (80% [39/49], 63% [31/49], 64% 

[32/50], and 61% [30/49] at 0, 20, 75, and 300 ppm, respectively), but the decreases were not 

significantly different from controls or dose-related. Survival in female mice was similar to controls. 

3.2.1.2 Systemic Effects 

Respiratory Effects. 

1,2-Dichlorobenzene. Periodic industrial hygiene surveys and medical examinations were conducted in a 

plant where an unreported number of men were exposed to 1,2-DCB at an average level of 15 ppm (range 

1–44 ppm) for an unreported duration (Hollingsworth et al. 1958). No nasal or eye irritation was 

attributable to exposure. Additionally, Hollingsworth et al. (1958) noted that his researchers detected 

1,2-DCB odor at a concentration of 50 ppm without eye or nasal irritation during repeated vapor 

inhalation experiments on animals. An earlier source (Elkins 1950) referenced by Hollingsworth (1958) 

reported that occupational exposure to 100 ppm of 1,2-DCB caused irritation of the eyes and respiratory 

passages. 

No changes in absolute lung weight or lung histology were reported in rats (20/sex), guinea pigs (8/sex), 

rabbits (2/sex), or monkeys (2 females) exposed to 93 ppm 1,2-DCB for 7 hours/day, 5 days/week for 6– 

7 months, or in mice (10 females) similarly exposed to 49 ppm 1,2-DCB (Hollingsworth et al. 1958). 

Relative lung weight was not determined. The scope of histological evaluations was not specifically 

reported; organs that were weighed are inferred to have been histologically examined. 
 

 

DICHLOROBENZENES 79 

3. HEALTH EFFECTS 

Histological examinations of the upper and lower respiratory tract were conducted in groups of 10 male 

Swiss OF1 mice that were exposed to 1,2-DCB in actual mean concentrations of 0, 64, or 163 ppm (0, 

385, or 980 mg/m3

) for 6 hours/day, 5 days/week for 4, 9, or 14 days (Zissu 1995). Histological 

examinations were performed on the upper and lower respiratory tracts. Nonrespiratory tissues were not 

evaluated. Histopathologic lesions were observed in the olfactory epithelium of the nasal cavity at 

≥64 ppm. The olfactory epithelial lesions were graded as very severe following the 4-day exposure and 

moderate after the 14-day exposure, indicating to the authors that a repair mechanism may take place 

despite continued exposure. The more severe cases were characterized by a complete loss of olfactory 

epithelium, which left only the partially denuded basement membrane. No histological alterations were 

observed in the respiratory epithelium of the nasal cavity, or in the trachea or lungs. The results suggest 

that the upper respiratory tract is a target for inhalation exposures to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding respiratory effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. A case of pulmonary granulomatosis was reported to have occurred in a 53-yearold woman who, for 12–15 years, had been inhaling 1,4-DCB crystals that were scattered on a weekly 

basis on the carpets and furniture of her home. A lung biopsy revealed the presence of 1,4-DCB crystals 

with the surrounding lung parenchyma being distorted by fibrosis, thickening of the alveolar walls, and 

marked infiltrates of lymphocytes and mononuclear phagocytes. Also, there was some thickening of the 

muscular walls of small arteries and focal fibrous thickening of the pleura (Weller and Crellin 1953). 

These effects are most likely related to the physical interaction of 1,4-DCB crystals (or any crystals when 

inhaled) with lung tissue, rather than to chemical toxicity. This conclusion by the authors of the study 

was based on exposure history of the patient, radiography, and histological examination of the lung tissue 

which showed the presence of birefringent crystals and a clear granulatomous reaction. 

A study of 58 men occupationally exposed for 8 hours/day, 5 days/week, continually or intermittently, for 

8 months to 25 years (average, 4.75 years) to 1,4-DCB found that the odor was faint at 15–30 ppm and 

strong at 30–60 ppm (Hollingsworth et al. 1956). Painful irritation of the nose and eyes was usually 

experienced at 50–80 ppm, although the irritation threshold was higher (80–160 ppm) in workers 

acclimated to exposure. At levels >160 ppm, the air was considered not breathable for unacclimated 

persons. The results of this study indicate that nose and eye irritation are critical effects of acute and 

repeated exposures to 1,4-DCB in humans. Because odor detection is a warning property expected to 
 

 

DICHLOROBENZENES 80 

3. HEALTH EFFECTS 

prevent irritation caused by 1,4 DCB (Hollingsworth et al. 1956), 15 ppm was designated a NOAEL for 

irritant effects and used to derive an MRL of 2 ppm for acute inhalation exposure to 1,4-DCB. 

Associations between blood concentrations of 1,4-DCB and 10 other volatile organic compounds (VOCs) 

and pulmonary function were evaluated in 953 adult participants in the Third National Health and 

Nutrition Examination Survey (NHANES III) (1988–1994) of the general population who had both blood 

VOC and pulmonary function measurements (Elliot et al. 2006). The mean age of the subjects was 

36.6 years (range 20–59), 43.1% were female, and 26.3% were current smokers. Pulmonary function 

measures included forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), peak 

expiratory flow rate (PEFR), and maximum mid-expiratory flow rate (MMEFR). Least squares 

regression models were used to evaluate the association between each VOC and each pulmonary function 

outcome. The models used natural log transformations of VOC concentrations, and were adjusted for 

race/ethnicity, age, standing height, body mass index, sex, smoking, and emphysema to account for 

differences in pulmonary function based on these characteristics. In the models unadjusted for smoking 

variables, reductions in at least one pulmonary function outcome were statistically significant for 

1,4-DCB, benzene, ethylbenzene, styrene, and toluene. When the models were adjusted for smoking 

variables, 1,4-DCB was the only VOC that was statistically significantly associated with reduced 

pulmonary function. Among all 1,4-DCB participants (n=846), there was a statistically significant 

(p<0.05) inverse relationship between 1,4-DCB level and FEV1 and MMEFR. The linear regression 

coefficient (β) was -96 mL (95% CI -182 to -11) for FEV1 and -198 mL/sec (95% CI -388 to -8) for 

MMEFR. The β coefficient estimates the expected change in lung function as the concentration of 

1,4-DCB increases from the 10th to 90th percentile (3.76 μg/L) on the natural log scale. Analysis by race 

and sex showed statistically significant results for FEV1 in non-Hispanic white females [β=-266 mL (95% 

CI -488 to -43)] and African-American males [β=-282 mL (95% CI -497 to -66)]. Analyses conducted in 

534 subjects using urinary concentrations of 1,4-DCB and its major metabolite, 2,5-dichlorophenol, 

showed statistically significant β coefficients for FEV1 for both 1,4-DCB (-96 mL, 95% CI not reported) 

and 2,5-dichlorophenol (-134 mL, 95% CI not reported). Analyses were also performed using nonlogarithmically transformed blood concentrations of 1,4-DCB that were categorized into deciles. Tests 

for linear trend across deciles were statistically significant for FEV1 and MMEFR. Compared with 

subjects in the lowest decile of 1,4-DCB concentration (0.10 ppb), subjects in the highest decile 

(>4.40 ppb) had FEV1 decrements of -153 mL (95% CI -297 to -8) and MMEFR decrements of 

-346 mL/sec (95% CI -667 to -24). The authors concluded that the findings of this study suggest that 

exposure to 1,4-DCB at levels found in the general population may result in decreases in lung function. 
DICHLOROBENZENES 81 

3. HEALTH EFFECTS 

In pregnant Alderley-Park rats, whole-body exposure to 1,4-DCB at air concentrations of 74.7, 198.6, or 

508.4 ppm, 6 hours/day on gestation days (Gd) 6–15 produced no adverse clinical or pathological signs in 

the lung tissues of the dams (Hodge et al. 1977). Mild histopathological changes of interstitial edema, 

congestion, and alveolar hemorrhage were observed in the lungs of male (but not female) rats, female 

guinea pigs, and one female rabbit after 16 days of exposure to 1,4-DCB at 173 ppm (Hollingsworth et al. 

1956). Congestion and emphysema were also reported in the lungs of two rabbits exposed to 798 ppm for 

12 weeks (Hollingsworth et al. 1956). These observations were derived from a large study using several 

species of laboratory animals; however, interspecies comparisons are difficult to make due to the various 

experimental designs used in this study. For example, at 798 ppm, 10 male rats, 15 female rats, 16 male 

guinea pigs, seven female guinea pigs, and 8 rabbits of each sex were exposed up to 62 times; at 173 ppm, 

five rats of each sex, five guinea pigs of each sex, and one rabbit of each sex were exposed for 16 days. 

These reported observations provide only qualitative evidence of respiratory effects as a result of 

intermediate-duration inhalation exposure to 1,4-DCB. 

An intermediate-duration study was conducted in which F344 rats and BDF1 mice were chamber–exposed 

to 25, 55, 120, 270, or 600 ppm of 1,4-DCB for 6 hours/day, 5 days/week for 13 weeks (Aiso et al. 

2005a). No histological changes in the respiratory tract were reported. This study apparently conformed 

to (OECD) (1981) testing guidelines for a 90-day inhalation toxicity study, indicating that the histological 

examinations included naso-pharyngeal tissues and lungs. 

In a chronic-duration study, male and female Wistar rats were exposed to 1,4-DCB at air concentrations 

of 75 or 490–499 ppm, 5 hours/day, 5 days/week for 76 weeks (Riley et al. 1980a). Rats in the highexposure group showed a small but significant increase in absolute lung weight at termination of the 

study (112 weeks). This response was not observed in rats sacrificed on week 76 or in rats exposed to 

75 ppm 1,4-DCB for 112 weeks. No treatment-related histological alterations were observed in the 

larynx, trachea, or lungs in this study. 

Another chronic inhalation study was conducted in which groups of 50 male and female F344/DuCrj rats, 

and 50 male and 50 female Crj:BDF1 mice, were exposed to 1,4-DCB in concentrations of 0, 20, 75, or 

300 ppm for 6 hours/day, 5 days/week for 104 weeks (Aiso et al. 2005b; Japan Bioassay Research Center 

1995). Histological examinations of the respiratory tract (nasal cavity, trachea, and lung) showed nasal 

epithelial effects in rats and mice. The nasal lesions in rats mainly included eosinophilic changes of 

moderate or greater severity in the olfactory epithelium in male rats at 300 ppm and female rats at 

≥75 ppm. Incidences of this lesion at 0, 20, 75, and 300 ppm were 1/50, 2/50, 2/50, and 7/50 in the male 
 

 

DICHLOROBENZENES 82 

3. HEALTH EFFECTS 

rats, and 28/50, 29/50, 39/50, and 47/50 in the female rats. The increases were significantly (p≤0.05) 

different than the control values and there was a trend of increasing response with increasing dose in both 

sexes. Additionally observed were significantly increased incidences of eosinophilic changes of the 

respiratory epithelium and respiratory metaplasia in the 300 ppm female rats only. The nasal lesions in 

mice included significantly increased incidences of respiratory metaplasia in the nasal gland (moderate 

severity) in males at 75 ppm (9/49, 12/49, 18/50, 11/49) and olfactory epithelium (slight severity) in 

males at 75 ppm (23/49, 30/49, 37/50, 22/49) and females at 300 ppm (7/50, 6/50, 2/49, 20/50), but the 

effects in the males were not dose-related (i.e., incidences were increased at 75 ppm but not at 300 ppm). 

The nasal lesions in female rats, the more sensitive species and sex, were selected as the critical effect for 

deriving a chronic-duration inhalation MRL of 0.01 ppm for 1,4-DCB. 

Cardiovascular Effects. 

1,2-Dichlorobenzene. No studies were located regarding cardiovascular effects in humans following 

inhalation exposure to 1,2-DCB. 

No changes in absolute heart weight or heart histology were reported for rats (20/sex), guinea pigs 

(8/sex), rabbits (2/sex), or monkeys (2 females) following exposure to 93 ppm 1,2-DCB for 7 hours/day, 

5 days/week for 6–7 months, or in mice (10 females) that were similarly exposed to 49 ppm 1,2-DCB 

(Hollingsworth et al. 1958). Relative heart weight was not determined. The scope of histological 

evaluations was not specifically reported; organs that were weighed are inferred to have been 

histologically examined. 

1,3-Dichlorobenzene. No studies were located regarding cardiovascular effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding cardiovascular effects in humans following 

inhalation exposure to 1,4-DCB. 

Limited information is available regarding cardiovascular effects in animals. No alterations in relative 

heart weight were observed in rats or guinea pigs exposed to 1,4-DCB at an air concentration of 173 ppm, 

7 hours/day, 5 days/week for up to 12 exposures (Hollingsworth et al. 1956). Similar results were 

reported after approximately 130 exposures to 1,4-DCB at an air concentration of 96 ppm using the same 
 

 

DICHLOROBENZENES 83 

3. HEALTH EFFECTS 

exposure protocol (Hollingsworth et al. 1956); no other cardiovascular end points were evaluated in this 

study. 

In pregnant Alderley-Park rats, whole-body exposure to 1,4-DCB at air concentrations of 74.7, 198.6, or 

508.4 ppm, 6 hours/day from Gd 6 to 15 produced no adverse clinical or pathological signs in the heart 

tissues of the dams (Hodge et al. 1977). 

A significant increase in absolute heart weight was reported in male and female rats exposed to 1,4-DCB 

at air concentrations of 490–499 ppm, 5 hours/day, 5 days/week for 76 weeks and allowed to recover until 

week 112 (Riley et al. 1980a). This effect was not seen at the 76-week interim sacrifice or at the lowerexposure concentration of 75 ppm. Examination of the heart and aorta at interim sacrifices or at 

termination of the study revealed no significant histological alterations related to 1,4-DCB treatment. 

Gastrointestinal Effects. 

1,2-Dichlorobenzene. No studies were located regarding gastrointestinal effects in humans or animals 

following inhalation exposure to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding gastrointestinal effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. Two case reports provide evidence of gastrointestinal effects in humans after 

exposure to unknown concentrations of 1,4-DCB. A 60-year-old man who had been exposed to vapors of 

1,4-DCB in his home for 3–4 months reported having several bowel movements a day with loose tarry 

stools for 10 days before being admitted to a hospital (Cotter 1953). The second case is that of a 34-yearold woman who had been exposed to vapors of 1,4-DCB at work and became acutely ill with nausea and 

vomiting, and was hospitalized with hemorrhage from the gastrointestinal tract (Cotter 1953). The 

physical and chemical findings led to the diagnosis of subacute yellow atrophy and cirrhosis of the liver 

from 1,4-DCB exposure. No further information was located. 

Limited information regarding gastrointestinal effects in animals is provided in a chronic-duration study. 

In that study (Riley et al. 1980a), the investigators found no effect on the organ weight or on gross and 

histopathological appearance of the caecum, colon, duodenum, jejunum, esophagus, pancreas, and 
 

 

DICHLOROBENZENES 84 

3. HEALTH EFFECTS 

stomach in male and female Wistar rats exposed to 1,4-DCB at air concentrations of up to 490–499 ppm, 

5 hours/day, 5 days/week for 76 weeks. 

Hematological Effects. 

1,2-Dichlorobenzene. Periodic industrial hygiene surveys and medical examinations were conducted in a 

plant where an unreported number of men were exposed to 1,2-DCB at an average level of 15 ppm (range 

1–44 ppm) for an unreported duration (Hollingsworth et al. 1958). No effects on clinical hematology 

indices (red blood cell count, total and differential white blood cell counts, hemoglobin, hematocrit, and 

mean corpuscular volume) were attributable to exposure. 

Red blood cell (RBC), total white blood cell (WBC), and leucocyte differential cell counts were assessed 

in groups of five male Sprague-Dawley rats that were exposed to 0, 5, 10, 16, or 29 ppm 1,2-DCB for 

4 hours (Brondeau et al. 1990). Total WBC counts were significantly (p≤0.05) reduced at ≥10 ppm 

without any changes in WBC differential or RBC counts. The effect of 1,2-DCB on total WBC count 

was further assessed in groups of 10 male Sprague-Dawley rats that were normal or adrenalectomized and 

exposed to 0 or 24 ppm for 4 hours. Adrenalectomy caused a significant increase in total WBCs (39.9% 

higher than normal controls), although exposure did not significantly affect WBC count in the 

adrenalectomized rats. Because the adrenal-dependent leucopenia was similar to that observed after 

exposure to various irritant stressors, and is thought to be a secondary manifestation of increased secretion 

of glucocorticosteroids, the authors considered the effect to be an associative response to sensory 

irritation. 

No hematological changes were reported in rabbits (2/sex) or monkeys (2 females) that were exposed to 

93 ppm 1,2-DCB for 7 hours/day, 5 days/week for 6–7 months (Hollingsworth et al. 1958). The 

hematology end points that were evaluated were not specified. 

1,3-Dichlorobenzene. No studies were located regarding hematological effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. Two reports of hematological effects in humans after inhalation exposure to 

1,4-DCB were located in the literature. Based on results from blood counts, anemia was diagnosed in two 

men; one had been exposed to unknown concentrations of 1,4-DCB vapors at home for 3–4 months and 

the other had been in a storage plant saturated with 1,4-DCB vapor. A woman exposed in a similar 
DICHLOROBENZENES 85 

3. HEALTH EFFECTS 

manner was diagnosed with borderline anemia (Cotter 1953). Early industrial hygiene surveys found no 

evidence of adverse hematological effects attributable to exposure to 1,4-DCB in workers at air 

concentrations ranging from 10 to 550 ppm for 8 months to 25 years (average 4.75 years) (Hollingsworth 

et al. 1956). 

Information regarding hematological effects in animals is scant. No hematologic effects (specific tests 

not provided) were observed in rats and rabbits exposed to 1,4-DCB vapors at concentrations of 96 or 

158 ppm, respectively, dosed for durations of 7 hours/day, 5 days/week for 5–7 months (Hollingsworth et 

al. 1956). In another intermediate-duration study, F344 rats and BDF1 mice were chamber-exposed to 25, 

55, 120, 270, or 600 ppm of 1,4-DCB for 6 hours/day, 5 days/week for 13 weeks (Aiso et al. 2005a). 

Hematological changes suggestive of microcytic anemia occurred in the male rats; effects included 

significantly decreased RBC count and hemoglobin concentration at ≥120 ppm, hematocrit at ≥270 ppm, 

and MCV and MCH at 600 ppm. The effects were not accompanied by any anemia-associated 

histopathological changes in hematopoietic tissues (e.g., increased extramedullary hematopoiesis or 

hemosiderosis in the spleen) and did not occur in the female rats or mice of either sex, leading the 

investigators to suggest that they were secondary to male rat-specific α2μ-globulin nephropathy-related 

effects on erythropoietin synthesis in the renal tubules. 

A chronic-duration study reported that some changes in blood chemistry and hematologic parameters 

were seen in rats exposed 5 hours/day, 5 days/week to 1,4-DCB at air concentrations of up to 490– 

499 ppm for 76 weeks; however, the reported changes showed no consistent trend with dose, sex, or 

exposure duration that would indicate treatment-related effects (Riley et al. 1980a). 

Musculoskeletal Effects. 

1,2-Dichlorobenzene. No studies were located regarding musculoskeletal effects in humans following 

inhalation exposure to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding musculoskeletal effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding musculoskeletal effects in humans after 

inhalation exposure to 1,4-DCB. 
DICHLOROBENZENES 86 

3. HEALTH EFFECTS 

One study was located that examined the musculoskeletal effects in laboratory animals after inhalation 

exposure to 1,4-DCB. No gross or histological alterations in skeletal muscle (unspecified parameters) 

were detected in rats exposed to 1,4-DCB at air concentrations of up to 490–499 ppm, 5 hours/day, 

5 days/week for 76 weeks (Riley et al. 1980a). 

Hepatic Effects. 

1,2-Dichlorobenzene. No studies were located regarding hepatic effects in humans following inhalation 

exposure to 1,2-DCB. 

Increased liver weight and marked central lobular necrosis occurred in rats that were exposed to 1,2-DCB 

at a concentration of 977 ppm for 0.5 or 1 hour, but not to 539 ppm for 3 hours (Hollingsworth et al. 

1958). No changes in absolute liver weight or hepatic histology were reported for rats (20/sex), guinea 

pigs (8/sex), rabbits (2/sex), or monkeys (2 females) exposed to 93 ppm 1,2-DCB for 7 hours/day, 

5 days/week for 6–7 months, or in mice (10 females) similarly exposed to 49 ppm 1,2-DCB 

(Hollingsworth et al. 1958). 

1,3-Dichlorobenzene. No studies were located regarding hepatic effects in humans or animals following 

inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. Hepatic effects have been reported in humans following long-term exposure to 

1,4-DCB via inhalation. A 60-year-old man and his wife who were exposed to moth ball vapor that 

"saturated" their home for 3–4 months both died of liver failure (acute liver atrophy) within a year of the 

initial exposure (Cotter 1953). Yellow atrophy and cirrhosis of the liver were reported in a 34-year-old 

woman who demonstrated 1,4-DCB products in a department store and in a 52-year-old man who used 

1,4-DCB occupationally in a fur storage plant for about 2 years (Cotter 1953). Duration of exposure was 

not estimated for the 34-year-old woman, but was indicated in the report to be >1 year. No estimates of 

the 1,4-DCB exposure levels (other than the use of the term “saturated”) were provided in any of these 

reports, nor was it verified that 1,4-DCB exposure was the only factor associated with the observed 

effects. History of alcohol consumption or prior liver disease factors were not mentioned for any of the 

cases reported by Cotter (1953). These case studies indicate that the liver is a target organ for 1,4-DCB in 

humans, but they do not provide quantitative information. 
 

 

DICHLOROBENZENES 87 

3. HEALTH EFFECTS 

In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-DCB at air 

concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours/day from Gd 6 to 15 produced no adverse clinical or 

pathological signs in the hepatic tissues of the dams (Hodge et al. 1977). In a similar study, New Zealand 

White rabbits exposed whole-body to 1,4-DCB 6 hours/day on Gd 6–18 experienced no adverse effects 

on absolute or relative maternal liver weights at air concentrations up to 800 ppm (Hayes et al. 1985). 

An intermediate-duration study was conducted in which F344 rats and BDF1 mice were chamber-exposed 

to 0, 25, 55, 120, 270, or 600 ppm of 1,4-DCB for 6 hours/day, 5 days/week for 13 weeks (Aiso et al. 

2005a). Hepatic effects in the rats included increases in absolute and relative liver weight (>10%) in 

males at ≥270 ppm and females at 600 ppm, serum total cholesterol and phospholipid in males at 

≥270 ppm and females at 600 ppm, serum albumin in females at ≥270 ppm and males at 600 ppm, total 

protein in both sexes at 600 ppm, and centrilobular hepatocellular hypertrophy in males at 600 ppm. 

Hepatic effects in the mice included increases in absolute and relative liver weight (>10%) in males at 

≥270 ppm and females at 600 ppm, serum ALT in males at ≥270 ppm and females at 600 ppm, serum 

AST in males at 600 ppm, serum total cholesterol and total protein in both sexes at 600 ppm, and 

centrilobular hepatocellular hypertrophy in males at ≥270 ppm and females at 600 ppm. The mouse liver 

was more responsive to 1,4-DCB than the rat liver as shown by the histological and serum enzyme 

changes. Hepatocellular hypertrophy occurred at a lower exposure level in the mice (270 ppm compared 

to 600 ppm in rats); incidences in the 0, 25, 120, 270, and 600 ppm male mice were 0/10, 0/10, 0/10, 

0/10; 10/10 and 10/10, respectively. At 600 ppm, the severity of the hepatocellular hypertrophy was 

classified as moderate in the mice and slight in the rats. Affected hepatocytes in the mice were 

characterized by cell enlargement, varying nuclear size and shape, and coarse chromatin and inclusion 

bodies in the nucleus, whereas such nuclear changes were not observed in the hypertrophic hepatocytes of 

the rats. Additionally, the hepatocellular hypertrophy in the mice was accompanied by single cell 

necrosis (both sexes, incidence not reported) and focal necrosis (2/10 males) at 600 ppm, as well as the 

increases in serum ALT at ≥270 ppm and AST at 600 ppm, whereas none of these indicators of 

hepatocellular damage occurred in the rats. 

In a cross-species comparative study, exposure to 1,4-DCB at air concentrations up to 158 ppm, 

7 hours/day, 5 days/week for 5–7 months produced no treatment-related effects on liver weight or 

microscopic appearance in male and female mice; in contrast, various hepatic effects were noted in rats, 

guinea pigs, and rabbits exposed to 1,4-DCB at various levels and durations of exposure (Hollingsworth 

et al. 1956). There was considerable variability in the species of animals exposed at each dose, the 

number of animals exposed, and the total number of exposures. When rats and rabbits inhaled 173– 
DICHLOROBENZENES 88 

3. HEALTH EFFECTS 

798 ppm of 1,4-DCB intermittently for 2–12 weeks, several hepatic effects were observed. Relative liver 

weight was increased in rats exposed to 173 ppm; histopathological examination at this exposure level 

revealed slight congestion and granular degeneration in female rats. At 798 ppm, liver changes included 

cloudy swelling and central necrosis in both sexes of rats and rabbits. In the same study, when rats 

inhaled 158–341 ppm 1,4-DCB intermittently for 5–7 months, male and female rats displayed cloudy 

swelling and central zone degeneration of the hepatic parenchymal cells in the liver, and increased 

relative liver weights at 158 ppm. These changes were not seen at a concentration of 96 ppm. In the 

same study, guinea pigs that were exposed to 341 ppm for a comparable duration or to 798 ppm for 2– 

4.5 weeks had focal necrosis and slight cirrhosis (in some animals) as well as hepatocyte swelling and 

degeneration. 

In a 2-generation study of the effects of inhalation exposure to 1,4-DCB in Sprague-Dawley rats, males 

and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-DCB 6 hours/day for 10 weeks prior to mating. 

The females were also exposed during mating, and on Gd 0–19 and postnatal days 5–27; males were 

exposed throughout the study. Marked hepatocellular hypertrophy, localized in the centrilobular area, 

was noted in F0 and F1 males and females in the 538 ppm dose group; no such effects were seen in the 

low- and mid-dose groups. Liver weights were significantly elevated in F0 males at the 211 and 538 ppm 

doses and in F0 females at the 538 ppm dose; liver weights were also significantly elevated in F1 males 

and females at the 538 ppm dose (Tyl and Neeper-Bradley 1989). The increased liver weight in F0 male 

rats was selected as the critical effect for deriving an intermediate-duration inhalation MRL of 0.2 ppm 

for 1,4-DCB. 

In a long-term inhalation study in rats, exposure to 1,4-DCB at air concentrations of 490–499 ppm 

5 hours/day, 5 days/week for 76 weeks resulted in an increase in absolute liver weight throughout the 

study in males and at weeks 27 and 112 in females (Riley et al. 1980a). This effect was not accompanied 

by histological alterations or by increased serum transaminase activities. No hepatic effects were noted at 

75 ppm. None of the adverse hepatic effects reported at lower concentrations of 1,4-DCB for shorter 

durations (Hollingsworth et al. 1956), as described above, were identified in the 76-week study. 

In another chronic study, groups of 50 male and female F344/DuCrj rats and 50 male and 50 female 

Crj:BDF1 mice were exposed to 1,4-DCB in concentrations of 0, 20, 75, or 300 ppm for 6 hours/day, 

5 days/week for 104 weeks (Aiso et al. 2005b; Japan Bioassay Research Center 1995). Histological 

examinations showed liver changes only in the high-dose male mice. The incidence of centrilobular 
DICHLOROBENZENES 89 

3. HEALTH EFFECTS 

hepatocellular hypertrophy was significantly increased in male mice at 300 ppm, as shown by incidences 

of 0/49, 0/49, 0/50, and 34/49 in the control to high dose groups. 

Renal Effects. 

1,2-Dichlorobenzene. Periodic industrial hygiene surveys and medical examinations were conducted in a 

plant where an unreported number of men were exposed to 1,2-DCB at an average level of 15 ppm (range 

1–44 ppm) for an unreported duration (Hollingsworth et al. 1958). No effects on clinical renal indices 

(blood urea nitrogen, sedimentation rate, or urinalysis) were attributable to exposure. 

No changes in absolute kidney weight or kidney histology were reported for rats (20/sex), guinea pigs 

(8/sex), rabbits (2/sex), or monkeys (2 females) exposed to 93 ppm 1,2-DCB for 7 hours/day, 

5 days/week for 6–7 months, or in mice (10 females) similarly exposed to 49 ppm 1,2-DCB 

(Hollingsworth et al. 1958). Relative kidney weight was not determined. The scope of histological 

evaluations was not specifically reported; organs that were weighed are inferred to have been 

histologically examined. Limited urinalysis was performed in the species exposed to 93 ppm; BUN 

determinations and qualitative tests for sugar, albumin, sediment, and blood showed no abnormalities. 

1,3-Dichlorobenzene. No studies were located regarding renal effects in humans or animals following 

inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding renal effects in humans after inhalation 

exposure to 1,4-DCB. 

In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-DCB at air 

concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours/day from Gd 6 to 15 produced no adverse clinical or 

pathological signs in the kidney tissues of the dams (Hodge et al. 1977). In a similar study, pregnant New 

Zealand White rabbits exposed whole-body to 1,4-DCB 6 hours/day on Gd 6–18 experienced no adverse 

effects with regard to either absolute or relative maternal kidney weights at air concentrations up to 

800 ppm (Hayes et al. 1985). 

In an intermediate-duration study, F344 rats and BDF1 mice were chamber-exposed to 25, 55, 120, 270, 

or 600 ppm of 1,4-DCB for 6 hours/day, 5 days/week for 13 weeks (Aiso et al. 2005a). Histological 

effects included kidney lesions indicative of α 2μ-globulin nephropathy (hyaline droplets, granular casts, 
 

 

DICHLOROBENZENES 90 

3. HEALTH EFFECTS 

tubular cell necrosis, cytoplasmic basophila, and papillary mineralization) in the male rats at ≥270 ppm. 

There were no histological changes in the kidneys of the female rats or mice of either sex. Other renal 

effects included increased relative and/or absolute kidney weights in male rats and male mice at 

≥270 ppm and female rats and female mice at 600 ppm, and increased serum BUN in male rats and male 

mice at 600 ppm. 

In rats, mice, and rabbits exposed by inhalation to 1,4-DCB at air concentrations ranging from 96 to 

798 ppm, 7 or 8 hours/day, for periods as long as 7 months, no renal effects were noted in mice or rabbits, 

while both male and female rats experienced increased relative kidney weights at the 173 ppm dose level. 

In addition, a slight cloudy swelling of the tubular epithelium was noted in female rats exposed to 

798 ppm. In the same study, inhalation of 1,4-DCB at 158 or 341 ppm intermittently for 5–7 months by 

rats caused a slight increase in relative kidney weight in males but not females (Hollingsworth et al. 

1956). This effect was not observed in groups of guinea pigs, in one monkey, or in two rabbits under the 

same experimental conditions (Hollingsworth et al. 1956). The findings in this study are consistent with 

those reported by Riley et al. (1980a) in a 76-week study in rats, described below. 

In a 2-generation study of the effects of inhalation exposure to 1,4-DCB in Sprague-Dawley rats, males 

and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-DCB 6 hours/day for 10 weeks prior to mating. 

The females were also exposed during mating, and on Gd 0–19 and postnatal days 5–27; males were 

exposed throughout the study. An increased incidence of nephrosis was seen in F0 males of all dose 

groups and in F1 males of the 211 and 538 ppm dose groups; lesions consisted of hyaline droplets, tubular 

protein nephrosis, granular cast formation, and interstitial nephritis. No renal lesions were noted in F0 or 

F1 females. Kidney weights were significantly elevated in F0 males at all doses and in F1 males at the 

538 ppm dose. In females, kidney weights were significantly elevated in the F0 generation at the 538 ppm 

dose, but were not elevated in the F1 generation (Tyl and Neeper-Bradley 1989). 

In a chronic-duration inhalation study in Wistar rats, exposure to 1,4-DCB at air concentrations of 490– 

499 ppm, 5 hours/day, 5 days/week for 76 weeks resulted in an increase in absolute kidney weight in 

males throughout the study and in females at weeks 27 and 112 weeks. Exposure to 75 ppm 1,4-DCB had 

no effect on kidney weight, and neither exposure level caused histopathological alterations in the kidneys 

(Riley et al. 1980a). In another chronic study, groups of 50 male and female F344/DuCrj rats and 50 male 

and 50 female Crj:BDF1 mice were exposed to 1,4-DCB in concentrations of 0, 20, 75, or 300 ppm for 

6 hours/day, 5 days/week for 104 weeks (Aiso et al. 2005b; Japan Bioassay Research Center 1995). 

Histological examinations showed kidney changes only in male rats at 300 ppm, where incidences of 
DICHLOROBENZENES 91 

3. HEALTH EFFECTS 

mineralization of the renal papilla and hyperplasia of the urothelium were significantly increased. In 

general, the renal effects observed in inhalation studies of 1,4-DCB are mild in contrast with the severe 

renal effects observed in oral studies as described in Section 3.2.2.2. 

Endocrine Effects. 

1,2-Dichlorobenzene. No studies were located regarding endocrine effects in humans or animals 

following inhalation exposure to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding endocrine effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding endocrine effects in humans following 

inhalation exposure to 1,4-DCB. 

The only information regarding endocrine effects in animals after inhalation exposure to 1,4-DCB is from 

a chronic-duration study in rats. In that study (Riley et al. 1980a), no gross or histopathological effects 

were observed in the adrenal, thyroid, or pituitary glands of male or female rats exposed to 1,4-DCB at air 

concentrations up to 490–499 ppm, 5 hours/day, 5 days/week for 76 weeks. No further information 

regarding endocrine effects was located. 

Dermal Effects. 

1,2-Dichlorobenzene. No studies were located regarding dermal effects in humans or animals following 

inhalation exposure to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding dermal effects in humans or animals following 

inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. Dermal effects resulting from 1,4-DCB exposure were reported in a 69-year-old 

man who had been exposed for approximately 3 weeks to 1,4-DCB used in his home, including on a chair 

on which he had been sitting. He gradually developed petechiae (small red spots), purpura (purple or 

brownish-red spots), and swelling of his hands and feet. His sensitivity to 1,4-DCB was established by an 
 

 

DICHLOROBENZENES 92 

3. HEALTH EFFECTS 

indirect basophil degranulation test that showed a strongly positive reaction (degenerative changes in 62% 

of his basophils when tested with 1,4-DCB, compared with a 6% reaction of normal serum with 1,4-DCB) 

(Nalbandian and Pearce 1965). The authors suggested that these effects were probably immunologically 

mediated. In a study of 58 men occupationally exposed to up to 725 ppm 1,4-DCB, 8 hours/day, 

5 days/week continually or intermittently for 8 months to 25 years (average: 4.75 years), medical 

examinations revealed no evidence of dermatological effects (Hollingsworth et al. 1956). 

No studies were located regarding dermal effects in animals after inhalation exposure to 1,4-DCB. 

Ocular Effects. 

1,2-Dichlorobenzene. Periodic industrial hygiene surveys and medical examinations were conducted in a 

plant where an unreported number of men were exposed to 1,2-DCB at an average level of 15 ppm (range 

1–44 ppm) for an unreported duration (Hollingsworth et al. 1958). No eye or nasal irritation was 

attributable to exposure. Additionally, Hollingsworth et al. (1958) noted that his researchers detected 

1,2-DCB odor at a concentration of 50 ppm without eye or nasal irritation during repeated vapor 

inhalation experiments on animals. An earlier source (Elkins 1950) referenced by Hollingsworth (1958) 

reported that occupational exposure to 100 ppm of 1,2-DCB caused irritation of the eyes and respiratory 

passages. 

1,3-Dichlorobenzene. No studies were located regarding ocular effects in humans or animals following 

inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. In a report on 58 men who had worked for 8 months to 25 years (average exposure 

4.75 years) in a plant that used 1,4-DCB, painful irritation of the nose and eyes were reported at levels 

ranging from 80 to 160 ppm (Hollingsworth et al. 1956). At levels >160 ppm, the air was considered 

unbreathable by unacclimated persons. Neither cataracts nor any other lens changes were found upon 

examination of their eyes. 

There is no clear, quantitative evidence of ocular effects resulting from inhalation exposure to 1,4-DCB in 

animal studies. Ocular effects, described as reversible, nonspecific eye ground changes (changes in the 

fundus or back of the eye), were seen in two rabbits exposed to 1,4-DCB at 798 ppm, 8 hours/day, 

5 days/week for 12 weeks (Hollingsworth et al. 1956). In the same study, no lens changes were observed 

in rats or guinea pigs exposed to 798 ppm 1,4-DCB, but eye irritation was reported in the three species 
DICHLOROBENZENES 93 

3. HEALTH EFFECTS 

tested. Ocular effects occurring during and/or after exposure to chemicals in air are likely to be due to 

direct contact of the chemical with the eye. 

A chronic-duration inhalation study in male and female Wistar rats reported no histopathological 

alterations in the eyes of rats exposed to 1,4-DCB at air concentrations up to 490–499 ppm, 5 hours/day, 

5 days/week for 76 weeks (Riley et al. 1980a). No further data were located. 

Body Weight Effects. 

1,2-Dichlorobenzene. Groups of male and female albino rats (20/sex) were exposed to 0, 49, or 93 ppm 

(0, 290, or 560 mg/m3

, respectively) of 1,2-DCB (99% pure) vapor for 7 hours/day, 5 days/week for 6– 

7 months (Hollingsworth et al. 1958). No compound related effects were found at 49 ppm. Effects 

observed at 93 ppm consisted of statistically significant (p≤0.05) decreased final body weight in the males 

(8.9% lower than controls). There were no body weight changes in guinea pigs (8/sex), rabbits (2/sex), or 

monkeys (2 females) similarly exposed to 93 ppm 1,2-DCB, or in mice (10 females) similarly exposed to 

49 ppm 1,2-DCB (Hollingsworth et al. 1958). 

1,3-Dichlorobenzene. No studies were located regarding body weight effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. A 60-year-old man who was exposed to vapors of 1,4-DCB in his home for 3– 

4 months was reported to have lost approximately 50 pounds in body weight in 3 months (Cotter 1953). 

His wife, who received similar exposure, also lost weight. A third case reported by the same author 

(Cotter 1953) is that of a 52-year-old man who was exposed to 1,4-DCB by using the chemical for 

preserving raw furs. On examination, this individual was described as being emaciated. Information 

regarding food consumption was not available in any of these cases. In the case of the 60-year-old man, 

persistent diarrhea may have contributed to the weight loss. 

In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-DCB at air 

concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours/day from Gd 6 to 15 had no effect on maternal body 

weight gain (Hodge et al. 1977). 

Body weight data are available for various animal species after exposure to 1,4-DCB 7–8 hours/day, 

5 days/week, for periods ranging from 2 weeks to 6 months (Hollingsworth et al. 1956). Rats, rabbits, 
DICHLOROBENZENES 94 

3. HEALTH EFFECTS 

and guinea pigs experienced weight loss when exposed to 798 ppm, 8 hours/day, 5 days/week. Rats 

exposed to up to 341 ppm 1,4-DCB for 5–7 months grew at a rate similar to that of unexposed controls. 

Similar results were obtained in rabbits exposed to 173 ppm for 16 days or to 158 ppm for about 

200 days. Slight growth depression was observed in male and female guinea pigs exposed to 158 ppm 

1,4-DCB for 157 days, but only males showed a slight delay in growth when the exposure level was 

341 ppm for 6 months. In male and female mice and in one female monkey, there were no effects on 

body weight after exposure to 1,4-DCB at air concentrations up to 158 ppm for as long as 7.1 months. In 

another intermediate-duration study, there were no effects on body weight gain in F344 rats and 

BDF1 mice that were exposed to 25, 55, 120, 270, or 600 ppm of 1,4-DCB for 6 hours/day, 5 days/week 

for 13 weeks (Aiso et al. 2005a). 

In a 2-generation study of the effects of inhalation exposure to 1,4-DCB in Sprague-Dawley rats, males 

and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-DCB 6 hours/day for 10 weeks prior to mating. 

The females were also exposed during mating, and on Gd 0–19 and postnatal days 5–27; males were 

exposed throughout the study. Male F0 body weight and body weight gain were significantly reduced in 

the 538 ppm group. Body weight gain was also significantly reduced in the 211 ppm group; however, the 

effect was seen at fewer observation periods. Female F0 body weights were equivalent across all 

treatment groups during the entire prebreeding period. The F1 generation males and females exposed to 

538 ppm 1,4-DCB had lower body weights than did controls; however, these decreases were accompanied 

by decreased food consumption (Tyl and Neeper-Bradley 1989). 

A chronic-duration inhalation study in male and female Wistar rats found that body weight was not 

significantly altered after exposure to 1,4-DCB at air concentrations up to 490–499 ppm, 5 hours/day, 

5 days/week for 76 weeks (Riley et al. 1980a). 

Other Systemic Effects. 

1,2-Dichlorobenzene. No studies were located regarding other systemic effects in humans or animals 

following inhalation exposure to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding other systemic effects in humans or animals 

following inhalation exposure to 1,3-DCB. 
 

 

DICHLOROBENZENES 95 

3. HEALTH EFFECTS 

1,4-Dichlorobenzene. No studies were located regarding other effects in humans following inhalation 

exposure to 1,4-DCB. Ascites, esophageal varices, hemorrhoids, and tarry stools are all secondary effects 

of subacute, yellow atrophy and cirrhosis of the liver (Cotter 1953). 

A chronic-duration inhalation study in male and female Wistar rats found that food and water 

consumption was not significantly altered after exposure to 1,4-DCB at air concentrations up to 490– 

499 ppm, 5 hours/day, 5 days/week for 76 weeks (Riley et al. 1980a). 

In a 2-generation study of the effects of inhalation exposure to 1,4-DCB in Sprague-Dawley rats, males 

and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-DCB 6 hours daily for 10 weeks prior to 

mating. The females were also exposed during mating, and on Gd 0–19 and postnatal days 5–27; males 

were exposed throughout the study. Exposure of the F0 and F1 generations to 538 ppm 1,4-DCB resulted 

in clinical signs of toxicity such as decreased grooming, unkempt appearance, decreased food 

consumption, and dehydration (Tyl and Neeper-Bradley 1989). 

3.2.1.3 Immunological and Lymphoreticular Effects 

1,2-Dichlorobenzene. No studies were located regarding immunological effects in humans following 

inhalation exposure to 1,2-DCB. 

No changes in absolute spleen weight or spleen histology were reported for rats (20/sex) or guinea pigs 

(8/sex) that were exposed to 93 ppm 1,2-DCB for 7 hours/day, 5 days/week for 6–7 months 

(Hollingsworth et al. 1958). Relative spleen weight was not determined. The scope of histological 

evaluations was not specifically reported; organs that were weighed appear to have been examined. 

1,3-Dichlorobenzene. No studies were located regarding immunological effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. As mentioned in Section 3.2.1.2, dermal effects observed in a 69-year-old man 

who had been exposed to 1,4-DCB in his home for approximately 3 weeks (Nalbandian and Pearce 1965) 

may have been mediated by immunological mechanisms. In addition to petechiae, purpura, and swelling 

of his hands and feet, his serum showed a strong positive reaction to 1,4-DCB in an indirect basophil 

degranulation test. The authors stated that, to their knowledge, this was the first reported case of allergic 

(anaphylactoid) purpura induced by exposure to 1,4-DCB. Enlargement of the spleen was reported in a 
 

 

DICHLOROBENZENES 96 

3. HEALTH EFFECTS 

woman who had been exposed to 1,4-DCB in her home for 3–4 months and in a man who used 1,4-DCB 

to preserve raw furs (Cotter 1953). This, however, was most likely a secondary response to 

hematological disturbances rather than an immunological effect. 

A slight decrease in relative spleen weight was observed in male guinea pigs exposed to 1,4-DCB at an 

air concentration of 173 ppm, 7 hours/day, 5 days/week for 16 days (Hollingsworth et al. 1956); no effect 

was seen in rats under the same experimental conditions. In a chronic-duration inhalation study, groups 

of male and female Wistar rats exposed to 1,4-DCB 5 hours/day, 5 days/week for 76 weeks exhibited no 

gross or histopathological alterations in the cervical, thoracic, and mesenteric lymph nodes; spleen; or 

thymus at air concentrations up to 500 ppm (Riley et al. 1980a). No other immunological end points were 

evaluated. 

No effects were found in an immunotoxicity study in which groups of 10 male SPF Hartley guinea pigs 

were exposed to 1,4-DCB by inhalation in concentrations of 0, 2, or 50 ppm for 12 weeks (schedule not 

specified) (Suzuki et al. 1991). The animals were sensitized with ovalbumin after 4 and 8 weeks of 

exposure to evaluate effects on antibody production. Determinations of serum IgE titers (passive 

cutaneous anaphylaxis test) and serum IgG and IgM titers (enzyme-linked immunosorbent assay) against 

ovalbumin, performed 1 and 2 weeks after the first sensitization and 1, 2, and 4 weeks after the second 

sensitization, showed no significant differences between the exposed and control groups. The passive 

cutaneous anaphylaxis test was also conducted with antiserum from the 50 ppm exposure group (collected 

1 and 2 weeks after the first sensitization and 1, 2, and 4 weeks after the second sensitization) to 

determine if IgE antibodies were produced against 1,4-DCB; no antibodies against the compound were 

detected. Active systemic anaphylaxis was also evaluated in the 0 and 50 ppm exposure groups. An 

antigen mixture of 1,4-DCB and guinea pig serum albumin did not cause an anaphylactic reaction when 

intravenously injected in the animals 14 days after the last exposure. This study was reported in the 

Japanese literature; relevant information was obtained from the English abstract and data tables. 

3.2.1.4 Neurological Effects 

1,2-Dichlorobenzene. No studies were located regarding neurological effects in humans or animals 

following inhalation exposure to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding neurological effects in humans or animals 

following inhalation exposure to 1,3-DCB. 
 

 

DICHLOROBENZENES 97 

3. HEALTH EFFECTS 

1,4-Dichlorobenzene. Information regarding neurological effects in humans exposed to 1,4-DCB via 

inhalation is limited to several case reports. A 60-year-old man whose home had been saturated with 

1,4-DCB moth ball vapor for 3 or 4 months complained of persistent headache, numbness, clumsiness, 

and a burning sensation in his legs (consistent with peripheral nerve damage); he also showed slurred 

speech (Cotter 1953). In a more recent case study, a 25-year-old woman was exposed to high 

concentrations of 1,4-DCB from her bedroom, bedding, and clothing. She had used this compound 

liberally as an insect repellant for 6 years. The subject sought medical assistance because of severe 

ataxia, speech difficulties, and moderate weakness of her limbs. Brainstem auditory-evoked potentials 

(BAEPs) showed marked delays of specific brainwave patterns. Her symptoms gradually improved over 

the next 6 months after cessation of exposure and the BAEPs examined 8 months later had returned to 

normal. This study suggests that there may be measurable but reversible neurological effects associated 

with human inhalation exposure to 1,4-DCB (Miyai et al. 1988). The level of 1,4-DCB exposure was 

neither known nor estimated in either of the human case studies. In addition, there is no certainty that 

exposure to 1,4-DCB was the only factor associated with the toxic effects reported. 

Neurological signs including marked tremors, weakness, and loss of consciousness were observed in rats, 

rabbits, and guinea pigs exposed to 798 ppm 1,4-DCB 8 hours/day, 5 days/week (Hollingsworth et al. 

1956). In a chronic-duration study in rats, exposure to up to 500 ppm 1,4-DCB 5 hours/day, 5 days/week 

for 76 weeks did not cause gross or histological alterations in the brain, sciatic nerve, or spinal cord, but 

absolute brain weight was slightly decreased at the termination of the study (Riley et al. 1980a). Adult 

rats exposed 6 hours/day for 10 weeks to 538 ppm 1,4-DCB during a 2-generation study displayed 

symptoms associated with compound neurotoxicity, including tremors, ataxia, and hyperactivity (Tyl and 

Neeper-Bradley 1989). The animals also decreased their grooming behavior and developed an unkempt 

appearance. At sacrifice, the relative brain weights of the males, but not the females, were significantly 

increased compared to the controls. 

3.2.1.5 Reproductive Effects 

1,2-Dichlorobenzene. No studies were located regarding reproductive effects in humans or animals 

following inhalation exposure to 1,2-DCB. 

A 2-generation inhalation reproduction study was conducted in which groups of Charles River CD 

(Sprague-Dawley derived) rats (30/sex/generation) were exposed to 1,2-DCB at levels of 0, 50, 150, or 
DICHLOROBENZENES 98 

3. HEALTH EFFECTS 

394 ppm (Bio/dynamics 1989). F0 adults were exposed for 6 hours/day, 7 days/week for a 10-week 

premating period and during mating. Following mating, F0 males were exposed 6 hours/day, 7 days/week 

until sacrifice at 3–4 weeks postmating. Bred F0 females were exposed for 6 hours/day on gestation days 

0–19 and lactation days 5–28, then sacrificed postweaning. F1 pups (29 days old) received similar 

exposures throughout an 11-week premating period, mating, gestation, and lactation. There were no 

exposure-related effects on reproductive performance or fertility indices in either generation. 

No changes in absolute testicular weight or testicular histology were reported for male rats or guinea pigs 

that were exposed to 93 ppm 1,2-DCB for 7 hours/day, 5 days/week for 6–7 months (Hollingsworth et al. 

1958). Relative testicular weight was not determined. The scope of histological evaluations in this study 

was not specifically reported; organs that were weighed also appear to have been examined. 

1,3-Dichlorobenzene. No studies were located regarding reproductive effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding reproductive effects in humans after inhalation 

exposure to 1,4-DCB. 

In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-DCB at air 

concentrations up to 508.4 ppm, 6 hours/day from Gd 6 to 15 did not adversely affect the number of 

implantations, resorptions, viable fetuses, corpora lutea, or sex ratios (Hodge et al. 1977). A similar study 

in inseminated New Zealand White rabbits exposed whole-body to 1,4-DCB at air concentrations of 100, 

300, or 800 ppm, 6 hours/day on Gd 6–18 found no differences between treated and control groups in the 

mean number of corpora lutea per dam, the mean number of implantation sites per dam, the mean number 

of resorptions per litter, or the number of totally resorbed litters. At 300 ppm, there was a significant 

increase (p≤0.05) in the percentage of resorbed implantations per litter and in the number of litters with 

resorptions; however, the results at 800 ppm were comparable to controls, and the percentage of litters 

with resorptions reported in the 300 ppm group was within the range reported for historical controls, 

suggesting this effect was not chemical- or dose-related (Hayes et al. 1985). 

Exposure of rats and guinea pigs to 1,4-DCB at an air concentration of 173 ppm, 7 hours/day, 

5 days/week for 2 weeks did not significantly alter relative testis weight. The same results were obtained 

after intermittently exposing rats and guinea pigs to 1,4-DCB at air concentrations up to 158 ppm for 5– 

7 months (Hollingsworth et al. 1956). There were no treatment-related effects on the reproductive organs 
DICHLOROBENZENES 99 

3. HEALTH EFFECTS 

of male or female Wistar rats exposed to 1,4-DCB at concentrations up to 490–499 ppm, 5 hours/day, 

5 days/week for 76 weeks (Riley et al. 1980a). The evaluation of reproductive end points included organ 

weights and histopathology. 

In another chronic inhalation study, groups of 50 male and female F344/DuCrj rats and 50 male and 

50 female Crj:BDF1 mice were exposed to 1,4-DCB in concentrations of 0, 20, 75, or 300 ppm for 

6 hours/day, 5 days/week for 104 weeks (Aiso et al. 2005b; Japan Bioassay Research Center 1995). 

Histological examinations included reproductive system tissues in both sexes (testis, epididymis, seminal 

vesicle, prostate, ovary, uterus, vagina, and mammary gland), but there were no exposure-related adverse 

findings in either species or sex (Aiso 2006). 

The effects of 1,4-DCB vapors on the reproductive performance of Sprague-Dawley rats was assessed in 

a 2-generation study in which animals of both sexes were exposed before and during mating (Tyl and 

Neeper-Bradley 1989). The females were then exposed on Gd 0–19 and postnatal days 5–27. Effects on 

body weight, liver and kidney weight, and hepatocellular hypertrophy were found in the adult rats at 

exposure concentrations of 211 and 538 ppm and were indicative of toxicity to the breeding animals. 

These effects did not occur with the 66.3 ppm exposure concentration. Both generations of offspring 

exposed to the 538 ppm concentration had lower body weights than the controls at lactation day 4; 

average litter size and survival rates were decreased. When selected animals from the first filial 

generation were allowed to recover from the 1,4-DCB exposure for a 5-week period, body weights of the 

538 ppm exposure group remained lower than those for the controls. The authors concluded that parental 

toxicity was the cause of the increased risk to offspring rather than inherent effects of 1,4-DCB on 

reproductive processes. In addition, no reduction in reproductive performance (as measured by the 

percentage of males successfully impregnating females) was observed in an inhalation study in which 

male mice were exposed to 1,4-DCB at 75–450 ppm for 6 hours/day for 5 days before being mated with 

virgin females (Anderson and Hodge 1976). These data are consistent with the data from the males used 

in the 2-generation study discussed above. 

3.2.1.6 Developmental Effects 

1,2-Dichlorobenzene. No studies were located regarding developmental effects in humans or animals 

following inhalation exposure to 1,2-DCB. 
 

 

DICHLOROBENZENES 100 

3. HEALTH EFFECTS 

1,3-Dichlorobenzene. No studies were located regarding developmental effects in humans or animals 

following inhalation exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding developmental effects in humans after 

inhalation exposure to 1,4-DCB. 

Exposure of pregnant Alderley-Park rats to 1,4-DCB via inhalation at levels up to 508 ppm for 

6 hours/day on Gd 6–15 did not result in developmental effects in the offspring (Hodge et al. 1977). End 

points examined included the number of viable fetuses, fetal weight, litter weight, sex ratio, external 

abnormalities, and skeletal and visceral abnormalities. 

In a 2-generation study of the effects of inhalation exposure to 1,4-DCB in Sprague-Dawley rats, males 

and females that were exposed to 0, 66.3, 211, or 538 ppm 1,4-DCB 6 hours daily for 10 weeks prior to 

mating were assessed. The females were also exposed during mating, and on Gd 0–19 and postnatal days 

5–27; males were exposed throughout the study. F1 and F2 pup body weights in the 538 ppm group were 

significantly reduced from postnatal day 0 to 28. The number of F1 and F2 pups that died during the 

perinatal period was significantly elevated in the 538 ppm group (Tyl and Neeper-Bradley 1989). 

The developmental effects of 1,4-DCB have been evaluated in New Zealand White rabbits (Hayes et al. 

1985). Pregnant rabbits were exposed to 1,4-DCB by inhalation at 800 ppm for 6 hours/day on Gd 6–18. 

At 300 ppm, there was a significant increase in the number of litters with resorptions and the percentages 

of resorbed implantations per litter; however, this effect was not seen at 800 ppm and was thus probably 

not treatment-related. An increased incidence of retroesophageal right subclavian artery present in the 

offspring was noted; it was not considered to constitute a teratogenic response to exposure to 1,4-DCB, 

but was considered only a minor variation. 

3.2.1.7 Cancer 

1,2-Dichlorobenzene. No studies were located regarding cancer in humans or animals following 

inhalation exposure to 1,2-DCB. 

1,3-Dichlorobenzene. No studies were located regarding cancer in humans or animals following 

inhalation exposure to 1,3-DCB. 
DICHLOROBENZENES 101 

3. HEALTH EFFECTS 

1,4-Dichlorobenzene. No studies were located regarding cancer in humans after inhalation exposure to 

1,4-DCB. 

No evidence of carcinogenicity was observed in a long-term inhalation study in rats that were exposed to 

1,4-DCB at 75 or 500 ppm intermittently for 76 weeks (Riley et al. 1980a). The reported lack of 

extensive organ toxicity in this study (compared with results seen in oral studies described in 

Section 3.2.2.2) strongly suggests that a maximum tolerated dose (MTD) was not achieved. In addition, a 

less-than-lifetime dosing regimen was used. The experimental design limitations preclude reliable 

evaluation of potential inhalation carcinogenicity based on this study. 

The carcinogenicity of 1,4-DCB was more recently evaluated in groups of 50 male and female 

F344/DuCrj rats, and 50 male and 50 female Crj:BDF1 mice, following exposure to concentrations of 0, 

20, 75, or 300 ppm for 6 hours/day, 5 days/week for 104 weeks (Aiso et al. 2005b; Japan Bioassay 

Research Center 1995). Comprehensive histological evaluations (including nasal cavity, trachea, and 

lungs) showed no compound-related neoplastic changes in rats, although incidences of liver and lung 

tumors were elevated in mice. The liver tumors were induced in mice of both sexes, generally increased 

only at 300 ppm, and were comprised of several tumor types. Liver tumors reported to be significantly 

increased (p≤0.05, Fisher’s Exact test) in male mice were hepatocellular carcinoma (12/49, 17/49, 16/50, 

38/49; p≤0.01 at high dose), hepatoblastoma (0/49, 2/49, 0/50, 8/49; p≤0.01 at high dose) and hepatic 

histiocytic sarcoma (0/49, 3/49, 1/50, 6/49; p≤0.05 at high dose). Liver tumors reported to be 

significantly increased in female mice were hepatocellular carcinoma (2/50, 4/50, 2/49, 41/50; p≤0.01 at 

high dose), hepatocellular adenoma (2/50, 10/50, 6/49, 20/50; p≤0.05 at low and high doses), 

hepatocellular carcinoma or adenoma (4/50, 13/50, 7/49, 45/50; p≤0.05 at low and high doses), and 

hepatoblastoma (0/50, 0/50, 0/49, 6/50; p≤0.05 at high dose). Although the hepatocellular adenomas 

were increased in female mice at 20 and 300 ppm, the relevance of the increase at 20 ppm is unclear 

given the lack of significant change at 75 ppm. Lung bronchoalveolar adenoma and carcinoma were 

significantly increased in female mice (1/50, 4/50, 2/49, 7/50; p≤0.05 at high dose). Except for 

hepatoblastoma, all of the aforementioned liver and lung tumor incidences were reported to have a 

significant positive linear trend by the Peto test and/or Cochran-Armitage test. 

3.2.2 Oral Exposure 

Most of the data described in this section were derived from laboratory studies in which 1,2-, 1,3-, and 

1,4-DCB were administered to test animals via gavage. In addition, two human case studies of 1,4-DCB 
 

 

DICHLOROBENZENES 102 

3. HEALTH EFFECTS 

consumption are described. Case studies are not generally scientifically equivalent to well-conducted 

epidemiologic studies or laboratory experiments and should be viewed only as providing contributory 

evidence that 1,4-DCB may have caused the reported effects. The available case studies do not provide 

unequivocal proof that 1,4-DCB is solely responsible for the reported toxicological effects in humans. 

The highest NOAEL and all reliable LOAEL values after oral exposure to 1,2-, 1,3-, and 1,4-DCB are 

recorded in Tables 3-3, 3-4, and 3-5, respectively, and plotted in Figures 3-3, 3-4, and 3-5, respectively. 

3.2.2.1 Death 

1,2-Dichlorobenzene. No studies were located regarding death in humans after oral exposure to 

1,2-DCB. 

Single-dose LD50 values of 500 and 1,516 mg/kg have been reported for 1,2-DCB in rats administered the 

compound in oil by gavage (Ben-Dyke et al. 1970; Monsanto 1989). Rats that were gavaged with a 25% 

solution of 1,2-DCB in peanut oil at a dose of 675 mg/kg/day for 3 days were considered unlikely to 

survive further exposures (DuPont 1982). Guinea pigs that were treated with a single gavage dose of 

1,2-DCB as a 50% solution in olive oil had no deaths at 800 mg/kg and 100% mortality at 2,000 mg/kg 

(Hollingsworth et al. 1958). 

Rats that were administered 1,2-DCB in oil by gavage for 14 consecutive days and observed until 

day 20 experienced 100% mortality at 1,000 mg/kg/day and no deaths at 500 mg/kg/day and lower doses 

(NTP 1985). Mice that were similarly treated with 1,2-DCB for 14 days had 80% mortality in both sexes 

at 250 mg/kg/day (lowest tested dose) and 80–100% mortality at ≥500 mg/kg/day (NTP 1985). The 

reliability of the 14-day findings is uncertain because there were no clear effects of gavage exposure to 

1,2-DCB in oil on survival in rats or mice exposed to ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 

1985), rats exposed to 400 mg/kg/day on 7 days/week for 90 days (Robinson et al. 1991), or rats or mice 

exposed to ≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985). Information in the longer-term 

NTP (1985) studies suggests that gavage error might have contributed to some of the deaths in the 14-day 

studies. 

1,3-Dichlorobenzene. No studies were located regarding death in humans after oral exposure to 

1,3-DCB. 
2090

500

2093

1500

2095

675

2098

1516

2057

1000

2059

250

2009

2000

2094

15001500

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

ACUTE EXPOSURE Death 

1 Rat once 500 (LD50) Ben-Dyke et al. 1970 (NS) (NS) 1,2-dichlorobenzene 

2 Rat once 1500 (lowest lethal dose) DuPont 1982 (NS) (GO) 1,2-dichlorobenzene 

3 Rat 3 d 675 (unlikely to survive DuPont 1982 1 x/d (NS) further exposure) 1,2-dichlorobenzene (GO) 

4 Rat once 1516 (LD50) Monsanto 1989 (NS) (G) 1,2-dichlorobenzene 

5 Rat 14 d 1000 (100% mortality) NTP 1985 7 d/wk (Fischer- 344) 1 x/d 1,2-dichlorobenzene 

(GO) 

6 Mouse 14 d 250 (80% mortality) NTP 1985 7 d/wk (B6C3F1) 1 x/d 1,2-dichlorobenzene 

(GO) 

7 Gn Pig once 2000 (100% mortality) Hollingsworth et al. 1958 (NS) (GO) 1,2-dichlorobenzene 

Systemic 

8 Rat once Hepatic 1500 (central necrosis) DuPont 1982 (NS) (GO) 1,2-dichlorobenzene 

Renal 1500 (albuminous fluid and 

casts in tubules) 
2096

675

2058

10005001000

1000

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Rat 3 d 9 (NS) 

Bd Wt 675 (10% body weight loss) DuPont 1982 1 x/d 

1,2-dichlorobenzene (GO) 

10 Rat 14 d Hepatic 1000 NTP 1985 7 d/wk (Fischer- 344) 1 x/d 1,2-dichlorobenzene 

(GO) 

b

Bd Wt 500 M 1000 M (12% reduced body

weight gain)

1000 F
2086

30030030030030015075

300150

300300300150300

300

2060

250

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

11 Rat 10 d Resp 300 M Robinson et al. 1991 7 d/wk (Sprague- 1 x/d 1,2-dichlorobenzene Dawley)

(GO)

Cardio 300Gastro 300 MHemato 300 MMusc/skel 300 MHepatic 150 M 300 M (slight necrosis,

increased serum ALT)

75 F 

c

b

150 F (increased liver weight)

Renal 300 MEndocr 300 MDermal 300

b

Bd Wt 150 M 300 M (10.9% reduced body

weight gain)

300 F

12 Mouse 14 d Hepatic 250 (hepatocellular NTP 1985 7 d/wk (B6C3F1) 1 x/d degeneration) 1,2-dichlorobenzene 

(GO) 
2062

500

500

2087

300

2072

200

2008

376

376

376376

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

13 Mouse 14 d Hepatic 500 (hepatocellular necrosis NTP 1985 7 d/wk (B6C3F1) 1 x/d and degeneration) 1,2-dichlorobenzene 

(GO) 

Bd Wt 500 

Immuno/ Lymphoret 

14 Rat 10 d 300 Robinson et al. 1991 7 d/wk (Sprague- 1 x/d 1,2-dichlorobenzene Dawley)

(GO)

Developmental 

15 Rat 10 d 200 F Ruddick et al. 1983 Gd 6-15 (Sprague- 1,2-dichlorobenzene Dawley) (G) 

INTERMEDIATE EXPOSURE Systemic 

16 Rat 192 d Hemato 376 F Hollingsworth et al. 1958 5 d/wk (NS) 1,2-dichlorobenzene 

Hepatic 376 F (slight to moderate

cloudy swelling)

Renal 376 F Bd Wt 376 F 
2033

50050050050050060 125250500

500

500500500250500

500

2083

455

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

17 Rat 13 wk Resp 500 5 d/wk (Fischer- 344) 1 x/d 

(GO) 

Cardio 500 Gastro 500 Hemato 500 Musc/skel 500 

d

Hepatic 60 125 (increased liver weight) 

b

Renal 250 M 500 M (renal tubular 

degeneration)

500 F 

Endocr 500 Dermal 500 Ocular 500 

b

Bd Wt 250 M 500 M 

500 F 

18 Rat 15 d Hepatic 455 M (necrosis and fatty 1 x/d (albino) changes, porphyria) (G) 

Reference Chemical Form Comments 

NTP 1985 1,2-dichlorobenzene Rimington and Ziegler 1963 1,2-dichlorobenzene 
2005

400400

400

400400

400

19 

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Rat 90 d Resp 400 M Robinson et al. 1991 7 d/wk (Sprague- 1 x/d 1,2-dichlorobenzene Dawley)

(GO)

Cardio 400 Hepatic 400 (centrilobular

degeneration, single cellnecrosis)

Renal 400 Endocr 400 M Bd Wt 400 M (12.8% decreased body

weight gain)
2040

500250

500

500500250

500

125250

250500

500500500500500

500

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

20 Mouse 13 wk Resp 500 NTP 1985 5 d/wk (B6C3F1) 1 x/d 1,2-dichlorobenzene 

(GO) 

Cardio 250 500 (mineralization of

myocardial fibers)

Gastro 500 Hemato 500 Musc/skel 250 500 (mineralization of

myocardial and skeletalmuscle fibers)

b b

Hepatic 125 M 250 M (single cell necrosis,

hepatocellular

250 F degeneration)

500 F 

Renal 500 Endocr 500 Dermal 500 Ocular 500 Bd Wt 500 500 (11-19% reduced body

weight gain)
2036

250

500

2028

400

2042

500

2037

500

2084

455

2029

400

2043

500

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Immuno/ Lymphoret 

21 Rat 13 wk 250 M 500 M (lymphoid depletion in NTP 1985 5 d/wk (Fischer- 344) 1 x/d thymus) 1,2-dichlorobenzene 

(GO) 

22 Rat 90 d 400 Robinson et al. 1991 7 d/wk (Sprague- 1 x/d 1,2-dichlorobenzene Dawley)

(GO)

23 Mouse 13 wk 500 NTP 1985 5 d/wk (B6C3F1) 1 x/d 1,2-dichlorobenzene 

(GO) 

Neurological 

24 Rat 13 wk 500 NTP 1985 5 d/wk (Fischer- 344) 1 x/d 1,2-dichlorobenzene 

(GO) 

25 Rat 15 d 455 M (ataxia, clonic Rimington and Ziegler 1963 1 x/d (albino) contractions) 1,2-dichlorobenzene (G) 

26 Rat 90 d 400 Robinson et al. 1991 7 d/wk (Sprague- 1 x/d 1,2-dichlorobenzene Dawley)

(GO)

27 Mouse 13 wk 500 NTP 1985 5 d/wk (B6C3F1) 1 x/d 1,2-dichlorobenzene 

(GO) 
2038

500

2044

500

2046

120120120120120120120120120120

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

Reproductive 

28 Rat 13 wk 

5 d/wk (Fischer- 344) 1 x/d (GO) 

29 Mouse 13 wk 

5 d/wk (B6C3F1) 1 x/d (GO) 

CHRONIC EXPOSURE Systemic 

30 Rat 103 wk 

5 d/wk (Fischer- 344) 1 x/d (GO) 

System 

Resp Cardio Gastro Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

500 NTP 1985

1,2-dichlorobenzene

500 NTP 1985

1,2-dichlorobenzene

120 NTP 1985

1,2-dichlorobenzene

120

120120

120120

120

120

120120
2052

12012012012012060

120

120120120120

2047

120

2053

120

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

31 Mouse 103 wk 

5 d/wk (B6C3F1) 1 x/d (GO) 

Immuno/ Lymphoret 

32 Rat 103 wk 

5 d/wk (Fischer- 344) 1 x/d (GO) 

33 Mouse 103 wk 

5 d/wk (B6C3F1) 1 x/d (GO) 

System 

Resp Cardio Gastro Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

120 NTP 1985

1,2-dichlorobenzene

120

120120

120

e

60 120 (renal tubular

regeneration)

120

120

120120120 NTP 1985

1,2-dichlorobenzene

120 NTP 1985

1,2-dichlorobenzene
2048

120

2054

120

2049

120

Table 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Neurological 

34 Rat 103 wk 120 NTP 1985 5 d/wk (Fischer- 344) 1 x/d 1,2-dichlorobenzene 

(GO) 

35 Mouse 103 wk 120 NTP 1985 5 d/wk (B6C3F1) 1 x/d 1,2-dichlorobenzene 

(GO) 

Reproductive 

36 Rat 103 wk 120 NTP 1985 5 d/wk (Fischer- 344) 1 x/d 1,2-dichlorobenzene 

(GO) 

a The number corresponds to entries in Figure 3-3. b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-3. Where such differences exist, only the levels of effect for the most sensitive gender are presented. c Study result used to derive an acute-duration oral Minimal Risk Level (MRL) of 0.7 mg/kg/day for 1,2-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on liver weight data to select a point of departure, which was divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). d Study result used to derive an intermediate-duration oral Minimal Risk Level (MRL) of 0.6 mg/kg/day for 1,2-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on liver weight data to select a point of departure, which was adjusted for daily exposure, then divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). e Study result used to derive a chronic-duration oral Minimal Risk Level (MRL) of 0.3 mg/kg/day for 1,2-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on incidences of kidney lesions to select a point of departure, which was adjusted for daily exposure, then divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). 

ALT = alamine aminotransferase; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = 

gestational day; Gn pig = guinea pig; (GO) = gavage in oil; Hemato = hematological; hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; occup = occupational; Resp = respiratory; x = time(s) 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Body Weight 

10000 

Figure 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral
	

Acute (≤14 days)
	

Systemic 

mg/kg/day 

7g 

2r 4r 8r 8r 

1000 5r 10r 10r 

3r 9r 

1r 13m 13m 10r 

11r 11r 11r 11r 11r 11r 11r 11r 11r 1

6m 12m 

11r 11r 11r 

100 

11r 

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
Respiratory 

Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic 

Figure 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (Continued

Intermediate (15-364 days)
	

Systemic 

mg/kg/day 

1000
	

20m
	 17r 20m 17r 20m 17r 20m 17r 20m 17r 20

18r 19r 19r 19r 

16r 16r 16

20m 20m 20m 17

20m 17r 

100
	

17r
	

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

0.1 
Body Weight 

Immuno/Lymphor Neurological Endocrine Dermal Ocular 

1000 

Figure 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (Continued

Intermediate (15-364 days)
	

Systemic
	

mg/kg/day 

20m 17r 20m 17r 20m 17r 20m 20m 17r 23m 21r 27m 24r 29m 

25r 19r 19r 22r 26r 16r 

17r 21r 

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
Respiratory 

Cardiovascular Gastrointestinal Musculoskeletal Hepatic Renal Endocrine Dermal Ocular 

Figure 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (Continued

Chronic (≥365 days)
	

Systemic

mg/kg/day 

1000 

31m 30r 31m 30r 31m 30r 31m 30r 31m 30r 31m 30r 31m 30r 31m 30r 31m 30r 

100 

31m 

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

0.1 
Immuno/Lymphor 

Neurological Reproductive 

Figure 3-3 Levels of Significant Exposure to 1,2-dichlorobenzene - Oral (Continued

Chronic (≥365 days)
	

mg/kg/day 

1000 

33m 32r 35m 34r 36r 

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
2091

12001000

2067

73573573573537147

368147

735735735368

735

2069

735

2068

735

Table 3-4 Levels of Significant Exposure to 1,3-dichlorobenzene - Oral 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

ACUTE EXPOSURE Death 

1 Rat once 

(Sprague- (G) Dawley) 

Systemic 

2 Rat 10 d 

7 d/wk (SpragueDawley) (GO)

Immuno/ Lymphoret 

3 Rat 10 d 

7 d/wk (SpragueDawley) (GO)

Neurological 

4 Rat 10 d 

7 d/wk (SpragueDawley) (GO)

System 

Resp Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

1200 M (14-day LD50) Monsanto 1980 

b 1,3-dichlorobenzene 1000 F (14-day LD50) 

735 McCauley et al. 1995

1,3-dichlorobenzene

735735735

c

37 M 368 (increased liver weight,

cytoplasmic

147 F vacuolization)

147 (increased liver weight)

735

735

735

368 735 (reduced body weight

gain)

735 McCauley et al. 1995

1,3-dichlorobenzene

735 McCauley et al. 1995

1,3-dichlorobenzene
2070

735

2073

200

Table 3-4 Levels of Significant Exposure to 1,3-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Reproductive 

5 Rat 10 d 735 McCauley et al. 1995 7 d/wk (Sprague- 1,3-dichlorobenzene Dawley) (GO) 

Developmental 

6 Rat 10 d 200 F Ruddick et al. 1983 Gd 6-15 (Sprague- 1,3-dichlorobenzene Dawley) (G) 
2063

58858837147

147588

588

937

5889

914737

588147

588

Table 3-4 Levels of Significant Exposure to 1,3-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

INTERMEDIATE EXPOSURE Systemic 

7 Rat 90 d Resp 588 McCauley et al. 1995 7 d/wk (Sprague- 1,3-dichlorobenzene Dawley) (GO) 

Gastro 588 

b b

Hemato 37 M 147 M (increased leukocyte

levels)

147 F

588 F (increased leukocyte 

levels) 

Musc/skel 588 

b

Hepatic 9 M (increased serum AST

and cholesterol levels)

37 F (increased serum AST 

and cholesterol levels) 

Renal 588 Endocr 9 F 9 M (reduced colloidal density

in thyroid follicles)

d

147 M (increased cytoplasmic 

vacuolization in pituitary pars distalis) 

37 F (reduced colloidal density 

in thyroid follicles) 

Dermal 588 Bd Wt 147 588 (body weight gain was

reduced 24% in malesand 10% in females)
2065

588

2064

588

Table 3-4 Levels of Significant Exposure to 1,3-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Immuno/ Lymphoret 

8 Rat 90 d 588 McCauley et al. 1995 7 d/wk (Sprague- 1,3-dichlorobenzene Dawley) (GO) 

Neurological 

9 Rat 90 d 588 McCauley et al. 1995 7 d/wk (Sprague- 1,3-dichlorobenzene Dawley) (GO) 

a The number corresponds to entries in Figure 3-4 b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-4. Where such differences exist, only the levels of effect for the most sensitive gender are presented. c Study result used to derive an acute-duration oral Minimal Risk Level (MRL) of 0.4 mg/kg/day for 1,3-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on liver weight data to select a point of departure, which was divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). d Study result used to derive an intermediate-duration oral Minimal Risk Level (MRL) of 0.02 mg/kg/day for 1,3-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on incidences of pituitary lesions to select a point of departure, which was divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). 

AST = aspartate aminotransferase; Bd Wt = body weight; d = day(s); Endocr = endocrine; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = gestational day; Gn pig = guinea 

pig; (GO) = gavage in oil; Hemato = hematological; hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; occup = occupational; ppm = parts per million; Resp = respiratory; wk = week(s) 
Death 

Respiratory Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Body Weight Immuno/Lymphor Neurological Reprodu

Figure 3-4 Levels of Significant Exposure to 1,3-dichlorobenzene - Oral
	

Acute (≤14 days)
	

Systemic 

mg/kg/day 

10000 

1000 1r 

2r 2r 2r 2r 2r 2r 2r 2r 3r 4r 5r 

2r 2r 

2r 2r 

100 

2r 

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
Respiratory 

Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Body Weight Immuno/Ly

Figure 3-4 Levels of Significant Exposure to 1,3-dichlorobenzene - Oral (Continued

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

1000 

7r 7r 7r 7r 7r 7r 8r 

7r 7r 7r 

100 

7r 7r 

10 7r 7r 7r 

1 

0.1 

0.01 

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
44

38633790

2135

4000

47

20001000

51

4000

52

2800

136

2790

95 475

54

250250

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral 

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

ACUTE EXPOSURE Death 

1 Rat once 3863 M (LD50) (Sherman) (GO) b

3790 F (LD50) 

2 Rat once 4000 (LD100) (NS) (GO) 3 Rat 14 d 2000 M (5/5 males died) 1 x/d (Fischer- 344) 

(GO) 1000 bF (4/5 females died) 

4 Mouse 14 d 4000 (10/10 deaths by day 4) 1 x/d (B6C3F1)

(GO)

5 Gn Pig once 2800 (LD100) (NS) (GO) 

Systemic 

6 Rat once Hemato 2790 M

(Fischer- 344) (GO) 

Hepatic 95 M (decreased relative liver 475 M (centrilobular vacuolar 

weight) degeneration) 

7 Rat 3 d Hepatic 250 F 1 x/d (Wistar) 

(G)

Bd Wt 250 F

Reference Chemical Form Comments 

Gaines and Linder 1986 1,4-dichlorobenzene Hollingsworth et al. 1956 1,4-dichlorobenzene NTP 1987 1,4-dichlorobenzene NTP 1987 1,4-dichlorobenzene Hollingsworth et al. 1956 1,4-dichlorobenzene 

Allis et al. 1992 1,4-dichlorobenzene Ariyoshi et al. 1975 1,4-dichlorobenzene 
510

10

20

57

300

650

58

650

511

500

500

59

120

169

600

600

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Rat 14 d 8 Hepatic 10 M 20 M (increase in glucuronyl Carlson and Tardiff 1976 1 x/d (albino) transferase and EPN 1,4-dichlorobenzene (GO) detoxification activities) 

9 Rat 14 d Hepatic 300 M 650 M (increased serum Carlson and Tardiff 1976 1 x/d (albino) isocitrate 1,4-dichlorobenzene (GO) dehydrogenase) 

10 Rat 14 d Hepatic 650 M (decreased hexobarbital Carlson and Tardiff 1976 1 x/d (albino) sleeping time; increased 1,4-dichlorobenzene (GO) serum isocitrate 

dehydrogenase) 

11 Rat once Renal 500 F 500 M (protein droplet Charbonneau et al. 1987 (Fischer- 344) (GO) formation) 1,4-dichlorobenzene 

12 Rat 7 d Renal 120 M (protein droplet Charbonneau et al. 1987 1 x/d (Fischer- 344) formation) 1,4-dichlorobenzene (GO) 

13 Rat once Hepatic 600 F (increased liver weight) Eldridge et al. 1992 (Fischer- 344) (GO) 1,4-dichlorobenzene 

Bd Wt 600 F 
171

600

1

25

75

300150

300

60

5001000

1000

61

500

1000

513

850

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

14 Rat once Hepatic 600 F (centrilobular hepatocyte Eldridge et al. 1992 (Fischer- 344) (GO) vacuolation) 1,4-dichlorobenzene 

15 Rat 1 wk Hepatic 25 M 75 M (increased microsomal Lake et al. 1997 5 d/wk (Fischer- 344) 1 x/d 7-pentaoxyresorufin O - 1,4-dichlorobenzene depentylase activity) (GO) 

Renal 300 M Bd Wt 150 M 300 M (approximately 10%

decreased body weightgain)

16 Rat 14 d b Bd Wt 500 M 1000 M (7-12% decrease in final NTP 1987 1 x/d (Fischer- 344) body weight) (GO) 1000 F 

17 Rat 14 d Bd Wt 500 1000 (13.5% reduction in final NTP 1987 1 x/d (Fischer- 344) body weight in males, 1,4-dichlorobenzene (GO) 16.7% in females) 

Rat 5 d 18 Hepatic 850 M (porphyria; degeneration Rimington and Ziegler 1963 1 x/d (albino) of hepatocytes; focal 1,4-dichlorobenzene (G) necrosis) 
62

770

770

770

168

600

600

170

600

2

300

600600

64

1000

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

19 Rat 5 d Hepatic 770 M (porphyria; degeneration Rimington and Ziegler 1963 1 x/d (albino) of hepatocytes; focal 1,4-dichlorobenzene (G) necrosis) 

Bd Wt 770 MOther 770 M (loss of appetite)

20 Mouse once Hepatic 600 (increased liver weight) Eldridge et al. 1992 (B6C3F1) (GO) 1,4-dichlorobenzene 

Bd Wt 600 

21 Mouse once Hepatic 600 (centrilobular hepatocyte Eldridge et al. 1992 (B6C3F1) (GO) vacuolation) 1,4-dichlorobenzene 

22 Mouse 1 wk Hepatic 300 M (increased relative liver Lake et al. 1997 5 d/wk (B6C3F1) 1 x/d weight) 1,4-dichlorobenzene 

(GO) 

Renal 600 MBd Wt 600 M

23 Mouse 14 d Bd Wt 1000 NTP 1987 1 x/d (B6C3F1) 1,4-dichlorobenzene (GO) 
65

250

175

300

600

204

1000

1800

205

1800

514

770

518

1000

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

24 Mouse 

(B6C3F1) 

25 Mouse 

(B6C3F1) 

26 Mouse 

(B6C3F1) 

27 Mouse 

(B6C3F1) 

Neurological 

28 Rat 

(albino) 

Reproductive 

29 Rat 

(CD) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

14 d Bd Wt 250 M (13.3% reduction in final NTP 1987 1 x/d body weight) 1,4-dichlorobenzene (GO) 

4 d Hepatic 300 (increased liver weight Umemura et al. 1992 1 x/d and hepatocyte 1,4-dichlorobenzene (GO) proliferation) 

Renal 600 

once Hepatic 1000 M 1800 M (increased ALT activity; Umemura et al. 1996 

severe centrilobular 1,4-dichlorobenzene hepatocyte swelling) 

once Hepatic 1800 M (increased ALT activity; Umemura et al. 1996 

increased BrdU labeling) 1,4-dichlorobenzene 

5 d 770 M (clonic contractions; Rimington and Ziegler 1963 1 x/d slight tremors; 1,4-dichlorobenzene (G) hemiparesis) 10 d 1000 F Giavini et al. 1986 Gd 6-15

1 x/d 1,4-dichlorobenzene(GO) 
66

250

500

67

12001500

69

1500

74

200

173

600

600

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Developmental 

Rat 10 d 30 (CD) 

250 F 500 F (increased incidence of Giavini et al. 1986 Gd 6-15 fetuses with an extra rib) 1,4-dichlorobenzene 1 x/d 

(GO) 

INTERMEDIATE EXPOSURE Death 

31 Rat 13 wk b 1200 M (5/10 died) NTP 1987 5 d/wk (Fischer- 344) 1,4-dichlorobenzene (GO) 1500 F (9/10 died) 

32 Mouse 13 wk 1500 (3/10 males and 5/10 NTP 1987 5 d/wk (B6C3F1) females died) 1,4-dichlorobenzene (GO) 

Systemic 

33 Rat 30-120 d Hepatic 200 F Carlson 1977 1 x/d (NS) 1,4-dichlorobenzene (GO) 

34 Rat 13 wk Hepatic 600 F (increased liver weight; Eldridge et al. 1992 5 d/wk (Fischer- 344) hypertrophic centrilobular 1,4-dichlorobenzene (GO) hepatocytes) 

Bd Wt 600 F 
76

188

188 376188

376

3

25

75

75

150

75

150

2134

2

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

35 Rat 192 d Hemato 188 F Hollingsworth et al. 1956 5 d/wk (NS) 1,4-dichlorobenzene (GO) 

Hepatic 188 F (slight increase in liver 376 F (slight cirrhosis, focal 

weight; not quantified) necrosis) 

Renal 188 F (slight increase in kidney

weight; not quantified)

Ocular 376 F 

36 Rat 4 or 13 wk Hepatic 25 M 75 M (increased relative liver Lake et al. 1997 5 d/wk (Fischer- 344) 1 x/d weight, induction of 1,4-dichlorobenzene microsomal P450 and (GO) 7-pentoxyresorufin 

O-depentylase activity) 

Renal 75 M 150 M (increased relative kidney

weight)

Bd Wt 75 M 150 M (approximately 10%

decreased body weightgain)

37 Rat 42 d Bd Wt 2 F Makita et al. 2004, 2005 Gd 1- pnd 21 (Wistar) 1,4-dichlorobenzene (F) 
88

600600600600600300600

600

600600600600

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

38 Rat 13 wk Resp 600 NTP 1987 5 d/wk (Fischer- 344) 1,4-dichlorobenzene (GO) 

Cardio 600Gastro 600Musc/skel 600Hepatic 600

b

Renal 300 M 600 M (tubular degeneration)

600 F

Endocr 600 Dermal 600 Ocular 600 Bd Wt 600 
89

900

1200

1500900

1200

300

300600

1500300900

600 1200

1500

300

150015009001200

12001500

900

3001200

39 

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Rat 13 wk Resp 900 1200 (epithelial necrosis of NTP 1987 5 d/wk (Fischer- 344) nasal turbinates) 1,4-dichlorobenzene (GO) 

Cardio 1500 Gastro 900 1200 (epithelial necrosis of 

small intestine mucosa) 

b

Hemato 300 F 300 M (slight decreases in RBC,

HCT, and hemoglobinconcentration)

600 F (decrease in mean 

corpuscular volume) 

Musc/skel 1500 

b

Hepatic 300 M 600 M (significant increase in 1200 (degeneration and 

serum cholesterol) necrosis of hepatocytes)

900 F 

Renal 1500 F 300 M (necrosis of renal cortical 

tubular epithelium) 

Endocr 1500 Dermal 1500 

b b

Ocular 900 M 1200 M (ocular discharge) 

1200 F 1500 F (ocular discharge) 

b

Bd Wt 900 F 300 M (11% decrease in final

body weight)

1200 F (11% decrease in final 

body weight) 
172

300

600

600

4

300

600600

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

40 Mouse 13 wk Hepatic 300 600 (increased liver weight; Eldridge et al. 1992 5 d/wk (B6C3F1) hypertrophic centrilobular 1,4-dichlorobenzene (GO) hepatocytes) 

Bd Wt 600 

41 Mouse 4 or 13 wk Hepatic 300 M (increased relative liver Lake et al. 1997 5 d/wk (B6C3F1) 1 x/d weight; induction of 1,4-dichlorobenzene microsomal (GO) 7-pentoxyresorufin 

O-depentylase activity) 

Renal 600 M Bd Wt 600 M 
90

1800180018001800

600

1800

600

1800180018001800

600

42 

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/

Duration/

a Frequency Key to Species (Route) Figure (Strain) System 

Mouse 13 wk Resp 5 d/wk (B6C3F1)

(GO)

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

1800 NTP 1987

1,4-dichlorobenzene

1800

18001800 F 600 M (34% reduced WBC

count)

1800 

600 (hepatocellular

degeneration in 7/10males and 9/10 females)

1800180018001800

600 (final body weight

reduced 13.9% in malesand 10.3% in females)
91

900900900900900338

675

900900900900900

2138

7510

50

75

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

43 Mouse 13 wk 

5 d/wk (B6C3F1) (GO) 

44 Dog 6 mo 

5 d/wk 1 x/d (C) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt Hemato Hepatic Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

900 NTP 1987

1,4-dichlorobenzene

900

900900900

338 675 (moderate

hepatocytomegaly inmales and females)

900

900

900

900900

75 Naylor and Stout 1996

1,4-dichlorobenzene

c

10 50 (increased serum

alkaline phosphatase)

75 
79

10001000

92

900

1200

93

1000

1500

94

9001200

12001500

80

1000

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

45 Rabbit 219 d Hepatic 1000 (cloudy swelling, very few Hollingsworth et al. 1956 92 doses (NS) areas of focal necrosis) 1,4-dichlorobenzene (GO) 

Bd Wt 1000 (weight loss, not

quantified)

Immuno/ Lymphoret 

46 Rat 13 wk 900 1200 (lymphoid depletion of NTP 1987 5 d/wk (Fischer- 344) thymus and spleen) 1,4-dichlorobenzene (GO) 47 Mouse 13 wk 1000 1500 (lymphoid necrosis in NTP 1987 5 d/wk (B6C3F1) thymus; lymphoid 1,4-dichlorobenzene (GO) depletion in the spleen; 

hematopoietic hypoplasia in spleen and bone marrow) 

Neurological 

48 Rat 13 wk b b 900 M 1200 M (tremors, poor motor NTP 1987 5 d/wk (Fischer- 344) response) 1,4-dichlorobenzene (GO) 1200 F 

1500 F (tremors, poor motor 

response) 

49 Rabbit 219 d 1000 (marked tremors) Hollingsworth et al. 1956 92 doses (NS) 1,4-dichlorobenzene (GO) 
2074

270

2130

2

96

1500

97

18001000

1500

2075

30

90

2133

2

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Reproductive 

50 Rat 77-156 d 270 Bornatowicz et al. 1994 7 d/wk (Sprague- premating- 1,4-dichlorobenzene Dawley) lactation,

two generations(GO)

51 Rat 42 d 2 F Makita et al. 2004, 2005 Gd 1- pnd 21 (Wistar) 1,4-dichlorobenzene (F) 

52 Rat 13 wk 1500 NTP 1987 5 d/wk (Fischer- 344) 1,4-dichlorobenzene (GO)

Mouse 13 wk 53 1800 M 1500 F (increase in relative NTP 1987 5 d/wk (B6C3F1) ovary weight) b 1,4-dichlorobenzene (GO) 1000 F 

Developmental 

54 Rat 77-156 d 30 F 90 F (increased Bornatowicz et al. 1994 7 d/wk (Sprague- postnatal/preweaning premating- 1,4-dichlorobenzene Dawley) mortality in F1 and F2 lactation, 

two pups)generations(GO)

55 Rat 42 d 2 Makita et al. 2004, 2005 Gd 1- pnd 21 (Wistar) 1,4-dichlorobenzene (F) 
81

300

2105

150

2071

500

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

CHRONIC EXPOSURE Death 

56 Rat 2 yr 300 M (26/50 deaths) NTP 1987 5 d/wk (Fischer- 344) 1,4-dichlorobenzene (GO) 

57 Dog 3 wk 150 (3/6 deaths) Naylor and Stout 1996 5 d/wk 

1 x/d 1,4-dichlorobenzene (C) 

58 Rabbit 367 d 500 (some deaths; not Hollingsworth et al. 1956 5 d/wk (NS) quantified) 1,4-dichlorobenzene (GO) 
98

300600300600300600300600300600300600

150

600 150300600300600150300

300600

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/

Duration/

a Frequency Key to Species (Route) Figure (Strain) System 

Systemic 

59 Rat 2 yr Resp 5 d/wk (Fischer- 344)

(GO)

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

b

300 M NTP 1987 

1,4-dichlorobenzene 600 F 

b

300 M 600 F 

b

300 M 600 F 

b

300 M 600 F 

b

300 M 600 F 

b

300 M 600 F 

150 M (moderate nephropathy) 

600 F 150 M (parathyroid hyperplasia) 

b

300 M 600 F 

b

300 M 600 F 

b b

150 M 300 M (12.5% decrease in body

weight gain)

300 F

600 F (12.4% decrease in body

weight gain)
99

600600600600600

300

300

600

300

600600600

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/

Duration/

a Frequency Key to Species (Route) Figure (Strain) System 

60 Mouse 2 yr Resp 5 d/wk (B6C3F1)

(GO)

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

600 NTP 1987 

1,4-dichlorobenzene 

600 

600 600 600 

300 (hepatocellular

degeneration, hepatocyteswelling and vacuolation)

300 (nephropathy, 

degeneration of cortical tubular epithelium) 

600 F 300 M (follicular cell hyperplasia

in thyroid; adrenalmedullary hyperplasia;focal hyperplasia ofadrenal gland capsule)

600 

600 600 
2106

75757550

75

7510

50

10

50

75757575

61 

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/

Duration/

a Frequency Key to Species (Route) Figure (Strain) System 

Dog 1 yr Resp 5 d/wk 

1 x/d (C) 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

Reference NOAEL Less Serious Serious 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

75 Naylor and Stout 1996 

1,4-dichlorobenzene 

75 

75 

50 75 (significantly reduced

RBC in females andHCT)

75 

d

10 50 (increases in serum

alkaline phosphatase andliver weight,hepatocellularhypertrophy)

10 50 (suggestive collecting

duct epithelialvacuolation)

75 75 75 

75 
84

500500

100

600

103

300

2107

75

101

600

104

600

85

500

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

62 Rabbit 367 d Hepatic 500 (cloudy swelling, some Hollingsworth et al. 1956 5 d/wk (NS) areas of focal necrosis) 1,4-dichlorobenzene (GO) 

Bd Wt 500 (weight loss, not

quantified)

Immuno/ Lymphoret 

63 Rat 2 yr 600 NTP 1987 5 d/wk (Fischer- 344) 1,4-dichlorobenzene (GO)

Mouse 2 yr 64 300 (lymphoid hyperplasia of NTP 1987 5 d/wk (B6C3F1) lymph nodes) 1,4-dichlorobenzene (GO) 

65 Dog 1 yr 75 Naylor and Stout 1996 5 d/wk 

1 x/d 1,4-dichlorobenzene (C) 

Neurological 

66 Rat 2 yr 600 NTP 1987 5 d/wk (Fischer- 344) 1,4-dichlorobenzene (GO) 

67 Mouse 2 yr 600 NTP 1987 5 d/wk (B6C3F1) 1,4-dichlorobenzene (GO) 

68 Rabbit 367 d 500 (marked tremors) Hollingsworth et al. 1956 5 d/wk (NS) 1,4-dichlorobenzene (GO) 
102

600

105

600

106

300

107

600

Table 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments 

Reproductive 

69 Rat 2 yr 600 NTP 1987 5 d/wk (Fischer- 344) 1,4-dichlorobenzene (GO) 

70 Mouse 2 yr 600 NTP 1987 5 d/wk (B6C3F1) 1,4-dichlorobenzene (GO) 

Cancer 

71 Rat 2 yr 300 M (CEL: renal tubular cell NTP 1987 5 d/wk (Fischer- 344) adenoma and 1,4-dichlorobenzene (GO) adenocarcinoma) 

72 Mouse 2 yr 600 (CEL: hepatocellular NTP 1987 5 d/wk (B6C3F1) adenoma and carcinoma) 1,4-dichlorobenzene (GO) 

a The number corresponds to entries in Figure 3-5 b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-5. Where such differences exist, only the levels of effect for the most sensitive gender are presented. c Study result used to derive an intermediate-duration oral minimal risk level (MRL) of 0.07 mg/kg/day for 1,4-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on serum alkaline phosphatase levels to select a point of departure, which was duration adjusted, then divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). d Study result used to derive a chronic-duration oral minimal risk level (MRL) of 0.07 mg/kg/day for 1,4-DCB, as described in detail in Appendix A. Benchmark dose analysis was performed on incidences of serum alkaline phosphatase levels to select a point of departure, which was duration adjusted, then divided by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). 

ALT = alamine aminotransferase; Bd Wt = body weight; BrdU = Bromodeoxyuridine; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = 

endocrine; EPN = O-ethyl O-p-nitrophenyl phenylphosphonothioate; (F) = feed; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = gestational day; Gn pig = guinea pig; (GO) = gavage in oil; HCT = hematocrit; Hemato = hematological; hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LD100 = lethal dose, 100% kill; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; occup = occupational; pnd = post-natal day; RBC = red blood cell; Resp = respiratory; x = time(s); WBC = white blood cell; wk = week(s); yr = year(s) 
Death 

Hematological Hepatic Renal Body 

Figure 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral 

Acute (≤14 days) 

Systemic 

mg/kg/day 

10000 

4m 2r 1r
	

5g
	 6r
	

26m
	 27m 

1000 3r 26m 23m 1

18r

19r 

9r 10r 20m 21m 13r 14r 22m 25m 20m 22m 1

11r 11r 1

6r
	

22m
	 25m 9r 15r 1

7r 24m 7

1

12r 

100 6r 

15r 

15r 

8r 

10 8r 

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
Reproductive 

Developmental Neurological 

Figure 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (Continued

Acute (≤14 days)
	

mg/kg/day 

10000 

1000 29r 

28r 

30r 

30r 

100 

10 

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
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic 

Figure 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (Continued

Intermediate (15-364 days)
	

Systemic 

mg/kg/day 

10000 

42m 42m 42m 42m 42m 

32m 39r 39r 

31r 39r 39r 39r 1000 45h 43m 39r 43m 43m 39r 43m 43m 

43m 38r 38r 38r 42m 38r 40m 42m 34r 38r 39r 

35r 43m 39r 39r 40m 41m 39r 

33r 35r 35r 

100 

44d 36r 

44d 

36r 

10 44d 

1 

0.1 

0.01 

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
Endocrine 

Dermal Ocular Body Weight Immuno/Lymphor Neurological Reprodu

10000 

Figure 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (Continued

Intermediate (15-364 days) 

Systemic
	

mg/kg/day 

42m 42m 42m 39r 39r 47m 53m 52r 39r 46r 48r 1000 45h 47m 49h 53m 43m 43m 43m 39r 43m 39r 46r 48r 

38r 38r 38r 40m 41m 42m 34r 38r 

35r 39r 50r 

36r 

100 

44d 36r 

10 

37r 51r 

1 

0.1 

0.01 

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
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocula

Figure 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (Continued

Chronic (≥365 days) 

Systemic 

mg/kg/day 

1000 

60m 60m 60m 60m 60m 60m 59r 60m 60m 

58h 62h 

56r 59r 59r 59r 59r 59r 60m 59r 60m 60m 59r 59r 

57d 59r 59r 

100 

61d 61d 61d 61d 61d 61d 61d 61d 

61d 61d 61d 

10 61d 61d 

1 

0.1 

0.01 

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
Immuno/Lymphor 

Neurological Reproductive Cancer * 

 

 

Figure 3-5 Levels of Significant Exposure to 1,4-dichlorobenzene - Oral (Continued

Chronic (≥365 days)
	

mg/kg/day 

1000 

63r 67m 66r 70m 69r 72m 68h 

64m 71r 

100
	

65d
	

10 

1 

0.1 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

response and do not imply the existence of a threshold for the cancer endpoint. 

0.01 

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
DICHLOROBENZENES 151 

3. HEALTH EFFECTS 

Acute oral LD50 values of 1,200 and 1,000 mg/kg were determined in male and female Sprague-Dawley 

rats, respectively, administered a single dose of 1,3-DCB by gavage and observed for the following 

14 days (Monsanto 1980). 

No mortality or overt signs of toxicity occurred in male or female Sprague-Dawley rats that were exposed 

to 1,3-DCB in corn oil by gavage in doses as high as 735 mg/kg/day for 10 consecutive days, or 

588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). 

1,4-Dichlorobenzene. No studies were located regarding death in humans after oral exposure to 

1,4-DCB. 

Animal mortality data for 1,4-DCB are available from acute-, intermediate-, and chronic-duration studies. 

In acute-duration animal studies, a single dose by gavage in olive oil of 1,000 mg/kg to rats and 

1,600 mg/kg to guinea pigs resulted in no deaths, while a single dose of 4,000 mg/kg to rats and 

2,800 mg/kg to guinea pigs resulted in 100% mortality (Hollingsworth et al. 1956). Similar results were 

seen in groups of adult male albino rats administered various doses of 1,4-DCB in corn oil once daily for 

14 days; administration of 1,4-DCB at doses up to 600 mg/kg did not result in any deaths (Carlson and 

Tardiff 1976). Oral LD50 (lethal dose, 50% kill) values for adult Sherman rats administered 1,4-DCB in 

peanut oil were calculated to be 3,863 and 3,790 mg/kg for males and females, respectively (Gaines and 

Linder 1986). In contrast, groups of male F344 rats (n=1/group) were administered 13–27,900 mg/kg 

body weight in corn oil via gavage. Twenty-four hours after dosing, the animals were weighed and 

exsanguinated. No mortality among the 1,4-DCB-treated rats was observed (Allis et al. 1992). 

In one series of studies (NTP 1987), the lethality data for 1,4-DCB, when administered for 14 days by 

gavage in corn oil to F344 rats and B6C3F1 mice, were rather inconsistent. In one of these studies, no 

1,4-DCB-related deaths occurred in rats of either sex that received doses up to 1,000 mg/kg/day; however, 

in the second rat study, four of five females (80%) at 1,000 mg/kg/day died, and all rats dosed at 

>2,000 mg/kg/day died. In one 14-day study in mice, no 1,4-DCB-related deaths occurred in either sex at 

levels up to 1,000 mg/kg/day; however, in a second 14-day mouse study, 70% of mice at 1,000 mg/kg/day 

died, and all mice that received 4,000 mg/kg/day died within 4 days. At 1,200 mg/kg/day, 5 of 10 male 

and 1 of 10 female rats died. No deaths occurred at 600 mg/kg/day. 

In 13-week gavage studies, 17 of 20 rats (8 of 10 males and 9 of 10 females) dosed with 1,4-DCB in corn 

oil 5 days/week at 1,500 mg/kg/day died. When dosed in like manner with 1,200 mg/kg/day, 5 of 
DICHLOROBENZENES 152 

3. HEALTH EFFECTS 

10 male and 1 of 10 female rats died. No deaths occurred at doses of ≤600 mg/kg/day (NTP 1987). 

Mortality rates in mice were somewhat lower; 8 of 20 (3 of 10 males and 5 of 10 females) animals dosed 

with 1,500 mg/kg/day 1,4-DCB in corn oil 5 days/week died. No deaths occurred in males or females at 

doses up to 900 and 1,000 mg/kg/day, respectively (NTP 1987). 

High mortality was reported in male rats that received 1,4-DCB 5 days/week by gavage in corn oil in a 

2-year study (NTP 1987). At 300 mg/kg/day, 26 of 50 males (52%) died; however, survival of female 

rats at 600 mg/kg/day was comparable to controls. There was no excess mortality in mice of either sex 

that received 1,4-DCB 5 days/week by gavage in corn oil for 2 years at levels up to 600 mg/kg/day (NTP 

1987). The high rate of mortality in male rats was probably related, in part, to the severe nephrotoxic 

effects and renal tumors that were reported in these animals and are described in more detail in 

Sections 3.2.2.2 and 3.2.2.7. 

Groups of five male and five female Beagle dogs were administered 1,4-DCB by capsule in dose levels of 

0, 10, 50, or 75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 1996). The 75 mg/kg/day dose is a 

time-weighted average level reflecting decreases from an initial high level of 150 mg/kg/day in response 

to severe toxicity. The main early effect was mortality during the first 25 days of the study; exposure to 

150 mg/kg/day caused one male dog to be sacrificed in extremis on day 12, one male death on day 25, and 

one female death on day 24. With the exception of one control male that died on day 83, all remaining 

dogs survived exposure to 75 mg/kg/day. 

3.2.2.2 Systemic Effects 

Respiratory Effects. 

1,2-Dichlorobenzene. No studies were located regarding respiratory effects in humans after oral 

exposure to 1,2-DCB. 

No gross or histological changes were observed in the respiratory tract (nasal cavity, trachea, lungs, 

and/or bronchi) of Sprague-Dawley or F344 rats that were administered 1,2-DCB in corn oil by gavage in 

doses of 300 mg/kg/day for 10 consecutive days (Robinson et al. 1991), 400 mg/kg/day for 

90 consecutive days (Robinson et al. 1991), ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), or 

≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985). There were no gross or histological effects in 
DICHLOROBENZENES 153 

3. HEALTH EFFECTS 

the respiratory system of B6C3F1 mice that were similarly treated with ≤500 mg/kg/day, 5 days/week for 

13 weeks (NTP 1985), or ≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding respiratory effects in humans after oral 

exposure to 1,3-DCB. 

No gross or histological changes were observed in the respiratory tract (nasal cavity and turbinates, lungs, 

and lower half of trachea) in male or female Sprague-Dawley rats that were exposed to 1,3-DCB in corn 

oil by gavage in doses of 735 mg/kg/day for 10 consecutive days or 588 mg/kg/day for 90 consecutive 

days (McCauley et al. 1995). 

1,4-Dichlorobenzene. No studies were located regarding respiratory effects in humans after oral 

exposure to 1,4-DCB. 

In a series of dose range-finding studies, groups of F344 rats were administered 1,4-DCB at 

concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks 

(NTP 1987). At sacrifice, animals were examined grossly and major tissues were examined 

histologically. No compound-related effects were observed in the lungs at any dose up to 900 mg/kg/day, 

while rats treated with 1,200 mg/kg/day or higher exhibited epithelial necrosis of the nasal turbinates 

(NTP 1987). In parallel studies, B6C3F1 mice were administered 1,4-DCB at concentrations ranging from 

84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks. No compound-related effects 

were observed in the lungs at any dose level (NTP 1987). 

In 2-year exposure studies in F344 rats, no respiratory effects were reported in males or females that 

received 1,4-DCB by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively (NTP 1987). 

In similarly dosed B6C3F1 mice, no respiratory effects were reported in either sex at doses up to 

600 mg/kg/day (NTP 1987). 

Cardiovascular Effects. 

1,2-Dichlorobenzene. No studies were located regarding cardiovascular effects in humans after oral 

exposure to 1,2-DCB. 
 

 

DICHLOROBENZENES 154 

3. HEALTH EFFECTS 

Mutifocal mineralization of the myocardial fibers of the heart (as well as skeletal muscle) was found in 

B6C3F1 mice that were administered 500 mg/kg/day of 1,2-DCB in corn oil by gavage 5 days/week for 

13 weeks (NTP 1985); this effect does not appear to have occurred in controls or lower dose groups 

(≤250 mg/kg/day). No gross or histological changes were observed in the heart of B6C3F1 mice that were 

similarly treated with ≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985), or in Sprague-Dawley or 

F344 rats that were similarly treated with 300 mg/kg/day for 10 consecutive days (Robinson et al. 1991), 

400 mg/kg/day for 90 consecutive days (Robinson et al. 1991), ≤500 mg/kg/day, 5 days/week for 

13 weeks (NTP 1985), or ≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding cardiovascular effects in humans after oral 

exposure to 1,3-DCB. 

No gross or histological changes in the aorta were observed in male or female Sprague-Dawley rats that 

were exposed to 1,3-DCB in corn oil by gavage in doses of 735 mg/kg/day for 10 consecutive days or 

588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). 

1,4-Dichlorobenzene. No studies were located regarding cardiovascular effects in humans after oral 

exposure to 1,4-DCB. 

In a series of dose range-finding studies, groups of F344 rats were administered 1,4-DCB at 

concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks 

(NTP 1987). At sacrifice, animals were examined grossly and major tissues were examined 

histologically. No compound-related cardiovascular effects were observed at any dose level. In parallel 

studies, B6C3F1 mice were administered 1,4-DCB at concentrations ranging from 84.4 to 

1,800 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks. As with the rats, no compound-related 

cardiovascular effects were observed in mice at any of the doses used (NTP 1987). 

In 2-year exposure studies in F344 rats, no cardiovascular effects were reported in males or females that 

received 1,4-DCB by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively (NTP 1987). 

In similarly dosed B6C3F1 mice, no cardiovascular effects were reported in either sex at doses up to 

600 mg/kg/day (NTP 1987). 
 

 

DICHLOROBENZENES 155 

3. HEALTH EFFECTS 

No gross or histological changes were found in the aorta or heart of Beagle dogs (5/sex/level) that were 

administered 1,4-DCB by capsule in doses as high as 75 mg/kg/day, 5 days/week for 1 year (Naylor and 

Stout 1996). 

Gastrointestinal Effects. 

1,2-Dichlorobenzene. No studies were located regarding gastrointestinal effects in humans after oral 

exposure to 1,2-DCB. 

No gross or histological changes were observed in the gastrointestinal tract (esophagus, stomach, small 

intestine, colon, and/or other tissues) of Sprague-Dawley or F344 rats that were administered 1,2-DCB in 

corn oil by gavage in doses of 300 mg/kg/day for 10 consecutive days (Robinson et al. 1991), 

≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), or ≤120 mg/kg/day, 5 days/week for 103 weeks 

(NTP 1985). Additionally, there were no gross or histological effects in the gastrointestinal tract of 

B6C3F1 mice that were similarly treated with ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), or 

≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding gastrointestinal effects in humans after oral 

exposure to 1,3-DCB. 

No gross or histological changes were observed in the gastrointestinal tract (esophagus, stomach, 

duodenum, jejunum, ileum, colon, cecum, rectum, tongue) in male or female Sprague-Dawley rats that 

were exposed to 1,3-DCB in corn oil by gavage in doses of 735 mg/kg/day for 10 consecutive days, or 

588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). 

1,4-Dichlorobenzene. No studies were located regarding gastrointestinal effects in humans after oral 

exposure to 1,4-DCB. 

In a series of dose range-finding studies, groups of F344 rats were administered 1,4-DCB at 

concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks 

(NTP 1987). At sacrifice, animals were examined grossly and major tissues were examined 

histologically. Gastrointestinal effects were observed at doses of 1,200 mg/kg/day or more and consisted 

of epithelial necrosis and villar bridging of the mucosa of the small intestines. No gastrointestinal effects 

were noted in rats treated with 1,4-DCB at doses of 900 mg/kg/day or less (NTP 1987). In parallel 
DICHLOROBENZENES 156 

3. HEALTH EFFECTS 

studies with B6C3F1 mice, no compound-related gastrointestinal effects were observed after 

administration of 1,4-DCB at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 

5 days/week for 13 weeks (NTP 1987). 

In 2-year exposure studies in Fischer 344 rats, no gastrointestinal effects were reported in males or 

females that received 1,4-DCB by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively 

(NTP 1987). In similarly dosed B6C3F1 mice, no gastrointestinal effects were reported in either sex at 

doses up to 600 mg/kg/day (NTP 1987). 

No gross or histological changes were found in the gastrointestinal tract of Beagle dogs (5/sex/level) that 

were administered 1,4-DCB by capsule in doses as high as 75 mg/kg/day, 5 days/week for 1 year (Naylor 

and Stout 1996). Nine regions of the gastrointestinal tract were examined. 

Hematological Effects. 

1,2-Dichlorobenzene. No studies were located regarding hematological effects in humans after oral 

exposure to 1,2-DCB. 

No hematological changes were observed in Sprague-Dawley or F344 rats that were administered 

1,2-DCB in corn oil by gavage in doses of ≤300 mg/kg/day for 10 consecutive days (Robinson et al. 

1991), ≤400 mg/kg/day for 90 consecutive days (Robinson et al. 1991), or ≤500 mg/kg/day, 5 days/week 

for 13 weeks (NTP 1985). Additionally, there were no hematological effects in B6C3F1 mice that were 

similarly treated with ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding hematological effects in humans after oral 

exposure to 1,3-DCB. 

No hematological changes (numbers of erythrocytes and leukocytes, hemoglobin level, hematocrit, or 

mean corpuscular volume) were observed in male or female Sprague-Dawley rats that were exposed to 

1,3-DCB in corn oil by gavage in doses of 735 mg/kg/day for 10 consecutive days, or 588 mg/kg/day for 

90 consecutive days (McCauley et al. 1995). 

1,4-Dichlorobenzene. A 21-year-old pregnant woman who had eaten 1–2 blocks of 1,4-DCB toilet air 

freshener per week throughout pregnancy developed severe microcytic, hypochromic anemia with 
 

 

DICHLOROBENZENES 157 

3. HEALTH EFFECTS 

excessive polychromasia and marginal nuclear hypersegmentation of the neutrophils. Heinz bodies were 

seen in a small number of the red cells. After she discontinued this practice (at about 38 weeks of 

gestation), her hemoglobin levels began to rise steadily. She gave birth to a normal infant with no 

hematological problems, and her own red blood cells were again normal at the final check 6 weeks after 

delivery (Campbell and Davidson 1970). Acute hemolytic anemia and were reported to have occurred in 

a 3-year-old boy who had played with 1,4-DCB crystals (Hallowell 1959). It is not clear whether this 

child had actually ingested any of the 1,4-DCB crystals. 

Hematological effects reported in animal studies mainly concern effects on red cells in rats and on white 

cells in mice. Groups of male F344 rats (n=1/group) were administered 13–2,790 mg/kg body weight of 

1,4-DCB once via corn oil gavage. Twenty-four hours after dosing, the animals were weighed and 

exsanguinated. No hematological alterations were noted in any of the treated rats (Allis et al. 1992). 

No adverse effects on hemoglobin levels or hematocrit were seen in adult male albino rats dosed with 

1,4-DCB by gavage in corn oil at levels up to 40 mg/kg/day for 90 days (Carlson and Tardiff 1976). 

In F344 rats administered 1,4-DCB by gavage in corn oil, 7 days/week for 13 weeks at doses of 75– 

600 mg/kg/day, no compound-related hematological effects were noted (Bomhard et al. 1988). In a series 

of experiments performed by Hollingsworth et al. (1956), male rats were administered 1,4-DCB by 

gavage in olive oil at doses of 10–500 mg/kg/day, 5 days/week for 4 weeks; female rats received 

1,4-DCB in like manner at doses of 18.8–376 mg/kg/day, 5 days/week for 192 days; and male and female 

rabbits received 500 mg/kg/day 1,4-DCB, 5 days/week for 367 days. Administration of 1,4-DCB 

produced no hematological effects at any dose. 

In another 13-week study in F344 rats, male rats that received 1,4-DCB at 300 mg/kg/day and above had 

decreased hematocrit levels, red blood cell counts, and hemoglobin concentrations (NTP 1987). None of 

these hematologic effects were consistently seen in female rats at the same dosage level; however, a 

decrease in mean corpuscular volume was noted in females at doses of 600 mg/kg/day or more. In a 

parallel study in male and female B6C3F1 mice dosed with 84.4–900 mg/kg/day 1,4-DCB for 13 weeks, 

no hematological effects were noted in male or female mice at doses up to 900 mg/kg/day (NTP 1987); 

however, in another study, B6C3F1 mice dosed with 600–1,800 mg/kg/day 1,4-DCB for 13 weeks showed 

hematologic effects including 34–50% reductions in the white cell counts in all male dose groups; these 

decreases were accompanied by 26–33% decreases in lymphocytes and 69–82% decreases in neutrophils. 

No hematological effects were noted in female B6C3F1 mice at doses up to 1,800 mg/kg/day (NTP 1987). 
 

 

DICHLOROBENZENES 158 

3. HEALTH EFFECTS 

No hematologic effects were reported in 2-year studies in which male F344 rats received 1,4-DCB at 

levels up to 300 mg/kg/day/day and female rats received levels up to 600 mg/kg/day (NTP 1987). Similar 

results were reported in B6C3F1 mice of both sexes exposed to 600 mg/kg/day 1,4-DCB for 2 years (NTP 

1987). 

Hematology was evaluated in groups of five male and five female Beagle dogs that were administered 

1,4-DCB by capsule in doses of 0, 10, 50, or 75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 

1996). Ten routine indices and one blood clotting measurement (activated partial thromboplastin time) 

were evaluated at 6 and 12 months. A mild anemia, as indicated by significantly reduced red blood cell 

count in females and hematocrit in males, was observed after 6 months at 75 mg/kg/day, but resolved by 

the end of the study. Histological findings in the bone marrow (erythroid hyperplasia in females) and 

spleen (excessive hematopoiesis and megakaryocyte proliferation in both sexes) at 75 mg/kg/day 

indicated a compensatory response to the earlier anemia. 

Musculoskeletal Effects. 

1,2-Dichlorobenzene. No studies were located regarding musculoskeletal effects in humans after oral 

exposure to 1,2-DCB. 

Mutifocal mineralization of the myocardial fibers of the heart and skeletal muscle was found in 

B6C3F1 mice (3/10 males, 8/10 females) that were administered 500 mg/kg/day of 1,2-DCB in corn oil by 

gavage 5 days/week for 13 weeks (NTP 1985); this effect does not appear to have occurred in controls or 

lower dose mice (≤250 mg/kg/day). No gross or histological changes were observed in muscle of 

B6C3F1 mice that were similarly treated with ≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985), 

or in Sprague-Dawley or F344 rats that were similarly treated with 300 mg/kg/day for 10 consecutive 

days (Robinson et al. 1991), ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), or ≤120 mg/kg/day, 

5 days/week for 103 weeks (NTP 1985). 

No gross or histological changes in bone were observed in any of the rat or mouse 10-day, 13-week, or 

103-week studies summarized above (NTP 1985; Robinson et al. 1991). 

1,3-Dichlorobenzene. No studies were located regarding musculoskeletal effects in humans after oral 

exposure to 1,3-DCB. 
DICHLOROBENZENES 159 

3. HEALTH EFFECTS 

No gross or histological changes were observed in thigh muscle or sternebrae in male or female SpragueDawley rats that were exposed to 1,3-DCB in corn oil by gavage in doses of 735 mg/kg/day for 

10 consecutive days or 588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). 

1,4-Dichlorobenzene. No studies were located regarding musculoskeletal effects in humans after oral 

exposure to 1,4-DCB. 

In a series of dose range-finding studies, groups of F344 rats were administered 1,4-DCB at 

concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks. At 

sacrifice, animals were examined grossly and major tissues were examined histologically. No 

musculoskeletal effects were noted in any of the 1,4-DCB-treated rats. In parallel studies with 

B6C3F1 mice, no compound-related musculoskeletal effects were observed after administration of 

1,4-DCB at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days/week for 

13 weeks (NTP 1987). 

In 2-year exposure studies in F344 rats, no musculoskeletal effects were reported in males or females that 

received 1,4-DCB by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively. In similarly 

dosed B6C3F1 mice, no musculoskeletal effects were reported in either sex at doses up to 600 mg/kg/day 

(NTP 1987). 

No gross or histological changes were found in skeletal muscle or bone of Beagle dogs (5/sex/level) that 

were administered 1,4-DCB by capsule in doses as high as 75 mg/kg/day, 5 days/week for 1 year (Naylor 

and Stout 1996). 

Hepatic Effects. 

1,2-Dichlorobenzene. No studies were located regarding hepatic effects in humans after oral exposure to 

1,2-DCB. 

The liver is a main target of toxicity in animals following oral exposure to 1,2-DCB. Necrosis and other 

degenerative hepatic changes were observed in acute-duration studies in which 1,2-DCB was 

administered in oil by gavage. A single 1,500 mg/kg dose (a lethal level) caused central necrosis of the 

liver in rats (number and gender not reported) (DuPont 1982). Severe liver damage, characterized by 
DICHLOROBENZENES 160 

3. HEALTH EFFECTS 

intense necrosis and fatty changes, occurred in three male rats administered 455 mg/kg/day for 

15 consecutive days (Rimington and Ziegler 1963). Other hepatic effects in this study included 

porphyria, manifested as increased mean peak urinary levels of coproporphyrin, uroporphyrin, 

porphobilinogen (PBG), and γ-aminolevulinic acid (ALA) that were approximately 10-fold higher than 

levels in controls. Liver changes in other acute-duration studies included necrosis and increased serum 

ALT in rats given 300 mg/kg/day for 10 consecutive days (Robinson et al. 1991). The necrosis was slight 

in severity and significantly (p=0.04) increased in males at 300 mg/kg/day [4/10 compared to 0/10 in 

controls; incidences in lower dose groups (37.5, 75, and 150 mg/kg/day) were not specifically reported 

and are assumed to be 0/10]. Incidences of other hepatic lesions were not significantly increased but 

included inflammation (characterized by lymphocyte and macrophage infiltrates) and degeneration of 

hepatocytes (characterized varying degrees of fibrillar or vacuolated cytoplasm and swelling with intact 

cell membranes). Liver weight was increased in females at ≥150 mg/kg/day and males at 300 mg/kg/day; 

the increased liver weight in female rats in this study (Robinson et al. 1991) was selected as the critical 

effect for deriving an acute-duration oral MRL of 0.7 mg/kg/day for 1,2-DCB. No liver histopathology 

was observed in male or female rats that were given doses as high as 500 or 1,000 mg/kg/day for 

14 consecutive days (NTP 1985). The inconsistency between these findings and those of Robinson et al. 

(1991) might be due to a small number of animals (5 rats/sex/dose level) in the NTP (1985) study and 

mild response (low incidence and severity of lesions) in the Robinson et al. (1991) study. Hepatic 

degeneration and necrosis were observed in mice exposed to 250 or 500 mg/kg/day for 14 consecutive 

days (NTP 1985), but this study is also limited by small numbers of animals (3–4 mice/sex/group). 

Liver histopathology was also the predominant finding in intermediate-duration studies of rats and mice 

exposed to 1,2-DCB (Hollingsworth et al. 1958; NTP 1985; Robinson et al. 1991). The compound was 

administered in oil vehicle by gavage in all of these studies. Slight to moderate cloudy swelling of the 

liver was found in female rats (strain not specified) dosed with 376 mg/kg/day, 5 days/week for 138 doses 

in 192 days, but not at lower dose levels of 18.8 or 188 mg/kg/day (Hollingsworth et al. 1958). The 

incidence of the lesion was not reported. Liver weight was increased at ≥188 mg/kg/day, but it is unclear 

whether this is an adaptive change or adverse effect due to the lack of histological or other evidence of 

tissue damage. 

Administration of 400 mg/kg/day for 90 consecutive days caused significantly increased incidences of 

lesions in Sprague-Dawley rats, including centrilobular degeneration, centrilobular hypertrophy, and 

single cell necrosis in 10/10, 9/10, and 7/10 males, respectively, and 8/10, 10/10, and 5/10 females, 

respectively (Robinson et al. 1991). Histology was not evaluated at other dose levels (25 or 
DICHLOROBENZENES 161 

3. HEALTH EFFECTS 

100 mg/kg/day), although no lesions occurred in controls of either sex. Absolute and relative liver 

weights and serum levels of ALT were significantly increased at ≥100 mg/kg/day, but the increases in 

ALT were not dose-related and other liver-associated enzymes (AST, LDH, AP) were not increased. The 

400 mg/kg/day dose is a LOAEL for hepatic effects based on histopathology. A reliable NOAEL cannot 

be identified because histology was not evaluated at lower doses, the increase in serum ALT was not 

dose-related or supported by changes in other serum indicators of liver damage, and an increase in liver 

weight without clear evidence of tissue damage is considered to be an adaptive response. 

NTP (1985) conducted subchronic studies in F344/N rats and B6C3F1 mice to determine doses to be used 

in chronic bioassays. Groups of 10 males and 10 females of each species were administered 1,2-DCB in 

doses of 0, 30, 60, 125, 250, or 500 mg/kg/day, 5 days/week for 13 weeks. Histology examinations of the 

liver were limited to the control and three highest dose groups. Degenerative lesions were significantly 

(p≤0.05) increased in both species at ≥250 mg/kg/day. Changes in the rats included necrosis of individual 

hepatocytes at ≥250 mg/kg/day and centrilobular degeneration at 500 mg/kg/day; total incidences of these 

lesions at 0, 125, 250, and 500 mg/kg/day were 0/10, 1/10, 4/9, and 8/10 in males, respectively, and 0/10, 

3/10, 5/10, and 7/8 in females, respectively. Relative liver weight was significantly increased at 

≥125 mg/kg/day in both sexes, but there were no increases in serum levels of liver enzymes (ALT, AP, or 

gamma-glutamyltranspeptidase [GGPT]) at any dose. Serum cholesterol was significantly increased in 

males at ≥30 mg/kg/day (50.0, 17.6, 26.5, 70.6, and 109% higher than controls in the low to high dose 

groups, not significant at 42.9 mg/kg/day) and females at ≥125 mg/kg/day (12.2, 12.2, 32.6, 26.5, and 

51.0%). Urinary concentrations of uroporphyrin and coproporphyrin were 3–5 times higher than controls 

in the 500 mg/kg/day males and females, but this increase was not considered indicative of porphyria 

because total porphyrin concentration in the liver was not altered at any dose level and no pigmentation 

indicative of porphyria was observed by ultraviolet light at necropsy. The increases in relative liver 

weight seen in male and female rats at 125 mg/kg/day are believed to represent the beginning of adverse 

hepatic effects, indicating that 125 mg/kg/day is a minimal LOAEL for this study. The increased liver 

weight in the female rats in this study (NTP 1985) was selected as the critical effect for deriving an 

intermediate-duration oral MRL of 0.6 mg/kg/day for 1,2-DCB. In the mice, no compound-related 

histopathological changes were observed in either sex at 0 and 125 mg/kg/day, or in females at 

250 mg/kg/day. Lesions that were significantly increased included necrosis of individual hepatocytes, 

hepatocellular degeneration and/or pigment deposition in 4/10 males at 250 mg/kg/day, and centrilobular 

necrosis, necrosis of individual hepatocytes, and/or hepatocellular degeneration in 9/10 males and 

9/10 females at 500 mg/kg/day. Relative liver weights were significantly increased at 500 mg/kg/day in 

both sexes, but there were no exposure-related changes in serum levels of ALT, AP, or GGPT in either 
DICHLOROBENZENES 162 

3. HEALTH EFFECTS 

sex at any dose (no other clinical chemistry indices were examined in the mice). The hepatic 

histopathology findings indicate that the NOAEL and LOAEL for liver effects in mice are 125 and 

250 mg/kg/day, respectively. 

In the NTP (1985) chronic study, groups of 50 male and 50 female F344/N rats and B6C3F1 mice were 

administered 1,2-DCB in corn oil by gavage in doses of 0, 60, or 120 mg/kg/day, 5 days/week for 

103 weeks. Histopathological examinations were performed in all animals, although liver weights and 

clinical chemistry indices were not evaluated. There were no exposure-related nonneoplastic liver lesions 

in either species, indicating that 125 mg/kg/day is the chronic NOAEL for liver effects in both rats and 

mice. 

1,3-Dichlorobenzene. No studies were located regarding hepatic effects in humans after oral exposure to 

1,3-DCB. 

Liver toxicity was evaluated in groups of 10 male and 10 female Sprague-Dawley rats that were exposed 

to 1,3-DCB in corn oil by daily gavage, in doses of 0, 37, 147, 368, or 735 mg/kg/day for 10 consecutive 

days, or 9, 37, 147, or 588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). Study end points 

included serum chemistry indices (AP, AST, ALT, LDH, cholesterol), liver weight, and gross appearance 

and histology of the liver. As discussed below, hepatic changes were found at ≥147 mg/kg/day in the 

10-day study and ≥9 mg/kg/day in the 90-day study. 

Hepatic effects in the 10-day rat study included significantly (p≤0.05) increased relative liver weight in 

males at ≥147 mg/kg/day and females at ≥368 mg/kg/day (absolute organ weight not reported), and 

histopathology at ≥368 mg/kg/day in both sexes. Increased liver weight in this study (McCauley et al. 

1995) was selected as the critical effect for deriving an acute-duration oral MRL of 0.4 mg/kg/day for 

1,3-DCB. The main hepatic histological change was dose-related centrilobular hepatocellular 

degeneration, characterized by varying degrees of cytoplasmic vacuolization and swelling with intact 

membranes. Respective incidences of this lesion at 368 and 735 mg/kg/day were 2/10 and 9/10 in males, 

and 6/10 and 10/10 females; incidences in the other groups were not reported, but are presumed to be 

0/10. Other hepatic alterations included hepatocellular necrosis that was sporadically noted in the 147, 

368, and 735 mg/kg/day groups. This change was usually minimal to mild, and tended to increase in 

incidence and severity in the males in a dose-related manner; however, incidences were not reported. 

Cholesterol was the only serum end point that had values exceeding the reference range. Serum 
DICHLOROBENZENES 163 

3. HEALTH EFFECTS 

cholesterol was significantly increased at 368 and 735 mg/kg/day in both sexes, but this change could be 

pituitary-related (see discussion of the 90-day study in Endocrine Effects). 

Hepatic effects in the 90-day study included significantly increased relative liver weight (absolute weight 

not reported) and histopathological changes at ≥147 mg/kg/day in both sexes. The liver lesions included 

inflammation, hepatocellular alterations (characterized by spherical, brightly eosinophilic homogeneous 

inclusions), and hepatocellular necrosis. Liver lesions that were significantly increased included 

hepatocellular cytoplasmic alterations of minimal to mild severity in males at ≥147 mg/kg/day 

(incidences in the control to high dose groups were 1/10, 2/10, 1/10, 6/10, and 7/9) and females at 

588 mg/kg/day (0/10, 2/10, 0/10, 1/10, and 7/9), and necrotic hepatocyte foci of minimal severity in both 

sexes at 588 mg/kg/day (1/10, 2/10, 1/10, 2/10, and 5/9 in males, and 0/10, 0/10, 0/10, 3/10, and 5/9 in 

females). Other statistically significant liver-associated effects included significantly increased serum 

AST levels (90–100% higher than controls) in males at ≥9 mg/kg/day and females at ≥37 mg/kg/day. 

Serum LDH levels were also reduced in males at ≥9 mg/kg/day, but the biological significance of a 

decrease in liver enzymes is unclear. Serum cholesterol values were significantly increased in males at 

≥9 mg/kg/day and females at ≥37 mg/kg/day, but this change could be pituitary-related (see Endocrine 

Effects). 

1,4-Dichlorobenzene. A single case study was located regarding hepatic effects in humans after oral 

exposure to 1,4-DCB. In this case report, the author describes a 3-year-old boy who had been playing 

with crystals containing 1,4-DCB for 4–5 days before being admitted to the hospital. On admission, the 

boy was jaundiced and his mucous membranes were pale. After a blood transfusion, the child gradually 

improved. It was unclear whether the boy actually ingested any of the 1,4-DCB (Hallowell 1959). 

The acute hepatotoxicity and response of hepatic cytochrome P-450 in response to dosing with 1,4-DCB 

were evaluated in groups of male F344 rats (n=1/group) given one dose of 13–2,790 mg/kg body weight 

by corn oil gavage. Twenty-four hours after dosing, the animals were weighed and sacrificed. Serum 

was collected and analyzed for total bilirubin, cholesterol, AST, alanine aminotransferase (ALT), and 

alkaline phosphatase. The liver was weighed and slices examined histopathologically. Liver microsomes 

were prepared and assayed for P-450, in addition to liver protein determinations. 1,4-DCB did not 

produce liver necrosis at any dose. There was also no effect observed on serum levels of ALT and AST. 

Hepatic cytochrome P-450 levels were increased about 30% by 1,4-DCB beginning at 380 mg/kg and 

remaining elevated at all higher doses. No consistent pattern of change was found for indicators of 
DICHLOROBENZENES 164 

3. HEALTH EFFECTS 

hepatobiliary damage, serum cholesterol, serum alkaline phosphatase, and total bilirubin (Allis et al. 

1992). 

The effects of 1,4-DCB were compared in male F344 rats given 0 (corn oil control), 25, 75, 150, and 

300 mg/kg/day 1,4-DCB (n=6–8/group/time) by daily oral gavage 5 days/week for 1 week. Replicative 

DNA synthesis was studied using subcutaneously implanted osmotic pumps containing 5-bromo2'-deoxyuridine (BrdU) to determine the hepatocyte labeling index. Livers were removed, weighed, and 

then immunostained. Morphological examination of the liver sections from all lobes was performed from 

control and 300 mg/kg group rats. 1,4-DCB treatment for 1 week did not produce morphological changes 

in the rat livers. 1,4-DCB produced significant dose-related increases in relative liver weight in the rats, 

which were also associated with mild centrilobular hypertrophy. At 300 mg/kg, relative liver weight was 

significantly increased. Significant dose-related increases in microsomal cytochrome P-450 content were 

observed in rats given 150 and 300 mg/kg 1,4-DCB for 1 week, with a significant dose-related induction 

of microsomal 7-pentoxyresorufin O-depentylase activity observed in rats given 75–300 mg/kg 1,4-DCB. 

The hepatocyte labeling index values were only increased in animals given 300 mg/kg 1,4-DCB (225% of 

controls) (Lake et al. 1997). 

In a series of experiments, Eldridge et al. (1992) studied the acute hepatotoxic effects of 1,4-DCB and the 

role of cell proliferation in hepatotoxicity in B6C3F1 mice and F344 rats. Mice and rats received a single 

dose of 1,4-DCB by gavage in corn oil of 600, 900, or 1,200 mg/kg/day. At 1, 2, 4, and 8 days after 

1,4-DCB treatment, selected animals were injected intraperitoneally with BrdU 2 hours prior to sacrifice 

to monitor cell proliferation. Other groups of mice and rats were sacrificed 24 or 48 hours after dosing, 

blood was collected for liver enzyme analysis, and liver sections were collected for histopathology. In 

mice dosed with 600 mg/kg/day 1,4-DCB, liver weights were significantly increased 48 hours after 

dosing. Labeling index (LI), indicative of cell proliferation, peaked 24 hours after dosing in females and 

48 hours in males. Activities of serum enzymes associated with liver damage (ALT, AST, LDH, sorbitol 

dehydrogenase) were not affected by 1,4-DCB. Twenty-four and 48 hours after administration of 

1,4-DCB, the livers of males showed periportal hepatocytes with vacuolated cytoplasm and centrilobular 

hepatocytes with granulated basophilic cytoplasm; the severity of these changes was dose-related at 

48 hours, but not at 24 hours. Similar but less pronounced effects were seen in females at 24 hours. In 

rats, liver weights were significantly increased at all time points after administration of 600 mg/kg/day 

1,4-DCB. The LI peaked 24 hours after dosing and was still elevated after 48 hours. Necrosis was not 

observed in the livers of mice or rats after treatment with 1,4-DCB. 
DICHLOROBENZENES 165 

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In pregnant CD rats administered 1,4-DCB in corn oil at doses of 250–1,000 mg/kg/day on Gd 6–15, no 

differences in maternal liver weight were noted (Giavini et al. 1986); however, hepatic effects have been 

reported in other oral studies in which 1,4-DCB has been administered to test animals by gavage 

(discussed below). These effects have ranged from temporary elevation of hepatic enzymes to hepatic 

degeneration and necrosis. 

The effects of 1,4-DCB were compared in male B6C3F1 mice given 0 (corn oil control), 300, and 

600 mg/kg/day 1,4-DCB (n=6–8/group/time) by daily oral gavage 5 days/week for 1 week. Replicative 

DNA synthesis was studied using subcutaneously implanted osmotic pumps containing BrdU to assess 

the hepatocyte labeling index. Livers were removed, weighed, and immunostained. Morphological 

examination of the liver sections was performed for control and 600 mg/kg groups. Biochemical analysis 

of liver whole homogenates was performed. 1,4-DCB produced significant dose-related increases in 

relative liver weight, which were associated with marked centrilobular hypertrophy. Relative liver 

weights were increased for mice in both the 300 and 600 mg/kg groups at all time points, with minimal 

centrilobular hypertrophy observed in 600 mg/kg group mice. No other histological abnormalities were 

observed in the liver sections. Administration of 1,4-DCB also produced a sustained induction of 

microsomal cytochrome P-450 content and 7-pentoxyresorufin O-depentylase activity. Significant doserelated induction of microsomal cytochrome P-450 content was induced in mice given 600 but not 

300 mg/kg 1,4-DCB. Microsomal 7-pentoxyresorufin O-depentylase activity was significantly induced in 

mouse liver microsomes at doses of 300 and 600 mg/kg 1,4-DCB. Western immunoblotting studies 

demonstrated that 1,4-DCB induced CYP2B isoenzyme(s) in mouse liver microsomes at 300 and 

600 mg/kg 1,4-DCB. The hepatocyte labeling index values were also significantly increased in mice 

given 300 and 600 mg/kg 1,4-DCB (Lake et al. 1997). 

In male B6C3F1 mice, single doses of 600, 1,000, or 1,800 mg/kg/day 1,4-DCB administered by gavage 

in corn oil resulted in significantly elevated BrdU labeling of hepatocytes at the 1,000 and 

1,800 mg/kg/day doses. In addition, single doses of 1,800 mg/kg resulted in a 4.5-fold increase in serum 

ALT activity and severe centrilobular hepatocyte swelling. In a companion time-course study, single 

doses of 1,800 mg/kg 1,4-DCB administered by gavage in corn oil resulted in significantly elevated BrdU 

labeling in hepatic samples on days 2, 3, and 4, but not days 1 or 7. ALT activity was significantly 

elevated in 1,4-DCB-treated mice on day 2 only. In all other aspects, hepatic toxicity was not evident in 

mice dosed with 1,800 mg/kg 1,4-DCB (Umemura et al. 1996). 
DICHLOROBENZENES 166 

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1,4-DCB has been shown to produce disturbances in porphyrin metabolism after high-level/acute-duration 

exposure. Increased excretion of porphyrins, especially coproporphyrin and uroporphyrin, are considered 

to be indicators of liver damage. Administration of 1,4-DCB in liquid paraffin to male rats at gradually 

increasing doses, until a dose level of 770 mg/kg/day was maintained for 5 days, resulted in high 

porphyrin excretion (Rimington and Ziegler 1963). Mean peak values of urinary coproporphyrin 

increased to about 10–15-fold above levels in controls. A 37–100-fold increase in urinary uroporphyrin 

levels occurred; porphobilinogen levels increased 200–530-fold; and a 10-fold increase in 

δ-aminolevulinic acid (δ-ALA) levels was observed. In the liver itself, coproporphyrin levels were 

similar to controls, uroporphyrin levels were increased 46-fold, and protoporphyrin levels were increased 

6-fold. These dramatic increases, which suggest severe damage to the liver, were not observed when 

1,4-DCB was administered to rats at higher levels (850 mg/kg/day) in 1% cellofas (Rimington and 

Ziegler 1963) or at lower levels for a longer period of time in another study (Carlson 1977), as discussed 

below. Also, Trieff et al. (1991) have used animal data on porphyrogenicity from various chlorinated 

benzenes to perform a QSAR study allowing prediction of ambient water criteria. 

Changes in other markers of liver function including cytochrome P-450 levels, and activities of some 

drug-metabolizing enzymes (aminopyrine N-demethylase and aniline hydroxylase) were investigated in 

rats treated with of 1,4-DCB by gavage at 250 mg/kg/day for up to 3 days (Ariyoshi et al. 1975). Activity 

of δ-ALA synthetase, an enzyme used in synthesis of the heme moiety found in cytochromes, was 

increased 42% by treatment with 1,4-DCB. However, the cytochrome P-450 content did not change, 

although the microsomal protein content of liver preparations was increased. The toxicological 

significance of these findings is not clear since δ-ALA synthetase activity did not correlate with 

cytochrome P-450 concentration. 

Effects on hepatic enzyme activities were reported to have occurred in adult male rats that were given 

1,4-DCB by gavage for 14 days (Carlson and Tardiff 1976). Significant decreases in hexobarbital 

sleeping time and a 6.5-fold increase in serum isocitrate dehydrogenase activity were observed after a 

14-day treatment regimen at 650 mg/kg/day. In addition, even at considerably lower levels (20 or 

40 mg/kg/day), increases were observed in the activities of hepatic microsomal xenobiotic metabolic 

systems including levels of glucuronyl transferase, and benzpyrene hydroxylase and O-ethyl-O-nitrophenyl phenylphosphorothionate (EPN) detoxification to nitrophenol. In a 90-day study at the same 

dosage levels, significant increases were seen in EPN detoxification, benzpyrene hydroxylase, and 

azoreductase levels. The former two levels were still elevated at 30 days after the cessation of 

administration of the compound. Most increases were noted at 20 mg/kg/day and above as in the 14-day 
 

 

DICHLOROBENZENES 167 

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studies; however, azoreductase levels were elevated even at 10 mg/kg/day (Carlson and Tardiff 1976). 

These observations are important because they demonstrate that hepatic effects occur at levels of 

1,4-DCB that are far below those associated with severe histopathology. 

The effects of 1,4-DCB were compared in male F344 rats given 0 (corn oil control), 25, 75, 150, and 

300 mg/kg/day 1,4-DCB (n=6–8/group/time) by daily oral gavage 5 days/week for 4 and 13 weeks. 

Replicative DNA synthesis was studied using subcutaneously implanted osmotic pumps containing BrdU 

during study weeks 3–4 and 12–13. Livers were removed, weighed, and then immunostained. 

Morphological examination of the liver sections was performed from control and 300 mg/kg group rats in 

the 13-week exposure group. 1,4-DCB treatment produced a mild centrilobular hypertrophy seen in rats 

given 300 mg/kg 1,4-DCB for 13 weeks. No other histological abnormalities were observed in the liver 

sections. 1,4-DCB produced significant dose-related increases in relative liver weight in the rats, which 

were associated with mild centrilobular hypertrophy. At 300 mg/kg, relative liver weight was 

significantly increased. Significant increases in relative liver weight were observed in rats given 75 and 

150 mg/kg 1,4-DCB for 4 weeks and 150 mg/kg 1,4-DCB for 13 weeks. Administration of 1,4-DCB also 

produced a sustained induction of microsomal cytochrome P-450 content and 7-pentoxyresorufin 

O-depentylase activity. Significant dose-related increases in microsomal cytochrome P-450 content were 

observed in rats given 25–300 mg/kg 1,4-DCB for 4 weeks and 75–300 mg/kg 1,4-DCB for 13 weeks. A 

significant dose-related induction of microsomal 7-pentoxyresorufin O-depentylase activity was observed 

in rats given 75–300 mg/kg 1,4-DCB for 4 weeks and 25–300 mg/kg 1,4-DCB for 13 weeks. Western 

immunoblotting studies demonstrated that 1,4-DCB induced CYP2B isoenzyme(s) in rat liver 

microsomes at 75 and 300 mg/kg 1,4-DCB (Lake et al. 1997). 

Histopathological effects in the liver, including cloudy swelling and centrilobular necrosis, were observed 

after gavage administration of 1,4-DCB in rats (two per group) at 500 mg/kg/day for 4 weeks; similar 

results (cloudy swelling, focal caseous necrosis) were obtained in rabbits (five per group) given 92 doses 

of 1,000 mg/kg/day 1,4-DCB in olive oil over a 219-day period (Hollingsworth et al. 1956). The 

interpretation of this study is limited by the size of the test groups and the fact that observations in 

controls were not presented. Histopathological changes were also reported in a 13-week study in which 

rats received 1,4-DCB by gavage (NTP 1987). Doses of 1,200 or 1,500 mg/kg/day produced 

degeneration and necrosis of hepatocytes. Serum cholesterol levels were increased by doses of 

600 mg/kg/day or more in male rats and by ≥900 mg/kg/day in female rats, while serum triglycerides and 

protein levels were reduced at doses of ≥300 mg/kg/day in male rats. Urinary porphyrins were increased 

in both sexes at ≥1,200 mg/kg/day. However, these increases were modest and considered by the authors 
 

 

DICHLOROBENZENES 168 

3. HEALTH EFFECTS 

to indicate mild porphyrinuria rather than hepatic porphyria. Liver porphyrins were not increased at any 

dose. In a second 13-week study in the same laboratory, hepatic effects were not observed in rats at 

dosage levels up to 600 mg/kg/day (NTP 1987). 

Similar hepatic effects were reported in two 13-week gavage studies in mice (NTP 1987). Hepatocellular 

degeneration was observed in both sexes at all doses (600–1,800 mg/kg/day). Serum cholesterol levels 

were increased in male mice at doses of 900 mg/kg/day or more, and serum protein and triglycerides were 

increased at doses of 1,500 mg/kg/day or more. These changes were thought by the authors to reflect the 

hepatic effects of this compound. Hepatic porphyria was not found in mice at any dose level in this study. 

Because hepatic effects were seen in mice in all dose groups in the first 13-week study, a second 13-week 

study was conducted at lower dosage levels. Hepatocellular cytomegaly was observed in mice at doses of 

675 mg/kg/day and above. The lowest level at which hepatic effects were observed in mice was 

600 mg/kg/day (in the first study). 

Other intermediate-duration oral studies with 1,4-DCB have reported liver toxicity. In female rats dosed 

with 1,4-DCB by gavage for about 6 months, doses of 188 mg/kg/day and above resulted in increased 

liver weights. At 376 mg/kg/day, slight cirrhosis and focal necrosis of the liver were also observed 

(Hollingsworth et al. 1956). No effects on the liver were seen at a dose of 18.8 mg/kg/day. 

The ability of 1,4-DCB to induce porphyria was investigated in female rats that were administered 

1,4-DCB by gavage for up to 120 days (Carlson 1977). Slight but statistically significant increases in 

liver porphyrins were seen in all dosed rats (50–200 mg/kg/day) at 120 days. Urinary excretion of 

δ-ALA, porphobilinogen, or porphyrins was not increased over control levels. These results indicated 

that 1,4-DCB had only a slight potential for causing porphyria at these doses in female rats compared with 

the far more pronounced porphyrinogenic effects reported earlier in male rats that received 

770 mg/kg/day for 5 days in a study by Rimington and Ziegler (1963). However, sex-related differences 

in susceptibility to 1,4-DCB's effects on these parameters cannot be ruled out in a comparison of these 

two studies. 

The role of cell proliferation in liver toxicity induced by 1,4-DCB was examined in groups of mice (5– 

7 per sex per dose level) administered 0 (vehicle only), 300, or 600 mg/kg 1,4-DCB in corn oil by gavage 

5 days/week for 13 weeks (Eldridge et al. 1992). The liver toxicity induced by 1,4-DCB was also 

examined in groups of female rats (5–7 per dose level) administered 0 (vehicle only) or 600 mg/kg 

1,4-DCB in corn oil by gavage 5 days/week for 13 weeks. At various times during the study, mice were 
DICHLOROBENZENES 169 

3. HEALTH EFFECTS 

implanted with osmotic pumps to deliver BrdU. Liver weights were significantly increased in high-dose 

male and female mice and in female rats throughout the 13-week study. Treated male mice showed a 

centrilobular pattern of labeled hepatocytes, whereas females were labeled throughout the lobules. At the 

lower-dose level, liver weight was increased in male and female mice at weeks 6 and 13. In a group of 

mice in which treatment with 600 mg/kg/day ceased after 5 weeks and the animals were allowed to 

recover for 1 week, liver weight returned to control values. The authors concluded that 1,4-DCB induced 

a mitogenic stimulation of cell proliferation in the liver rather than a regenerative response following 

cytotoxicity. This was evidenced by an increase in liver weight without increase in liver-associated 

plasma enzymes (Eldridge et al. 1992). 

The effects of 1,4-DCB were determined in male B6C3F1 mice given 0 (corn oil control), 300, and 

600 mg/kg/day 1,4-DCB (n=6–8/group/time) by daily oral gavage 5 days/week for 4 and 13 weeks. 

Replicative DNA synthesis was studied using subcutaneously implanted osmotic pumps containing BrdU 

during study weeks 3–4 and 12–13. Livers were removed, weighed, and immunostained. Morphological 

examination of the livers was performed for control and 600 mg/kg group mice at 13 weeks. Biochemical 

analysis of liver whole homogenates was also performed. 1,4-DCB produced significant dose-related 

increases in relative liver weight in the mice, which were associated with marked centrilobular 

hypertrophy. Relative liver weights were increased for mice in both the 300 and 600 mg/kg groups at all 

time points. At 13 weeks, a marked centrilobular hypertrophy was observed in the 600 mg/kg group. No 

other histological abnormalities were observed in the liver. Administration of 1,4-DCB also produced a 

sustained induction of microsomal cytochrome P-450 content and 7-pentoxyresorufin O-depentylase 

activity. Significant dose-related induction of microsomal cytochrome P-450 content was induced in 

mice given 600 but not 300 mg/kg 1,4-DCB for treatments of 4 and 13 weeks. Microsomal 

7-pentoxyresorufin O-depentylase activity was significantly induced in mouse liver microsomes at doses 

of 300 and 600 mg/kg 1,4-DCB. Western immunoblotting studies demonstrated that 1,4-DCB induced 

CYP2B isoenzyme(s) in mouse liver microsomes at 300 and 600 mg/kg 1,4-DCB. Hepatocyte labeling 

index values were significantly increased in mice given 300 and 600 mg/kg 1,4-DCB for 4 weeks 

(420 and 395% of controls, respectively) (Lake et al. 1997). 

A 1-year study in dogs indicates that this species is more sensitive than rats or mice to hepatic effects of 

1,4-DCB. Groups of five male and five female Beagle dogs were administered 1,4-DCB by capsule in 

dose levels of 0, 10, 50, or 75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 1996). Liver effects 

occurred after 6 and 12 months at ≥50 mg/kg/day in both sexes as shown by changes in liver enzymes, 

increased liver weight, and/or histopathology. Serum levels of ALT, AST, GGT, and AP were measured 
DICHLOROBENZENES 170 

3. HEALTH EFFECTS 

after 6 and 12 months. Statistically significant increases were found for serum AP in males at 

50 mg/kg/day, and females at 50 and 75 mg/kg/day, at months 6 and 12 (330–761% higher than controls); 

ALT in females at 75 mg/kg/day and month 12 (253% higher than controls); and GGT in females at 

75 mg/kg/day and months 6 and 12 (131–161% higher than controls). Serum albumin was significantly 

decreased in males at ≥50 mg/kg/day (months 6 and 12) and females at 75 mg/kg/day (month 6). 

Absolute and relative liver weights were significantly increased in both sexes at 50 and 75 mg/kg/day 

(except absolute liver weight in 50 mg/kg/day males). Hepatic lesions included hepatocellular 

hypertrophy in all males and females at 50 and 75 mg/kg/day (as well as one female at 10 mg/kg/day), 

hepatocellular pigment deposition at 50 and 75 mg/kg/day (two males and one female at each level), bile 

duct/ductule hyperplasia at 75 mg/kg/day (one male and one female), and hepatic portal inflammation at 

50 and 75 mg/kg/day (periportal accumulation of neutrophils in an unspecified number of males). The 

6- and 12-month increased serum AP levels in dogs (Naylor and Stout 1996) were used to derive 

intermediate- and chronic-duration oral MRLs of 0.07 mg/kg/day for 1,4-DCB. 

Studies of the hepatic effects of chronic 1,4-DCB exposure are sparse. The toxicity of 1,4-DCB was 

evaluated in a group of seven rabbits administered 1,4-DCB in olive oil at a dose of 500 mg/kg/day a total 

of 263 times over a 367-day period. Slight changes in the liver (cloudy swelling and a few areas of focal 

caseous necrosis) were noted at sacrifice (Hollingsworth et al. 1956). 

In the only study of lifetime oral exposure to 1,4-DCB in laboratory animals, groups of male and female 

F344 rats were administered 1,4-DCB by gavage in corn oil 5 days/week for 103 weeks at doses of 150 or 

300 mg/kg/day (males) or 300 or 600 mg/kg/day (females). Groups of male and female B6C3F1 mice 

were administered 1,4-DCB at doses of 300 or 600 mg/kg/day by gavage in corn oil, 5 days/week for 

103 weeks. No hepatic effects were seen in rats; in mice, the incidence of hepatocellular degeneration 

was greatly increased in treated mice (in males: 0/50 control, 36/49 low-dose, 39/50 high-dose; in 

females 0/50 control, 8/48 low-dose, 36/50 high-dose). The primary degenerative change was cellular 

swelling with clearing or vacuolation of the cytoplasm. Individual hepatocytes had pyknotic or 

karyorrhectic nuclei and condensed eosinic cytoplasm. Some necrotic hepatocytes formed globular 

eosinophilic masses in the sinusoids (NTP 1987). 

Renal Effects. 

1,2-Dichlorobenzene. No studies were located regarding renal effects in humans after oral exposure to 

1,2-DCB. 
DICHLOROBENZENES 171 

3. HEALTH EFFECTS 

A single 1,500 mg/kg gavage dose of 1,2-DCB in peanut oil (a lethal level) caused accumulation of 

albuminous fluid and casts in the renal tubules of rats (number and gender not reported) (DuPont 1982). 

Sprague-Dawley rats (10/sex/level) that were administered 1,2-DCB in corn oil by gavage in doses of 

300 mg/kg/day for 10 consecutive days or 400 mg/kg/day for 90 consecutive days (Robinson et al. 1991). 

In subchronic studies performed by NTP (1985), F344 rats and B6C3F1 mice (10/sex/level/species) were 

administered 1,2-DCB in doses of 0, 30, 60, 125, 250, or 500 mg/kg/day in corn oil by gavage 

5 days/week for 13 weeks. Histology examinations of the kidneys were limited to the 0 and 

≥125 mg/kg/day dose groups in the rats and 0 and 500 mg/kg/day groups in the mice. Renal effects 

occurred only in the 500 mg/kg/day male rats; these included tubular degeneration (6/10 incidence 

compared to 0/10 in lower dose and control groups) and increased urine volume (57% higher than 

controls). There were no exposure-related increases in BUN in either species. In chronic studies 

performed by NTP (1985), there were no nonneoplastic tissue changes in the kidneys of male or female 

F344 rats (50/sex/level) exposed to 0, 60, or 120 mg/kg/day in corn oil by gavage for 5 days/week for 

103weeks. In similarly-exposed B6C3F1 mice (50/sex/level) exposure to 120 mg/kg/day, but not to 

60 mg/kg/day, resulted in a significantly increased incidence of renal tubular regeneration (controls: 

8/48; low dose: 12/50; high dose: 17/49) relative to controls. The incidence data for renal tubular 

regeneration in mice (NTP 1985) were used to derive a chronic-duration oral MRL of 0.3 mg/kg/day for 

1,2-DCB. Renal end points other than histology were not assessed in the chronic studies. 

1,3-Dichlorobenzene. No studies were located regarding renal effects in humans after oral exposure to 

1,3-DCB. 

No gross or histological changes were observed in the kidneys or urinary bladder in male or female 

Sprague-Dawley rats that were exposed to 1,3-DCB in corn oil by gavage in doses of 735 mg/kg/day for 

10 consecutive days or 588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). Blood urea 

nitrogen (BUN) and kidney weight was measured in both studies, although only relative organ weights 

were reported. There was a statistically significant increase in relative kidney weight at ≥147 mg/kg/day 

in males and 735 mg/kg/day in females in the 90-day study, but this is not considered to be an adverse 

effect due to decreases in body weight gain and lack of changes in BUN and renal histology. 

1,4-Dichlorobenzene. No studies were located regarding renal effects in humans after oral exposure to 

1,4-DCB. 
DICHLOROBENZENES 172 

3. HEALTH EFFECTS 

The role of cell proliferation in kidney toxicity induced by 1,4-DCB was examined in groups of male and 

female B6C3F1 mice and F344 rats (Umemura et al. 1992). Mice were administered 300 or 600 mg/kg 

1,4-DCB; in rats, males received 150 or 300 mg/kg 1,4-DCB while females received 300 or 600 mg/kg 

1,4-DCB. All doses were administered by gavage in corn oil for 4 consecutive days. Cell proliferation 

was evaluated by means of immunohistochemical measurement of BrdU-labeled cells. In mice, kidney 

weights and cell proliferation in the kidney tubules were not altered by 1,4-DCB treatment; in rats, kidney 

weight was significantly increased in male rats at both dose levels, but was not affected in females. Cell 

proliferation was greatly increased in the proximal convoluted tubule from high-dose males. A lesser 

increase was seen in the proximal straight tubule from high-dose males; no increase was observed in the 

distal tubule from males or in any kidney region from treated female rats. 

The effects of 1,4-DCB were compared in male F344 rats given 0 (corn oil control), 25, 75, 150, and 

300 mg/kg/day 1,4-DCB (n=6–8/group/time) and male B6C3F1 mice given 0 (corn oil control), 300, and 

600 mg/kg/day 1,4-DCB (n=6–8/group/time) by daily oral gavage 5 days/week for 1 week. Replicative 

DNA synthesis was studied using subcutaneously implanted osmotic pumps containing 5-bromo2'-deoxyuridine during study weeks 0–1, 3–4, and 12–13. After sacrifice, the kidneys were removed, 

weighed, and immunostained. In rats, significant increases in relative kidney weight were observed in 

those rats administered 150 and 300 mg/kg 1,4-DCB for 4 and 13 weeks. 1,4-DCB treatment produced 

significant increases in rat renal P1/P2 proximal tubule cell labeling index values at all time points. 

Significant increases were seen in the following groups: 75 mg/kg 1,4-DCB at 4 weeks (250% of 

controls); 150 mg/kg 1,4-DCB at 4 and 13 weeks (400 and 440% of controls, respectively); and 

300 mg/kg 1,4-DCB at 1, 4, and 13 weeks (170, 475, and 775% of controls, respectively). A significant 

increase in rat P3 renal proximal tubule cell labeling index values was observed in 300 mg/kg 1,4-DCB 

group rats at weeks 4 (185% of controls) and 13 (485% of controls). In contrast, some reduction in rat 

P3 renal proximal tubule cell labeling index values was observed in 75–300 mg/kg 1,4-DCB group rats at 

1 week. In contrast, 1,4-DCB treatment produced little effect on mouse renal P1/P2 proximal tubule cell 

labeling index values at all time points tested. No significant increase was seen in 300 or 600 mg/kg 

1,4-DCB groups for 1 and 13 weeks, but significant increases were seen at 4 weeks (205 and 170% of 

controls, respectively). Neither 300 nor 600 mg/kg 1,4-DCB for 1, 4, or 13 weeks had much effect on 

mouse P3 renal proximal tubule cell labeling index values (Lake et al. 1997). 

In a study that examined the role of the protein α2μ-globulin in 1,4-DCB-induced nephrotoxicity in male 

rats, NCI-Black-Reiter (NBR) rats, known not to synthesize the hepatic form of the α2μ-globulin, were 

administered 500 mg/kg/day 1,4-DCB by gavage in corn oil for 4 consecutive days. Positive controls 
 

 

DICHLOROBENZENES 173 

3. HEALTH EFFECTS 

consisted of F344 male rats treated with lindane; the results were also compared with those obtained in a 

group of female F344 rats treated with lindane. End points examined consisted of kidney lesions and 

protein droplet evaluation. α2μ-Globulin was detected in kidney sections from male F344 rats, but not in 

male NBR or female F344 rats. No lesions or hyaline droplets were detected in treated or control male 

NBR and female F344 rats (Dietrich and Swenberg 1991). 

Renal tubular degeneration has been observed in male but not female F344 rats in two 13-week gavage 

studies (NTP 1987). These effects were severe in male rats receiving ≥300 mg/kg/day in the first study, 

but in the second study, only slight changes were seen at 300 mg/kg/day, while moderate tubular 

degeneration was present at 600 mg/kg/day. Renal effects reported in another intermediate-duration 

gavage study in rats included increased renal weights at doses of ≥188 mg/kg/day (Hollingsworth et al. 

1956). Renal effects were not observed in mice in either of two 13-week gavage studies using dosage 

regimens of 600–1,800 and 84.4–900 mg/kg/day (NTP 1987). 

In a study designed to investigate the mechanism of renal toxicity for 1,4-DCB reported in the NTP 

(1987) studies, 1,4-DCB administered by gavage to male F344 rats at 7 daily doses of 120 or 

300 mg/kg/day significantly increased the level of protein droplet formation in the kidneys of males but 

not females (Charbonneau et al. 1987). Administration of a single dose of 14C-1,4-DCB by gavage at 

500 mg/kg gave similar results. An analysis of the renal tissue of animals administered radio-labeled 

1,4-DCB indicated that it was reversibly associated with the protein α2μ-globulin. In a study designed to 

correspond to the experimental conditions of the 13-week NTP (1987) study in rats, 1,4-DCB was 

administered to F344 rats by gavage at 75–600 mg/kg/day for 13 weeks; interim sacrifices were 

performed at 4 weeks (Bomhard et al. 1988). At 4 weeks, females had no structural damage to the 

kidneys, while males experienced damage at the corticomedullary junction at doses of 150 mg/kg or 

more; damage consisted of dilated tubules with granular and crystalline structures, hyaline droplets, and 

desquamated epithelia. At all dose levels in the males, hyaline bodies were seen in the proximal tubule 

epithelial cells. At 13 weeks, males exhibited an increase urinary excretion of LDH and of epithelial cells 

over the entire dose range tested. These changes did not always appear to be dose-related. No signs of 

structural damage were seen in the females' kidneys. In males, a dose-dependent incidence of hyaline 

droplets in the cortical tubular epithelium was seen at 75 mg/kg/day and above. At ≥150 mg/kg/day, 

single-cell necrosis was observed, and at 300 and 600 mg/kg/day, epithelial desquamation of longer parts 

of the tubules were occasionally seen. 
 

 

 

DICHLOROBENZENES 174 

3. HEALTH EFFECTS 

In the only available study of chronic-duration oral exposure to 1,4-DCB, renal effects were observed to 

occur preferentially in male rats. Male F344 rats exposed to 1,4-DCB at 150 and 300 mg/kg/day by 

gavage for 2 years exhibited the following effects with greater severity and in greater numbers: 

nephropathy, epithelial hyperplasia of the renal pelvis, mineralization of the collecting tubules in the renal 

medulla, and focal hyperplasia of renal tubular epithelium (NTP 1987). There was also increased 

incidence of nephropathy in female rats dosed with 1,4-DCB at 300 and 600 mg/kg/day, but there was 

minimal hyperplasia of the renal pelvis or tubules. Administration of 1,4-DCB at 300 and 600 mg/kg/day 

for 2 years also increased the incidence of nephropathy in male B6C3F1 mice. Renal tubular degeneration 

was noted in female mice, but these changes occurred at a lower frequency and were qualitatively 

different from those in male rats (NTP 1987). 

In a study with dogs, groups of five male and five female Beagles were administered 1,4-DCB by capsule 

in dose levels of 0, 10, 50, or 75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 1996). 

Histopathological changes were observed in the kidneys that included collecting duct epithelial 

vacuolation in one male at 75 mg/kg/day, and in females at all dose levels (one at 10 mg/kg/day, one at 

50 mg/kg/day, and two at 75 mg/kg/day). This renal lesion was considered to be a possible effect of 

treatment at ≥50 mg/kg/day where it was accompanied by increased relative kidney weight (50 mg/kg/day 

females) and gross observed renal discoloration (two females at 75 mg/kg/day). No gross or histological 

changes were found in the urinary bladder. 

Endocrine Effects. 

1,2-Dichlorobenzene. No studies were located regarding endocrine effects in humans after oral exposure 

to 1,2-DCB. 

No gross or histological changes were observed in the adrenal or pancreas of Sprague-Dawley rats that 

were administered 1,2-DCB in corn oil by gavage in a dose of 300 mg/kg/day for 10 consecutive days, or 

in the adrenal (pancreas not examined) in rats similarly exposed to 400 mg/kg/day for 90 consecutive 

days (Robinson et al. 1991). No gross or histological changes were observed in the adrenal, pancreas, 

thyroid, parathyroid, or pituitary of F344 rats or B6C3F1 mice that were treated with 1,2-DCB in corn oil 

by gavage in doses ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), or ≤120 mg/kg/day, 

5 days/week for 103 weeks (NTP 1985). 
 

 

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1,3-Dichlorobenzene. No studies were located regarding endocrine effects in humans after oral exposure 

to 1,3-DCB. 

Gross and histological examinations of adrenals, pancreas, pituitary, thyroid, parathyroids, and gonads 

were performed in groups of 10 male and 10 female Sprague-Dawley rats that were exposed to 1,3-DCB 

in oil by daily gavage, in doses of 0 or 735 mg/kg/day for 10 consecutive days or 588 mg/kg/day for 

90 consecutive days (McCauley et al. 1995). The 90-day study additionally included examinations of 

thyroid and pituitary at lower dose levels of 9, 37, and 147 mg/kg/day. No compound-related endocrine 

effects were observed in the 10-day study. As discussed below, the 90-day study found histological 

effects in the thyroid at ≥9 mg/kg/day and the pituitary at ≥147 mg/kg/day. The only other tissue with 

histological changes in the 90-day study was the liver (see Hepatic Effects). 

Inflammatory and degenerative lesions in the McCauley et al. (1995) 90-day study were graded on a 

relative scale from one to four depending on severity (minimal, mild, moderate, or marked). In the 

thyroid, colloidal density in the follicular cells was significantly (p≤0.05) increased in male rats at 

≥9 mg/kg/day and female rats at ≥37 mg/kg/day. The incidences of this lesion in the 0, 9, 37, 147, and 

588 mg/kg/day dose groups were 2/10, 8/10, 10/10, 8/9, and 8/8 in males and 1/10, 5/10, 8/10, 8/10, and 

8/9 in females. Depletion of colloid density in the thyroid was characterized by decreased follicular size 

with scant colloid and follicles lined by cells that were cuboidal to columnar. The severity of the colloid 

density depletion generally ranged from mild to moderate, increased with dose level, and was greater in 

males than females. For example, in the 147 and 588 mg/kg/day groups, severity was classified as 

moderate in males and mild for the females. Incidences of male rats with thyroid colloidal density 

depletion of moderate or marked severity were significantly increased at ≥147 mg/kg/day (0/10, 0/10, 

2/10, 5/9, and 6/8). The lowest tested dose, 9 mg/kg/day, is considered to be a minimal LOAEL because 

the morphological alterations (reduced colloidal density in follicles) are unlikely to be associated with 

functional changes in the thyroid. The pituitary effect was cytoplasmic vacuolization in the pars distalis 

and only found in the male rats. Incidences of this lesion were significantly (p≤0.05) increased in males 

at ≥147 mg/kg/day (2/10, 6/10, 6/10, 10/10, and 7/7); incidences in the 9 and 37 mg/kg/day groups were 

marginally increased (p=0.085). The vacuoles were variably sized, irregularly shaped, and often poorly 

defined, and severity (number of cells containing vacuoles) ranged from minimal to mild. The severity of 

the lesions generally increased with increasing dose level, and incidences of male rats with pituitary 

cytoplasmic vacuolization of moderate or marked severity were significantly increased at 588 mg/kg/day 

(1/10, 0/10, 2/10, 3/9, and 7/7). The pituitary lesion was reported to be similar to “castration cells” found 

in gonadectomized rats, and considered to be an indicator of gonadal deficiency. No compound-related 
DICHLOROBENZENES 176 

3. HEALTH EFFECTS 

pituitary lesions were observed in female rats. The incidences of pituitary lesions in male rats (McCauley 

et al. 1995) were used to derive an intermediate-duration oral MRL of 0.02 mg/kg/day for 1,3-DCB. 

Other effects in this 90-day study included significant increases in serum cholesterol in males at 

≥9 mg/kg/day and females at ≥37 mg/kg/day, and serum calcium in both sexes at ≥37 mg/kg/day. The 

study authors suggested that these serum chemistry changes might reflect a disruption of hormonal 

feedback mechanisms, or target organ effects on the pituitary, hypothalamus, and/or other endocrine 

organs. 

1,4-Dichlorobenzene. No studies were located regarding endocrine effects in humans after oral exposure 

to 1,4-DCB. 

In a series of dose range-finding studies, groups of F344 rats were administered 1,4-DCB at 

concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks. At 

sacrifice, animals were examined grossly and major tissues were examined histologically. No endocrine 

organs were affected in any of the 1,4-DCB-treated rats. In parallel studies with B6C3F1 mice, no 

compound-related endocrine effects were observed after administration of 1,4-DCB at concentrations 

ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks (NTP 1987). 

In the only study of lifetime oral exposure to 1,4-DCB in laboratory animals (NTP 1987), groups of male 

and female F344 rats were administered 1,4-DCB by gavage in corn oil, 5 days/week for 103 weeks at 

doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females). Groups of male and female 

B6C3F1 mice were administered 1,4-DCB at doses of 300 or 600 mg/kg/day by gavage in corn oil, 

5 days/week for 103 weeks. In the F344 rats, an increased incidence of parathyroid hyperplasia was 

observed in males (4/42 controls, 13/42 low-dose, 20/38 high-dose), while no effect was seen in females. 

In mice, the incidence of thyroid follicular cell hyperplasia increased with dose in males (1/47 control, 

4/48 low-dose, 10/47 high-dose), but not in females. The incidence of adrenal medullary hyperplasia and 

focal hyperplasia of the adrenal gland capsule also increased with dose in males (controls, 11/47; lowdose, 21/48; high-dose, 28/49). 

No gross or histological changes were found in the adrenal, thyroid, parathyroid, pancreas, or pituitary 

glands of Beagle dogs (5/sex/level) that were administered 1,4-DCB by capsule in doses as high as 

75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 1996). 
 

 

DICHLOROBENZENES 177 

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Dermal Effects. 

1,2-Dichlorobenzene. No studies were located regarding dermal effects in humans after oral exposure to 

1,2-DCB. 

No gross or histological changes were observed in the skin of Sprague-Dawley or F344 rats that were 

administered 1,2-DCB in corn oil by gavage in doses of 300 mg/kg/day for 10 consecutive days 

(Robinson et al. 1991), ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), or ≤120 mg/kg/day, 

5 days/week for 103 weeks (NTP 1985). Additionally, there were no gross or histological effects in the 

skin of B6C3F1 mice that were similarly treated with ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 

1985) or ≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding dermal effects in humans after oral exposure to 

1,3-DCB. 

No gross or histological changes were observed in the skin in male or female Sprague-Dawley rats that 

were exposed to 1,3-DCB in corn oil by gavage in doses of 735 mg/kg/day for 10 consecutive days or 

588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). 

1,4-Dichlorobenzene. A 19-year-old black woman who had been eating 4–5 moth pellets made of 

1,4-DCB daily for 2.5 years developed symmetrical, well demarcated areas of increased pigmentation in a 

bizarre configuration over various parts of her body. After she discontinued this practice, the skin 

discolorations gradually disappeared over the next 4 months (Frank and Cohen 1961). 

In laboratory animals, groups of F344 rats were administered 1,4-DCB at concentrations ranging from 

37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks. No dermal effects were noted 

in any of the 1,4-DCB-treated rats. In parallel studies with B6C3F1 mice, no compound-related dermal 

effects were observed after administration of 1,4-DCB at concentrations ranging from 84.4 to 

1,800 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks (NTP 1987). 

In the only study of lifetime oral exposure to 1,4-DCB in laboratory animals (NTP 1987), groups of male 

and female F344 rats were administered 1,4-DCB by gavage in corn oil, 5 days/week for 103 weeks at 

doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females). Groups of male and female 

B6C3F1 mice were administered 1,4-DCB at doses of 300 or 600 mg/kg/day by gavage in corn oil, 
DICHLOROBENZENES 178 

3. HEALTH EFFECTS 

5 days/week for 103 weeks. No dermal effects have been reported in rats or mice at any of the studied 

doses. 

No gross or histological changes were found in the skin of Beagle dogs (5/sex/level) that were 

administered 1,4-DCB by capsule in doses as high as 75 mg/kg/day, 5 days/week for 1 year (Naylor and 

Stout 1996). 

Ocular Effects. 

1,2-Dichlorobenzene. No studies were located regarding ocular effects in humans after oral exposure to 

1,2-DCB. Opthalmoscopic examinations showed no effects in Sprague-Dawley rats that were dosed with 

400 mg/kg/day of 1,2-DCB in corn oil by gavage for 90 consecutive days (Robinson et al. 1991). No 

gross or histological changes were observed in eyes of F344 rats or B6C3F1 mice that were similarly 

exposed to ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985) or ≤120 mg/kg/day, 5 days/week for 

103 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding ocular effects in humans or animals after oral 

exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding the ocular effects in humans after oral exposure 

to 1,4-DCB. 

In a series of intermediate-duration studies, groups of F344 rats were administered 1,4-DCB at 

concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days/week for 13 weeks. 

Ocular discharge was noted prior to death in males dosed with 1,200 mg/kg and in all rats exposed to 

1,500 mg/kg. In parallel studies with B6C3F1 mice, no compound-related ocular effects were observed 

after administration of 1,4-DCB at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in 

corn oil 5 days/week for 13 weeks (NTP 1987). 

The ocular effects of oral administration of 1,4-DCB were examined in groups of white (strain not 

reported) female rats and male and female rabbits. Rats received 1,4-DCB in olive oil at doses of 18.8– 

376 mg/kg/day, 5 days/week for 192 days; rabbits received 1,4-DCB in olive oil at a dose of 

1,000 mg/kg/day for 219 days. Under the study conditions, administration of 1,4-DCB did not produce 

cataracts in either species (Hollingsworth et al. 1956). 
 

 

DICHLOROBENZENES 179 

3. HEALTH EFFECTS 

In chronic-duration toxicity studies in laboratory animals, Hollingsworth et al. (1956) found no evidence 

of cataract formation in rabbits administered a total of 263 doses of 500 mg/kg/day 1,4-DCB in olive oil 

over a 367-day period. 

In two lifetime oral exposure studies (NTP 1987), groups of male and female F344 rats were administered 

1,4-DCB by gavage in corn oil, 5 days/week for 103 weeks at doses of 150 or 300 mg/kg/day (males) or 

300 or 600 mg/kg/day (females); groups of male and female B6C3F1 mice were administered 1,4-DCB at 

doses of 300 or 600 mg/kg/day by gavage in corn oil, 5 days/week for 103 weeks. In both species, no 

ocular effects were noted at any of the studied doses. 

Opthalmoscopic examination showed no ocular effects in Beagle dogs (5/sex/level) that were 

administered 1,4-DCB by capsule in doses as high as 75 mg/kg/day, 5 days/week for 1 year (Naylor and 

Stout 1996). 

Body Weight Effects. 

1,2-Dichlorobenzene. No studies were located regarding body weight effects in humans after oral 

exposure to 1,2-DCB. 

Gavage exposure to 1,2-DCB in oil has adversely affected body weight gain in rodent at doses that also 

caused other signs of toxicity. Decreases in body weight gain in the range of 10–20% were observed in 

rats exposed to 300 mg/kg/day for 10 consecutive days (Robinson et al. 1991), 400 mg/kg/day for 

90 consecutive days (Robinson et al. 1991), 1,000 mg/kg/day for 14 consecutive days (NTP 1985), and 

500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), as well as in mice exposed to 500 mg/kg/day, 

5 days/week for 13 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding body weight effects in humans after oral 

exposure to 1,3-DCB. 

Body weight was measured in groups of 10 male and 10 female Sprague-Dawley rats that were exposed 

to 1,3-DCB in corn oil by daily gavage, in doses of 0, 37, 147, 368, or 735 mg/kg/day for 10 consecutive 

days, or 9, 37, 147, or 588 mg/kg/day for 90 consecutive days (McCauley et al. 1995). Decreases in body 

weight gain occurred in both sexes at the high dose in both studies. In the 10-day study, final body 
DICHLOROBENZENES 180 

3. HEALTH EFFECTS 

weights at 735 mg/kg/day were 20 and 13% lower than controls in males and females, respectively. The 

weight loss was progressive throughout the exposure period and, in males, accompanied by significantly 

reduced food consumption (12%, normalized by body weight). In the 90-day study, final body weights at 

588 mg/kg/day were 24 and 10% lower than controls in males and females, respectively. The weight loss 

was progressive throughout the exposure period, and occurred despite increased food and water 

consumption. 

1,4-Dichlorobenzene. No studies were located regarding body weight effects in humans after oral 

exposure to 1,4-DCB. 

The effects of acute exposure to 1,4-DCB on body weight were examined in female Wistar rats given 

1,4-DCB suspended in 2% tragacanth gum solution (a suspending agent obtained from the dried gummy 

exudation of Astragalus gummifer) at a dose of 250 mg/kg/day for 3 days. Under these conditions, no 

effects on body weight were seen (Ariyoshi et al. 1975). Male and female mice and female rats dosed 

once with 600 mg/kg/day 1,4-DCB also showed no discernible changes in body weight (Eldridge et al. 

1992). Male rats administered 770 mg/kg/day of 1,4-DCB once a day for 5 days showed no changes in 

body weight (Rimington and Ziegler 1963). Pregnant CD rats that were administered 250– 

1,000 mg/kg/day 1,4-DCB in corn oil on Gd 6–15 experienced a reversible loss in maternal body weight 

(Giavini et al. 1986). 

Body weight changes were observed in three studies in rats and mice (NTP 1987). In the first, both sexes 

of mice and female rats dosed at concentrations up to 1,000 mg/kg/day for 14 days by gavage 

demonstrated no changes in body weight during the test period. Male rats dosed at 500 mg/kg/day also 

showed no changes in body weight; however, a 7–12% decrease in body weight was noted in the 

1,000 mg/kg/day dose group. In the second study (same route and duration as the first), male mice 

experienced a 13.3% decrease in body weight at the 250 mg/kg/day dose and a 14.7% decrease in body 

weight at the 2,000 mg/kg/day dose; however, results of intermediate doses demonstrated that there was 

no observable dose-response relationship for body weight changes. Neither male nor female rats dosed 

with 500 mg/kg/day showed any effects on body weights; however, a dose of 1,000 mg/kg/day resulted in 

a 13.5% decrease in weight for males and a 16.7% decrease in females. In the third study, male rats 

gavaged with 0, 25, 75, or 150 mg/kg of 1,4-DCB in corn oil for 7 days showed no changes in body 

weight; however, rats dosed at 300 mg/kg showed an approximately 10% decrease in body weight gain 

(Lake et al. 1997). The same study in male mice dosed with 0, 300, or 600 mg/kg of 1,4-DCB in corn oil 

for 7 days showed no changes in body weight at any dose level (Lake et al. 1997). 
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3. HEALTH EFFECTS 

In intermediate-duration studies, no compound-related effects on weight gain were noted in albino or 

F344 rats administered 1,4-DCB by gavage in corn oil at doses up to 600 mg/kg/day, 7 days/week for 

13 weeks (Bomhard et al. 1988; Carlson and Tardiff 1976). Male rats gavaged with 0 or 25 mg/kg of 

1,4-DCB in corn oil for 7 days showed no changes in body weight; however, rats dosed at 75, 150, or 

300 mg/kg showed an approximately 10% decrease in body weight gain (Lake et al. 1997). The same 

study in male mice dosed with 0, 300, or 600 mg/kg of 1,4-DCB in corn oil for 7 days showed no changes 

in body weight at any dose level (Lake et al. 1997). Male and female mice and female rats dosed with 

concentrations of 600 mg/kg/day 1,4-DCB 5 days/week for 13 weeks also showed no discernible changes 

in body weight (Eldridge et al. 1992). In a series of dose range-finding studies, groups of F344 rats were 

administered 1,4-DCB at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil, 

5 days/week for 13 weeks (NTP 1987). In the first of these studies, there were no treatment-related 

effects on body weight at doses up to 600 mg/kg/day. In the second study, final body weight was 

decreased by 11% in low-dose males (300 mg/kg/day) relative to controls; in high-dose males 

(1,500 mg/kg/day), the reduction was 32%. The effect was less marked in females (6% reduction at 

900 mg/kg/day; 11% reduction at 1,200 mg/kg/day). In parallel studies with B6C3F1 mice, no compoundrelated effects on body weight were observed after administration of 1,4-DCB at concentrations up to 

900 mg/kg/day; however, in the second study, final body weight was reduced in all males receiving 

1,4-DCB (11.4% at 1,500 mg/kg/day to 13.9% at 600 mg/kg/day) and in females at 600 mg/kg/day 

(10.3%) (NTP 1987). 

In two lifetime oral exposure studies, groups of male and female F344 rats and B6C3F1 mice were 

administered 1,4-DCB by gavage in corn oil, 5 days/week for 103 weeks. Fischer 344 rats were 

administered 1,4-DCB at doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females); 

mice were administered 1,4-DCB at doses of 300 or 600 mg/kg/day (NTP 1987). In mice, no effects on 

body weight attributable to treatment with 1,4-DCB were observed at doses up to 600 mg/kg/day. In rats, 

body weight gain was depressed by 12.5% in high-dose males (300 mg/kg/day) and by 12.4% in highdose females (600 mg/kg/day) relative to vehicle controls. 

There were no adverse body weight changes in Beagle dogs (5/sex/level) that were administered 1,4-DCB 

by capsule in doses as high as 75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 1996). 
DICHLOROBENZENES 182 

3. HEALTH EFFECTS 

3.2.2.3 Immunological and Lymphoreticular Effects 

1,2-Dichlorobenzene. No studies were located regarding immunological or lymphoreticular effects in 

humans after oral exposure to 1,2-DCB. 

Immunological function has not been assessed in animals orally exposed to 1,2-DCB. No gross or 

histological changes were observed in the spleen, thymus, or lymph nodes of male or female SpragueDawley rats that were administered 1,2-DCB in corn oil by gavage in doses of 300 mg/kg/day for 

10 consecutive days or 400 mg/kg/day for 90 consecutive days (Robinson et al. 1991). Gross and 

histological examinations of lymph nodes, spleen, thymus, and bone marrow were performed in F344 rats 

and B6C3F1 mice that were exposed to 1,2-DCB in corn oil by gavage 5 days/week in doses 

≤500 mg/kg/day for 13 weeks or ≤120 mg/kg/day for 103 weeks (NTP 1985). The only changes in these 

tissues occurred at 500 mg/kg/day in the 13-week study; effects included lymphoid depletion in the 

thymus (4/10 male rats, 2/10 male mice, 2/10 female mice) and spleen (4/10 male mice, 2/10 female 

mice). 

1,3-Dichlorobenzene. No studies were located regarding immunological or lymphoreticular effects in 

humans after oral exposure to 1,3-DCB. 

Immunological function has not been assessed in animals orally exposed to 1,3-DCB. No gross or 

histological changes were observed in the spleen, thymus, or mandibular and mesenteric lymph nodes of 

male or female Sprague-Dawley rats that were exposed to 1,3-DCB in corn oil by gavage in doses of 

735 mg/kg/day for 10 consecutive days, or 588 mg/kg/day for 90 consecutive days (McCauley et al. 

1995). Spleen and thymus weight was measured in both studies, although only relative organ weights 

were reported. In the 10-day study, relative spleen weight was significantly decreased in females at 

≥368 mg/kg/day and males at 735 mg/kg/day, and relative thymus weight was significantly decreased in 

both sexes at 735 mg/kg/day. These changes are not considered adverse because body weight gain was 

decreased and they were not observed after 90 days or accompanied by histological alterations. 

1,4-Dichlorobenzene. No studies were located regarding immunological effects in humans after oral 

exposure to 1,4-DCB. Symmetrical lesions with a bizarre pattern of skin pigmentation over most of her 

body were reported in the case study of a 19-year-old black woman who ingested 4–5 moth pellets of 

1,4-DCB per day for a 2.5-year period (Frank and Cohen 1961). The lesion disappeared 4 months after 
DICHLOROBENZENES 183 

3. HEALTH EFFECTS 

cessation. The described lesions may have been the result an immunological response to 1,4-DCB. 

However, this possibility was not addressed by the authors. 

Groups of F344 rats were administered 1,4-DCB at concentrations ranging from 300 to 1,500 mg/kg/day 

by gavage in corn oil, 5 days/week for 13 weeks (NTP 1987). Treatment-related immunological and 

lymphoreticular effects noted in the study included hypoplasia of the bone marrow and lymphoid 

depletion of the spleen and thymus in males and females at doses of 1,200 mg/kg/day and above. In 

parallel studies with B6C3F1 mice administered 1,4-DCB at concentrations ranging from 300 to 

1,500 mg/kg/day, lymphoid necrosis in the thymus, lymphoid depletion in the spleen, and hematopoietic 

hypoplasia of the spleen and bone marrow were noted in both males and females at doses of 

1,500 mg/kg/day and above (NTP 1987). 

Minimal lymphoreticular changes were noted in a chronic-duration study (NTP 1987). Male rats 

administered doses of 150 or 300 mg/kg/day and female rats given 300 or 600 mg/kg/day of 1,4-DCB by 

gavage 5 days/week for 2 years showed no discernible changes in the lymphoreticular system; however, 

mice dosed in a similar fashion and at a dose of 600 mg/kg/day showed an increased incidence of lymph 

node hyperplasia. 

No gross or histological changes were found in spleen, thymus, or lymph nodes of Beagle dogs 

(5/sex/level) that were administered 1,4-DCB by capsule in doses as high as 75 mg/kg/day, 5 days/week 

for 1 year (Naylor and Stout 1996). 

3.2.2.4 Neurological Effects 

1,2-Dichlorobenzene. No studies were located regarding neurological effects in humans after oral 

exposure to 1,2-DCB. 

Neurobehavioral function has not been assessed in animals orally exposed to 1,2-DCB. Ataxia and clonic 

contractions were observed in a small group of rats (three males) administered 1,2-DCB in liquid paraffin 

by gavage in a porphyrinogenic dose regimen of 455 mg/kg/day for 15 consecutive days (Rimington and 

Ziegler 1963). No clinical signs of neurotoxicity or histological changes in the brain were found in 

Sprague-Dawley or F344 rats that were administered 1,2-DCB in corn oil by gavage in doses of 

300 mg/kg/day for 10 consecutive days (Robinson et al. 1991), 400 mg/kg/day for 90 consecutive days 

(Robinson et al. 1991), ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), or ≤120 mg/kg/day, 
DICHLOROBENZENES 184 

3. HEALTH EFFECTS 

5 days/week for 103 weeks (NTP 1985). The 10-day rat study also found no histological changes in 

sciatic nerve tissue, and the 90-day rat study also found no changes in absolute or relative brain weight 

(Robinson et al. 1991). Additionally, there were no signs of neurotoxicity or histological effects in the 

brain of B6C3F1 mice that were gavaged with ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985) or 

≤120 mg/kg/day, 5 days/week for 103 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding immunological effects in humans after oral 

exposure to 1,3-DCB. 

Neurobehavioral function has not been assessed animals orally exposed to 1,3-DCB. No clinical signs of 

neurotoxicity, or histological changes in the nervous system (brain or sciatic nerve), occurred in male or 

female Sprague-Dawley rats that were exposed to 1,3-DCB in corn oil by gavage in doses of 

735 mg/kg/day for 10 consecutive days, or 588 mg/kg/day for 90 consecutive days (McCauley et al. 

1995). 

1,4-Dichlorobenzene. Two case studies have reported neurological effects in humans exposed to 

1,4-DCB via ingestion have been reported in two case studies. A 21-year-old pregnant woman developed 

pica (a craving for unnatural substances) for 1,4-DCB toilet bowl deodorizer blocks, which she consumed 

at the rate of 1–2/week throughout pregnancy (Campbell and Davidson 1970). Reported neurological 

effects included fatigue, dizziness, and mild anorexia. These effects, however, are common general 

symptoms that occur in many women during normal pregnancy. A 19-year-old black woman who 

ingested 4–5 pellets of 1,4-DCB daily for about 2.5 years developed tremors and unsteadiness after she 

stopped eating this chemical. However, in the opinion of the neurologist who evaluated the woman in 

this case report, the effects were considered to be psychological rather than the physiological effects of 

withdrawal from 1,4-DCB (Frank and Cohen 1961). 

Two studies in laboratory animals indicate that oral exposure to 1,4-DCB may result in adverse 

neurological effects. In a study performed by Rimington and Ziegler (1963), three male albino rats were 

administered daily doses of 1,4-DCB in liquid paraffin at gradually increasing doses until a dose was 

reached (770 mg/kg/day), which resulted in high porphyrin excretion with very few fatalities; this dose 

was given for 5 days. Clinical symptoms associated with highly porphyric rats included extreme 

weakness, ataxia, clonic contractions, and slight tremors (a rarity). One rat receiving 1,4-DCB developed 

left-sided hemiparesis. In F344 rats administered 1,4-DCB by gavage in corn oil 5 days/week for 

13 weeks, tremors and poor motor response were observed in males at 1,200 mg/kg/day and above, and in 
DICHLOROBENZENES 185 

3. HEALTH EFFECTS 

both sexes at 1,500 mg/kg/day. However, administration of 1,4-DCB had no effect on brain weight or on 

the microscopical appearance of the brain, sciatic nerve, or spinal cord (NTP 1987). 

In a chronic-duration study (NTP 1987), no neurological effects were noted either in rats dosed with 

300 mg/kg/day of 1,4-DCB, 5 days/week for 2 years, or in mice dosed with 600 mg/kg/day, 5 days/week 

for 2 years. 

No gross or histological changes were found in the brain, spinal cord (three levels), or peripheral or optic 

nerves of Beagle dogs (5/sex/level) that were administered 1,4-DCB by capsule in doses as high as 

75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 1996). 

3.2.2.5 Reproductive Effects 

1,2-Dichlorobenzene. No studies were located regarding reproductive effects in humans after oral 

exposure to 1,2-DCB. 

Reproductive function has not been assessed in animals orally exposed to 1,2-DCB. No gross or 

histological changes were observed in the testes, seminal vesicles, prostate, or ovaries of Sprague-Dawley 

rats that were administered 1,2-DCB in corn oil by gavage in a dose of 300 mg/kg/day for 10 consecutive 

days (Robinson et al. 1991). There were no changes in testis or ovary weight (absolute or relative) or 

histology in Sprague-Dawley rats that were similarly exposed to 400 mg/kg/day for 90 consecutive days 

(Robinson et al. 1991). Additionally, no gross or histological changes occurred in reproductive tissues of 

male (prostate, testes) or female (ovaries, uterus) F344 rats and B6C3F1 mice that were similarly exposed 

to ≤500 mg/kg/day, 5 days/week for 13 weeks (NTP 1985) or ≤120 mg/kg/day, 5 days/week for 

103 weeks (NTP 1985). 

1,3-Dichlorobenzene. No studies were located regarding reproductive effects in humans after oral 

exposure to 1,3-DCB. 

Reproductive function has not been assessed in animals orally exposed to 1,3-DCB. No histological 

changes occurred in male or female reproductive tissues (testes, seminal vesicles, prostate, preputial 

gland, clitoral gland, ovaries, or mammary gland).of Sprague-Dawley rats that were exposed to 1,3-DCB 

in corn oil by gavage in doses of 735 mg/kg/day for 10 consecutive days or 588 mg/kg/day for 

90 consecutive days (McCauley et al. 1995). Testis and ovary weight was measured in both studies, 
DICHLOROBENZENES 186 

3. HEALTH EFFECTS 

although only relative organ weights were reported. There was a statistically significant but small 

decrease (10.6% less than controls) in relative testes weight at 735 mg/kg/day in the 10-day study, but this 

is not considered to be an adverse effect because the magnitude of change was small, body weight gain 

was decreased, and there were no accompanying testicular histological alterations. 

1,4-Dichlorobenzene. No studies were located regarding reproductive effects in humans after oral 

exposure to 1,4-DCB. 

1,4-DCB was administered to female CD rats by gavage in corn oil on Gd 6–15 in a developmental 

toxicity study (Giavini et al. 1986). Doses up to 1,000 mg/kg/day had no adverse effect on the mean 

number of corpora lutea, mean number of implantations, mean percentage of pre- or postimplantation 

losses, or mean percentage of dams with resorptions (Giavini et al. 1986). In another developmental 

toxicity study of 1,4-DCB, female Wistar rats were exposed to a reported estimated dietary dose of 

2 mg/kg/day from gestation day (Gd) 1 to postnatal day (Pnd) 21 for a total of 42 days (Makita 2005). 

There were no exposure-related effects on fertility, litter size, or sex ratio, and examinations of the pups at 

6 weeks of age showed no changes in serum levels of reproductive hormones (leutinizing hormone [LH] 

and follicle stimulating hormone [FSH] in both sexes, testosterone in males) or weight or histology of 

reproductive tissues (testes, epididymides, prostate, seminal vesicles, ovaries, and uterus). 

Intermediate- and chronic-duration toxicity studies were conducted in which F344/N and B6C3F1 mice 

were treated with 1,4-DCB in corn oil by gavage 5 days/week (NTP 1987). No gross or histological 

changes were observed in reproductive tissues (testis, ovary, uterus, or mammary gland) of rats exposed 

to ≤1,500 mg/kg/day for 13 weeks or ≤300 mg/kg/day for 103 weeks, or mice exposed to 

≤1,800 mg/kg/day for 13 weeks or ≤600 mg/kg/day for 103 weeks. No gross or histological changes 

were found in the testes, ovaries, or uterus of Beagle dogs that were administered 1,4-DCB by capsule in 

doses as high as 75 mg/kg/day, 5 days/week for 1 year (Naylor and Stout 1996). 

In a 2-generation study, 1,4-DCB was administered by daily gavage in olive oil to male and female 

Sprague-Dawley rats at dose levels of 0, 30, 90, or 270 mg/kg/day (Bornatowicz et al. 1994). Groups of 

24 F0 rats/sex/ dose were treated for 77 days (males) and 14 days (females) before mating, followed by 

exposure of both sexes for 21 days during mating and females during gestation. Groups of 

24 F1 weanlings/sex/dose were treated for 84 days before mating, followed by exposure of both sexes for 

30 days during mating and females during gestation (21 days) and lactation (21 days). There were no 

effects on mating or fertility in either generation as shown by duration between mating and successful 
DICHLOROBENZENES 187 

3. HEALTH EFFECTS 

copulation, and fertility index (percentage of pregnant animals out of the number of inseminated animals). 

Additional reproductive indices were not evaluated as the emphasis of the study was on postnatal 

developmental toxicity. As discussed in Section 3.2.2.6, developmental effects included reduced birth 

weight in F1 pups and increased F2 pup deaths between birth and postnatal day 4 at ≥90 mg/kg/day. 

3.2.2.6 Developmental Effects 

1,2-Dichlorobenzene. No studies were located regarding developmental effects in humans after oral 

exposure to 1,2-DCB. 

A limited amount of information is available on the prenatal developmental effects of 1,2-DCB in 

animals. In a gavage study inadequately reported as an abstract, Sprague-Dawley rats were administered 

50, 100, or 200 mg/kg/day of 1,2-DCB on days 6–15 of gestation (Ruddick et al. 1983). Maternal end 

points included body weight gain, 15 unspecified biochemical parameters, and histology. Fetal toxicity 

was assessed by evaluating litter size, fetal weight, deciduoma, and skeletal, visceral, and histological 

changes. The maternal and fetal histological examinations included liver and thyroid; other tissues were 

not specified. No teratological effects or maternal toxicity were reported. Additional relevant 

information on the design and results of this study was not included in the abstract. 

1,3-Dichlorobenzene. No studies were located regarding developmental effects in humans after oral 

exposure to 1,3-DCB. 

The developmental toxicity study of 1,3-DCB is from a gavage study inadequately reported as an abstract 

(Ruddick et al. 1983). Sprague-Dawley rats were administered 50, 100, or 200 mg/kg/day of 1,2-DCB on 

days 6–15 of gestation (use of controls not specified). Maternal end points included body weight gain, 

15 unspecified biochemical parameters, and histology. Fetal toxicity was assessed by evaluating litter 

size, fetal weight, deciduoma, and skeletal, visceral, and histological changes. The maternal and fetal 

histological examinations included liver and thyroid; other tissues were not specified. No teratological 

effects or maternal toxicity were reported. Additional relevant information on the design and results of 

this study was not included in the abstract. 

1,4-Dichlorobenzene. No studies were located regarding developmental effects in humans after oral 

exposure to 1,4-DCB. 
 

 

 

DICHLOROBENZENES 188 

3. HEALTH EFFECTS 

A dose-related increase in the incidence of an extra rib was observed in the fetuses of pregnant CD rats 

administered 1,4-DCB by gavage on Gd 6–15 at doses of 500, 750, and 1,000 mg/kg/day (Giavini et al. 

1986). A reduction in fetal weight was observed at 1,000 mg/kg/day. The reduction in fetal weight was 

not considered to be a fetotoxic effect since it was associated with a decrease in maternal weight gain at 

the same dosage level. The structural anomaly observed in these fetuses was dose-dependant, but was not 

considered to be a true adverse effect by the authors. However, these results raise the question of whether 

1,4-DCB ingested by the dams reached developing fetal tissue and elicited a developmental effect. 

Additional information on prenatal developmental effects of orally administered 1,4-DCB is available 

from a gavage study inadequately reported as an abstract (Ruddick et al. 1983). Sprague-Dawley rats 

were administered 50, 100, or 200 mg/kg/day of 1,4-DCB on days 6–15 of gestation (use of controls not 

specified). Maternal end points included body weight gain, 15 unspecified biochemical parameters, and 

histology. Fetal toxicity was assessed by evaluating litter size, fetal weight, deciduoma, and skeletal, 

visceral, and histological changes. The maternal and fetal histological examinations included liver and 

thyroid; other tissues were not specified. No teratological effects or maternal toxicity were reported. 

Additional relevant information on the design and results of this study was not included in the abstract. 

In a dietary study of 1,4-DCB, female Wistar rats were exposed to a reported estimated dose of 

2 mg/kg/day from Gd 1 to Pnd 21 for a total of 42 days (Makita 2005). There were no maternal effects as 

shown by clinical signs or changes in body weight and food consumption. No fetal examinations were 

performed but perinatal evaluations showed no gross external malformations or effects on litter size, sex 

ratio, or pup viability on Pnd 1. Postnatal assessments of the offspring until 6 weeks of age showed no 

effects on body weight gain, anogenital distance, times of eye and vaginal opening and preputial 

separation, or serum levels of reproductive hormones (LH and FSH in both sexes and testosterone in 

males at 6 weeks). Examination of the liver, kidneys, spleen, thymus, testes, epididymides, prostate, 

seminal vesicles, ovaries, uterus, and thymus at 6 weeks showed no effects on organ weight or histology, 

except for increased absolute thymus weight (approximately 20% higher than controls) in the female 

pups. The biological significance of this effect is unclear because it did not occur in the male offspring 

and was not accompanied by any histological changes. 

A 2-generation study was conducted in which 1,4-DCB in olive oil was administered by daily gavage to 

male and female Sprague-Dawley rats at dose levels of 0, 30, 90, or 270 mg/kg/day (Bornatowicz et al. 

1994). Groups of 24 F0 rats/sex/dose were treated for 77 days (males) and 14 days (females) before 

mating, followed by exposure of both sexes for 21 days during mating and of females during gestation. 
DICHLOROBENZENES 189 

3. HEALTH EFFECTS 

Exposure in the F0 females was continued throughout lactation until weaning of the F1 pups on postnatal 

day 21. Groups of 24 F1 weanlings/sex/dose were treated for 84 days before mating, followed by 

exposure of both sexes for 30 days during mating, and of females during gestation and lactation. The 

study was ended following weaning of the F2 pups on postnatal day 21. The F0 and F1 males were 

sacrificed 21 days after the end of the mating period (it is unclear if exposure continued postmating), and 

the F0 and F1 females were sacrificed after their pups were weaned. Study end points included clinical 

observations in adults and pups, body weight and food consumption in maternal animals (during gestation 

and lactation) and pups (from birth to day 21), reproductive indices, gestation length, litter size, numbers 

of live and dead pups, postnatal survival, postnatal developmental milestones (times to erect ears and 

eyelid separation), and neurobehavioral effects in pups at weaning (auricle reflex, orientation reaction, 

grasping, and draw-up reflexes). Necropsies were performed on all adult males and females, as well as on 

pups that died during the first 4 days or were killed on day 4 (i.e., those not selected for continuation in 

the study). Liver, kidney, and spleen weights were measured in males and females of both generations. 

Histopathological examinations were performed on selected tissues (liver, kidneys, spleen, vagina, cervix, 

uterus, ovaries, mammary gland, testes, epididymides, penis, prostate, seminal vesicles, and spermatic 

cord) from F0 and F1 adult animals that had no living young, died prematurely, or were killed as moribund, 

as well as on gross lesions in all animals. 

There were no exposure-related effects in adult rats or pups at 30 mg/kg/day (Bornatowicz et al. 1994). 

Body weight was significantly reduced in F1 pups at birth at ≥90 mg/kg/day (4.4, 5.7, and 22.6% lower 

than control group at 30, 90, and 270 mg/kg/day), in F1 pups on postnatal days 7–21 at 270 mg/kg/day, 

and in F2 pups at birth and on postnatal days 4–21. The total number of deaths from birth to postnatal 

day 4 was significantly increased in F1 pups at 270 mg/kg/day and F2 pups at ≥90 mg/kg/day (33, 467, and 

1,033% higher than controls at 30, 90, and 270 mg/kg/day). None of the data in this study were reported 

on a per-litter basis or analyzed for dose-related trends. Decreased offspring survival at 270 mg/kg/day is 

also indicated by reduced total number of live F1 and F2 pups at birth, increased total dead F1 and F2 pups 

at birth, and increased total dead F1 and F2 pups during postnatal days 5–21. Other postnatal effects in the 

offspring included delayed eye opening (first day of appearance or day shown in all pups) in F1 and 

F2 pups at 270 mg/kg/day, delayed ear erection (day shown in all pups) in F2 pups at 270 mg/kg/day, and 

reduced percentage of rats per litter with a positive draw-up reflex in the F1 pups at 270 mg/kg/day and in 

F2 pups at ≥90 mg/kg/day. Clinical manifestations occurred in pups of both generations at 

≥90 mg/kg/day, including dry and scaly skin until approximately postnatal day 7 (0, 0, ≈70, and 100% of 

the litters at 0, 30, 90, and 270 mg/kg/day), and tail constriction that appeared between days 4 and 21 in 

all or nearly all litters (percentages not reported) and occasionally led to loss of parts of the tail. 
DICHLOROBENZENES 190 

3. HEALTH EFFECTS 

Additionally, the number of F1 pups described as cyanotic after birth was increased (not quantified) at 

270 mg/kg/day. 

Effects in adult animals were generally not quantified, but included reduced average body weight in 

F1 males and females at 270 mg/kg/day at all time points during gestation and lactation, increased relative 

liver weight in F1 males at ≥90 mg/kg/day, and changes in absolute and/or relative organ weights in 

kidneys (increased) and spleen (reduced) in F1 males at 270 mg/kg/day. There were no effects on organ 

weights in female rats of either generation. The only histopathological finding attributed to exposure was 

unspecified kidney damage in both generations (effect levels, possible male specificity, and other 

information not reported). There were no effects on mating and fertility indices in any group (see 

Section 3.2.2.5). 

3.2.2.7 Cancer 

1,2-Dichlorobenzene. No studies were located regarding carcinogenic effects in humans after oral 

exposure to 1,2-DCB. 

Carcinogenicity was evaluated in groups of 50 male and 50 female F344/N rats and 50 male and 

50 female B6C3F1 mice that were exposed to 1,2-DCB (>99% pure) in corn oil by gavage in doses of 0, 

60, or 120 mg/kg, 5 days/week for 103 weeks (NTP 1985). Evaluations in both species included clinical 

signs, body weight, and necropsy and histology on all animals. As discussed below, no exposure-related 

tumors were found in either species, although it is unclear whether a maximum tolerated dose (MTD) was 

achieved in either species. 

In rats, survival to termination in the high-dose males was significantly reduced compared with controls 

(19/50 vs. 42/50, p<0.001), but NTP (1985) concluded that the difference was likely mainly from causes 

incidental to treatment. Due to the probable gavage-related deaths in the high-dose male rats, the lower 

survival of this group does not necessarily mean that the MTD was either reached or exceeded. No 

clinical signs were reported. Mean body weight was slightly reduced (≈5% less than controls) in males 

throughout the study at 85.7 mg/kg/day; the only effect in females was a small increase compared to 

controls after week 32 in both dose groups (final body weights were 11–12% increased at 42.9 and 

85.7 mg/kg/day). There were no exposure-related increased tumor incidences in the rats. The incidence 

of adrenal gland pheochromocytomas was significantly (p≤0.05) increased in low-dose males by the life 

table test (mortality adjusted incidence of 20.9, 40.5, and 21.7% in the control, low-dose, and high-dose 
DICHLOROBENZENES 191 

3. HEALTH EFFECTS 

groups, respectively), but not statistically significant by the incidental tumor test, which was considered to 

be the more appropriate mortality-adjusted test for analysis of nonfatal types of tumors. The increased 

incidence of pheochromocytomas in the low-dose males also was not significant in the Fisher Exact test 

(without mortality adjustment), and there was no significant dose-related trend in the Cochran-Armitage 

test. No increase in pheochromocytomas was seen in high-dose males. The increased incidence of 

pheochromocytomas in the low-dose male rats was discounted by NTP (1985) because there was no doseresponse trend or high-dose effect, no increased incidence in females, no observation of malignant 

pheochromocytomas, and questionable toxicological significance of the life table test results 

(pheochromocytomas were not considered to be a life-threatening condition). Incidences of interstitialcell tumors of the testis were elevated in control and treated groups (47/50, 49/50, 41/50), and occurred 

with a significant positive trend when analyzed by the life-table test. However, the increase detected by 

the life-table test was discounted by NTP because this tumor is not considered to be life threatening, and 

no significant results were obtained by the incidental tumor test, which is the more appropriate test for 

nonfatal tumors. The Cochran-Armitage test showed a significant negative trend for the interstitial cell 

tumors. 

There were no clinical signs or effects on body weight or survival in the mice, indicating that it is unclear 

whether an MTD was achieved in this species (NTP 1985). There were no clear compound-related 

increased incidences of neoplasms in the mice. Incidences of malignant histiocytic lymphomas showed a 

significant positive dose-related trend in male mice (0/50, 1/50, 4/50) and female mice (0/49, 0/50, 3/49), 

but NTP considered numbers of animals with all types of lymphomas to be a more appropriate basis for 

comparison. Because malignant lymphocytic lymphomas occurred in male mice (7/50, 0/50, 0/50) with a 

significant negative dose-related trend, and the combined incidence of all types of lymphomas was not 

significantly different than that in controls for the male mice (8/50, 2/50, 4/50) or female mice (11/49, 

11/50, 13/49) by any of the statistical tests, the increase in histiocytic lymphomas was discounted by 

NTP. Alveolar/bronchiolar carcinomas were significantly increased in the high dose male mice (4/50, 

2/50, 10/50). The incidences showed a significant positive increasing trend by the Cochran-Armitage 

test, but not by the life-table or incidental tumor test. The increase in alveolar/bronchiolar carcinomas 

was discounted by NTP because the more appropriate combined incidence of male mice with 

alveolar/bronchiolar adenomas or carcinomas (8/50, 8/50, 13/50) was not significantly greater than 

controls in any of the tests. 

1,3-Dichlorobenzene. No studies were located regarding carcinogenic effects in humans or animals after 

oral exposure to 1,3-DCB. 
DICHLOROBENZENES 192 

3. HEALTH EFFECTS 

1,4-Dichlorobenzene. No studies were located regarding carcinogenic effects in humans after oral 

exposure to 1,4-DCB. 

1,4-DCB was found to be carcinogenic in B6C3F1 mice and male (but not female) F344 rats exposed to 

1,4-DCB for 2 years in a carcinogenesis bioassay (NTP 1987). 1,4-DCB was administered by gavage to 

male rats at doses of 150 or 300 mg/kg/day and female rats at doses of 300 or 600 mg/kg/day. Significant 

dose-related increases in the incidence of renal tubular cell adenocarcinomas were reported in male rats 

(controls, 2%; low-dose, 6%; high-dose, 14%). Spontaneous tumors of this type are uncommon in male 

F344 rats; they have been diagnosed in only 4 of 1,098 (0.4%) of the corn oil-gavage controls in previous 

NTP studies. There were no tubular cell tumors in dosed or vehicle-control female rats. There also was a 

marginal increase in the incidence of mononuclear cell leukemia in dosed male rats that was only slightly 

higher than the incidence in historical controls from the same laboratory. The NTP study concluded that 

1,4-DCB was carcinogenic in male rats, but not in female rats. 

In a 2-year bioassay in B6C3F1 mice that received 1,4-DCB at 300 or 600 mg/kg/day (NTP 1987), 

increased incidences of hepatocellular carcinomas were observed in high-dose male mice (controls, 28%; 

low-dose, 22.5%; high-dose, 64%) and high-dose female mice (controls, 10%; low-dose, 10.4%; highdose, 38%). Hepatocellular adenomas were increased in high- and low-dose male mice (controls, 10%; 

low-dose, 26.2%; high-dose, 32%) and in high-dose female mice (controls, 20%; low-dose, 12.5%; highdose, 42%). Female control mice in this bioassay had a substantially higher incidence of liver tumors 

than did historical controls. Hepatoblastomas (a rare form of hepatocellular carcinoma) were observed in 

four high-dose male mice along with other hepatocellular carcinomas. This tumor type had not been 

previously observed in 1,091 male vehicle-control mice in NTP studies. An increase in thyroid gland 

follicular cell hyperplasia was observed in dosed male mice, and there was a marginal positive trend in 

the incidence of follicular cell adenomas of the thyroid gland in female mice. The incidence of 

pheochromocytomas (tumors of chromaffin tissue of the adrenal medulla or sympathetic pregangliar, 

benign and malignant, combined) of the adrenal gland was 0 of 47 (control), 2 of 48 (low dose), and 3 of 

49 (high dose), and the incidence of adrenal gland medullary hyperplasia and focal hyperplasia of the 

adrenal gland capsule were increased as well in dosed male mice. 

The observation that kidney tumors are induced in male rats, but not female rats, in response to exposure 

to certain chemicals has been the subject of recent research. It has been hypothesized that the male rat 

kidney is susceptible to the induction of certain tumors because it contains the protein α2μ-globulin, which 
 

 

DICHLOROBENZENES 193 

3. HEALTH EFFECTS 

has not been found at significant levels in either female rats, or in mice and humans of either sex 

(Charbonneau et al. 1987, 1989a, 1989b). Chemicals like 1,4-DCB, which reversibly bind to this protein, 

cause the formation of hyalin droplets in the proximal convoluted tubules of male rats. The hyalin 

droplet-protein complex is resistant to degradation by lysosomal enzymes and accumulates in the tubule, 

leading to localized hyperplasia of the epithelium (Borghoff et al. 1991; EPA 1991i). It is hypothesized 

that the resulting cellular damage and cell proliferation enhances tumor formation via a mechanism not 

yet elucidated. It has also been demonstrated that the same effects can be elicited in male rats 

administered other α2μ-globulin-binding chemicals such as [hexachloroethane, d-limonene 1-methyl4(1-methylethenyl)cyclohexene], unleaded gasoline, and pentachloroethane (EPA 1991i). Based on these 

data, EPA (1991) concluded that tumors associated with α2μ-globulin and hyalin droplets are specific to 

species that produce this protein in large quantities, and that these tumors should be distinguished from 

other renal tumors. 

The finding of hepatocellular carcinomas and adenomas in mice in the NTP (1987) study has been the 

subject of scientific debate. There was a high incidence of these tumors in both male and female control 

animals, but this is fairly common in mice. However, in this case, the tumor incidence in the female 

controls was substantially higher than the historical control value. In addition, 1,4-DCB has not been 

demonstrated to be mutagenic in any of the microbial or mammalian systems tested (NTP 1987), 

suggesting that the liver tumors are not the result of genotoxicity. Hepatocellular degeneration with 

resultant initiation of tissue repair was present in both male and female treated mice. This led NTP 

(1987) to speculate that 1,4-DCB acted as a tumor promotor rather than a tumor initiator during the 

formation of the liver tumors found in male and female mice. 

As shown in Table 3-5, 300 mg/kg/day is the cancer effect level (CEL) for renal tubular cell adenomas in 

male rats and 600 mg/kg/day is the CEL for hepatocellular carcinomas and hepatoblastomas in mice 

(NTP 1987). 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

1,2-Dichlorobenzene. No studies were located regarding death in humans or animals after dermal 

exposure to 1,2-DCB. 
DICHLOROBENZENES 194 

3. HEALTH EFFECTS 

1,3-Dichlorobenzene. No studies were located regarding death in humans or animals after dermal 

exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding death in humans after dermal exposure to 

1,4-DCB. 

The dermal LD50 for 1,4-DCB in Sherman rats was >6,000 mg/kg/day (Gaines and Linder 1986). It is not 

clear how many rats died after dermal exposure to 1,4-DCB in this study, and there are no toxicokinetic 

data that address the question of absorption of 1,4-DCB by the dermal route. 

3.2.3.2 Systemic Effects 

1,2-Dichlorobenzene. No studies were located regarding systemic toxicity in humans or animals after 

dermal exposure to 1,2-DCB. 

Application of two drops of undiluted 1,2-DCB into the eyes of rabbits caused some pain and slight 

irritation of the conjunctival membranes, which healed completely within 1 week (Hollingsworth et al. 

1958). The irritation was reduced by prompt rinsing with water. Additional relevant information was not 

reported. 

1,3-Dichlorobenzene. No studies were located regarding systemic effects in humans or animals after 

dermal exposure to 1,3-DCB. 

1,4-Dichlorobenzene. No studies were located regarding systemic effects in humans or animals after 

dermal exposure to 1,4-DCB. 

Industrial experience indicates that solid particles of 1,4-DCB are painful in the eyes of humans 

(Hollingsworth et al. 1956). Solid 1,2-DCB has a negligible irritating action on intact, uncovered human 

skin, but can produce a burning sensation when held in close dermal contact for an unspecified excessive 

period of time (Hollingsworth et al. 1956). Prolonged and repeated contact to strong solutions of 

1,4-DCB also could cause slight irritation in intact skin (Hollingsworth et al. 1956). 
 

 

 

 

DICHLOROBENZENES 195 

3. HEALTH EFFECTS 

No studies were located regarding the following health effects in humans or animals after dermal 

exposure to 1,2-, 1,3-, or 1,4-DCB: 

3.2.3.3 Immunological and Lymphoreticular Effects 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

In vivo and in vitro genotoxicity studies of DCBs are summarized in Tables 3-6 and 3-7, respectively. 

1,2-Dichlorobenzene. No studies were located regarding genotoxic effects in humans after inhalation, 

oral, or dermal exposure to 1,2-DCB. 

A limited amount of information is available on the genotoxicity of 1,2-DCB in animals. Micronuclei 

were induced in bone marrow erythrocytes of mice that were administered two 93.5–375 mg/kg doses by 

intraperitoneal injection 24 hours apart; lower dose levels were not tested (Mohtashamipur et al. 1987). A 

single 0.4 mg/kg intraperitoneal dose of 1,2-DCB caused covalent binding to liver, lung, kidney, and 

stomach DNA in rats and mice (Colacci et al. 1990). 

In vitro reverse mutation assays of 1,2-DCB in microbial systems were negative in Salmonella 

typhimurium with or without metabolic activation (Connor et al. 1985; NTP 1985; Shimizu et al. 1983; 

Waters et al. 1982), negative in Escherichia coli without metabolic activation (Waters et al. 1982), and 

positive results in Saccharomyces cerevisiae with metabolic activation (Paolini et al. 1998). In mouse 

lymphoma cells, 1,2-DCB was negative for forward mutation without metabolic activation, but positive 

with S9 activation mixture (Myhr and Caspary 1991). In vitro exposure to 1,2-DCB induced DNA 

damage in E. coli and S. cerevisiae, but not in Bacillus subtilis (Waters et al. 1982), and did not cause 

replicative DNA synthesis in cultured human lymphocytes (Perocco et al. 1983) or increased DNA repair 

in primary rat hepatocytes (Williams et al. 1989). 1,2-DCB did not cause chromosomal aberrations, 

either with or without metabolic activation, in Chinese hamster ovary (CHO) cells, but did induce sisterchromatid exchanges only in the presence of S9 metabolic activation preparation (Loveday et al. 1990). 
 

 

DICHLOROBENZENES 196 

3. HEALTH EFFECTS 

Table 3-6. Genotoxicity of Dichlorobenzenes In Vivo 

Species (test system) End point Results Reference 

1,2-Dichlorobenzene 

Mammalian cells 

Mouse bone marrow 

erythrocytesa 

Micronucleus formation + Mohtashampir et al. 1987 

Rat liver, lung, kidney and 

stomach cellsb 

Covalent binding to DNA + Colacci et al. 1990 

Mouse liver, lung, kidney 

and stomach cellsb 

Covalent binding to DNA + Colacci et al. 1990 

1,3-Dichlorobenzene 

Mammalian cells 

Mouse bone marrow Micronucleus formation + Mohtashampir et al. 1987 

erythrocytesc 

1,4-Dichlorobenzene 

Mammalian cells 

Rat bone marrow cellsd

 Chromosomal aberrations – Anderson and Richardson 1976 

Mouse bone marrow cells Micronucleus formation – Shelby and Witt 1995 

 Mouse erythrocytese Micronucleus formation – NTP 1987 

Rat kidney cellsf

 Unscheduled DNA synthesis – Steinmetz and Spanggord 1987b 

Increased DNA replication +g

 Mouse hepatocytesh

 Unscheduled DNA synthesis – Steinmetz and Spanggord 1987a 

Rat kidney cellsi Increased DNA replication + Charbonneau et al. 1989b 

Mouse bone marrow Micronucleus formation + Mohtashamipur et al. 1987 

erythrocytesj 

Rat renal tubular cells Cumulative replicating fraction – Umemura et al. 1998 

and hepatocytesk 

Mouse renal tubular cells Cumulative replicating fraction + Umemura et al. 1998 

and hepatocytesk 

a

Exposed to 1,2-dichlorobenzene via two intraperitoneal injections of 93.5, 187.5, 281, or 375 mg/kg (24 hours apart) 

and sacrificed 6 hours after the second injection. Males only were tested. 

b

Exposed to 1,2-dichlorobenzene via one intraperitoneal injection of 0.4 mg/kg. c

Exposed to 1,3-dichlorobenzene via two intraperitoneal injections of 87.5, 175, 262.5, or 700 mg/kg (24 hours apart) 

and sacrificed 6 hours after the second injection. Males only were tested. 

d

Exposed to 1,4-dichlorobenzene via inhalation for 2 hours at 299 or 682 ppm; for 5 days, 5 hours/day at 75 or 

500 ppm; or for 3 months, 5 days/week, 5 hours/day at 75 or 500 ppm. 

e

Exposed to 1,4-dichlorobenzene via gavage for 13 weeks, 5 days/week at 600–1,800 mg/kg/day.
 f

Exposed to 1,4-dichlorobenzene via gavage in corn oil at 300, 600, or 1,000 mg/kg at 16 hours before sacrifice for 

unscheduled DNA synthesis experiment or at 96 hours before sacrifice for DNA replication experiment. g

Results were positive for male rats only in which a significant S-phase response was induced. h

Exposed to 1,4-dichlorobenzene via gavage in corn oil at 300, 600, or 1,000 mg/kg at 16 or 48 hours before 

sacrifice. 

i

Exposed to 1,4-dichlorobenzene via gavage in corn oil at 120 or 300 mg/kg/day for 7 days and sacrificed 24 hours 

after the last dose. 

j

Exposed to 1,4-dichlorobenzene via two intraperitoneal injections of 355, 710, 1,065, or 1,420 mg/kg (24 hours 

apart) and sacrificed 6 hours after the second injection. Males only were tested. k

Exposed to 1,4-dichlorobenzene via gavage for 1 week or 4 weeks at 150, 300, or 600 mg/kg/day. 

+ = positive result; – = negative result; DNA = deoxyribonucleic acid 
DICHLOROBENZENES 197 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Dichlorobenzenes In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

1,2-Dichlorobenzene 

Microbial systems 

 Salmonella Gene mutation ND – Waters et al. 1982 

typhimurium TA98, 

TA100, TA1535, 

TA1537, and TA1538 

S. typhimurium TA98, Gene mutation – – Connor et al. 1985 

TA100, UTH8413, and 

UTH8414 

S. typhimurium TA98, Gene mutation – – NTP 1985 

TA100, TA1535, and 

TA1537 

S. typhimurium TA98, Gene mutation – – Shimizu et al. 1983 

TA100, TA1535, 

TA1537, and TA1538 

S. typhimurium	 Gene induction (umu) – – Nakamura et al. 1987 

Escherichia coli Prophage lambda DeMarini and Brooks 

induction 1992 

E. coli WP2 uvra	 Gene mutation ND – Waters et al. 1982 

E. coli polA- DNA damage ND + Waters et al. 1982 

Bacillus subtilis recA- DNA damage ND + Waters et al. 1982 

 Saccharomyces Gene mutation – ND Paolini et al. 1998 

cerevisiae 

S. cerevisiae D3	 DNA damage ND + Waters et al. 1982 

Mammalian cells 

Mouse lymphoma cells Gene mutation + – Myhr and Caspary 1991 

Chinese hamster ovary Chromosomal aberrations – – Loveday et al. 1990 

cells 

Chinese hamster ovary Sister-chromatid + – Loveday et al. 1990 

cells exchange 

 Rat primary Increased DNA repair ND – Williams et al. 1989 

hepatocytes 

Human lymphocytes Replicative DNA synthesis – – Perocco et al. 1983 

1,3-Dichlorobenzene 

Microbial systems 

S. typhimurium TA98, Gene mutation ND – Waters et al. 1982 

TA100, TA1535, 

TA1537, and TA1538 

S. typhimurium TA98, Gene mutation – – Connor et al. 1985 

TA100, UTH8413, and 

UTH8414 
 

 

DICHLOROBENZENES 198 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Dichlorobenzenes In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

S. typhimurium TA98, Gene mutation – – Shimizu et al. 1983 

TA100, TA1535, 

TA1537, and TA1538 

E. coli WP2 uvra Gene mutation ND – Waters et al. 1982 

E. coli polA- DNA damage ND + Waters et al. 1982 

B. subtilis recA- DNA damage ND + Waters et al. 1982 

S. cerevisiae D3 DNA damage ND – Waters et al. 1982 

Mammalian cells 

Human lymphocytes Replicative DNA synthesis – – Perocco et al. 1983 

1,4-Dichlorobenzene 

Microbial systems 

S. typhimuriuma 

TA98, TA100, TA1535, 

and TA1538 

S. typhimuriumb 

TA98, TA100, and 

TA1538 

S. typhimuriumb 

TA1535 

S. typhimurium 

TA98, TA100, TA1535, 

TA1537, and TA1538 

S. typhimurium 

TA98, TA100, TA1535, 

and TA1537 

S. typhimurium 

TA98, TA100, 

UTH8413, and 

UTH8414 

E. coli WP2 uvra 

E. coli polAB. subtilis recAS. cerevisiae 

S. cerevisiae D3 

Mammalian cells 

mouse lymphoma cells 

L5178Y/TK± 

mouse lymphoma cells 

L5178Y/TK± 

Chinese hamster lung 

cells 

Chinese hamster ovary 

cells 

Gene mutation – – 

Gene mutation – – 

Gene mutation + – 

Gene mutation – – 

Gene mutation – – 

Gene mutation – – 

Gene mutation ND – 

DNA damage ND -

DNA damage ND -

Gene mutation + ND 

DNA damage ND -

Gene mutation (=) – 

Gene mutation + (=) 

Gene mutation – – 

Chromosomal aberrations – – 

Anderson 1976 

Anderson 1976 

Anderson 1976 

Shimizu et al. 1983; 

Waters et al. 1982 

Haworth et al. 1983; NTP 

1987 

Connor et al. 1985 

Waters et al. 1982 

Waters et al. 1982 

Waters et al. 1982 

Paolini et al. 1998 

Waters et al. 1982 

NTP 1987 

McGregor et al. 1988 

Instituto di Ricerche 

Biomediche 1986b 

Anderson et al. 1990; 

NTP 1987 
DICHLOROBENZENES 199 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Dichlorobenzenes In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Chinese hamster ovary Sister chromatid – – Anderson et al. 1990; 

cells exchanges NTP 1987 

Rat hepatocytes DNA fragmentation ND - Canonero et al. 1997 

Rat hepatocytes Micronucleus formation ND (=) Canonero et al. 1997 

Rat kidney cells DNA damage ND + Robbiano et al. 1997 

Rat kidney cells Micronucleus formation ND + Robbiano et al. 1997 

Human kidney cells DNA damage ND + Robbiano et al. 1997 

Human kidney cells Micronucleus formation ND + Robbiano et al. 1997 

Human hepatocytes DNA fragmentation ND - Canonero et al. 1997 

Human hepatocytes Micronucleus formation ND - Canonero et al. 1997 

Human lymphocytes Replicative DNA synthesis – – Perocco et al. 1983 

 Human lymphocytes Sister-chromatid – – Carbonell et al. 1991 

exchanges 

 Human lymphocytes Unscheduled DNA – – Perocco et al. 1983; 

synthesis Instituto di Ricerche 

Biomediche 1987 

 HeLa cells Unscheduled DNA – – Instituto di Ricerche 

synthesis Biomediche 1986a 

Plant systems 

Root tips (16 species of Chromosomal aberrations ND + Sharma and Battachary 

dicotyledons and 1956 

monocotyledons) 

Lens esculenta (L.) Mitotic abnormalities ND + Sarbhoy 1980 

Moench 

Aspergillus nidulans Back mutation frequency ND + Prasad 1970 

Tribe viceae Chromosomal aberrations ND + Srivastava 1966 

a

Exposed to 1,4-dichlorobenzene gas. 

b

Exposed to 1,4-dichlorobenzene in DMSO. 

– = negative result; + = positive result; (=) = equivocal; DNA = deoxyribonucleic acid; ND = not determined 
DICHLOROBENZENES 200 

3. HEALTH EFFECTS 

1,3-Dichlorobenzene. No studies were located regarding genotoxic effects in humans after inhalation, 

oral, or dermal exposure to 1,3-DCB. 

A limited amount of information is available on the genotoxicity of 1,3-DCB. Micronuclei were induced 

in bone marrow erythrocytes of mice following administration of two 87.5–700 mg/kg doses by 

intraperitoneal injection 24 hours apart; lower dose levels were not tested (Mohtashamipur et al. 1987). 

In vitro exposure to 1,3-DCB did not induce reverse mutations in S. typhimurium (Connor et al. 1985; 

Shimizu et al. 1983; Waters et al. 1982) or E. coli (Waters et al. 1982). 1,3-DCB caused DNA damage in 

E. coli, but not in B. subtilis or S. cerevisiae (Waters et al. 1982), and did not increase replicative DNA 

synthesis in cultured human lymphocytes (Perocco et al. 1983). 

1,4-Dichlorobenzene. No studies were located regarding genotoxic effects in humans after inhalation, 

oral, or dermal exposure to 1,4-DCB. 

Cytogenetic studies have been conducted using bone marrow cells of rats following inhalation exposure 

to 1,4-DCB (Anderson and Richardson 1976). Three series of exposures were carried out: (1) one 

exposure at 299 or 682 ppm for 2 hours; (2) exposures at 75 or 500 ppm, 5 hours/day for 5 days; and 

(3) exposures to 75 or 500 ppm, 5 hours/day, 5 days/week for 3 months. Bone marrow cells from both 

femurs were examined for chromosome or chromatid gaps, chromatid breaks, fragments, or other 

complex abnormalities. In all three experiments, exposure to 1,4-DCB failed to induce any effects 

indicative of chromosomal damage. 

Gavage administration of 1,4-DCB to B6C3F1 mice and F344 rats at single doses of 300–1,000 mg/kg/day 

did not result in unscheduled deoxyribonucleic acid (DNA) synthesis in the mouse hepatocytes or in the 

renal tissue of the rats in an in vivo/in vitro assay (Steinmetz and Spanggord 1987a, 1987b). However, 

1,4-DCB at the highest level did induce an increase in DNA replication (S-phase of cell division) in the 

renal tissue of the male rats and in the hepatocytes of the male mice. Based on a comparison with 

historical controls, the authors concluded that levels of DNA replication were also significantly elevated 

in the hepatocytes of female mice. 

No evidence of a clastogenic effect was found in mouse bone marrow erythroblasts after a single gavage 

administration of 1,4-DCB at 2,500 mg/kg/day (Herbold 1986a). Similarly, no evidence of clastogenic 

effects was found in mouse bone erythroblasts after a single oral administration of 2,5-dichlorophenol 
 

 

DICHLOROBENZENES 201 

3. HEALTH EFFECTS 

(the major metabolite of 1,4-DCB) at 1,500 mg/kg/day (Herbold 1986b). 2,5-Dichlorophenol with or 

without metabolic activation did not induce an increase in mutagenic response in the Chinese hamster 

ovary HGPRT forward mutation assay (Litton Bionetics 1986a). This compound was also inactive in the 

Balb/3T3 in vitro transformation assay (Litton Bionetics 1985). 

Cytogenetic effects were not found in bone marrow cells from mice treated with 1,4-DCB by gavage at 

levels up to 1,800 mg/kg/day in a 13-week study (NTP 1987). No increase in micronucleated cells 

occurred even at levels that were extremely toxic to the test animals, resulting in liver toxicity and 

decreased survival rates. As noted by the authors of that study, the observed carcinogenic activity of 

1,4-DCB cannot be adequately predicted on the basis of the available genotoxicity data; all of the 

available information strongly suggests that 1,4-DCB acts as a tumor promoter rather than as a mutagen. 

However, gavage administration of a single 1,000 mg/kg/day dose of 1,4-DCB to mice and rats resulted 

in an increase in DNA replication in the renal tissue of the male rats and in the hepatocytes of mice of 

both sexes (Steinmetz and Spanggord 1987a, 1987b). Increased 3

H-thymidine incorporation into renal 

DNA has also been demonstrated in rats dosed with 1,4-DCB by gavage at 120 mg/kg/day for 7 days 

(Charbonneau et al. 1989b). These observations suggest that 1,4-DCB promotes cell division, a finding 

that may help to elucidate the mechanism of carcinogenic action of 1,4-DCB in male rat kidneys and 

mouse liver in the NTP (1987) bioassay. However, it is important to note that in these studies; only 

kidney tissue was tested in the rat for increased DNA replication, and in the mouse, only liver tissue was 

tested. Therefore, it is not clear whether increased cell replication also occurs in other tissue in each 

species or is limited to the tissues in which the carcinogenic effects occurred. 

The in vivo genotoxicity of 1,4-DCB is summarized in Table 3-6. As discussed above, the in vivo testing 

showed positive results for increased DNA replication in the livers of orally exposed mice (Steinmetz and 

Spanggord 1987a) and in the kidneys of orally exposed rats (Charbonneau et al. 1989b; Steinmetz and 

Spanggord 1987b), and mixed positive and negative findings for induction of micronuclei in bone marrow 

cells of orally exposed mice (Mohtashampir et al. 1987; NTP 1987). 

In vitro genotoxicity studies of 1,4-DCB are summarized in Table 3-7. Microbial reverse mutation tests 

were predominantly negative in S. typhimurium (Anderson 1976; Connor et al. 1985; NTP 1987; Shimizu 

et al. 1983; Waters et al. 1982) and E. coli (Waters et al. 1982), but positive in S. cerevisiae (Paolini et al. 

1998). Assays for DNA damage in E. coli, B. subtilis, and S. cerevisiae were negative (Waters et al. 

1982). 1,4-DCB did not induce replicative DNA synthesis (Perocco et al. 1983) or DNA strand breaks 
 

 

DICHLOROBENZENES 202 

3. HEALTH EFFECTS 

(Canonero et al. 1997) in rat and human hepatocytes, although DNA damage was increased in rat and 

human kidney cells (Robbiano et al. 1999). Forward mutation assays in mouse lymphoma cells were 

equivocal (McGregor et al. 1988; NTP 1987), and mixed positive and negative results were found for 

chromosomal aberrations and sister-chromatid exchanges in CHO cells (Anderson et al. 1990; Carbonell 

et al. 1991; NTP 1987). Tests for micronucleus formation were equivocal in human and rat hepatocytes 

(Canonero et al. 1997) and positive in human and rat kidney cells (Robbiano et al. 1999). In vitro testing 

in plant systems showed genotoxic effects that included chromosomal aberrations, mitotic abnormalities, 

and back mutations (Prasad 1970; Sarbhoy 1980; Sharma and Battacharya 1956; Srivastava 1966). 

3.4 TOXICOKINETICS 

1,2-DCB is quickly and extensively absorbed through both the gastrointestinal tract and the respiratory 

tract; studies describing the absorption of 1,2-DCB following dermal exposure are not available. 

Following absorption, 1,2-DCB is distributed throughout the body, but tends to be found in greatest levels 

in the fat, kidney, and liver. 1,2-DCB is initially metabolized by cytochrome P-450 enzymes, specifically 

P4502E1, to an active epoxide followed by hydrolysis to 2,3-dichlorophenol or 3,4-dichlorophenol. The 

dichlorophenols may be further oxidized or, more often, be conjugated to glutathione, sulfate, or to form 

the glucuronide; conjugation occurs extensively, with virtually no unconjugated metabolites reported in 

the available studies. Metabolism is believed to occur mainly in the liver, but may occur at lower levels 

in other tissues, such as the kidney or lung. Elimination of 1,2-DCB from the body is rapid, with the 

majority of a single dose being removed within the first 75 hours postexposure; elimination occurs 

primarily in the urine as metabolites. 

Information on the quantitative absorption of 1,3-DCB in humans and animals is not available for any 

route of exposure; however, absorption of the compound can be inferred from studies that have detected 

1,3-DCB or metabolites in the breast milk, blood, and fat of humans and in the bile and urine of exposed 

animals. Distribution is believed to be similar to the other DCB isomers, but data demonstrating this are 

not presently available. Similar to the other DCB isomers, 1,3-DCB is initially metabolized by 

cytochrome P-450 enzymes, followed by extensive conjugation, primarily to glutathione, has been 

reported. 1,3-DCB is eliminated mainly in the urine, similar to the other DCB isomers. 

Absorption of 1,4-DCB is rapid and essentially complete following inhalation or oral exposure. 

Information on the quantitative absorption of 1,4-DCB following dermal exposure are not available; 

however, absorption is believed to be very low, based on a very high (>6 g/kg) dermal LD50 for 1,4-DCB 
 

 

 

 

DICHLOROBENZENES 203 

3. HEALTH EFFECTS 

in rats, and on a lack of systemic effects in humans who held solid 1,4-DCB in their hands. Similar to the 

other dichlorobenzene isomers, 1,4-DCB is distributed throughout the body, but tends to be found in 

greatest levels in fat, liver, and kidney. Metabolism of 1,4-DCB is similar to that of 1,2-DCB, with an 

initial oxidation to an epoxide, followed by hydrolysis to 2,5-dichlorophenol. Extensive phase II 

metabolism occurs subsequently, with eliminated metabolites found mainly as the sulfate, glucuronide, or 

mercapturic acid. 1,4-DCB is eliminated almost exclusively in the urine, primarily as conjugates of 

2,5-dichlorophenol. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

1,2-Dichlorobenzene. Quantitative data on the absorption of 1,2-DCB in humans following inhalation 

exposure are not available. However, evidence for absorption of 1,2-DCB in humans comes from 

numerous studies that have detected 1,2-DCB in human tissues, including the blood (Bristol et al. 1982), 

urine (Kumagai and Matsunaga 1995, 1997; Zenser et al. 1997), adipose tissue (Jan 1983), and in breast 

milk (Jan 1983; Mes et al. 1986). While these studies do not provide a quantitative measure of the rate or 

extent of 1,2-DCB and cannot provide information concerning possible exposure route, they provide 

evidence of 1,2-DCB absorption in humans. 

Quantitative data on the absorption of 1,2-DCB in animals are similarly not available. However, 

numerous studies presenting evidence of systemic toxicity (see Section 3.2) following inhalation of 

1,2-DCB provide qualitative evidence for the absorption of 1,2-DCB. 

1,3-Dichlorobenzene. Quantitative data on the absorption of 1,3-DCB in humans following inhalation 

exposure are not available. However, evidence for absorption of 1,3-DCB in humans comes from studies 

that have detected 1,3-DCB in breast milk (Mes et al. 1986), blood (Bristol et al. 1982), and adipose 

tissue (Jan 1983). While these studies do not provide a quantitative measure of the rate or extent of 

1,3-DCB and cannot provide information concerning possible exposure route, they provide evidence of 

1,3-DCB absorption in humans. 

Quantitative inhalation absorption data for 1,3-DCB are not available, but absorption characteristics are 

likely to be similar to those of the other isomers based on similarities in chemical and physical properties. 
 

 

DICHLOROBENZENES 204 

3. HEALTH EFFECTS 

1,4-Dichlorobenzene. Quantitative data on the absorption of 1,4-DCB in humans following inhalation 

exposure are not available. However, evidence for absorption of 1,4-DCB in humans comes from 

numerous studies that have detected 1,4-DCB in human tissues, including the blood (Bristol et al. 1982; 

Hill et al. 1995), urine (Ghittori et al. 1985; Hill et al. 1995; Pagnotto and Walkley 1965), adipose tissue 

(Jan 1983), and breast milk (Jan 1983). While these studies do not provide a quantitative measure of the 

rate or extent of 1,4-DCB and cannot provide information concerning possible exposure route, they 

provide evidence that 1,4-DCB is absorbed by humans. 

Studies presenting quantitative data on the rate and/or extent of absorption of 1,4-DCB following 

inhalation exposure in animals are not available. However, numerous studies presenting evidence of 

systemic toxicity (see Section 3.2) following inhalation exposure provide qualitative evidence for the 

absorption of 1,4-DCB. Additional evidence comes from studies that have reported the presence of the 

compound or its metabolites in peripheral tissues following inhalation exposure. Following a single or 

multiple 3-hour inhalation exposures of radiolabeled 1,4-DCB in rats, label was detected in all evaluated 

tissues (liver, kidneys, lungs, muscle, fat, and blood plasma), indicating that considerable absorption had 

occurred (Hawkins et al. 1980). Levels of label in tissues did not appreciably increase with increasing the 

number of exposures beyond one (Hawkins et al. 1980). Similarly, following a single 24-hour inhalation 

exposure in rats, 1,4-DCB levels in the liver, kidney, fat, and blood increased sharply during the first 

6-hour evaluation period, then rose slowly but steadily for the remainder of the exposure period 

(Umemura et al. 1998), indicating an initial rapid absorption, followed by a slower total absorption as 

equilibration of body and blood levels is approached. 

3.4.1.2 Oral Exposure 

1,2-Dichlorobenzene. Quantitative data on the absorption of 1,2-DCB in humans following oral 

exposure are not available. However, absorption of 1,2-DCB in humans can be concluded based on the 

results of numerous studies that have detected 1,2-DCB in human tissues, including the blood (Bristol et 

al. 1982), urine (Kumagai and Matsunaga 1995, 1997; Zenser et al. 1997), and in breast milk (Jan 1983; 

Mes et al. 1986). While these studies do not provide a quantitative measure of the rate or extent of 

1,2-DCB and cannot provide information concerning possible exposure route, they provide evidence of 

1,2-DCB absorption in humans. 

In male Wistar rats given single oral doses of 5, 50, and 250 mg/kg body weight of 14C-labeled 1,2-DCB, 

radioactivity in urine (collected for up to 175 hours after dosing) accounted for about 75, 84, and 75% of 
DICHLOROBENZENES 205 

3. HEALTH EFFECTS 

the radioactivity for administered doses, respectively (Hissink et al. 1996a). Radioactivity in feces 

accounted for about 16, 12, and 7% of the respective administered doses. These results indicate 

absorption of at least 75–84% of the administered dose (assuming that none of fecal radioactivity was 

absorbed) occurred, and up to 82–96% of the dose (assuming that all radiolabel in the feces was first 

absorbed and later excreted in the bile) may have been absorbed. Rapid absorption was indicated since 

peak levels of radioactivity in blood samples occurred at about 6, 10, and 24 hours after administration of 

5, 50, and 250 mg/kg doses, respectively (Hissink et al. 1996a). Other studies have identified the 

presence of metabolites of 1,2-DCB in the urine following oral exposure (Azouz et al. 1955; Hissink et al. 

1996c). 

1,3-Dichlorobenzene. Quantitative data on the absorption of 1,3-DCB in humans following oral 

exposure are not available. However, evidence for absorption of 1,3-DCB in humans comes from studies 

that have detected 1,3-DCB in breast milk (Mes et al. 1986), blood (Bristol et al. 1982), and adipose 

tissue (Jan 1983). While these studies do not provide a quantitative measure of the rate or extent of 

1,3-DCB and cannot provide information concerning possible exposure route, they provide evidence of 

1,3-DCB absorption in humans. 

Evidence for absorption of 1,3-DCB following oral exposure of animals comes from the detection of 

metabolites in the urine and bile. Kimura et al. (1992) identified at least 12 metabolites in the bile of rats 

given 1,3-DCB by gavage, indicating that absorption and transport to the liver had occurred. In rabbits 

given oral 1,3-DCB, glucuronide, sulfur esters, mercapturic acid, and catechol metabolites were identified 

in the urine (Parke and Williams 1955), and suggested that 50–75% of the compound was absorbed, based 

on the presence of these metabolites. 

1,4-Dichlorobenzene. Quantitative data on the absorption of 1,4-DCB in humans following oral 

exposure are not available. However, evidence for absorption of 1,4-DCB in humans comes from 

numerous studies that have detected 1,4-DCB in human tissues, including the blood (Bristol et al. 1982; 

Hill et al. 1995), urine (Hill et al. 1995; Ghittori et al. 1985; Pagnotto and Walkley 1965), adipose tissue 

(Jan 1983), and breast milk (Jan 1983). While these studies do not provide a quantitative measure of the 

rate or extent of 1,4-DCB and cannot provide information concerning possible exposure route, they 

provide evidence that 1,4-DCB is absorbed by humans. 

Evidence for absorption of 1,4-DCB in animals includes studies demonstrating toxicity following oral 

exposure (see Section 3.2), as well as studies demonstrating the presence of 1,4-DCB or metabolites in 
 

 

 

 

DICHLOROBENZENES 206 

3. HEALTH EFFECTS 

peripheral tissues following one or more oral exposures that indicate that 1,4-DCB is rapidly and nearly 

completely absorbed. Following a single or multiple oral exposures of radiolabeled 1,4-DCB in rats, 

label was detected in all evaluated tissues (liver, kidneys, lungs, muscle, fat, and blood plasma), 

indicating that considerable absorption had occurred (Hawkins et al. 1980). Additional support for a 

near-complete absorption comes from data showing that levels in tissues were similar following 10 oral 

exposures or 10 subcutaneous injections of 250 mg/kg. Levels of label in tissues did not appreciably 

increase with increasing the number of exposures beyond one (Hawkins et al. 1980). Similarly, Hissink 

et al. (1996b) reported that 70–85% of a single radiolabeled dose of 1,4-DCB was eliminated in the urine 

within 72 hours of exposure, indicating that 1,4-DCB was rapidly and extensively absorbed. By contrast, 

Klos and Dekant (1994) reported that ~41% of a labeled oral dose of 1,4-DCB was recovered in the urine 

72 hours postexposure. 

3.4.1.3 Dermal Exposure 

1,2-Dichlorobenzene. Studies examining the absorption of 1,2-DCB in humans or animals following 

dermal exposure are not available. 

1,3-Dichlorobenzene. Studies examining the absorption of 1,3-DCB in humans or animals following 

dermal exposure are not available. 

1,4-Dichlorobenzene. No studies were located that specifically address the rate or amount of absorption 

of 1,4-DCB by humans or animals after dermal exposure to 1,4-DCB. Solid 1,4-DCB produces a burning 

sensation when held closely to the skin for an excessive period of time, but it does not produce irritation 

or systemic effects (Hollingsworth et al. 1956). In a study of the acute dermal toxicity of 1,4-DCB in 

adult Sherman rats, the dermal LD50 was estimated to be >6,000 mg/kg/day in both sexes (Gaines and 

Linder 1986). These data do not indicate that 1,4-DCB is absorbed to any extent after dermal exposure; 

dermal exposure to 1,4-DCB is associated with low systemic toxicity in both humans and laboratory 

animals. 
DICHLOROBENZENES 207 

3. HEALTH EFFECTS 

3.4.2 Distribution 

1,2-Dichlorobenzene. Quantitative data on the distribution of 1,2-DCB in humans are not available. 

1,2-DCB has been detected in the blood (Bristol et al. 1982), urine (Kumagai and Matsunaga 1995, 1997; 

Zenser et al. 1997), and breast milk (Jan 1983; Mes et al. 1986) of humans. 

The most comprehensive animal study of the distribution of 1,2-DCB following a single oral 

administration (10 mg/kg) is the study of Hissink et al. (1996a), which followed the distribution of the 

compound in exposed rats for up to 75 hours in 19 tissues, as well as the residual carcass and 

gastrointestinal tract. The results are presented in Table 3-8. 1,2-DCB was detected in all evaluated 

tissues, but at greatest concentrations in the urinary bladder, kidney, fat, and liver. Retention half-times 

ranged from 8.7 hours (urinary bladder) to 19.3 hours (brain), with only small levels of activity detectable 

in any tissue at 75 hours postexposure. In a separate study in the same manuscript, approximately 60% of 

an oral dose was found in the bile, indicating that considerable enterohepatic circulation occurs. 

Twenty-two hours after a single intraperitoneal injection in Wistar rats or BALB/c mice, 1,2-DCB was 

found covalently bound to DNA, RNA, and proteins of liver, kidney, lung, and stomach (Colacci et al. 

1990). 

1,3-Dichlorobenzene. Quantitative data on the distribution of 1,3-DCB in humans are not available. 

However, 1,3-DCB has been detected in breast milk (Mes et al. 1986), blood (Bristol et al. 1982), and 

adipose tissue (Jan 1983), suggesting a wide distribution throughout the body. 

Data are not available on the distribution of 1,3-DCB following inhalation exposure in animals. Kimura 

et al. (1983) reported the presence of 1,3-DCB or metabolites in the liver and kidney following oral 

exposure. Following oral exposure, 1,3-DCB undergoes enterohepatic circulation, as demonstrated by the 

data of Kimura et al. (1992), who identified at least 12 biliary metabolites in rats exposed to 1,3-DCB by 

gavage. 

1,4-Dichlorobenzene. Quantitative data on the distribution of 1,4-DCB in humans are not available. 

However, 1,4-DCB has been detected in the blood (Bristol et al. 1982; Hill et al. 1995), urine (Hill et al. 

1995; Ghittori et al. 1985; Pagnotto and Walkley 1965), adipose tissue (Jan 1983), and breast milk (Jan 

1983) of humans, indicating distribution at least to those tissues. 
 

 

DICHLOROBENZENES 208 

3. HEALTH EFFECTS 

Table 3-8. Tissue Concentrations (nmol/g tissue) of Radioactivity in Male Wistar 

Rats at Four Time Points after Oral Administration of 10 mg/kg 14C-Labeled 

1,2-Dichlorobenzene in Corn Oil 

Tissue 6 hours 15 hours 30 hours 75 hours t1/2 (hours) 

Liver 32.7±3.4 9.4±1.9 3.1±1.1 1.4±0.4 17.0 

Kidney 132.5±107 15.7±4.8 3.8±0.7 1.5±0.4 13.1 

Spleen 8.0±5.3 2.0±0.9 0.59±0.14 0.2±0.07 15.2 

Pancreas 9.5±5.6 2.6±0.9 1.11±0.4 0.26±0.08 14.5 

Lung 6.6±0.6 3.4±0.9 1.02±0.12 0.29±0.11 16.0 

Heart 4.7±0.8 2.6±0.8 0.7±0.08 0.18±0.03 15.1 

Brain 1.1±0.1 0.7±0.08 0.3±0.08 0.08±0.04 19.3 

Skin 18.8±10.9 2.9±1.1 1.11±0.46 0.41±0.12 15.1 

Femur 5.2±2.6 1.3±0.4 0.55±0.18 0.14±0.0 15.1 

Skeletal muscle 4.7±3.1 1.3±0.6 0.45±0.2 0.09±0.04 13.5 

Perirenal fat 33.4±12.1 14.0±2.6 2.18±0.3 0.18±0.03 9.4 

Testis 3.6±0.8 1.9±0.4 1.13±0.9 0.2±0.07 17.2 

Urinary bladder 183±121 17.3±13.6 6.6±6.4 0.32±0.04 8.7 

Stomach 6.5±1.7 1.7±0.2 0.98±0.46 0.16±0.03 14.3 

Small intestine 29.1±9.3 10.7±0.6 3.5±2.4 0.43±0.28 11.6 

Caecum 16.4±4.8 16.7±1.1 2.8±2.2 0.27±0.07 11.1 

Colon 7.5±2.2 12.0±2.4 1.4±0.9 0.20±0.07 12.0 

Plasma 22.3±2.0 8.8±3.0 1.8±0.1 0.41±0.14 12.5 

Red blood cells 9.2±1.0 3.4±0.6 1.6±0.4 0.57±0.22 18.8 

Residual carcass 13±3% 4±2% 1±0.2% 0.3±0.07% No data 

Gastrointestinal tract contents 13±4% 15±4% 2±1% 0.1±0.04% No data 

Source: Hissink et al. 1996a 
DICHLOROBENZENES 209 

3. HEALTH EFFECTS 

Studies in animals indicate that following absorption, 1,4-DCB is rapidly distributed throughout the body. 

Initially, 1,4-DCB accumulates in adipose tissue, but is not retained long-term. While distributed rapidly 

throughout the body, studies have demonstrated that very little of a dose of 1,4-DCB remains in tissues 

72 hours postexposure (Hissink et al. 1996b; Klos and Dekant 1994; Umemura et al. 1998). 

Following a single 24-hour inhalation exposure in rats, serum concentrations of 1,4-DCB rose sharply 

during the first 6 hours, then slowly for the next 18 hours. A sharp increase was seen in serum 1,4-DCB 

levels during the first 3 hours postexposure, which decreased rapidly thereafter. The greatest tissue 

concentrations of 1,4-DCB were found in the fat; concentrations in fat increased rapidly for the first 

12 hours, then leveled off, remaining more or less steady until 6 hours postexposure, at which time they 

declined sharply (Umemura et al. 1990). Levels in the liver and kidney were approximately equivalent, 

although 10- to 20-fold lower than those in fatty tissues; in both liver and kidney, there was a steady 

increase in 1,4-DCB concentration for the 24 hours of exposure. In parallel with serum 1,4-DCB levels, 

there was a sharp, unexplained jump in the concentration of 1,4-DCB in both liver and kidney at 3 hours 

postexposure that resolved by 6 hours postexposure; concentrations fell rapidly thereafter. Following 

single or multiple inhalation exposures to radiolabeled 1,4-DCB, the greatest concentrations of label were 

found in the fat, with levels 10- to 20-fold greater than any other examined tissue (Hawkins et al. 1980). 

In nonfat tissues, the kidney showed the greatest amounts of label, on a per gram of tissue basis, followed 

by the liver, blood plasma, lungs, and muscle (Hawkins et al. 1980). 

Following single or multiple oral exposures to radiolabeled 1,4-DCB, the greatest concentrations of label 

were found in the fat, with levels 6- to 15-fold greater than any other examined tissue (Hawkins et al. 

1980). In nonfat tissues, the kidney showed the greatest amounts of label, on a per gram of tissue basis, 

followed by the liver, blood plasma, lungs, and muscle (Hawkins et al. 1980). Hissink et al. (1997a) 

reported that after a single oral dose of radiolabeled 1,4-DCB, a steady increase in radiolabel found in the 

blood, and in the plasma compartment, was seen for the first 8–10 hours, after which concentrations 

decreased steadily for the next 40 hours. 

Within 12 hours after exposure of male rats to a single oral dose of 1,4-DCB, two sulfur-containing 

metabolites, 2,5-dichlorophenyl methyl sulfoxide, and 2,5-dichlorophenyl methyl sulfone (M2), were 

found in the blood, urine, fat, liver, and kidneys (Kimura et al. 1979). These metabolites remained in the 

blood after most of the 1,4-DCB had fallen below the detection limits of the assay. The maximum 

concentration of 2,5-dichlorophenyl methyl sulfoxide in blood was reached 15 hours after dosing and 

declined rapidly thereafter. For 2,5-dichlorophenyl methyl sulfone, two peaks were detected at 18 and 
DICHLOROBENZENES 210 

3. HEALTH EFFECTS 

48 hours after dosing, which suggested to the authors that 2,5-dichlorophenyl methyl sulfone might 

undergo enterophepatic circulation. Changes in the levels of these metabolites in blood and tissues over a 

120-hour period led the authors to suggest that 2,5-dichlorophenyl methyl sulfone might arise from 

2,5-dichlorophenyl methyl sulfoxide. 

3.4.3 Metabolism 

Fisher et al. (1995) compared the metabolism and toxicity of the DCB isomers in liver slices prepared 

from human donor tissues, and from male Sprague-Dawley and F344 rats. At 2 and 6 hours, the 

metabolism of 1,4-DCB in human liver slices was similar to that seen in Sprague-Dawley and F344 rats. 

In human and F344 rat liver slices, the metabolism of 1,4-DCB was intermediate to that of 1,3- and 

1,2-DCB at 2 hours; at 6 hours, the metabolism of 1,4-DCB was lower than that of 1,3- or 1,2-DCB. In 

Sprague-Dawley rats, the hepatic metabolism of 1,4-DCB was greater than that of 1,3- and 1,2-DCB at 

2 hours, while at 6 hours, the metabolism of 1,4-DCB was intermediate to that of 1,3- or 1,2-DCB. In all 

three species, the metabolism of 1,4-DCB was not linear over time; the amount metabolized at 6 hours 

was only slightly higher than that metabolized after 2 hours. At both 2 and 6 hours, the amount of 

glucuronide and sulfate conjugates produced from 1,4-DCB was similar across all of the tested species. 

1,2-Dichlorobenzene. The initial step in the metabolism of 1,2-DCB is metabolism by cytochrome 

P-450 isozymes, mainly P4502E1, to an active epoxide. This epoxide can either react directly with 

cellular components, be conjugated to glutathione or glucuronic acid, or be hydrolyzed to form 

2,3-dichlorophenol or 3,4-dichlorophenol. The dichlorophenol metabolites can be further metabolized by 

conjugation with glutathione, glucuronic acid, or sulfate, or further oxidized to catechols. An additional 

oxidation to form dichlorohydroquinone metabolites has also been proposed. 

Microsomal studies have implicated cytochrome P-450, and particularly P4502E1, as a major component 

of 1,2-DCB metabolism, resulting in the formation of dichlorophenols, dichlorocatechols, and 

dichlorohydroquinones. After exposure to 1,2-DCB in rat liver microsomes, dichlorohydroquinone 

metabolites>dichlorophenol metabolites>dichlorocatechol metabolites (den Besten et al. 1992). 

Increasing dose results in a greater formation of dichlorohydroquinone metabolites, with less 

dichlorophenol and dichlorocatechol metabolites, and a greater covalent binding to proteins. When 

1,2-DCB was added to hepatic microsomes from animals treated with P-450 inducers, the major 

metabolites were dichlorophenols and dichlorohydroquinones (den Besten et al. 1992). 1,2-DCB in this 

system was also metabolized to a species that bound covalently with protein; addition of ascorbic acid 
 

 

DICHLOROBENZENES 211 

3. HEALTH EFFECTS 

decreased the binding to protein by 68% (den Besten et al. 1992). Microsomes from rats and mice 

pretreated with benzene to induce cytochrome P-450 resulted in greater levels of metabolism of 1,2-DCB, 

both to soluble or covalently-bound products, than in untreated animals (Nedelcheva et al. 1998). 

Addition of diethyldithiocarbamate, a P-450 inhibitor, decreased 1,2-DCB metabolism by ≥90% in both 

normal and pretreated hepatic microsomes from rats and mice, and in normal human liver microsomes. 

Addition of glutathione to the reaction mixture containing human or rat microsomes results in 

considerable (50–70%) formation of the glutathione-epoxide conjugate; addition of glutathione 

S-transferase enhances this proportion (Hissink et al. 1996c). 

The metabolism of 1,2-DCB by isolated microsomes containing human cytochrome P-450 isozymes is 

accomplished mainly by cytochrome P4502E1 (Hissink et al. 1996a, 1996b). Incubation of 1,2-DCB 

with microsomes from cells expressing human cytochrome P-450 enzymes indicated that the 

3,4-dichlorophenol was formed in greater amounts than the 2,3-dichlorophenol, and that in both cases, 

cytochrome P4502E1 was the most active isozyme (Bogaards et al. 1995). 

Experiments using rat and human liver slices have detected the presence of sulfatase, glucuronide, and 

glutathione/cysteine conjugates following exposure to 1,2-DCB (Fisher et al. 1990, 1995). Covalent 

binding of 1,2-DCB metabolites to proteins has also been shown in experiments using rat and liver slices 

(Fisher et al. 1990, 1995). 

Fisher et al. (1990) reported that in rat liver slices, the majority (>70%) of 1,2-DCB was found conjugated 

to glutathione, or as a cysteine conjugate, with only small amounts of the glucuronide or sulfate detected; 

only the conjugation status of the metabolite was reported. In human liver slices, the pattern was 

different, with approximately equal distribution of glucuronide and glutathione conjugates, and only 

minor amounts of the sulfate. Human liver slices metabolized approximately 50% more 1,2-DCB than 

did slices from F344 rats, and approximately 4-fold as much as slices from Sprague-Dawley rats (Fisher 

et al. 1995). Human liver slices formed 7–30-fold greater levels of glucuronide conjugates, 1.5–2-fold 

more sulphatase conjugates, and 1.5–2-fold more glutathione/cysteine conjugates of 1,2-DCB than rat 

liver slices (Fisher et al. 1995). Human fetal liver slices metabolized 1,2-DCB only about 10% as much 

as adult liver, and did so predominantly with conjugation to glutathione-S-transferase (GSH) (Fisher et al. 

1990). 
 

 

DICHLOROBENZENES 212 

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Azouz et al. (1955) identified urinary metabolites of 1,2-DCB in rabbits exposed to a single in vivo dose; 

2,3- and 3,4-dichlorophenol were detected, as were considerable levels of glucuronide and sulfate 

conjugates; the presence of dihydroquinone metabolites was not reported. Pretreatment of F344 rats with 

inducers of cytochrome P-450 (phenobarbital, β-naphthoflavone, or pyridine) resulted in an increased 

toxicity of intraperitoneal 1,2-DCB while treatment with piperonyl butoxide, a P-450 inhibitor, reduced 

the toxicity of 1,2-DCB (Valentovic et al. 1993b). Evidence for binding of 1,2-DCB or its metabolites to 

glutathione includes the depletion of hepatic glutathione following a single intraperitoneal injection of 

3.6 mmol/kg of 1,2-DCB in F344 or SD rats (Younis et al. 2000); depletion was nearly complete at 

8 hours postinjection, and remained nearly complete at 12 hours postinjection. Fischer 344 rats recovered 

by 24 hours postinjection, but SD rats remained depleted. 

Kumagai and Matsunaga (1995, 1997) reported that in occupationally-exposed humans, conjugated 

urinary metabolites of 1,2-DCB consisted of 3,4- and 4,5-dichlorocatechol and 2,3- and 

3,4-dichlorophenol; there was a linear correlation between exposure concentration and the levels of these 

four metabolites in the urine. 

1,3-Dichlorobenzene. Data on the metabolism of 1,3-DCB are less available than for the other two 

isomers of DCB. However, the available studies indicate that 1,3-DCB is metabolized by cytochrome 

P-450 to an epoxide and later to a dichlorophenol, followed by considerable secondary metabolism, 

similar to 1,2- and 1,4-DCB. 

Fisher et al. (1990) reported that in rat liver slices, the majority (~70%) of 1,3-DCB was found conjugated 

to glutathione, or as a cysteine conjugate, with only small amounts of the glucuronide or sulfate detected. 

In human liver slices, the pattern was different, with approximately equal distribution (~40% each) of 

glucuronide and glutathione conjugates, and ~20% of the metabolites as the sulfate. 

Human liver slices metabolized greater amounts of 1,3-DCB than did slices from F344 or SpragueDawley rats (Fisher et al. 1995). Human liver slices formed 2–9-fold greater levels of glucuronide 

conjugates, 1–4-fold greater levels of sulphatase conjugates, and 1–4-fold greater levels of 

glutathione/cysteine conjugates of 1,3-DCB than rat liver slices (Fisher et al. 1995). 

Following in vivo exposure of rats to 1,3-DCB, the major sulfur-containing metabolites in the urine were 

2,4- and 3,5-dichlorophenyl methyl sulfoxides and 3,5- and 2,4-dichlorophenyl methyl sulfones (Kimura 

et al. 1983). Kimura et al. (1992) identified 18 different biliary metabolites in rats exposed to a single 
DICHLOROBENZENES 213 

3. HEALTH EFFECTS 

dose of 1,3-DCB; these were all heavily conjugated dichlorophenyl metabolites, with evidence of both 

mono- and diol formation, but no conjugated quinone derivatives. 

Parke and Williams (1955) reported that following administration of 1,3-DCB to rabbits, the major 

urinary metabolites were 3,5-dichlorophenol and 2,4-dichlorophenol; the urine also contained 

2,4-dichlrophenylmercapturic acid. 

1,4-Dichlorobenzene. In general, the basic steps in metabolism of 1,4-DCB are similar to those of the 

other DCB isomers. The initial metabolic step is oxidation by cytochrome P-450, primarily P4502E1, to 

an epoxide and further to 2,5-dichlorophenol. The dichlorophenol may be further oxidized to 

dichlorocatechols, or possibly a dichlorohydroquinone, or may be conjugated by several phase II 

metabolism pathways. Support for the cytochrome P-450-mediated oxidation of 1,4-dichlorophenol, and 

subsequent conjugation reactions, comes from studies in isolated microsomes, liver slices, and exposures 

in vivo. 

Analysis of the urine specimens of a 3-year-old boy who had been playing with 1,4-DCB yielded 

2,5-dichlorophenol as well as four other unidentified phenols. These compounds were shown to be 

conjugated with glucuronic and sulfuric acids (Hallowell 1959). 

After treatment of F344 rats with 1,4-DCB, the major biotransformation reaction is P-450-dependent 

oxidation to 2,5-dichlorophenol, which is then primarily conjugated to sulphate or glucuronic acid and 

eliminated in the urine (Hissink et al. 1996b; Klos and Dekant 1994); mercapturic acids were also 

identified in the urine of exposed rats. Following a single oral exposure of 1,4-DCB to male Wistar rats, 

the main sulfur-containing metabolites found in the urine were 2,5-dichlorophenyl methyl sulfoxide (M1) 

and 2,5-dichlorophenyl methyl sulfone (M2); levels of M2 in the blood were greater, and more persistant, 

following a single oral dose of 1,4-DCB (Kimura et al. 1979). 

Hissink et al. (1997a) exposed male Wistar rats to 0, 10, 50, or 250 mg/kg of 1,4-DCB. Approximately 

90% of the DCB was metabolized to the 2,5-dichlorophenol, which was detected in the urine as its sulfate 

(50–60%), glucuronide (20–30%), and the free form (5–10%); in the bile, the major metabolite was the 

glucuronide of 2,5-dichlorophenol. The remaining metabolites consisted of N-acetyl-cysteine-S-dihydrohydroxy-1,4-DCB and N-acetyl-cysteine-S-1,4-DCB. No evidence for the formation of hydroquinones 

was seen, even under conditions of induced oxidative metabolism. 
DICHLOROBENZENES 214 

3. HEALTH EFFECTS 

Following oral administration to Chinchilla rabbits, 1,4-DCB was also oxidized, principally to 

2,5-dichlorophenol. A very high percentage of this metabolite was eliminated in the urine as conjugates 

of glucuronic or sulfuric acids (Azouz et al. 1955). Sulfur metabolites (methyl sulfides and methyl 

sulfones) of 2,5-dichlorophenol have been shown to induce cytochrome P450 activity (Kimura et al. 

1983). 

Fisher et al. (1990) reported that in rat liver slices, the majority (>60%) of 1,4-DCB was found conjugated 

to glutathione, or as a cysteine conjugate, with small amounts of the sulfate detected as well (~10% of 

total metabolites). In human liver slices, the pattern was different, with glutathione still being the 

predominant metabolite (~55%), but with an approximately equal distribution of glucuronide and sulfate 

conjugates (22–24%). In a later study, Fisher et al. (1995) reported that the total metabolism of 1,4-DCB 

was similar in liver slices from F344 rats, Sprague-Dawley rats, and humans. Human liver slices formed 

greater levels (~20–50%) of glucuronide conjugates of 1,4-DCB than rat liver slices; levels of formation 

of sulphatase and glutathione conjugates were similar in rats and humans (Fisher et al. 1995). 

After a single exposure to 1,4-DCB in rat liver microsomes, dichlorohydroquinone metabolites were 

formed at greater levels than dichlorophenol metabolites, which in turn were more prevalent than 

dichlorocatechol metabolites (den Besten et al. 1992). Increasing the concentration does not change the 

percent formation of 2,5-dichlorohydroquinone, but decreases the formation of dichlorophenols in favor 

of increased covalent binding to proteins. Hissink et al. (1997b) reported that incubation of 1,4-DCB with 

microsomes of rat or mouse liver, in the presence of glutathione but lacking ascorbic acid or glutathione 

transferase enzymes, resulted primarily in the formation of S-glutathionyl-dichlorocatechol metabolites, 

2,5-dichlorophenol, and 2,5-dichlorohydroquinone; rats appeared to be more efficient at forming a 

glutathione conjugate of the 2,3-epoxide than did mice, and formed less unconjugated 2,5-dichlorophenol 

and 2,5-dichlorhydroquinone. 

Incubation of 1,4-DCB with microsomes from cells expressing human cytochrome P-450 enzymes 

indicated that the 2,5-dichlorophenol was the only isomer formed, and that cytochrome P4502E1 was the 

most active isozyme in its formation (Bogaards et al. 1995; Hissink et al. 1996a, 1996b). In human 

microsomes, metabolism of 1,4-DCB was lower than in rodents, with 2,5-dichlorophenol as the major 

metabolite, even in the presence of added GSH (Hissink et al. 1997b). Using cell lines expressing 

individual human cytochrome P-450 isozymes, it was revealed that CYP2E1, and not 1A1, 1A2, 2B6, 

2C9, 2D6, 2A6, or 3A4, participated in 1,4-DCB metabolism. 
 

 

DICHLOROBENZENES 215 

3. HEALTH EFFECTS 

Addition of diethyldithiocarbamate, a P-450 inhibitor, decreased 1,2-DCB metabolism by ≥90% in both 

normal or pretreated hepatic microsomes from rats and mice, and in normal human liver microsomes 

(Nedelcheva et al. 1998), providing additional evidence for the involvement of cytochrome P-450 in 

1,4-DCB metabolism. 

3.4.4 Elimination and Excretion 

1,2-Dichlorobenzene. Following absorption, 1,2-DCB is eliminated primarily in the urine of both 

humans and animals, as metabolites rather than as the parent compound. Studies have detected the 

metabolites of 1,2-DCB in the urine of occupationally exposed humans (Kumagai and Matsunaga 1995, 

1997; Zenser et al. 1997). While a linear correlation between airborne concentration and urinary 

metabolite levels has been demonstrated, a quantitative assessment of the percent urinary elimination has 

not been determined. 

Quantitative data on elimination of 1,2-DCB comes from the study of Hissink et al. (1996a), which 

reported that following a single oral exposure to radiolabeled 1,2-DCB, 75–84% of the activity was 

detected in the urine 175 hours postexposure, with 7–16% being detected in the feces. Azouz et al. 

(1955) has also reported the elimination of 1,2-DCB and metabolites in the urine of exposed animals, 

although quantitative assessments of elimination were not presented. 

1,3-Dichlorobenzene. Data on the elimination of 1,3-DCB in humans are not available. 

Following a single dose of 1,3-DCB in rabbits, 50–75% of the compound was detected as urinary 

metabolites, indicating that the major route of elimination for 1,3-DCB is via the urine (Parke and 

Williams 1955). Kumura et al. (1984) also reported the presence of urinary metabolites of 1,3-DCB, 

although quantitative data were not presented. Additional data on the elimination of 1,3-DCB are not 

available. 

1,4-Dichlorobenzene. Quantitative data on the elimination of 1,4-DCB in humans are not available. 

However, metabolites of 1,4-DCB have been detected in the urine of exposed humans (Ghittori et al. 

1985; Hill et al. 1995; Pagnotto and Walkley 1965), demonstrating the urinary elimination of 1,4-DCB in 

humans. 
 

 

 

DICHLOROBENZENES 216 

3. HEALTH EFFECTS 

Animal studies of 1,4-DCB elimination have demonstrated that the compound is eliminated mainly in the 

urine, regardless of exposure route; elimination occurs in the form of metabolites, rather than as the parent 

compound. Male Wistar rats given single oral doses of 10, 50, or 250 mg/kg of 14C-1,4-DCB excreted the 

majority of 14C derived from 1,4-DCB in the urine as either the sulfate conjugate (60%) or the 

glucuronide (30%). Bile contained 5 and 30% of the total radioactivity after the low and high doses, 

respectively. Only minor amounts of mercapturic acid were found (Hissink et al. 1996b). In a later study, 

Hissink et al. (1997a) reported that following a single oral dose of 1,4-DCB in male Wistar rats, 75–85% 

of the dose was recovered in the urine, with only 2–5% being detected in the feces; clearance half-times 

did not vary with increasing dose level. Biliary excretion was dose-related, ranging from <5% at 

10 mg/kg to 30% at 250 mg/kg (Hissink et al. 1997a). In male and female F344 rats administered a single 

dose of 900 mg/kg/day 14C-1,4-DCB by gavage in corn oil, the excretion of radioactivity in the urine 

reached a peak in both males and females between 24 and 36 hours after dosing. Seventy-two hours after 

dosing, 41.3 and 3.6% of the dose was found in the urine and feces, respectively, of males; corresponding 

values in the urine and feces of females were 41.3 and 3.6% (Klos and Dekant 1994). Following oral or 

inhalation exposure in rats, levels of 1,4-DCB and its metabolites decreased only slightly over the first 

8 hours postexposure in the liver, kidneys, fat, and plasma, but then fell rapidly and were nearly 

undetectable 120 hours after the final exposure (Hawkins et al. 1980). Elimination was primarily urinary, 

with 97% of the total recovered label found in the urine (Hawkins et al. 1980). Elimination in the expired 

air was negligible, being 1% of the total or less (Hawkins et al. 1980). 

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 
DICHLOROBENZENES 217 

3. HEALTH EFFECTS 

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 

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 3-6 shows a conceptualized representation of a PBPK model. 

If PBPK models for dichlorobenzenes 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. 
DICHLOROBENZENES 218 

3. HEALTH EFFECTS 

Figure 3-6. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax Km 

Ingestion 

Inhaled chemical Exhaled chemical 

GI 

Tract 

Feces 

Urine

 Chemicals in air 

contacting skin 

Source: adapted from Krishnan et al. 1994 

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. 
DICHLOROBENZENES 219 

3. HEALTH EFFECTS 

PBPK models are available for 1,2-DCB in rats and humans (Hissink et al. 1997b). No PBPK models 

have been developed for 1,3- or 1,4-DCB. 

The rat and human PBPK models for 1,2-DCB were developed for oral exposure and do not include 

respiratory or dermal portals of entry (Hissink et al. 1997b). Both models have four compartments 

connected by blood flows: rapidly perfused tissues including the lung, kidneys, and spleen; slowly 

perfused tissues comprising muscle and skin; fat; and the liver, the only compartment in which 

metabolism is assumed to take place. The models assume that gastrointestinal tract uptake proceeds as a 

dose-dependent first-order kinetic process in which 1,2-DCB is deposited directly in the liver. For each 

of the nonmetabolizing compartments, differential equations describe the influx and efflux of 1,2-DCB. 

Equations are also used for the liver compartment to accounted for 1,2-DCB metabolism and reduced 

glutathione (GSH) synthesis, turnover, and consumption. Physiologic parameters, partition coefficients, 

biochemical parameters, and absorption rate constants used in the models are shown in Table 3-9. 

Absorption rate constants were estimated by fitting of the parameters to data for rats exposed to 5, 50, or 

250 mg/kg 1,2-DCB. 

Metabolism in the model is described as the initial, P-450-mediated, saturable formation of an epoxide, 

followed by epoxide transformation via three competing pathways that are assumed to independently 

follow pseudo first-order kinetics (i.e., are non-saturable): (1) conversion into dichlorophenol; 

(2) covalent binding to cellular macromolecules; and (3) conjugation with GSH. Michaelis-Menten 

constants, Vmax and Km, for the saturable cytochrome-P-450 oxidation of 1,2-DCB were initially 

estimated (in units of nmol/min-mg protein) from in vitro experiments with rat and human liver 

microsomes (Table 3-9). Scaling for use in the models assumed rat and human values of 45 and 77 mg 

microsomal protein/g liver, respectively. However, in order to obtain adequate fits to rat data for blood 

concentrations of parent material or total amount of metabolites, a “best-fit” Vmax value of 17 μmol/hour 

was used, along with the in vitro Km of 4.8 μM (Table 3-9). This “best-fit” value was about 4-fold higher 

than the rat in vitro Vmax scaled to units of μmol/hour (4.3 μmol/hour; see Table 3-9). Based on the rat 

data analysis, a factor of four was used to derive a “best-fit” Vmax value of 10,840 μmol/hour from the 

human in vitro Vmax (2,742 μmol/hour; see Table 3-9). The ratio of rate constants for the three epoxidetransforming pathways in rats (5:30:65) was estimated based on the relative amounts of in vitro covalent 

binding (5%), in vitro and in vivo dichlorophenol formation (25 and 30%), and in vitro and in vivo GSH 

conjugation (70 and 60%). For the rat model, the first-order rate constant for covalent binding was 

arbitrarily set at 50 hour-1; the resultant constants for dichlorophenol formation and GSH conjugation 
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Table 3-9. Parameters in PBPK Models for 1,2-Dichlorobenzene 

Parameter Rat Human 

Physiologic parameters (as per Gargas et al. 1986) 

Body weight (kg) 0.258 70 

Percentages of body weight 

Liver 4 3.14 

Fat 7 23.1 

 Rapidly perfused 5 2.66 

 Slowly perfused 75 62.1 

Flows (L/hour) [QC or QP= 15 L/hour (body weight)0.74] 

Cardiac output (QC) 5.50 348.0 

Alveolar ventilation (QP) 5.50 348.0 

Percentages of cardiac output 

Liver 25 25 

Fat 9 9 

 Rapidly perfused 51 51 

 Slowly perfused 15 15 

Partition coefficients 

[calculated by methods of Droz et al. (1989) based on water:air, oil:air, and blood:air partition 

coefficients] 

Blood:air 423 423 

Liver:blood 2.7 2.7 

Fat:blood 66.4 66.4 

Rapidly perfused:blood 2.7 2.7 

Slowly perfused: blood 1.3 1.3 

Biochemical parameters 

1,2-Dichlorobenzene oxidation 

Vmax (nmol/min-mg) (in vitro derived) 0.142 (4.3 μmol/hour) 0.27 (2,742 μmol/hour) 

Km (μM) (in vitro derived) 4.8 7.5 

Vmax (μmol/hour) (“best-fit” values) 17 10,840 

GSH conjugation of epoxide (hour-1) 650 650 

Formation of dichlorophenol (hour-1) 300 360 

Formation of reactive metabolites (hour-1) 50 5 

GSH turnover rate (hour-1) 0.14 0.14 

Absorption rate constants 

(estimated by fitting parameters to data for rats at indicated dose levels) 

Ka (hour-1) 

5 mg/kg 0.5 No data 

50 mg/kg 0.18 No data 

 250 mg/kg 0.06 0.06 

Source: Hissink et al. 1997b 
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were 300 and 650 hour-1, respectively (Table 3-9). In vitro data with human microsomes similarly formed 

the basis of the rate constants for these pathways: 5 hour-1 for covalent binding, 360 hour-1 for 

dichlorophenol formation, and 650 hour-1 for GSH conjugation (Table 3-9). A GSH turnover rate of 

0.14 hour-1, determined in another study with rats (Potter and Tran 1993), was used in both the rat and 

human models (see Table 3-9). 

The rat model was used to predict hepatic concentrations of covalently bound metabolites following an 

oral dose of 250 mg/kg 1,2-DCB that was expected to be toxic to the liver (Hissink et al. 1997b). The 

hepatic concentration in rats, 24 hours after dosing, was 1,459 μM. Versions of the human model using 

different Vmax values predicted that this administered dose level produced much lower hepatic 

concentrations of covalently bound metabolites in humans. Increasing the human in vitro-derived Vmax 

values by a factor of 10 did not increase the predicted human hepatic concentrations, 24 hours after 

dosing, to a value above about 240 μM. Therefore, the models predicted that equivalent administered 

doses in rats and humans would produce rat hepatic concentrations of covalently bound metabolites that 

are at least 6-fold higher in rats than humans. 

The PBPK models were also used to predict hepatic concentrations of GSH (expressed as a percentage of 

an assumed baseline concentration of 6.5 mM) following an oral dose of 250 mg/kg 1,2-DCB (Hissink et 

al. 1997b). The rat model predicted that maximum depletion of GSH (about 70% depletion) occurred at 

15 hours after dosing with 250 mg/kg. In contrast, the human model (using a Vmax value of 

10,840 μmol/hour; see Table 3-9) predicted that maximum depletion of GSH (essentially 100% depletion) 

occurred at 10 hours after dosing. The models therefore predicted that humans may be more susceptible 

to 1,2-DCB depletion of hepatic GSH levels than are rats. Hissink et al. (1997b) noted that (1) if 

depletion of GSH is the only factor involved in acute 1,2-DCB hepatotoxicity, the models predict that 

humans may be more susceptible than rats at the same administered dose levels, and (2) if covalent 

binding of reactive metabolites is the critical factor, humans may be less susceptible to 1,2-DCB acute 

hepatotoxicity than rats. However, at present, the majority of parameters of the human model are based 

on direct scaling from the rodent data, rather than having been calibrated and validated using human data. 

Because the predictive ability of the human model has not been established, its usefulness is unclear. 
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3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. Quantitative inhalation, oral, or dermal absorption studies in humans are not available for 

1,4-DCB. In the few studies available in laboratory animals, absorption was demonstrated to occur 

during a 3-hour inhalation exposure to 1,000 ppm of 1,4-DCB (Hawkins et al. 1980) as evidenced by 

accumulation of 14C in liver, kidney, plasma, and adipose tissue. No studies were located that described 

the absorption characteristics of 1,4-DCB after oral exposure; however, given the structural and 

physicochemical similarity to benzene, oral absorption is thought to be at or near 100% (EPA 1987a; 

Hawkins et al. 1980). A study assessing dermal absorption reported a dermal LD50 of >6,000 mg/kg/day 

in rats (Gaines and Linder 1986). Given the physicochemical properties, similarity to benzene, and lipidsoluble properties of 1,4-DCB, absorption by the inhalation, oral, and dermal routes of exposure is most 

likely by simple diffusion across cellular lipid membranes. No information is available that describes 

site-specific absorption within the respiratory tract (nasal epithelial absorption as opposed to alveolar 

absorption) or in the gastrointestinal tract. 

Distribution. Quantitative inhalation, oral, or dermal distribution studies in humans are not available 

for 1,4-DCB. 1,4-DCB has been detected in human blood, adipose tissue, and breast milk after an 

assumed inhalation exposure in Tokyo residents (Morita and Ohi 1975; Morita et al. 1975), as well as 

people in some parts of the United States (EPA 1983b, 1986f). The available data indicate that after 

inhalation, oral, and subcutaneous exposure, 1,4-DCB preferentially distributes to the fat tissue and 

organ-specific sites within the body (Hawkins et al. 1980), following the order: adipose > kidney > liver 

> blood (Charbonneau et al. 1989b; Hawkins et al. 1980). Although 1,4-DCB is originally distributed 

primarily to adipose tissue, significant amounts of 1,4-DCB are not retained in that tissue after exposure 

ceases. Regardless of exposure route, most of the 1,4-DCB falls to near- or below-detectable assay limits 

in all tissues of the body except adipose tissues 48–72 hours after exposure, depending on the dose 

(Charbonneau et al. 1989b; Kimura et al. 1979). 1,4-DCB was detected in adipose tissue at 120 hours 

after exposure (Charbonneau et al. 1989b). In the kidney, 50% of the 1,4-DCB appears to localize within 

the cytosol in male F344 rats (Charbonneau et al. 1987). 1,4-DCB also does not appear to bind to tissue 

proteins (Klos and Dekant 1994). 

Metabolism/Excretion. Quantitative inhalation, oral, or dermal metabolism and excretion studies in 

humans are not available for 1,4-DCB. One case study involving a 3-year-old boy who may have 

ingested 1,4-DCB reported the presence of 2,5-dichlorophenol in the urine (Hallowell 1959). Several 
 

 

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laboratory animal studies have indicated that 1,4-DCB is metabolized by phase I metabolism to 2,5-dichlorophenol (probably by cytochrome P-450), which then undergoes phase II metabolism/conjugation to 

the glucuronide or sulfate (Azouz et al. 1955; Hawkins et al. 1980; Hissink et al. 1996a; Kimura et al. 

1979; Klos and Dekant 1994). Minor amounts of 2,4-dichlorohydroquinone may also be present (Klos 

and Dekant 1994). Metabolism occurs in the liver. None of the detected metabolites have been reported 

to be associated with the toxic effects seen with 1,4-DCB. Metabolites are excreted mostly in the urine 

(Azouz et al. 1955; Hissink et al. 1996a; Kimura et al. 1979); however, some metabolites (mainly the 

glucuronide conjugate) may also be excreted in the bile and feces (Hissink et al. 1996a). The role of 

enterohepatic circulation in the metabolism and excretion of metabolites is not completely known; 

however, it has been suggested that enterohepatic circulation may occur with some sulfated metabolites 

(Kimura et al. 1979). This phase I and II metabolic pathway mechanism (see below) seems plausible, in 

that other chemicals with similar (halogenated- and lipid-soluble) physicochemical properties undergo 

very similar metabolic routines to become more water-soluble and excreted. The data suggest that 

metabolism and excretion are similar in several species. It is likely that human metabolic pathways are 

similar, if not identical, to those established in laboratory animals. 

3.5.2 Mechanisms of Toxicity 

The precise mechanism of 1,4-DCB oxidation to 2,5-dichlorophenol has not thoroughly been 

investigated. 1,4-DCB is known to be metabolized by cytochrome P-450 (Azouz et al. 1955; Hawkins et 

al. 1980) in order to be presented to phase II metabolic pathways to increase its water solubility for 

excretion. A proposed metabolic pathway involving cytochrome P-450 with intermediate formations of 

metabolites has been outlined for 1,4-DCB (Den Besten et al. 1992). No information was available 

regarding specific or altered mechanisms of action for 1,4-DCB in children. The hepatotoxicity and 

nephrotoxicity observed in laboratory animals are likely due to the formation of toxic intermediates 

formed while converting 1,4-DCB to 2,5-dichlorophenol by cytochrome P-450, or by depletion of GSH at 

higher doses of 1,4-DCB, or both. Some indirect evidence of this was provided by Mizutani et al. (1994). 

In mice pretreated with DL-buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, a single dose 

of 300 mg/kg 1,4-DCB caused significant elevations of ALT and liver calcium, both peaking between 

24 and 32 hours after dosing and declining thereafter, indicative of hepatic damage. Necrotic changes 

were observed at those times as well as hemorrhage, fatty changes, and appearance of altered eosinophilic 

cells. A single 1,200 mg/kg dose of 1,4-DCB did not significantly alter ALT or liver calcium, but doses 

of 100 mg/kg or higher in mice pretreated with BSO produced dose-related alterations in these 

parameters. Increasing cellular GSH with GSH monoethyl ester protected the liver from the combination 
 

 

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of 1,4-DCB and BSO. In addition, pretreatment with microsomal cytochrome P-450-dependent 

monooxygenase inhibitors also protected the liver from the combined toxicity of 1,4-DCB and BSO. 

Pretreatment with the P-450 inducer beta-naphthoflavone did not significantly alter the effect of 1,4-DCB 

plus BSO. Pretreatment with phenobarbital partially blocked the effect of 1,4-DCB plus BSO on ALT 

and completely prevented the increase in liver calcium. PCBs prevented the effect on both ALT and liver 

calcium. Treatment with BSO alone or in combination with 1,4-DCB (300 mg/kg) greatly decreased 

hepatic GSH concentration, the effect being more pronounced with the combination. 1,4-DCB alone had 

no such effect. Depletion of GSH also has been reported to increase the toxicity of 1,4-DCB in rats (Stine 

et al. 1991). The data provide a strong indication that the mechanism behind the hepatic (and probably 

renal) toxicity of 1,4-DCB lies in the intermediate steps of metabolite formation and conjugation by 

cytochrome P-450. Formation of 2,5-dichlorophenol from 1,4-DCB via cytochrome P-450 metabolism 

likely produces some intracellular, intermediate metabolite(s) that are also hepatotoxic when sufficient 

amounts accumulate intracellularly. These yet unidentified metabolites are detoxified by GSH, but when 

GSH depletion occurs, which is likely to occur at higher oral doses, toxicity is enhanced. Hepatocytes 

respond to these insults by releasing intracellular enzymes (Carlson and Tardiff 1976; Umemura et al. 

1996), degeneration, vacuolation (Eldridge et al. 1992; NTP 1987; Rimington and Ziegler 1963), 

necrosis, and increases in gross liver weight (Hollingsworth et al. 1956; Riley et al. 1980a). However, 

these changes are not specific to 1,4-DCB and likely occur in a dose-responsive manner. At lower doses, 

cellular proliferation in the liver in the absence of these toxic-type responses has been observed (Eldridge 

et al. 1992; Umemura et al. 1996); however, the mechanism behind this response needs to be more clearly 

defined. Exposure to 1,4-DCB likely follows similar metabolic pathways in the kidneys and would be 

responsible for the toxicity (increased organ weight, tubular degeneration, nephropathy) observed in that 

organ, and may also be linked to the known formation of cancer-linked α2μ-globulin in male rats. 

The metabolism of 1,4-DCB could involve the formation of an arene oxide intermediate, as has been 

proposed to occur in the oxidative metabolism of many halogenated aromatic hydrocarbons (Jerina and 

Daly 1974). 1,4-DCB has not been shown to be mutagenic in microbial or mammalian systems, a result 

that may be viewed as further suggestive evidence that an arene oxide intermediate is not involved in its 

metabolism. 

1,4-DCB has also been reported to produce hematological effects associated with exposure in humans and 

laboratory animals. These findings have been limited to red and white blood cell anomalies (NTP 1987) 

in rats and mice, and may take place within the bone marrow at the time of red and white cell formation, 

although a precise and careful mechanism behind this finding has not been produced. Acute hemolytic 
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anemia and methemoglobinemia reportedly occurred in a 3-year-old boy who had played with, and 

possibly ingested, 1,4-DCB crystals (Hallowell 1959). A 21-year-old pregnant woman who had eaten 1– 

2 blocks of 1,4-DCB toilet air freshener per week throughout pregnancy developed severe microcytic, 

hypochromic anemia with excessive polychromasia and marginal nuclear hypersegmentation of the 

neutrophils. Heinz bodies were seen in a small number of the red cells. After she discontinued this 

practice (at about 38 weeks of gestation), her hemoglobin levels began to rise steadily. The mechanism 

behind these findings in the human exposures is unknown, but it appears that 1,4-DCB may have some 

local effect on the hemoglobin content of the red blood cell (hemolysis, methemoglobinemia, Heinz 

bodies). These are rare events in humans and only occur at very high exposure doses in laboratory 

animals. The clinical finding of Heinz-body formation in red blood cells and methemoglobinemia 

suggest that some form of oxidative stress is occurring to produce these findings, although the 

mechanisms behind these end points are not known. While there may not be any direct evidence, it is not 

unreasonable to suspect that oxidant metabolites of 1,4-DCB may inhibit glucose-6-phosphate 

dehydrogenase (G6PD), as do metabolites of aniline, leading to Heinz body production, 

methemoglobinemia, and hemolysis (Trieff et al. 1993). The effect on the red and white blood cell 

production processes in the bone marrow (anemia, polychromasia) is quite likely an effect related to 

blood loss associated with bleeding from esophageal varices which form secondary to liver cirrhosis. 

3.5.3 Animal-to-Human Extrapolations 

No studies were identified that specifically addressed the use of animal data applied to human exposure 

issues specifically related to 1,4-DCB. No physiologically based pharmacokinetic models are available to 

estimate risk associated with human exposure to 1,4-DCB. It is difficult to compare the toxicity of 

1,4-DCB in laboratory animals to the toxicity observed in humans, since little reliable human data are 

available for examination (see Section 3.2). From the little data available, it appears that humans do have 

the potential to exhibit the same toxicological features of 1,4-DCB toxicosis as demonstrated or observed 

in the laboratory animal models studied. Although the mechanisms have not been outlined, human 

hematological responses (Campbell and Davidson 1970) and liver responses (Hallowell 1959) to 

1,4-DCB have been similar to the responses of laboratory animals tested (Hollingsworth et al. 1956; NTP 

1987). (However, the human hematological responses were vague and quite possibly unrelated.) 

Although the data are not sufficient to make direct comparisons, the possibility strongly exists that human 

responses may be similar to those of laboratory animals, and animal data should be taken into 

consideration until better human data become available. With the exception of the α2μ-globulin 

observation in the male rat kidney (Bomhard et al. 1988), all of the detoxication pathways present in the 
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laboratory animal models are present in humans. This means that humans are likely to detoxify 1,4-DCB 

in a similar or identical manner to that of the laboratory animals, and suggests that humans are susceptible 

to the liver and possibly the renal lesions outlined for the laboratory animals studied (see Section 3.5.2). 

Due to the lack of acceptable dosing and exposure data in humans, it is not possible at present to 

definitively determine the magnitude of these human toxicological responses, the dose-response 

relationship, or whether humans are more or less susceptible to these effects on a mg/kg/day (oral and 

dermal) or ppm (inhalation) basis. It is also unknown whether the sex predilection found in male rats to 

1,4-DCB renal or endocrine toxicity occurs in the human male. 

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) and again by Colborn et al. (1993), was also used in 

1996 when Congress mandated the EPA to develop a screening program for “...certain substances [which] 

may have an effect produced by a naturally occurring estrogen, or other such endocrine effect[s]...”. To 

meet this mandate, EPA convened a panel called the Endocrine Disruptors Screening and Testing 

Advisory Committee (EDSTAC), and in 1998, the EDSTAC completed its deliberations and made 

recommendations to EPA concerning endocrine disruptors. In 1999, the National Academy of Sciences 

released a report that referred to these same types of chemicals as hormonally active agents. The 

terminology endocrine modulators has also been used to convey the fact that effects caused by such 

chemicals may not necessarily be adverse. Many scientists agree that chemicals with the ability to disrupt 

or modulate the endocrine system are a potential threat to the health of humans, aquatic animals, and 

wildlife. However, others think that endocrine-active chemicals do not pose a significant health risk, 

particularly in view of the fact that hormone mimics exist in the natural environment. Examples of 

natural hormone mimics are the isoflavinoid phytoestrogens (Adlercreutz 1995; Livingston 1978; Mayr et 

al. 1992). These chemicals are derived from plants and are similar in structure and action to endogenous 

estrogen. Although the public health significance and descriptive terminology of substances capable of 

affecting the endocrine system remains controversial, scientists agree that these chemicals may affect the 

synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body responsible 

for maintaining homeostasis, reproduction, development, and/or behavior (EPA 1997c). Stated 

differently, such compounds may cause toxicities that are mediated through the neuroendocrine axis. As 
 

 

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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). 

Concern has been raised that many industrial chemicals, including DCBs, are endocrine-active 

compounds capable of having widespread effects on humans and wildlife (Colborn et al. 1993; Crisp et al. 

1998; Daston et al. 1997; Safe and Zacharewski 1997; Versonnen et al. 2003). Particular attention has 

been paid to the possibility of these compounds mimicking or antagonizing the action of estrogen. 

Estrogen influences the growth, differentiation, and functioning of many target tissues, including female 

and male reproductive systems, such as mammary gland, uterus, vagina, ovary, testes, epididymis, and 

prostate. Most estrogenic chemicals have a ring structure included in the molecule, and para-substituted 

phenols generally bind better to the estrogen receptor and are more likely to exert xenoestrogenic effects 

than ortho- or meta-substituted compounds. In addition, there is evidence that some of these chemicals 

alter the thyroid hormone system, which is an important system for normal structural and functional 

development of sexual organs and the brain. 

Insufficient information is available to adequately assess the endocrine disruptor potential of DCBs. 

Testing of 1,2-, 1,3-, and 1,4-DCB in the in vitro yeast estrogen screen (YES) assay showed that the 1,3- 

and 1,4- isomers were active in a concentration-responsive manner, although estrogenic potency was 

extremely weak (Versonnen et al. 2003). The relative potency relative to 17β-estradiol was 1.04x10-8 for 

1,3-DCB and 2.2x10-7 for 1,4-DCB. The negative results for 1,2-DCB in this system are consistent with a 

lack of estrogenic activity of 1,2-DCB in in vitro yeast two-hybrid assays (Eguchi et al. 2003; Nishihara 

et al. 2000). The in vivo estrogenic activity of 1,2-, 1,3-, and 1,4-DCB was tested by measuring plasma 

vitellogenin (VTG) production in zebrafish (Danio rerio) that were exposed to each isomer for 14 days 

(Versonnen et al. 2003). VTG is a yolk protein precursor in teleosts and other oviparous vertebrates that 

is synthesized in response to estradiol stimulation. Elevated VTG levels were found in fish exposed to 

≥10 mg/L of 1,4-DCB, but estrogenic potency was weak in comparison to ethynylestradiol, which 

increased VTG at ≥5 ng/L. 

Histopathological changes occurred in the thyroid and pituitary glands of rats orally exposed to 1,3-DCB 

for 90 days (McCauley et al. 1995). Effects in the thyroid occurred at ≥9 mg/kg/day, the lowest tested 

dose, and included depletion of colloid density, characterized by decreased follicular size with scant 

colloid and follicles lined by cells that were cuboidal to columnar. Effects in the pituitary occurred at 

≥147 mg/kg/day and included cytoplasmic vacuolization of the pars distalis. Increases in serum 
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cholesterol and serum calcium also occurred and were also believed to be related to effects on endocrine 

end points, possibly reflecting a disruption of hormonal feedback mechanisms, or target organ effects on 

the pituitary, hypothalamus, and/or other endocrine organs. Histopathological changes in endocrine 

tissues were not observed in intermediate- and chronic-duration studies of 1,2-DCB (NTP 1985; 

Robinson et al. 1991) or 1,4-DCB (Aiso et al. 2005b; Japan Bioassay Research Center 1995; Naylor and 

Stout 1996; NTP 1987) in rats, mice, or dogs. Measurements of thyroid and other endocrine hormones 

have not been conducted in any study of DCBs. 

Effects of 1,2- and 1,3-DCB on reproductive function have not been investigated. There were no effects 

on fertility or mating in 2-generation studies of 1,4-DCB in rats exposed orally to ≤270 mg/kg/day 

(Bornatowicz et al. 1994) or by inhalation to ≤211 ppm (Tyl and Neeper-Bradley 1989). No adverse 

histopathological changes in reproductive tissues were observed in intermediate- and chronic-duration 

oral studies of 1,2-DCB (NTP 1985; Robinson et al. 1991), 1,3-DCB (McCauley et al. 1995), and 

1,4-DCB (Naylor and Stout 1996; NTP 1987). 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 
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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 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

There is little credible scientific information available on the susceptibility and toxicological effects of 

1,4-DCB in children. The risk for exposure is apparently high. A study by Hill et al. (1995) measured 

blood levels of 1,4-DCB and urine levels of its metabolites in 1,000 adults, finding that exposure to 

1,4-DCB was widespread, with 98% of the adults having measurable concentrations of 1,4-DCB 

metabolites in their urine. There is no evidence to indicate that children are likely to be exposed to lower 

amounts of 1,4-DCB from everyday living, suggesting that children are perhaps equally at risk for 

exposure and potential toxic side-effects. 
 

 

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Some information on possible health effects of DCBs in children is available from two case reports of 

1,4-DCB exposure. Campbell and Davidson (1970) reported a case of a 21-year-old woman eating 1– 

2 toilet air-freshener blocks per week while pregnant. The mother developed hematological aberrations 

(hypochromic, microcytic anemia, polychromasia); however, she delivered an apparently normal female 

infant with no apparent hematological problems. Another report describes a 3-year-old boy who had been 

playing with crystals containing 1,4-DCB for 4–5 days before being admitted to the hospital. On 

admission, the boy was jaundiced, his mucous membranes were pale, and he was diagnosed with anemia 

and methemoglobinemia. After a blood transfusion, the child gradually improved, but it was unclear 

whether the boy actually ingested any of the 1,4-DCB (Hallowell 1959). These case reports are consistent 

with an expectation that health effects in children and adults are similar. Although there are no known 

differences in the toxicity of DCBs between adults and children, there is no evidence to substantiate the 

presumption. 

Information on the reproductive toxicity of DCBs is essentially limited to a 2-generation oral study of 

1,4-DCB in rats (Bornatowicz et al. 1994). There were no effects on mating or fertility in either 

generation, as assessed by a minimal number of end points (duration between mating and successful 

copulation and fertility index). The is a report of morphologically abnormal sperm in rats exposed to a 

high dose of 1,4-DCB by intraperitoneal injection (Murthy et al. 1987), but there are no studies that 

investigated transgenerational effects of exposure to DCBs. 

Information on the developmental toxicity of 1,2-, 1,3-, and 1,4-DCB is available from oral and inhalation 

studies in rats and rabbits (Bio/dynamics 1989; Bornatowicz et al. 1994; Giavini et al. 1986; Hayes et al. 

1985; Hodge et al. 1977; Ruddick et al. 1983; Tyl and Neeper-Bradley 1989). These studies provide no 

indications that DCBs are teratogenic, although fetotoxicity occurred at exposure levels that were also 

maternally toxic. A multigeneration study in rats that were orally exposed to 1,4-DCB found toxic effects 

in the pups during the nursing period, including increased neonatal mortality, dermal effects and other 

clinical manifestations, and reduced neurobehavioral performance (Bornatowicz et al. 1994). The 

postnatal developmental toxicity occurred at dose levels that were not maternally toxic and below those 

causing systemic toxicity in other animal studies. The results of this study indicate that postnatal 

developmental toxicity is the most sensitive end point in animals, and suggest a basis for potential 

concern in exposed children. Effects of DCBs on the immune and endocrine systems have not been 

adequately studied. 
DICHLOROBENZENES 231 

3. HEALTH EFFECTS 

No studies are available that describe potential differences in the toxicokinetics or the mechanism of 

action of 1,4-DCB in children. No data are available that specifically describe whether 1,4-DCB or its 

major metabolites will cross the placenta; however, all three DCB isomers have been detected in placental 

tissues (Erickson et al. 1980; Pellizzari et al. 1982; Reichrtova et al. 1999). Because 1,4-DCB is not 

known to be genotoxic, it poses no threat to the DNA in parental germ cells. No PBPK models are 

available for children, fetuses/pregnant women, or infants/lactating women exposed to 1,4-DCB. 

As discussed in Section 3.4, Toxicokinetics, the specific toxicokinetic behavior of 1,4-DCB in children 

(and immature laboratory animals) has not been reported. Based on its physicochemical properties, it is 

anticipated that the absorption, distribution, metabolism, and excretion of 1,4-DCB and its metabolites 

would be quite similar to that of the adult human (or animal), even when taking into account differences 

in body weight, total body water, body fat, volumes of distribution (VD), and perhaps lower activities of 

some metabolizing enzymes (cytochrome P-450) during the natal and neonatal periods. 1,4-DCB is a 

lipid-soluble toxicant and is likely to pass across the placental membranes. It will likely accumulate in 

many of the same tissues in the fetus that it would normally be expected to accumulate in the adult, with 

the possible exception of fat storage in the fetus (Li et al. 1995). Some amount of 1,4-DCB accumulates 

in human breast milk (EPA 1983b), given its high lipid (milk fat) content, thereby providing a potential 

route of exposure to a nursing child, although there is no concrete data to support this relay exposure 

hypothesis. Some studies have noted that 1,4-DCB will preferentially distribute to adipose tissues in 

relatively high amounts, compared to accumulations in the liver and kidneys (Charbonneau et al. 1989b; 

Hawkins et al. 1980; Klos and Dekant 1994). Loss of maternal body fat may potentially mobilize 

1,4-DCB from fat storage deposits in exposed mothers. This mobilization could result in increased blood 

levels and/or excretion of 1,4-DCB and its metabolites from the mother, as well as redistribution to other 

fat deposition sites, such as the high fat content found in breast milk. 

No studies have described the interactions of 1,4-DCB with other chemicals in children, or the means by 

which to reduce peak absorption of 1,4-DCB after exposure. 

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). 
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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 dichlorobenzenes are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by dichlorobenzenes 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 Dichlorobenzenes 

Exposure to DCBs can be identified by measuring levels of the isomers in blood (Bristol et al. 1982; Hill 

et al. 1995; Jan 1983; Langhorst and Nestrick 1979; Pellizzari et al. 1985), urine (Ghittori et al. 1985; Hill 
 

 

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et al. 1995; Kumagai and Matsunaga 1995, 1997; Zenser et al. 1997), adipose tissue (Jan 1983), and 

breast milk (Jan 1983; Mes et al. 1986). Toxicokinetic studies (Section 3.4) indicate that DCBs are 

present in blood for a limited time after exposure and eliminated from the body over a period of several 

days, primarily in the urine as metabolites (Hissink et al. 1996a, 1996b; Kimura et al. 1979; Parke and 

Williams 1955). Measurement of urinary metabolites is likely to provide a better indication of recent 

exposure than blood or other measurements since DCBs can be excreted for several days post-exposure 

(Hallowell 1959). Urinary 2,5-dichlorophenol is a well-documented biomarker for monitoring worker 

exposure to 1,4-DCB (McKinney et al. 1970; Pagnotto and Walkley 1965). Urinary 2,3- and 

3,4-dichlorophenols, as well as 3,4- and 4,5-dichlorocatechols, have been shown to be useful indicators of 

exposure to 1,2-DCB (Kumagai and Matsunaga 1997). Because the basic steps in the metabolism of the 

three DCB isomers are similar, likely biomarkers of exposure to 1,3-DCB include 2,4- and 3,5-dichlorophenols (Kimura et al. 1992). The presence of a DCB isomer and/or its conjugates in urine is not 

completely specific for exposure to the DCB. For example, several chlorophenols, including 

2,5-dichlorophenol, have been identified as metabolites of lindane in laboratory animals. Because DCBs 

tend to accumulate in fat, measurements of adipose levels of the parent isomers are likely to provide 

useful information on long-term exposures (Jan 1983; Morita et al. 1975). There are currently no data 

available to assess a potential correlation between the values obtained with these measurements and the 

toxic effects observed in humans or laboratory animal species. Information on the analytical methods 

commonly used to detect and quantify 1,4-DCB in biological samples is presented in Section 6.1. 

No information is available describing specific biomarkers of exposure to 1,4-DCB in children. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Dichlorobenzenes 

There are no known specific biomarkers of effects for 1,2-, 1,3-, or 1,4-DCB because none of the health 

effects identified in humans or animals appear to be uniquely associated with exposure to any isomer. 

Biomarkers of effects for DCBs are likely to be common to the general class of halogenated aromatic 

hydrocarbons because DCBs and other structurally similar chemicals cause generally similar effects. For 

example, DCBs and other chlorinated aromatics induce a similar spectrum of hepatic effects ranging from 

liver enlargement and increased microsomal enzyme activities at lower levels of exposure to degenerative 

lesions at higher doses. 

It is well documented that 1,4-DCB induces hyaline droplet formation and tubular degeneration in the 

kidneys of male rats at moderate-to-high levels of oral exposure. Saito et al. (1996) studied the effect of 
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3. HEALTH EFFECTS 

oral treatment with 1,4-DCB on the urinary excretion of kidney-type α2μ-globulin (aG-K) in male 

Sprague-Dawley rats. Groups of 3 rats received placebo or 1,4-DCB (1.5 mmol/kg/day; 220 mg/kg/day) 

by gavage in corn oil for 7 days. Concentrations of aG-K in the urine of 1,4-DCB-treated rats ranged 

from 0.04 to 0.18 mg/mL; urine concentrations increased steadily throughout the study. In contrast, aG-K 

concentrations were undetectable in the urine of controls at all time points. The mean concentration of 

aG-K in the kidneys of rats treated with 1,4-DCB was 1.15 mg/mg of soluble protein, compared to 

0.35 mg/mg protein in the control group. The authors concluded that measurement of urinary aG-K 

would be a good indicator of 1,4-DCB exposure; however, this response is neither unique to 1,4-DCB nor 

applicable to human exposure cases. As discussed earlier in Section 2.5, this particular protein is 

produced in large amounts by male rats, accounting for 26% of their total urinary protein, but not in 

human males, where it was found to be present at 1% of the amount measured in male rats (Olson et al. 

1990). Also, this protein is produced in only minimal quantities by females of any species or the males of 

other laboratory species including mice (EPA 1991i). These observations have led to suggestions that 

humans are probably not at risk for the type of nephropathy induced by 1,4-DCB in male rats, and that the 

α2μ-globulin biomarker is inappropriate to use in humans (EPA 1991i). 

No information was available describing specific biomarkers of effect in children to 1,4-DCB. 

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC 

Subcommittee Report on Biological Indicators of Organ Damage (1990) and for information on 

biomarkers for neurological effects, see OTA (1990). 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Little information is available regarding possible interactions of 1,2-, 1,3-, or 1,4-DCB with other 

chemicals. Because DCBs are liver toxins, they might interact with other chemicals that are liver 

toxicants. These toxicants are many, and include ethanol, halogenated hydrocarbons (chloroform, carbon 

tetrachloride, etc.), benzene, and other haloalkanes and haloalkenes. DCB hepatotoxicity could also be 

exacerbated by concurrent exposure to acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, 

pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such 

interactions are likely to be additive or synergistic. One study found that pretreatment with DCB 

increased LD50 values for parathion in mice (EPA 1985a). 
 

 

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Regarding the effect of 1,4-DCB on hemolysis and formation of Heinz bodies, methemaglobinemia, and 

hemolytic anemia, it is likely that additive or synergistic interaction would occur with other oxidants, 

such as aniline and acrolein, which are known to inhibit G6PD. A human case study reported a possible 

interactive effect between DCB and naphthalene in a woman who developed aplastic anemia (EPA 

1985a). 

Perinatal evaluations were performed in offspring of female Wistar rats were exposed to diets containing 

25 ppm 1,4-DCB (estimated dose 2 mg/kg/day) alone or combined with 125 ppm p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE) from Gd 1 to Pnd 21 for a total of 42 days (Makita 2005). There were no 

maternal effects in either group as shown by clinical signs or changes in body weight and food 

consumption. Perinatal evaluations showed no gross external malformations or effects on litter size, sex 

ratio, or pup viability on Pnd 1 in either group. Assessments of the offspring until 6 weeks of age showed 

no postnatal effects on body weight gain, anogenital distance, times of eye and vaginal opening and 

preputial separation, or serum levels of reproductive hormones (LH and FSH in both sexes and 

testosterone in males at 6 weeks) in either group. Examination of the liver, kidneys, spleen, thymus, 

testes, epididymides, prostate, seminal vesicles, ovaries, uterus, and thymus at 6 weeks showed no effects 

on organ weight or histology in either group, except for increased absolute thymus weight (approximately 

20% higher than controls) in female pups exposed to 1,4-DCB alone. The biological significance of this 

effect is unclear because it did not occur in the male offspring and was not accompanied by any 

histological changes. There was no effect on thymus weight or histology in male or female pups exposed 

to the mixture of 1,4-DCB and p,p’-DDE. 

No information was located on interactions between DCBs and other chemicals in children. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to dichlorobenzenes than will most 

persons exposed to the same level of dichlorobenzenes 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 dichlorobenzenes, or compromised 

function of organs affected by dichlorobenzenes. Populations who are at greater risk due to their 

unusually high exposure to dichlorobenzenes are discussed in Section 6.7, Populations with Potentially 

High Exposures. 
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No population has been identified as exhibiting an unusual susceptibility to the effects of exposure to 

1,4-DCB. However, based on data from studies in humans and animals, individuals with compromised 

liver function, infants and children with immature liver function (Hallowell 1959), and elderly people 

(Cotter 1953; Nalbandian and Pearce 1965) may be more at risk than the general population. Individuals 

having a genetic susceptibility to methemoglobin formation (such as those individuals with a deficiency 

of G6PD in their red blood cells) may also be at increased risk from inhalation or oral exposure to 

1,4-DCB. 

No information was available describing specific susceptibilities of children to 1,4-DCB. There is no 

direct evidence that children differ in their susceptibility to the health effects of 1,4-DCB from adults. It 

should be noted that postnatal neurodevelopmental toxicity is a sensitive end point in 1,4-DCB-exposed 

rats (Bornatowicz et al. 1994), suggesting a basis for potential concern in exposed children. This issue is 

discussed in detail in Section 3.7 Children’s Susceptibility. 

The extent to which men and women may differ in susceptibility to DCBs is not known. Available 

animal data do not provide a clear pattern for gender differences in the toxicity of DCBs, although some 

subchronic and chronic studies found that males were more sensitive than females for some end points. 

For example, a multigeneration inhalation study of 1,4-DCB in rats observed increases in adult liver 

weight that were more pronounced in males than females (Tyl and Neeper-Bradley 1989). In a 

subchronic oral study of 1,3-DCB in rats, histopathological changes in the thyroid were generally more 

severe in males than in females (McCauley et al. 1995). This study also found histopathology in the 

pituitary of male rats, but not female rats. The pituitary lesion was reported to be similar to those induced 

in gonadectomized rats and was considered to be an indicator of gonadal deficiency (McCauley et al. 

1995). Though these animal studies provide an indication that males may be more sensitive to DCBs 

exposure, the evidence is insufficient for extrapolating to humans. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to dichlorobenzenes. 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 dichlorobenzenes. 

When specific exposures have occurred, poison control centers and medical toxicologists should be 
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3. HEALTH EFFECTS 

consulted for medical advice. The following texts provide specific information about treatment following 

exposures to dichlorobenzenes: 

Aaron CK, Howland MA, eds. 1994. Goldfrank's toxicologic emergencies. Norwalk, CT: Appleton and 

Lange. 

Dreisback RH, ed. 1987. Handbook of poisoning. Norwalk, CT: Appleton and Lange. 

Ellenhorn MJ, Barceloux, DG, eds. 1997. Medical toxicology: Diagnosis and treatment of human 

poisoning. New York, NY: Elsevier Publishing. 

Grossel TA, Bricker JD. 1994. Principles of clinical toxicology. 3rd edition, New York, NY: Raven 

Press. 

Haddad LM, Winchester JF, eds. 1990. Clinical management of poisoning and drug overdose. 2nd 

edition, Philadelphia, PA: WB Saunders. 

3.11.1 Reducing Peak Absorption Following Exposure 

Human exposure to 1,4-DCB can occur by inhalation, ingestion, or dermal contact. General 

recommendations for reducing absorption of 1,4-DCB following acute-duration inhalation exposure have 

included moving the patient to fresh air and administration of 100% humidified supplemental oxygen 

with assisted ventilation (HSDB 1996). General recommendations for reducing absorption following 

acute ingestion exposure have included inducing vomiting (unless the patient is or could rapidly become 

obtunded, comatose, or convulsing, and considering the risk of aspiration of vomitus), gastric lavage, or 

administration of a charcoal slurry (HSDB 1996). Intake of fatty foods, which would promote absorption, 

should be avoided. In the case of eye exposure, irrigation with copious amounts of water has been 

recommended (HSDB 1996). For dermal exposure, and to minimize dermal absorption, the removal of 

contaminated clothing and a thorough washing of any exposed areas with soap and water has been 

recommended (HSDB 1996). 

3.11.2 Reducing Body Burden 

1,4-DCB distributes to fatty tissues and is probably retained there at low concentrations (EPA 1986d; 

Hawkins et al. 1980; Morita and Ohi 1975; Morita et al. 1975). However, most of an absorbed dose is 

excreted within 5 days of exposure (Hawkins et al. 1980), and there is no evidence suggesting that the low 

levels of 1,4-DCB that are likely to remain in fatty tissues would cause adverse effects. For these reasons, 
DICHLOROBENZENES 238 

3. HEALTH EFFECTS 

methods for enhancing elimination of 1,4-DCB shortly after high-dose exposure could reduce toxic 

effects; however, no such methods have been identified. Methods that could enhance the elimination of 

1,4-DCB after high- or low-dose exposure in humans or laboratory animals have not been reported. 

While it might be possible to develop methods to alter metabolism of 1,4-DCB to promote formation of 

metabolites that are more easily excreted, this could be difficult because the current lack of knowledge of 

the specific metabolic pathways of 1,4-DCB precludes speculation concerning which pathways it might 

be most beneficial to stimulate or inhibit. One pathway for which stimulation may be contraindicated is 

sulfate conjugate formation (Kimura et al. 1979). Methylation of 1,4-DCB sulfate conjugates can occur, 

and these methylated conjugates are excreted less rapidly than nonmethylated conjugates (Kimura et al. 

1979). Since little is known concerning the toxicity of these conjugates, it is presently not possible to 

determine the consequences of promoting formation of these metabolites. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The mechanism of action for liver effects of 1,4-DCB has not been clearly delineated; however, based on 

in vitro experiments, induction of P-450 metabolism by pretreatment with phenobarbital may enhance 

hepatotoxicity (Fisher et al. 1991a). This suggests that one mechanism of hepatotoxicity may be the 

production of reactive intermediates through phase I P-450-mediated oxidation, although it should be 

noted that the P-450 inhibitors metyrapone and SKF 525-A did not block hepatotoxicity of 1,4-DCB in 

human liver tissue in vitro (Fisher et al. 1991a). Lattanzi et al. (1989) provide evidence indicating that the 

microsomal mixed-function oxidase system and microsomal glutathione transferases and, to a lesser 

degree, cytosolic glutathione transferases, can be involved in the bioactivation of 1,4-DCB. More 

information concerning the mechanism of action for hepatic effects is needed before methods for blocking 

that mechanism and reducing toxic effects can be developed. 

The mechanisms of action for nephrotoxic (with the exception of α2μ-globulin-mediated nephropathy 

specific to male rats) or hematotoxic effects have not been clearly delineated, and with the available 

information, it is difficult to speculate how 1,4-DCB might cause such effects. More information 

concerning the mechanisms of action for blood and kidney effects are needed before methods for 

blocking those mechanism and reducing toxic effects can be developed. 
 

 

DICHLOROBENZENES 239 

3. HEALTH 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 dichlorobenzenes 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 dichlorobenzenes. 

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. 

3.12.1 Existing Information on Health Effects of Dichlorobenzenes 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

dichlorobenzenes are summarized in Figures 3-7, 3-8, and 3-9. The purpose of this figure is to illustrate 

the existing information concerning the health effects of dichlorobenzenes. 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. 

Some limited information (i.e., anecdotal, single acute-duration exposure, and workplace exposure) is 

available on the health effects of human exposure to 1,2- and 1,4-DCB via inhalation and 1,4-DCB by the 

oral route. For persons exposed via inhalation, there is information on death, systemic effects, neurologic 

effects. There is also information on systemic effects in humans resulting from acute-, intermediate-, and 

chronic-duration oral exposure. It is important to note that most of this oral information was obtained 

from case studies in which levels and durations of exposure to 1,4-DCB were unknown or uncertain. 
 

Figure 3-7. Existing Information on Health Effects of 1,2-Dichlorobenzene 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 

DICHLOROBENZENES 240 

3. HEALTH EFFECTS 
 

Figure 3-8. Existing Information on Health Effects of 1,3-Dichlorobenzene 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 

DICHLOROBENZENES 241 

3. HEALTH EFFECTS 
 

Figure 3-9. Existing Information on Health Effects of 1,4-Dichlorobenzene 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 

DICHLOROBENZENES 242 

3. HEALTH EFFECTS 
DICHLOROBENZENES 243 

3. HEALTH EFFECTS 

Data available on health effects of DCBs in animals are more extensive than in humans. Most of the 

information is for 1,2- and 1,4-DCB, whereas all data on 1,3-DCB are from one oral study. The most 

extensively studied isomer is 1,4-DCB. Information is available on the developmental, reproductive, 

genotoxic, and carcinogenic effects of inhalation exposure to 1,4-DCB, as well as on the systemic effects 

resulting from intermediate-duration exposure. In studies using oral exposure, information is available on 

death; systemic effects resulting from acute-, intermediate-, and chronic-duration exposure; and 

developmental, genotoxic, and carcinogenic effects. Only data on the lack of a lethal effect are available 

in studies using dermal exposure. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. A limited amount of information is available on health effects in people 

who were occupationally exposed to 1,2-DCB (Hollingsworth et al. 1958). This information includes 

exposure levels associated with eye and respiratory tract irritation and results of periodic medical 

examinations, but the data are insufficient for identifying sensitive systemic end points in humans or for 

inhalation MRL derivation purposes. The limited information on irritation effects of 1,2-DCB in humans 

is consistent with histological findings of nasal olfactory epithelial lesions in mice that were intermittently 

exposed to 1,2-DCB vapor for up to 14 days (Zissu 1995). The severity of the nasal lesions ranged from 

moderate to severe in severity and occurred at concentrations lower than those that caused acute systemic 

effects (liver and kidney lesions) in rats (DuPont 1982; Hollingsworth et al. 1958) or developmental 

effects in rats and rabbits (Hayes et al. 1985). A NOAEL was not identified for the serious nasal effects, 

precluding derivation of an acute inhalation MRL. Additional studies could characterize the threshold 

region for nasal effects, confirm that the nasal cavity is more sensitive than systemic end points, and 

provide a sufficient basis for inhalation MRL derivation. 

There is no information on the toxicity of 1,2-DCB in orally-exposed humans. Information on effects of 

acute oral exposure to 1,2-DCB in animals essentially consists of findings in three systemic toxicity 

studies in rats and mice (NTP 1985; Rimington and Ziegler 1963; Robinson et al. 1991) and one 

developmental toxicity study in rats (Ruddick et al. 1983). These studies collectively identify the liver as 

the most sensitive target, but two are limited by small numbers of animals and lack of a NOAEL due a 

single dose level (Rimington and Ziegler 1963) or lack of histopathology evaluations at doses lower than 

the LOAEL (NTP 1985). The third systemic toxicity study (Robinson et al. 1991) is well designed, 

identified a critical NOAEL and LOAEL for hepatoxicity, and was used to derive an acute oral MRL. 
DICHLOROBENZENES 244 

3. HEALTH EFFECTS 

Additional studies are needed to establish whether liver toxicity is the most sensitive end point for acute 

exposure and the most appropriate basis for the MRL. The oral database for 1,2-DCB particularly lacks 

adequate assessments of neurotoxicity, immunotoxicity, and end points shown to be sensitive to other 

DCB isomers (e.g., thyroid and pituitary). 

No inhalation toxicity data are available for 1,3-DCB in humans or animals, indicating that a welldesigned inhalation toxicity study could provide a basis for an acute inhalation MRL. The acute oral 

database for 1,3-DCB essentially consists of one well-designed 10-day systemic toxicity study (McCauley 

et al. 1995) that was sufficient for estimation of an MRL. Additional studies could determine whether the 

critical effect in this study, increased liver weight, is the most appropriate and sensitive end point for 

MRL derivation. 

A limited amount of information is available on the toxicity of inhaled 1,4-DCB in humans. Case reports 

of people who inhaled 1,4-DCB provide indications that the liver and nervous system are systemic targets 

of inhalation toxicity in humans, but are limited by lack of adequate quantitative exposure information 

and/or verification that 1,4-DCB was the only factor associated with the effects (Cotter 1953; Miyai et al. 

1988; Reygagne et al. 1992). An occupational health survey identified odor detection and eye/nose 

irritation thresholds for 1,4-DCB (Hollingsworth et al. 1956). Information on effects of acute-duration 

inhalation exposure to 1,4-DCB in animals is available from short-term systemic toxicity studies in rats 

and guinea pigs (Hollingsworth et al. 1956), a male reproduction study rats (Anderson and Hodge 1976), 

and developmental toxicity studies in rats and rabbits (Hayes et al. 1985; Hodge et al. 1977). These 

animal studies identified the lung as the target of concern, and are consistent with chronic inhalation data 

(Aiso et al. 2005b; Japan Bioassay Research Center 1995) as well as the human occupational experience 

(Hollingsworth et al. 1956), but are insufficient for deriving an acute inhalation MRL. Studies in animals 

investigating potentially sensitive systemic end points (e.g., respiratory, endocrine, neurological, 

immunological) are needed to identify an appropriate end point and effect level for MRL derivation. 

Information on effects of non-lethal acute-duration oral exposures to 1,4-DCB is essentially limited to 

hepatic and renal changes of unclear toxicological significance observed in animal studies designed to 

elucidate mechanisms of liver and kidney toxicity in rats and mice. Appropriately designed acute oral 

studies are needed to provide a suitable basis for MRL derivation. 

The only available study using the dermal route is a lethality study that attempted to determine a dermal 

LD50 level for 1,4-DCB in rats (Gaines and Linder 1986). There are no available toxicokinetic data that 
 

 

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3. HEALTH EFFECTS 

have examined absorption of 1,4-DCB via the dermal route. If dermal absorption and systemic 

distribution of 1,4-DCB could be demonstrated, acute-duration studies using this route would be useful 

since humans are commonly exposed to it by handling various consumer products in the home and being 

exposed to the vapor form. 

Intermediate-Duration Exposure. Information on the toxicity of intermediate-duration inhalation 

exposure to 1,2-DCB is limited to the findings of a multispecies subchronic study (Hollingsworth et al. 

1958) and a 2-generation reproduction study in rats (Bio/dynamics 1989). These studies identified 

NOAELs and LOAELs for liver and body weight effects, but possible effects in the nasal cavity, a known 

sensitive target of 1,2-DCB based on acute data, were not evaluated. Derivation of an intermediateduration inhalation MRL for 1,2-DCB is precluded because the acute-duration serious LOAEL for nasal 

effects (Zissu 1995) is lower than the available intermediate-duration LOAELs for systemic and 

developmental effects. Additional studies could verify the nasal cavity is more sensitive than systemic 

end points and provide exposure-response data useful for inhalation MRL derivation. 

No information was located regarding the toxicity of inhaled 1,3-DCB in humans or animals, indicating 

that appropriate studies are needed to provide a basis for derivation of an intermediate-duration inhalation 

MRL for this isomer. The database for intermediate-duration oral exposure to 1,3-DCB consists of one 

well-designed 90-day systemic toxicity study (McCauley et al. 1995) that was sufficient for estimation of 

an intermediate oral MRL. The thyroid, pituitary, and liver were identified as sensitive targets and 

incidences of pituitary lesions were used to derive an intermediate oral MRL. 

Case studies are available on humans exposed to 1,4-DCB via inhalation and the oral route for 

intermediate-duration exposure. These include the report of a 69-year-old man who developed skin 

discolorations and swelling of his hands and feet after about 3 weeks of exposure to 1,4-DCB in his home 

(Nalbandian and Pearce 1965), the cases of a 60-year-old man and his wife who both died of liver atrophy 

after their home had been saturated with moth ball vapor for 3–4 months (Cotter 1953), and the case of a 

21-year-old woman who developed hypochromic, microcytic anemia as a result of ingesting 1,4-DCB 

toilet air freshener blocks throughout pregnancy (Campbell and Davidson 1970). All of these case studies 

lack critical dosing amounts and durations. It would be helpful if future reports of accidental or 

intentional exposure included dose information (measured or estimated) that could be used to help 

characterize dose-response relationships in humans. 
DICHLOROBENZENES 246 

3. HEALTH EFFECTS 

Information on effects of intermediate-duration inhalation exposure to 1,4-DCB in animals is available 

from a multispecies subchronic toxicity study (Hollingsworth et al. 1956), a 13-week toxicity study in rats 

and mice (Aiso et al. 2005a), and a 2-generation reproductive/developmental toxicity study in rats (Tyl 

and Neeper-Bradley 1989). The 13-week and 2-generation studies identified a NOAEL and LOAEL for 

increased relative liver weight, and increased liver weight was used to derive an MRL. A chronic 

inhalation study (Aiso et al. 2005b; Japan Bioassay Research Center 1995) found that nasal lesions in rats 

and testicular effects in mice were more sensitive than liver effects. No nasal or testicular lesions were 

reported in the 13-week rat and mouse study, and these tissues were not examined in the multispecies 

subchronic study. Additional studies could verify that liver weight is the most appropriate basis for the 

intermediate inhalation. 

Information on the systemic toxicity of intermediate-duration oral exposure to 1,4-DCB is available from 

a number of studies conducted in rodents, mainly rats and mice, as well as one study in dogs (Bomhard et 

al. 1988; Hollingsworth et al. 1956; NTP 1985; Lake et al. 1997; Naylor and Stout 1996; Umemura et al. 

1998). Liver and kidney effects were the most consistently observed, best characterized, and most 

sensitive findings in these studies. Liver effects were used as the basis for intermediate-duration oral 

MRLs for 1,2-DCB (NTP 1985) and 1,4-DCB (Naylor and Stout 1996). 

Studies using the dermal route for intermediate-duration exposure would be useful if absorption and 

systemic distribution of 1,4-DCB by this route could first be demonstrated in toxicokinetic studies. 

Chronic-Duration Exposure and Cancer. No studies were located regarding the chronic 

inhalation toxicity of 1,2-DCB in humans or animals, indicating that data are needed to provide a basis for 

estimation of an inhalation MRL. Regarding chronic oral toxicity of 1,2-DCB, the only available study is 

a two-dose-level NTP (1985) bioassay that was conducted in rats and mice. The only exposure-related 

effect in either species was a significantly increased incidence of renal tubular regeneration in male mice. 

A NOAEL and LOAEL were identified for this lesion and incidences of renal tubular regeneration were 

used to derive a chronic oral MRL for 1,2-DCB. No information is available on the carcinogenicity of 

1,2-DCB in humans. Data on cancer in animals are limited to the NTP (1985) chronic bioassay, in which 

no exposure-related tumors were found in male and female rats and mice exposed to two dose levels of 

1,2-DCB for 103 weeks. This is a well-designed chronic study with respect to exposure duration and 

scope of histological examinations, but it is uncertain whether an MTD was achieved in either species. 

Additional studies that include multiple dose levels and clear MTDs, as well as toxicity end points that 

could be more sensitive than kidney lesions (e.g., endocrine and immunological), could be used determine 
DICHLOROBENZENES 247 

3. HEALTH EFFECTS 

if the MRL is based on the most appropriate effect level and also provide an better assessment of 

carcinogenic potential. 

No studies were located regarding the chronic inhalation or oral toxicity of 1,3-DCB in humans or 

animals, indicating that data are needed to provide the bases for chronic MRL and carcinogenicity 

assessments. 

Several case studies of chronic human exposure to 1,4-DCB have been reported. Reported effects 

resulting mainly from chronic inhalation included pulmonary granulomatosis in a 53-year-old woman 

who had been inhaling 1,4-DCB crystals in her home for 12–15 years (Weller and Crellin 1953); atrophy 

and cirrhosis of the liver in a 34-year-old woman who was exposed to 1,4-DCB-containing products in a 

small enclosed booth in a department store for 1 or more years (Cotter 1953); jaundice and liver atrophy 

in a 52-year-old man after 2 years of exposure to 1,4-DCB in the fur storage plant where he worked 

(Cotter 1953); and ataxia, speech difficulties, limb weakness, and altered brainwave activity in a 25-yearold woman who had been exposed to high concentrations of 1,4-DCB in her bedroom, bedding, and 

clothes for about 6 years (Miyai et al. 1988). A limited occupational health survey reported that nasal and 

ocular irritation, but no major systemic health effects, were the only 1,4-DCB-related complaints 

(Hollingsworth et al. 1956). Further occupational health data on individuals exposed chronically to 

1,4-DCB would be useful for both cancer and noncancer health effect end points already mentioned. The 

only data located relating to chronic oral human exposure to 1,4-DCB come from a case report of a 

19-year-old black woman who developed an increase in skin pigmentation as a result of eating 1,4-DCB 

moth pellets daily for about 2.5 years (Frank and Cohen 1961). All of these case studies lacked dosing 

amounts and durations, which makes it difficult to characterize dose-response relationships for effects in 

humans exposed to 1,4-DCB. No studies of chronic dermal exposure to 1,4-DCB were located, although 

it seems likely that chronic inhalation and oral exposure scenarios, both in the home and in the workplace, 

have also involved dermal contact with 1,4-DCB. 

A limited amount of additional information is available on the chronic toxicity of inhaled 1,4-DCB in 

humans. Periodic health examinations of workers who were exposed to 1,4-DCB for an average of 

4.75 years (range, 8 months to 25 years) showed no changes in standard blood and urine indices 

(Hollingsworth et al. 1956). The data from this occupational study are inadequate for chronic MRL 

derivation due to poor characterization of exposure levels, insufficient investigation of systemic health 

end points, and poor reporting as well as other study deficiencies. However, eye and nose irritation 

findings in this study are consistent with nasal effects observed in chronically exposed animals. 
 

 

DICHLOROBENZENES 248 

3. HEALTH EFFECTS 

Information on the chronic inhalation toxicity of 1,4-DCB in animals is available from two studies in rats 

and mice (Aiso et al. 2005b; Japan Bioassay Research Center 1995; Riley et al. 1980a, 1980b). One of 

these studies (Aiso et al. 2005b; Japan Bioassay Research Center 1995) identified nasal lesions in rats and 

provided a sufficient basis for MRL estimation. 

Information on the chronic oral effects of 1,4-DCB is available from one study each in rats, mice, and 

rabbits (Hollingsworth et al. 1956; NTP 1987). Lesions were observed in the kidneys and liver, and the 

lowest tested dose was a LOAEL for renal effects in rats (NTP 1987). Naylor and Stout (1996) identified 

liver effects (increased liver weight, changes in liver enzymes, and histopathology) in dogs administered 

1,4-DCB for 1 year; these liver effects provided a sufficient basis for chronic oral MRL estimation. 

Information on carcinogenicity of 1,4-DCB is available from the chronic oral and inhalation studies in 

rats and mice. The oral study (NTP 1987) found evidence of carcinogenicity based on increased tumor 

incidences in male rat kidneys and in the livers of male and female mice. The kidney tumors are not 

relevant to humans because the mechanism (α2μ-globulin nephropathy) is specific to male rats. One of the 

inhalation studies (Aiso et al. 2005b; Japan Bioassay Research Center 1995) similarly showed tumor 

induction in the livers of male and female mice, although there was no tumor formation in either sex of 

rats. The other inhalation study (Riley et al. 1980a, 1980b) found no neoplastic changes in rats or mice, 

but the adequacy of the study for carcinogenicity evaluation is limited by failure to reach the maximum 

tolerated dose, less-than-lifetime exposure durations, and short observation periods in both species. There 

is sufficient evidence of 1,4-DCB carcinogenicity in animals based on the induction of liver tumors in 

mice exposed by both the oral and inhalation routes. Unlike the kidney tumors in male rats, the 

mechanistic basis of the liver tumors in mice is not adequately defined, indicating that additional studies 

could help to better assess their relevance to humans. 

Data on the effects of chronic dermal exposure to 1,4-DCB might be useful if dermal absorption and 

systemic distribution of 1,4-DCB can be demonstrated from toxicokinetic studies, since chronic dermal 

exposure to 1,4-DCB occurs as a result of bathing and showering in drinking water that contains low 

levels of this chemical in many U.S. communities. 

Genotoxicity. Genotoxic effects of 1,2- and 1,3-DCB have been investigated in various animal test 

systems with generally mixed results. The genotoxicity of 1,4-DCB has been extensively studied in a 

wide variety of in vitro and in vivo animal assays with a preponderance of negative results. Additional 

studies could help to clarify the mechanism of carcinogenesis for 1,4-DCB-induced liver tumors in mice. 
DICHLOROBENZENES 249 

3. HEALTH EFFECTS 

There are considerable data supporting a sustained proliferative response following 1,4-DCB exposure as 

the mode of action for liver tumor formation; however, the existing evidence is incomplete. 

Reproductive Toxicity. The reproductive toxicity of 1,2-DCB has been evaluated in a 2-generation 

inhalation study in rats (Bio/dynamics 1989), but not by the oral route. The inhalation study found no 

effects on reproduction in either generation at exposure levels higher than those causing liver effects in 

the parental animals, indicating that it can be used to partially address the data gap for oral exposure. 

No information was located on possible reproductive effects of 1,3-DCB, indicating that reproductive 

toxicity is a data need for both inhalation and oral exposure to this isomer. 

The reproductive toxicity of 1,4-DCB has been evaluated in inhalation and oral 2-generation studies in 

rats with no exposure-related effects on reproductive function (Bornatowicz et al. 1994; Tyl and NeeperBradley 1989). An inhalation study of male mice exposed to 1,4-DCB for 5 days did not find an adverse 

impact on their ability to impregnate females (Anderson and Hodge 1976). Incidences of morphologically abnormal sperm were increased in rats that were intraperitoneally injected with 1,4-DCB 

(Murthy et al. 1987). Histopathology evaluations of 1,4-DCB-exposed animals have not demonstrated 

changes in reproductive tissues in the preponderance of studies. Based on the available data, there is no 

compelling need for additional reproductive toxicity studies of 1,4-DCB. 

Developmental Toxicity. The developmental toxicity of inhaled 1,2-DCB was evaluated in an 

adequate study of gestationally-exposed rats and rabbits (Hayes et al. 1985). Skeletal variations, but no 

teratogenic effects, occurred in rats at a concentration that also caused maternal toxicity. A poorly 

reported oral study in which rats were gestationally exposed to 1,2-DCB (Ruddick et al. 1983) found no 

effects on fetuses and indicates that developmental toxicity, if induced, would only occur at levels that 

were maternally toxic. No information is available on possible neurodevelopmental effects of 1,2-DCB, 

indicating that this is a data need. 

No information was located on the developmental toxicity of 1,3-DCB, indicating that this is a data need 

for both inhalation and oral exposure to this isomer. 

The developmental toxicity of inhaled 1,4-DCB was evaluated in adequate studies of gestationallyexposed rats and rabbits (Hayes et al. 1985; Hodge et al. 1977). No maternal or prenatal developmental 

toxicity occurred in the rats, although there was evidence of fetotoxicity (a minor variation of the 
DICHLOROBENZENES 250 

3. HEALTH EFFECTS 

circulatory system) in the rabbits at a concentration that was maternally toxic and higher than LOAELs 

for systemic toxicity in other studies. Information on developmental toxicity of ingested 1,4-DCB is 

available from an 2-generation oral study in rats (Bornatowicz et al. 1994). Fetuses were not examined 

for prenatal changes, but various effects occurred in the offspring perinatally and during the later preweaning period, including decreased neonatal survival and impaired neurobehavioral development in 

F1 and F2 pups. This finding suggests that postnatal neurobehavioral development is a sensitive end point 

for 1,4-DCB that could be better characterized by additional studies. 

Immunotoxicity. No information is available on immunological function in humans or animals 

exposed to 1,2-DCB or 1,3-DCB by the inhalation or oral routes. Lymphoid depletion in the thymus was 

observed histologically in rats that were exposed to a high oral dose of 1,2-DCB for 13 weeks (NTP 

1985), suggesting that the immune system is a possible target of concern and providing an additional 

indication of the need for adequate assessments of immunotoxicity. 

No studies were located that directly assess the potential immunotoxic effects of 1,4-DCB in humans 

exposed by inhalation, oral, or dermal routes. However, case reports of skin reactions in a 69-year-old 

man who was exposed via inhalation (Nalbandian and Pearce 1965) and a 19-year-old woman who 

ingested moth pellets (Frank and Cohen 1961) suggest that the immune system may be a target for 

1,4-DCB. Oral exposure to high doses of 1,4-DCB for 13 weeks caused lymphoid necrosis in the thymus, 

lymphoid depletion in the spleen, and hematopoietic hypoplasia in the spleen and bone marrow of mice, 

and lymphoid depletion of the thymus and spleen in rats (NTP 1987). Effects of oral 1,4-DCB exposure 

on function of the immune system have not been studied, although there were no functional decrements in 

a 12-week inhalation immunotoxicity study in guinea pigs that assessed a limited number of indices 

(Suzuki et al. 1991). Comprehensive immunological testing would help to adequately assess the 

immunotoxic potential of 1,4-DCB. 

Neurotoxicity. Comprehensive neurobehavioral assessments have not been performed for any of the 

DCB isomers. Clinical signs neurotoxicity (e.g., ataxia and clonic contractions) were observed in rats that 

were orally exposed to a high dose of 1,2-DCB for 15 days (Rimington and Ziegler 1963), but similar 

effects were not found in rats or mice in other studies of this isomer. No signs of neurotoxicity occurred 

in rats were orally exposed to 1,3-DCB for up to 90 days (McCauley et al. 1995). 

Neurological effects including dizziness, weakness, headaches, nausea, vomiting, numbness, clumsiness, 

speech difficulties, and altered patterns of certain brainwaves have been reported to have occurred in case 
 

 

DICHLOROBENZENES 251 

3. HEALTH EFFECTS 

studies of persons exposed to 1,4-DCB via inhalation (Cotter 1953; Miyai et al. 1988), as well as with 

other halogenated hydrocarbons. There are no data on neurological effects in humans exposed to 

1,4-DCB through the oral or dermal routes. Neurotoxic effects of 1,4-DCB occurred in rats, rabbits, and 

guinea pigs following inhalation exposure to high concentrations; effects included tremors, weakness, and 

periods of unconsciousness. Similar neurological responses were observed following oral exposure to 

high doses of 1,4-DCB (NTP 1987; Rimington and Ziegler 1963). No studies were located that reported 

neurological effects after a dermal route of exposure. Additional information, particularly on subtle 

behavioral changes at low levels of inhalation and oral exposure, is needed to adequately assess the 

neurotoxic potential of 1,4-DCB and for quantifying dose-response relationships. 

Epidemiological and Human Dosimetry Studies. A limited amount of information is available 

on the inhalation toxicity of 1,2- and 1,4-DCB in humans from observations in exposed workers, mainly 

from assessments of symptoms and standard blood and urine indices as determined by periodic 

occupational health examinations (Hollingsworth et al. 1956, 1958). No information is available on the 

toxicity of ingested 1,2- or 1,3-DCB in humans. Information on toxic effects of 1,4-DCB in orally 

exposed humans is limited to two case reports describing hematological changes, particularly anemia, 

following known or presumed repeated ingestion of unknown doses of the compound in commercial 

products (Campbell and Davidson 1970; Hallowell 1959). The limited available information suggests 

that inhalation or oral exposure to DCBs can cause effects in humans similar to those found in animals, 

particularly in the respiratory tract, liver, and hematological systems. There are no case studies or 

epidemiological data that suggest that levels of DCBs found in the environment are associated with 

significant human exposure. The available data suggest that levels of DCBs in outside air are relatively 

insignificant, although the compounds are widespread (IARC 1982; Scuderi 1986; Wallace et al. 1986b). 

Levels in groundwater and surface water are also relatively low (Coniglio et al. 1980; Dressman et al. 

1977; IJC 1989; Oliver and Nicol 1982a; Page 1981; Staples et al. 1985). These observations indicate 

that the most likely population to exhibit effects of DCB exposures would be occupationally exposed 

groups. Human epidemiological studies that provide a more definitive dose-response relationship 

between exposure, clinical manifestations, and target organ toxicity (i.e., hepatic, hematological, and 

neurological systems) would be useful. 

Biomarkers of Exposure and Effect. 

Exposure. Exposure to DCBs can be identified by measuring levels of the isomers in blood (Bristol et al. 

1982; Hill et al. 1995; Jan 1983; Langhorst and Nestrick 1979; Pellizzari et al. 1985), urine (Ghittori et al. 
DICHLOROBENZENES 252 

3. HEALTH EFFECTS 

1985; Hill et al. 1995; Kumagai and Matsunaga 1995, 1997; Zenser et al. 1997), adipose tissue (Jan 

1983), and breast milk (Jan 1983; Mes et al. 1986), as well as metabolites in the urine. Urinary 

2,5-dichlorophenol is a well-documented biomarker for monitoring worker exposure to 1,4-DCB 

(McKinney et al. 1970; Pagnotto and Walkley 1965), and urinary 2,3- and 3,4-dichlorophenols, as well as 

3,4- and 4,5-dichlorocatechols, have been shown to be useful indicators of exposure to 1,2-DCB 

(Kumagai and Matsunaga 1997). Additional data with which to correlate these measurements to exposure 

levels, particularly by the inhalation route, and potential health effects, would be useful. 

Effect. There are no health effects that are uniquely associated with exposure to DCBs. Therefore, 

studies to identify a specific biomarker of effect for DCBs would be useful. 

Absorption, Distribution, Metabolism, and Excretion. There are no data on the toxicokinetics 

of any DCB isomer in humans. Experiments with laboratory animals indicate that DCBs are absorbed via 

oral or inhalation exposure and distributed mainly to adipose tissue, with some distribution to the liver 

and kidney, and minor amounts to other organs (Hawkins et al. 1980; Kimura et al. 1979). Absorbed 

DCBs are principally metabolized to dichlorophenol metabolites (e.g., 2,5-dichlorophenol from 1,4-DCB) 

by oxidation and is rapidly eliminated, primarily in urine (Azouz et al. 1955; Hawkins et al. 1980). The 

available data indicate that the route of exposure is likely to have little effect on the subsequent 

metabolism and excretion of DCBs. Scant data are available on absorption and systemic distribution 

resulting from exposure via the dermal route. Dermal absorption data would be particularly useful 

considering that the inhalation MRLs are based on whole-body exposure. 1,4-DCB produces a burning 

sensation when applied to the skin for a prolonged period of time, indicating at least minimal penetration 

to nerve endings within the skin (Hollingsworth et al. 1956). The little information that is available 

suggests that dermal exposure is associated with low systemic toxicity in both humans and laboratory 

animals. It would be useful to confirm this because it could provide a basis for assessing the likelihood of 

toxic effects resulting from dermal exposure and the need to conduct various toxicity studies via the 

dermal route. Additional toxicokinetic data would be useful for quantitating route-specific absorption 

rates. 

Comparative Toxicokinetics. There are no available studies that compare the toxicokinetics of any 

of the DCB isomers across species. This has been an important area of concern in interpreting the results 

of animal studies with 1,4-DCB with respect to their relevance to humans, most notably in the 

observations of renal toxicity and carcinogenicity in male rats. Although this specific issue has been 

largely resolved, it would be useful to have further data comparing the toxicokinetics of 1,4-DCB across 
DICHLOROBENZENES 253 

3. HEALTH EFFECTS 

species in order to understand better which animal model is likely to compare most directly with humans 

with regard to other toxic effects in response to 1,4-DCB exposure. From the available data in humans 

and laboratory animals, the primary metabolite produced after exposure to 1,4-DCB is 2,5-dichlorophenol. This metabolite appears mainly in the urine after undergoing phase II metabolism, principally to 

the sulfate and glucuronide conjugates, with some exiting via the bile (Azouz et al. 1955; Fisher et al. 

1995; Hissink et al. 1997a; Hallowell 1959; Kimura et al. 1979; Klos and Dekant 1994). 

Methods for Reducing Toxic Effects. Based on the chemical and physical properties of DCBs, 

absorption is most likely to occur by passive diffusion. However, this has not been investigated. Studies 

that investigate the mechanism by which DCBs are absorbed could be useful in developing methods for 

reducing its absorption. Standard methods exist for reducing the absorption of DCBs across the skin, 

lungs, and gastrointestinal tract (HSDB 1996) and are described in more detail in Chapter 7 of this profile; 

however, none of these are specific for exposures to 1,2-, 1,3-, or 1,4-DCB. DCBs can be retained in fatty 

tissues at low levels (EPA 1986f; Hawkins et al. 1980; Morita and Ohi 1975; Morita et al. 1975). 

Additional studies that characterize the metabolic pathways that enhance excretion may be useful in 

developing a method for reducing body burden. However, since most of an absorbed dose is likely to be 

eliminated within several days (Hawkins et al. 1980), it seems unlikely that methods for reducing body 

burden would be of much benefit. There is limited evidence that DCBs are metabolically activated to 

hepatotoxic intermediates (Fisher et al. 1991a; Lattanzi et al. 1989). Additional studies that further 

characterize the metabolic activation of DCBs could be useful for understanding how metabolites interact 

and to develop methods for interfering with the mechanism of action. 

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. 

Essentially all of the studies on effects of exposure of humans to DCBs have focused on adults. It is 

unknown whether children differ from adults in their susceptibility to health effects from DCBs. Only 

two case reports of 1,4-DCB specifically referenced potential exposure to a child (Campbell and 

Davidson 1970; Hallowell 1959). Data relating to health effects in general for children are lacking. 

There are no data describing the developmental effects in humans. Such data, although potentially useful, 

would be difficult to obtain. See the Developmental Toxicity subsection above for related data needs. 
DICHLOROBENZENES 254 

3. HEALTH EFFECTS 

Although there is no reason to suspect that the pharmacokinetics of DCBs differs in children and adults, 

scant data are available to support or disprove this statement. Studies of absorption, distribution, 

metabolism, and excretion in children would aid in determining if children are at an increased risk, 

particularly if conducted in an area where a high-dose acute or low-dose chronic exposure to an 

environmental source were to occur. With regard to exposure during development, additional research on 

maternal and fetal/neonatal toxicokinetics, placental biotransformation, the mechanism of action in 

children, and the risk associated with the transfer of DCBs to an infant via breast milk would be useful in 

obtaining a more complete picture of prenatal and neonatal development. Direct evidence on whether 

DCBs crosses the placenta and on the kinetics associated with that transfer is also needed. Data needs 

exist for determining if specific biomarkers of exposure or effect exist in children (and how those differ 

from adults) and how DCBs interact with other chemicals (i.e., other organochlorine pesticides, drugs, 

etc.) Data needs also exist for methods to reduce peak absorption after exposure, to reduce body burden, 

and to interfere with the mechanism of action for toxic effects targeted for adults as well as for children. 

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 

No known ongoing studies related to the toxicity or toxicokinetics of DCBs were identified. 
 

 

DICHLOROBENZENES 255 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Dichlorobenzenes (DCBs) are chlorinated aromatic compounds. 1,2-DCB is used primarily as a 

precursor for 3,4-dichloroaniline herbicides (CMR 1996). 1,3-DCB is used in the production of various 

herbicides, insecticides, pharmaceuticals, and dyes (Krishnamurti 2001). 1,4-DCB is used as a deodorant 

for restrooms (Howard 1989), for moth control (O’Neil 2001), and as an insecticide (Farm Chemicals 

Handbook 1983). Information regarding the chemical identity of 1,2-, 1,3-, and 1,4-DCB is located in 

Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

The dichlorobenzene isomers, 1,2-DCB and 1,3-DCB, are colorless volatile liquids at room temperature 

(EPA 1985a). 1,2-DCB has a pleasant odor, while the odor of 1,3-DCB is unspecified (EPA 1985a; 

NIOSH 2005). 1, 4-DCB is a combustible crystalline solid that tends to sublime at ordinary room 

temperatures. It possesses a distinctive odor reportable to be noticeable at airborne concentrations 

between 30 and 60 ppm (by weight [ppm-w] or by volume [ppm-v] not specified; presumably "ppm" 

would refer to ppm by weight). Information regarding the physical and chemical properties of 1,2-, 1,3-, 

and 1,4-DCB is located in Table 4-2. 
DICHLORORBENZENES 256 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of 1,2-, 1,3-, and 1,4-Dichlorobenzene 

Characteristic Value Reference 

Chemical name 1,2-Dichlorobenzene Lide 2000 

Synonyms o-Dichlorobenzene; o-dichlorobenzol; RTECS 2005 

orthodichlorobenzene 

Trade names	 Chloroben; Cloroben; Dilatin DB; HSDB 2005; RTECS 2005 

Dowtherm E; Dizene; Special termite 

fluid; Termitkil 

Chemical formula C6H4Cl2 RTECS 2005 

Chemical structure Cl 

Cl 

Identification numbers: 

CAS Registry 95-50-1 Lide 2000 

 NIOSH RTECS CZ4500000 RTECS 2005 

EPA Hazardous Waste U070; F002 HSDB 2005 

 OHM/TADS No data 

DOT/UN/NA/IMCO Shipping UN 1591; IMO 6.1 HSDB 2005 

HSDB 521 HSDB 2005 

NCI NCI-C54944 RTECS 2005 
 

DICHLORORBENZENES 257 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of 1,2-, 1,3-, and 1,4-Dichlorobenzene 

Characteristic Value Reference 

Chemical name 1,3-Dichlorobenzene Lide 2000; HSDB 2005 

Synonyms m-Dichlorobenzene; m-DCB; RTECS 2005 

m-dichlorobenzol; m-phenylene 

dichloride 

Trade names No data 

Chemical formula C6H4Cl2 RTECS 2005 

Chemical structure Cl 

Cl 

Identification numbers: 

CAS Registry 541-73-1 Lide 2000 

 NIOSH RTECS CZ4499000 RTECS 2005 

EPA Hazardous Waste U071 HSDB 2005 

 OHM/TADS No data 

DOT/UN/NA/IMCO Shipping No data 

HSDB 522 HSDB 2005 

NCI No data 
DICHLORORBENZENES 258 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of 1,2-, 1,3-, and 1,4-Dichlorobenzene 

Characteristic Value Reference 

Chemical name 1,4-Dichlorobenzene Lide 2000 

Synonyms para-Dichlorobenzene; p-dichloro- RTECS 2005 

benzene; p-chlorophenyl chloride; 

PDB; PDCB; p-dichlorobenzol 

Trade names Paracide; Paradow; Paradi; RTECS 2005 

Santochlor; Paramoth; Paranuggets; 

Parazene; Persia-perazol; Para 

crystals; Global; Evola; Di-chloricide 

Chemical formula C6H4Cl2 RTECS 2005 

Chemical structure Cl 

Cl 

Identification numbers: 

CAS Registry 106-46-7 Lide 2000 

 NIOSH RTECS CZ4550000 RTECS 2005 

EPA Hazardous Waste U072; D027 HSDB 2005 

 OHM/TADS No data 

DOT/UN/NA/IMCO Shipping UN 1592; IMO 6.1 HSDB 2005 

HSDB 523 HSDB 2005 

NCI NCI-C54955 RTECS 2005 

CAS = Chemical Abstracts Service; 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; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances 
DICHLORORBENZENES 259 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of 1,2-, 1,3-, and 

1,4-Dichlorobenzene 

Property Value Reference 

Chemical name 1,2-Dichlorobenzene Lide 2000 

Molecular weight 147.00 Lide 2000 

Color Colorless to pale yellow NIOSH 2005 

Physical state Liquid Lewis 1997 

Melting point -16.7 °C Lide 2000 

Boiling point 180 °C Lide 2000 

Density at 20 °C 1.3059 g/mL Lide 2000 

Odor Pleasant, aromatic NIOSH 2005 

Odor threshold: 

 Water 0.01 mg/L Verschueren 2001 

Air 50 ppm (301 mg/m3

) Verschueren 2001 

Solubility: 

Water 156 mg/L at 25 °C Banerjee et al. 1980 

Organic solvents Miscible with alcohol, ether, benzene O’Neil 2001 

Partition coefficients: 

Log octanol/water 3.43 Hansch et al. 1995 

 Log Koc 2.51 Chiou et al. 1983 

Vapor pressure at 25 °C 1.36 mm Hg Daubert and Danner 1992 

Henry's law constant at 25 °C 1.92x10-3 atm m3

/mol Shiu and Mackay 1997 

Autoignition temperature 640 °C Krishnamurti 2001 

Flashpoint 28 °C (closed cup) Krishnamurti 2001 

Flammability limits No data 

Conversion factors 1 mg/m3

=0.116 ppm at 25 °C and Verschueren 2001 

760 mm Hg; 

1 ppm=6.01 mg/m3

 at 25 °C and 

760 mm Hg 

Explosion limits 2–9% by volume in air Leber and Bus 2001 
DICHLORORBENZENES 260 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of 1,2-, 1,3-, and 

1,4-Dichlorobenzene 

Property Value Reference 

Chemical name 1,3-Dichlorobenzene Lide 2000 

Molecular weight 147.00 Lide 2000 

Color Colorless Lewis 1997 

Physical state Liquid Lewis 1997 

Melting point -24.8 °C Lide 2000 

Boiling point 173 °C Lide 2000 

Density at 20 °C 1.2884 g/mL Lide 2000 

Odor No data 

Odor threshold: 

 Water 0.02 mg/L Verschueren 2001 

Air No data 

Solubility: 

Water 125 mg/L at 20 °C Miller et al. 1984 

Organic solvents Soluble in alcohol, ether O’Neil 2001 

Partition coefficients: 

Log octanol/water 3.53 Hansch et al. 1995 

 Log Koc 2.47 Chiou et al. 1983 

Vapor pressure at 25 °C 2.15 mm Hg Daubert and Danner 1992 

Henry's law constant at 25 °C 2.8x10-3 atm m3

/mol Staudinger and Roberts 1996 

Autoignition temperature >500 °C Krishnamurti 2001 

Flashpoint No data 

Flammability limits No data 

Conversion factors 1 mg/ m3

=0.116 ppm at 25 °C and HSDB 2005 

760 mm Hg; 

1 ppm=6.01 mg/m3

 at 25 °C and 

760 mm Hg 

Explosion limits No data 
DICHLORORBENZENES 261 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of 1,2-, 1,3-, and 

1,4-Dichlorobenzene 

Property Value Reference 

Chemical name 1,4-Dichlorobenzene Lide 2000 

Molecular weight 147.00 Lide 2000 

Color Colorless or white NIOSH 2005 

Physical state Solid Lewis 1997 

Melting point 52.7 °C Lide 2000 

Boiling point 174 °C Lide 2000 

Density at 20 °C 1.46 g/mL O’Neil 2001 

Odor Mothball-like; penetrating Lewis 1997; NIOSH 2005 

Odor threshold: 

Water 0.011 mg/L Amoore and Hautala 1983 

Air 0.18 ppm (1.1 mg/m3

) Amoore and Hautala 1983 

Solubility: 

Water 80.0 mg/L Yalkowsky and He 2003 

Organic solvents Soluble in alcohol, ether, benzene, O’Neil 2001 

chloroform, carbon disulfide 

Partition coefficients: 

Log octanol/water 3.44 Hansch et al. 1995 

 Log Koc 2.44 Chiou et al. 1983 

Vapor pressure at 25 °C 1.77 mm Hg Daubert and Danner 1992 

Henry's law constant at 25 °C 2.41x10-3 atm m3

/mol Shiu and Mackay 1997 

Autoignition temperature >500 °C Krishnamurti 2001 

Flashpoint 67 °C (closed cup) Krishnamurti 2001 

Flammability limits 6.2–16% Leber and Bus 2001 

Conversion factors 1 ppm=6.01 mg/m3

 at 25 °C and Verschueren 2001 

760 mm Hg; 

1 mg/m3

=0.166 ppm at 25 °C and 

760 mm Hg 

Explosion limits No data 
DICHLORORBENZENES 262 

4. CHEMICAL AND PHYSICAL INFORMATION 

This page is intentionally blank. 
 

 

DICHLOROBENZENES 263 

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

5.1 PRODUCTION 

Chlorinated benzenes are produced typically by reacting liquid benzene with gaseous chlorine in the 

presence of a catalyst at moderate temperature (unspecified) and atmospheric pressure (IARC 1999; 

Rossberg et al. 2002). This reaction yields a mixture of chlorobenzene isomers with varying degrees of 

chlorination. A maximum dichlorobenzene yield of 98% is obtainable in a batch process in which 

2 moles of chlorine is used per mole of benzene (mass ratio approximately 1.8:1) in the presence of ferric 

chloride and sulfur monochloride (IARC 1999). 1,2- and 1,4- DCB are the major DCB isomers formed in 

this process, with 1,2:1,4 ratios dependant on the type of catalyst used (Table 5-1). 1,3-DCB is also 

formed, but in much smaller quantities (Krishnamurti 2001). The DCB isomers are typically separated by 

crystallization and distillation. 

Production of 1,4-DCB in the United States has risen from approximately 15 million pounds 

(6,800 metric tons) in 1981 to approximately 72 million pounds (32,600 metric tons) in 1993 (IARC 

1999). The production volume of 1,4-DCB reported by manufacturers in 1998 and 2002 was within the 

range of greater then 50 million pounds to 100 million pounds (>23,000–45,000 metric tons) (EPA 

2002e). The historical rate of growth of this chemical from 1989–1998 was 1.1 percent per year (CMR 

1999). 

Production of 1,2-DCB in the United States fell from approximately 54 million pounds (24,700 metric 

tons) in 1975 to approximately 35 million pounds (15,800 metric tons) in 1993 (IARC 1999). The 

production volume of 1,2-DCB reported by manufacturers in 1998 was within the range of >50 million 

pounds to 100 million pounds (>23,000–45,000 metric tons) (EPA 2002e). In 2002, companies reported 

production within the range of <10 million pounds to 50 million pounds (<5,000–23,000 metric tons) 

(EPA 2002e). The historical rate of growth of this chemical from 1986–1995 was 0.7 percent per year 

(CMR 1996). 

Production of 1,3-DCB in the United States was <1 million pounds (500 metric tons) in 1983 (IARC 

1999). The production volume of this chemical reported by manufacturers was within 10 thousand 

pounds to 500 thousand pounds (5–200 metric tons) during reporting year 1986, >1 million pounds to 

10 million pounds (500–5,000 metric tons) during reporting year 1990, and >500 thousand pounds to 
 

 

 

 

DICHLOROBENZENES 264 

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

Table 5-1. Influence of Catalysts on the Ratio 1,4-:1,2-Dichlorobenzene 

Proportion of 1,4-dichlorobenzene Ratio 1,4- : 1,2-diCatalyst (in percent) in the dichlorobenzene fraction chlorobenzene 

MnCl2 + H2O ca. 50 1.03 

SbCl5 1.5 

FeCl3 or Fe ca. 59 1.49–1.55 

Metallosilicon organic 61–74 1.56–2.8 

compounds 

AlCl3 – SnCl4 2.21 

AlCl3 – TiCl4 2.25 

Fe – S – PbO ca. 70 

FeCl3 – diethyl ether 2.38 

Aluminum silicate­ 2.7 

hexamethylene-diamine 

FeCl3 – S2Cl2 ca. 76 

FeCl3 – divalent organic sulfur ca. 77 3.3 

compounds 

L-type zeolite ca. 88 8.0 

TiCl4 (chlorinating agent is 20–30 

FeCl3) 

Source: Rossberg et al. 2002 
 

 

DICHLOROBENZENES 265 

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

1 million pounds (>200–500 metric tons) in reporting years 1994 and 1998 (EPA 2002e). Production 

volume data were not listed for reporting year 2002. 

1,4-DCB is the most important of the three DCB isomers commercially (Elovaara 1998). However, the 

high 1,2- to 1,4-DCB ratio has traditionally created an isomer imbalance in the DCB market (CMR 1999). 

Decreasing demand for 1,2-DCB in recent years has resulted in an increased economic disadvantage for 

the companies producing these chemicals. 

1,4-DCB and 1,2-DCB are currently produced by 2 U.S. companies at 2 different locations: Solutia Inc., 

in Sauget, Illinois and PPG Industries, Inc., in Natrium, West Virginia (SRI 2005). Current annual 

1,4-DCB production capacity for Solutia Inc. and PPG Industries, Inc. are 39 and 40 million pounds 

(17,700 and 18,100 metric tons), respectively (SRI 2005). Total annual production capacity for this 

isomer has fluctuated during the last 2 decades. The annual production capacity was 119 (54,000), 

132 (59,900), 371 (168,000), 144 (65,000), 145(66,000), 154(70,000), and 79 (35,800) million pounds 

(metric tons) in 1983, 1988, 1995, 1997, 1999, 2001, and 2003 respectively (SRI 1984, 1988, 1995, 1997, 

1999, 2001, 2003). Current annual 1,2-DCB production capacity for Solutia and PPG are 13 and 

20 million pounds (5,900 and 9,000 metric tons), respectively (SRI 2005). The annual production 

capacity for the 1,2- isomer was 78 (35,000), 81 (37,000), 81 (37,000), 76 (34,000), 80 (36,000), 

83 (38,000), and 33 (15,000) million pounds (metric tons) in 1983, 1988, 1995, 1997, 1999, 2001, and 

2003 respectively (SRI 1984, 1988, 1995, 1997, 1999, 2001, 2003). 

Tables 5-2, 5-3, and 5-4 list the facilities in each state that manufacture or process 1,2-, 1,3-, and 

1,4-DCB, respectively. These tables give the intended use and the range of maximum amounts of each 

DCB isomer that are stored on site. The data listed in Tables 5-2 through 5-4 are derived from the Toxics 

Release Inventory (TRI03 2005). Only certain types of facilities were required to report (EPA 1997b). 

Therefore, this is not an exhaustive list. 

5.2 IMPORT/EXPORT 

In 1978, about 1.09x104 kg (24,030 pounds) of 1,4-DCB were imported into the United States (HSDB 

2005; NTP 1989). Import volumes of 1,4-DCB were 867,441 kg (1.9 million pounds), 1,113,676 kg 

(2.5 million pounds), 996,649 kg (2.2 million pounds), 3,283,759 kg (7.2 million pounds), and 

3,019,233 kg (6.7 million pounds) for 1990, 1991, 1992, 1993, and 1994, respectively. U.S. 
DICHLOROBENZENES 266 

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

Table 5-2. Facilities that Produce, Process, or Use 1,2-Dichlorobenzene 

Minimum amount Maximum 

Number of on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 3 1,000 999,999 6, 11, 12 

AR 12 100 49,999,999 2, 3, 6, 7, 10, 12 

AZ 1 1000 9,999 11 

CA 15 100 9,999,999 2, 3, 7, 8, 9, 11, 12 

CO 1 1,000 9,999 7 

CT 2 1,000 99,999 12 

DE 6 1,000 9,999,999 1, 3, 4, 6, 7, 9 

FL 2 10,000 99,999 7, 11 

GA 3 1,000 99,999 7, 8 

IL 3 1,000 9,999,999 1, 4, 12 

IN 8 100 999,999 2, 3, 7, 10, 12 

KS 3 100 99,999 12 

KY 2 10,000 999,999 1, 3, 6 

LA 12 100 999,999 1, 5, 6, 10, 12 

MA 8 100 999,999 7, 10, 11, 12 

MI 4 0 9,999 7, 8, 9, 12 

MN 1 1,000 9,999 12 

MO 6 100 99,999,999 7, 9, 12 

MS 5 0 999,999 1, 3, 9, 11, 12 

NC 12 100 999,999 2, 3, 6, 7, 10, 11, 12 

NE 2 10,000 999,999 12 

NH 1 0 99 12 

NJ 22 1,000 9,999,999 2, 3, 6, 7, 8, 9, 10, 12, 14 

NY 8 1,000 999,999 10, 11, 12 

OH 8 1,000 9,999,999 3, 7, 9, 10, 11, 12 

OK 1 1,000 9,999 12 

OR 2 10,000 99,999 8, 12 

PA 9 0 999,999 3, 7, 10, 11, 12 

RI 4 1,000 99,999 7, 8, 10 

SC 6 100 999,999 6, 10, 11, 12 

TN 3 10,000 999,999 10, 11 

TX 31 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13 

VA 2 10,000 999,999 12 

WI 3 10,000 999,999 9, 10 

WV 6 100,000 49,999,999 1, 4, 10, 11 

Source: TRI03 2005 (Data are from 2003) 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
DICHLOROBENZENES 267 

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

Table 5-3. Facilities that Produce, Process, or Use 1,3-Dichlorobenzene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AR 1 1,000 9,999 12 

CA 1 100 999 12 

DE 7 100 9,999,999 1, 3, 4, 5, 6, 13 

IL 5 1,000 9,999,999 1, 4, 5, 12, 13 

IN 1 100 999 12 

KY 1 10,000 99,999 1, 3, 6 

LA 4 1,000 999,999 1, 5 

MI 2 100,000 999,999 2, 3, 6 

MO 3 100 99,999 6, 12 

MS 1 100 999 12 

NJ 3 100 999,999 3, 6, 10, 12 

OH 2 1,000 99,999 12 

SC 1 10,000 99,999 6 

TX 7 0 99,999 1, 5, 11, 12, 13 

WV 3 100,000 9,999,999 1, 4, 5, 13 

Source: TRI03 2005 (Data are from 2003) 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
DICHLOROBENZENES 268 

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

Table 5-4. Facilities that Produce, Process, or Use 1,4-Dichlorobenzene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AR 6 1,000 99,999 1, 2, 6, 7, 12, 13 

CA 2 100 999 3, 4, 9, 12 

DE 2 1,000,000 49,999,999 1, 3, 4, 6 

FL 4 10,000 99,999 4, 7, 9 

GA 9 1,000 999,999 7, 8, 9, 12 

IL 8 0 9,999,999 1, 2, 3, 4, 7, 9, 11, 12, 14 

IN 6 100 99,999 7, 8, 11, 12 

KS 8 100 999,999 7, 9, 12 

KY 3 1,000 99,999 2, 4, 12 

LA 8 0 999,999 1, 5, 6, 13 

MA 5 1,000 999,999 2, 3, 7, 11 

MI 2 1,000 99,999 2, 5 

MO 4 100 999,999 1, 5, 8, 12 

NC 5 100 999,999 2, 3, 6, 11, 12 

NE 1 10,000 99,999 12 

NJ 12 1,000 999,999 2, 3, 4, 7, 8, 9, 12 

NY 1 100 999 2, 4 

OH 13 1,000 999,999 1, 2, 3, 4, 7, 8, 9, 10, 11, 12 

OK 4 1,000 99,999 2, 3, 6, 8 

PA 6 100 99,999 3, 7, 9, 10, 11, 12 

SC 2 10,000 99,999 6, 12 

TX 12 0 49,999,999 1, 2, 3, 5, 6, 7, 12, 13 

UT 1 1,000 9,999 12 

VA 1 1,000 9,999 12 

WV 1 1,000,000 9,999,999 1, 4 

Source: TRI03 2005 (Data are from 2003) 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
 

 

DICHLOROBENZENES 269 

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

imports of 1,2-DCB were 6,300 kg in 1972 and 1,230,000 kg in 1975 (HSDB 2005). U.S. imports of 

1,3-DCB were 56,600 kg in 1983 (HSDB 2005). More recent import data for the DCB isomers were not 

available. 

In 1972, U.S. exports of 1,4-DCB were reported to be 4.5x106 kg (9.9 million pounds) (HSDB 2005). 

Exports of 1,4-DCB have expanded through the 1980s at about 1–2% per year due to the growth in 

production of polyphenylene sulfide (PPS) resin overseas (HSDB 2005; NTP 1989). In 1990, the United 

States exported about 25% (about 33 million pounds) of its 1,4-DCB production volume (CMR 1990). 

Export volumes of 1,4-DCB were 11,925,179 kg (24.1 million pounds), 11,185,034 kg (24.7 million 

pounds), 10,651,337 kg (23.5 million pounds), 13,390,545 kg (29.5 million pounds), and 11,078,150 kg 

(24.4 million pounds) for 1990, 1991, 1992, 1993, and 1994, respectively. 1,4-DCB exports during 

1994–1997 averaged 25 million pounds (11,000 metric tons) (CMR 1999). U.S. exports of 1,2-DCB 

averaged 14 million pounds (6,000 metric tons) per year during 1991–1995 (CMR 1996). Export data for 

1,3-DCB were not available. 

Based on a 1993 production volume value of 72 million pounds (32,600 metric tons), an import value of 

7 million pounds (3,000 metric tons), and an export value of 30 million pounds (14,000 metric tons), the 

total amount of 1,4-DCB available for use in U.S. commerce in 1993 was 49 million pounds 

(22,000 metric tons). Based on a 1993 production volume value of 35 million pounds (15,800 metric 

tons) and an export value of 14 million pounds (6,000 metric tons), the total amount of 1,2-DCB 

remaining in the United States in 1993 was 21 million pounds (10,000 metric tons) assuming that imports 

of this chemical during that year were negligible. It should be noted, however, that not all of the 1,2-DCB 

that is produced is expected to be available for use since large quantities of this chemical are more likely 

to be disposed of when it is produced as a byproduct in the production of 1,4-DCB. Although reported 

export values for 1,2- and 1,4-DCB show that considerable amounts of these chemicals have been sent to 

other countries in previous years, the production volumes for these chemicals have been consistently 

higher suggesting that more than half of the amounts produced each year have remained in the United 

States. 

5.3 USE 

For the past 20 years, 1,4-DCB has been used principally (25–55% of all uses) as a space deodorant for 

toilets and refuse containers, and as a fumigant for control of moths, molds, and mildews. In recent years, 

the use of 1,4-DCB in the production of polyphenylene sulfide (PPS) resin has increased steadily (25– 
 

 

 

 

DICHLOROBENZENES 270 

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

50% of its total use). 1,4-DCB is also used as an intermediate in the production of other chemicals such 

as 1,2,4-trichlorobenzene (approximately 10%). Minor uses of 1,4-DCB include its use in the control of 

certain tree-boring insects and ants, and in the control of blue mold in tobacco seed beds (CMR 1999; 

HSDB 2005). 

1,2-DCB is used primarily as a precursor to 3,4-dichloroaniline herbicides. Other uses of 1,2-dichloroaniline include its use as a solvent, in the synthesis of dyes, and in odor control products (CMR 1996; 

HSDB 2005). 

1,3-DCB has been used in the production of herbicides and insecticides as well as in the production of 

pharmaceuticals and dyes (IARC 1999). 

5.4 DISPOSAL 

Wastes containing DCBs are considered hazardous if they meet certain criteria specified by law. 

Hazardous wastes are subject to the handling, transport, treatment, storage, and disposal regulations as 

promulgated under the Resource Conservation and Recovery Act (HSDB 2005; IRPTC 1985). 

Regulations governing the treatment and disposal of wastes containing DCBs are detailed in Chapter 8. 

Incineration by appropriate means is the recommended method for the disposal of waste 1,4-DCB (HSDB 

2005). 1,4-DCB may be disposed of by making packages of the chemical in paper or other disposable 

material and burning in a suitable combustion chamber equipped with an appropriate effluent gas cleaning 

device or by dissolving the chemical in a flammable solvent (such as alcohol) and atomizing in a suitable 

combustion chamber equipped with an appropriate effluent gas cleaning device (IRPTC 1985). 

Halogenated compounds may be disposed of by incineration provided they are blended with other 

compatible wastes or fuels so that the composite contains <30% halogens. Liquid injection, rotary kiln, 

and fluidized bed incinerators are typically used to destroy liquid halogenated wastes. Temperatures of at 

least 2,000–2,200 °F are necessary. Residence times of seconds are required for liquids and gases, while 

hours are required for solids (HSDB 2005). 1,2-DCB is produced in large quantities as a byproduct 

during the production of 1,4-DCB. Unused supplies may be disposed of or released directly into the 

environment. 

No data were located regarding historic disposal trends or the amounts of 1,2-, 1,3-, or 1,4-DCB disposed 

of by different means. 
 

 

DICHLOROBENZENES 271 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

1,2-, 1,3- and 1,4-Dichlorobenzene (DCB) have been identified in at least 281, 175, and 330, respectively, 

of the 1,662 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities 

List (NPL), respectively (HazDat 2005). However, the number of sites evaluated for these DCB isomers 

is not known. The frequency of these sites can be seen in Figures 6-1, 6-2, and 6-3. Of these sites, all are 

located within the United States. 

1,4-DCB is a widely used chemical that enters the environment primarily as releases to air during its use 

as a space deodorant, toilet deodorizer, and moth repellant. 1,2- and 1,3-DCB are expected to be released 

to the environment during their use in herbicide production or during the use of other products containing 

these isomers. However, 1,2- and 1,3-DCB are used much less than the 1,4-isomer. Disposal of 

1,2-DCB, which is produced as a by-product in the manufacture of 1,4-DCB, may be a significant 

pathway by which 1,2-DCB is released into the environment. DCBs are not known to occur naturally in 

the environment and are solely produced by commercial, industrial, and consumer activities. 

DCBs are degraded in the atmosphere by reaction with hydroxyl radicals, with a calculated atmospheric 

lifetime of 14-31 days (Atkinson 1989; Howard 1989). DCBs will exist predominantly in the vaporphase in the atmosphere, and their detection in rainwater suggests that atmospheric removal via washout 

is possible (Ligocki et al. 1985). Depending on soil type, DCBs are expected to be moderately mobile in 

soil. They are also expected to volatilize from surface water and soil surfaces to the atmosphere. 

Volatilization, sorption, biodegradation, and bioaccumulation are likely to be competing processes, with 

the dominant fate being determined by local environmental conditions. 

The principal route of exposure to DCBs for the general population (including children) is via inhalation, 

with average daily adult intakes from ambient air estimated at about 35 μg for 1,4-DCB, 1.8 μg for 

1,2-DCB, and 0.8 μg for 1,3-DCB (EPA 1985a; Singh et al. 1981a, 1981b). Recent data suggest that 

exposure to 1,4-DCB from indoor air may be an order of magnitude higher than exposures from ambient 

outdoor air (Wallace et al. 1986b). Indoor inhalation exposure to 1,2- or 1,3-DCB is not expected to be as 

high as 1,4-DCB since these substances are not used in household and consumer products to the extent 

that 1,4-DCB is. Consumer contact with 1,4-DCB associated with its use in moth repellant crystals and 
DICHLOROBENZENES 272

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with 1,2-Dichlorobenzene Contamination 

Frequency of 

NPL Sites

1-2
 

3-4
 

5-6
 

7-11
 

Derived from HazDat 2005
 12-26

27-37
 
DICHLOROBENZENES 273

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-2. Frequency of NPL Sites with 1,3-Dichlorobenzene Contamination 

Frequency of 

NPL Sites

1-2
 

3-4
 

5-6
 

7-8
 

Derived from HazDat 2005 9-15 
 

16-23
 
DICHLOROBENZENES 274

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-3. Frequency of NPL Sites with 1,4-Dichlorobenzene Contamination 

Frequency of 

NPL Sites

1-2
 

3-5
 

6-9
 

10-15
 

Derived from HazDat 2005
 16-25
 

42
 
 

 

DICHLOROBENZENES 275 

6. POTENTIAL FOR HUMAN EXPOSURE 

toilet deodorizers is the most frequent means of exposure to this compound in the home (Wallace et al. 

1986b, 1989). DCBs have been detected in various types of foods and drinking water, although generally 

in low concentrations (Heikes et al. 1995; IARC 1999; Page and Lacroix 1995; Young and Heesen 1978; 

Young et al. 1980). DCB exposure through these pathways is not expected to be important. Children 

may be accidentally exposed to 1,4-DCB if they eat moth balls or toilet deodorizers. Occupational 

exposure is primarily through inhalation or dermal contact with DCBs, with the highest exposure 

resulting from production or processing of these chemicals (IARC 1999). 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

According to the TRI, in 2003, a total of 92,973 pounds (42 metric tons) of 1,2-DCB was released to the 

environment from 39 large processing facilities (TRI03 2005). Table 6-1 lists amounts released from 

these facilities. Of this total, an estimated 87,443 pounds (40 metric tons) were released to air, 

1,240 pounds (0.6 metric tons) were released to water, 1,784 pounds (0.8 metric tons) were released to 

land, and 2,500 pounds (1 metric ton) were released via underground injection. The total amount of 

1,2-DCB released on-site was estimated as 91,868 pounds (42 metric tons). The total amount released 

off-site was estimated as 1,104 pounds (0.5 metric tons) (TRI03 2005). 

According to the TRI, in 2003, a total of 1,966 pounds (0.9 metric tons) of 1,3-DCB was released to the 

environment from eight large processing facilities (TRI03 2005). Table 6-2 lists amounts released from 
DICHLOROBENZENES 276 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use 1,2-Dichlorobenzenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek On- and off-site 

AR 4 78 No data 0 0 0 78 0 78 

CA 1 640 No data 0 0 0 640 0 640 

IL 2 8,961 No data 0 5 5 8,961 10 8,971 

IN 1 9,700 750 0 0 0 10,450 0 10,450 

KS 1 2 No data 0 0 0 2 0 2 

KY 1 3 0 0 0 0 3 0 3 

LA 2 7,800 8 2,500 110 0 10,308 110 10,418 

MA 1 360 No data 0 0 0 360 0 360 

MS 2 510 No data 0 0 0 510 0 510 

NC 2 1,250 No data 0 0 0 1,250 0 1,250 

NE 1 5 No data 0 0 0 5 0 5 

NJ 2 652 13 0 1,267 0 1,225 707 1,932 

NY 1 5 No data 0 0 0 5 0 5 

OH 1 5 5 0 255 0 10 255 265 

PA 2 10 No data 0 0 0 10 0 10 

RI 1 2,068 4 0 22 0 2,072 22 2,094 

SC 2 9,707 5 0 0 0 9,712 0 9,712 

TN 1 No data No data No data No data No data No data 0 0 

TX 9 5,137 3 0 110 0 5,251 0 5,251 

WV 2 40,550 452 0 15 0 41,017 0 41,017 

Total 39 87,443 1,240 2,500 1,784 5 91,868 1,104 92,973 

Source: TRI03 2005 (Data are from 2003) 

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 
DICHLOROBENZENES 277 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or 

Use 1,3-Dichlorobenzenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf Landh On-sitej

 Off-sitek On- and off-site 

AR 1 0 No data 0 0 0 0 

IL 1 451 No data 0 451 0 451 

KY 1 2 0 0 2 0 2 

OH 1 5 5 255 10 255 265 

SC 1 182 5 0 187 0 187 

TX 2 43 3 0 47 0 47 

WV 1 664 350 0 1,014 0 1,014 

Total 8 1,347 363 255 1,711 255 1,966 

Source: TRI03 2005 (Data are from 2003) 

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 
DICHLOROBENZENES 278 

6. POTENTIAL FOR HUMAN EXPOSURE 

these facilities. Of this total, an estimated 1,347 pounds (0.6 metric tons) were released to air, 363 pounds 

(0.2 metric tons) were released to water, 255 pounds (0.1 metric tons) were released to land, and 0 pounds 

were released via underground injection. The total amount of 1,3-DCB released on-site was estimated as 

1,711 pounds (0.8 metric tons). The total amount released off-site was estimated as 255 pounds 

(0.1 metric tons) (TRI03 2005). 

According to the TRI, in 2003, a total of 96,993 pounds (44 metric tons) of 1,4-DCB was released to the 

environment from 21 large processing facilities (TRI03 2005). Table 6-3 lists amounts released from 

these facilities. Of this total, an estimated 85,463 pounds (39 metric tons) were released to air, 

815 pounds (0.4 metric tons) were released to water, 270 pounds (0.1 metric tons) were released to land, 

and 10,408 pounds (5 metric tons) were released via underground injection. The total amount of 

1,4-DCB released on-site was estimated as 96,696 pounds (44 metric tons). The total amount released 

off-site was estimated as 297 pounds (0.1 metric tons) (TRI03 2005). The TRI data should be used with 

caution because only certain types of facilities are required to report. This is not an exhaustive list. 

1,2-, 1,3-, and 1,4-DCB have been identified in a variety of environmental media (air, surface water, 

groundwater, soil, and sediment) collected at 281, 175, and 330 of the 1,662 NPL hazardous waste sites, 

respectively (HazDat 2005). The number of these sites located in each state can be seen in Figures 6-1, 

6-2, and 6-3. 

Quantitative information on releases of DCBs to specific environmental media is discussed below. 

6.2.1 Air 

According to the TRI, estimated releases of 1,2-DCB of 87,443 pounds (40 metric tons) to the air from 

39 large processing facilities accounted for about 93% of the total TRI environmental releases in 

2003 (TRI03 2005). Table 6-1 lists amounts of 1,2-DCB released from these facilities. Estimated 

releases of 1,3-DCB of 1,347 pounds (0.6 metric tons) to the air from eight large processing facilities 

accounted for about 69% of the total TRI environmental releases in 2003 (TRI03 2005). Table 6-2 lists 

amounts of 1,3-DCB released from these facilities. Estimated releases of 1,4-DCB of 85,463 pounds 

(38 metric tons) to the air from 20 large processing facilities accounted for about 88% of the total TRI 

environmental releases in 2003 (TRI03 2005). Table 6-3 lists amounts of 1,4-DCB released from these 

facilities. The TRI data should be used with caution because only certain types of facilities are required 

to report (EPA 1997b). Therefore, this is not an exhaustive list. 
DICHLOROBENZENES 279 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Releases to the Environment from Facilities that Produce, Process, or 

Use 1,4-Dichlorobenzenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek 

On- and offsite 

AR 2 3 No data 0 0 0 3 0 3 

GA 1 No data No data No data No data No data No data 0 0 

IL 2 25,111 5 0 0 0 25,116 0 25,116 

KS 2 2,105 No data 0 5 0 2,105 5 2,110 

KY 1 2 No data 0 0 0 2 0 2 

MO 1 766 No data 0 0 0 766 0 766 

NC 1 11,515 6 0 0 0 11,521 0 11,521 

OH 2 1,385 5 0 255 0 1,390 255 1,645 

OK 1 569 No data 0 0 0 569 0 569 

PA 1 10 No data 0 0 0 10 0 10 

SC 1 No data No data No data No data No data No data 0 0 

TX 3 14,725 3 10,408 10 0 25,146 0 25,146 

UT 2 2 No data 0 0 37 2 37 39 

WV 1 29,270 796 0 0 0 30,066 0 30,066 

Total 21 85,463 815 10,408 270 37 96,696 297 96,993 

Source: TRI03 2005 (Data are from 2003) 

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 
 

 

DICHLOROBENZENES 280 

6. POTENTIAL FOR HUMAN EXPOSURE 

Because 1,4-DCB is a volatile substance that sublimes at room temperature, most environmental releases 

are to the atmosphere. In 1972, 70–90% of the annual U.S. production of 1,4-DCB was estimated to have 

been released into the atmosphere primarily as a result of its use in toilet bowl and garbage deodorants, 

and its use in moth control as a fumigant (IARC 1982). It has been estimated that about 40% of the 

domestic use of 1,4-DCB is for space deodorants moth repellents (CMR 1999). Assuming that 90% of 

the space deodorants and all of the moth repellents are released to the atmosphere (EPA 1981a), and using 

current production data (50–100 million pounds or 23,000–45,000 metric tons) (EPA 2002e), about 20– 

40 million pounds (9,000–18,000 metric tons) of 1,4-DCB were released to the air in 1994 from these 

sources. 1,4-DCB may also be emitted to air from other sources, such as hazardous waste sites (EPA 

1981a), during its use as a fumigant (EPA 1981a), or from emissions from waste incinerator facilities (Jay 

and Stieglitz 1995). These emissions are likely to be a minor contribution to the total atmospheric 

loading of 1,4-DCB, but may be locally important. There are no known natural sources of 1,4-DCB 

(IARC 1999). 

1,2- and 1,3-DCB, which are volatile liquids at room temperature, are also expected to be released 

primarily to air. Unlike 1,4-DCB, however, the 1,2- and 1,3- isomers are not widely used in household or 

consumer products and thus are not released into the air of homes and buildings to the extent of the 1,4- 

isomer. 1,2- and 1,3-DCB are expected to be released to the air during their use in herbicide production, 

during the use of other products containing these isomers, or from air emissions at hazardous waste sites 

and incinerator facilities. Another significant source for the release of 1,2-DCB to air may be from the 

disposal of this substance when it is produced as a by-product in the production of 1,4-DCB. There are 

no known natural sources of 1,2- or 1,3-DCB (IARC 1999). 

The concentrations of 1,2-, 1,3-, and 1,4-DCB in the emissions of a municipal waste incineration plant 

were 2.32x10-6, 2.44x10-6, and 5.92x10-5 ppm, respectively (Jay and Stieglitz 1995). DCBs were detected 

in emissions from municipal solid waste composting facilities at concentrations of 1.16x10-4 ppm for 

1,2-DCB, 2.32x10-4 ppm for 1,3-DCB, and 1.04x10-2 ppm for 1,4-DCB (Eitzer 1995). Garcia et al. 

(1992) measured 1,4-DCB concentrations ranging from 3.48x10-5 to 4.99x10-4 ppm in the emissions of 

coal-fired power stations. 1,2-DCB was detected in landfill gas at the Fresh Kills municipal solid waste 

landfill in New York City with a mean concentration of 2.17 ppm (Eklund et al. 1998). 

1,2-DCB has been identified in air samples collected at 15 of the 281 NPL hazardous waste sites, 

respectively, where it has been detected in at least one environmental medium (HazDat 2005). 1,3-DCB 

has been identified in air samples collected at 9 of the 175 NPL hazardous waste sites where it has been 
 

 

DICHLOROBENZENES 281 

6. POTENTIAL FOR HUMAN EXPOSURE 

detected in some environmental media (HazDat 2005). 1,4-DCB has been identified in air samples 

collected at 23 of the 330 NPL hazardous waste sites where it has been detected in some environmental 

media (HazDat 2005). 

6.2.2 Water 

According to the TRI, the estimated releases of 1,2-DCB of 1,240 pounds (0.6 metric tons) to water from 

39 large processing facilities accounted for 1% of the total TRI environmental releases in 

2003 (TRI03 2005). An additional 1,104 pounds (0.5 metric tons) (1% of total TRI environmental 

releases) were released off-site, which includes release to publicly owned treatment works (POTWs). 

Table 6-1 lists amounts of 1,2-DCB released from these facilities. Estimated releases of 1,3-DCB of 

363 pounds (0.2 metric tons) to water from eight large processing facilities accounted for 18% of the total 

TRI environmental releases in 2003 (TRI03 2005). An additional 255 pounds (0.1 metric tons) (13% of 

total TRI environmental releases) were released off-site, which includes release to POTWs. 

Table 6-2 lists amounts of 1,3-DCB released from these facilities. Estimated releases of 1,4-DCB of 

815 pounds (0.4 metric tons) to water from 21 large processing facilities accounted for 0.8% of the total 

TRI environmental releases in 2003 (TRI03 2005). An additional 297 pounds (0.1 metric tons) (0.3% of 

total TRI environmental releases) were released off-site, which includes release to POTWs. 

Table 6-3 lists amounts of 1,4-DCB released from these facilities. The TRI data should be used with 

caution because only certain types of facilities are required to report (EPA 1997b). Therefore, this is not 

an exhaustive list. 

Less than 1% of environmental releases of 1,4-DCB are to surface water (EPA 1981a). The main route 

for the release of this substance to surface water is expected to be through its extensive use in urinal 

deodorant blocks (IARC 1999). 1,2-DCB is released into industrial waste water during its production and 

use. 1,2-DCB might also be released into waste water during the disposal of this substance when it is 

produced as a by-product in the production of 1,4-DCB. Data concerning the release of 1,3-DCB to water 

are lacking. Release of this substance to water may occur during its production, use, or disposal. DCBs 

have been identified in industrial and municipal waste waters from several sources, at concentrations 

ranging from <3 to >900 ppb (Oliver and Nichol 1982a; Perry et al. 1979; Young and Heesen 1978; 

Young et al. 1980, 1981). 1,2- and 1,4-DCB were both detected in 1% of 84 possible detections in 

influent samples from the New York City municipal waste water treatment system at concentrations of 

22 and 4 ppb, respectively (Stubin et al. 1996). 1,2-DCB was detected in 2% while 1,4-DCB was 

detected in 1% of 84 possible detections in effluent samples at concentrations of 4–6 and 3 ppb, 
 

 

 

DICHLOROBENZENES 282 

6. POTENTIAL FOR HUMAN EXPOSURE 

respectively. The concentrations of 1,2-DCB were higher than those of 1,4-DCB, which is contrary to 

what is expected for these substances in residential and domestic waste water. However, no explanation 

was offered for this. The concentration of 1,4-DCB in the effluent of the North Regional Wastewater 

Treatment Plant in Broward County, Florida was approximately 1.2 ppb (Tansel and Eyma 1999). 

1,4-DCB was detected above “standard levels” (unspecified) in sediment at the end of the Macaulay Point 

and Clover Point waste water outfalls off the coast of Vancouver, British Columbia (Taylor et al. 1998). 

DCB (unspecified isomers) has been reported in the leachate from industrial and municipal landfills at 

concentrations from 0.007 to 0.52 ppm (7–520 ppb) (Brown and Donnelly 1988). Eganhouse et al. 

(2001) identified 1,4-DCB at a concentration of 0.1–5.6 ppb in a landfill leachate plume in groundwater 

from a municipal landfill located in Norman, Oklahoma. DCBs have also been detected in wetlandtreated leachate water at a municipal solid waste landfill in central Florida (Chen and Zoltek 1995). 

Groundwater samples contained 1,2-DCB at concentrations of 0.09–1.56 ppb, 1,3-DCB at concentrations 

of 0.08–8.95 ppb, and 1,4-DCB at concentrations of 0.08–10.71 ppb. Hallbourg et al. (1992) detected 

DCB (unspecified isomers) in groundwater at several landfill sites in Orange County, Florida. These 

authors reported mean concentrations of DCBs of 0.37–21.2, 6–46.4, and <1–7.4 ppb at the Orange 

County Landfill, Alachua County Southwest Landfill, and the Alachua County Northeast Landfill, 

respectively. In their study, DCB was one of the 10 most frequently detected volatile organic compounds 

(VOCs). Plumb (1991) also reported 1,2-, 1,3-, and 1,4-DCB in groundwater samples collected at 36, 16, 

and 34 of 479 hazardous waste sites, respectively. 

1,4-DCB was monitored for, but not detected, in 86 samples of urban storm water runoff in the National 

Urban Runoff Program (Cole et al. 1984). DCBs were detected in four rivers (Aire, Calder, Don, and 

Trent) that drain an industrial catchment from the United Kingdom into the North Sea (Meharg et al. 

2000). Annual fluxes in these rivers ranged from 1.37 to 32.91 kg/year for 1,2-DCB, 0.12 to 9.33 kg/year 

for 1,3-DCB, and 6.80 to 28.96 kg/year for 1,4-DCB. 

1,2-DCB has been identified in surface water and groundwater samples collected at 29 and 186 of the 

281 NPL hazardous waste sites, respectively, where it was detected in at least one environmental medium 

(HazDat 2005). 1,3-DCB has been identified in surface water and groundwater samples collected at 

13 and 107 of the 175 NPL hazardous waste sites, respectively, where it was detected in some 

environmental media (HazDat 2005). 1,4-DCB has been identified in surface water and groundwater 

samples collected at 31 and 213 of the 330 NPL hazardous waste sites, respectively, where it was detected 

in some environmental media (HazDat 2005). 
DICHLOROBENZENES 283 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.2.3 Soil 

According to the TRI, releases of 1,2-DCB to land of 1,784 pounds (0.8 metric tons) from 39 large 

processing facilities accounted for 2% of total TRI environmental releases in 2003 (TRI03 2005). An 

estimated 2,500 pounds (1 metric ton) (3% of total TRI environmental releases) were released via 

underground injection. Table 6-1 lists amounts of 1,2-DCB released from these facilities. Releases of 

1,3-DCB of 255 pounds (0.1 metric tons) to the land from eight large processing facilities accounted for 

13% of total TRI environmental releases in 2003 (TRI03 2005). Table 6-2 lists amounts of 1,3-DCB 

released from these facilities. There were no releases of 1,3-DCB to the underground in 2003 as shown in 

Table 6-2. Releases of 1,4-DCB of 270 pounds (0.1 metric tons) to the land from 21 large processing 

facilities accounted for 0.2% of total TRI environmental releases in 2003 (TRI03 2005). In addition, an 

estimated 10,408 pounds (0.5 metric tons) (11% of total environmental releases) were released via 

underground injection. Table 6-3 lists amounts of 1,4-DCB released from these facilities. The TRI data 

should be used with caution because only certain types of facilities are required to report (EPA 1997b). 

Therefore, this is not an exhaustive list. 

The principal sources of 1,4-DCB release to land are disposal of industrial waste in landfills, application 

of sewage sludge containing 1,4-DCB to agricultural land, and atmospheric deposition (Wang and Jones 

1994b; Wang et al. 1995). Municipal wastes may include unused space deodorants and moth repellents 

containing 1,4-DCB, but these releases are not expected to be significant (EPA 1981a). A survey of 

204 sewage sludges conducted in Michigan that analyzed for 73 organic compounds reported a 

concentration range of 0.04–633 mg/kg dry weight (ppm) for 1,4-DCB and mean and median 

concentrations of 12.0 and 2.02 ppm, respectively (Jacobs and Zabik 1983). 1,4-DCB from this source 

may be released to soils during land applications of sludge to agricultural soils. A similar survey of 

sewage sludges in England found 1,4-DCB ranging from 561 to 2,320 μg/kg (0.561–2.32 ppm wet 

weight) in all 12 of the samples tested (Wang and Jones 1994b). Wang et al. (1995) reported, however, 

that 1,4-DCB concentrations increased during the 1960s in both plots receiving sewage sludge 

applications and in control soil plots. The authors concluded that atmospheric deposition during the 

1960s in particular, which corresponded to a period of increased production of many organochlorine 

compounds, was a likely source. 1,2-DCB was detected in all 12 sewage sludge samples at 

concentrations ranging from 71.3 to 4,110 μg/kg (ppb) dry weight (3.57–152 ppb wet weight). The 

concentrations of 1,2-DCB in industrial sewage sludge was considerably higher than in urban sewage 
 

 

DICHLOROBENZENES 284 

6. POTENTIAL FOR HUMAN EXPOSURE 

sludge. 1,3-DCB was detected in 9 out of 12 sewage sludge samples at concentrations ranging from 

below the detection limit to 467 μg/kg (ppb) dry weight (below the detection limit–13.5 ppb wet weight). 

1,2-DCB is produced in large quantities as a by-product in the production of 1,4-DCB. The TRI data for 

this substance suggest that 1,2-DCB may be released into the ground during the disposal of unused 

supplies. Data concerning the release of 1,3-DCB to soil were lacking. Based on TRI data, the 

production volume of these chemicals, and their uses, releases of this isomer to soil are expected to be 

minor compared to the other DCB isomers. 

1,2-DCB has been identified in soil and sediment samples collected at 111 and 37 of the 281 NPL 

hazardous waste sites, respectively, where it was detected in at least one environmental medium (HazDat 

2005). 1,3-DCB has been identified in soil and sediment samples collected at 64 and 25 of the 175 NPL 

hazardous waste sites, respectively, where it was detected in at least one environmental medium (HazDat 

2005). 1,4-DCB has been identified in soil and sediment samples collected at 112 and 52 of the 330 NPL 

hazardous waste sites, respectively, where it was detected in at least one environmental medium (HazDat 

2005). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Whereas 1,2- and 1,3-DCB are liquids at room temperature, 1,4-DCB is a solid that sublimes readily. 

Sublimation rates of 1,4-DCB from consumer products were measured at 1.6x10-3 to 4.6x10-3 g/minute at 

temperatures ranging from 21 to 24 °C during a 19-day test period (Scuderi 1986). DCBs tend to 

volatilize to the atmosphere from soil and water at a relatively rapid rate. The estimated volatilization 

half-life for these chemicals was 4 hours in a model river and 120 hours from a model lake (HSDB 2005). 

The reported volatilization half-lives for 1,4-DCB measured in coastal seawater ranged from 10 to 

18 days (Wakeham et al. 1983). 1,2-DCB (100 ppm) and 1,4-DCB (300 ppm) both volatilized 

completely from nonaerated distilled water in <3 days and from aerated distilled water in <4 hours 

(Garrison and Hill 1972). Volatilization from surface soil may be an important transport mechanism for 

DCBs (Wang and Jones 1994a), but adsorption to soil particulates may inhibit volatilization (Wilson et al. 

1981). 
 

 

DICHLOROBENZENES 285 

6. POTENTIAL FOR HUMAN EXPOSURE 

Since DCBs are slightly soluble in water (80.0–156 mg/L) (Banerjee et al. 1980; Miller et al. 1984; 

Yalkowsky and He 2003), partitioning to clouds, rain, or surface water may occur. Henry's Law constant 

values ranging from 1.74x10-3 to 2.63x10-3 atm-m3

/mol at 25 °C (Shiu and Mackay 1997; Staudinger and 

Roberts 1996) indicate that partitioning from air to water is likely to be minor relative to the reverse 

process of volatilization of the compound from water to air. However, DCBs have been detected in 

rainwater and snow (Laniewski et al. 1998, 1999; Ligocki et al. 1985). The concentration of 1,4-DCB 

detected in 6 of 7 rainwater samples collected in Portland, Oregon, ranged from 3 to 7 ppt (ng/L), while 

the concentration of 1,2-DCB detected in 5 out of 7 rainwater samples ranged from 0.13 to 0.62 ppt 

(Ligocki et al. 1985). DCBs have been detected in surficial snow from Antarctica (Laniewski et al. 

1998), which suggests that these substances can be transported over long distances through the 

atmosphere. 

Based on measured soil organic carbon partition coefficient (Koc) values, which range from 275 to 

1,833 in different soils (Bahnick and Doucette 1988; Chiou et al. 1983; Newsom 1985; Schwartzenbach 

and Westall 1981; Wilson et al. 1981), DCBs are expected to sorb moderately to soils and sediments. 

Sorption is primarily to the soil organic phase (Chiou et al. 1983) and, therefore, depends on the organic 

content of the soil. However, sorption is likely to be reversible; therefore, DCBs may leach from 

hazardous waste sites and be transported to groundwater, or may migrate from surface water through the 

soil to groundwater (Newsom 1985; Schwartzenbach and Westall 1981). In a sandy soil with low organic 

matter, 26–49% of 1,4-DCB percolated through the soil to a depth of 140 cm (Wilson et al. 1981). 

DCBs are expected to bioconcentrate in aquatic organisms. High log octanol-water partition coefficient 

(log Kow) values of 3.43–3.53 (Hansch et al. 1995) also suggest that DCBs have a moderate to high 

potential for bioaccumulation. A calculated bioconcentration factor (BCF) of 267 was reported for the 

fathead minnow (Pimephales promelas) (ASTER 1995). Measured mean BCF values of 370 and 

720 were experimentally determined at equilibrium for rainbow trout exposed to water concentrations of 

28 ng/L (ppb) and 670 ng/L (ppb), respectively, of 1,4-DCB for up to 119 days in laboratory aquaria 

(Oliver and Niimi 1983). BCF values measured in this study for 1,2-DCB were 270 (47 ng/L in water) 

and 560 (940 ng/L in water), while BCF values measured for 1,3-DCB were 420 (28 ng/L in water) and 

740 (690 ng/L in water). A study of chlorobenzenes in sediments, water, and selected fish from the Great 

Lakes indicated that many chlorobenzenes are bioconcentrated by fish, but that DCBs are concentrated to 

a smaller extent than some of the more highly chlorinated chlorobenzene compounds such as 

pentachlorobenzene and hexachlorobenzene (Oliver and Niimi 1982a). For example, equilibrium/steady­
 

 

DICHLOROBENZENES 286 

6. POTENTIAL FOR HUMAN EXPOSURE 

state BCF values measured in fish maintained in flowing water systems typically increased with 

increasing chlorination as shown in Table 6-4. 

DCBs can enter soil-plant systems through many routes including atmospheric deposition, sewage sludge 

application to agricultural land, and through industrial activities (Wang and Jones 1994a). Wang and 

Jones (1994c) studied the uptake of several chlorobenzene compounds in carrots grown in spiked and 

sewage-amended soils. The transfer of chlorobenzenes from soils to plants and subsequent 

bioaccumulation is of interest because chlorobenzenes are ubiquitous in sewage sludge. Chlorobenzenes 

are also lipophilic and volatile compounds that can be taken up by plants by both root and foliage 

pathways. Carrots were grown for 100 days in control soil, chemically-spiked soil, and in low and high 

rate sludge-amended soils. DCB concentration in the soils did not remain constant throughout the growth 

period. BCF values are not traditional steady-state values since measurements were taken for only one 

time interval. The authors reported that concentrations of 1,4-DCB in soil before sowing and after the 

harvest were 5.9 and 2.6 ppb dry weight in the control, 16 and 11 ppb in the chemically-spiked soil, 

10 and 7.4 ppb in the low rate sewage-amended soil, and 38 and 30 ppb in the high rate sewage-amended 

soils, respectively. Concentrations of 1,4-DCB in carrot foliage and the corresponding bioconcentration 

factors (BCFs) were 13 ppb (BCF=3.1) for the control, 17 ppb (BCF=1.3) for the spiked soil, 22 ppb 

(BCF=2.5) for the low rate sewage-amended soil, and 49 ppb (BCF=1.5) for the high rate sewageamended soil. The concentrations of 1,2-DCB in soil before sowing and after the harvest were both 

below the detection limit (unspecified) in the control, 29 and 17 ppb in the chemically-spiked soil, 13 and 

7.3 ppb in the low rate sewage-amended soil, and 60 and 45 ppb in the high rate sewage-amended soils, 

respectively. Concentrations of 1,2-DCB in carrot foliage and the corresponding BCFs were 6.7 ppb 

(BCF not given) for the control, 9.6 ppb (BCF=0.42) for the spiked soil, 12 ppb (BCF=1.2) for the low 

rate sewage-amended soil, and 26 ppb (BCF=0.49) for the high rate sewage-amended soil. The 

concentrations of 1,3-DCB in soil before sowing and after the harvest were both below the detection limit 

(unspecified) in the control, 4.2 and 2.9 ppb in the chemically-spiked soil, 2.3 and 0.98 ppb in the low rate 

sewage-amended soil, and 8.2 and 5.8 ppb in the high rate sewage-amended soils, respectively. 

Concentrations of 1,3-DCB in carrot foliage and the corresponding BCFs were 0.72 ppb (BCF not given) 

for the control, 0.83 ppb (BCF=0.24) for the spiked soil, 1.3 ppb (BCF=0.80) for the low rate sewageamended soil, and 2.2 ppb (BCF=0.31) for the high rate sewage-amended soil. The application of the 

low-rate sewage sludge stimulated both the carrot foliage and root production to the greatest extent. The 

authors concluded that foliar uptake of all chlorobenzenes tested, including the DCBs, was an important 

bioaccumulation pathway. 
DICHLOROBENZENES 287 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Comparison of Bioconcentration Factors (BCFs) for Various 

Chlorinated Benzenes in Fish 

Compound BCF (range) 

Monochlorobenzene 12–450 

1,2-Dichlorobenzene 89–560 

1,3-Dichlorobenzene 66–740 

1,4-Dichlorobenzene 15–720 

1,2,3-Trichlorobenzene 700–2,600 

1,2,4-Trichlorobenzene 182–3,200 

1,3,5-Trichlorobenzene 760–4,100 

1,2,3,4-Tetrachlorobenzene 3,800–12,000 

1,2,3,5-Tetrachlorobenzene 1,800–3,900 

1,2,4,5-Tetrachlorobenzene 4,000–13,000 

Pentachlorobenzene 3,400–20,000 

Hexachlorobenzene 12,000–44,437 

Source: EPA 1985a 
DICHLOROBENZENES 288 

6. POTENTIAL FOR HUMAN EXPOSURE 

The concentrations (dry weight) of the DCBs in the carrot peel were typically equal to or slightly lower 

than the concentrations in the carrot core (Wang and Jones 1994a). This indicated that DCBs, when 

present in carrots, penetrate into the core. For carrot roots, the concentrations of 1,4-DCB in the core and 

peel were 9.4 μg/kg (ppb) (BCF=2.2) and 7.0 ppb (BCF=1.6) for the control, 5.9 ppb (BCF=0.44) and 

7.3 ppb (BCF=0.54) for the chemically-spiked soil, 5.9 ppb (BCF=0.68) and 5.8 ppb (BCF=0.67) for the 

low-rate sewage application, and 9.6 ppb (BCF=0.28) and 4.3 ppb (BCF=0.13) for the high-rate sewage 

treatment, respectively. The concentrations of 1,2-DCB in the core and peel were 1.5 μg/kg (ppb) (BCF 

not given) and 1.4 ppb (BCF not given) for the control, 5.8 ppb (BCF=0.25) and 5.3 ppb (BCF=0.23) for 

the chemically-spiked soil, 0.0 ppb (BCF=0.0) and 0.84 ppb (BCF=0.085) for the low-rate sewage 

application, and 2.8 ppb (BCF=0.053) and 1.5 ppb (BCF=0.029) for the high-rate sewage treatment, 

respectively. 1,3-DCB was only detected in the core of the chemically-spiked soil at 1.0 ppb (BCF=0.29) 

and in the core of the high-rate sewage treatment at 1.8 ppb (BCF=0.26). 1,3-DCB concentrations in the 

root peels as well as the root core of the control were below the detection limit (unspecified). Overall, 

<1% of the DCBs and other chlorobenzenes in the soil were accumulated by the carrots, which is minor 

compared with the other loss pathway from the soil, principally volatilization. 

Wang et al. (1996) found that a 1 ppm solution of 1,4-DCB was taken up by carrots (Daucus carota, 

49%), soybeans (Glycine max, 50%), and red goosefoot (Chenopodium rubrum, 62%), but not by 

tomatoes (Lycopersicon esculentum). Only the soybean cell cultures provided evidence of the existence 

of metabolites of this compound, probably conjugates of chlorophenol. The authors further observed that 

the uptake, metabolism, and toxicity of 1,4-DCB differed among the species tested. 

Zhang et al. (2005) studied DCB uptake in vegetables grown in urban areas of China. DCB 

concentrations in spinach, Chinese cabbage, and celery were highest in roots, followed by leaves. 

Concentrations in radishes and carrots were highest in leaves, followed by stems. The authors reported 

that the accumulation of chlorinated benzenes in these vegetables was affected by the lipid contents of the 

vegetables, the volatilities of the chemicals, and the physiological characteristics of the vegetables. 

Data on biomagnification of DCBs through aquatic or terrestrial food chains were not located. 
 

 

 

DICHLOROBENZENES 289 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

The main degradation pathway for DCBs in air is reaction with photochemically generated hydroxyl 

radicals (Cuppitt 1980; EPA 1985a). Reactions with ozone or other common atmospheric species are not 

expected to be significant (Cuppitt 1980; EPA 1985d). Therefore, the atmospheric lifetime of the DCBs 

may be predicted from an assumed hydroxyl radical concentration in air and the rate of reaction. The 

reported rate for reaction of hydroxyl radicals with DCBs is 3.2–7.2x10-13 cm3

/mol-sec (Atkinson 1989; 

Howard 1989), and the estimated atmospheric half-life for DCBs is about 14–31 days (Howard 1989). 

Since this degradation process is relatively slow, DCBs may become widely dispersed, but are not likely 

to accumulate in the atmosphere. The degradation pathways for 1,4-DCB in the atmosphere are shown in 

Figure 6-4. 

Reports of smog chamber studies of chlorobenzene degradation have indicated degradation after 5 hours 

of 21.5% of 1,2-DCB (EPA 1985a). Chloronitrobenzenes and chloronitrophenols were identified as 

degradation products. Irradiation of chlorobenzenes with natural sunlight was reported to produce 

polychlorinated biphenyls (PCBs). Whether this occurs under natural atmospheric conditions is 

unknown, but it would appear to be unlikely because of the normally low concentrations of 

chlorobenzenes in ambient air. 

6.3.2.2 Water 

Biodegradation may be an important transformation process for DCBs in water under aerobic, but not 

anaerobic, conditions (Bouwer and McCarty 1982, 1983, 1984; Schwartzenbach et al. 1983; Spain and 

Nishino 1987; Tabak et al. 1981). Although volatilization of 1,4-DCB may interfere with biodegradation 

studies, 14C studies indicate that significant biodegradation of 1,4-DCB does occur (Spain and Nishino 

1987). Longer acclimation periods are required when 1,4-DCB is the sole carbon source (Spain and 

Nishino 1987). 

Several aerobic screening tests have been performed on the DCB isomers. 1,2- and 1,3-DCB, both at 

initial concentrations of 30 mg/L, reached 0% of their theoretical BOD in 4 weeks using an activated 

sludge inoculum at 100 mg/L and the Japanese MITI test (CITI 1992). During an OECD closed bottle 

test, removal of 1,4-DCB was 97.1%. However, volatilization was considered to be the major mechanism 
 

Figure 6-4. The Decomposition of 1,4-Dichlorobenzene in Air 

Cl 

NO2 

OH2 + 

Cl 

NO2 

Cl Cl Cl

OH OH

. O2 . + .OH H HO2 +

Cl Cl Cl

O2 

Cl 

OH 

. O3, NO, O2 . Aliphatic OO H HO2 + chlorinated 

dicarbonyls 

Cl 

DICHLOROBENZENES 290 

6. POTENTIAL FOR HUMAN EXPOSURE 
 

 

DICHLOROBENZENES 291 

6. POTENTIAL FOR HUMAN EXPOSURE 

for removal. During a modified porous pot test operated under normal conditions at a lower aeration rate, 

temperatures of 8, 15, and 20 °C, and sludge retention times of 3 and 6 days, removal of 1,4-DCB was 

>95%. The author reported that the major mechanism for 1,4-DCB removal in this test was 

biodegradation. Using acetate as the primary carbon source under aerobic conditions and after an 

acclimation period of 10 days, rapid bacterial degradation of 96% of a 1,2-DCB sample, 28% of a 

1,3-DCB sample, and 98% of a 1,4-DCB sample was reported (Bouwer and McCarty 1982). 1,4-DCB 

was completely mineralized to inorganic end products. Possible explanations for the lower 1,3-DCB 

biodegradation rate were biodegradation with slow utilization kinetics or sorption removal. The 

biodegradation rate of 1,2-DCB in a heterogeneous unconfined aquifer at Columbus Air Force Base in 

Columbus, Mississippi was measured to be 0.0059 day-1 (Stauffer et al. 1994). This corresponds to a 

half-life of 117 days. Biodegradation of 1,2-DCB in aquifer samples from Vejen and Grindsted, Denmark 

was slow, with >30% of the test compound remaining after 50 days. 1,4-DCB was not degraded in these 

samples after 50 days. 1,2-DCB (initial concentrations, 20 ppm) underwent 30–50% biodegradation in 

river water and 15–30% biodegradation in sea water after 3 days during an aerobic screening test (Kondo 

et al. 1988). 1,4-DCB (initial concentrations, 4 ppm) underwent 0% biodegradation in both the river 

water and sea water inocula after 3 days. In-situ biodegradation rate constants were measured for 1,2- 

and 1,4-DCB in an aerobic aquifer (Nielsen et al. 1996). Rate constants and lag phases were 0.02– 

0.06 day-1 (half-life, 12-35 days) and 0-20 days, respectively, for 1,2-DCB and 0.01–0.05 day-1 (half-life, 

14–69 days) and 0–22 days, respectively, for 1,4-DCB. Half-lives reported for 1,4-DCB in seawater 

mesocosm experiments performed at various temperatures ranged from 10 to 18 days (Wakeham et al. 

1983). The authors noted that volatilization was the dominant removal process. No degradation of DCBs 

was reported under denitrification or methanogenic conditions (Bouwer and McCarty 1983, 1984). 

Degradation pathways for 1,4-DCB in water are shown in Figure 6-5. 

6.3.2.3 Sediment and Soil 

Based on the Henry’s law constants of 1,2- and 1,3-DCB and the tendency of 1,4-DCB to sublime, 

volatilization rather than transformation is the most likely fate process for DCBs from surface soil. 

Transformation of DCBs by biodegradation, photolysis, chemical hydrolysis, and oxidation appear to be 

relatively minor processes. Leaching of DCBs to groundwater from subsurface soils under certain 

conditions may occur (EPA 1985a). 

Wang and Jones (1994a) studied the fate of chlorobenzenes including DCBs in chemically-spiked and 

sewage-amended soils to determine the rate of volatilization, biodegradation, photolysis, and other 
 

 

 

 

Figure 6-5. The Decomposition of 1,4-Dichlorobenzene in Soil and Water 

Cl Cl Cl
 

OH
 O2 COOH
 

COOH
 OH
 

Cl Cl Cl
 

O2 

1,4-Dichlorobenzene 1,4-Dichlorobenzene 2,5-Dichloro-cis, 

dihydrodiol cis-muconic acid 

Cl COOH Cl C 

C 

decarboxylation COOH O CH3 COOH 

O 2-Chloroaceto­

 acrylic acid Cl 

2-Chloromaleylacetic acid 

Cl 

C O 

O 

COOH 

Cl 

proposed 

DICHLOROBENZENES 292 

6. POTENTIAL FOR HUMAN EXPOSURE 
 

 

 

DICHLOROBENZENES 293 

6. POTENTIAL FOR HUMAN EXPOSURE 

possible loss processes. These authors used sewage sludge collected from a sewage treatment facility 

serving a municipal (~60%) and industrial (~40%) catchment. The sewage sludge or chemically-spiked 

solutions containing chlorobenzenes were added to five experimental systems; (1) normal soil, 

(2) sterilized soil (with 1% [weight] of sodium azide), (3) sterilized soil shaded with aluminum foil, 

(4) sterilized soil, shaded and sealed with a Teflon-coated septum, and (5) a control (untreated soil). The 

mesocosms were incubated at 20–30 °C over a 259-day period. Loss of all chlorobenzenes including 

DCBs was best represented by a two-step first-order kinetics model. In the normal condition containing 

unsterilized soil exposed to sunlight and open to the air, during the first 35 days, 79.9% of the 1,2-DCB, 

85.1% of the 1,3-DCB, and 70.5% of the 1,4-DCB were lost with half-life values of 13.2, 12.4, and 

17.4 days, respectively. From day 35 to day 259, only 4.29% of 1,2-DCB, 3.93% of 1,3-DCB, and 11.3% 

of 1,4-DCB were lost with half-life values of 892, 579, and 294 days, respectively. For the chemicallyspiked soil treatment, the first phase (days 0–17) loss was 75.6% for 1,2-DCB, 73.3% for 1,3-DCB, and 

73.2% for 1,4-DCB with half-life values of 8.63, 8.42, and 8.57 days. The second phase (days 17–259) 

loss was 13.9% for 1,2-DCB, 25.4% for 1,3-DCB, and 11.2% for 1,4-DCB with half-lives of 191, 189, 

and 131 days, respectively. Although the DCB loss rates in the sewage-amended soil were slower than 

those in the chemically-spiked soil, the total percentage losses of DCBs after 259 days were comparable. 

Based on the results of losses of DCBs observed in the other microcosm systems, the authors concluded 

that transformation processes including biodegradation, photolysis, and other abiotic losses (chemical 

hydrolysis and oxidation) were minor processes compared to volatilization. The experimental results of 

Wang and Jones (1994a) showed that, during the first phase, volatilization rates were high and substantial 

portions of the DCBs were lost. The second phase was much slower and portions of the DCBs remained 

in the soil for a much longer period. 

Neither 1,3- nor 1,4-DCB were biotransformed in an aerobic Rhine River sediment column (closed 

system) after 12 months (Bosma et al. 1990). 1,2-DCB was completely degraded after 4 months 

following a lag period of 60–100 days. DCBs (unspecified isomers) were degraded slowly in alkaline 

para-brown soil (100 g soil per 2 mg compound) with 6.3% of theoretical CO2 evolution in a closed 

system after 10 weeks (Haider et al. 1974). Half-lives corresponding to the biodegradation of 1,2-, 1,3-, 

and 1,4-DCB in anaerobic estuarine sediment from the Tsurumi River, Japan were 36.9, 433.2, and 

385.1 days, respectively (Masunaga et al. 1996). Between 25 and 90% of 1,2- and 1,4-DCB were 

removed from an aerobic soil column (closed system) after 300 days of continuous operation, while 

<25% of 1,3-DCB was removed (Van der Meer et al. 1992). These studies show that the rate of loss of 

DCBs in soils and sediments is much lower when volatilization is minimized. This supports the 

conclusion of Wang and Jones (1994a) that biodegradation is slow compared to volatilization. 
DICHLOROBENZENES 294 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to dichlorobenzenes depends in part on the 

reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of dichlorobenzenes 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 dichlorobenzenes 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 dichlorobenzenes in a variety of environmental media are detailed in Chapter 7. 

Due to their use and volatile nature, DCBs are detected much more frequently and at higher 

concentrations in air than in other environmental compartments such as soil, water, or sediment. 

6.4.1 Air 

1,4-DCB has been detected in indoor air, ambient outdoor air, and in occupational settings. A summary 

of levels of 1,4-DCB detected in indoor air is shown in Table 6-5. An update of the 1980 national 

ambient VOCs database prepared for the EPA summarized concentrations of 1,4-DCB by site type (Shah 

and Heyerdahl 1988). The median indoor air concentration of 1,4-DCB detected at 2,121 sites was 

0.283 ppb (mean 3.988 ppb), and the median concentration detected from personal air monitoring of 

1,650 individuals was 0.416 ppb (Shah and Heyerdahl 1988); for reference, the American Conference of 

Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) (8-hour time-weighted 

average [TWA] for 1,4-DCB is 10 ppm (ACGIH 2005). The authors concluded that these values are a 

result of the use of 1,4-DCB in air fresheners and to control moths that could damage woolen clothing. 

Because of its indoor uses, reports of indoor air monitoring show higher concentrations of 1,4-DCB than 

those observed in ambient outdoor air. This was also observed during the Total Exposure Assessment 

Methodology (TEAM) Study conducted by EPA between 1979 and 1985 in an effort to measure 

exposures to 20 VOCs in personal air, outdoor air, and drinking water. Data from the TEAM study were 

presented for the sum of 1,3- and 1,4-DCB (Wallace et al. 1986a). Because 1,4-DCB is produced and 

used in much greater volume than 1,3-DCB, the authors assumed that the concentrations found were 

almost all 1,4-DCB. The authors concluded that the major cause for the higher personal air 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 295 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Levels of 1,4-Dichlorobenzene in Indoor Air 

Concentration (ppm) 

Conditions Range Mean Median Maximum Reference 

Bathroom with one 7.80x10-2– Scuderi 1986 

deodorizer block 1.26x10-1 

Bathroom with one 1.16x10-1– 

deodorizer block in one 2.20x10-1 

urinal and one toilet 

Inside closet with moth 2.19x10-1– 

flakes in closed garment bag 5.45x10-1 

Outside closet with moth 1.03x10-2– 

flakes in closed garment bag 7.10x10-2 

Inside wardrobe air 0.197 Morita and Ohi 1975 

Inside closet air 0.036 

Bedroom air 0.012 

2,121 Indoor sites 4x10-3 2.83x10-4 Shah and 

Heyerdahl 1988 

1,650 Personal air monitors 4.16x10-4 

1256 Dwellings 1.33x10-3 Brown et al. 1994 

Ventilated office air Field et al. 1992 

Prior to pollution event 4.43x10-3– 

7.75x10-3 

5.14x10-3 4.89x10-3 

During pollution event 3.54x10-3– 

7.29x10-3 

4.51x10-3 4.48x10-3 

32 Smoking homes 2.79x10-3 1.51x10-4 5.03x10-2 Heavner et al. 1996 

61 Nonsmoking homes 8.62x10-4 9.65x10-5 2.03x10-2 

757 Homes 2.61x10-3 Meek et al. 1994 

12 Homes 1.66x10-4– 2.50x10-3 Chan et al. 1990 

1.78x10-2 

Over 100 homes (United 

States, Germany, 

2.16x10-3 

(3.99x10-3 

2.66x10-1 IARC 1999 

Netherlands) in the 

United 

States) 

Inside four test houses 3.65x10-4– 1.2x10-3– Wallace et al. 1989 

4x10-2 1.22x10-1 

With solid deodorizer 5.64x10-2 

With spray deodorizer 6.14x10-3 

With liquid deodorizer 4.15x10-3 

With no deodorizer 4.32x10-3 

26 Normal houses 1.08x10-4 1.33x10-5 1.5x10-3 Kostiainen 1995 
 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 296 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Levels of 1,4-Dichlorobenzene in Indoor Air 

Concentration (ppm) 

Conditions Range Mean Median Maximum Reference 

Nationwide study of Fellin and Otson 

Canadian homes 1994 

Winter 5.93x10-3

 Spring 2.5x10-3

 Summer 1.75x10-3

 Fall 2.5x10-3

 0 °C 3.92x10-3

 0–15 °C 3.66x10-3

 15 °C 2.0x10-3 
 

 

DICHLOROBENZENES 297 

6. POTENTIAL FOR HUMAN EXPOSURE 

concentrations was the use of 1,4-DCB sources such as moth crystals and room deodorizers in the home 

(Wallace et al. 1986b). 

Wallace et al. (1989) studied the influence of personal activities on exposure to VOCs. These authors 

reported that the median 1,4-DCB concentration in ambient outdoor air sampled 3 times/day over a 3-day 

monitoring period at each of three test houses was <1 μg/m3 (0.17 ppb) and the maximum concentration 

was 17 μg/m3 (2.8 ppb). The median indoor 1,4-DCB air concentrations sampled individually at each of 

four study houses ranged from 2.2 to 240 μg/m3 (0.37–40 ppb), while the maximum concentrations ranged 

from 7.2 to 740 μg/m3 (1.2–123.3 ppb). The mean personal air concentration for seven individuals living 

in the study houses was 81 μg/m3 (13.5 ppb) (range 4.0–240 μg/m3 [0.7–40 ppb]), while the outdoor mean 

1,4-DCB personal air concentration was 1 μg/m3 (0.17 ppb). The personal air to outdoor air ratio 

of 81 was 4 times higher than the ratios calculated for the other VOCs tested. Two individuals living in 

the same house both had mean personal air concentrations of 240 μg/m3 (40 ppb); the median levels of 

1,4-DCB in their breath were 40 and 47 μg/m3 (6.7 and 7.8 ppb), which was higher than the median breath 

level of 1.5 μg/m3 (0.3 ppb) in an individual receiving a personal exposure of 5.7 μg/m3 (1.5 ppb). 

Wallace et al. (1989) further studied the activities associated with increased personal exposure to, or 

increased indoor air concentrations of, 1,4-DCB. The activities that increased both personal exposure and 

indoor air concentrations of 1,4-DCB were the use of solid toilet deodorizers, followed by spray 

deodorizers and liquid deodorizers, compared to the use of no deodorizers at all. The median personal 

exposure concentrations to 1,4-DCB were 330 μg/m3 (55 ppb) (maximum, 500 μg/m3 [83.3 ppb]), 

33 μg/m3 (5.5 ppb) (maximum, 84 μg/m3 [14 ppb]), 12 μg/m3 (2 ppb) (maximum, 28 μg/m3 [4.7 ppb]), and 

2.4 μg/m3 (0.4 ppb) (maximum, 6.6 μg/m3 [1.1 ppb]) for solid, spray, liquid, and no deodorizer use, 

respectively. Median indoor air concentrations were 340 μg/m3 (56.7 ppb) (maximum, 

630 μg/m3 [105 ppb]), 37 μg/m3 (6.2 ppb) (maximum, 59 μg/m3 [9.8 ppb]), 25 μg/m3 (4.2 ppb) (maximum, 

30 μg/m3 [5 ppb]), and 2.6 μg/m3 (0.43 ppb) (maximum, 5.2 μg/m3 [0.87 ppb]) for solid, spray, liquid, and 

no deodorizer use, respectively. 

More recently, Kostianen (1995) identified >200 VOCs in the indoor air of 26 normal houses. 1,4-DCB 

was detected in 100% of the houses studied. 1,4-DCB was detected at a mean concentration of 

0.65 μg/m3 (0.1 ppb) (median 0.08 μg/m3 [0.013 ppb], minimum 0 μg/m3 [0 ppb], and maximum 

8.94 μg/m3 [1.5 ppb]) in the houses studied. Forty-eight compounds (including 1,4-DCB) were selected 

for further quantitative analysis in 50 normal houses and 38 “sick houses,” which had poor quality indoor 

air that was linked to odors and to a number of physiological follow-up study of normal and “sick 

houses,” the median concentration of 1,4-DCB (0.88 μg/m3 [0.15 ppb]) in the normal houses was 
 

 

DICHLOROBENZENES 298 

6. POTENTIAL FOR HUMAN EXPOSURE 

exceeded by 5–10% in 6% of the normal houses and by 10–50% in 18% of the normal houses, while in 

the “sick houses,” the median concentration was exceeded by 5–10% in 7.9% of the “sick houses”, by 10– 

50% in 2.6% of the sick houses, and by 50–200% in 5.3% of the “sick houses.” The median 

concentrations of 1,4-DCB reported in the 38 “sick houses” ranged from 0.00 to 5.36 μg/m3 (0–0.89 ppb). 

During a study of exposure of volatile organic compounds in the air of three photocopy centers, 1,4-DCB 

was detected in the breathing zone of photocopier operators at concentrations ranging from 0.1 to 3.7 ppb 

(Stefaniak et al. 2000). 1,4-DCB was not listed with the compounds detected in building background 

samples. 

A nationwide study of indoor air concentrations of 26 VOC compounds was conducted in Canada in 

1991 (Fellin and Otson 1994). The authors reported that mean 1,4-DCB concentrations were 

35.75 μg/m3 (5.96 ppb) (winter), 15 μg/m3 (2.5 ppb) (spring), 10.54 μg/m3 (1.76 ppb) (summer), and 

15 μg/m3 (2.5 ppb) (fall), and that the concentrations declined with an increase in ambient air temperature. 

At ≤0, 0–15, and ≥15 °C, the 1,4-DCB mean concentrations were 23.64, 22.02, and 11.83 μg/m3 (3.94, 

3.67, and 1.97 ppb), respectively. Analysis revealed that 1,4-DCB concentrations were associated with 

use of household products and moth repellant crystals. These authors concluded that indoor sources of 

1,4-DCB (household products and moth repellant crystal) are likely to have a more significant influence 

on indoor air concentrations than climatic variables. Summer conditions and outdoor temperatures 

>15.1 °C gave the lowest indoor air concentrations of 1,4-DCB. Moth repellant crystals are also deployed 

in a manner that gives reasonably constant emissions over several weeks. This compound produced a 

trend consistent with expected ventilation results. The highest average concentrations were observed 

during the winter or when temperatures were <0 °C, when ventilation is expected to be lowest. 

Intermediate values were measured during the fall and spring, while the lowest values were measured 

during the summer, when ventilation of homes is expected to be highest. Zhu et al. (2005) detected 1,2- 

and 1,4-DCB in the indoor air samples from 5 and 81% of 75 randomly selected dwellings in Ottawa, 

Canada, respectively. Arithmetic mean concentrations in these air samples were 0.77 μg/m3

 for 1,4-DCB 

and 0.01 μg/m3 for 1,2-DCB. 

Kinney et al. (2002) measured home outdoor, home indoor, and personal air concentrations of 1,4-DCB 

for selected students that attend school in the West Central Harlem section of New York City as part of 

the Toxic Exposure Assessment (TEACH) study. Mean winter concentrations of 1,4-DCB were 

5.03 μg/m3 in 36 home outdoor samples, 54.9 μg/m3 in 36 home indoor samples, and 43.4 μg/m3 in 

36 personal air samples. Mean summer concentrations of 1,4-DCB were 5.03 μg/m3 in 29 home outdoor 
 

 

DICHLOROBENZENES 299 

6. POTENTIAL FOR HUMAN EXPOSURE 

samples, 54.9 μg/m3 in 36 home indoor samples, and 43.4 μg/m3 in 40 personal air samples. Similar 

results were obtained from TEACH study measurements in Los Angeles, California (Sax et al. 2004). 

Mean outdoor 1,4-DCB concentrations were 2.0 μg/m3

 in 35 samples collected during the winter and 

3.5 μg/m3

 in 32 samples collected during the fall. Mean indoor 1,4-DCB concentrations were 40 μg/m3 in 

40 samples collected during the winter and 52 μg/m3

 in 32 samples during the fall. Personal air 

concentrations measured in Los Angeles were not reported in this study. Shendell et al. (2004) measured 

1,4-DCB concentrations ranging from not detected to 3.36 μg/m3

 in the air of 13 portable modular 

classroom structures and from not detected to 10 μg/m3

 in the air of 7 main building classrooms (Shendell 

et al. 2004). Mean and median 1,4-DCB concentrations in air from 3 urban communities in Minnesota 

(Battle Creek, East St. Paul, and Phillips) were measured to be 0.1 and 0.1 μg/m3

, respectively, in 

132 outdoor air samples, 1.2 and 0.2 μg/m3

, respectively, in 292 indoor air samples, and 3.2 and 

0.4 μg/m3

, respectively, in 288 personal air samples (Sexton et al. 2004). 

1,4-DCB has been detected in ambient air samples in several monitoring studies, as shown in Table 6-6. 

Kelly et al. (1994) reported that the median concentration of 1,4-DCB was below detection limits based 

on 1,447 samples collected from 57 different locations. MacLeod and Mackay (1999) reported a 

1,4-DCB background concentration of 3.36x10-5 ppm for the Southern Ontario, Canada region. The mean 

and median concentrations of 1,4-DCB in air from 25 sites across the state of Minnesota were 

3.36x10-5 and 2.55x10-5 ppm, respectively (Pratt et al. 2000). Concentrations were not quantifiable in 

rural air (Shah and Heyerdahl 1988), but increasingly higher concentrations were detected in suburban 

and urban air. Air samples from Mexicali, Mexico, a residential industrial area, contained 1,4-DCB with 

concentrations ranging from 6.0x10-5 to 2.22x10-2 ppm (mean=1.75x10-3 ppm), while air samples from 

Rosarito, Mexico, a beach resort town, contained 1,4-DCB with concentrations ranging from 2.0x10-5 to 

1.8x10-4 ppm (mean=8.0x10-5 ppm). Hartwell et al. (1992) reported that ambient outdoor concentrations 

of 1,4-DCB are considerably higher in the winter compared to the summer. The authors concluded that 

this effect may be due to reduced levels of sunlight in the winter, which would hinder atmospheric 

removal by photooxidation. Mean concentrations of 1,4-DCB in air, and in the vicinity of hazardous 

waste sites and sanitary landfill sites, generally average <4.2x10-3 ppm, but indoor air concentrations of 

1,4-DCB may be 1–3 orders of magnitude higher where 1,4-DCB is used as a space deodorizer or moth 

repellent (IARC 1982; Scuderi 1986; Wallace et al. 1986a, 1986b) (see Table 6-5). 

Concentrations of 1,4-DCB in workplace air were, not unexpectedly, the highest concentrations measured 

(IARC 1982), as shown in Table 6-7; concentrations ranged from 33–52 mg/m3 (5.4–8.7 ppm) detected in 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 300 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Levels of 1,4-Dichlorobenzene in Outdoor Air 

Concentration (ppm) 

Location Mean Median Maximum Range Reference 

Rural 0.00a Shah and 

Heyerdahl 1988 

Semi-rural 2.0x10-5– 1.7x10-4–4.6x10-3c Bozzelli and 

(NJ) 2.1x10-4b Kebbekeus 1979 

Suburban 4.8x10-5 Shah and 

Heyerdahl 1988 

Suburban 1.5x10-4 5.0x10-5– Delfino et al. 2003 

5.0x10-4 

Suburban 2.8x10-3 <1.66x10-4–2.8x10-3 Wallace et al. 1989 

Suburban 4.06x10-4 Bevan et al. 1991 

Urban 5x10-5 Shah and 

Heyerdahl 1988 

Urban (NJ) Harkov et al. 1984 

Summer 4x10-5–7x10-5d

 Winter 2x10-5d 

Urban (NJ) 6x10-5d 

5x10-5–6.6x10-4b

 4.3x10-4–2x10-2c Bozzelli and 

Kebbekeus 1979 

Urban (DC) 1.5x10-4 1.57x10-3 Hendler and Crow 

1992 

Urban 6.96x10-5 0.0–2.44x10-4 Fraser et al. 1998 

Urban 1.42x10-4 <2.0x10-4–1.3x10-3 Loscutoff and 

Poore 1993 

Urban 0.00–7.00x10-5 2.20x10-4 Zielinska et al. 

1998 

Urban 2.0x10-2 

2.9x10-1

 2.9x10-2 

1.0x101

 Grosjean 1991 

Urban 4.18x10-4 Bevan et al. 1991 

Hazardous 3x10-5–5.4x10-4b 4.2x10-3 Harkov et al. 1984 

waste sites 

(seven sites) 

Hazardous 

waste sites 

4x10-5–5.1x10-4b 

2x10-5–2.2x10-4e

 3.8x10-4–4.2x10-3c LaRegina et al. 

1986 

and sanitary 

landfill sites 

Waste dump 1.24x10-5–6.41x10-5 Nerin et al. 1996 

a

Level not quantifiable 

b

Range in arithmetic mean concentrations 

c

Range in maximum concentrations detected

d

Geometric mean 

e

Range in geometric mean concentrations 
DICHLOROBENZENES 301 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-7. Levels of 1,4-Dichlorobenzene Detected in Workplace Air 

Concentration (ppm) 

Occupation Maximum Range 

Monochlorobenzene manufacturing plant 8.7 5.4–8.7 

Abrasive-wheel plant 11.5 8–11.5 

Mothball manufacturing plant 25 9–25 

Chlorobenzene manufacturing plant 34 24–34 

1,4-Dichlorobenzene manufacturing plant 548 12–548 

Monochlorobenzene and dichlorobenzene manufacturing plant 724 – 

Source: IARC 1982 
 

 

 

DICHLOROBENZENES 302 

6. POTENTIAL FOR HUMAN EXPOSURE 

air sampled at a monochlorobenzene manufacturing facility to 4,350 mg/m3 (724 ppm) detected in air 

sampled at a plant manufacturing monochlorobenzene and DCB. 

1,2- and 1,3-DCB have also been detected in air samples from various locations, though at much lower 

concentrations than 1,4-DCB. Because these isomers are not used in household products to the extent that 

1,4-DCB is, they are not prevalent in indoor air. For example, mean indoor air concentrations in a 

ventilated office in London were approximately 3.5x10-3 ppm for 1,4-DCB compared to 1.4x10-4 ppm for 

1,2-DCB (Field et al. 1992). Mean indoor air concentrations of 1,2-DCB from residences in some 

California communities were 1.39x10-5 ppm during the winter and 3.48x10-6 ppm during the summer 

(Pellizzari et al. 1986). 1,3-DCB was detected in the air from a university art building where there is 

heavy use of printmaking solvents. Mean concentrations of 1,3-DCB were 0.4 μg/m3

 (median=0.8 μg/m3) 

on the studio floor and 0.8 μg/m3

 (median below 0.5–1.5 ppb) on a non-use floor (Ryan et al. 2002). 

Some studies have reported 1,3-DCB air sample concentrations in combination with 1,4-DCB 

concentrations. However, based the production volumes of these isomers, it is expected that these 

concentrations represent 1,4-DCB almost entirely. The concentrations of 1,2- and 1,3-DCB measured in 

ambient outdoor air are shown in Tables 6-8 and 6-9, respectively. Based on the data in these tables, 

ambient outdoor air concentrations generally range from 0.01 to 0.1 ppb for 1,2-DCB, and from 0.001 to 

0.1 ppb for 1,3-DCB. Concentrations of 1,2- and 1,3-DCB in workplace air were not located. 

6.4.2 Water 

DCBs have generally been detected at low concentrations in finished drinking water, surface water, and 

groundwater in the United States. Finished drinking water samples from 20 of the 113 cities monitored in 

the National Organics Monitoring Survey (NOMS) had levels of 1,4-DCB ranging from 0.01 to 1.54 ppb, 

with a median value of 0.03 ppb (Dressman et al. 1977), and the compound was detected in about 13% of 

finished drinking water supplies using surface water sources (Coniglio et al. 1980). 1,2-, 1,3- and 

1,4-DCB were reported in drinking water samples from three cities on Lake Ontario at concentrations 

ranging from not detectable (ND) to 2 ppt, from ND to 7 ppt, and from 8 to 20 ppt, respectively (Oliver 

and Nicol 1982a). DCB isomers were detected in 0–3% of drinking water samples from selected 

locations in New Jersey, North Carolina, and North Dakota locations (Wallace et al. 1986a). 

Concentrations of 1,3- and 1,4-DCB were generally <1 μg/L in treated and raw water samples taken from 

30 Canadian potable water treatment facilities that serve about 5.5 million consumers (Otson et al. 1982). 
 

 

 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 303 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-8. Levels of 1,2-Dichlorobenzene in Outdoor Air 

Concentration (ppm) 

Location Mean Median Maximum Range Reference 

Semi-rural (New Jersey) 2x10-5–2.4x10-4a 2.1x10-4– 

3.9x10-3b

 Bozzelli and 

Kebbekeus 1979 

Beach resort town 3.0x10-5 1.0x10-5– Zielinska et al. 2001 

8.0x10-5 

Background (Southern 1.28x10-6 MacLeod and 

Ontario) Mackay 1999 

25 Sites across Minnesota 1.62x10-5 1.28x10-5 2.44x10-5 Pratt et al. 2000 

Urban (New Jersey) Harkov et al. 1984 

Summer 1x10-5–3x10-5c

 Winter 3x10-5–6x10-5c 

Urban (New Jersey) 4.8x10-5c 

2x10-5–1.0x10-3a

 5.2x10-4– 

1x10-2b

 Bozzelli and 

Kebbekeus 1979 

Urban (seven U.S. cities) 4.0x10-6– 

2.60x10-5 

1.0x10-6– 

2.36x10-4 

Singh et al. 1981a, 

1981b 

Urban 2.0x10-5 1.0x10-5– Zielinska et al. 2001 

6.0x10-5 

Urban 8.6x10-5 <1.0x10-4– Loscutoff and Poore 

6.0x10-4 1993 

Urban 0.0d

–8.80x10-4 1.02x10-3 Zielinska et al. 1998 

Urban 1.0x10-3– 

1.3x10-1 

1.7x10-3– 

3.1x10-1d 

 Grosjean 1991 

5.6x10-2 6.6x10-1

Hazardous waste sites and 

sanitary landfill sites 

6x10-5–7.7x10-4a 

2x10-5–2.3x10-4e

 6.9x10-4– 

8.4x10-3b 

LaRegina et al. 1986 

Waste dump 1.58x10-5– 

9.13x10-5 

Nerin et al. 1996 

a

Range in arithmetic mean concentrations 

b

Range in maximum concentrations detected 

c

Geometric mean 

d

Level not quantifiable 

e

Range in geometric mean concentrations 
 

 

 

 

 

 

 

 

DICHLOROBENZENES 304 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-9. Levels of 1,3-Dichlorobenzene in Outdoor Air 

Concentration (ppm) 

Location Mean Median Maximum Range Reference 

Beach resort town 0.00a Zielinska et al. 2001 

Background (Southern 1.39x10-6 MacLeod and 

Ontario) Mackay 1999 

25 Sites across 2.55x10-5 1.28x10-5 9.87x10-4 Pratt et al. 2000 

Minnesota 

Urban (seven U.S. 

cities) 

4.0x10-6–8.7x10-6 1.0x10-6– 

4.7x10-5 

Singh et al. 1981a, 

1981b 

Urban 0.00a Zielinska et al. 2001 

Urban 1.01x10-4 <2.0x10-4– Loscutoff and Poore 

3.0x10-4 1993 

Urban 0.0a

–8.80x10-4 1.02x10-3 Zielinska et al. 1998 

Urban 4.0x10-3–7.7x10-2 

8.3x10-2

 9x10-3–1.5x10-1b 

2.2 

 Grosjean 1991 

Waste dump 1.43x10-6– 

6.70x10-6 

Nerin et al. 1996 

a

Level not quantifiable 

b

Range in maximum concentrations detected 
 

 

DICHLOROBENZENES 305 

6. POTENTIAL FOR HUMAN EXPOSURE 

During a national groundwater supply survey, 1,4-DCB was detected in 2 out of 280 (0.7%) random 

sample sites serving <10,000 persons and in 3 out of 186 (1.6%) random sample sites serving 

>10,000 persons above a quantitation limit of 0.5 μg/L (Westrick et al. 1984). The mean positive 

concentration and maximum value were 0.60 and 0.68 μg/L, respectively, for the sites serving 

<10,000 persons and 0.66 and 1.3 μg/L, respectively, for the sites serving >10,000 persons. 1,2- and 

1,3-DCB were not detected above the quantitation limit (0.5 μg/L) in any of the random samples. 

1,4-DCB was detected above 0.5 μg/L in 4 out of 321 (1.2%) nonrandom sample sites serving 

<10,000 persons with a median positive concentration of 0.74 μg/L and a maximum value of 0.90 μg/L. 

This compound was not detected above 0.5 μg/L in 158 nonrandom sample sites serving >10,000 persons. 

1,2-DCB was detected above 0.5 μg/L in 1 out of 321 (0.3%) nonrandom sample sites serving 

<10,000 persons at a concentration of 2.2 μg/L and in 1 out of 158 (0.6%) nonrandom sample sites 

serving >10,000 persons at a concentration of 2.7 μg/L. 1,3-DCB was not detected above 0.5 μg/L in any 

of the nonrandom samples. Stackelberg et al. (2001) detected 1,2-, 1,3-, and 1,4-DCB in approximately 8, 

4, and 8%, respectively, of samples collected from 30 public supply wells in southern New Jersey. 

Concentrations or limits of detection were not reported. 1,4-DCB had two detections at concentrations 

that were both below a laboratory reporting limit of 0.05 μg/L in samples from 178 active public supply 

wells in the Los Angeles physiographic basin (Shelton et al. 2000). 1,2- and 1,3-DCB were analyzed for, 

but were not detected in any of the samples from these wells. The laboratory reporting limits used for 

1,2-DCB were 0.031 and 0.048 μg/L. The laboratory reporting limits used for 1,3-DCB were 0.03 and 

0.054 μg/L. 

1,2-DCB was detected in 0.6% of 1,077 surface water samples recorded in the STORET database at a 

median concentration of <10 ppb (Staples et al. 1985). 1,3-DCB was detected in 0.3% of 986 surface 

water samples recorded in the STORET database at a median concentration of <10 ppb. 1,4-DCB was 

detected in 3% of 8,576 surface water samples recorded in the STORET database at a median 

concentration of <0.1 ppb. 1,4-DCB was detected in 100% of 91 surface water samples from the Great 

Lakes at mean concentrations ranging from 0.28 ppt in Lake Huron to 1.5 ppt in Lake Ontario (IJC 1989). 

Oliver and Nicol (1982a) also reported concentrations of DCBs in water samples collected from the Great 

Lakes region. Mean 1,2-DCB concentrations were 5 ppt (range, 2–7 ppt) in samples from Lake Ontario 

and 6 ppt (range, ND–31 ppt) in samples from the Grand River. 1,2-DCB was not detected in samples 

from Lake Huron. Mean 1,3-DCB concentrations were 1 ppt (range, ND–4 ppt) in samples from the 

Grand River. 1,3-DCB was not detected in samples from Lake Ontario or Lake Huron. Mean 1,4-DCB 

concentrations were 45 ppt (range, 33–64 ppt) in samples from Lake Ontario, 4 ppt (range, 3–6 ppt) in 

samples from Lake Huron, and 10 ppt (range, ND–42 ppt) in samples from the Grand River. During a 
 

 

DICHLOROBENZENES 306 

6. POTENTIAL FOR HUMAN EXPOSURE 

study of contaminants in 139 streams located in 30 states, 1,4-DCB was detected in 25.9% of samples in 

which it was searched for, with a median concentration of 0.09 μg/L and a maximum concentration of 

4.3 μg/L (Kolpin et al. 2002). 

Concentrations of 1,2-, 1,3- and 1,4-DCB from the Niagara River sampled in 1980 ranged from ND to 

56 ppt, from ND to 56 ppt, and from 1 to 94 ppt. The highest concentration of 1,2- and 1,4-DCB 

occurred just below a chemical manufacturing plant’s effluent discharge, while the highest concentration 

of 1,3-DCB occurred just below a waste disposal dump (Oliver and Nicol 1982a). 1,2-, 1,3-, and 

1,4-DCB were also reported in waste water effluent samples collected from four plants on the Great 

Lakes at mean concentrations of 13 ppt (range, 6–22 ppt), 14 ppt (range, 7–13 ppt), and 660 ppt (range, 

484–920 ppt) (Oliver and Nicol 1982a). In a New Jersey survey, 1,2-, 1,3- and 1,4-DCB were detected in 

3, 4, and 6%, respectively, of 463 surface water samples (Page 1981). Maximum concentrations were 

8.2 ppb for 1,2-DCB, 242 ppb for 1,3-DCB, and 31 ppb for 1,4-DCB. DCBs have been reported in 

surface waters in the vicinity of hazardous waste sites at unspecified concentrations (Elder et al. 1981) 

and at a concentrations of 9 ppt (1,2-DCB), 18 ppt (1,3-DCB), and 52 ppt (1,4-DCB) (Oliver and Nicol 

1982a). 

DCBs were monitored in wetland-treated leachate water at a municipal solid waste landfill site in central 

Florida from 1989 to 1990 and from 1992 to 1993 (Chen and Zoltek 1995). During the first sampling 

period, surface water samples contained 1,2-DCB at concentrations ranging from 0.02 to 0.10 ppb, 

1,3-DCB at concentrations ranging from 0.02 to 0.10 ppb, and 1,4-DCB at concentrations ranging from 

0.04 to 0.13 ppb. Groundwater samples contained 1,2-DCB at concentrations ranging from 0.09 to 

1.56 ppb, 1,3-DCB at concentrations ranging from 0.08–8.95 ppb, and 1,4-DCB at concentrations ranging 

from 0.08 to 10.71 ppb. During the second sampling period (1992–1993), the three DCB isomers were 

not detected in surface water samples. 1,2- and 1,4-DCB were each detected in two groundwater samples 

at concentrations ranging from 0.75 to 0.84 ppb and from 0.45 to 3.74 ppb, respectively. 1,3-DCB was 

not detected in groundwater samples collected during the second sampling period. No detection limits 

were given. DCB (isomers unspecified) was detected in a study of three landfills in central Florida 

(Hallbourg et al. 1992). These authors reported DCB concentration ranges in groundwater of 0.37–21.2, 

6–46.4, and <1–7.4 μg/L (ppb) at three different landfill sites. Plumb (1991) reported that 1,2-, 1,3-, and 

1,4-DCB were detected in groundwater collected at 36, 16, and 34 of 479 hazardous waste sites, 

respectively. This author reported that 1,2-DCB was detected in 240 samples collected from 36 sites in 

9 of the 10 EPA regions, 1,3-DCB was detected in 82 samples collected from 16 sites in 8 of the 10 EPA 

regions, and 1,4-DCB was detected in 191 samples collected from 34 sites in 9 of the 10 EPA regions. 
DICHLOROBENZENES 307 

6. POTENTIAL FOR HUMAN EXPOSURE 

Untreated, ambient groundwater samples from 406 urban wells and 2,542 rural wells from across the 

conterminous United States were collected between 1985 and 1995 as a part of the National WaterQuality Assessment Program (NAWQA) of the U.S. Geological Survey (Squillace et al. 1999). 1,2-DCB 

was detected in 1.4% of the urban well samples with a median concentration of approximately 0.2 μg/L 

(range 0.2–100 μg/L). This compound was detected in 0.2% of the rural well samples with a median 

concentration of approximately 1 μg/L (range 0.3-5 μg/L). 1,4-DCB was detected in 1.8% of the urban 

well samples with a median concentration of approximately 1 μg/L (range 0.3–50 μg/L). It was detected 

in 0.2% of the rural well samples with a median concentration of approximately 1.5 μg/L (range 0.6– 

8 μg/L). 1,3-DCB was not included in this study. Similar results were reported by Moran et al. (2004) in 

a summary of 1985-1999 NAWQA monitoring data involving chemical concentrations measured in 

1,926 rural private wells. 1,2- and 1,3-DCB were not detected at all, while 1,4-DCB was detected in only 

1 out of 1,925 samples at a concentration of 1.2 μg/L. 1,2-, 1,3-, and 1,4-DCB were detected in 

approximately 25, 15, and 10%, respectively, of samples collected from 95 monitoring wells in southern 

New Jersey, respectively (Stackelberg et al. 2001). Concentrations or limits of detection were not 

reported. In a separate New Jersey survey, 1,2-, 1,3-, and 1,4-DCB were detected in 3, 2, and 3 of 

685 groundwater samples (Page 1981). Maximum concentrations were 6,800 ppb for 1,2-DCB, 237 ppb 

for 1,3-DCB, and 995 ppb for 1,4-DCB. 1,4-DCB had a frequency of detection of approximately 10% 

and a maximum concentration of 1.7 μg/L in groundwater samples from 29 alluvial wells beneath the 

Denver, Colorado area (Bruce and McMahon 1996). The authors also analyzed for 1,3-DCB, although it 

was not detected above the minimum detection level (0.2 μg/L) in any of the samples. 1,3-DCB was 

detected in two groundwater samples from five developing urban sites in the Upper Colorado River Basin 

with an estimated maximum concentration of 0.01 μg/L (Apodaca et al. 2002). 

6.4.3 Sediment and Soil 

Little information on soil concentrations of DCBs was located for the United States. One study 

conducted in England, however, reported DCB concentrations in agricultural soils increased during the 

1960s, corresponding to a period of increased production of chlorobenzene compounds (Wang et al. 

1995). The mean 1,4-DCB soil concentration reported for agricultural land was 2.17 ppb in 1942, 

0.75 ppb in 1951, 1.73 ppb in 1960, 9.82 ppb in 1967, 3.9 ppb in 1972, 3.06 ppb in 1980, 1.4 ppb in 1984, 

and 0.4 ppb in 1991. The mean 1,3-DCB soil concentration was 0.20 ppb in 1960, 0.31 ppb in 1967, 

0.36 ppb in 1972, and 0.30 ppb in 1980. 1,3-DCB soil concentrations were below the detection limit 

(0.2 ppb) in 1942, 1951, 1984, and 1991. 1,2-DCB soil concentrations were below the detection limit 
 

 

DICHLOROBENZENES 308 

6. POTENTIAL FOR HUMAN EXPOSURE 

(0.2 ppb) during all 8 sampling years. It should be noted that 1,4-DCB has been reported to occur in soils 

as a result of lindane degradation (EPA 1980a; IARC 1982), so the detection of 1,4-DCB may not be 

indicative of 1,4-DCB disposal per se. 

1,2-DCB was detected in 0.9% of 352 sediment samples, 1,3-DCB was detected in 0.3% of 357 sediment 

samples, and 1,4-DCB was detected in 2% of 357 sediment samples recorded on the STORET database 

(Staples et al. 1985). DCBs have been detected in sediments near hazardous waste sites (Elder et al. 

1981; Hauser and Bromberg 1982). During a study of semivolatile organic compounds in streambed 

sediment, 1,2-DCB was detected in 0.6% of samples collected at 516 sites from 20 major river basins in 

the United States during 1992–1995 with a maximum concentration of 86 μg/kg (95th percentile, 

<50 μg/kg) (Lopes and Furlong 2001). 1,4-DCB was detected in 1.2% of samples collected at 518 sites 

with a maximum concentration of 140 μg/kg (95th percentile, <50 μg/kg). 1,3-DCB was not detected in 

samples collected from 516 sites. The concentrations of 1,2- and 1,4-DCB were both <100 μg/kg in 

streambed sediment samples from 9 out of 14 river sites in the New England Coastal Basin (USGS 2002). 

Both of these compounds were at concentrations below the minimum reporting level (50 μg/kg) in 

samples from the remaining five river sites. Redmond et al. (1996) detected 1,2-, 1,3-, and 1,4-DCB at 

concentrations up to 4.4, 7.2, and 3.6 mg/kg, respectively, in the sediment of the Calcasieu River estuary, 

Louisiana. 

Oliver and Nicol (1982a) reported DCB concentrations in surficial sediments from 13 sites in Lake 

Superior, 42 sites in Lake Huron, 5 sites in Lake Erie, and 11 sites in Lake Ontario. Mean 1,2-DCB 

concentrations detected were 1 ppb (range, ND–1 ppb), 8 ppb (range, ND–56 ppb), 2 ppb (range, 1– 

4 ppb), and 11 ppb (range, 4–27 ppb) for Lakes Superior, Huron, Erie, and Ontario, respectively. Mean 

1,3-DCB concentrations detected were 2 ppb (range, ND–7 ppb), 2 ppb (range, ND–14 ppb), 4 ppb 

(range, 1–9 ppb), and 74 ppb (range, 15–250 ppb) for Lakes Superior, Huron, Erie, and Ontario, 

respectively. Mean 1,4-DCB concentrations detected were 5 ppb (range, ND–9 ppb), 16 ppb (range, 2– 

100 ppb), 9 ppb (range, 3–20 ppb), and 94 ppb (range, 22–210 ppb) for Lakes Superior, Huron, Erie, and 

Ontario, respectively. These authors also reported detecting DCB concentrations in deep sediment layers 

in Lake Ontario from core samples from the Niagara Basin. Concentrations of 1,2-DCB in various depths 

of the sediment cores were as follows: 14 ppb (0–1 cm), 15 ppb (1–2 cm), 19 ppb (2–3 cm), 16 ppb (3– 

4 cm), 26 ppb (4–5 cm), 13 ppb (5-6 cm), and 2 ppb (6–7 cm). Concentrations of 1,3-DCB in various 

depths of the sediment cores were as follows: 240 ppb (0–1 cm), 330 ppb (1–2 cm), 190 ppb (2–3 cm), 

48 ppb (3–4 cm), 38 ppb (4–5 cm), 17 ppb (5–6 cm), and 4 ppb (6–7 cm). Concentrations of 1,4-DCB in 

various depths of the sediment cores were as follows: 110 ppb (0–1 cm), 120 ppb (1–2 cm), 88 ppb (2– 
DICHLOROBENZENES 309 

6. POTENTIAL FOR HUMAN EXPOSURE 

3 cm), 230 ppb (3–4 cm), 88 ppb (4–5 cm), 29 ppb (5-6 cm), and 17 ppb (6–7 cm). None of the DCBs 

were detected in the 7–8 cm sediment core. Chapman et al. (1996a, 1996b) also reported detecting 

1,4-DCB in sediments collected around the diffuser of a large marine municipal sewage discharge outfall 

at Macaulay Point in Victoria, Canada. Sediment quality guidelines are set by the government to protect 

indigenous sediment-dwelling organisms. 1,4-DCB was detected at concentrations exceeding sediment 

quality guidelines (110 μg/kg [ppb] dry weight) and showed a distinctive concentration gradient, which 

peaked at the outfall at concentrations up to 1,710 ppb dry weight and decreased with increasing distance 

from the outfall. The authors attributed the source of the 1,4-DCB in the relatively untreated municipal 

sewage effluent to the extensive use of toilet block deodorizers. 

In a recent study conducted in England, Wang and Jones (1994b) analyzed the chlorobenzene content of 

contemporary sewage sludge collected from 12 waste water treatment plants. Most of the plants surveyed 

received waste water from urban and industrial effluent and all of the sewage-treatment plants used 

primary treatment. 1,2- and 1,4-DCB were detected in 100% of the samples tested. 1,3-DCB was 

detected in 75% of the samples tested. Concentrations of 1,2-DCB ranged from 71.3 to 4,110 μg/kg (ppb) 

dry weight (3.57–152 ppb wet weight). For 1,2-DCB, the mean and median concentrations for the 

12 plants were 877 and 237 ppb (dry weight), respectively. The authors reported that except for the 

monochlorobenzenes, 1,2-DCB had the highest concentration in the industrial sludges. This was believed 

to be the result of industrial uses of 1,2-DCB as a solvent, cleaner, degreaser, polish, and deodorant. 

Concentrations of 1,3-DCB ranged from below the detection limit to 467 μg/kg (ppb) dry weight (from 

below the detection limit to 13.5 ppb wet weight). For 1,3-DCB, the mean and median concentrations for 

the 12 plants were 82.3 and 30 ppb (dry weight), respectively. Concentrations of 1,4-DCB ranged from 

561 to 2,320 μg/kg (ppb) dry weight (21.9–187 ppb wet weight). For 1,4-DCB, the mean and median 

concentrations for the 12 plants were 1,310 and 1,250 ppb (dry weight), respectively. The authors also 

reported that 1,4-DCB was the most abundant compound detected (exclusive of the monochlorobenzenes) 

and was detected at higher concentrations in the urban sludges compared to the sludges dominated by 

industrial sources. The authors believe that this was a result of the extensive use of the compound in 

moth repellent crystals, insecticides, germicides, and space deodorants. Since 1,4-DCB also has industrial 

uses, the absolute content of this compound was not lower in the industrial sludges as compared to the 

urban sludges. The authors also found that the 1,4-DCB content and that of other chlorobenzene 

compounds in sewage sludges from the same treatment plant were consistent over time. Wang et al. 

(1995) further reported that at a site in Woburn, England, sewage sludge applied to agricultural land from 

1942 to 1961 contained 1,2-DCB concentrations of ND to 126 ppb (mean, 17.4 ppb; median, 6.60 ppb), 

1,3-DCB concentrations of ND to 101 ppb (mean, 17.4 ppb; median, 6.60 ppb), and 1,4-DCB 
DICHLOROBENZENES 310 

6. POTENTIAL FOR HUMAN EXPOSURE 

concentrations of 7.76–71.8 ppb (mean, 29.8 ppb; median, 25.5 ppb). These authors found that while 

concentrations of the other chlorobenzenes remained stable during the 1960s after the sludge applications 

were halted in 1961, the concentrations of 1,4-DCB in both the sludge-amended and control soils actually 

increased. The authors concluded that the 1,4-DCB could have increased in both soil plots as a result of 

pesticide applications since 1,4-DCB was often found as an impurity in many organochlorine pesticides 

or by atmospheric deposition of airborne emissions from industrial facilities or municipal waste 

incinerators. 

6.4.4 Other Environmental Media 

DCBs have been detected in meat, poultry, fish, and other types of foodstuffs. Pork meat has reportedly 

been tainted with a disagreeable odor and taste as a result of the use of deodorant blocks in pig stalls 

(EPA 1980a; IARC 1982). Eggs also have been similarly tainted after hens were exposed to 20– 

30 mg/m3 (3.3–5.0 ppm) of 1,4-DCB (IARC 1982). 1,4-DCB was detected in 69 out of 234 table-ready 

food items from the FDA’s total diet study at concentrations ranging from 4.26 to 114 ppb 

(mean=10.7 ppb) (Heikes et al. 1995). 1,2-DCB was detected in 45 of the 234 food items at 

concentrations ranging from 7.80 to 24.4 ppb (mean=9.47 ppb). 1,3-DCB was detected in 6 of the food 

items at concentrations ranging from 5.31 to 9.76 ppb (mean=7.36). The highest level food items were 

chocolate chip cookies (1,4-DCB), cake doughnuts (1,2-DCB), and sandwich cookies (1,3-DCB). Page 

and Lacroix (1995) detected 1,4-DCB in both noncitrus based soft drinks and 10% butterfat cream at 

0.1 μg/kg during a study of contaminants in Canadian foods. 1,4-DCB concentrations in different brands 

of butter, margarine, and peanut butter were 1.3–2.7, 12.2–14.5, and 1.2–8.8 μg/kg, respectively. Flour 

contained 1,2-DCB at 1.1 μg/kg and 1,4-DCB at 7.3 μg/kg, while pastry mix contained these isomers at 

concentrations of 1.0 and 22.0 μg/kg, respectively. Fresh food composites grown in Ontario, Canada 

were tested for the presence of DCBs (detection limits=0.0001 μg/g) as well as other contaminants 

(Davies 1988). Only 1,3-DCB was detected in fruit and root vegetables at concentrations of 0.0044 and 

0.0011 μg/kg, respectively, while 1,2-DCB was the only isomer detected in the eggs/meat food group at a 

concentration of 0.0018 μg/kg. Both 1,3- and 1,4-DCB were detected in milk at concentrations of 

0.00014 and 0.00055 μg/kg, respectively. None of the DCBs in this study were detected in leafy 

vegetables. The concentrations of 1,4-DCB in retail vegetables from the United Kingdom were 

0.198 μg/kg (carrot cores), 0.416 μg/kg (carrot peels), 0.224 μg/kg (potato peels), 0.214 μg/kg 

(cauliflower stems), 0.529 μg/kg (cauliflower flowers), 0.237 μg/kg (inner lettuce leaves), and 

0.118 μg/kg (outer lettuce leaves) (Wang and Jones 1994d). 1,2- and 1,3-DCB were detected only in 

potato cores at 0.328 and 0.096 μg/kg, respectively. 
DICHLOROBENZENES 311 

6. POTENTIAL FOR HUMAN EXPOSURE 

All three DCB isomers were detected in lake and rainbow trout from the Great Lakes at concentrations 

ranging from 0.3 to 1 ppb for 1,2-DCB, from 0.3 to 3 ppb for 1,3-DCB, and from 1 to 4 ppb for 1,4-DCB, 

(Oliver and Nicol 1982a). DCBs were detected in biota collected in the vicinity of an industrial outfall in 

the Calcasieu River estuary, Louisiana (Pereira et al. 1988). The concentrations of 1,2-, 1,3-, and 

1,4-DCB in catfish ranged from not detected to 0.11 ppm, from 0.03 to 0.19 ppm, and from 0.17 to 

0.47 ppm, respectively. The concentrations of DCBs in Atlantic croakers, blue crabs, spotted sea trout, 

and blue catfish collected from the Calcasien River estuary were 0.08, 0.26, 0.06, and 0.06 ppm, 

respectively for 1,2-DCB, 0.19, 0.356, 0.09, and 0.12 ppm, respectively, for 1,3-DCB, and 0.24, 0.60, 

0.90, and 2.5 ppm, respectively, for 1,4-DCB. Chung (1999) detected 1,4-DCB in the leg meat, body 

meat, and carapace meat of Charybdis feriatus, a popularly consumed edible crab in Asia, at concentrations of 0.5, 0.6, and 5.1 ppm, respectively. DCBs were detected in the edible tissue of various species 

of trout, nase, whiting, mullet, and pilichard fresh water fish from rivers in Slovenia and the Gulf of 

Triest, Yugoslavia (Jan and Movnersic 1980). 1,4-DCB concentrations in these fish ranged from trace to 

0.45 ppb, while 1,2-DCB concentrations ranged from trace to 1.14 ppb. The mean upper limit of 

1,4,-DCB concentrations detected in livers of flatfish (Dover sole) collected off Los Angeles, California, 

was <77 ppb wet weight; the mean upper limit of concentrations found in muscle tissue was <7 ppb 

(Young and Heesen 1978). 1,2-DCB was also detected in these fish at mean liver concentrations at or 

below 4.0 ppb (Young et al. 1980). Concentrations of 1,4-DCB reported in mackerel from Japanese 

coastal water ranged up to 0.05 ppm wet weight (50 ppb) (EPA 1980a; IARC 1982). Jori et al. (1982) 

reported that 1,4-DCB has been detected in carp at 0.1 ppm and in farmed fish at 0.04 ppm. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Inhalation is the predominant route of exposure to DCBs for the general population. According to data 

from the TEAM study, which includes exhaled breath measurements from about 800 individuals, 

1,4-DCB was found in 44–100% of air and breath samples from several U.S. locations, and indoor air 

levels were up to 25 times higher than ambient outdoor levels for DCB (1,3- and 1,4-DCB) (Wallace et al. 

1986b). Mean concentrations of 1,3- and 1,4-DCB measured together in breath samples collected in New 

Jersey and California ranged from 2.9 to 8.1 μg/m3 (Wallace 1986b). Median concentrations of these 

isomers in breath samples from New Jersey, California, North Dakota, and North Carolina ranged from 

0.3 to 1.3 μg/m3 (Wallace et al. 1987, 1996). 1,2-DCB was detected above quantifiable limits (0.2– 

2 μg/m3

) in only 2% of the breath samples collected in New Jersey (Wallace et al. 1986c). Mean 

1,2-DCB concentrations ranged from 0.08 to 0.1 μg/m3 in breath samples collected in California (Wallace 
DICHLOROBENZENES 312 

6. POTENTIAL FOR HUMAN EXPOSURE 

et al. 1988). The EPA has estimated that adult exposure to 1,4-DCB is about 35 μg/day, based on a mean 

ambient air concentration of 1.6 μg/m3 (0.27 ppb) (EPA 1985a). In a separate study, average intake 

values for persons exposed to 1,2- and 1,3-DCB were estimated to be 1.8 and 0.8 μg/day, respectively, 

based on the concentrations of these substances in ambient outdoor air samples from seven large cities in 

the United States and a total air intake of 23 m3

/day (Singh et al. 1981a, 1981b). Inhalation exposure to 

1,4-DCB may be considerably higher indoors where space deodorants or moth repellents that contain this 

chemical are used. Indoor inhalation exposure of the general population to 1,2- or 1,3-DCB is not 

expected to be important since these substances are not used in household and consumer products to the 

extent that 1,4-DCB is. However, one study reported that 1,3-DCB was detected in the air from a 

university art building where there is heavy use of printmaking solvents. Mean concentrations of 

1,3-DCB were 0.4 μg/m3

 (median=0.8 μg/m3) on the studio floor and 0.8 μg/m3 (median below 

0.5-1.5 ppb) on a non-use floor (Ryan et al. 2002). During this study, mean and median personal 

exposure concentrations for this compound were 2.0 and 2.3 μg/m3

, respectively. 

Because water and food concentrations of DCBs are generally quite low, exposure from sources other 

than air is unlikely to be important. For example, drinking water containing 0.1 ppb 1,4-DCB would 

provide an additional intake of only 0.2 μg per day for an adult drinking 2 L of water per day. In the past, 

concentrations of all three DCB isomers have been detected in some freshwater fish from the Great Lakes 

region (Oliver and Nicol 1982a). In addition, concentrations of 1,2- and 1,4-DCB have been found in 

marine fishes, especially in areas near effluent discharges (Young and Heesen 1978; Young et al. 1980). 

However, more recent information on concentrations in edible fish and shellfish tissues is lacking. 

Results of the National Human Adipose Tissue Survey (NHATS) conducted in 1982, which estimated the 

general population exposure to toxic organic chemicals, found that 1,4-DCB was detected in 100% of 

46 composite human adipose tissue specimens analyzed at levels ranging from 12 to 500 ppb while 

1,2-DCB was detected in 63% of the 46 specimens at levels ranging from <0.1–2 ppb (EPA 1986f, 

1989d). These measurements indicate widespread exposure of the general population to DCBs. Using 

the same data, ranks for each of the 9 census regions were assigned according to the composite sample 

concentrations for 1,2- and 1,4-DCB or the means of multiple composite sample concentrations (Phillips 

and Birchard 1991). These authors reported that exposure to 1,4-DCB was highest for children (aged 0– 

14 years) living in the west south central (Arkansas, Louisiana, Oklahoma, and Texas), east south central 

(Kentucky, Tennessee, Alabama, and Mississippi), and south Atlantic regions (Delaware, Maryland, the 

District of Columbia, Virginia, West Virginia, North Carolina, South Carolina, Georgia, and Florida); for 

15- to 44-year-olds, exposure was highest in the south Atlantic, middle Atlantic (New Jersey, New York, 
DICHLOROBENZENES 313 

6. POTENTIAL FOR HUMAN EXPOSURE 

and Pennsylvania), and east north central regions (Illinois, Indiana, Michigan, Ohio, and Wisconsin); and 

for adults 45 years and older, exposure was highest nationally in the east south central, west south central, 

and east north central regions. Exposure to 1,2-DCB was highest for children (0–14 years) living in the 

New England (Maine, New Hampshire, Vermont, Massachusetts, Rhode Island, and Connecticut), east 

north central, and west north central regions (Minnesota, Iowa, Missouri, Nebraska, Kansas, North 

Dakota, and South Dakota); for 15- to 44-year-olds, exposure was highest in the New England, mid 

Atlantic, and Pacific regions (California, Hawaii, Washington, Oregon, and Alaska); and for adults 

45 years and older, exposure was highest nationally in the mid Atlantic, west north central, and west south 

central regions. 

Table 6-10 summarizes concentrations of 1,4-DCB in blood samples from various studies. Morita and 

Ohi (1975) found that 1,4-DCB was present in all 34 adipose tissue and 6 blood samples taken from 

residents of the Tokyo, Japan metropolitan area. 1,4-DCB concentrations in the adipose tissue samples 

ranged from 0.2 to 11.7 ppm in the adipose tissue samples with an average concentration of 2.3 ppm and 

from 4 to 16 ng/ml (ppb) in the blood samples with an average concentration of 9.5 ng/mL (ppb). 

1,2-DCB was detected in paired blood and biopsy fat samples obtained from 25 patients (7 male and 

18 female) from British Columbia, Canada (Mes 1992). Median concentrations in whole blood, biopsy 

fatty tissue, blood lipids, and adipose tissue were <3.12, 28.1, <3, and 38 ppb, respectively. Maximum 

concentrations of 1,2-DCB in these media were 14.29, 154.5, 20,005, and 194 ppb, respectively. 

Concentrations of 1,4-DCB in blood samples of 48 individuals in Alaska during February 1995 ranged 

from below the limit of detection (0.040 ppb) to 7.10 ppb with median values ranging from 0.02 to 

0.04 ppb (Backer et al. 1997). During the Third National Health and Nutrition Evaluation Survey 

(NHANES III), 1,4-DCB was detected in 94.6% of 1,100 blood samples at a median concentration of 

0.33 μg/L and a 95th percentile value of 9.2 μg/L (Buckley et al. 1997). Blood samples collected from 

July 1995 to May 1997 during the National Human Exposure Assessment Survey (NHEXAS) in EPA 

Region 5 (Minnesota, Wisconsin, Michigan, Illinois, Indiana, and Ohio) contained 1,4-DCB (Pellizzari et 

al. 2001). It was detected in approximately 80 out of 145 samples with a median concentration of 

0.10 ppb, an arithmetic mean concentration of 0.38 ppb, and a maximum concentration of 45 ppb 

(Bonanno et al. 2001). Ashley et al. (1994, 1996) reported a mean blood level of 1,4-DCB of 1.9 ppb 

(median 0.33 ppb) in 1,037 samples collected from a reference group of nonoccupationally exposed 

individuals. Concentrations of VOCs in blood samples from a group of 126 nonsmokers and 42 smokers 

were also studied (Ashley et al. 1995). These authors found that mean 1,4-DCB blood levels were 

3.2 ng/L (ppb) (median, 0.45 ppb; range ND–96 ppb) for nonsmokers and 2.2 ppb (median, 0.47 ppb; 
 

 

DICHLOROBENZENES 314 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Concentrations of 1,4-Dichlorobenzene in Blood Samples 

Test subjects Range (ppb) Median (ppb) Mean (ppb) Reference 

British Columbia, Canada ≤14.29 <3.12 Mes 1992 

(n=25) 

Alaska, United States <0.040a

–7.10 0.02–0.04 Backer et al. 1997 

(n=48) 

NHANES III (n=1,100) 0.33 Buckley et al. 1997 

EPA Region 5 (n=145) ≤45 0.10 0.38 Pellizzari et al. 2001 

Non-occupationally 0.33 1.9 Ashley et al. 1994, 1996 

exposed individuals 

(n=1,037) 

Nonsmokers (n=126) ND–96 0.45 3.2 Ashley et al. 1995 

Smokers (n=42) ND–17 0.47 2.2 Ashley et al. 1995 

Residents of the Love 0.15–68 EPA 1985a 

Canal area, Niagara Falls, 

New York 

World Trade Center 0.274 Edelman et al. 2003 

firefighters present during 

the collapse (n=148) 

World Trade Center 0.289 Edelman et al. 2003 

firefighters arriving within 

2 days of the collapse 

(n=142) 

World Trade Center 0.343 Edelman et al. 2003 

special operations 

command individuals 

(n=95) 

Other World Trade Center 0.231 Edelman et al. 2003 

firefighters 

SHIELD—children in 0.21 4.22 Sexton et al. 2005 

Minneapolis, Minnesota 

(n=134) 

Adults in the United States ≤49 0.33 2.1 Hill et al. 1995 

(n=1,000) 

a

Below the limit of detection 
 

 

DICHLOROBENZENES 315 

6. POTENTIAL FOR HUMAN EXPOSURE 

range, ND–17 ppb) for smokers. Blood levels of 1,4-DCB were not dependent on whether the subject 

was from the smoking or control group. All three DCB isomers have been detected in blood samples 

from residents of the Love Canal area in Niagara Falls, New York (IARC 1999). DCB concentrations in 

blood samples from nine Love Canal residents ranged from 0.15 to 68 ppb (EPA 1985a). 1,4-DCB 

concentrations (geometric mean) in blood samples collected from firefighters responding to the World 

Trade Center fire and collapse were 0.274 μg/L for 148 firefighters who were present during the collapse 

and 0.289 μg/L for 142 firefighters who arrived after the collapse (within 2 days) (Edelman et al. 2003). 

The mean concentrations in the blood of 95 special operations command individuals were 0.343 μg/L 

compared to 0.231 μg/L in the blood of other firefighters. 

Hill et al. (1995) analyzed both blood and urine samples of 1,000 adults in the United States. These 

authors reported that 96% of the individuals in the study had detectable concentrations of 1,4-DCB in 

their blood and 98% had detectable concentrations of 2,5-dichlorophenol (the metabolite of 1,4-DCB) in 

their urine. 1,4-DCB levels in the blood ranged up to 49 μg/L (ppb), with median and mean 

concentrations of 0.33 ppb and 2.1 ppb, respectively. Urinary 2,5-dichlorophenol concentrations ranged 

up to 8,700 μg/L (ppb), with median and mean concentrations of 30 ppb and 2,000 ppb, respectively. 

There was a highly significant correlation (p<0.0001) between 2,5-dichlorophenol in the urine and 

1,4-DCB in the blood. The authors concluded that 1,4-DCB is a common, worldwide environmental 

contaminant. Metabolites of 1,2-DCB (2,3- and 3,4-dichlorophenol and 3,4- and 4,5-dichlorocatechol) 

have been detected in the urine of chemical factory workers at unspecified concentrations (Kumagai and 

Matsunaga 1995, 1997). These workers had been exposed to 1,2-DCB used as a solvent during the work 

shift prior to sample collection. 

DCB (all isomers) was identified in 100% of 42 samples of human breast milk collected in five urban 

areas of the United States at concentrations of 0.04–68 ppb (Erickson et al. 1980). DCB (all isomers) was 

identified in human breast milk in 8 of 12 women who were residents of Bayonne, New Jersey 

(6 women), Jersey City, New Jersey (2 women), Bridgeville, Pennsylvania (2 women), and Baton Rouge, 

Louisiana (2 women); however, concentrations were not specified (Pellizzari et al. 1982). DCB (all 

isomers) was identified in breast milk samples collected from five different regions across Canada in 

1982 (Mes et al. 1986). 1,2-DCB was identified in 97% of the 210 samples collected with mean and 

maximum milk concentrations of 3 and 29 ppb, respectively and mean and maximum concentrations in 

milkfat of 84 and 890 ppb, respectively. 1,3- and 1,4-DCB were identified together in 100% of the 

210 samples collected with mean and maximum milk concentrations of 6 and 75 ppb, respectively and 

mean and maximum concentrations in milkfat of 161 and 4,180 ppb, respectively. Mean concentrations 
DICHLOROBENZENES 316 

6. POTENTIAL FOR HUMAN EXPOSURE 

of 1,2-, 1,3-, and 1,4-DCB in breast milk samples collected in Slovenia, Yugoslavia in 1981 were 9, <5, 

and 25 μg/kg, respectively (Jan 1983). 1,2- and 1,4-DCB concentrations in the milkfat of these samples 

were 230 and 640 μg/kg, respectively. 

Occupational exposure to DCBs may be important in several industries associated with the production of 

various chlorobenzene compounds. Workers may be exposed to DCBs during production, processing, 

and industrial use of these compounds, including the production and handling of products that contain 

these compounds (IARC 1999). Workplace air levels of 1,4-DCB ranging up to 4,350 mg/m3 (724 ppm) 

were measured at facilities producing or using the compound (IARC 1982). A summary of the levels of 

1,4-DCB detected in various occupational settings is presented in Table 6-7. Currently, workers in the 

industries identified in Table 6-7 are likely to have the highest potential for exposure to 1,4-DCB. Levels 

of 1,2- and 1,3-DCB in workplace air were not found. NIOSH estimated that about 34,000 workers were 

potentially exposed to 1,4-DCB, about 92,000 workers were potentially exposed to 1,2-DCB, and about 

400 workers were potentially exposed to 1,3-DCB in the early 1980s (NOES 1990). 

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). 

There have been no measurements of the levels of DCBs in amniotic fluid, meconium, cord blood, or 

neonatal blood to investigate prenatal exposure. However, DCBs have been detected in full-term 

placentas collected from five regions of the Slovak Republic (Reichrtova et al. 1999, 2001). Over 

40 placentas were sampled from each region. DCB concentrations measured in these placentas are 

provided in Table 6-11. DCBs were found most frequently in placentas from Bratislava, Slovakia 
DICHLOROBENZENES 317 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-11. Dichlorobenzene Concentrations (μg/kg) in Human Placentas from 

Five Slovak Regions 

1,2-DCB 1,3- and 1,4-DCB 

Region % Detected Median Maximum % Detected Median Maximum 

1. Bratislava 82 0.8 46.9 81 1.4 218.0 

2. Nove Zamky 75 0.1 1.3 55 0.2 10.2 

3. Spisska Nova Ves 10 0.0 0.2 34 0.0 45.0 

4. Kosice 10 0.0 0.8 40 0.0 99.5 

5. Stara Lubovna 82 8.1 64.3 79 0.8 26.9 

Source: Reichrtova et al. 1999, 2001 
DICHLOROBENZENES 318 

6. POTENTIAL FOR HUMAN EXPOSURE 

(industrial region–petrol, pesticide, and rubber industries), Nove Zamky, Slovakia (agricultural region 

with high use of fertilizers), and Stara Lubovna, Slovakia (partially agricultural rural region with 

increasing cross-county traffic). DCBs were found less frequently in samples from Spisska Nova Ves and 

Kosice (industrial regions with heavy metal pollution). 

Consumption of human milk can potentially expose nursing infants to DCB. DCB (all isomers) was 

detected in 100% of 42 samples of human milk collected in five urban areas of the United States at 

concentrations ranging from 0.04–68 ppb; however, concentrations of the individual isomers were not 

specified (Erickson et al. 1980). DCB (all isomers) was also identified in human breast milk in 8 of 

12 women who were residents of Bayonne, New Jersey (6 women); Jersey City, New Jersey (2 women); 

Bridgeville, Pennsylvania (2 women); and Baton Rouge, Louisiana (2 women); however, concentrations 

of the individual isomers were not specified (Pellizzari et al. 1982). DCB (all isomers) were identified in 

breast milk samples collected from five different regions across Canada in 1982 (Mes et al. 1986). 

1,2-DCB was identified in 97% of the 210 samples collected with mean and maximum milk concentration 

of 3 and 29 ppb, respectively, and mean and maximum concentrations in milkfat of 84 and 890 ppb, 

respectively. 1,3-and 1,4-DCB were identified together in 100% of the 210 samples collected with mean 

and maximum milk concentrations of 6 and 75 ppb, respectively, and mean and maximum concentrations 

in milkfat of 161 and 4,180 ppb, respectively. Mean concentrations of 1,2-, 1,3-, and 1,4-DCB in breast 

milk samples collected in Slovenia, Yugoslavia in 1981 were 9, <5, and 25 μg/kg, respectively (Jan 

1983). 1,2- and 1,4-DCB concentrations in the milkfat of these samples were 230 and 640 μg/kg, 

respectively. 

Children are exposed to 1,4-DCB primarily by inhalation of vapors from toilet deodorants, moth proofing 

crystals, and moth balls used in the home or by consumption of moth balls. Consumption of DCBs in 

foods (see Section 6.4.4) and drinking water (see Section 6.4.2) contaminated with DCBs is thought to be 

a minor exposure pathway. There have been no body burden measurements made on children. 

The National Human Adipose Tissue Survey (NHATS) conducted in 1982, estimated general population 

exposure to a variety of toxic organic chemicals. 1,4-DCB was detected in 100% of 46 composite human 

adipose tissue specimens analyzed at levels ranging from 12 to 500 ppb, whereas 1,2-DCB was detected 

in 63% of the 46 specimens at levels ranging from <0.1 to 2 ppb (EPA 1986f, 1989d). These measurements indicate widespread exposure of the general population including children (aged 0–14 years) to 

DCBs. Using this same data, ranks for each of the nine census regions were assigned according to the 

composite adipose tissue concentration of 1,4-DCB or the mean of multiple adipose composite samples 
DICHLOROBENZENES 319 

6. POTENTIAL FOR HUMAN EXPOSURE 

(Phillips and Birchard 1991). These authors reported that exposure to 1,4-DCB based on adipose tissue 

levels was highest nationally for children (aged 0–14 years) in the west south central (Arkansas, 

Louisiana, Oklahoma, and Texas), east south central (Kentucky, Tennessee, Alabama, and Mississippi), 

and south Atlantic regions (Delaware, Maryland, the District of Columbia, Virginia, West Virginia, North 

Carolina, South Carolina, Georgia and Florida) as compared to other areas of the United States. Exposure 

to 1,2-DCB was highest for children (0–14 years) living in the New England (Maine, New Hampshire, 

Vermont, Massachusetts, Rhode Island, and Connecticut), east north central (Illinois, Indiana, Michigan, 

Ohio, and Wisconsin), and west north central regions (Minnesota, Iowa, Missouri, Nebraska, Kansas, 

North Dakota, and South Dakota). 2,5-Dichlorophenol, a metabolite of 1,4-DCB, and 3,4-dichlorophenol, a metabolite of 1,2-dichlorophenol, were detected in urine samples from 197 Arkansas children 

(Hill et al. 1989). 2,5-Dichlorophenol was detectable in 96% of the samples with median and maximum 

concentrations of 9 and 1,200 ppb, respectively. 3,4-Dichlorophenol was detectable in 6% of the samples 

with median and maximum concentrations of <1 ppb (detection limit) and 9 ppb. 

Childhood exposures can be reduced by appropriate use of 1,4-DCB-containing compounds in the home 

and appropriate supervision of young children. Small children, because of their hand-to-mouth activity, 

may receive significant exposure from ingestion of 1,4-DCB. Moth balls look like candy; a young child 

may be tempted to eat them. Accidental poisoning by consumption of this household chemical is likely to 

occur if the moth balls and/or crystals are placed in a location easily accessed by children and under 

conditions where children are not properly supervised. It is also important that children not be allowed to 

play around toilet deodorants and air fresheners unsupervised. Since some 1,4-DCB is applied as a 

crystalline form, children may be exposed dermally, orally (in hand-to-mouth activities), or by inhalation 

of dust particles or vapors while playing on floors or carpeting where 1,4-DCB-contaminated particles 

may have fallen after moth proofing activities in the home. It is important that children not be allowed 

entry into 1,4-DCB-treated storage areas until the moth crystals have sublimated and the vapors have 

dissipated. 

Children living in homes of adults that are occupationally exposed to DCBs must not be exposed to the 

contaminated work clothes or shoes of adults (DHHS 1995). While the vast majority of occupational 

exposures are likely to be by inhalation of DCB vapors by workers, a potential route of exposure to other 

members of the worker’s family including children may occur if DCB contaminated work clothes are 

brought home for laundering. The chemical contamination on the clothing may then vaporize releasing 

DCBs into the indoor air of the workers’ home. Occupational protection statements for the end use DCB 

products state that individuals occupationally exposed to these products should take off all wet or 
 

 

DICHLOROBENZENES 320 

6. POTENTIAL FOR HUMAN EXPOSURE 

contaminated work clothes and shoes and shower using soap and water, and then put on clean clothes 

(NIOSH 1997). Although no studies were found that investigated this pathway of exposure, it is 

conceivable that poor hygiene practices among occupationally exposed adults could potentially result in 

domestic exposures of other family members to DCBs carried home on work clothes and subsequently to 

the vapors released. 

As discussed in Section 6.5 of this profile, inhalation of indoor air is the major exposure route for both 

adults and children in the general population; however, several other minor pathways may also result in 

exposure. Like adults, children living in proximity to hazardous waste sites may be exposed to DCBs in 

contaminated groundwater. If residential wells are the primary source of drinking water, this may pose a 

risk to human health by consumption of contaminated water and by increased inhalation of, and dermal 

contact with DCBs during showering and bathing. 

Little information on the levels of DCB concentrations in infant and toddler foods and in baby formula 

was located. Page and Lacroix (1995) analyzed a variety of beverage and food samples for 32 different 

volatile contaminants, including 1,4-DCB, and found residue levels to be quite low (range, 0.1–22 ppb). 

Soft drink samples contained 0.1 μg/kg (ppb), while cream with 10% butterfat, butter, margarine, peanut 

butter, flour, and pastry mix contained concentrations of 0.1, 1.3–2.7, 12.2–14.5, 1.2–8.8, 7.3, and 22 ppb, 

respectively. 1,2-, 1,3-, and 1,4-DCB were detected in 45, 6, and 69 out of 234 table-ready food items 

from the FDA’s total diet study, respectively. Positive detections of all three isomers had concentrations 

within a range of 4.26 to 114 ppb (Heikes et al. 1995). No information was located to determine whether 

children differed in their weight-adjusted intake of 1,4-DCB. 

There are some parental exposures to DCBs that might result in potential exposures of children to this 

chemical. DCBs are not genotoxic and, thus, there should be no concern about exposure to parental germ 

cells (see Table 3-3 and 3-4 for further information). Additional information on the genotoxicity of these 

compounds can be found in Section 3.7, Children’s Susceptibility. Because DCBs have been widely 

detected in samples of human adipose tissue, the potential exists for these compounds to be stored in 

maternal tissues from preconception exposures and mobilized during gestation or lactation so that the 

developing fetus or embryo or nursing infant is exposed even after external exposure to the mother has 

ceased. Like all organochlorine compounds, DCBs are stored in fatty tissue. 1,4-DCB was detected in 

100% of adipose tissue samples of adults and children analyzed as part of the National Adipose Tissue 

study (EPA 1986f). As previously mentioned, there have been measurements of all DCB isomers 
DICHLOROBENZENES 321 

6. POTENTIAL FOR HUMAN EXPOSURE 

(combined) in human breast milk (Erickson et al. 1980; Pellizzari et al. 1982). For additional information 

on developmental effects of this compound, please see Section 3.7, Children’s Susceptibility. 

During the Minnesota Children’s Pesticide Exposure Study, 1,4-DCB was detected above 0.2 μg/m3

 in 

70 of 73 personal air samples, 83 of 101 indoor air samples, and 42 of 100 outdoor air samples collected 

from households with children (Adgate et al. 2004). The mean concentration of 1,4-DCB was 

1.4 μg/m3

 in the personal air samples, 0.9 μg/m3 in the indoor air samples, and 0.3 μg/m3 in the outdoor 

air samples. During the School Health Initiative: Environment, Learning, Disease (SHIELD) study, the 

median concentrations of 1,4-DCB 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 were 0.1, 0.5, 0.7, 

and 1.0 μg/m3

, respectively, during the winter and 0.2, 0.5, 0.9, and 1.3 μg/m3, respectively, during the 

summer (Adgate et al. 2004). The mean, median, and 95th percentile concentrations of 1,4-DCB 

measured in the blood of 134 children during the SHIELD study were 4.22, 0.21, and 24.5 μg/m3

, 

respectively (Sexton et al. 2005). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

In addition to individuals who are occupationally exposed to DCBs (see Section 6.5), several groups 

within the general population have potentially higher exposures (higher than background levels) to DCBs 

than the general population. These populations include individuals living near sites where DCB are 

produced or used in manufacturing and sites where DCBs are disposed. 

Those individuals living or working near industrial facilities or hazardous waste sites with higher than 

average levels of DCBs in the air would have the potential for above-average exposures. In addition, 

individuals using space deodorants (air fresheners), toilet block deodorants, or moth repellents (moth balls 

or crystal) containing 1,4-DCB in their homes have the potential for high exposure to this compound 

(Scuderi 1986). Indoor air concentrations resulting from the use of these products in bathrooms and 

closets have been measured at levels up to 1.3 mg/m3 (0.22 ppm) (Scuderi 1986). 

Individuals living in proximity to hazardous waste sites may also be exposed to DCB by contaminated 

groundwater. If residential wells are the primary source of drinking water, this may pose a risk to human 

health by consumption of contaminated water and by increased inhalation of and dermal contact with 

DCBs during showering and bathing. 
 

 

 

 

DICHLOROBENZENES 322 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of dichlorobenzenes 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 dichlorobenzenes. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of the DCBs are 

sufficiently well characterized to allow estimation of its environmental fate (Amoore and Hautala 1983; 

Chiou et al. 1983; Howard 1989; Lide and Frederikse 1994; Newsom 1985; NFPA 1994; Sax and Lewis 

1987; Schwartzenbach and Westall 1981; Verschueren 1983; Wilson et al. 1981). On this basis, it does 

not appear that further research in this area is required. 

Production, Import/Export, Use, Release, and Disposal. Data on the production and uses of 

DCBs in the United States are available (CMR 1990; HSDB 2005; IRPTC 1985; SRI 1996; TRI03 2005). 

Incineration is the recommended disposal method for DCBs (HSDB 2005; IRPTC 1985). Disposal of this
 

compound is controlled by federal regulations (HSDB 2005; IRPTC 1985). Available information 

appears to be sufficient for assessing the potential for release of, and exposure to, DCBs. 

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 2003, became available in May of 2005. This 

database is updated yearly and should provide a list of industrial production facilities and emissions. 
DICHLOROBENZENES 323 

6. POTENTIAL FOR HUMAN EXPOSURE 

Environmental Fate. The environmental fate of the DCBs has been well characterized. Their 

volatilization into air from other media, reaction with hydroxyl radicals in the atmosphere, transport 

through soil, and biodegradation by water and soil microorganisms seem to be well understood (Bouwer 

and McCarty 1982, 1983, 1984; Chiou et al. 1983; Cuppitt 1980; EPA 1985d; Garrison and Hill 1972; 

Howard 1989; Ligocki et al. 1985; Newsom 1985; Schwartzenbach and Westall 1981; Singh et al. 1981a, 

1981b; Scuderi 1986; Spain and Nishino 1987; Tabak et al. 1981; Wakeham et al. 1983; Wang and Jones 

1994a, 1994b, 1994c; Wilson et al. 1981). Volatilization, sorption, biodegradation, and bioaccumulation 

appear to be competing processes for the removal of DCBs from water (Spain and Nishino 1987). 

Additional data on the rates of these reactions under various environmental conditions would be useful, 

but do not appear to be essential to understand the behavior of DCBs in the environment. 

Bioavailability from Environmental Media. DCBs have been shown to be well absorbed by 

laboratory animals via inhalation and oral exposure (Hawkins et al. 1980; Kimura et al. 1979). No 

information has been located regarding absorption by the dermal route. Although no information has 

been located on the absorption of this substance from breathing contaminated air or ingesting DCBs that 

are contained in soil or plant material are expected to be well absorbed from these media. It would be 

useful to have information on whether, and to what extent, absorption of DCBs can occur as a result of 

dermal contact with soil or from swimming in surface water or bathing or showering in groundwater that 

contains DCBs. 

Food Chain Bioaccumulation. Bioconcentration of DCBs has been documented for several aquatic 

species (ASTER 1995; Chiou 1985; Oliver and Nicol 1982a; Oliver and Niimi 1983). Based on the 

relatively high Kow, it appears that bioaccumulation does occur (Leo et al. 1971). Oliver and Nicol 

(1982a) measured concentrations of chlorobenzenes in sediments, water, and selected fish from the Great 

Lakes. Their limited fish analyses indicate that chlorobenzenes, including DCBs, are bioconcentrated by 

fish, but to a much smaller extent than compounds such as DDT or PCBs. DCBs have also been shown to 

be accumulated by terrestrial plants (Wang et al. 1996). No data were located on biomagnification of 

DCBs through terrestrial or aquatic food chains. Additional information on bioconcentration of DCBs by 

commercially important fish, shellfish, and plant species and biomagnification would be helpful in 

evaluating the potential importance of food chain bioaccumulation to human exposure. 

Exposure Levels in Environmental Media. Several studies are available documenting levels of 

DCBs in indoor and ambient outdoor air, water, and soil and sediments in rural, suburban, and urban 

areas and in the environs of hazardous waste sites (Bozzelli and Kebbekus 1979; Coniglio et al. 1980; 
DICHLOROBENZENES 324 

6. POTENTIAL FOR HUMAN EXPOSURE 

Dressman et al. 1977; Elder et al. 1981; Fellin and Otson 1994; Harkov et al. 1984, 1985; Hauser and 

Bromberg 1982; IARC 1982; IJC 1989; Kostianen 1995; LaRegina et al. 1986; Oliver and Nicol 1982a; 

Page 1981; Scuderi 1986; Shah and Heyerdahl 1988; Staples et al. 1985; Wallace et al. 1986a, 1986b, 

1989). It would be valuable to have more recent monitoring data to better estimate the potential for 

current human exposure levels from these media, especially in the vicinity of hazardous waste sites. 

Although there is little information on DCB levels in food (IARC 1982; Oliver and Niimi 1983; Page and 

Lacroix 1995), it does not appear that this is an important source of human exposure. However, 

additional data on DCB levels in foodstuffs, especially commercially important fish, shellfish, and plants, 

would be useful to confirm this assumption. 

Reliable monitoring data for the levels of dichlorobenzenes in contaminated media at hazardous waste 

sites are needed so that the information obtained on levels of dichlorobenzenes in the environment can be 

used in combination with the known body burden of dichlorobenzenes to assess the potential risk of 

adverse health effects in populations living in the vicinity of hazardous waste sites. 

Exposure Levels in Humans. Detection of DCBs in breath, adipose tissue, breast milk, and blood 

can be used as indicators of human exposure (Ashley et al. 1994, 1995; EPA 1986f, 1989d; Erickson et al. 

1980; Hill et al. 1995; Pellizzari et al. 1982; Wallace et al. 1986b). Levels of DCBs in breath appear to 

provide rough estimates of recent preceding exposure (Wallace et al. 1986b), while levels in adipose 

tissue may be useful to indicate less recent past exposure (EPA 1986f, 1989d). The level of 2,5-dichlorophenol (a metabolite of 1,4-DCB) has also been reported in urine of 1,000 individuals (Hill et al. 1995), 

and is highly correlated to 1,4-DCB in blood. Additional data correlating levels in environmental media 

with human tissue levels, particularly for populations living in the vicinity of hazardous waste sites that 

contain DCBs, would be helpful in establishing levels of the chemical to which humans have been 

exposed. Additional monitoring data on the occupational exposure of workers to DCBs would be helpful. 

Additional studies reporting inhalation exposure through the use of toilet air fresheners and mothballs that 

contain DCBs would be useful. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Children, like all members of the general population, are exposed to DCBs 

primarily by inhalation. No exposure or body burden studies were specifically located related to children. 

Studies to quantify the amount of DCBs in amniotic fluid, meconium, cord blood, or neonatal blood 
DICHLOROBENZENES 325 

6. POTENTIAL FOR HUMAN EXPOSURE 

would be useful in assessing prenatal exposure. Maternal-fetal exposure should be evaluated since there 

is some genotoxic potential. Studies on the amount of the DCBs specifically in breast milk would be 

useful in assessing exposures in nursing infants. Although inhalation of 1,4-DCB is the most important 

exposure pathway in humans, consumption of moth crystals or moth balls by young children also may 

result in additional exposure of concern. It is not known whether children are different from adults in 

their weight-adjusted intake of 1,4-DCB. Studies on this topic with respect to inhalation and dietary 

intake are needed. Childhood exposure to this chemical can be decreased by the appropriate use of this 

compound particularly in the home and by appropriate supervision of young children. Education 

programs for parents and young children may be appropriate to reduce poisoning incidents. Studies on 

exposures of janitorial personnel and other occupationally exposed adults would also be helpful in 

determining the amount of 1,4-DCB that may accumulate on work clothes and whether crystalline 

particles of the toilet deodorants or moth crystal can be carried home on work clothing leading to 

additional domestic exposures from crystals and subsequently to vapors. 

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 dichlorobenzenes 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 

sub-registries 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 

A search of Federal Research in Progress (FEDRIP 2005) identified one ongoing study that is related to 

dichlorobenzenes. James Heist of Ftc Acquisition Corporation is being funded by the Air Force to study 

material recycling and waste minimization using a freeze crystallization process. Dichlorobenzenes are 

among the substances for which recycling via this method will be considered. 
DICHLOROBENZENES 326 

6. POTENTIAL FOR HUMAN EXPOSURE 

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DICHLOROBENZENES 327 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring dichlorobenzenes, its metabolites, and other biomarkers of exposure and 

effect to dichlorobenzenes. The intent is not to provide an exhaustive list of analytical methods. Rather, 

the intention is to identify well-established methods that are used as the standard methods of analysis. 

Many of the analytical methods used for environmental samples are the methods approved by federal 

agencies and organizations such as EPA and the National Institute for Occupational Safety and Health 

(NIOSH). Other methods presented in this chapter are those that are approved by groups such as the 

Association of Official Analytical Chemists (AOAC) and the American Public Health Association 

(APHA). Additionally, analytical methods are included that modify previously used methods to obtain 

lower detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Methods are available for measuring levels of DCBs in blood, urine, tissue, and breath. Representative 

methods are summarized in Table 7-1. Methods include sample collection, preparation, cleanup, and 

determination. Sample preparation techniques are usually required to separate the compound of interest 

from the complex biological sample medium. Gas purge and solvent extraction are used most frequently 

to separate DCBs from blood, urine, and tissues. The breath matrix is relatively simple and does not 

require preparation steps; however, special techniques such as use of a spirometer are required to provide 

pure air for inhalation and a mechanism for collection of exhaled air. Gas chromatography (GC) is used 

most frequently to detect DCBs in biological materials. Detectors used to identify DCBs in biological 

materials include the electron capture detector (ECD) (Bristol et al. 1982; Jan 1983), the photoionization 

detector (PID) (Langhorst and Nestrick 1979), and mass spectrometry (MS) (Ashley et al. 1992; Michael 

et al. 1980). ECD and PID provide some selectivity, but confirmation using a different GC column or 

detector is often recommended. MS provides identification as well as quantitation of analytes. 

Separation of DCBs from biological samples may be accomplished by extraction with hexane (Bristol 

et al. 1982; Jan 1983), or carbon tetrachloride (Langhorst and Nestrick 1979), or by purging with an inert 

gas and trapping on a sorbent material. Solvent extraction permits concentration, thereby increasing 

sensitivity, but the extraction solvents can interfere with the analysis, and evaporative losses can result in 

low recovery. Gas purge techniques may be static (headspace) or dynamic (purge-and-trap). The static 


DICHLOROBENZENES 328 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Dichlorobenzenes in 

Biological Materials 

Sample 

matrix Analytical Sample Percent 

(analyte) Sample preparation method detection limit recovery Reference 

Blood Headspace purge; cap. GC/MS 3 ng/mL 86.3 IARC Method 

(1,3-DCB) thermal desorption 25; Pellizzari et 

al. 1985 

Blood Headspace purge; cap. GC/MS Low-ppb 86– Michael et al. 

(model thermal desorption 120 (model 1980 

compounds) compounds) 

Blood Solvent extraction; GC/PID 3.6 ppb 85 Langhorst and 

(1,2-DCB) silica gel column Nestrick 1979 

clean-up 

Blood Solvent extraction; GC/PID 2.8 ppb 82 Langhorst and 

(1,3-DCB) silica gel column Nestrick 1979 

clean-up 

Blood Solvent extraction; GC/PID 3.0 ppb 89 Langhorst and 

(1,4-DCB) silica gel column Nestrick 1979 

clean-up 

Blood Solvent extraction GC/ECD 1.4 ppb 76.6 Bristol et al. 

(1,2-DCB) 1982 

Blood Solvent extraction GC/ECD 1.3 ppb 74.5 Bristol et al. 

(1,3-DCB) 1982 

Blood Solvent extraction GC/ECD 2 ppb 81.6 Bristol et al. 

(1,4-DCB) 1982 

Blood Purge and trap cap. GC/MS 0.05 ppb 77–122 Ashley et al. 

(1,2-DCB) 1992 

Blood Purge and trap cap. GC/MS 0.04 ppb 130–162 Ashley et al. 

(1,3-DCB) 1992 

Blood Purge and trap cap. GC/MS 0.04 ppb 93–98 Ashley et al. 

(1,4-DCB) 1992 

Blood, urine Purge-and-trap, GC/MS No data No data Barkley et al. 

(unspecified thermal desorption 1980 

DCBs) cap 

Urine Solvent extraction; GC/PID 0.90 ppb 83 Langhorst and 

(1,2-DCB) silica gen column Nestrick 1979 

clean-up 

Urine Solvent extraction; GC/PID 0.70 ppb 78 Langhorst and 

(1,3-DCB) silica gen column Nestrick 1979 

clean-up 

Urine Solvent extraction; GC/PID 0.75 ppb 81 Langhorst and 

(1,4-DCB) silica gen column Nestrick 1979 

clean-up 

Urine Headspace purge; cap. GC/MS Low-ppb 48– Michael et al. 

(model thermal desorption 110 (model 1980 

compounds) compounds) 
DICHLOROBENZENES 329 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Dichlorobenzenes in 

Biological Materials 

Sample 

matrix Analytical Sample Percent 

(analyte) Sample preparation method detection limit recovery Reference 

Adipose Maceration; cap. GC/MS Low-ppb 13– Michael et al. 

tissue headspace purge; 80 (model 1980 

(model thermal desorption compounds) 

compounds) 

Human milk Headspace purge; GC/MS 0.6 62.9 Erickson et al. 

(chloro­ thermal desorption 1980 

benzene) 

Human milk Solvent extraction; GC/ECD No data >80 Jan 1983 

(unspecified cleanup with sulfuric 

DCBs) acid, Florisil 

Adipose Solvent extraction; GC/ECD No data >80 Jan 1983 

tissue cleanup with sulfuric 

(unspecified acid, Florisil 

DCBs) 

Tissue Maceration; cap. GC/MS 6 ng/g 56.5 IARC Method 

(1,3-DCB) headspace purge; 25; Pellizzari et 

thermal desorption al. 1985 

Breath Collection using a GC/MS No data No data Barkley et al. 

(unspecified spirometer; 1980 

DCBs) adsorption on Tenax 

traps; thermal 

desorption cap 

Breath Collection into cap. GC/MS-SIM low-μg/m3 49–80 Thomas et al. 

(1,4-DCB) canisters using 1991 

spirometer; 

cryofocussing; 

thermal desorption 

cap. = capillary; ECD = electron capture device; GC = gas chromatography; MS = mass spectrometry; PID = photoionization detector; SIM = selected ion monitoring 
DICHLOROBENZENES 330 

7. ANALYTICAL METHODS 

headspace technique is relatively simple, but may be less sensitive than the purge-and-trap method. The 

purge-and-trap method, while providing increased sensitivity, requires more complex instrumentation and 

may result in artifact formation (Seto 1994). 

Although a variety of methods are available for determination of DCBs in blood, few are well 

characterized and validated. A method has been developed which utilizes headspace purge followed by 

thermal desorption of the trapped, purged analytes. DCBs are then determined by capillary GC/MS 

(Michael et al. 1980; Pellizzari et al. 1985). Recovery is very good (>85%) and detection limits are in the 

low-ppb range for model compounds (Michael et al. 1980; Pellizzari et al. 1985). A sensitive and reliable 

method for identification and quantitation of DCBs in samples of whole blood has been developed by 

Ashley and coworkers at the Centers for Disease Control and Prevention (CDC) (Ashley et al. 1992). The 

method involves purge-and-trap of a 10 mL blood sample with analysis by capillary GC/high resolution 

MS. Anti-foam procedures are utilized as well as special efforts to remove background levels of volatile 

organic compounds (VOCs) from reagents and equipment. The method is sensitive enough (ppt levels) to 

determine background levels of VOCs in the population. Percent recoveries were 77–122% for 1,2-DCB, 

130–162% for 1,3-DCB, and 93–98% for 1,4-DCB. 

Methods are available for monitoring DCBs in urine and tissues, particularly adipose tissue and mother's 

milk. Solvent extraction, silica gel column clean-up, and GC/ECD or GC/PID analysis has been used for 

urine (Langhorst and Nestrick 1979), mother's milk (Jan 1983), and adipose tissue (Jan 1983). Recovery 

is good (>80% recovery) and detection limits are in the low-ppb range (Jan 1983; Langhorst and Nestrick 

1979). Headspace purge followed by capillary GC/MS analysis has been utilized for urine (Michael et al. 

1980), mother's milk (Erickson et al. 1980), and tissue (Pellizzari et al. 1985). Recovery, where reported, 

is adequate (>60%) (Erickson et al. 1980), and detection limits are in the low-ppb range (Erickson et al. 

1980). 

Breath samples are usually collected through a spirometer onto a sorbent cartridge (Barkley et al. 1980) or 

into passivated canisters (Thomas et al. 1991). Analytes are concentrated cryogenically from a portion of 

the canister contents or after thermal desorption from the sorbent, then analyzed by GC/MS. Recovery of 

1,4-DCB using Tenax cartridges was 86–101% and the detection limit was about 1 μg/m3

. The method is 

sufficiently sensitive and reliable for monitoring exposure to DCBs. Recovery for collection of 1,4-DCB 

in canisters was 49–80% and the detection limits were in the low-μg/m3 range (Thomas et al. 1991). The 

spirometer system utilizing canisters is compact, and may be useful as a field screening method (Thomas 

et al. 1991). 
DICHLOROBENZENES 331 

7. ANALYTICAL METHODS 

7.2 ENVIRONMENTAL SAMPLES 

Methods are available for determining DCBs in a variety of environmental matrices. A summary of 

representative methods is shown in Table 7-2. Validated methods, approved by agencies and 

organizations such as EPA, ASTM, APHA, and NIOSH, are available for air, water, and solid waste 

matrices. These methods for analysis of drinking water, waste water, and soil/sediment samples are 

included in Table 7-2. Many of the methods published by APHA and ASTM for water are equivalent to 

the EPA methods. 

GC is the most widely used analytical technique for quantifying concentrations of DCBs in environmental 

matrices. Various detection devices used for GC include the flame ionization detector (FID), ECD, Hall 

electroconductivity detector (HECD), and PID. Confirmation using a second column is usually 

recommended. MS provides identification as well quantitation for GC analysis. Because of the 

complexity of the sample matrix and the usually low concentrations of VOCs in environmental media, 

sample concentration is generally required prior to GC analysis. Methods suitable for determining trace 

amounts of DCBs in aqueous and other environmental media include three basic approaches to the 

pretreatment of the sample: gas purge-and-trap technique, headspace-gas extraction, and extraction with 

solvent. Care must be taken during sample collection and processing to avoid evaporative losses. 

Contamination is another potential analytical problem and monitoring is required. 1,4-DCB is a relatively 

common chemical compound and can contaminate reagents and glassware. 

Charcoal adsorbent is used for collection of DCBs in occupational air. The compounds are desorbed with 

carbon disulfide and analyzed by GC/FID. The method is sufficiently sensitive and reliable for 

determining occupational exposure to DCBs (NIOSH 1994). 

Ambient air samples are collected on adsorbents such as Tenax (Wallace 1987), or multisorbent (Heavner 

et al. 1992; Oliver et al. 1996), or in passivated canisters (EPA 1988a). Tenax traps are thermally 

desorbed, concentrated cryogenically, and analyzed by capillary GC/MS (Wallace et al. 1987). Recovery 

is good (81–110%), precision for side-by-side samples is acceptable (9–45% RSD), and the detection 

limit is ≈1 μg/m3 (Wallace 1987). Multisorbent traps may be solvent desorbed and analyzed by capillary 

GC/MS. Recovery and precision are good and detection limits as low as 0.019 ppb have been reported 

(Oliver et al. 1996). Collection of air samples in passivated stainless steel canisters is also widely utilized 
DICHLOROBENZENES 332 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Dichlorobenzenes in 

Environmental Samples 

Sample 

matrix Analytical Sample Percent 

(analyte) Sample preparation method detection limit recovery Reference 

Occupational 

air 

Collection on charcoal 

tubes; desorption with 

GC/FID 0.01 mg/ 

samplea 

±13.7 Method 1003 

NIOSH 1994 

(1,2-DCB) CS2 

Occupational 

air 

Collection on charcoal 

tubes; desorption with 

GC/FID 0.01 mg/ 

samplea 

±12.5 Method 1003 

NIOSH 1994 

(1,4-DCB) CS2 

Ambient air Collection in cap. GC with FID, No data No data Method TO-14 

(VOCs canisters; ECD or MS EPA 1988a 

including cryofocussing; 

DCBs) thermal desorption 

Air-emission MM5 sampling train cap. GC/MS No data -13 to -16 Method 0010 

sources (condensate, filter, EPA 1994f 

(selected adsorbent); 

compounds) condensate, impinger 

and rinses, solvent 

extraction, 

evaporation; XAD2 adsorbent and 

filters, Soxhlet 

extraction, 

concentration 

Air-emission VOST sampling train GC/MS No data No data Method 0030 

sources (sorbent traps); EPA 1994h 

(volatile thermal desorption 

organics) 

Drinking Purge and trap GC/HECD; conf. <0.01 μg/L for 95 Method 502.1 

water on second col. or most VOCs EPA 1991a 

(1,2- and GC/MS 

1,3-DCB) 

Drinking Purge and trap GC/HECD; conf. <0.01 μg/L for 90 Method 502.1 

water on second col. or most VOCs EPA 1991a 

(1,4-DCB) GC/MS 

Drinking Purge and trap GC/PID-HECD; 0.03–0.05 μg/L 97–102 (PID); Method 502.2 

water conf. by GC/MS (PID); 0.02– 98– EPA 1991b 

(1,2-DCB) 0.04 μg/L 100 (HECD) 

(HECD) 

Drinking Purge and trap GC/PID-HECD; 0.02 μg/L (PID); 97–104 (PID); Method 502.2 

water conf. by GC/MS 0.02–0.07 μg/L 97– EPA 1991b 

(1,3-DCB) (HECD) 106 (HECD) 

Drinking Purge and trap GC/PID-HECD; 0.01–0.03 μg/L 97–103 (PID); Method 502.2 

water conf. by GC/MS (PID); 0.01– 97– EPA 1991b 

(1,4-DCB) 0.04 μg/L 98 (HECD) 

(HECD) 

Drinking 

water 

Purge and trap GC/PID; conf. on 

second col. or 

0.02 μg/L 75–85 Method 503.1 

EPA 1991c 

(1,2-DCB) GC/MS 
DICHLOROBENZENES 333 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Dichlorobenzenes in 

Environmental Samples 

Sample 

matrix Analytical Sample Percent 

(analyte) Sample preparation method detection limit recovery Reference 

Drinking Purge and trap GC/PID; conf. on 0.006 μg/L 91 Method 503.1 

water second col. or EPA 1991c 

(1,3-DCB) GC/MS 

Drinking Purge and trap GC/PID; conf. on 0.006 μg/L 91–107 Method 503.1 

water second col. or EPA 1991c 

(1,4-DCB) GC/MS 

Drinking Purge and trap cap. GC/MS 0.03–0.05 μg/L 93–97 Method 524.2 

water EPA 1992a 

Drinking Purge and trap cap. GC/MS 0.05–0.12 μg/L 87–100 Method 524.2 

water EPA 1992a 

Drinking Purge and trap cap. GC/MS 0.03–0.04 μg/L 93–103 Method 524.2 

water EPA 1992a 

Waste water Purge and trap GC/HECD; conf. 0.15 μg/L ND–208 Method 601 

on second col. or EPA 2002c 

GC/MS 

Waste water Purge and trap GC/HECD; conf. 0.32 μg/L 7–187 Method 601 

on second col. or EPA 2002c 

GC/MS 

Waste water Purge and trap GC/HECD; conf. 0.24 μg/L 42–143 Method 601 

on second col. or EPA 1984c; 

GC/MS EPA 2002c 

Waste water Purge and trap GC/PID; conf. on 0.4 μg/L 37–154 Method 602 

second col. or EPA 2002d 

GC/MS 

Waste water Purge and trap GC/PID; conf. on 0.3 μg/L 50–141 Method 602 

second col. or EPA 2002d 

GC/MS 

Waste water Purge and trap GC/PID; conf. on 0.3 μg/L 42–143 Method 602 

second col. or EPA 1984f; 

GC/MS EPA 2002d 

Waste water Solvent extraction; GC/ECD 1.14 μg/L 9–160 Method 612 

optional Florisil EPA 2002b 

column clean-up 

Waste water Solvent extraction; GC/ECD 1.19 μg/L DL–150 Method 612 

optional Florisil EPA 2002b 

column clean-up 

Waste water Solvent extraction; GC/ECD 1.34 μg/L 13–137 Method 612 

optional Florisil EPA 1984c; 

column clean-up EPA 2002b 

Waste water Purge and trap GC/MS No data 18–190 Method 624 

(1,2- and EPA 1984d; 

1,4-DCB) EPA 2002a 

Waste water Purge and trap GC/MS No data 59–156 Method 624 

(1,3-DCB) EPA 1984d; 

EPA 2002a 

Waste water Purge and trap cap. GC/MS 0.031 μg/L 106 Method 6200B 

APHA 1998 
DICHLOROBENZENES 334 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Dichlorobenzenes in 

Environmental Samples 

Sample 

matrix Analytical Sample Percent 

(analyte) Sample preparation method detection limit recovery Reference 

Waste water Purge and trap cap. GC/MS 0.045 μg/L 108 Method 6200B 

APHA 1998 

Waste water Purge and trap cap. GC/MS 0.033 μg/L 106 Method 6200B 

APHA 1998 

Waste water/ Purge and trap cap GC/HECD, 0.023 μg/L 93 (HECD); Method 6200 

Drinking PID (HECD); 67 (PID) APHA 1998 

water 0.031 μg/L (PID) 

(1,2-DCB) 

Waste water/ Purge and trap cap GC/HECD, 0.017 μg/L 95 (HECD); Method 6200 

Drinking PID (HECD); 70 (PID) APHA 1998 

water 0.028 μg/L (PID) 

(1,3-DCB) 

Waste water/ Purge and trap cap GC/HECD, 0.059 μg/L 91 (HECD); Method 6200 

Drinking PID (HECD); 70 (PID) APHA 1998 

water 0.061 μg/L (PID) 

(1,4-DCB) 

Drinking Purge and trap GC low μg/L 99 Method D 3871 

water ASTM 1994 

(VOCs) 

Solid waste Closed system purge GC/ECD, FID, Not reported Not reported Method 5035 

(VOCs) and trap and MS EPA 1996c 

extraction 

Solid waste Purge and trap, direct GC/HECD, PID 0.02 μg/L 100 (HECD); Method 8021B 

(1,2-DCB) injection, headspace, (HECD); 102 (PID) EPA 1996d 

or vacuum distillation 0.05 (PID) 

Solid waste Purge and trap, direct GC/HECD, PID 0.02 μg/L 106 (HECD); Method 8021B 

(1,3-DCB) injection, headspace, (HECD); 104 (PID) EPA 1996d 

or vacuum distillation 0.02 (PID) 

Solid waste Purge and trap, direct GC/HECD, PID 0.01 μg/L 98 (HECD); Method 8021B 

(1,4-DCB) injection, headspace, (HECD); 103 (PID) EPA 1996d 

or vacuum distillation 0.07 (PID) 

Solid waste Solvent extraction Single or dual 270 ng/L 102 Method 8121 

(1,2-DCB) cap. GC/ECD EPA 1994l 

Solid waste Solvent extraction Single or dual 250 ng/L 103 Method 8121 

(1,3-DCB) cap. GC/ECD EPA 1994l 

Solid waste Solvent extraction Single or dual 890 ng/L 104 Method 8121 

(1,4-DCB) cap. GC/ECD EPA 1994l 

a

Estimated limit of detection 

cap. = capillary; conf. = confirmation; col. = column; DL = detection limit; ECD = electron capture detector; 

FID = flame ionization detector; GC = gas chromatography; HECD = Hall electrolytic conductivity detector; 

MS = mass spectrometry; ND = not detected; PID = photoionization detector; VOC = volatile organic compound 
 

 

DICHLOROBENZENES 335 

7. ANALYTICAL METHODS 

(EPA 1988a), but performance data are unavailable. Passive sampling devices are also widely used, due 

in part to their ease of use and small size (Lewis et al. 1985). 

For water, soil, or sediment samples, DCBs are purged from the sample with an inert gas such as helium 

or nitrogen, and then passed through the sorbent (EPA 1984a, 1984b, 1991a, 1991b, 1991c, 1992a, 1994a, 

1994f). The analytes are thermally desorbed and analyzed by GC/HECD, GC/PID, GC/ECD, or GC/MS 

techniques. Detection limits for waste waters and solid wastes are in the low-ppb range, which is 

probably well below levels of health concern. Detection limits for drinking water samples are generally 

in the ppt range (0.006–0.05 μg/L) (EPA 1991a, 1991b, 1991c, 1992a). 

Several physical parameters may interfere with analytical accuracy. High sampling flow rates and high 

temperature and humidity may cause decreased adsorption of DCB vapor on the solid sorbent (APHA 

1995a). Interference by other VOCs with similar retention times may be resolved by using different GC 

column materials and temperatures or be using MS techniques. 

The use of capillary columns rather than packed column GC has improved resolution and sensitivity and 

shortened the analysis time (Washall and Wampler 1988). However, more stringent sample clean-up 

procedures are required for capillary column GC (Oliver and Nicol 1982b). The development of methods 

using whole column cryotrapping (Pankow and Rosen 1988; Pankow et al. 1988) and cryogenic 

refocusing (Washall and Wampler 1988) provide even greater sensitivity and resolution for GC analysis. 

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 dichlorobenzenes 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 dichlorobenzenes. 

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 
DICHLOROBENZENES 336 

7. ANALYTICAL METHODS 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Exposure to DCBs may be evaluated by measuring the levels of these compounds in blood, 

breath, milk, and adipose tissue, and by measuring the level of 2,5-dichlorophenol, a metabolite of 

1,4-DCB, or the levels of 2,3-dichlorophenol, 3,4-dichlorophenol, 3,4-dichlorocatechol, and 

4,5-dichlorocatechol, metabolites of 1,2-DCB, in urine (Bristol et al. 1982; Erickson et al. 1980; Jan 

1983; Kumagai and Matsunaga 1995, 1997; Langhorst and Nestrick 1979; Mage et al. 2004; Pellizzari 

et al. 1985). Sensitive analytical methods are available for measurements in blood. Development of 

methods with improved specificity and sensitivity for other tissues and breath would be valuable in 

identifying individuals with low-level exposure. Development of standardized procedures would permit 

comparison of data and facilitate the study of correlations between exposure and measured levels 

biological samples. Interlaboratory studies are also needed to provide better performance data for 

methods currently in use. 

Effect. There are no known health effects such as elevated liver enzymes that are uniquely associated 

with exposure to DCBs. Therefore, the identification of specific health effects and the development of 

analytical methods to determine biomarkers of effect for DCBs would be useful. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Air is the environmental medium of most concern for human exposure to DCBs. Exposure 

from drinking water may also be of concern in some areas, such as near hazardous waste sites. Existing 

analytical methods can measure DCBs in these and other environmental media at background levels (EPA 

1988a, 1984a, 1984b, 1991a, 1991b, 1991c, 1992a, 1994a, 1994f; NIOSH 1994). The accuracy and 

precision of the methods for water and wastes are well documented and MS provides adequate specificity. 

Performance data for measurements in ambient and indoor air would be helpful. Development of 

techniques to improve the accuracy and ease of sample preparation and transfer for these methods would 

also be helpful. 
DICHLOROBENZENES 337 

7. ANALYTICAL METHODS 

7.3.2 Ongoing Studies 

No ongoing studies involving analytical techniques for DCBs were found in a search of the Federal 

Research in Progress database (FEDRIP 2005). 
DICHLOROBENZENES 338 

7. ANALYTICAL METHODS 

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DICHLOROBENZENES 339 

8. REGULATIONS AND ADVISORIES 

The international, national, and state regulations and guidelines pertaining to dichlorobenzenes in air, 

water, and other media are summarized in Table 8-1. 

ATSDR has derived an MRL of 2 ppm for acute-duration inhalation exposure to 1,4-DCB. The acute 

inhalation MRL is based on a NOAEL of 15 ppm for irritant effects in humans exposed to 1,4-DCB in the 

workplace (Hollingsworth et al. 1956). An uncertainty factor of 10 for human variability was applied. 

ATSDR has derived an MRL of 0.2 ppm for intermediate-duration inhalation exposure to 1,4-DCB. The 

intermediate inhalation MRL is based on benchmark dose analysis of liver weight increases in male rats 

exposed to 1,4-DCB vapors for 6 hours/day for 15 weeks (Tyl and Neeper-Bradley 1989). The resulting 

BMCL1sd of 92.45 ppm was duration-adjusted from intermittent to continuous exposure, converted to a 

human equivalent concentration (23 ppm), and divided by an uncertainty factor of 100 (10 for 

extrapolating from animals to humans and 10 for human variability). 

ATSDR has derived an MRL of 0.01 ppm for chronic-duration inhalation exposure to 1,4-DCB. The 

chronic inhalation MRL is based on benchmark dose analysis of incidences of nasal lesions in female rats 

exposed to 1,4-DCB vapors for 6 hours/day, 5 days/week for 104 weeks (Aiso et al. 2005b). The 

resulting BMCL10 of 9.51 ppm was duration-adjusted from intermittent to continuous exposure, converted 

to a human equivalent concentration (0.27 ppm), and divided by an uncertainty factor of 30 (3 for 

extrapolating from animals to humans and 10 for human variability). 

ATSDR has derived an MRL of 0.7 mg/kg/day for acute-duration oral exposure to 1,2-DCB. The acute 

oral MRL is based on benchmark dose analysis of liver weight increases in female rats administered 

1,2-DCB by daily oral gavage for 10 days (Robinson et al. 1991). The resulting BMDL1sd of 

67.73 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolating from animals to 

humans and 10 for human variability). 

ATSDR has derived an MRL of 0.6 mg/kg/day for intermediate-duration oral exposure to 1,2-DCB. The 

intermediate oral MRL is based on benchmark dose analysis of liver weight increases in female rats 

administered 1,2-DCB by oral gavage on 5 days/week for 13 weeks (NTP 1985). The resulting BMDL1sd 

of 89.27 mg/kg/day was duration-adjusted from intermittent to daily exposure (63.76 mg/kg/day) and 
 

 

DICHLOROBENZENES 340 

8. REGULATIONS AND ADVISORIES 

divided by an uncertainty factor of 100 (10 for extrapolating from animals to humans and 10 for human 

variability). 

ATSDR has derived an MRL of 0.3 mg/kg/day for chronic-duration oral exposure to 1,2-DCB. The 

chronic oral MRL is based on benchmark dose analysis of incidences of kidney lesions in male mice 

administered 1,2-DCB by oral gavage on 5 days/week for 103 weeks (NTP 1985). The resulting 

BMDL10 of 43.04 mg/kg/day was duration-adjusted from intermittent to daily exposure 

(30.74 mg/kg/day) and divided by an uncertainty factor of 100 (10 for extrapolating from animals to 

humans and 10 for human variability). 

ATSDR has derived an MRL of 0.4 mg/kg/day for acute-duration oral exposure to 1,3-DCB. The acute 

oral MRL is based on benchmark dose analysis of liver weight increases in female rats administered 

1,3-DCB by oral gavage for 10 days (McCauley et al. 1995). The resulting BMDL1sd of 36.32 mg/kg/day 

was divided by an uncertainty factor of 100 (10 for extrapolating from animals to humans and 10 for 

human variability). 

ATSDR has derived an MRL of 0.02 mg/kg/day for intermediate-duration oral exposure to 1,3-DCB. 

The intermediate oral MRL is based on benchmark dose analysis of incidences of pituitary lesions in male 

rats administered 1,3-DCB by daily oral gavage for 90 days (McCauley et al. 1995). The resulting 

BMDL10 of 2.1 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolating from animals 

to humans and 10 for human variability). 

ATSDR has derived an MRL of 0.07 mg/kg/day for intermediate-duration oral exposure to 1,4-DCB. 

The intermediate oral MRL is based on benchmark dose analysis of serum alkaline phosphatase levels in 

female dogs administered 1,4-DCB by capsule on a presumed 5 days/week for 6 months (Naylor and 

Stout 1996). The resulting BMDL1sd of 9.97 mg/kg/day was duration-adjusted from intermittent to daily 

exposure (7 mg/kg/day) and divided by an uncertainty factor of 100 (10 for extrapolating from animals to 

humans and 10 for human variability). 

ATSDR has derived an MRL of 0.07 mg/kg/day for chronic-duration oral exposure to 1,4-DCB. The 

chronic oral MRL is based on benchmark dose analysis of serum alkaline phosphatase levels in female 

dogs administered 1,4-DCB by capsule on a presumed 5 days/week for 1 year (Naylor and Stout 1996). 

The resulting BMDL1sd of 10 mg/kg/day was duration-adjusted from intermittent to daily exposure 
DICHLOROBENZENES 341 

8. REGULATIONS AND ADVISORIES 

(7 mg/kg/day) and divided by an uncertainty factor of 100 (10 for extrapolating from animals to humans 

and 10 for human variability). 

EPA has verified an oral reference dose (RfD) of 0.09 mg/kg/day for 1,2-DCB based on a NOAEL of 

85.7 mg/kg/day for kidney effects in rats and an uncertainty factor of 1,000 (IRIS 2005). EPA also 

verified an inhalation reference concentration (RfC) of 0.8 mg/m3

 (0.1 ppm) for 1,4-DCB based on a 

NOAEL of 75 mg/m3

 for liver effects in rats and an uncertainty factor of 100 (IRIS 2005). 

EPA has determined that 1,2-DCB and 1,3-DCB are not classifiable as to human carcinogenicity and 

assigned them cancer weight-of-evidence classification Group D (IRIS 2005). IARC similarly 

determined that 1,2-DCB and 1,3-DCB are not classifiable as to carcinogenicity to humans (Group 3) 

(IARC 1999). IARC additionally determined that 1,4-DCB is possibly carcinogenic to humans 

(Group 2B) (IARC 1999). The Department of Health and Human Services (DHHS) concluded that 

1,4-DCB is reasonably anticipated to be a human carcinogen (NTP 2005). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 342 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Dichlorobenzenes 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

 IARC Carcinogenicity classification 

 1,2-Dichlorobenzene Group 3a

 1,3-Dichlorobenzene Group 3a

 1,4-Dichlorobenzene Group 2Bb
 

WHO Air quality guideline No data 

Drinking water guideline 

 1,2-Dichlorobenzene 1 mg/Lc

Toxicological data are 

insufficient to permit 1,3-Dichlorobenzene derivation of health-based 

guideline value 

 1,4-Dichlorobenzene 0.3 mg/Lc 

NATIONAL 

Regulations and Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 

 1,2-Dichlorobenzene 25 ppm 

STEL 50 ppm 

 Carcinogenicity classification A4d

 1,4-Dichlorobenzene 10 ppm 

 Carcinogenicity classification A3e
 

EPA Hazardous air pollutant 

 1,4-Dichlorobenzene Yes 

NIOSH REL (10-hour TWA) 

1,2-Dichlorobenzene (ceiling limit) 50 ppm 

 1,4-Dichlorobenzene Carcinogen 

IDLH 

 1,2-Dichlorobenzene 200 ppm 

 1,4-Dichlorobenzene 150 ppm 

PEL (8-hour TWA) for general OSHA industry 

1,2-Dichlorobenzene (ceiling limit) 50 ppm 

 1,4-Dichlorobenzene 75 ppm 

PEL (8-hour TWA) for construction 

industry 

1,2-Dichlorobenzene (ceiling limit) 50 ppm 

 1,4-Dichlorobenzene 75 ppm 

IARC 1999 

WHO 2000 

WHO 2004 

ACGIH 2003 

EPA 2004h 

42USC7412 

NIOSH 2004

OSHA 2004c 

29CFR1910.1000, 

Table Z-1 

OSHA 2004b
 

29CFR1926.55, 

Appendix A 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 343 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Dichlorobenzenes 

Agency Description Information Reference 

NATIONAL (cont.) 

PEL (8-hour TWA) for shipyard industry 

1,2-Dichlorobenzene (ceiling limit) 

 1,4-Dichlorobenzene 

b. Water 

Designated as a hazardous substances 

EPA pursuant to Section 311(b) of the Clean 

Water Act 

 1,2-Dichlorobenzene 

 1,4-Dichlorobenzene 

Drinking water standard 

 1,2-Dichlorobenzene 

 1,4-Dichlorobenzene 

Drinking water standards and health 

advisories 

1,2-Dichlorobenzene and 1,3-dichlorobenzene 

1-Day HA for a 10-kg child 

10-Day HA for a 10-kg child 

DWEL 

Lifetime HA (70-kg adult) 

 1,4-Dichlorobenzene 

1-Day HA for a 10-kg child 

10-Day HA for a 10-kg child 

DWEL 

Lifetime HA (70-kg adult) 

MCL 

 1,2-Dichlorobenzene 

 1,4-Dichlorobenzene 

MCLG 

 1,2-Dichlorobenzene 

 1,4-Dichlorobenzene 

FDA Bottled water 

 1,2-Dichlorobenzene 

 1,4-Dichlorobenzene 

c. Food 

No data 

d. Other 

EPA Carcinogenicity classification 

 1,2-Dichlorobenzene 

 1,3-Dichlorobenzene 

 1,4-Dichlorobenzene 

RfC 

50 ppm 

75 ppm 

Yes 

Yes 

0.6 mg/L 

0.075 mg/L 

9 mg/L 

9 mg/L 

3 mg/L 

0.6 mg/L 

11 mg/L 

11 mg/L 

4 mg/L 

0.075 mg/L 

0.6 mg/L 

0.075 mg/L 

0.6 mg/L 

0.075 mg/L 

0.6 mg/L 

0.075 mg/L 

Group Df

Group Df

No data 

OSHA 2004a 

29CFR1915.1000, 

Table Z 

EPA 2004m 

40CFR116.4 

EPA 2004g 

40CFR141.32 

EPA 2004a 

EPA 2004f 

40CFR141.61 

EPA 2004d 

40CFR141.50 

FDA 2003 

21CFR165.110 

IRIS 2004 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 344 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Dichlorobenzenes 

Agency Description Information Reference 

 1,2-Dichlorobenzene No data 

NATIONAL (cont.)

 1,3-Dichlorobenzene No data 

 1,4-Dichlorobenzene 8x10-1 mg/m3

 EPA RfD 

 1,2-Dichlorobenzene 

 1,3-Dichlorobenzene 

9x10-2 mg/kg/day 

No data 

IRIS 2004 

 1,4-Dichlorobenzene No data 

Community right-to-know; toxic chemical EPA 2004j 

release reporting; effective date 40CFR372.65 

 1,2-Dichlorobenzene 01/01/1987 

 1,3-Dichlorobenzene 01/01/1987 

 1,4-Dichlorobenzene 01/01/1987 

Hazardous waste identification 

 1,2-Dichlorobenzene 

 1,3-Dichlorobenzene 

 1,4-Dichlorobenzene 

U070 

U071 

U072 

EPA 2004c 

40CFR261, 

Appendix VIII 

Chemical information rules; 

manufacturers reporting period for 

1,2-dichlorobenzene and 1,4-dichloro- EPA 2004k 

benzene 40CFR712.30 

Effective date 08/04/1995 

Sunset date 10/03/1995 

Superfund; reportable quantity 

 1,2-Dichlorobenzeneg

 100 pounds EPA 2004b 

 1,3-Dichlorobenzeneh

 100 pounds 40CFR302.4

 1,4-Dichlorobenzenei

 100 pounds 

NTP Carcinogenicity classification 

 1,2-Dichlorobenzene No data 

 1,3-Dichlorobenzene No data NTP 2005 

Reasonably anticipated 

 1,4-Dichlorobenzene to be a human 

carcinogen 

STATE 

a. Air 

 No data 

b. Water 

Drinking water standards and guidelines HSDB 2005 

 Arizona 1,2-Dichlorobenzene 620 μg/L 

 1,3-Dichlorobenzene 620 μg/L 

 1,4-Dichlorobenzene 75 μg/L 

California 1,3-Dichlorobenzene 130 μg/L 

 1,4-Dichlorobenzene 5 μg/L 
 

 

 

 

 

 

DICHLOROBENZENES 345 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Dichlorobenzenes 

Agency Description Information Reference 

 Florida 1,3-Dichlorobenzene 10 μg/L 

STATE (cont.)

 Maine 1,2-Dichlorobenzene 63 μg/L 

 1,4-Dichlorobenzene 21 μg/L 

 Massachusetts 1,4-Dichlorobenzene 5 μg/L 

 Minnesota 1,2-Dichlorobenzene 600 μg/L 

 1,4-Dichlorobenzene 10 μg/L 

 New Jersey 1,2-Dichlorobenzene 600 μg/L 

 1,3-Dichlorobenzene 600 μg/L 

 Wisconsin 1,3-Dichlorobenzene 1,250 μg/L 

c. Food 

 No data 

d. Other 

 No data 

a

Group 3: Not classifiable as to its carcinogenicity to humans. 

b

Group 2B: Possibly carcinogenic to humans. 

c

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. 

d

Group A4: Not classifiable as a human carcinogen. 

e

Group A3: Confirmed animal carcinogen with unknown relevance to humans. 

f

Group D: Not classifiable as to human carcinogenicity. 

g

Designated as a hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act, Section 307(a) of the 

Clean Water Act, and Section 3001 of RCRA. 

h

Designated as a hazardous substance pursuant to Section 307(a) of the Clean Water Act and Section 3001 of 

RCRA. 

i

Designated as a hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act, Section 307(a) of the 

Clean Water Act, Section 112 of the Clean Air Act, and Section 3001 of RCRA. 

ACGIH = American Conference of Governmental Industrial Hygienists; CFR = Code of Federal Regulations; 

DWEL = drinking water equivalent level; EPA = Environmental Protection Agency; FDA = Food and Drug
 

Administration; HA = health advisory; HSDB = Hazardous Substances Data Bank; IARC = International Agency for 

Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System; 

MCL = maximum contaminant level; MCLG = maximum contaminant level goal; NIOSH = National Institute for 

Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health
 

Administration; PEL = permissible exposure limit; RCRA = Resource Conservation and Recovery Act; 

REL = recommended exposure limit; RfC = reference concentration; RfD = reference dose; STEL = short-term 

exposure limit; TLV = threshold limit values; TWA = time-weighted average; USC = United States Codes; 

WHO = World Health Organization 
DICHLOROBENZENES 346 

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DICHLOROBENZENES 347 

9. REFERENCES 

*Aaron CK, Howland MA, eds. 1994. Goldfrank's toxicologic emergencies. Norwalk, CT: Appleton 

and Lange. 

*ACGIH. 1996. Threshold limit values for chemical substances and physical agents and biological 

indices for 1995/1996. Dichlorobenzenes. Cincinnati, OH: American Conference of Governmental 

Industrial Hygienists, 18-19. 

*ACGIH. 2001. Documentation of the threshold limit values and biological exposure indices. 7th ed. 

Cincinnati, OH: American Conference of Governmental Industrial Hygienists. 

*ACGIH. 2005. Threshold limit values for chemical substances and physical agents and biological 

exposure indices. 2003 TLVs and BEIs. Cincinnati, OH: American Conference of Governmental 

Industrial Hygienists, 25. 

*Adgate JL, Eberly LE, Stroebel C, et al. 2004. Personal, indoor, and outdoor VOC exposures in a 

probability sample of children. J Expo Anal Environ Epidemiol 14:S4-S13. 

*Adinolfi M. 1985. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 

27:532-537. 

*Adlercreutz H. 1995. Phytoestrogens: Epidemiology and a possible role in cancer protection. Environ 

Health Perspect 103(7):103-112. 

*Agency for Toxic Substances and Disease Registry. 1989. Decision guide for identifying substancespecific data needs related to toxicological profiles. Atlanta, GA: Agency for Toxic Substances and 

Disease Registry, Division of Toxicology. 

*Agency for Toxic Substances and Disease Registry/CDC. 1990. Subcommittee report on biological 

indicators of organ damage. Atlanta, GA: Agency for Toxic Substances and Disease Registry, Centers 

for Disease Control and Prevention. 

*Aiso S. 2006. Written communication (June 28) to Stephen Bosch, Syracuse Research Corporation, 

regarding testicular mineralization in mice in 2-year inhalation study of 1,4-DCB. 

*Aiso S, Arito H, Nishizawa T, et al. 2005a. Thirteen-week inhalation toxicity of p-dichlorobenzene in 

mice and rats. J Occup Health 47(3):249-260. 

*Aiso S, Takeuchi T, Arito H, et al. 2005b. Carcinogenicity and chronic toxicity in mice and rats 

exposed by inhalation to para-dichlorobenzene for two years. Toxicology 67:1019-1029. 

Alarie Y, Nielsen GD, Andonian-Haftvan J, et al. 1995. Physicochemical properties of nonreactive 

volatile organic chemicals to estimate RD50: Alternatives to animal studies. Toxicol Appl Pharmacol 

134(1):92-99. 

* Cited in text 
 

 

DICHLOROBENZENES 348 

9. REFERENCES 

Alarie Y, Schaper M, Nielsen GD, et al. 1996. Estimating the sensory irritating potency of airborne 

nonreactive volatile organic chemicals and their mixtures. SAR QSAR Environ Res 5:151-165. 

Alarie Y, Schaper M, Nielsen GD, et al. 1998. Structure-activity relationships of volatile organic 

chemicals as sensory irritants. Arch Toxicol 72(3):125-140. 

*Albrechtsen H-J, Smith PM, Nielsen P, et al. 1997. Importance of sediment fines in laboratory studies 

on the degradation of organic chemicals in aquifers. Water Res 31(9):2287-2299. 

Alexander M, Lustigman BK. 1966. Effects of chemical structure on microbial degradation of 

substituted benzenes. J Agric Food Chem 14:410-413. 

*Allis JW, Simmons JE, House DE, et al. 1992. The differential hepatotoxicity and cytochrome P450 

responses of Fischer-344 rats to the three isomers of dichlorobenzene. J Biochem Toxicol 7(4):257-264. 

Almeida CM, Boas LV. 2003. Analysis of BTEX and other substituted benzenes in water using 

headspace SPME-GC-FID: Method validation. J Environ Monit 6(1):80-88. 

*Altman PK, Dittmer DS. 1974. In: Biological handbooks: Biology data book, Volume III, second 

edition. Bethesda, MD: Federation of American Societies for Experimental Biology, 1987-2008, 2041. 

Ambre J, Ruo TI, Smith-Coggins R. 1986. Mothball composition: Three simple tests for distinguishing 

paradichlorobenzene from naphthalene. Ann Emerg Med 15:724-726. 

*Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor thresholds compared with 

threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl 

Toxicol 3:272-290. 

*Andersen ME, Krishman K. 1994. Relating in vitro to in vivo exposures with physiologically based 

tissue dosimetry and tissue response models. In: Salem, H, ed. Animal test alternatives. New York, 

NY: Marcel Dekker, Inc., 9-25. 

*Andersen ME, Clewell HJ III, Gargas ML, et al. 1987. Physiologically based tissue dosimetry and 

tissue response models. In: Salem H, ed. Animal test alternatives: Refinement, reduction, replacement. 

New York: Marcel Dekker Inc., 9-25. 

*Andersen ME, MacNaughton MG, Clewell HJ, et al. 1987. Adjusting exposure limits for long and 

short exposure periods using a physiological pharmacokinetic model. Am Ind Hyg Assoc J 48(4):335­

343. 

*Anderson D. 1976. Paradichlorobenzene: Estimation of its mutagenic potential in the Salmonella 

typhimurium plate incorporation mutagenicity assay. ICI Report No. CTL/P/298. 

Anderson EL. 1983a. Quantitative approaches in use to assess cancer risk. Risk Anal 3:377-295. 

Anderson GE. 1983b. Human exposure to atmospheric concentrations of selected chemicals. Vol. 2. 

Research Triangle Park, NC: U.S. Environmental Protection Agency. PB83265249. 

*Anderson D, Hodge MC. 1976. Paradichlorobenzene: Dominant lethal study in the mouse. ICI Report 

No. CTL/P/296. 
DICHLOROBENZENES 349 

9. REFERENCES 

*Anderson D, Richardson CR. 1976. Paradichlorobenzene: Cytogenic study in the rat. ICI Report No. 

CTL/P/293. 

*Anderson BE, Zeigler E, Shelby MD, et al. 1990. Chromosome aberration and sister chromatid 

exchange test results with 42 chemicals. Environ Mol Mutagen 16(18):55-137. 

Anderson KJ, Leighty EG, Takahashi MT. 1972. Evaluation of herbicides for possible mutagenic 

properties. J Agric Food Chem 20:649-656. 

Anonymous. 1988. Ortho-, meta, and para-dichlorobenzene. Rev Environ Contam Toxicol 106:51-68. 

Anonymous. 1992. Notice of intended changes- o-dichlorobenzene, dimethylamine, and dinitrotoluene. 

Appl Occup Environ Hyg 7(1):55-58. 

Anonymous. 2004. Safety assessment of MIBK (methyl isobutyl ketone). Int J Toxicol 23(Suppl 1):29­

57. 

Antoine SR, DeLeon IR, O'Dell-Smith RM. 1986. Environmentally significant volatile organic 

pollutants in human blood. Bull Environ Contam Toxicol 36:364-371. 

APHA. 1977. Methods of air sampling and analysis. 2nd ed. Washington, DC: American Public 

Health Association, 894-902. 

APHA. 1989. Standard methods for the examination of water and wastewater. 17th ed. Washington, 

DC: American Public Health Association. 

*APHA. 1995a. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6210 B. 

APHA. 1995b. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6210 C. 

APHA. 1995c. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6210 D. 

APHA. 1995d. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6220 B. 

APHA. 1995e. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6220 C. 

APHA. 1995f. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6230 B. 

APHA. 1995g. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6230 C. 

APHA. 1995h. Standard methods for the examination of water and wastewater. 19th ed. Washington, 

DC: American Public Health Association. 6230 D. 
 

 

 

 

DICHLOROBENZENES 350 

9. REFERENCES 

*APHA. 1998. Standard methods for the examination of water and wastewater. 20th ed. Washington, 

DC: American Public Health Association. 6200B. Purge and trap capillary-column gas 

chromatographic/mass spectrometric method. 

*Apodaca LE, Bails JB, Smith CM. 2002. Water quality in shallow alluvial aquifers, upper Colorado 

River Basin, Colorado, 1997. J Am Water Res Assoc 38(1):133-149. 

*Ariyoshi T, Ideguchi K, Iwasaki K, et al. 1975. Relationship between chemical structure and activity. 

II. Influences of isomers of dichlorobenzene, trichlorobenzene and tetrachlorobenzene on the activities of 

drug-metabolizing enzymes. Chem Pharm Bull 23:824-830. 

*Ashley DL, Bonin MA, Cardinali FL, et al. 1992. Determining volatile organic compounds in human 

blood from a large sample population by using purge and trap gas chromatography/mass spectrometry. 

Anal Chem 64(9):1021-1029. 

*Ashley DL, Bonin MA, Cardinali FL, et al. 1994. Blood concentrations of volatile organic compounds 

in a nonoccupationally exposed US population and in groups with suspected exposure. Clin Chem 

40(7):1401-1404. 

*Ashley DL, Bonin MA, Cardinali FL, et al. 1996. Measurement of volatile organic compounds in 

human blood. Environ Health Perspect 104:871-877. 

*Ashley DL, Bonin MA, Hamar B, et al. 1995. Removing the smoking confounder from blood volatile 

organic compounds measurements. Environ Res 71(1):39-45. 

*ASTER. 1995. ASTER (Assessment Tools for the Evaluation of Risk) ecotoxicity profile. Duluth, 

MN: U.S. Environmental Protection Agency. Environmental Research Laboratory. 

*ASTM. 1994. Standard test method for purgeable organic compounds in water using headspace 

sampling. Section 11. Water and Environmental Technology. 11.02:204-207. 

Astrand I. 1975. Uptake of solvents in the blood and tissues of man: A review. Scand J Work Environ 

Health 1:199-208. 

*Atkinson R. 1989. Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with 

organic compounds. J Phys Chem Ref Data 1:218-219. 

Axelrad DA, Morello-Frosch RA, Woodruff TJ, et al. 1999. Assessment of estimated 1990 air toxics 

concentrations in urban areas in the United States. Environ Sci Policy 2:397-411. 

*Azouz WM, Parke DV, Williams RT. 1955. Studies in detoxication. The metabolism of 

halogenobenzenes. Ortho- and para-dichlorobenzenes. Biochem J 59:410-415. 

*Backer LC, Egeland GM, Ashley DL, et al. 1997. Exposure to regular gasoline and ethanol oxyfuel 

during refueling in Alaska. Environ Health Perspect 105(8):850-855. 

Baehr AL, Stackelberg PE, Baker RJ. 1999. Evaluation of the atmosphere as a source of volatile organic 

compounds in shallow groundwater. Water Resource Res 35:127-136. 

*Bahnick DA, Doucette WJ. 1988. Use of molecular connectivity indices to estimate soil sorption 

coefficients for organic chemicals. Chemosphere 17:1703-1715. 
DICHLOROBENZENES 351 

9. REFERENCES 

Bahrami F, Bergman U, Brittebo EB, et al. 2000. Persistent olfactory mucosal metaplasia and increased 

olfactory bulb glial fibrillary acidic protein levels following a single dose of methylsulfonyldichlorobenzene in mice: Comparison of the 2,4- and 2,5-dichlorinated isomers. Toxicol Appl 

Pharmacol 162(1):49-59. 

Bahrami F, Brittebo EB, Bergman A, et al. 1999. Localization and comparative toxicity of 

methylsulfonyl-2,5- and 2,6-dichlorobenzene in the olfactory mucosa of mice. Toxicol Sci 49(1):116­

123. 

Bahrami F, van Hezik C, Bergman A, et al. 2000. Target cells for methylsulphonyl-2,6-dichlorobenzene 

in the olfactory mucosa in mice. Chem Biol Interact 128:97-113. 

Ballschmiter K, Scholz C. 1980. Microbial decomposition of chlorinated aromatic substances. VI. 

Formation of dichlorophenols and dichloropyrocatechol from dichlorobenzenes in a micromolar solution 

by Pseudomonas species. Chemosphere 9:457-467. 

Ban M, Hettich D, Goutet M, et al. 1998. Serum-borne factor(s) of 1,1-dichloroethylene and 1,2­

dichlorobenzene-treated mice inhibited in vitro antibody forming cell response and natural killer cell 

activity. Toxicol Lett 94:93-101. 

*Banerjee S, Yalkowsky SH, Valvani SC. 1980. Water solubility and octanol/water coefficients of 

organics. Limitations of the solubility-partition coefficient correlation. Environ Sci Technol 

14(10):1227-1229. 

*Barkley J, Bunch J, Bursey JT, et al. 1980. Gas chromatography mass spectrometry computer analysis 

of volatile halogenated hydrocarbons in man and his environment - A multimedia environmental study. 

Biomed Mass Spectrom 7(4):139-147. 

*Barnes DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments. 

Regul Toxicol Pharmacol 8:471-486. 

Barter JA, Sherman JH. 1999. An evaluation of the carcinogenic hazard of 1,4-dichlorobenzene based on 

internationally recognized criteria. Regul Toxicol Pharmacol 29:64-79. 

Bellar TA, Lichtenberg JJ, Kroner RC. 1974. The occurrence of organohalides in chlorinated drinking 

waters. J Am Water Works Assoc 66:703-706. 

*Ben-Dyke R, Sanderson DM, Noakes DN. 1970. Acute toxicity for pesticides (1970). World Rev Pest 

Control 9:119-127. 

*Berger GS. 1994. Epidemiology of endometriosis. In: Berger GS, ed. Endometriosis. Advanced 

management and surgical techniques. New York, NY: Springer-Verlag. 

*Bevan MAJ, Proctor CJ, Baker-Rogers J, et al. 1991. Exposure to carbon monoxide, respirable 

suspended particulates, and volatile organic compounds while commuting by bicycle. Environ Sci 

Technol 25:788-791. 

*Bio/dynamics. 1989. An inhalation two-generation reproduction study in rats with 

orthodichlorobenzene. Project No. 87-3157. Washington, DC: Chemical Manufacturers Association. 
DICHLOROBENZENES 352 

9. REFERENCES 

*Bogaards JJP, VanOmmen B, Wolf CR, et al. 1995. Human cytochrome P450 enzyme selectives in the 

oxidation of chlorinated benzenes. Toxicol Appl Pharmacol 132:44-52. 

*Bomhard E, Luckhaus G, Voight WH, et al. 1988. Induction of light hydrocarbon nephropathy by pdichlorobenzene. Arch Toxicol 61:433-439. 

Bomhard EM, Schmidt U, Loser E. 1998. Time course of enzyme induction in liver and kidneys and 

absorption, distribution and elimination of 1,4-dichlorobenzene in rats. Toxicology 131:73-91. 

*Bonanno LJ, Freeman NCG, Greenberg M, et al. 2001. Multivariate analysis on levels of selected 

metals, particulate matter, VOC, and household characteristics and activities from the midwestern states 

NHEXAS. Appl Occup Environ Hyg 16(9):859-874. 

*Bonnet P, Morele Y, Raoult G, et al. 1982. Determination de la concentration lethale50 des principaux 

hydrocarbures aromatiques chez le rat. Arch Mal Prof 43:261-265. 

*Borghoff SJ, Andersen ME, Conolly RB. 1991. Protein nephropathy and kidney cancer in male rats: 

Qualitative and quantitative issues and human relevance. CIIT Activities 11(1):107. 

*Bornatowicz N, Antes A, Winker N. 1994. 2-generational reproduction study with 1,4-dichlorobenzol 

in rats. Wierner klinische Wochenschrift [Vienna Clinical Weekly] 106/11:345-353. 

*Bosma TMP, te Wescher RAG, Schraa G. 1990. Microbial aspects of the behaviour of chlorinated 

compounds during soil passage. Proceedings of the 6th European Symposium on organic micropollutants 

in the aquatic environment. Lisbon, Portugal, May 22-24, 1990. 

*Bouwer EJ, McCarty PL. 1982. Removal of trace chlorinated organic compounds by activated carbon 

and fixed-film bacteria. Environ Sci Technol 16:836-843. 

*Bouwer EJ, McCarty PL. 1983. Transformations of halogenated organic compounds under 

dentrification conditions. Appl Environ Microbiol 45:1295-1299. 

*Bouwer EJ, McCarty PL. 1984. Modeling of trace organics biotransformation in the subsurface. 

Ground Water 22:433-440. 

*Bozzelli JW, Kebbekus BB. 1979. Analysis of selected volatile organic substances in ambient air. New 

Jersey Department of Environmental Protection, Program on Environmental Cancer and Toxic 

Substances. 

Bozzelli JW, Kebbekus BB. 1982. A study of some aromatic and halocarbon vapors in the ambient 

atmosphere of New Jersey. J Environ Sci Health A17:693-713. 

Brantley AS, Townsend TG. 1999. Leaching of pollutants from reclaimed asphalt pavement. Environ 

Eng Sci 16(2):105-116. 

*Bristol DW, Crist HL, Lewis RG, et al. 1982. Chemical analysis of human blood for assessment of 

environmental exposure to semivolatile organochlorine chemical contaminants. J Anal Toxicol 6:269­

275. 
DICHLOROBENZENES 353 

9. REFERENCES 

Brodzinsky R, Singh HB. 1983. Volatile organic chemicals in atmosphere: An assessment of available 

data. Research Triangle Park, NC: U.S. Environmental Protection Agency, Environmental Research 

Laboratory. EPA600383027(A). 

Brondeau MT, Ban M, Bonnet P, et al. 1986. Concentration-related changes in blood and tissue 

parameters of hepatotoxicity and their interdependence in rats exposed to bromobenzene and 1,2­

dichlorobenzene. Toxicol Lett 31:159-166. 

Brondeau MT, Ban M, Bonnet P, et al. 1989. Acetone compared to other ketones in modifying the 

hepatotoxicity of inhaled 1,2-dichlorobenzene in rats and mice. Toxicol Lett 49:69-78. 

Brondeau MT, Bonnet P, Gueniuer JP, et al. 1983. Short-term inhalation test for evaluating industrial 

hepatotoxicants in rats. Toxicol Lett 19:139-146. 

*Brondeau MT, Bonnet P, Guenier JP, et al. 1990. Adrenal-dependent leucopenia after short-term 

exposure to various airborne irritants in rats. J Appl Toxicol 10(2):83-86. 

Brondeau MT, Hesbert A, Beausoleil C, et al. 1999. To what extent are biomonitoring data available in 

chemical risk assessment? Hum Exp Toxicol 18:322-326. 

*Brown KW, Donnelly KC. 1988. An estimation of the risk associated with the organic constituents of 

hazardous and municipal waste landfill leachates. Haz Waste Haz Mater 5:1-30. 

*Brown SK, Sim MR, Abramson MJ, et al. 1994. Concentrations of volatile organic compounds in 

indoor air- a review. Indoor Air 4:123-134. 

*Bruce BW, McMahon PB. 1996. Shallow ground-water quality beneath a major urban center: Denver, 

Colorado, USA. J Hydrol 186:129-151. 

Brunce N, Kumar Y, Ravanal L, et al. 1978. Photochemistry of chlorinated byphenyls in iso-octane 

solution. J Chem Soc Perkin Transact II, 880-884. 

*Buckley TJ, Liddle J, Ashley DL, et al. 1997. Environmental and biomarker measurements in nine 

homes in the lower Rio Grande Valley: Multimedia results for pesticides, metals, PAHs, and VOCs. 

Environ Int 23(5):705-732. 

*Bush B, Smith RM, Narang AS, et al. 1984. Photoionization conductivity detection limits for 

environmental pollutants with and without chromophores. Anal Lett 17:467-547. 

*Campbell DM, Davidson RJ. 1970. Toxic haemolytic anemia in pregnancy due to a pica for 

paradichlorobenzene. J Obstet Gynaecol Br Commonw 77:657-659. 

*Canonero R, Campart GB, Mattioli F, et al. 1997. Testing of p-dichlorobenzene and hexachlorobenzene 

for their ability to induce DNA damage and micronucleus formation in primary cultures of rat and human 

hepatocytes. Mutagenesis 12(1):35-39. 

*Carbonell E, Puig N, Creus A, et al. 1991. Sister-chromatid exchanges (SCE) induced by pdichlorobenzene in cultured human lymphocytes. Mutat Res 263:57-59. 

*Carlson GP. 1977. Chlorinated benzene induction of hepatic porphyria. Experientia 33:1627-1629. 
 

 

DICHLOROBENZENES 354 

9. REFERENCES 

*Carlson GP, Tardiff R. 1976. Effect of chlorinated benzenes on the metabolism of foreign organic 

compounds. Toxicol Appl Pharmacol 36:383-394. 

Carlsson C, Fredriksson A, Brandt I. 2003. 2,6-Dichlorophenyl methylsulphone induced behavioural 

impairments in rats and mice in relation to olfactory mucosal metaplasia. Pharmacol Toxicol 93(4):156­

168. 

CCRIS. 1990. Chemical Carcinogenesis Research Information Systems. Bethesda, MD: National 

Library of Medicine. July 6, 1990. 

CESARS. 1990. Chemical Evaluation Search and Retrieval System. Baltimore, MD: Chemical 

Information Systems, Inc. July 26, 1990. 

*Chan CC, Valner L, Martin JW, et al. 1990. Determination of organic contaminants in residential 

indoor air using an adsorption-thermal desorption technique. J Air Waste Manage Assoc 40:62-67. 

*Chapman PM, Downie J, Maynard A. 1996a. Coal and deodorizer residues in marine sediments 

contaminants or pollutants. Environ Toxicol Chem 15(5):638-642. 

*Chapman PM, Paine MD, Arthur AD, et al. 1996b. A triad study of sediment quality associated with a 

major, relatively untreated marine sewage discharge. Mar Pollut Bull 32(1):47-64. 

*Charbonneau M, Short B, Lock E, et al. 1987. Mechanism of petroleum-induced sex-specific protein 

droplet nephropathy and renal cell proliferation in Fischer-344 rats: Relevance to humans. In: Hemphill 

DD, ed. Trace substances in environmental health, 21st Annual Conference, St. Louis, MO. Columbia, 

MO: University of Missouri, 263-273. 

*Charbonneau M, Strasser J, Lock EA, et al. 1989a. 1,4-Dichlorobenzene-induced nephrotoxicity: 

Similarity with unleaded gasoline (UG)-induced renal effects. In: Bach P, Lock EA, eds. 

Nephrotoxicity: In vitro to in vivo. Animals to man. New York, NY: Plenum Press, 557-562. 

*Charbonneau M, Strasser J, Lock EA, et al. 1989b. Involvement of reversible binding to α2μ-globulin 

in 1,4-dichlorobenzene-induced nephrotoxicity. Toxicol Appl Pharmacol 99:122-132. 

Chemline. 1990. Chemical dictionary online. Bethesda, MD: National Library of Medicine, National 

Toxicology Information Program. July 5, 1990. 

*Chen CS, Zoltek J. 1995. Organic priority pollutants in wetland-treated leachates at a landfill in central 

Florida. Chemosphere 31(6):3455-3464. 

*Chiou CT. 1985. Partition coefficients of organic compounds in lipid-water systems and correlations 

with fish bioconcentration factors. Environ Sci Technol 19:57-62. 

Chiou CT, Freed VH, Schmedding DW, et al. 1977. Partition coefficient and bioaccumulation of 

selected organic chemicals. Environ Sci Technol 11:475-478. 

*Chiou CT, Porter PE, Schmedding DW. 1983. Partition equilibria of nonionic organic compounds 

between soil organic matter and water. Environ Sci Technol 17:227-231. 

*Chung HY. 1999. Volatile components in crabmeats of Charybdis feriatus. J Agric Food Chem 

47:2280-2287. 
 

 

DICHLOROBENZENES 355 

9. REFERENCES 

*CITI. 1992. o-Dichlorobenzene and 1,3-Dichlorobenzene. In: Biodegradation and bioaccumulation 

data of existing chemicals based on the CSCL Japan. Chemicals Inspection and Testing Institute, 3-11-3­

12. 

Clayton GD, Clayton FE, eds. 1981. Patty's industrial hygiene and toxicology. 3rd ed. Vol. 2B, 

Toxicology. New York: John Wiley and Sons, Inc., 3617. 

*Clewell HJ III, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. 

Toxicol Ind Health 1:111-113. 

CLPSD. 1990. Contract Laboratory Program Statistical Database. Viar and Company, Management 

Service Division, Alexandria, VA. July 1990. 

*CMR. 1990. Chemical profile: p-dichlorobenzene. Chemical Marketing Reporter, July 16, 1990. 

*CMR. 1996. Chemical profile. o-dichlorobenzene. Chemical Marketing Reporter. September 09, 

1996. 

*CMR. 1999. Chemical profile. p-dichlorobenzene. Chemical Market Reporter. June 07, 1999. 

Cohen S, Svrjcek A, Durborrow T, et al. 1999. Ground water quality: Water quality impacts by golf 

courses. J Environ Qual 28:798-809. 

*Colacci A, Bartoli S, Bonora B, et al. 1990. In vivo and in vitro interaction of 1,2-dichlorobenzene with 

nucleic acids and proteins of mice and rats. Tumori 76:339-344. 

*Colborn T, Clement C, eds. 1992. Chemically-induced alterations in sexual and functional 

development: The wildlife human connection. In: Advances in modern environmental toxicology, Vol. 

XXI, Princeton, NJ: Princeton Scientific Publishing. 

*Colborn T, vom Saal FS, Soto AM. 1993. Developmental effects of endocrine-disrupting chemicals in 

wildlife and humans. Environ Health Perspect 101(5):378-384. 

*Cole RH, Frederick RE, Healy RP, et al. 1984. Preliminary findings of the priority pollutant monitoring 

project of the nationwide urban runoff program. J Water Pollut Control Fed 56:898-908. 

Coleman WE, Lingg RD, Melton RG, et al. 1975. The occurrence of volatile organics in five drinking 

water supplies using gas chromatography/mass spectrometry. In: Keith LW, ed. Identification and 

analysis of organic pollutants in water. Ann Arbor, MI: Ann Arbor Science Publishers, Inc., 305-327. 

Cone MV, Baldauf MF, Opresko DM, et al. 1983. Chemicals identified in human breast milk, a 

literature search. Oak Ridge National Laboratory report under EPA/DOE IAG No. DW930139-01-1. 

Office of Pesticides and Toxic Substances. EPA560583009. 

*Coniglio WA, Miller K, MacKeever D. 1980. The occurrence of volatile organics in drinking water. 

Washington, DC: U.S. Environmental Protection Agency, Criteria and Standards Division. 

*Connor TH, Theiss JC, Hanna HA, et al. 1985. Genotoxicity of organic chemicals frequently found in 

the air of mobile homes. Toxicol Lett 25:33-40. 
 

 

DICHLOROBENZENES 356 

9. REFERENCES 

*Cotter LH. 1953. Paradichlorobenzene poisoning from insecticides. NY State J Med (July 15):1690­

1692. 

Cramer PH, Boggess KE, Hosenfeld JM, et al. 1988. Determination of organic chemicals in human 

whole blood: Preliminary method development for volatile organics. Bull Environ Contam Toxicol 

40:612-618. 

CRIS/USDA. 1990. Current Research Information System. Palo Alto, CA: U.S. Department of 

Agriculture. Dialog Information Systems, Inc. July 6, 1990. 

*Crisp TM, Clegg ED, Cooper RL, et al. 1998. Environmental endocrine disruption: An effects 

assessment and analysis. Environ Health Perspect 106(1):11-56. 

*Cuppit LT. 1980. Fate of toxic and hazardous materials in the air environment. Research Triangle 

Park, NC: U.S. Environmental Protection Agency, Environmental Sciences Research Laboratory. 

PB80221948. 

Daft JL. 1989. Determination of fumigants and related chemicals in fatty and nonfatty foods. J Agric 

Food Chem 37:560-564. 

*Daston GP, Gooch JW, Breslin WJ, et al. 1997. Environmental estrogens and reproductive health: A 

discussion of the human and environmental data. Reprod Toxicol 11(4):465-481. 

*Daubert TE, Danner RP. 1992. 1,4-Dichlorobenzene. In: Physical and thermodynamic properties of 

pure chemicals. Part 3. Philadelphia, PA: Taylor & Francis. 

*Davies K. 1988. Concentrations and dietary intake of selected organochlorines, including PCBs, 

PCDDs and PCDFs in fresh food composites grown in Ontario, Canada. Chemosphere 17(2):263-276. 

Deceaurriz J, Gagnaire F, Ban M, et al. 1988. Assessment of the relative hazard involved with airborne 

irritants with additional hepatotoxic or nephrotoxic properties in mice. J Appl Toxicol 8:417-422. 

Deichmann WB, Mergard EG. 1948. Comparative evaluation of methods employed to express the 

degree of toxicity of a compound. J Ind Hyg Toxicol 30:373-378. 

*Delfino RJ, Gong H Jr., Linn WS, et al. 2003. Asthma symptoms in Hispanic children and daily 

ambient exposures to toxic and criteria air pollutants. Environ Health Perspect 111(4):647-656. 

*DeMarini DM, Brooks HG. 1992. Induction of phophage lambda by chlorinated organics: Detection of 

some single-species/single-site carcinogens. Environ Mol Mutagen 19:98-111. 

*Den Besten C, Ellenbroek M, Van Der Ree MAE, et al. 1992. The involvement of primary and 

secondary metabolism in the covalent binding of 1,2 and 1,4,-dichlorobenzenes. Chem Biol Interact 

84:259-275. 

*Den Besten C, Jurgen JRM, Besselink HT, et al. 1991. The liver, kidney, and thyroid toxicity of 

chlorinated benzenes. Toxicol Appl Pharmacol 111:69-81. 

*DHHS. 1995. Report to Congress on workers' home contamination study conducted under the workers' 

family protection act (29 USC. 671a). Cincinnati, OH: U.S. Department of Health and Human Services. 

National Institute for Occupational Safety and Health. 
DICHLOROBENZENES 357 

9. REFERENCES 

*Dietrich DR, Swenberg JA. 1991. NCI-black-Reiter (NBR) male rats fail to develop renal disease 

following exposure to agents that induce delta-2μ-globulin (2μ) nephropathy. Fundam Appl Toxicol 

16:749-762. 

DOT. 1990a. Department of Transportation. Code of Federal Regulations. 49 CFR 172.101. 

DOT. 1990b. Department of Transportation. Code of Federal Regulations. 49 CFR 172.101, App. A. 

DOT. 1990c. Department of Transportation. Code of Federal Regulations. 49 CFR 172.101, App. B. 

Dowty BJ, Carlisle DR, Laseter JL. 1975. New Orleans drinking water sources tested by gas 

chromatography-mass spectrometry. Environ Sci Technol 9:762-765. 

*Dreisbach RH, ed. 1987. Handbook of poisoning. Norwalk, CT: Appleton and Lange. 

*Dressman RC, Fair J, McFarren EF. 1977. Determinative method for analysis of aqueous sample 

extracts for bis(2-chloro)ethers and dichlorobenzenes. Environ Sci Technol 11:719-721. 

Dunovant VS, Clark CS, Que Hee SS, et al. 1986. Volatile organics in the wastewater and airspaces of 

three wastewater treatment plants. J Water Pollut Control Fed 58:886-895. 

*DuPont. 1982. Comparative toxicity of ortho dichlorobenzene (ODCB) and trichlorobenzene (TCB). 

E.I. DuPont Denemours and Company, Inc. Submitted to the U.S. Environmental Protection Agency 

under TSCA Section 8D. OTS0215033. 

*Edelman P, Osterloh J, Pirkle J, et al. 2003. Biomonitioring of chemical exposure among New York 

City firefighters responding to the world trade center fire and collapse. Environ Health Perspect 

111(16):1906-1911. 

*Eganhouse RP, Cozarelli IM, Scholl MA, et al. 2001. Natural attenuation of volatile organic 

compounds (VOC's) in the leachate plume of a municipal landfill: Using alkylbenzenes as process 

probes. Ground Water 39:192-202. 

Eguchi K, Ozawa M, Endoh YS, et al. 2003. Validity test for a yeast two-hybrid assay to screen for 

estrogenic activity and its application to insecticides and disinfectants for veterinary use. Bull Environ 

Contam Toxicol 70(2):226-232. 

*Eitzer BD. 1995. Emissions of volatile organic chemicals from municipal solid waste composting 

facilities. Environ Sci Technol 29:896-902. 

*Eklund B, Anderson EP, Walker BL, et al. 1998. Characterization of landfill gas composition at the 

fresh kills municipal solid-waste landfill. Environ Sci Technol 32(32):2233-2237. 

Elcombe CR, Odum J, Foster JR, et al. 2002. Prediction of rodent nongenotoxic carcinogenesis: 

evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP 

carcinogens. Environ Health Perspect 110(4):363-375. 

*Elder VA, Proctor BL, Hites RA. 1981. Organic compounds found near dump sites in Niagara Falls, 

NY. Environ Sci Technol 15:1237-1243. 
DICHLOROBENZENES 358 

9. REFERENCES 

*Eldridge SR, Goldsworthy TL, Popp JA. 1992. Mitogenic stimulation of hepatocellular proliferation in 

rodents following 1,4 dichlorobenzene administration. Carcinogenesis 13(3):409-415. 

*Eldridge SR, Tilbury LF, Goldsworthy TL, et al. 1990. Measurement of chemically induced cell 

proliferation in rodent liver and kidney: A comparison of 5-bromo-2'-deoxyuridine and [3

H]thymidine 

administered by injection or osmotic pump. Carcinogenesis 11(12):2245-2251. 

Elkilani AS, Baker CGJ, Al-Shammari QH, et al. 2003. Sorption of volatile organic compounds on 

typical carpet fibers. Environ Int 29:575-585. 

*Elkins HB. 1950. The chemistry of industrial toxicology. New York, NY: John Wiley and Sons, Inc., 

147, 205-206, 221-223. (As cited in Hollingsworth et al. 1958) 

*Ellenhorn MJ, Barceloux, DG, eds. 1997. Medical toxicology: Diagnosis and treatment of human 

poisoning. New York, NY: Elsevier Publishing. 

*Elliot L, Longnecker MP, Kissling GE, et al. 2006. Volatile organic compounds and pulmonary 

function in the Third National Health and Nutrition Examination Survey, 1988-1994. Environ Health 

Perspect 114(8):1210-1214. 

*Elovaara E. 1998. Dichlorobenzenes. The Nordic expert group for criteria documentation of health 

risks from chemicals. In: Arbete och Halsa. Soina, Sverige: Arbetslivsinstitutet & Forfattarna, 1-76. 

EPA. 1975. Identification of organic compounds in effluents from industrial sources. Washington, DC: 

U.S. Environmental Protection Agency, Office of Toxic Substances. 

EPA. 1977. Investigation of selected potential environmental contaminants: Halogenated benzenes. 

Washington, DC: U.S. Environmental Protection Agency, Office of Toxic Substances. EPA560277004. 

EPA. 1978. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 116.4. 

EPA. 1979a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 401.15. 

EPA. 1979b. Water-related environmental fate of 129 priority pollutants. Vol. I. Introduction and 

technical background, metals and inorganics, pesticides and PCBs. Washington, DC: U.S. 

Environmental Protection Agency, Office of Water Planning and Standards. EPA440479029A. 

PB80204373. 

*EPA. 1980a. Ambient water quality criteria for dichlorobenzenes. Washington, DC: U.S. 

Environmental Protection Agency, Environmental Criteria and Assessment Office for the Office of Water 

Regulations and Standards. EPA440580039. 

EPA. 1980b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261.33. 

*EPA. 1981a. An exposure and risk assessment for dichlorobenzenes. Washington, DC: U.S. 

Environmental Protection Agency, Office of Water Regulations and Standards. 

*EPA. 1981b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 413.02. 

*EPA. 1981c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261, 

App. VII. 
DICHLOROBENZENES 359 

9. REFERENCES 

EPA. 1982a. Chlorinated hydrocarbons. Test method - method 612. Cincinnati, OH: U.S. 

Environmental Protection Agency, Environmental Monitoring Systems Laboratory. 

EPA. 1982b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 712.30. 

EPA. 1982c. Purgeables. Test method - method 624. Cincinnati, OH: U.S. Environmental Protection 

Agency, Environmental Monitoring Systems Laboratory. 

EPA. 1982d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 423.17 and
 

Appendix A.
 

EPA. 1982e. Purgeable halocarbons: Test method - method 601. Cincinnati, OH: U.S. Environmental 

Protection Agency, Environmental Monitoring Systems Laboratory. 

EPA. 1982f. Test method - Base/neutrals and acids. Method-625. In: Method for determination of 

organic compounds in drinking water. Cincinnati, OH: U.S. Environmental Protection Agency, 

Environmental Monitoring Systems Laboratory. EPA600782039. 

EPA. 1982g. U.S. Environmental Protection Agency. Fed Regist 47:26992, 27007-27008. 

EPA. 1982h. 1,4-Dichlorobenzene. In: Kayser R, Sterling D, Viviani D, eds. Intermedia priority
 

pollutant guidance documents. Washington, DC: U.S. Environmental Protection Agency, Office of 

Pesticides and Toxic Substances. 

EPA. 1982i. Purgeable aromatics. Test method - method 602. Cincinnati, OH: U.S. Environmental 

Protection Agency, Environmental Monitoring Systems Laboratory. 

*EPA. 1983a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 60.489. 

*EPA. 1983b. Chemicals identified in human breast milk. A literature search. Washington, DC: U.S. 

Environmental Protection Agency, Office of Pesticides and Toxic Substances. EPA560583009. 

EPA. 1983c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 122, App. 

D. 

*EPA. 1983d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 433.11. 

EPA. 1983e. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261, App. 

III. 

EPA. 1983f. Methods for chemical analysis of water and wastes. Cincinnati, OH: U.S. Environmental 

Protection Agency, Office of Research and Development, Environmental Monitoring and Support 

Laboratory. EPA600479020. 

EPA. 1983g. Treatability manual. Vol. I. Treatability data. Washington, DC: U.S. Environmental 

Protection Agency, Office of Research and Development. EPA600282001a. 

*EPA. 1984a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 125. 
DICHLOROBENZENES 360 

9. REFERENCES 

*EPA. 1984b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 136, App. 

A. 

*EPA. 1984c. Method 612. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 

CFR 136. 

*EPA. 1984d. Method 624. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 

CFR 136. 

EPA. 1984e. Method 601. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 

CFR 136. 

EPA. 1984f. Method 602. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 

CFR 136. 

*EPA. 1985a. Health assessment document for chlorinated benzenes. Final report. Washington, DC: 

U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. 

EPA600884015F. 

*EPA. 1985b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 117.3. 

*EPA. 1985c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 302.4. 

*EPA. 1985d. Atmospheric fates of organic chemicals: Prediction of ozone and hydroxyl radical 

reaction rates and mechanisms. Research Triangle Park, NC: U.S. Environmental Protection Agency, 

Office of Research and Development. EPA600385063. 

EPA. 1986a. Aromatic volatile organics - method 8020. In: Test methods for evaluating solid waste. 

3rd ed. SW-846. Washington, DC: U.S. Environmental Protection Agency, Office of Solid Waste and 

Emergency Response. 

EPA. 1986b. Gas chromatography/mass spectrometry for semivolatile organics: Capillary column 

technique-method 8270. In: Test methods for evaluating solid waste. 3rd ed. SW-846. Washington, 

DC: U.S. Environmental Protection Agency, Office of Solid Waste and Emergency Response. 

*EPA. 1986c. Halogenated volatile organics - method 8010. In: Test methods for evaluating solid 

waste. 3rd ed. SW-846. Washington, DC: U.S. Environmental Protection Agency, Office of Solid 

Waste and Emergency Response. 

*EPA. 1986d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 403. 

App. B. 

EPA. 1986e. Identification of wastes to be evaluated by May 8, 1990. U.S. Environmental Protection 

Agency. Code of Federal Regulations. 40 CFR 268.12. 

EPA. 1986f. Broad scale analysis of the FY 82 national human adipose tissue survey specimens. 

Volume II: Volatile organic compounds. Washington, DC: U.S. Environmental Protection Agency. 

Office of Toxic Substances. EPA560586036. 

EPA. 1986g. Superfund public health evaluation manual. Washington, DC: U.S. Environmental 

Protection Agency: Office of Emergency and Remedial Response. EPA540186060. 
DICHLOROBENZENES 361 

9. REFERENCES 

EPA. 1986h. Volatile aromatic and unsaturated organic compounds in water by purge and gas trap 

chromatography. Method 503.1. In: Methods for the determination of organic compounds in drinking 

water. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Monitoring Systems 

Laboratory. EPA600488039. 

*EPA. 1987a. Health effects assessment for dichlorobenzene. Cincinnati, OH: U.S. Environmental 

Protection Agency, Environmental Criteria and Assessment Office. EPA600888028. PB88179387. 

EPA. 1987b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 141.32. 

*EPA. 1987c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.25. 

*EPA. 1987d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.35. 

*EPA. 1987e. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.45. 

*EPA. 1987f. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.55. 

*EPA. 1987g. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.65. 

*EPA. 1987h. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.75. 

*EPA. 1987i. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.85. 

*EPA. 1987j. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.91. 

*EPA. 1987k. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.101. 

EPA. 1987l. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 264, App. 

IX. 

EPA. 1987m. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 268, App. 

III. 

EPA. 1987n. Preliminary use and substitutes analysis of para-dichlorobenzene. Washington, DC: U.S. 

Environmental Protection Agency, Office of Toxic Substances. 

EPA. 1987o. The total exposure assessment methodology (TEAM) study: Summary and analysis: 

Volume I. Washington, DC: U.S. Environmental Protection Agency, Office of Research and 

Development. EPA600687002a. 

EPA. 1987p. Final draft criteria document for ortho-dichlorobenzene, meta-dichlorobenzene, paradichlorobenzene. Washington, DC: U.S. Environmental Protection Agency. Criteria and Standards 

Division, Office of Drinking Water. 

*EPA. 1988a. Method T014-1. Compendium of methods for the determination of toxic organic 

compounds in ambient air. U.S. Department of Commerce. EPA600489017. 

*EPA. 1988b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261, App. 

VIII. 
 

 

DICHLOROBENZENES 362 

9. REFERENCES 

*EPA. 1988c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 372.65. 

*EPA. 1988d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 716.120. 

*EPA. 1988e. Recommendations for and documentation of biological values for use in risk assessment. 

Cincinnati, OH: U.S. Environmental Protection Agency. PB88179874. 

EPA. 1989a. Interim methods for development of inhalation reference doses. Washington, DC: U.S. 

Environmental Protection Agency, Office of Health and Environmental Assessment. EPA600888066F. 

EPA. 1989b. Measurement of purgeable organic compounds in water by capillary column gas 

chromatography/mass spectrometry-method 524.2. In: Methods for the determination of organic 

compounds in drinking water. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental 

Monitoring Systems Laboratory. EPA600488039. 

EPA. 1989c. Measurement of purgeable organic compounds in water by packed column gas 

chromatography/mass spectrometry-method 524.1 In: Methods for the determination of organic 

compounds in drinking water. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental 

Monitoring Systems Laboratory. EPA600488039. 

*EPA. 1989d. NHATS broad scan analysis: Population estimates from fiscal year 1982 specimens. 

Washington, DC: U.S. Environmental Protection Agency, Office of Toxic Substances. EPA560590001. 

EPA. 1989e. Volatile halogenated organic compounds in water by purge and trap gas chromatographymethod 502.1. In: Methods for the determination of organic compounds in drinking water. Cincinnati, 

OH: U.S. Environmental Protection Agency, Environmental Monitoring System Laboratory. 

EPA600488039. 

EPA. 1989f. Volatile organic compounds in water by purge and trap capillary column gas 

chromatography with protoionization and electrolytic conductivity detectors in series-method 502.2. In: 

Methods for the determination of organic compounds in drinking water. Cincinnati, OH: U.S. 

Environmental Protection Agency, Environmental Monitoring Systems Laboratory. EPA600488039. 

EPA. 1990a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261.24. 

EPA. 1990b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 268.35. 

EPA. 1990c. Standards of performance for volatile organic compounds (VOC) emissions from synthetic 

organic chemical manufacturing industry (SOCMI) distillation operation. U.S. Environmental Protection 

Agency. Code of Federal Regulations. 40 CFR 60.667. 

*EPA. 1990d. Interim methods for development of inhalation reference concentrations. Washington, 

DC: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Office of 

Research and Development, Environmental Criteria and Assessment Office. EPA600890066A. 

*EPA. 1991a. Method 502.1. Methods for the determination of organic compounds in drinking water. 

U.S. Department of Commerce. U.S. Environmental Protection Agency. EPA600488039. 

*EPA. 1991b. Method 502.2. Methods for the determination of organic compounds in drinking water. 

U.S. Department of Commerce. U.S. Environmental Protection Agency. EPA600488039. 
 

 

DICHLOROBENZENES 363 

9. REFERENCES 

*EPA. 1991c. Method 503.1. Methods for the determination of organic compounds in drinking water. 

U.S. Department of Commerce. U.S. Environmental Protection Agency. EPA600488039. 

EPA. 1991d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 258, App. 

I. 

EPA. 1991e. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 258, App. 

II. 

EPA. 1991f. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 266, App. 

IV. 

EPA. 1991g. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 266, App. 

VII. 

EPA. 1991h. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 268, App. 

IV. 

*EPA. 1991i. α2μ-Globulin: Association with chemically induced renal toxicity and neoplasia in the 

male rat. Washington, DC. U.S. Environmental Protection Agency. Risk Assessment Forum.
 

EPA625391019F. 

EPA. 1991j. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 141.61. 

EPA. 1991k. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 142.62. 

EPA. 1991l. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 257, App. I. 

*EPA. 1992a. Method 524.2. Methods for determination of organic compounds in drinking water. 

Supplement II. U. S. Department of Commerce. EPA600R92129. 

EPA. 1992b. Health effects assessment summary tables. Washington, DC: U.S. Environmental 

Protection Agency, 1-25; 3-12. OERR 9200.6-303(92-1). 

EPA. 1993. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 455.50, 

Tables 4, 5, and 6. 

*EPA. 1994a. Method 5030A. Purge-and-trap. U.S. Environmental Protection Agency. 

*EPA. 1994b. Method 8010B. Halogenated volatile organics by gas chromatography. U.S.
 

Environmental Protection Agency. 

EPA. 1994c. Method 8020A. Aromatic volatile organics by gas chromatography. U.S. Environmental 

Protection Agency. 

EPA. 1994d. Method 8021A. Halogenated volatiles by gas chromatography using photoionization and 

electrolytic conductivity detectors in series: Capillary column technique. U. S. Environmental Protection 

Agency, 1-22. 
 

 

 

DICHLOROBENZENES 364 

9. REFERENCES 

EPA. 1994e. Method 8120A. Chlorinated hydrocarbons by gas chromatography. U.S. Environmental 

Protection Agency. 

*EPA. 1994f. Method 0010. Modified method 5 sampling train. U.S. Environmental Protection 

Agency. 

EPA. 1994g. Method 8260A. Volatile organic compounds by gas chromatography/mass spectrometry 

(GC/MS): Capillary column technique. U.S. Environmental Protection Agency. 

*EPA. 1994h. Method 0030. Volatile organic sampling train. U.S. Environmental Protection Agency. 

*EPA. 1994i. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 63.106. 

*EPA. 1994j. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 63.110, 

Appendix, Table 9. 

*EPA. 1994k. Methods for derivation of inhalation reference concentrations and application of 

inhalation dosimetry. .U.S. Environmental Protection Agency, Environmental Criteria and Assessment 

Office. EPA600890066F 

*EPA. 1994l. Method 8121. Chlorinated hydrocarbons by gas chromatography: Capillary column 

technique. On-line test methods for evaluating solid wastes physical/chemical methods. SW-846. U.S. 

Environmental Protection Agency. http://www.epa.gov/epaoswer/hazwaste/test/main.htm. October 3, 

2005. 

*EPA. 1996a. Drinking water regulations and health advisories. Office of Water. U.S. Environmental 

Protection Agency. 

*EPA. 1996b. Data Evaluation Record (DER) for p-dichlorobenzene – chronic oral toxicity in dogs 

(MRID# 439888-01 and -02) for Section 6 (a) (2) and reregistration need. U.S. Environmental Protection 

Agency, Office of Prevention, Pesticides and Toxic Substances. 

*EPA. 1996c. Method 5035. Closed-system purge-and-trap and extraction for volatile organics in soil 

and waste samples. On-line test methods for evaluating solid wastes physical/chemical methods. SW846. U.S. Environmental Protection Agency. http://www.epa.gov/epaoswer/hazwaste/test/main.htm. 

September 23, 2005. 

*EPA. 1996d. Method 8021B. Aromatic and halogenated volatiles by gas chromatography using 

photoionization and/or electrolytic conductivity detectors. On-line test methods for evaluating solid 

wastes physical/chemical methods. SW-846. U.S. Environmental Protection Agency. 

http://www.epa.gov/epaoswer/hazwaste/test/main.htm. September 26, 2005. 

EPA. 1996e. Method 8121. U.S. Environmental Protection Agency Office of Solid Waste. 

EPA. 1997a. Land disposal restrictions: Correction of tables; Treatment standards for hazardous wastes 

and universal treatment standards. (Technical amendment to final rule). U.S. Environmental Protection 

Agency. Fed Regist 62:7502. 

*EPA. 1997b. Toxic chemical release inventory reporting form R and instructions (revised 1996 

version). Washington, DC: U.S. Environmental Protection Agency, Office of Pollution Prevention and 

Toxics. EPA745K97001. 
 

 

 

 

DICHLOROBENZENES 365 

9. REFERENCES 

*EPA. 1997c. Special report on environmental endocrine disruption: An effects assessment and 

analysis. Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum. 

EPA630R96012. 

EPA. 1997d. Automated Form R for Windows: User’s guide (RY97). Washington, DC: U.S. 

Environmental Protection Agency, Office of Pollution Prevention and Toxics. 

*EPA. 2002a. Method 624- Purgeables. Methods for organic chemical analysis of municipal and 

industrial wastewater. Washington, DC: U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 136, Appendix A. 

*EPA. 2002b. Method 612- Chlorinated hydrocarbons in water by GCECD. Washington, DC: U.S. 

Environmental Protection Agency. Code of Federal Regulations. 40 CFR 136, Appendix A. 

*EPA. 2002c. Method 601-Purgeable halocarbons. Washington, DC: U.S. Environmental Protection 

Agency Code of Federal Regulations. 40 CFR 136, Appendix A. 

*EPA. 2002d. Method 602- Purgeable aromatics. Washington, DC: U.S. Environmental Protection 

Agency. Code of Federal Regulations. 40 CFR 136, Appendix A. 

*EPA. 2002e. Inventory Update Rule (IUR). Toxic Substances Control Act (TSCA) Inventory Update 

Database. Washington, DC: U.S. Environmental Protection Agency. 

http://www.epa.gov/oppt/uiru/iur02/index.htm. 

*EPA. 2004a. 2004 edition of the drinking water standards and health advisories. Washington, DC: 

U.S. Environmental Protection Agency, Office of Water. EPA822R04005. 

www.epa.gov/waterscience/drinking/standards/dwstandards. June 06, 2004. 

*EPA. 2004b. Designation, reportable quantities, and notification: Designation of hazardous substances. 

Washington, DC: U.S. Environmental Protection Agency. Code of Federal Regulations. 40CFR 302.4. 

www.epa.golv/epahome/cfr40.htm. June 06, 2004. 

*EPA. 2004c. Identification and listing of hazardous waste: Hazardous constituents. Washington, DC: 

U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261, Appendix VIII. 

www.epa.gov/epahome/cfr40.htm. June 06, 2004. 

*EPA. 2004d. National primary drinking water regulations: Maximum contaminant level goals for 

organic contaminants. Washington, DC: U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 141.50. www.epa.gov/epahome/cfr.htm. June 06, 2004. 

EPA. 2004e. National primary drinking water regulations: Maximum contaminant levels for inorganic 

contaminants. Washington, DC: U.S. Environmental Protection Agency. Code of Federal Regulations. 

40CFR 141.62. www.epa.gov/epahome/cfr40.htm. June 06, 2004. 

*EPA. 2004f. National primary drinking water regulations: Maximum contaminant levels for organic 

contaminants. Washington, DC: U.S. Environmental Protection Agency. Code of Federal Regulations. 

40CFR 141.61. www.epa.gov/epahome/cfr40.htm. June 06, 2004. 
 

 

DICHLOROBENZENES 366 

9. REFERENCES 

*EPA. 2004g. National primary drinking water regulations: Public notification. Washington, DC: U.S. 

Environmental Protection Agency. Code of Federal Regulations. 40CFR 141.32. 

www.epa.gov/epahome/cfr40.htm. June 06, 2004. 

*EPA. 2004h. Program and activities: Hazardous air pollutants. Washington, DC: U.S. Environmental 

Protection Agency. United States Code. 42USC7412. www.epa.gov/epahome/cfr40.htm. June 06, 

2004. 

EPA. 2004i. Standards for the management of specific hazardous wastes and specific types of hazardous 

waste management facilities: Reference air concentrations. Washington, DC: U.S. Environmental 

Protection Agency. www.epa.gov/epahome/cfr40.htm. June 06, 2004. 

*EPA. 2004j. Toxic chemical release reporting: Community right-to-know: Chemicals and chemical 

categories to which this part applies. Washington, DC: U.S. Environmental Protection Agency. Code of 

Federal Regulations. 40CFR 372.65. www.epa.gov/epahome/cfr40.htm. June 06, 2004. 

*EPA. 2004k. Toxic Substances Control Act: Chemical information rules: Chemical lists and reporting 

periods. Washington, DC: U.S. Environmental Protection Agency. Code of Federal Regulations. 

40CFR 712.30. www.epa.gov/epahome/cfr40.htm. June 06, 2004. 

EPA. 2004l. Toxic Substances Control Act: Health and safety data reporting: Substances and listed 

mixtures to which this subpart applies. Washington, DC: U.S. Environmental Protection Agency. 

*EPA. 2004m. Water programs: Designation of hazardous substances. Washington, DC: U.S. 

Environmental Protection Agency. Code of Federal Regulations. 40CFR 116.4. 

www.epa.gov/epahome/cfr40.htm. June 06, 2004. 

*EPA. 2005. Toxic chemical release inventory reporting forms and instructions: Revised 2004 version. 

Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of the Superfund 

Amendments and Reauthorization Act of 1986). U.S. Environmental Protection Agency. Office of 

Environmental Information. EPA260B05001. 

*Erickson MD, Harris BS, Pellizzari ED, et al. 1980. Acquisition and chemical analysis of mother's milk 

for selected toxic substances. Washington, DC: U.S. Environmental Protection Agency, Office of 

Pesticides and Toxic Substances. EPA5601380029. 

Fabbri A, Crescentini G, Mangani F, et al. 1987. Advances in the determination of volatile organic 

solvents and other organic pollutants by gas chromatography with thermal desorption sampling and 

injection. Chromatographia 23:856-860. 

*Farm Chemicals Handbook. 1983. Directory of chemicals. Willoughby, OH: Meister Publishing 

Company. 

*FDA. 2003. Bottled water. Washington, DC: U.S. Food and Drug Administration. Code of Federal 

Regulation. 21CFR165.110. 

*FDA. 2004. CFR Title 40: Protection of environment. Washington, DC: U.S. Food and Drug 

Administration. 

*FEDRIP. 2005. Dichlorobenzenes. Federal Research in Progress. Dialog Information Service. 

October 12, 2005. 
DICHLOROBENZENES 367 

9. REFERENCES 

*Fellin P, Otson R. 1994. Assessment of the influence of climatic factors on concentration levels of 

volatile organic compounds (VOCs) in Canadian homes. Atmos Environ 28(22):3581-3586. 

Fernandez-Villarrenga V, Lopez-Mahia P, Muniategui-Lorenzo S, et al. 2004. C1 to C9 volatile organic 

compound measurements in urban air. Sci Total Environ 334-335:167-176. 

*Field RA, Phillips JL, Goldstone ME, et al. 1992. Indoor/outdoor interactions during an air pollution 

event in Central London. Environ Technol 13:391-408. 

*Fisher R, Barr J, Zuloski CF, et al. 1991a. In-vitro hepatotoxicity of three dichlorobenzene isomers in 

human liver slices. Hum Exp Toxicol 10:357-363. 

Fisher R, McCarthy S, Sipes IG, et al. 1991b. Metabolism of dichlorobenzenes in organ cultured liver 

slices. Adv Exp Med Biol 283:717-723. 

Fisher R, Smith PF, Sipes IG, et al. 1990. Toxicity of chlorobenzenes in cultured rat liver slices. J Mol 

Cell Toxicol 3:181-194. 

Fisher RL, Gandolfi AJ, Sipes IG, et al. 1993. Culture medium composition affects the relative toxicities 

of chlorobenzenes in rat liver slices and the isolated perfused liver. Drug Chem Toxicol 16(4):321-339. 

*Fisher RL, Hasal SJ, Sipes IG, et al. 1995. Comparative metabolism and toxicity of dichlorobenzenes 

in Sprague-Dawley, Fischer-344 and human liver slices. Hum Exp Toxicol 14:414-421. 

*Foman SJ. 1966. Body composition of the infant (Part I: The male reference infant). In: Falkner F, 

ed. Human development. Philadelphia, PA: WB Saunders, 239-246. 

*Foman, SJ, Haschke F, Ziegler EE, et al. 1982. Body composition of reference children from birth to 

age 10 years. Am J Clin Nutr 35:1169-1175. 

Foureman P, Mason JM, Valencia R, et al. 1994. Chemical mutagenesis testing in Drosophila, IX. 

Results of 50 coded compounds tested for the National Toxicology Program. Environ Mol Mutagen 

23(1):51-63. 

*Frank SB, Cohen HJ. 1961. Fixed drug eruption due to paradichlorobenzene. NY State J Med 61:4079. 

*Fraser MP, Cass GR, Simoneit RT, et al. 1998. Air quality model evaluation data for organics. 5. C6­

C22 nonpolar and semipolar aromatic compounds. Environ Sci Technol 32:1760-1770. 

FSTRAC. 1995. Summary of state and federal drinking water standards and guidelines. Washington, 

DC: U.S. Environmental Protection Agency. 

Gaffney PE. 1976. Carpet and rug industry case study II: Biological effects. J Water Pollut Contr Fed 

48:2731-2737. 

*Gaines TB, Linder RE. 1986. Acute toxicity of pesticides in adult and weanling rat. Fundam Appl 

Toxicol 7:299-308. 

*Garcia JP, Beyne-Masclet S, Mouvier G. 1992. Emissions of volatile organic compounds by coal-fired 

power stations. Atmos Environ 26A(9):1589-1597. 
 

 

DICHLOROBENZENES 368 

9. REFERENCES 

*Garrison AW, Hill DW. 1972. Organic pollutants from mill persist in downstream waters. Am 

Dyestuff Rep (February):21-24. 

Ghassemi M, Quinlivan S, Bachmaier J. 1984. Characteristics of leachates from hazardous waste 

landfills. J Environ Sci Health A19:579-620. 

*Ghittori S, Imbriani M, Pezzagno G, et al. 1985. Urinary elimination of p-dichlorobenzene (p-DCB and 

weighted exposure concentration. Ital Med Lav 7:59-63. 

*Giavini E, Broccia ML, Prati M, et al. 1986. Teratologic evaluation of p-dichlorobenzene in the rat. 

Bull Environ Contam Toxicol 37:164-168. 

*Giwercman A, Carlsen E, Keiding N, et al. 1993. Evidence for increasing incidence of abnormalities of 

the human testis: A review. Environ Health Perspect Suppl 101(2):65-71. 

Gobba F, Ghitorri S, Imbriani M, et al. 1997. The urinary excretion of solvents and gases for the 

biological monitoring of occupational exposure: A review. Sci Total Environ 199:3-12. 

Goldberg MS, Al-Homsi N, Goulet L, et al. 1995. Incidence of cancer among persons living near a 

municipal solid waste landfill site in Montreal, Quebec. Arch Environ Health 50:416-424. 

Gosselin RE, Smith RP, Hodge HC, et al. 1984. Clinical toxicology of commercial products. 5th ed. 

Baltimore, MD: Williams and Wilkins, II-170. 

*Grosjean D. 1991. Atmospheric fate of toxic aromatic compounds. Sci Total Environ 100:367-414. 

*Grossel TA, Bricker JD. 1994. Principles of clinical toxicology. 3rd edition, New York, NY: Raven 

Press. 

Gunawardhana L, Sipes IG. 1991. Dichlorobenzene hepatotoxicity strain differences and structure 

activity relationships. Adv Exp Med Biol 283(731-734) 

Gunawardhana L, Morley SA, Sipes IG. 1993. Modulation of 1,2-dichlorobenzene hepatotoxicity in the 

Fischer-344 rat by a scavenger of superoxide anions and an inhibitor of kupffer cells. Toxicol Appl 

Pharmacol 119(2):205-213. 

Gupta KC. 1972. Effects of some antimitotics on the cytology of fenugreek roots in vivo and in vitro. 

Cytobios 5:179-187. 

Gustafson DL, Coulson AL, Feng L, et al. 1998. Use of a medium-term liver focus bioassay to assess the 

heptocarcinogenicity of 1,2,4,5-tetrachlorobenzene and 1,4-dichlorobenzene. Cancer Lett 129:39-44. 

Gustafson DL, Long ME, Thomas RS, et al. 2000. Comparative hepatocarcinogenicity of 

hexachlorobenzene pentachlorobenzene, 1,2,4,5-tetrachlorobenzene, and 1,4-dichlorobenzene: 

Application of a medium-term liver focus bioassay and molecular and cellular indices. Toxicol Sci 

53:245-252. 

*Guzelian PS, Henry CJ, Olin SS. 1992. Similarities and differences between children and adults: 

Implications for risk assessment. Washington, DC: International Life Sciences Institute Press. 
 

 

 

DICHLOROBENZENES 369 

9. REFERENCES 

Haag WR, Yao CCD. 1992. Rate constants for reaction of hydroxyl radicals with several drinking water 

contaminants. Environ Sci Technol 26:1005-1013. 

*Haider K, Jagnow G, Kohnen R, et al. 1974. Degradation of chlorinated benzenes, phenols, and 

cyclohexane derivatives by benzene and phenol utilizing soil bacteria under aerobic conditions. Arch 

Microbiol 96:183-200. 

*Haddad LM, Winchester JF, eds. 1990. Clinical management of poisoning and drug overdose. 2nd 

edition, Philadelphia, PA: WB Saunders. 

*Hallbourg RR, Delfino JJ, Miller WL. 1992. Organic priority pollutants in groundwater and surface 

water at three landfills in North Central Florida. Water Air Soil Pollut 65:307-322. 

*Hallowell M. 1959. Acute haemolytic anaemia following the ingestion of paradichlorobenzene. Arch 

Dis Child 34:74-75. 

Hamar GB, McGeehin MA, Phifer BL, et al. 1996. Volatile organic compound testing of a population 

living near a hazardous waste site. J Expo Anal Environ Epidemiol 6(2):247-251. 

*Hansch C, Leo A, Hoekman D. 1995. o-Dichlorobenzenes and p-dichlorobenzenes. In: Exploring 

QSAR. Hydrophobic, electronic, and steric constants. Washington, DC: American Chemical Society. 

*Harkov R, Gianti SJ, Bozzelli JW, et al. 1985. Monitoring volatile organic compounds at hazardous 

and sanitary landfills in New Jersey. J Environ Sci Health 5:491-501. 

*Harkov R, Kebbekus B, Bozzelli JW, et al. 1984. Comparison of selected volatile organic compounds 

during the summer and winter at urban sites in New Jersey. Sci Total Environ 38:259-274. 

*Hartwell TD, Perritt RL, Pelizzari ED, et al. 1992. Results from the 1987 total exposure assessment 

methodology (team) study in Southern California. Atmos Environ 26a:1519-1527. 

Hasmall SC, Roberts RA. 1997. Hepatic ploidy, nuclearity, and distribution of DNA synthesis: A 

comparison of nongenotoxic hepatocarcinogens with noncarcinogenic liver mitogens. Toxicol Appl 

Pharmacol 144:287-293. 

*Hasmall SC, Pyrah ITG, Soames AR, et al. 1997. Expression of the immediate-early genes, c-fos, cjun, and c-myc: A comparison in rats of nongenotoxic hepatocarcinogens with noncarcinogenic liver 

mitogens. Fundam Appl Toxicol 40:129-137. 

*Hauser TR, Bromberg SM. 1982. EPA's monitoring program at Love Canal 1980. Environ Monit 

Assess 2:249-271. 

*Hawkins DR, Chasseaud LF, Woodhouse RN, et al. 1980. The distribution, excretion and 

biotransformation of p-dichloro[14C]benzene in rats after repeated inhalation, oral and subcutaneous 

doses. Xenobiotica 10:81-95. 

*Haworth S, Lawlor T, Mortelmans K, et al. 1983. Salmonella mutagenicity test results for 250 

chemicals. Environ Mutagen (Suppl 1):3-142. 

*Hayes WC, Hanley TR Jr, Gushow TS, et al. 1985. Teratogenic potential of inhaled dichlorobenzenes 

in rats and rabbits. Fundam Appl Toxicol 5:190-202. 
DICHLOROBENZENES 370 

9. REFERENCES 

*HazDat. 2005. 1,2-Dichlorobenzene, 1,3-dichorobenzene, and 1,4-dichlorobenzene. HazDat Database. 

ATSDR’s Hazardous Substance Release and Health Effects Database. Atlanta, GA: Agency for Toxic 

Substances and Disease Registry. www.atsdr.cdc.gov/hazdat.html. September 12, 2005. 

Hazelton Labs. 1984. Toxicity and primary dermal irritation study. Hazelton Labs Amer Inc. TSCA. 

OTS0535865. 

HEAST. 1990. Health Effects Assessment Summary Tables. 3rd quarter FY-1990. Washington, DC: 

U.S. Environmental Protection Agency. 

HEAST. 1992. Health Effects Assessment Summary Tables. 3rd quarter FY-1992. Washington, DC: 

U.S. Environmental Protection Agency. 

*Heavner DL, Morgan WT, Ogden MW. 1996. Determination of volatile organic compounds and 

respirable suspended particulate matter in New Jersey and Pennsylvania homes and workplaces. Environ 

Int 22:159-183. 

*Heavner DL, Ogden MW, Nelson PR. 1992. Multisorbent thermal desorption/gas selective detection 

method for the determination of target volatile organic compounds in indoor air. Environ Sci Technol 

26:1737-1746. 

*Heikes DL, Jensen SR, Fleming-Jones ME. 1995. Purge and trap extraction with GC-MS determination 

of volatile organic compounds in table-ready foods. J Agric Food Chem 43:2869-2875. 

*Hendler AH, Crow WL. 1992. Preliminary results of the Chemical Manufacturers Association urban 

baseline VOC measurement program. Proceedings of the Annual Meeting of the Air and Waste 

Management Association. 85th Meeting, Vol 2B. 

Henry B, Grant SG, Klopman G, et al. 1998. Induction of forward mutations at the thymidine kinase 

locus of mouse lymphoma cells: evidence for electrophilic and non-electrophilic mechanisms. Mutat Res 

397(2):313-335. 

*Herbold B. 1986a. Investigation of p-dichlorobenzene for clastogenic effects in mice using the 

micronucleus test. Institute of Toxicology. Report No. 14694. 

*Herbold B. 1986b. Investigation of 2,5-dichlorophenol for clastogenic effects in mice using the 

micronucleus test. Institute of Toxicology. Report No. 14693. 

Herr DW, Boyes WK. 1997. A comparison of the acute neuroactive effects of dichloromethane, 1,3­

dicloropropane, and 1,2-dichlorobenzene on rat flash evokes potentials (FEPs)1,2. Fundam Appl Toxicol 

35:31-48. 

Hiatt MH. 1999. Leaves as an indicator of exposure to airborne volatile organic compounds. Environ 

Sci Technol 33:4126-4133. 

*Hill RH, Ashley DL, Head SL, et al. 1995. p-Dichlorobenzene exposure among 1000 adults in the 

United States. Arch Environ Health 50(4):277-280. 

*Hill RH, To T, Holler JS, et al. 1989. Residues of chlorinated phenols and phenoxy acid herbicides in 

the urine of Arkansas children. Arch Environ Contam Toxicol 18:469-474. 
DICHLOROBENZENES 371 

9. REFERENCES 

Hissink AM, Dunnewijk R, Van Ommen B, et al. 1997a. Kinetics and metabolism of 1,4­

dichlorobenzene in male Wistar rats: No evidence for quinone metabolites. Chem Biol Interact 103:17­

33. 

*Hissink AM, Oudshoorn MJ, Van Ommen B, et al. 1996b. Differences in cytochrome P450-mediated 

biotransformation of 1,2-dichlorobenzene by rat and man: Implications for human risk assessment. 

Chem Res Toxicol 9:1249-1256. 

*Hissink AM, Oudshoorn MJ, Van Ommen B, et al. 1997b. Species and strain differences in the hepatic 

cytochrome P450-mediated biotransformation of 1,4-dichlorobenzene. Toxicol Appl Pharmacol 149:1-9. 

Hissink AM, Van Ommen B, Kruse J, et al. 1997c. A physiologically based pharmacokinetic (PB-PK) 

model for 1,2-dichlorobenzene linked to two possible parameters of toxicity. Toxicol Appl Pharmacol 

145:301-310. 

*Hissink AM, Van Ommen B, Van Bladeren PJ. 1996a. Dose-dependent kinetics and metabolism of 1,2­

dichlorobenzene in rat: effect of pretreatment with phenobarbital. Xenobiotica 26(1):89-105. 

*Hissink E, Van Ommen B, Bogaards JJ, et al. 1996c. Hepatic epoxide concentrations during 

biotransformation of 1,2 and 1,4,-dichlorobenzene. Biological reactive intermediates V. New York: 

Plenum Press. 

*Hodge MCE, Palmer S, Wilson J, et al. 1977. Paradichlorobenzene: Teratogenicity study in rats. ICI 

Report No. CRL/P/340. July 27, 1976. 

Hoekstra PF, Braune BM, O'Hara TM, et al. 2003. Organochlorine contaminant and stable isotope 

profiles in Arctic fox (Alopex lagopus) from the Alaskan and Canadian Arctic. Environ Pollut 122:422­

433. 

*Hoel DG, Davis DL, Miller AB, et al. 1992. Trends in cancer mortality in 15 industrialized countries, 

1969-1986. J Natl Cancer Inst 84(5):313-320. 

*Hollingsworth RL, Rowe VK, Oyen F, et al. 1956. Toxicity of paradichlorobenzene: Determinations 

on experimental animals and human subjects. AMA Arch Ind Health 14:138-147. 

*Hollingsworth RL, Rowe VK, Oyen F, et al. 1958. Toxicity of o-dichlorobenzene. AMA Arch Ind 

Health 17:180-187. 

Holmes TJ, Rainsford KD. 2001. Differential effects of non-genotoxic carcinogens and proliferating 

agents on cell growth, survival and apoptosis in hepatic cells in vitro. Life Sci 69(25-26):2975-2992. 

Houk VS, Demarini DM. 1988. Use of the microscreen phage-induction assay to assess the genotoxicity 

of 14 hazardous industrial wastes. Environ Mol Mutagen 11(1):13-30. 

Hovander L, Malmberg T, Athanasiadou M, et al. 2002. Identification of hydroxylated PCB metabolites 

and other phenolic halogenated pollutants in human blood plasma. Arch Environ Contam Toxicol 

42:105-117. 

*Howard PH. 1989. 1,4-dichlorobenzene. In: Handbook of environmental fate and exposure data for 

organic chemicals. Chelsea, MI: Lewis Publishers, Inc.,1, 250-262. 
 

 

DICHLOROBENZENES 372 

9. REFERENCES 

Howd RA, Brown JP, Morry DW, et al. 2000. Development of California public health goals (PHGs) for 

chemicals in drinking water. J Appl Toxicol 20:365-380. 

*HSDB. 1996. Hazardous Substances Data Bank. Bethesda, MD: National Library of Medicine. 

National Toxicology Program. 

*HSDB. 2005. 1,4-Dichlorobenzene. Hazardous Substances Data Bank. Bethesda, MD: National 

Library of Medicine http://toxnet.nlm.nih.gov. September 2, 2005. 

Hughes CS. 1983. CEH product review: Chlorobenzenes. In: Chemical Economics Handbook. Menlo 

Park, CA: SRI International, 633.5030A-633.5031M. 

*IARC. 1982. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans: 

Some industrial chemicals and dyestuffs. Vol. 29. Lyon, France: International Agency for Research on 

Cancer. 

*IARC. 1987. IARC monographs on the evaluation of carcinogenic risks to humans. Overall 

evaluations of carcinogenicity: An updating of IARC monographs volumes 1 to 42. Supplement 7. 

Lyon, France: International Agency for Research on Cancer. 

*IARC. 1999. IARC monographs on the evaluation of carcinogenic risks to humans. Some chemicals 

that cause tumours of the kidney or urinary bladder in rodents and some other substancesDichlorobenzenes. Lyon, France: International Agency for Research on Cancer. 

*ICF. 1987. ICF Incorporated. Preliminary use and substitutes analysis of para-dichlorobenzene. Draft. 

Washington, DC: U.S. Environmental Protection Agency. July 1987. 

IJC. 1983. An inventory of chemical substances identified in the Great Lakes ecosystem. Vol. I -

Summary. Windsor, Ontario: International Joint Commission, Great Lakes Water Quality Board. 

*IJC. 1989. 1989 Report on Great Lakes water quality. Presented at Hamilton, Ontario, October 1989. 

Windsor, Ontario: International Joint Commission, Great Lakes Water Quality Board. 

*Instituto di Ricerche Biomediche. 1986a. Study of the capacity of the test article para-dichlorobenzene 

to induce "unscheduled DNA synthesis" in cultured HeLa cells. Experiment No. M1032/1-2. 

*Instituto di Ricerche Biomediche. 1986b. Study of the capacity of the test article para-dichlorobenzene 

to induce gene mutation in V79 Chinese hamster lung cells. Experiment No. 1030. 

*Instituto di Ricerche Biomediche. 1987. Study of the capacity of the test article para-dichlorobenzene 

to induce chromosome aberrations in human lymphocytes cultured in vitro. Experiment No. 1031. 

*IRIS. 2004. RfDs and RfCs for 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene. 

Integrated Risk Information System. http://www-cie.iarc.fr/htdocs/monographs/vol71/032-111trich.html. 

June 06, 2004. 

*IRIS. 2005. Dichlorobenzenes. Washington, DC: Integrated Risk Information System. U.S. 

Environmental Protection Agency. http://www.epa.gov/iris/subst/. October 15, 2005. 
DICHLOROBENZENES 373 

9. REFERENCES 

*IRPTC. 1985. IRPTC data profile on: DCB. Geneva, Switzerland: International Register of 

Potentially Toxic Chemicals, United Nations Environment Programme. January 1989. 

Jackson JA, Diliberto JJ, Burnbaum LS. 1993. Estimation of octanol-water partition coefficients and 

correlation with dermal absorption for several polyhalogenated aromatic hydrocarbons. Fundam Appl 

Toxicol 21:334-344. 

*Jacobs LW, Zabik MJ. 1983. Importance of sludge-borne organic chemicals for land application 

programs. Sixth Annual Madison Conference on Application, Research, Practices, Municipalities and 

Industrial Waste. University of Wisconsin. 

James NH, Soames AR, Roberts RA. 1998. Suppression of hepatocyte apoptosis and induction of DNA 

synthesis by the rat and mouse hepatocarcinogen diethylhexylphlathate (DEHP) and the mouse 

hepatocarcinogen 1,4-dichlorobenzene (DCB). Arch Toxicol 72:784-790. 

*Jan J. 1983. Chlorobenzene residues in human fat and milk. Bull Environ Contam Toxicol 30:595-599. 

*Jan J, Malnersic S. 1980. Chlorinated benzene residues in fish in Slovenia (Yugoslavia). Bull Environ 

Contam Toxicol 24:824-827. 

*Japan Bioassay Research Center. 1995. Toxicology and carcinogenesis studies of p-dichlorobenzene in 

344/DuCrj rats and Crj:BDF1 mice. Two-year inhalation studies. Japan Industrial Safety and Health 

Association. This study was carried under contract with the Ministry of Labour of Japan. 

*Jay K, Stieglitz L. 1995. Identification and quantification of volatile organic components in emissions 

of waste incineration plants. Chemosphere 30(7):1249-1260. 

*Jerina DM, Daly JW. 1974. Arene oxides: A new aspect of drug metabolism. Science 185:573-582. 

*Johanson CE. 1980. Permeability and vascularity of the developing brain: Cerebellum vs cerebral 

cortex. Brain Res 190:3-16. 

*Jori A, Calamari D, Cattabeni F, et al. 1982. Ecotoxicological profile of p-dichlorobenzene. Ecotoxicol 

Environ Saf 6:413-432. 

Kanerva RL, Ridder GM, Lefever FR, et al. 1987. Comparison of short-term renal effects due to oral 

administration of decalin or d-limonene in young adult male Fisher-344 rats. Food Chem Toxicol 

25:345-353. 

Kato Y, Kimura R. 1997. Role of 3,4-dichlorophenyl methyl sulfone, a metabolite of o-dichlorobenzene, 

in the changes in hepatic microsomal drug-metabolizing enzymes caused by o-dichlorobenzene 

administration in rats. Toxicol Appl Pharmacol 145:277-284. 

Kato Y, Kogure T, Sato M. 1986. Evidence that methylsulfonyl metabolites on m-dichlorobenzene are 

causative substances of induction of hepatic microsomal drug-metabolizing enzymes by the parent 

compound in rats. Toxicol Appl Pharmacol 82:505-511. 

Kato Y, Kogure T, Sato M, et al. 1988a. Contribution of methylsulfonyl metabolites of mdichlorobenzene to the heme metabolic enzyme induction by the parent compound in rat liver. Toxicol 

Appl Pharmacol 96:550-559. 
DICHLOROBENZENES 374 

9. REFERENCES 

Kato Y, Kogure T, Sato M, et al. 1988b. Effects of chlorobenzenes and their methyl sulfone metabolites 

on microsomal enzymes associated with drug metabolism in rat liver. J Pharmacobiodyn 11(11):758-762. 

*Kelly TJ, Mukund R, Spicer CW, et al. 1994. Concentrations and transformations of hazardous air 

pollutants. Environ Sci Technol 28(8):378-387. 

Kenaga EE. 1980. Predicted bioconcentration factors and soil sorption coefficients of pesticides and 

other chemicals. Ecotox Environ Saf 4:26-38. 

*Kimura R, Hayashi T, Sato M, et al. 1979. Identification of sulfur-containing metabolites of pdichlorobenzene and their disposition in rats. J Pharm Dyn 2:237-244. 

Kimura R, Kawai M, Sato M, et al. 1983. Induction of hepatic microsomal drug-metabolizing enzymes 

by sulfur-containing metabolites of chlorinated benzenes in rats. Toxicol Appl Pharmacol 67:338-345. 

Kimura R, Kawai M, Kato Y, et al. 1985. Role of 3,5-dichlorophenyl methyl sulfone, a metabolite of mdichlorobenzene, in the induction of hepatic microsomal drug-metabolizing enzymes by mdichlorobenzene in rats. Toxicol Appl Pharmacol 78:300-309. 

*Kimura R, Ohishi N, Kato Y, et al. 1992. Identification of biliary metabolites of m-dichorobenzene in 

rats. Drug Metab Dispos 20:161-171. 

King JW. 1989. Fundamentals and applications of supercritical fluid extraction in chromatographic 

science. J Chromatogr Sci 27:355-364. 

*Kinney PL, Chillrud SN, Ramstrom S, et al. 2002. Exposures to multiple air toxics in New York City. 

Environ Health Perspect 110(Suppl. 4):539-546. 

*Klos C, Dekant W. 1994. Comparative metabolism of the renal carcinogen 1,4-dichlorobenzene in rat: 

Identification and quantitation of metabolites. Xenobiotica 24(10):965-976. 

*Kolpin DW, Furlong ET, Meyer MT, et al. 2002. Pharmaceuticals, hormones, and other organic 

wastewater contaminants in US streams, 1999-2000: A national reconnaissance. Environ Sci Technol 

36:1202-1211. 

Kolpin DW, Squillace PJ, Zogorski JS, et al. 1997. Pesticides and volatile organic compounds in 

shallow urban groundwater of the United States. In: Chilton et al. Groundwater in the urban 

environment: Processes and management. 1. Iowa City: U.S. Geological Survey, 469-474. 

*Komori M, Nishio K, Kitada M, et al. 1990. Fetus-specific expression of a form of cytochrome P-450 

in human liver. Biochemistry 29:4430-4433. 

*Kondo M, Nishihara T, Shimamoto T, et al. 1988. Biodegradation test of chemicals by cultivation 

method. Eisei Kagaku 34(2):188-195. 

Kong JT, Schmiesing C. 2005. Concealed mothball abuse prior to anesthesia: Mothballs, inhalants, and 

their management. Acta Anaesthesiol Scand 49(1):113-116. 

Kool HJ, Van Kreijl CF, Zoeteman BC. 1982. Toxicology assessment of organic compounds in drinking 

water. CRC Crit Rev Environ Control 12:307-350. 
 

 

 

DICHLOROBENZENES 375 

9. REFERENCES 

Kopfler FC, Melton RG, Mullaney JL, et al. 1977. Human exposure to water pollutants. Adv Environ 

Sci Technol 8:419-433. 

Kopperman HL, Keuhl DW, Glass GE. 1978. Chlorinated compounds found in waste treatment effluents 

and their capacity to bioaccumulate. In: Jolley RL, ed. Water chlorination: Environmental impact and 

health effects. Volume 1. Ann Arbor, MI: Ann Arbor Science Publishers, Inc., 311-328. 

*Kostianen R. 1995. Volatile organic compounds in the indoor air of normal and sick houses. Atmos 

Environ 29(6):693-702. 

Kraaij H, Connell DW. 1997. Bioconcentration and uptake kinetics of chlorobenzenes in soy-bean roots. 

Chemosphere 34(12):2607-2620. 

*Krishnamurti R. 2001. Chlorinated benzenes. In: Kirk Othmer’s encyclopedia of chemical technology. 

John Wiley & Sons, Inc. http://www.mrw.interscience.wiley.com/kirk/kirk_search_fs.html. July 13, 

2003. 

*Krishnan K, Andersen ME. 1994. Physiologically-based pharmacokinetic modeling in toxicology. In: 

Hayes W, ed. Principles and methods of toxicology. 3rd edition. New York, NY: Raven Press, Ltd. 

*Krishnan K, Andersen ME, Clewell HJ III, et al. 1994. Physiologically-based pharmacokinetic 

modeling of chemical mixtures. In: Yang, RSA, ed. Toxicology of chemical mixtures. New York, NY: 

Academic Press. 

Krzymien M, Day M, Shaw K, et al. 1999. An investigation of odors and volatile organic compounds 

released during composting. J Air Waste Manage Assoc 49:804-813. 

Kulkarni SG, Mehendale HM. 1995. The equalized outcome of liver injury induced by 1,2­

dichlorobenzene in Fischer 344 and Sprague-Dawley rats is due to differential tissue repair. FASEB J 

9:A695. 

Kulkarni SG, Harris AJ, Casciano DA, et al. 1999. Differential protooncogene expression in Sprague 

Dawley and Fischer 344 rats during 1,2-dichlorobenzene-induced hepatocellular regeneration. 

Toxicology 139:119-127. 

Kulkarni SG, Warbritton A, Bucci TJ, et al. 1997. Antimitotic intervention with colchicine alters the 

outcome of o-DCB-induced hepatotoxicity in Fischer 344 rats. Toxicology 120:79-88. 

*Kumagai S, Matsunaga I. 1995. Identification of urinary metabolites of human subjects exposed to odichlorobenzene. Int Arch Occup Environ Health 67:207-209. 

*Kumagai S, Matsunaga I. 1997. Quantitative determination of urinary metabolites of o-dichlorobenzene 

using a gas chromatograph. Ind Health 35:399-403. 

*Lake BG, Cunninghame ME, Price RJ. 1997. Comparison of the hepatic and renal effects of 1,4­

dichlorobenzene in the rat and mouse. Fund Appl Toxicol 39:67-75. 

*Langhorst ML, Nestrick TJ. 1979. Determination of chlorobenzenes in air and biological samples by 

gas chromatography with photoionization detection. Anal Chem 51:2018-2025. 
DICHLOROBENZENES 376 

9. REFERENCES 

Langner HJ, Hillinger HG. 1971. [Taste variation of the egg caused by the deodorant p-dichlorobenzene. 

Analytical proof.] Berlin Muenchen Tierairztl 84:851. (German) 

*Laniewski K, Boren H, Grimvall A. 1999. Fractionation of halogenated organic matter present in rain 

and snow. Chemosphere 38(2):392-409. 

*LaRegina J, Bozzelli JW, Harkov R, et al. 1986. Volatile organic compounds at hazardous waste sites 

and a sanitary landfill in New Jersey: An up-to-date review of the present situation. Environ Prog 5:18­

27. 

Larsen GL, Bakke JE, Huwe JK. 1990. Methylsulphone metabolites of m-dichlorobenzene as ligands for 

α2μ-globulin in rat kidney and urine. Xenobiotica 20(1):7-17. 

*Lattanzi G, Bartoli S, Bonora B, et al. 1989. The different genotoxicity of p-dichlorobenzene in mouse 

and rat: Measurement of the in vivo and in vitro covalent interaction with nucleic acids. Tumori 75:305­

310. 

*Leber AP, Bus JS. 2001. Halogenated benzenes. In: Bingham E, Cohrssen B, Powell CH, eds. Patty’s 

toxicology. John Wiley & Sons, Inc. 

http://www.mrw.interscience.wiley.com/pattys/tox/articles/tox067/sect1_2.html. April 16, 2001. 

Lebret E, Van de Wiel H, Bos H, et al. 1986. Volatile organic compounds in Dutch homes. Environ Int 

12:323-332. 

*Leeder JS, Kearns GL. 1997. Pharmacogenetics in pediatrics: Implications for practice. Pediatr Clin 

North Am 44:55-77. 

Lehman-McKeeman LD, Rivera-Torres MI, Caudill D. 1990. Lysosomal degradation of α2μ-globulin 

and α2μ-globulin-xenobiotic conjugates. Toxicol Appl Pharmacol 103:539-554. 

*Leo A, Hansch C, Elkins D. 1971. Partition coefficients and their uses. Chem Rev 71:525,568. 

*Leung H. 1993. Physiologically-based pharmacokinetic modeling. In: Ballantine B, Marro T, Turner 

T, eds. General and applied toxicology. Vol. I. New York, NY: Stockton Press,153-164. 

*Lewis RG, Mulik JD, Coutant RW, et al. 1985. Thermally desorbable passive sampling device for 

volatile organic chemicals in ambient air. Anal Chem 57:214-219. 

*Lewis RJ. 1997. m-dichlorobenzene, p-dichlorobenzene and o-dichlorobenzene. In: Hawley’s 

condensed chemical dictionary. New York, NY: John Wiley & Sons, Inc., 362. 

*Li X, Weber LWD, Rozman KK. 1995. Toxicokinetics of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) 

in female Sprague-Dawley rats including placental and lactational transfer to fetuses and neonates. 

Fundam Appl Toxicol 234:70-76. 

*Lide DR, ed. 2000. Physical constants of organic compounds- o-dichlorobenzene, m-dichlorobenzene, 

and p-dichlorobenzene. In: CRC handbook of chemistry and physics. 81st edition. Boca Raton, FL: 

CRC Press, 3-39. 

*Lide DR, Frederikse HPR. 1994. CRC handbook of chemistry and physics. 74th edition. CRC Press, 

83. 
 

 

DICHLOROBENZENES 377 

9. REFERENCES 

*Ligocki MP, Levenberger C, Pankow JF. 1985. Trace organic compounds in rain. II. Gas scavenging 

of neutral organic compounds. Atmos Environ 19:1609-1617. 

*Litton Bionetics. 1985. Evaluation of 2,5-dichlorophenol in the in vitro transformation of BALB/3T3 

cells assay. West Germany: Bayer AG Institut Fuer Toxicology. 

*Litton Bionetics. 1986a. Mutagenicity evaluation of 2,5-dichlorophenol in the CHO HGPRT forward 

mutation assay. West Germany: Bayer AG Institut Fuer Toxicology. 

Litton Bionetics. 1986b. Mutagenicity evaluation of p-dichlorobenzene in the CHO HGPRT forward 

mutation assay. West Germany: Bayer AG Institut Fuer Toxicology. 

Liu W, Zheng M, Wang D, et al. 2004. Formation of PCDD/Fs and PCBs in the process of production of 

1,4-dichlorobenzene. Chemosphere 57(10):1317-1323. 

Liu W, Zheng M, Xing Y, et al. 2004. Polychlorinated dibenzo-p-dioxins and polychlorinated 

dibenzofurans in 1,4-dichlorobenzene mothballs. Bull Environ Contam Toxicol 73(1):93-97. 

*Livingston AL. 1978. Forage plant estrogens. J Toxicol Environ Health 4:301-324. 

*Loeser E, Litchfield MH. 1983. Review of recent toxicology studies on p-dichlorobenzene. Food 

Chem Toxicol 21:825-832. 

*Lopes TJ, Furlong ET. 2001. Occurrence and potential adverse effects of semivolatile organic 

compounds in streambed sediment, United States, 1992-1995. Environ Toxicol Chem 20(4):727-737. 

Lopes TJ, Furlong ET, Pritt JW. 1997. Occurrence and distribution of semivolatile organic compounds 

in stream bed sediments, United States, 1992-95. In: Little EE, Greenberg BM, DeLonay AJ, eds. 

Environmental toxicology and risk assessment: Seventh volume. West Conshohocken, PA, 105-119. 

*Loscutoff WV, Poore MW. 1993. Ambient air toxics data from California’s toxic air contaminant 

monitoring program. In: Chow, W, Conner, KK, Mueller, P, Wyzga, R, Porcella, D, Levin, L, Chang, R, 

eds. Managing hazardous air pollutants: State of the art. Boca Raton, FL: Lewis Publishers, 191-203. 

*Loveday KS, Anderson BE, Resnick BE, et al. 1990. Chromosome aberration and sister chromatid 

exchange tests in Chinese hamster ovary cells in vitro: V. Results with 46 chemicals. Environ Mol 

Mutagen 16(4):272-303. 

Lowenheim FA, Morgan MK. 1975. Faith, Keyes and Clark's industrial chemicals. 4th ed. New York, 

NY: John Wiley and Sons, 258-265. 

Lu P, Metcalf RL. 1975. Environmental fate and biodegradability of benzene derivatives as studied in a 

model aquatic ecosystem. Environ Health Perspect 10:269-284. 

Mabey WR, Smith JH, Podoll RT, et al. 1982. Aquatic fate process data for organic priority pollutants. 

Washington, DC: U.S. Environmental Protection Agency, Office of Water Regulations and Standards. 

EPA440481014. 

*Macleod M, Mackay D. 1999. An assessment of the environmental fate and exposure of benzene and 

the chlorobenzenes in Canada. Chemosphere 38(8):1777-1796. 
DICHLOROBENZENES 378 

9. REFERENCES 

*Mage DT, Allen RH, Gondy G, et al. 2004. Estimating pesticide dose from urinary pesticide 

concentration data by creatinine correction in the Third National Health and Nutrition Examination 

Survey. J Expo Anal Environ Epidemiol 14(6):457-465. 

*Makita Y. 2005. Effects of perinatal combined exposure to 1,4-dichlorobenzene and 1,1-dichloro-2,2­

bis (p-chlorophenyl)ethylene on rat male offspring. Basic Clin Pharmacol Toxicol 96(5):361-365. 

Makita Y, Omura M, Ogata R. 2004. Effects of perinatal simultaneous exposure to tributyltin (TBT) and 

p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene) on male offspring of Wistar rats. J Toxicol 

Environ Health A 67(5):385-395. 

Mally A, Chipman JK. 2002. Non-genotoxic carcinogens: Early effects on gap junctions, cell 

proliferation and apoptosis in the rat. Toxicology 180:233-248. 

*Masunaga S, Susarla S, Yonezawa Y. 1996. Dechlorination of chlorobenzenes in anaerobic estuarine 

sediment. Water Sci Technol 33(6):173-180. 

Matsushima T, Nagano K, Nishizawa T, et al. 1998. Long term inhalation toxicity studies of five 

chlorinated hydrocarbons in F344 rats and BDF1 mice [Abstract]. J Toxicol Sci 23(Suppl II):296. 

*Mayr U, Butsch A, Schneider S. 1992. Validation of two in vitro test systems for estrogenic activities 

with zearalenone, phytoestrogens and cereal extracts. Toxicology 74:135-149. 

*McCauley PT, Robinson M, Daniel FB, et al. 1995. Toxicity studies of 1,3-dichlorobenzene in 

Sprague-Dawley rats. Drug Chem Toxicol 18(2 & 3):201-221. 

*McGregor DB, Brown A, Cattanach P, et al. 1988. Responses of L5178Y tk+

/tkmouse lymphoma cell 

forward mutation assay: III. 72 Coded chemicals. Environ Mol Mutagen 12:85-154. 

*McKinney JD, Fishbein L, Fletcher CE, et al. 1970. The electron-capture gas chromatography of 

paradichlorobenzene metabolites as a measure of exposure. Bull Environ Contam Toxicol 5:354-361. 

*Meek MA, Giddings M, Gomes R. 1994. 1,2-Dichlorobenzene: Evaluation of risks to health from 

environmental exposure in Canada. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 12:269­

275. 

*Meharg AA, Wright J, Osborn D. 2000. Chlorobenzenes in rivers draining industrial catchments. Sci 

Total Environ 251/252:243-253. 

Meister RT, ed. 1989. Farm chemicals handbook. Willoughby, OH: Meister Publishing Company, 

C219. 

*Mes J. 1992. Organochlorine residues in human blood and biopsy fat and their relationship. Bull 

Environ Contam Toxicol 48:815-820. 

*Mes J, Davies DJ, Turton D, et al. 1986. Levels and trends of chlorinated hydrocarbon contaminants in 

the breast milk of Canadian women. Food Addit Contam 3:313-322. 

*Michael LC, Erickson MD, Parks SP, et al. 1980. Volatile environmental pollutants in biological 

matrices with a headspace purge technique. Anal Chem 52:1836-1841. 
 

 

 

 

DICHLOROBENZENES 379 

9. REFERENCES 

Michael LC, Pellizzari ED, Wiseman RW. 1988. Development and evaluation of a procedure for 

determining volatile organics in water. Environ Sci Technol 26:265-570. 

*Miller MM, Ghoodbane S, Wasik SP, et al. 1984. Aqueous solubilities, octanol/water partition 

coefficients, and entropies of melting of chlorinated benzenes and biphenyls. J Chem Eng 29:184-190. 

Mio T, Sumino K. 1988. Mechanism of biosynthesis of methylsulfones from PCBs and related 

compounds. Environ Health Perspect 59:129-135. 

Miranda CL, Wang JL, Henderson MC, et al. 1984. Effects of chlorobenzenes on hepatic porphyrin and 

drug metabolism in chick embryo and day-old chick. Res Commun Chem Pathol Pharmacol 46:13-24. 

MIS. 1990. Agency for Toxic Substances and Disease Registry. Office of External Affairs, Exposure 

and Disease Registry Branch, Atlanta, GA. September 24, 1990. 

Mitchell AD. 1993. Does the in situ approach yield a more accurate assessment of induced mutation 

frequencies than the standard L5178Y tk-/-mouse lymphoma assay? Environ Mol Mutagen 21:49. 

*Miyai I, Hirono N, Fujita M, et al. 1988. Reversible ataxia following chronic exposure to paradichlorobenzene. J Neurol Neurosurg Psychiatry 51:453-454. 

*Mizutani T, Nakohori Y, Yamamoto K. 1994. p-Dichlorobenzene-induced hepatotoxicity in mice 

depleted of glutathione by treatment with buthionine sulfoximine. Toxicology 94:57-67. 

Mohtashamipur E, Norpoth K. 1987. Chromosome damaging effects of alkylated and halogenated 

benzenes on bone marrow of mice [abstract]. Environ Mutagen 9:75. 

*Mohtashamipur E, Triebel R, Straeter H, et al. 1987. The bone marrow clastogenicity of eight 

halogenated benzenes in male NMRI mice. Mutagenesis 2:111-113. 

*Monsanto Co. 1980. Toxicity data on chlorinated benzenes and m-dichlorobenzene. St. Louis, MO: 

Monsanto Company. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS0206232. 

Monsanto Co. 1986. Material safety data sheet for Santochlor (para-dichlorobenzene). St. Louis, MO: 

Monsanto Company. 

*Monsanto Co. 1989. Health effects assessment for ortho-dichlorobenzene at the Krummrich Plant. St. 

Louis, MO: Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS0521597. 

*Moran MJ, Lapham WW, Rowe BL, et al. 2004. Volatile organic compounds in ground water from 

rural private wells, 1986 to 1999. J Am Water Resour Assoc 40(5):1141-1157. 

*Morita M, Ohi G. 1975. Para-dichlorobenzene in human tissue and atmosphere in Tokyo metropolitan 

area. Environ Pollut 8:269-274. 

*Morita M, Mimura S, Ohi G, et al. 1975. A systematic determination of chlorinated benzenes in human 

adipose tissue. Environ Pollut 9:175-179. 
DICHLOROBENZENES 380 

9. REFERENCES 

*Morselli PL, Franco-Morselli R, Bossi L. 1980. Clinical pharmacokinetics in newborns and infants. 

Clin Pharmacokin 5:485-527. 

Mortimer MR, Connell DW. 1995. Effect of exposure to chlorobenzenes on growth rates of the crab 

Portunus pelagicus (L) Environ Sci Technol 29:1881-1886. 

Mottram DS, Edwards RA, MacFie HJH. 1982. A comparison of the flavour volatiles from cooked beef 

and pork meat systems. J Sci Food Agric 33:934-944. 

Muelenberg CJW, Vijverberg HPM. 2000. Empirical relations predicting human and rat tissue: Air 

partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol 165(3):206-216. 

Muller J, Greff G. 1984. Research on the relations between toxicity of molecules of industrial interest 

and physicohemical properties: irritation test of the upper respiratory tract applied to four families of 

chemicals. Food Chem Toxicol 22:661-664. 

*Murthy RC, Migally N, Doye A, et al. 1987. Effect of para-dichlorobenzene on testes of rats. Adv 

Contracept Delivery Syst 3:35-40. 

*Myhr BC, Caspary WJ. 1991. Chemical mutagenesis at the thymidine kinase locus in L5178Y mouse 

lymphoma cells: Results for 31 coded compounds in the National Toxicology Program. Environ Mol 

Mutagen 18:51-83. 

*Nakamura S, Oda Y, Shimada T, et al. 1987. SOS-inducing activity of chemical carcinogens and 

mutagens in Salmonella typhimurium TA1535/pSK1002: Examination with 151 chemicals. Mutat Res 

192:239-246. 

*Nalbandian RM, Pearce JS. 1965. Allergic purpura induced by exposure to 1,4-dichlorobenzene. 

JAMA 194:238-239. 

NAS. 1977. Drinking water and health. Washington, DC: National Academy of Sciences, 681-686. 

*NAS/NRC. 1989. Biologic markers in reproductive toxicology. National Academy of 

Sciences/National Research Council. Washington, DC: National Academy Press, 15-35. 

NATICH. 1989. National Air Toxics Information Clearinghouse: NATICH database report on state, 

local and EPA air toxics activities. Research Triangle Park, NC: U.S. Environmental Protection Agency, 

Office of Air Quality Planning and Standards. EPA45038929. 

NATICH. 1992. National Air Toxics Information Clearinghouse. Report on state, local, and EPA air 

toxics activities. Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air 

Quality Planning and Standards. December 1992. 

*Naylor MW, Stout LD. 1996. One year study of p-dichlorobenzene administered orally via capsule to 

beagle dogs. Environmental Health Laboratory, Monsanto Company, St. Louis, MO. Study No. ML-94­

210, March 25, 1996. MRID43988802. Unpublished study. 

*Nedelcheva V, Gut I, Soucek P, et al. 1998. Cytochrome P450 catalyzed oxidation of 

monochlorobenzene, 1, 2- and 1,4-dichlorobenzene in rat, mouse, and human liver microsomes. Chem 

Biol Interact 115:53-70. 
 

 

 

 

DICHLOROBENZENES 381 

9. REFERENCES 

Neptune D. 1980. Descriptive statistic for detected priority pollutants and tabulation listings. 

Washington, DC: U.S. Environmental Protection Agency, Office of Water Planning and Standards. 

TRDB-0280-001. 

*Nerin C, Polo T, Domeno C, et al. 1996. Determination of some organochlorine compounds in the 

atmosphere. Int J Environ Anal Chem 65:83-94. 

*Newsom JM. 1985. Transport of organic compounds dissolved in ground water. Ground Water Monit 

Rev 5:28-36. 

*NFPA. 1994. Fire protection guide to hazardous materials. 11th Edition. Quincy, MA: National Fire 

Protection Association. 

*Nielsen PH, Bjerg PL, Nielsen P, et al. 1996. In situ and laboratory determined first-order degradation 

rate constants of specific organic compounds in aerobic aquifer. Environ Sci Technol 30:31-37. 

NIOSH. 1984. NIOSH manual of analytical methods. 3rd ed. Vol. 2. Cincinnati, OH: U.S. 

Department of Health and Human Services, National Institute for Occupational Safety and Health. 

NIOSH. 1985. NIOSH pocket guide to chemical hazards. Washington, DC: U.S. Department of Health 

and Human Services, National Institute for Occupational Safety and Health. 

NIOSH. 1990. U.S. Department of Health and Human Services. National Institute for Occupational 

Safety and Health. 

NIOSH. 1992. NIOSH Recommendations for occupational safety and health-compendium of policy 

document and statements. Cincinnati, OH: National Institute for Occupational Safety and Health. 

Department of Health and Human Services. Publication No. 92-100. 

*NIOSH. 1994. Method 1003. NIOSH manual of analytical methods. 4th edition. U.S. Department of 

Health and Human Services. National Institute for Occupational Safety and Health. 

*NIOSH. 1997. NIOSH pocket guide to chemical hazards. U.S. Department of Health and Human 

Services. Public Health Services. Centers for Disease Control and Prevention. National Institute for 

Occupational Safety and Health. 

*NIOSH. 2004. NIOSH pocket guide to chemical hazards. U.S. Department of Health and Human 

Services. Public Health Services. Centers for Disease Control and Prevention. National Institute for 

Occupational Safety and Health. 

*NIOSH. 2005. NIOSH pocket guide to chemical hazards. U.S. Department of Health and Human 

Services. Public Health Services. Centers for Disease Control and Prevention. National Institute for 

Occupational Safety and Health. 

NIOSH/OSHA. 1981. Occupational health guidelines for chemical hazards, p-dichlorobenzene. DHHS 

(NIOSH) Publication No. 81-123. 

*Nishihara T, Nishikawa J, Kanayama T, et al. 2000. Estrogenic activities of 517 chemicals by yeast 

two-hybrid assay. J Health Sci 46(4):282-298. 
DICHLOROBENZENES 382 

9. REFERENCES 

*NOES. 1990. National Occupational Exposure Survey. Cincinnati, OH: National Institute of 

Occupational Safety and Health. July 16, 1990. 

NOES. 1996. National Occupational Exposure Survey 1981-1983. Cincinnati, OH: U.S. Department of 

Health and Human Services, National Institute for Occupational Safety and Health. 

*NRC. 1993. Pesticides in the diets of infants and children. National Research Council. Washington 

DC: National Academy Press. 

*NTP. 1985. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene (o-dichlorobenzene) in 

F344/N rats and B6C3F1 mice (gavage studies). Research Triangle Park, NC: National Toxicology 

Program. NTP TR 255. NIH Publication No. 86-2511. 

*NTP. 1987. Toxicology and carcinogenesis studies of 1,4-dichlorobenzene in F344/N rats and B6C3F1 

mice (gavage studies). Research Triangle Park, NC: National Toxicology Program. NTP TR 319. NIH 

Publication No. 87-2575. 

*NTP. 1989. National Toxicology Program. Fifth annual report on carcinogens: Summary 1989. 

Research Triangle Park, NC: National Institute of Environmental Health Sciences, 103-106. NTP 89239. 

*NTP. 1995. Printed long term technical reports and short term toxicity study reports. Division of 

Toxicology Research and Testing. Research Triangle Park, NC: National Toxicology Program. National 

Institute of Environmental Health Sciences. 

*NTP. 2002. 1,4-Dichlorobenzene. Tenth report on carcinogens. National Toxicology Program. 

National Institute of Environmental Health Sciences. 

*NTP. 2005. NTP. 2005. Report on carcinogens. 11th edition. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC. http://ntpserver.niehs.nih.gov/ntp/roc/toc11.html. February 15, 2004. 

Odin M, Bosch S, Osier M, et al. 2003. Evaluation of mode of action in assessment of cancer risk 

associated with exposure to 1,4-dichlorobenzene. Toxicol Sci 72(S-1):138-139. 

*OECD. 1981. OECD guidelines for the testing of chemicals. Section 4: Health effects. Test No. 413: 

Subchronic inhalation toxicity: 90-day study. Organisation for Economic Co-operation and 

Development. http://caliban.sourceoecd.org/vl=1117056/cl=38/nw=1/rpsv/home.htm. September 29, 

2005. 

Ogata M, et al. 1981. Effects of chlorinated mono aromatic hydrocarbons on mitochondrial oxidative 

phosphorylation in rats liver. Ind Health 19:31-36. 

OHM/TADS. 1990. Oil and Hazardous Materials/Technical Assistance Data System. Baltimore, MD: 

Chemical Information Systems, Inc. July 26, 1990. 

Oikawa S, Kawanishi S. 1996. Copper-mediated DNA damage by metabolites of p-dichlorobenzene. 

Carcinogenesis 17(12):2733-2739. 

*Oliver BG, Nicol KD. 1982a. Chlorobenzenes in sediments, water and selected fish from Lakes 

Superior, Huron, Erie and Ontario. Environ Sci Technol 16:532-536. 
DICHLOROBENZENES 383 

9. REFERENCES 

*Oliver BG, Nicol KD. 1982b. Gas chromatographic determination of chlorobenzenes and other 

chlorinated hydrocarbons in environmental samples using fused silica capillary columns. 

Chromatrographia 16:336-340. 

*Oliver BG, Niimi AJ. 1983. Bioconcentration of chlorobenzenes from water by rainbow trout: 

Correlations with partition coefficients and environmental residues. Environ Sci Technol 17:287-291. 

*Oliver KD, Adams JR, Daughtrey EH, et al. 1996. Technique for monitoring ozone precursor 

hydrocarbons in air at photochemical assessment monitoring stations: Sorbent preconcentration, closedcycle cooler cryofocusing, and GC-FID analysis. Atmos Environ 30(15):2751-2757. 

*Olson MJ, Johnson JT, Reidy CA. 1990. A comparison of male rat and human urinary proteins: 

Implications for human resistance to hyaline droplet nephropathy. Toxicol Appl Pharmacol 102:524-536. 

*Oltmanns RH, Rast HG, Reineke W. 1988. Degradation of 1,4-dichlorobenzene by enriched and 

constructed bacteria. Appl Environ Microbiol 28:609-616. 

*O’Neil MJ, ed. 2001. o-Dichlorobenzene and p-dichlorobenzene. In: The Merck index. An 

encyclopedia of chemicals, drugs, and biologicals. Whitehouse Station, NJ: Merck Research 

Laboratories, 537-538. 

Ono Y, Somiya I, Kawamura M. 1991. Genotoxicity of the by-products produced in chlorination and 

ozonation processes. Mutat Res 252:102. 

*OSHA. 1974. U.S. Occupational Safety and Health Administration. Code of Federal Regulations. 29 

CFR 1910.1000. 

OSHA. 1986. Occupational Safety and Health Administration. OSHA Computerized Information 

System (OCIS), SIC IH information file for p-dichlorobenzene. Salt Lake City, Utah: U.S. Department 

of Labor, Occupational Safety and Health Administration. 

*OSHA. 1989. Air Contaminants. Occupational Safety and Health Administration: Part III. Fed Regist 

54:2332-2335, 2923-2933. 

OSHA. 1993. Air contaminants. U.S. Department of Labor. Occupational Safety and Health 

Administration. Fed Regist 58:35338. 

*OSHA. 2004a. Air contaminants. U.S. Department of Labor. Occupational Safety and Health 

Administration. Code of Federal Regulations. 29 CFR 1915.1000. 

*OSHA. 2004b. Gases, vapors, fumes, dusts, and mists. U.S. Department of Labor. Occupational 

Safety and Health Administration. Code of Federal Regulations. 40 CFR 1926.55. 

*OSHA. 2004c. Limits for air contaminants- Table Z-1. U.S. Department of Labor. Occupational 

Safety and Health Administration. Code of Federal Regulations. 29 CFR 1910.1000. 

*OTA. 1990. Neurotoxicology: Identifying and controlling poisons of the nervous system. Washington, 

DC: Office of Technology Assessment. OTA-BA-438. 

*Otson R, Williams DT, Bothwell PD. 1982. Volatile organic compounds in water at thirty Canadian 

potable water treatment facilities. J Assoc Off Anal Chem 65(6):1370-1374. 
 

 

DICHLOROBENZENES 384 

9. REFERENCES 

Ott WR, Roberts JW. 1998. Everyday exposure to toxic pollutants. Sci Am 278:86-91. 

Ou YC, Conolly RB, Thomas RS, et al. 2003. Stochastic simulation of hepatic preneoplastic foci 

development for four chlorobenzene congeners in a medium-term bioassay. Toxicol Sci 73(2):301-314. 

Overcash MR, Weber JB, Tucker WP. 1986. Toxic and priority organics in municipal sludge land 

treatment systems. Cincinnati, OH: U.S. Environmental Protection Agency, Wastewater Research 

Division. EPA600286010. PB86150208. 

*Owen GM, Brozek J. 1966. Influence of age, sex, and nutrition on body composition during childhood 

and adolescence. In: Falkner F, ed. Human development. Philadelphia, PA: Saunders, 222-238. 

*Page DB, Lacroix GM. 1995. On-line distillation/purge and trap analysis of halogenated, nonpolar, 

volatile contaminants in foods. J Assoc Off Anal Chem Int 78(6):1416-1428. 

*Page GW. 1981. Comparison of groundwater and surface water for patterns and levels of 

contamination by toxic substances. Environ Sci Technol 15:1475-1481. 

*Pagnotto LD, Walkley JE. 1965. Urinary dichlorophenol as an index of para-dichlorobenzene exposure. 

J Am Ind Hyg Assn 26:137-142. 

*Pankow JF, Rosen ME. 1988. Determination of volatile compounds in water by purging directly to a 

capillary column with whole column cryotrapping. Environ Sci Technol 22:398-405. 

*Pankow JF, Ligocki MP, Rosen ME, et al. 1988. Adsorption/thermal desorption with small cartridges 

for the determination of trace aqueous semivolatile organic compounds. Anal Chem 60:40-47. 

*Paolini M, Pozetti L, Silingardi P, et al. 1998. Isolation of a novel metabolizing system enriched in 

phase-II enzymes for short-term genotoxicity bioassays. Mutat Res 413:205-217. 

*Parke DV, Williams RT. 1955. Studies in detoxification: The metabolism of halogenobenzenes. (a) 

Meta-dichlorobenzene. (b) Further observations on the metabolism of chlorobenzene. Biochem J 

59:415-422. 

Paschke A, Popp P. 2004. Diffusion-based calibration for solid-phase microextraction of benzene, 

toluene, ethylbenzene, p-xylene and chlorobenzenes from aqueous samples. J Chromatogr A 1025:11-16. 

*Pellizzari ED, Hartwell TD, Benjamin SH. 1982. Purgeable organic compounds in mother’s milk. Bull 

Environ Contam Toxicol 28:322-328. 

*Pellizzari ED, Hartwell TD, Perritt RL, et al. 1986. Comparison of indoor and outdoor residential 

levels of volatile organic chemicals in five USA geographical areas. Environ Int 12(6):619-624. 

*Pellizzari ED, Sheldon LS, Bursey JT. 1985. GC/MS determination of volatile halocarbons in blood 

and tissue. Method 25. In: Fishbein L, O'Neal IK, eds. Environmental carcinogens selected methods of 

analysis. Vol. 7. Lyon, France: International Agency for Research on Cancer, 435-444. 

*Pellizzari ED, Smith DJ, Clayton CA, et al. 2001. An assessment of the data quality for NHEXAS-Part 

I: exposure to metals and volatile organic chemicals in Region 5. J Expo Anal Environ Epidemiol 

11:140-154. 
DICHLOROBENZENES 385 

9. REFERENCES 

*Pereira WE, Rostad CE, Chiou CT, et al. 1988. Contamination of estuarine water, biota, and sediment 

by halogenated organic compounds: A field study. Environ Sci Technol 22(7):772-778. 

*Perocco P, Bolognesi S, Alberghini W. 1983. Toxic activity of seventeen industrial solvents and 

halogenated compounds on human lymphocytes cultured in vitro. Toxicol Lett 16:69-75. 

*Perry DL, Chuang CC, Jungclaus GA, et al. 1979. Identification of organic compounds in industrial 

effluent discharges. Athens, GA: U.S. Environmental Protection Agency, Office of Research and 

Development. EPA600479016. 

Petit G, Champeix J. 1948. [Does an intoxication caused by paradichlorobenzene exist?] Arch des 

Malad Prof de Med 9:311-312. (French) 

*Phillips LJ, Birchard GF. 1991. Regional variations in human toxics exposure in the USA: An analysis 

based on the national human adipose tissue survey. Arch Environ Contam Toxicol 21:159-168. 

*Plumb RH. 1991. The occurrence of Appendix IX organic constituents in disposal site ground water. 

Ground Water Monit Rev 11:157-164. 

*Prasad I. 1970. Mutagenic effects of the herbicide 3,4-dichloroproprionanilide and its degradation 

products. Can J Microbiol 16:369-372. 

Prasad I, Pramer D. 1968. Mutagenic activity of some chloroanilines and chlorobenzenes. Genetics 

20:212-213. 

Pratt GC, Bock D, Stock TH, et al. 2005. A field comparison of volatile organic compound measurement 

using passive organic vapor monitors and stainless steel canisters. Environ Sci Technol 39(9):3261-3268. 

*Pratt GC, Palmer K, Wu CY, et al. 2000. An assessment of air toxics in Minnesota. Environ Health 

Perspect 108:815-825. 

Preston BD, Miller JA, Miller EC. 1983. Non-arene oxide aromatic ring hydroxylation of 2,2,5,5'­

tetrachlorobiphenyl as the major metabolic pathway catalyzed by phenobarbital-induced rat liver 

microsomes. J Biol Chem 258:8304-8311. 

Quack B, Suess E. 1999. Volatile halogenated hydrocarbons over the western Pacific between 43 ̊ and 4 ̊

N. J Geophys Res 104(D1):1663-1678. 

Rall DP. 1987. Carcinogenicity of p-dichlorobenzene. Science 236:897-898. 

Rautio AW. 1988. Chlorobenzene Producers Association comments on the draft toxicological profile for 

1,4-dichlorobenzene. Agency for Toxic Substances and Disease Registry. March 7, 1988. 

*Redmond MS, Crocker PA, McKenna KM, et al. 1996. Sediment toxicity testing with the amphipod 

Ampelisca abdita in Calcasieu Estuary, Louisiana. Arch Environ Contam Toxicol 30:53-61. 

*Reichrtova E, Ciznar P, Prachar V, et al. 1999. Cord serum immunoglobin E related to the 

environmental contamination of human placentas with organochlorine compounds. Environ Health 

Perspect 107(11):895-899. 
DICHLOROBENZENES 386 

9. REFERENCES 

*Reichrtova E, Prachar V, Palkovicova L, et al. 2001. Contamination of human placentas with 

organochlorine compounds in five Slovak regions related to different environmental characteristics. 

Fresenius Environ Bull 10(10):772-776. 

*Reygagne A, Garnier R, Chataigner D, et al. 1992. Encephalopathie due a l'inhalation volontaire 

repetee de paradichlorobenzene. Presse Med 21:267. 

*Riley RA, Chart IS, Doss A, et al. 1980a. para-Dichlorobenzene: Long-term inhalation study in the rat. 

ICI Report No. CTL/P/447. Imperial Chemical Industries Limited, Central Toxicology Laboratory, 

Alderly Park, Macclesfield, Chesire, UK. 

*Riley RA, Chart IS, Gaskell B, et al. 1980b. para-Dichlorobenzene. Long-term inhalation study in the 

mouse. Report No CTL/P448. Imperial Chemical Industries Limited, Central Toxicology Laboratory, 

Alderly Park, Macclesfield, Chesire, UK. (As cited in Loeser and Litchfield 1983) 

*Rimington GE, Ziegler G. 1963. Experimental porphyria in rats induced by chlorinated benzenes. 

Biochem Pharmacol 12:1387-1397. 

Rippen G, Klopffer W, Frische R, et al. 1984. The environmental model segment approach for 

estimating potential environmental concentrations. Ecotoxicol Environ Saf 8:363-377. 

*Robbiano L, Carrozzino R, Porta Puglia CP, et al. 1999. Correlation between induction of DNA 

fragmentation and micronuclei formation in kidney cells from rats and humans and tissue-specific 

carcinogenic activity. Toxicol Appl Pharmacol 161:153-159. 

*Robinson M, Bercz JP, Ringhand HP, et al. 1991. Ten and ninety-day toxicity studies of 1,2­

dichlorobenzene administered by oral gavage to Sprague-Dawley rats. Drug Chem Toxicol 14(1&2):83­

112. 

*Rossberg M, Aktiengesellschaft H, Lendle W, et al. 2002. Chlorinated hydrocarbons. In: Ullmann’s 

encyclopedia of industrial chemistry. Weinheim, Germany: Wiley-VCH-Verlag. 

RTECS. 1990. Registry of Toxic Effects of Chemical Substances. Bethesda, MD: National Library of 

Medicine, National Toxicology Information Program. July 18, 1990. 

*RTECS. 2004. Registry of Toxic Effects of Chemical Substances. Bethesda, MD: National Library of 

Medicine, National Toxicology Information Program. 

*Ruddick JA, Black WD, Villeneuve DC, et al. 1983. A teratological evaluation following oral 

administration of trichloro- and dichlorobenzene isomers to the rat. Teratology 27(2):73A-74A. 

*Ryan TJ, Hart EM, Kappler LL. 2002. VOC exposures in a mixed-use university art building. Am Ind 

Hyg Assoc J 63:703-708. 

*Safe SH, Zacharewski T. 1997. Organochlorine exposure and risk for breast cancer. In: Aldaz CM, 

Gould MN, McLachlan, et al., eds. Etiology of breast and gynecological cancers. New York, NY: John 

Wiley & Sons, 133-145. 

Saito K, Kaneko H, Isobe N, et al. 1992. Differences in α2μ- globulins increased in male rat kidneys 

following treatment with several α2μ-globulin accumulating agents: Cystein protease(s) play(s) an 

important role in production of kidney-type-α2μ-globulin. Toxicology 76:177-186. 
DICHLOROBENZENES 387 

9. REFERENCES 

*Saito K, Uwagawa S, Kaneko H, et al. 1996. α2μ-Globulins in the urine of male rats: A reliable 

indicator for α2μ-globulin accumulation in the kidney. Toxicology 106:149-157. 

Salkinoja-Salonen MS, Jokela JK. 1991. Measurement of organic halogen compounds in urine as an 

indicator of exposure. Scand J Work Environ Health 17(1):75-78. 

*Sarbhoy RK. 1980. Effect of para-dichlorobenzene on the somatic chromosomes and mitosis of Lens 

esculenta (L.) Moench. Cytologia 45:381-388. 

Saunders M, Fox DJ, Salisbury C, et al. 2004. Placental transfer and fetal uptake of pesticides. Toxicol 

Appl Pharmacol 197(3):341. 

*Sax NI, Lewis RJ Sr. 1987. Hawley's condensed chemical dictionary. 11th ed. New York, NY: Van 

Nostrand Reinhold Company, 376. 

*Sax SN, Bennett DH, Chillrud SN, et al. 2004. Differences in source emission rates of volatile organic 

compounds in inner-city residences of New York City and Los Angeles. J Expo Anal Environ Epidemiol 

14(Supp 1):S95-S109. 

Schaeffer V. 1991. Briefing package: Hazard evaluation of consumer products containing 1,4­

dichlorobenzene. Washington, DC: U.S. Consumer Product Safety Commission, Division of Health 

Effects. Directorate for Health Sciences. 

Schlede E, Mischke U, Roll R, et al. 1992. A national validation study of the acute-toxic-class methodan alternative to the LD50 test. Arch Toxicol 66(7):455-470. 

*Schraa G, Boone ML, Jetten MSM, et al. 1986. Degradation of 1,4 dichlorobenzene by Alcaligenes sp. 

strain A175. Appl Environ Microbiol 52(6):1374-1381. 

*Schwarzenbach RP, Westall J. 1981. Transport of nonpolar organic compounds from surface water to 

groundwater. Laboratory sorption studies. Environ Sci Technol 15:1360-1367. 

*Schwartzenbach RP, Giger W, Hoehn E, et al. 1983. Behavior of organic compounds during infiltration 

of river valley to groundwater. Field Studies. Environ Sci Technol 17(8):472-479. 

*Scuderi R. 1986. Determination of para-dichlorobenzene releases from selected consumer products. 

Washington, DC: U.S. Environmental Protection Agency, Office of Toxic Substances. 

Serrano-Trespalacios PI, Ryan L, Spengler JD. 2004. Ambient, indoor and personal exposure 

relationship of volatile organic compounds in Mexico City Metropolitan Area. J Expo Anal Environ 

Epidemiol 14:S118-S132. 

*Setchell BP, Waites GMH. 1975. The blood testis barrier. In: Creep RO, Astwood EB, eds., Geiger 

SR, executive ed. Handbook of physiology: Endocrinology V (Chapter 6). Washington DC: American 

Physiological Society. 

*Seto Y. 1994. Determination of volatile substances in biological samples by headspace gas 

chromatography. J Chromatogr A 674:25-62. 
DICHLOROBENZENES 388 

9. REFERENCES 

*Sexton K, Adgate JL, Church TR, et al. 2005. Children's exposure to volatile organic compounds as 

determined by longitudinal measurements in blood. Environ Health Perspect 113(3):342-349. 

*Sexton K, Adgate JL, Ramachandran G, et al. 2004. Comparison of personal, indoor, and outdoor 

exposures to hazardous air pollutants in three urban communities. Environ Sci Technol 38:423-430. 

*Shah JJ, Heyerdahl EK. 1988. National ambient volatile organic compounds (VOCs): Data base 

update. Research Triangle Park, NC: U.S. Environmental Protection Agency, Atmospheric Sciences 

Research Laboratory. EPA600388010A. 

Shah JJ, Singh HB. 1988. Distribution of volatile organic chemicals in outdoor and indoor air: A 

national VOCs data base. Environ Sci Technol 22:1381-1388. 

*Sharma AK, Battacharya NK. 1956. Chromosome breakage through paradichlorobenzene treatment. 

Cytologia 21:353-360. 

Sharma AK, Sarkar SK. 1957. A study of the comparative effect of chemicals on chromosomes of roots, 

pollen mother cells and pollen grains. Proc Ind Acad Sci B 45:288-293. 

*Shelby MD, Witt KL. 1995. Comparison of results from mouse bone marrow chromosome aberration 

and micronucleus tests. Environ Mol Mutagen 25:302-313. 

Shelby MD, Erexson GL, Hook GJ, et al. 1993. Evaluation of a three-exposure mouse bone marrow 

micronucleus protocol: Results with 49 chemicals. Environ Mol Mutagen 21(2):160-179. 

Sheldon LS, Hites RA. 1978. Organic compounds in the Delaware River. Environ Sci Technol 12:1188­

1194. 

*Shelton JL, Burow KR, Belitz K, et al. 2000. Low-level volatile organic compounds in active public 

supply wells as ground-water tracers in the Los Angeles physiographic basin, California, 2000. 

California State Water Resources Control Board. Water Resources Investigation Report 01-4188. 

Shen TT. 1982. Estimation of organic compound emissions from waste lagoons. J Air Pollut Control 

Assoc 32:79-82. 

*Shendell DG, Winer AM, Stock TH, et al. 2004. Air concentrations of VOCs in portable and traditional 

classrooms: Results of a pilot study in Los Angeles County. J Expo Anal Environ Epidemiol 14:44-59. 

*Sherman JH, Nair RS, Steinmetz KL, et al. 1998. Evaluation of unscheduled DNA synthesis (UDS) 

and replicative DNA synthesis (RDS) following treatment of rats and mice with p-dichlorobenzene. 

Teratog Carcinog Mutagen 18:309-318. 

*Shimizu N, Yasui Y, Matsumoto N. 1983. Structural specificity of aromatic compounds with special 

reference to mutagenic activity in Salmonella typhimurium - a series of chloro- or fluoro-nitrobenzene 

derivatives. Mutat Res 116:217-238. 

Shiraishi H, Pilkington NH, Otsuki A, et al. 1985. Occurrence of chlorinated polynuclear aromatic 

hydrocarbons in tap water. Environ Sci Technol 19:585-590. 

*Shiu W-Y, Mackay D. 1997. Henry’s law constants on selected aromatic hydrocarbons, alcohols, and 

ketones. J Chem Eng Data 42:27-30. 
DICHLOROBENZENES 389 

9. REFERENCES 

Siegel E, Wason S. 1986. Mothball toxicity. Pediatr Clin North Am 33:369-374. 

Simmon VF, Riccio ES, Peirce MV. 1979. In vitro microbiological genotoxicity tests of chlorobenzene, 

m-dichlorobenzene, o-dichlorobenzene, and p-dichlorobenzene. Final Report. U.S. Environmental 

Protection Agency. EPA68022947. 

Singh HB, Salas LJ, Smith A, et al. 1980. Atmospheric measurements of selected hazardous organic 

chemicals. Research Triangle Park, NC: U.S. Environmental Protection Agency, Environmental 

Sciences Research Laboratory. 

*Singh HB, Salas LJ, Smith AJ, et al. 1981a. Measurements of some potentially hazardous organic 

chemicals in urban environments. Atmos Environ 15:601-612. 

*Singh HB, Salas LJ Smith R, et al. 1981b. Atmospheric measurements of selected hazardous organic 

chemicals. Research Triangle Park, NC: U.S. Environmental Protection Agency. Environmental Science 

Research Laboratory. 

Sinkkonen S, Welling L, Vattulainen A, et al. 1996. Short chain aliphatic halocarbons and 

polychlorinated biphenyls in pine needles: Effects of metal scrap plant emissions. Chemosphere 

32(10):1971-1982. 

Sittig M. 1985. Handbook of toxic and hazardous chemicals and carcinogens. 2nd ed. Park Ridge, NJ: 

Noyes Publications, 313-316. 

*Spain JC, Nishino SF. 1987. Degradation of 1,4-dichlorobenzene by a Pseudomonas sp. Appl Environ 

Microbiol 53:1010-1019. 

Spicer CW, Riggin RM, Holdren MW, et al. 1985. Atmospheric reaction products from hazardous air 

pollutant degradation. Research Triangle Park, NC: U.S. Environmental Protection Agency, Office of 

Research and Development. EPA600385028. PB85185841. 

*Spiess E, Sommer C, Gorisch H. 1995. Degradation of 1,4-dichlorobenzene by Xanthobacter flavus 14 

p1. Appl Environ Microbiol 61(11):3884-3888. 

Spirtas R, Stewart PA, Lee JS, et al. 1991. Retrospective cohort mortality study of workers at an aircraft 

maintenance facility. I. Epidemiological results. Br J Ind Med 8:515-530. 

*Squillace PJ, Moran MJ, Lapham WW, et al. 1999. Volatile organic compounds in untreated ambient 

groundwater of the United States, 1985-1995. Environ Sci Technol 33(23):4176-4187. 

*SRI. 1984. Directory of chemical producers. United States of America. Menlo Park, CA: SRI 

International, 525-526 

SRI. 1987. Directory of chemical producers: United States of America. Menlo Park, CA: SRI 

International, 568-569. 

*SRI. 1988. Directory of chemical producers: United States of America. Menlo Park, CA: SRI 

International, 558-559. 
 

 

 

 

 

 

 

 

 

DICHLOROBENZENES 390 

9. REFERENCES 

*SRI International. 1995. 1995 Directory of chemical producers - United States of America. Menlo 

Park, CA: SRI International, 542. 

*SRI. 1996. 1996 Directory of chemical producers - United States of America. Menlo Park, CA: SRI 

International, 536. 

*SRI International. 1997. 1997 Directory of chemical producers - United States of America. Menlo 

Park, CA: Stanford Research Institute International, 542. 

SRI International. 1998. 1998 Directory of chemical producers- United States of America. Menlo Park, 

CA: Stanford Research Institute, 548. 

*SRI International. 1999. 1999 Directory of chemical producers- United States of America. Menlo Park, 

CA: SRI, 549. 

SRI International. 2000. 2000 Directory of chemical producers- United States of America. Menlo Park, 

CA: SRI International, 548. 

*SRI International. 2001. 2001 Directory of chemical producers- United States of America. Menlo Park, 

CA: SRI International, 544. 

SRI International. 2002. 2002 Directory of chemical producers- United States of America. Menlo Park, 

CA: SRI International, 543-544. 

*SRI International. 2003. 2003 Directory of chemical producers- United States of America. Menlo Park, 

CA: SRI International, 538. 

*SRI. 2005. 2005 Directory of Chemical Producers. Menlo Park, California: SRI Consulting.:317,368­

369,546. 

*Srivastava LM. 1966. Induction of mitotic abnormalities in certain genera of tribe Vicieae by 

paradichlorobenzene. Cytologia 31:166-171. 

*Stackelberg PE, Kauffman LJ, Ayers MA, et al. 2001. Frequently co-occurring pesticides and volatile 

organic compounds in public supply and monitoring wells, Southern New Jersey, USA. Environ Toxicol 

Chem 20(4):853-865. 

*Stanley JS. 1986. Broad scan analysis of the FY 82 National Human Adipose Tissue Survey 

specimens. Vol. I - Executive summary. Washington, DC: U.S. Environmental Protection Agency, 

Office of Toxic Substances. EPA560586035. 

*Staples CA, Werner AF, Hoogheen TJ. 1985. Assessment of priority pollutant concentrations in the 

United States using STORET database. Environ Toxicol Chem 4:131-142. 

*Staudinger J, Roberts PV. 1996. A critical review of Henry’s law constants for environmental 

applications. Crit Rev Environ Sci Tech 26(3):205, 268-269. 

*Stauffer TB, Antworth CP, Boggs JM, et al. 1994. A natural gradient tracer experiment in an 

heterogeneous aquifer with measured in situ biodegradation rates: A case for natural attenuation. 

Symposium on intrinsic bioremediation in ground water, 73-84. 
DICHLOROBENZENES 391 

9. REFERENCES 

*Stefaniak AB, Breysse PN, Murray MPM, et al. 2000. An evaluation of employee exposure to volatile 

organic compounds in three photocopy centers. Environ Res 83:162-173. 

*Steinmetz KL, Spanggord RJ. 1987a. Examination of the potential of p-dichlorobenzene to induce 

unscheduled DNA synthesis or DNA replication in the in vivo - in vitro mouse hepatocyte DNA repair 

assay. Final Report. SRI International. 

*Steinmetz KL, Spanggord RJ. 1987b. Evaluation of the potential of p-dichlorobenzene to induce 

unscheduled DNA synthesis or DNA replication in the in vivo-in vitro rat kidney DNA repair assay. 

Final Report. SRI International. 

Stewart PA, Lee JS, Marano DE, et al. 1991. Retrospective cohort mortality study of workers at an 

aircraft maintenance facility. II. Exposures and their assessment. Br J Ind Med 48:531-537. 

*Stine ER, Gunawardhana L, Sipes IG. 1991. The acute hepatotoxicity of the isomers of 

dichlorobenzene in Fischer 344 and Sprague-Dawley rats: Isomer specific and strain specific differential 

toxicity. Toxicol Appl Pharmacol 109:472-481. 

*Stubin AI, Brosnan TM, Porter KD, et al. 1996. Organic priority pollutants in New York City 

municipal wastewaters: 1989-1993. Water Environ Res 68:1037-1044. 

*Suzuki A, Nagai H, Hiratsuka H, et al. 1991. [Effects of 1,4-dichlorobenzene on antibody production in 

guinea pigs.] Oyo Yakuri 42(2):197-208. (Japanese) 

Symons JM, Bellar TA, Carswell JK, et al. 1975. National organics reconnaissance survey for 

halogenated organics. J Am Water Works Assoc (November):634-648. 

*Tabak HH, Quave SA, Mashni CI, et al. 1981. Biodegradability studies with organic priority pollutant 

compounds. J Water Pollut Control Fed 53:1503-1518. 

Tananaki C, Zotou A, Thrasyvoulou A. 2005. Determination of 1,2-dibromoethane, 1,4-dichlorobenzene 

and naphthalene residues in honey by gas chromatography--mass spectrometry using purge and trap 

thermal desorption extraction. J Chromatogr A 1083(1-2):146-152. 

*Tansel B, Eyma RR. 1999. Volatile organic contaminant emissions from wastewater treatment plants 

during secondary treatments. Water Air Soil Pollut 112:315-325. 

*Taylor LA, Chapman PM, Miller RA, et al. 1998. The effects of untreated municipal sewage discharge 

to the marine environment off Victoria, British Columbia, Canada. Water Sci Technol 38(10):282-292. 

Tegethoff K, Herbold BA, Bomhard EM. 2000. Investigations on the mutagenicity of 1,4­

dichlorobenzene and its main metabolite 2,5-dichlorophenol in vivo and in vitro. Mutat Res 470:161-167. 

*Thomas KW, Pellizzari ED, Cooper SD. 1991. A canister based method for collection and GC/MS 

analysis of volatile organic compounds in human breath. J Anal Toxicol 15:54-59. 

*Topping B. 1987. The biodegradability of para-dichlorobenzene and its behaviour in model activated 

sludge plants. Water Res 21(3):293-300. 
 

 

 

 

DICHLOROBENZENES 392 

9. REFERENCES 

*TRI03. 2005. TRI explorer: Providing access to EPA’s toxics release inventory data. Washington, 

DC: Office of Information Analysis and Access, Offices of Environmental Information, U.S. 

Environmental Protection Agency. Toxic Release Inventory. http://www.epa.gov/triexplorer/. August, 

2005. 

*Trieff NM, Ficklen D, Gan J. 1993. In vitro inactivation of glucose-6-phosphate dehydrogenase from 

human red blood cells by acrolein: A possible biomarker of exposure. Toxicol Lett 69:121-127. 

*Trieff NM, Ramanujam VMS, Stara JF, et al. 1991. Water quality criteria assessment for chlorinated 

benzenes using the quantitative structure activity relation approach and porphyrogenic endpoint in rats. 

Int J Environ Health Res 1:215-230. 

*Tyl RW, Neeper-Bradley TL. 1989. Paradichlorobenzene: Two generation reproductive study of 

inhaled paradichlorobenzene in Sprague-Dawley (CD) rats. Laboratory Project 86-81-90605. 

Washington, DC: Chemical Manufacturers Association, Chlorobenzene Producers Association. 

*Umemura T, Saito M, Takagi A, et al. 1996. Isomer-specific acute toxicity and cell proliferation in 

livers of B6C3F1 mice exposed to dichlorobenzene. Toxicol Appl Pharmacol 137:268-274. 

Umemura T, Takada K, Ogawa Y, et al. 1990. Sex difference in inhalation toxicity of p-dichlorobenzene 

(p-DCB) in rats. Toxicol Lett 52:209-214. 

*Umemura T, Takada K, Schulz C, et al. 1998. Cell proliferation in the livers of male mice and rats 

exposed to the carcinogen p-dichlorobenzene: Evidence for thresholds. Drug Chem Toxicol 21(1):57-66. 

*Umemura T, Tokumo K, Williams GM. 1992. Cell proliferation induced in the kidneys and livers of 

rats and mice by short term exposure to the carcinogen p-dichlorobenzene. Arch Toxicol 66(7):503-507. 

*U.S. Congress. 1986. Superfund amendments and reauthorization act of 1986. Title III-Emergency 

Planning and Community Right-to-Know. Ninety-ninth Congress of the United States of America. 

*U.S. Congress. 1990. Clean Air Amendments. Title III, Hazardous Air Pollutants, Section 112(b), 

Hazardous Air Pollutants as Amended, October 26, 1990. One Hundred and First Congress of the United 

States of America, 2nd Session Report 101-952. 

*USGS. 2002. Trace elements and organic compounds in streambed sediment and fish tissue of coastal 

New England streams, 1998-1999. Pembroke, NH: U.S. Geological Survey. Report 024179. 

USITC. 1987. Synthetic organic chemicals: United States production and sales, 1987. Washington, DC: 

U.S. International Trade Commission. USITC publication 2118, 3-2, 3-7. 

Valentovic MA, Ball JG, Anestis D, et al. 1993a. Acute hepatic and renal toxicity of dichlorobenzene 

isomers in Fischer 344 rats. J Appl Toxicol 13(1):1-7. 

Valentovic MA, Ball JG, Anestis D, et al. 1993b. Modification of P450 activity and its effect on 1,2­

dichlorobenzene toxicity in Fischer 344 rats. Toxicology 79:169-180. 

*van der Meer JR, Bosma TNP, de Bruin WP, et al. 1992. Versatility of soil column experiments to 

study biodegradation of halogenated compounds under environmental conditions. Biodegradation 3:265­

284. 
DICHLOROBENZENES 393 

9. REFERENCES 

Van Wezel AP, DeVries DAM, Sijm DTHM, et al. 1996. Use of the lethal body burden in the evaluation 

of mixture toxicity. Ecotoxicol Environ Saf 35(3):236-241. 

van Wezel AP, Sijm DTHM, Seinen W. 1995. Use of lethal body burdens to indicate species differences 

in susceptibility to narcotic toxicants. Chemosphere 31(5):3201-3209. 

*Verschueren K. 1983. Handbook of environmental data on organic chemicals. 2nd ed. New York, 

NY: Van Nostrand Reinhold Company, 477-478. 

*Verschueren K. 2001. o-dichlorobenzene, m-dichlorobenzene and p-dichlorobenzene. In: Handbook 

of environmental data on organic chemicals. Volume 1. New York, NY: John Wiley & Sons, Inc. 

*Versonnen BJ, Arijs K, Verslycke T, et al. 2003. In vitro and in vivo estrogenicity and toxicity of o-, 

m-, and p-dichlorobenzene. Environ Toxicol Chem 22(2):329-335. 

*Vieira I, Sonnier M, Cresteil T. 1996. Developmental expression of CYP2E1 in the human liver: 

hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238:476-483. 

*Wakeham SG, Davis AC, Karas JL. 1983. Mesocosm experiments to determine the fate and persistence 

of volatile organic compounds in coastal seawater. Environ Sci Technol 17:611-617. 

*Wallace L, Buckley T, Pellizzari E, et al. 1996. Breath measurements as volatile organic compound 

biomarkers. Environ Health Perspect 104(Suppl 5):861-869. 

*Wallace L, Pellizzari E, Hartwell T, et al. 1986c. Concentrations of 20 volatile organic compounds in 

the air and drinking water of 350 residents of New Jersey compared with concentrations in their exhaled 

breath. J Occup Med 28(8):603-608. 

*Wallace L, Pellizzari E, Sheldon L, et al. 1986a. The total exposure assessment methodology (TEAM) 

study: Direct measurement of personal exposures through air and water for 600 residents of several U.S. 

cities. In: Cohen Y, ed. Pollutants in a multimedia environment. New York, NY: Plenum Publishers 

Corporation, 289-315. 

*Wallace LA. 1986. Personal exposures, indoor and outdoor air concentrations, and exhaled breath 

concentrations of selected volatile organic compounds measured for 600 residents of New Jersey, North 

Dakota, North Carolina and California. Toxicol Environ Chem 12:215-236. 

*Wallace LA. 1987. The total exposure assessment methodology (TEAM) study: Summary and 

analysis: volume I. U.S. Environmental Protection Agency. Office of Research and Development. 

600687002a. 

Wallace LA. 1991. Personal exposure to 25 volatile organic compounds. EPA’s 1987 team study in Los 

Angeles, California. Toxicol Ind Health 7(5/6):203-208. 

Wallace LA, Pellizzari E, Hartwell T, et al. 1985. Personal exposures, indoor-outdoor relationships, and 

breath levels of toxic air pollutants measured for 335 persons in New Jersey. Atmos Environ 19:1651­

1661. 

*Wallace LA, Pellizzari ED, Hartwell TD, et al. 1986b. Total exposure assessment methodology 

(TEAM) study: Personal exposures, indoor-outdoor relationships, and breath levels of volatile organic 

compounds in New Jersey. Environ Int 12:369-387. 
DICHLOROBENZENES 394 

9. REFERENCES 

*Wallace LA, Pellizzari ED, Hartwell TD, et al. 1987. The team study: Personal exposures to toxic 

substances in air, drinking water, and breath of 400 residents of New Jersey, North Carolina, and North 

Dakota. Environ Res 43:290-307. 

*Wallace LA, Pellizzari ED, Hartwell TD, et al. 1988. The California team study: Breath concentrations 

and personal exposures to 26 volatile compounds in air and drinking water of 188 residents of Los 

Angeles, Antioch, and Pittsburg, CA. Atmos Environ 22:2141-2163. 

*Wallace LA, Pellizzari ED, Hartwell TD, et al. 1989. The influence of personal activities on exposure 

to volatile organic compounds. Environ Res 50:37-55. 

Wang L, Zhou Q, Zhang BS, et al. 2003. The biodegradation of 1,3-dichlorobenzene by an adapted 

strain Bacillus cereus PF-11 derived from town-gas industrial effluent. J Environ Sci Health Part A 

38(9):1837-1848. 

*Wang M-J, Jones KC. 1994a. Behavior and fate of chlorobenzenes in spiked and sewage sludgeamended soil. Environ Sci Technol 28:1843-1852. 

*Wang M-J, Jones KC. 1994d. Occurrence of chlorobenzenes in nine United Kingdom retail vegetables. 

J Agric Food Chem 42:2332-2338. 

*Wang M-J, Jones KC. 1994b. The chlorobenzene content of contemporary U.K. sewage sludges. 

Chemosphere 28(6):1201-1210. 

*Wang M-J, Jones KC. 1994c. Uptake of chlorobenzenes by carrots from spiked and sewage sludgeamended soil. Environ Sci Technol 28:1260-1267. 

*Wang M-J, Bokern M, Boehmen C, et al. 1996. Phytotoxicity uptake and metabolism of 1,4­

dichlorobenzene by plant cells. Environ Toxicol Chem 15(7):1109-1114. 

*Wang M-J, McGrath SP, Jones KC. 1995. Chlorobenzenes in field soil with a history of multiple 

sewage sludge applications. Environ Sci Technol 29(2):356-362. 

*Washall JW, Wampler TP. 1988. Purge and trap analysis of aqueous samples with cryofocusing. Am 

Lab (July):70-74. 

*Waters MD, Snadhu SS, Simmon VF, et al. 1982. Study of pesticide genotoxicity. Basic Life Sci 

21:275-326. 

Weintraub E, Gandhi D, Robinson C. 2000. Medical complications due to mothball abuse. South Med J 

91(4):427-429. 

*Weller RW, Crellin AJ. 1953. Pulmonary granulomatosis following extensive use of 

paradichlorobenzene. Arch Intern Med 91:408-413. 

*West JR, Smith HW, Chasis H. 1948. Glomerular filtration rate, effective renal blood flow, and 

maximal tubular excretory capacity in infancy. J Pediatr 32a:10-18. 

*Westrick JJ, Mello JW, Thomas RF. 1984. The groundwater supply survey. J Am Water Works Assoc 

76:52-59. 
 

 

DICHLOROBENZENES 395 

9. REFERENCES 

*WHO. 1996. Guidelines for drinking-water quality. Second Edition. Volume 2. Health criteria and 

other supporting information. Geneva, Switzerland: World Health Organization. 

*WHO. 2000. Air quality guidelines. 2nd edition. World Health Organization. Geneva, Switzerland. 

http://www.euro.who.int/document/aiq/3summary.pdf. September 7, 2005. 

*WHO. 2004. Guidelines for drinking-water quality. 3rd edition. World Health Organization. Geneva, 

Switzerland. http://www.who.int/water_sanitation_health/dwq/gdwq3/en/index.html. August 31, 2005. 

*Widdowson EM, Dickerson JWT. 1964. Chapter 17: Chemical composition of the body. In: Comar 

CL, Bronner F, eds. Mineral metabolism: An advanced treatise, volume II - the elements part A. New 

York: Academic Press. 

Williams RT. 1959. The metabolism of halogenated aromatic hydrocarbons. In: Detoxication 

mechanisms. 2nd ed. New York, NY: John Wiley and Sons, 237-258. 

*Williams GM, Mori H, McQueen CA. 1989. Structure-activity relationships in the rat hepatocyte 

DNA-repair test for 300 chemicals. Mutat Res 221:263-286. 

*Wilson JT, Enfield CG, Dunlap WJ, et al. 1981. Transport and fate of selected organic pollutants in a 

sandy soil. J Environ Qual 10:501-506. 

Witt KL, Knapton A, Wehr CM, et al. 2000. Micronucleated erythrocyte frequency in peripheral blood 

of B6C3F1 mice from short-term, prechronic, and chronic studies on the NTP Carcinogenesis Bioassay 

Program. Environ Mol Mutagen 36:163-194. 

Won D, Corsi RL, Rynes M. 2001. Sorptive interactions between VOCs and indoor materials. Indoor 

Air 11:246-256. 

Woodruff TJ, Axelrad DA, Caldwell J, et al. 1998. Public health implications of 1990 air toxics 

concentrations across the United States. Environ Health Perspect 106:245-251. 

*Yalkowsky SH, He Y. 2003. 1,4-dichlorobenzene and 1,3-dichlorobenzene. In: Handbook of aqueous 

solubility data. Boca Raton, FL: CRC Press, 207-208. 

Yang KH, Peterson Re. 1977. Differential effects of halogenated aromatic hydrocarbons on pancreatic 

excretory function in rats. Fed Proc 36:356. 

Yasunaga K, Kiyonari A, Oikawa T, et al. 2004. Evaluation of the Salmonella umu test with 83 NTP 

chemicals. Environ Mol Mutagen 44(4):329-345. 

Yoshida T, Andoh K, Fukuhara M. 1998. Estimation of absorption of environmental contaminants in 

low-level exposure by pharmacokinetic analysis. J Toxicol Environ Health A 54(2):145-158. 

Yoshida T, Andoh K, Fukuhara M. 2002a. Urinary 2,5-dichlorphenol as biological index for pdichlorobenzene exposure in the general population. Arch Environ Contam Toxicol 43:481-485. 

Yoshida T, Andoh K, Kosaka H, et al. 2002b. Inhalation toxicokinetics of p-dichlorobenzene and daily 

absorption and internal accumulation in chronic low-level exposure to humans. Arch Toxicol 76(5­

6):306-315. 
DICHLOROBENZENES 396 

9. REFERENCES 

*Young DR, Heesen TC. 1978. DDT, PCB and chlorinated benzenes in the marine ecosystem off 

Southern California. In: Jolley RL, Gorchev H, Hamilton DH Jr., eds. Water chlorination: 

Environmental impact and health effects, Volume 2. Ann Arbor, MI: Ann Arbor Science Publishers, 

Inc., 267-290. 

*Young DR, Gossett RW, Baird RB, et al. 1981. Wastewater inputs and marine bioaccumulation of 

priority pollutant organics off Southern California. In: Jolley RL, Brungs WA, Cotruvo JA, et al., eds. 

Water chlorination environmental impact and health effects, Vol. 4, Book 2. Ann Arbor, MI: Ann Arbor 

Science Publishers, Inc., 871-884. 

*Young DR, Heesen TC, Gossett RW. 1980. Chlorinated benzenes in Southern California municipal 

wastewaters and submarine discharge zones. In: Jolley RL, Brungs WA, Cumming RB, eds. Water 

chlorination: Environmental impact and health effects, Volume 3. Ann Arbor, MI: Ann Arbor Science 

Publishers, Inc., 471-486. 

Young WF, Horth H, Crane R, et al. 1996. Taste and odour threshold concentrations of potential potable 

water contaminants. Water Res 30(2):331-340. 

*Younis HS, Hoglen NC, Kuester RK, et al. 2000. 1,2-Dichlorobenzene-mediated hepatocellular 

oxidative stress in Ficher-344 and Sprague-Dawley rats. Toxicol Appl Pharmacol 163:141-148. 

Zapata-Gayon C, Zapata-Gayon N, Gonzalex-Angulo A. 1982. Clastogenic chromosomal aberrations in 

26 individuals accidentally exposed to ortho dichlorobenzene vapors in the National Medical Center in 

Mexico City. Arch Environ Health 37:231-235. 

*Zenser L-P, Lang A, Knecht U. 1997. N-Acetyl-S-(dichlorophenyl)cysteines as suitable biomarkers for 

the monitoring of occupational exposure to 1,2-dichlorobenzene. Int Arch Occup Environ Health 69:252­

254. 

*Zhang J, Zhao W, Pan J, et al. 2005. Tissue-dependent distribution and accumulation of 

chlorobenzenes by vegetables in urban area. Environ Int 31(6):855-860. 

*Zhu J, Newhook R, Marro L, et al. 2005. Selected volatile organic compounds in residential air in the 

city of Ottawa, Canada. Environ Sci Technol 39(11):3964-3971. 

*Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr 

Res 12:29-34. 

*Zielinska B, Fujita E, Sagebiel J, et al. 1998. Arizona hazardous air pollutants monitoring program. J 

Air Waste Manage Assoc 48:1038-1050. 

*Zielinska B, Sagebiel J, Harshfield G, et al. 2001. Volatile organic compound measurements in the 

California/Mexico border region during SCOS97. Sci Total Environ 276:19-31. 

*Zissu D. 1995. Histopathological changes in the respiratory tract of mice exposed to ten families of 

airborne chemicals. J Appl Toxicol 15(3):207-213. 

Zupko, A, Edwards L. 1949. A toxicological study of p-dichlorobenzene. J Am Pharm Assoc 38:124­

131. 
DICHLOROBENZENES 397 

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. 
DICHLOROBENZENES 398 

10. GLOSSARY 

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. 

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. 
DICHLOROBENZENES 399 

10. GLOSSARY 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

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. 
DICHLOROBENZENES 400 

10. GLOSSARY 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

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. 
DICHLOROBENZENES 401 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3

 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 
 

 

DICHLOROBENZENES 402 

10. GLOSSARY 

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. 

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. 
DICHLOROBENZENES 403 

10. GLOSSARY 

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. 
DICHLOROBENZENES 404 

10. GLOSSARY 

This page is intentionally blank. 
DICHLOROBENZENES 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. 
DICHLOROBENZENES A-2 

APPENDIX A 

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 

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. 
 

 

 

 

 

 

 

DICHLOROBENZENES A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,4-Dichlorobenzene (1,4-DCB) 

CAS Numbers: 106-46-7 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 1 

Species: Human 

Minimal Risk Level: [ ] mg/kg/day [2] ppm 

Reference: Hollingsworth RL, Rowe VK, Oyen F, et al. 1956. Toxicity of paradichlorobenzene: 

Determinations on experimental animals and human subjects. AMA Arch Ind Health 14:138-147. 

Experimental design: Periodic occupational health examinations were conducted on 58 men who had 

worked in unspecified industrial operations involving the handling of 1,4-DCB, generally for 8 hours/day 

and 5 days/week, continually or intermittently for periods of 8 months to 25 years (average 4.75 years). 

Effects of different workplace exposure levels on eye and nose irritation were summarized. The medical 

evaluations included careful examination of the eyes, blood cell counts (RBC, WBC, and differential), 

hemoglobin, hematocrit, mean corpuscular volume, blood urea nitrogen, sedimentation rate, and 

urinalysis. 

Effects noted in study and corresponding doses: Observations in the workers provide information 

relevant to acute exposures. The odor was found to be faint at 15–30 ppm and strong at 30–60 ppm. 

Painful irritation of the eyes and nose was usually experienced at 50–80 ppm, although the irritation 

threshold was higher (80–160 ppm) in workers acclimated to exposure. Concentrations above 160 ppm 

caused severe irritation and were considered intolerable to people not adapted to it. The odor and 

irritation properties were considered to be fairly good acute warning properties and were expected to 

prevent excessive exposures, although the industrial experience indicated that it is possible for people to 

become sufficiently acclimated to tolerate high concentrations of the vapor. No cataracts or any other 

lens changes in the eyes, or effects on the clinical indices were attributable to exposure. 

Dose and end point used for MRL derivation: 

[15] NOAEL [] LOAEL 

As discussed above, eye and nose irritation are critical effects of acute inhalation exposure to 1,4-DCB in 

humans. Because odor detection is a warning property expected to prevent irritation caused by 1,4-DCB, 

the highest level at which an odor was detected that was simultaneously without irritant effects, 30 ppm, 

was designated a minimal LOAEL for irritation for the purposes of derivation of the MRL; the 15 ppm 

level was therefore designated a NOAEL for irritant effects. 

Uncertainty Factors used in MRL derivation: 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 
DICHLOROBENZENES A-4 

APPENDIX A 

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. 

Other additional studies or pertinent information that lend support to this MRL: A limited amount of 

information is available on the toxicity of inhaled 1,4-DCB in humans. Case reports of people who 

inhaled 1,4-DCB provide indications that the liver and nervous system are systemic targets of inhalation 

toxicity in humans, but are limited by lack of adequate quantitative exposure information and/or 

verification that 1,4-DCB was the only factor associated with the effects (Cotter 1953; Miyai et al. 1988; 

Reygagne et al. 1992). 

Information on effects of acute-duration inhalation exposure to 1,4-DCB in animals is available from 

short-term systemic toxicity studies in rats and guinea pigs (Hollingsworth et al. 1956), a male 

reproduction study rats (Anderson and Hodge 1976), and developmental toxicity studies in rats and 

rabbits (Hayes et al. 1985; Hodge et al. 1977). In the systemic toxicity study, five rats of each sex and 

five guinea pigs of each sex were exposed to 175 ppm of 1,4-DCB for 7 hours/day, 5 days/week for 

16 days (Hollingsworth et al. 1956). Mild histological effects of interstitial edema, congestion, and 

alveolar hemorrhage were observed in the lungs of male rats and female guinea pigs. The experimental 

design and report of this study have a number of deficiencies, such that reported observations provide 

only qualitative evidence of exposure-related respiratory effects. In the reproduction study (a dominant 

lethal test), a NOAEL of 450 ppm was identified for reproductive performance in male mice that were 

exposed for 6 hours/day for 5 days prior to weekly mating with unexposed females for 8 weeks 

(Anderson and Hodge 1976). No maternal or developmental toxicity occurred in rats that were exposed 

to 75–500 ppm for 6 hours/day on days 6–15 of gestation (Hodge et al. 1977), indicating that the highest 

NOAEL for reproductive effects in rats is 500 ppm. A developmental study in which rabbits were 

exposed to 100–800 ppm for 6 hours/day on gestation days 6–18 found evidence of fetotoxicity (a minor 

variation of the circulatory system) only at 800 ppm, which was also maternally toxic as shown by body 

weight loss early in gestation (Hayes et al. 1985), indicating that 800 ppm is a LOAEL for maternal and 

developmental effects in rabbits. 

The lung appears to be a target of concern for inhaled 1,4-DCB in rats and guinea pigs exposed to 

173 ppm (Hollingsworth et al. 1956), because the only effects observed in the reproductive and 

developmental studies were indications of maternal and fetotoxicity in rabbits at a much higher levels of 

800 ppm (Hayes et al. 1985). Support for the respiratory tract as a sensitive target for 1,4-DCB inhalation 

in animals is provided by the induction of nasal lesions in rats intermittently exposed to levels as low as 

75 ppm for 104 weeks in the study used to derive the chronic inhalation MRL for 1,4-DCB (Japan 

Bioassay Research Center 1995). Additionally, the animal data are consistent with the human experience, 

indicating that occupational exposure to 1,4-DCB causes painful nose and eye irritation in the range of 

50–160 ppm (Hollingsworth et al. 1956). 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

 

DICHLOROBENZENES A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,4-Dichlorobenzene (1,4-DCB) 

CAS Numbers: 106-46-7 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 14 

Species: Rat 

Minimal Risk Level: [ ] mg/kg/day [0.2] ppm 

References: Aiso A, Arito H, Nishizawa T, et al. 2005a. Thirteen-week inhalation toxicity of 

p-dichlorobenzene in mice and rats. J Occup Health 47:249-260. 

Tyl RW, Neeper-Bradley TL. 1989. Paradichlorobenzene: Two generation reproductive study of 

inhaled paradichlorobenzene in Sprague-Dawley (CD) rats. Laboratory Project 86-81-90605. 

Washington, DC: Chemical Manufacturers Association, Chlorobenzene Producers Association. 

Experimental design and effects noted (Aiso et al. 2005a): This is a systemic toxicity study in which 

groups of 10 male and 10 female F344 rats and 10 male and 10 female BDF1 mice were chamber-exposed 

to 1,4-DCB vapor (>99.9% pure) at target concentrations of 0, 25, 55, 120, 270, or 600 ppm for 

6 hours/day, 5 days/week for 13 weeks. Deviations in mean observed concentrations from the target 

concentrations were <9.6%. End points evaluated during the study included clinical signs (daily) and 

body weight and food consumption (weekly). End points evaluated at the end of the 13-week exposure 

period included hematology (RBC, Hb, Hct, MCV, MCH), blood biochemistry (total protein, albumin, 

total cholesterol, triglyceride, phospholipid, AST, ALT, AP, BUN, creatine), organ weights, and 

histopathology. The histological examinations were comprehensive and included the nasal cavity, in 

accordance with OECD test guidelines for a 90-day inhalation study (Aiso 2005a; OECD 1981). 

There were no exposure-related effects on survival, clinical signs, or body weight gain in the rats. 

Hematological changes suggestive of microcytic anemia occurred in male rats, including significantly 

decreased RBC count and hemoglobin concentration at ≥120 ppm, hematocrit at ≥270 ppm, and MCV 

and MCH at 600 ppm. Serum biochemical changes included significant increases in total protein in both 

sexes at 600 ppm, albumin in females at ≥270 ppm and males at 600 ppm, and total cholesterol and 

phospholipid in males at ≥270 ppm and females at 600 ppm, and significant decreases in triglycerides in 

males at 600 ppm, AST in both sexes at 600 ppm, and ALT and AP in males at ≥270 ppm. Organ weight 

changes included >10% increases in absolute and relative weights of liver in males at ≥270 ppm and 

females at 600 ppm, kidneys in males at ≥270 ppm, and spleen in males at 600 ppm. Histological effects 

included significantly increased incidences of liver centrilobular hepatocellular hypertrophy in male rats 

at 600 ppm (incidences in the control to high dose groups were 0/10, 0/10, 0/10, 0/10, 3/10, and 10/10), 

and kidney lesions indicative of α2μ-globulin nephropathy (hyaline droplets, granular casts, tubular cell 

necrosis, cytoplasmic basophila, and papillary mineralization) in male rats at ≥270 ppm. There were no 

histopathological changes in hematopoietic tissues (e.g., increased extramedullary hematopoiesis or 

hemosiderosis in the spleen), leading the investigators to suggest the possibility that the anemia in the 

male rats was secondary to α2μ-globulin nephropathy-related effects on erythropoietin synthesis in the 

renal tubules. 

There were no exposure-related effects on survival, clinical signs, or body weight gain in the mice. Organ 

weight changes in the mice included >10% increases in liver weight in males at ≥270 ppm (relative) and 
 

 

 

DICHLOROBENZENES A-6 

APPENDIX A 

600 ppm (absolute) and females at 600 ppm (absolute and relative); relative liver weights were 9.7, 9.7, 

10.1, 23.9, and 62.6% higher than controls in the low- to high-dose males. There were no significant 

hematological changes in either sex. Serum ALT levels were significantly increased in males at 

≥270 ppm (18.2, 9.1, 18.2, 54.5, and 164% higher than controls in the low- to high-dose groups). Other 

serum biochemical changes included significant increases in ALT in females at 600 ppm, AST in males at 

600 ppm, and total cholesterol and total protein in both sexes at 600 ppm. Histological examinations 

showed significantly (p≤0.01) increased incidences of centrilobular hepatocellular hypertrophy at in male 

mice at ≥270 ppm and female mice at 600 ppm; incidences in the control to high dose groups were 0/10, 

0/10, 0/10, 0/10, 10/10, and 10/10 in the males and 0/10, 0/10, 0/10, 0/10, 0/10, and 10/10 in the females. 

Affected hepatocytes were characterized by cell enlargement, varying nuclear size and shape, and coarse 

chromatin and inclusion bodies in the nucleus; the severity of these lesions was rated as slight at 270 ppm 

(males) and moderate at 600 ppm (both sexes). The moderate hepatocellular hypertrophy in the 600 ppm 

male mice was accompanied by single cell necrosis (1/10) and focal liver necrosis (2/10). 

The lowest effect level is 270 ppm based on the kidney and hematological effects in male rats and liver 

effects in rats and mice. The kidney and hematological effects are consistent with α2μ-globulin 

nephropathy, which is specific to male rats and not relevant to humans. The mice were more sensitive to 

the liver effects of 1,4-DCB than the rats because the only hepatic change in the 270 ppm rats was 

increased liver weight, whereas hepatocellular hypertrophy and increased serum ALT occurred in 

addition to increased liver weight in the 270 ppm mice. Additionally, at the next highest tested level of 

600 ppm, the mice had nuclear changes and evidence of necrosis in the hypertrophic hepatocytes, and 

increased serum AST as well as ALT, whereas none of these indicators of hepatocellular damage 

occurred in the rats. Based on increased relative liver weight (>10%) in both species and histological and 

serum ALT changes in the mice, this study identified a NOAEL of 120 ppm and a LOAEL of 270 ppm 

for hepatic effects. The identification of the liver as a critical target of 1,4-DCB is supported by findings 

of increased liver weight and serum liver enzymes, as well as histopathologic liver lesions in dogs 

administered 1,4-DCB orally for up to 1 year (Naylor and Stout 1996). 

Experimental design and effects noted (Tyl and Neeper-Bradley 1989): This is a two-generation study in 

which groups of 28 Sprague-Dawley rats of each sex were exposed to actual mean 1,4-DCB 

concentrations of 0, 66, 211, and 538 ppm for 6 hours/day, 7 days/week. Additional groups of 10 females 

were similarly exposed for 10 weeks in a satellite study. The animals in the main study were paired 

within groups for a 3-week mating period to produce the F1 generation. Main study males that did not 

successfully mate in the first 10 days of the mating period were paired with the satellite females for 

10 days. Main study females that did not successfully mate during the first 10 days of the mating period 

were paired with proven males for the remaining 11 days of the mating period. Exposures of the main 

study F0 females were continued throughout the mating period and the first 19 days of gestation, 

discontinued from gestation day 20 through postnatal day 4, and then resumed until sacrifice at weaning 

on postnatal day 28. Exposures of the satellite F0 females were continued through mating until sacrifice 

on gestation day 15. Exposures of the F0 males continued until sacrificed at the end of the study and 

satellite mating periods (F0 males were exposed for a total of 15 weeks). Groups of 28 F1 weanlings/sex 

and satellite groups of 10 F1 female weanlings were exposed for 11 weeks and mated as described above 

to produce the F2 generation. Additionally, 20 F1 weanlings/sex from the control and high exposure 

groups served as recovery animals that were observed without exposure for 5 weeks prior to sacrifice. 

Complete necropsies were performed on all F0 and F1 adult (parental) animals, F1 recovery animals, 

F1 weanlings not used in the rest of the study, and F2 weanlings, and histology was evaluated in the F0 and 

F1 parental animals. Histological examinations were conducted on the liver and kidneys in all groups and 

on selected other tissues (pituitary, vagina, uterus, ovaries, testes, epididymides, seminal vesicles, 

prostate, and tissues with gross lesions) in the control and high exposure groups. The kidney evaluation 

included examination for the presence of α2μ droplets. Additional end points evaluated in the parental 

generations included clinical observations, mortality, body weight, and food consumption. Mating and 
 

 

DICHLOROBENZENES A-7 

APPENDIX A 

fertility indices were determined for F0 and F1 males and females, and gestational, live birth, postnatal 

survival (4-, 7-, 14-, 21-, and 28-day), and lactation indices were determined for the F1 and F2 litters. 

There were no effects on reproductive parameters in either generation, although systemic toxicity 

occurred at all dose levels in F0 and F1 adult rats. Hyaline droplet nephropathy was found in F0 and 

F1 adult males at ≥66 ppm. Manifestations of this male rat-specific renal syndrome included α2μ-globulin 

accumulation and increased kidney weights at ≥66 ppm, and other characteristic histological changes at 

538 ppm. Body weights and weight gain were significantly reduced in F0 and F1 adult males and F1 adult 

females during the pre-breed exposure periods at 538 ppm. Absolute liver weights were increased in 

F0 males by 6, 16, and 38% in the 66, 211, and 538 ppm groups, respectively; the differences were 

statistically significantly different from control in the 211 and 538 ppm groups. In F0 females, absolute 

liver weights were increased by 9 and 31% at 211 and 538 ppm, respectively, but statistical significance 

was achieved only at 538 ppm. Similar changes were seen in relative liver weights of the F0 generation, 

with respective increases of 5, 14, and 52% in the 66, 211, and 538 ppm males and 4, 9, and 31% in the 

66, 211, and 538 ppm females; all groups of treated males, and the 211 and 538 ppm female groups, were 

statistically significantly different from controls. Relative liver weights were also significantly increased 

in F1 adult males at ≥211 ppm and F1 adult females at 538 ppm. Hepatocellular hypertrophy was 

observed in the livers of F0 and F1 males and females at 538 ppm; no hepatic histological changes were 

induced at the lower exposure concentrations. Other effects also occurred in the F0 and F1 males and 

females at 538 ppm, indicating that there was a consistent pattern of adult toxicity at the high exposure 

level, including reduced food consumption and increased incidences of clinical signs (e.g., tremors, 

unkempt appearance, urine stains, salivation, and nasal and ocular discharges); these effects only 

sporadically occurred at 211 ppm. Other effects at 538 ppm included reduced gestational and lactational 

body weight gain, and postnatal toxicity, as evidenced by increased number of stillborn pups, reduced pup 

body weights, and reduced postnatal survival in F1 and/or F2 litters. This study identified a (1) a NOAEL 

of 66 ppm and LOAEL of 211 ppm for increased (>10% above controls) relative liver weight in adult 

rats, and (2) a serious LOAEL of 538 ppm for systemic toxicity (central nervous system and other clinical 

signs) in adult rats and developmental toxicity (increased stillbirths and perinatal mortality) in their 

offspring. The identification of increased liver weight as a critical effect of 1,4-DCB toxicity is supported 

by findings of increased liver weight and serum liver enzyme levels and histopathologic liver lesions 

following repeated oral exposure (Naylor and Stout 1996). 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMCL 

As discussed below, a BMCL1sd of 92.45 ppm for increased liver weight in rats was used as the point of 

departure for the MRL. 

Benchmark dose (BMD) analysis was conducted using the Tyl and Neeper-Bradley (1989) data for 

relative liver weight in adult male rats (Table A-1) and the Aiso et al. (2005a) serum ALT data in male 

rats (Table A-2). A benchmark response (BMR) of 1 standard deviation change from the control mean 

was selected in the absence of a biological rationale for using an alternative BMR. BMD analysis of the 

relative liver weight data from the Aiso et al. (2005a) study is precluded by insufficient information 

(standard deviations were not reported). Incidences of hepatocellular hypertrophy in the male mice of the 

Aiso et al. (2005a) study were not subjected to BMD analysis because the response was observed in 0% 

of control, 25, 55, and 120 ppm animals and in 100% of the 270 and 600 ppm animals. The F1 and 

F2 postnatal survival data (Tyl and Neeper-Bradley 1989) were not subjected to BMD analysis because 

the 211 ppm exposure level represents a NOAEL and the next higher exposure level (538 ppm) represents 

a frank effect level (FEL) for 4-day survival (12.6 and 28.1% reductions in 4-day survival of F1 and 

F2 pups, respectively) and clinical signs in F0 males and females. 
DICHLOROBENZENES A-8 

APPENDIX A 

Table A-1. Relative Liver Weight Data for F0 Male Rats Exposed to 

1,4-Dichlorobenzene Vapors 6 Hours/Day for 15 Weeks 

Mean measured exposure concentration (ppm) 

0 66 211 538 

Group size 27 

Relative liver weight 

(%) 

3.465±0.2328a 

28 

3.631±0.2080b 

28 

3.945±0.2592c 

28 

5.271±0.2474c 

a

Mean ± standard deviation 

b

Significantly different (p<0.05) from control group 

c

Significantly different (p<0.01) from control group 

Source: Tyl and Neeper-Bradley 1989 

Table A-2. Serum ALT Data for Male Rats Exposed to1,4-Dichlorobenzene 

Vapors 6 Hours/Day, 5 Days/Week for 13 Weeks 

Mean measured exposure concentration (ppm) 

0 25 55 120 270 600 

Group size 

Serum ALT (IU/L)a 

10 

11±2 

10 

13±8 

10 

12±4 

10 

13±4 

10 

17±3b 

10 

29±6c 

a

Mean ± standard deviation 

b

Significantly different (p<0.05) from control group 

c

Significantly different (p<0.01) from control group 

Source: Aiso et al. 2005a 

All appropriate continuous-variable (linear, polynomial, power) models in the EPA Benchmark Dose 

Software (Version 1.3.2) were fit to the serum ALT data from the male rats of the Aiso et al. (2005a) 

study (the Hill model was excluded due to an insufficient number of exposure groups). An assumption of 

constant variance resulted in a p-value <0.0005 for the test of constant variance and a non-homogeneous 

variance assumption was suggested. However, the assumption of non-homogeneous variance resulted in 

inadequately modeled variance (p-value <0.0005) and BMD analysis of the serum ALT data from the 

male rats of the Aiso et al. (2005a) study was considered an inadequate method for selecting a point of 

departure for deriving an intermediate-duration inhalation MRL for 1,4-DCB. 

Available continuous-variable models were also fit to the Tyl and Neeper-Bradley (1989) data for 

changes in liver weight. A BMR of 1 standard deviation change from the control mean was selected in 

the absence of a biological rationale for using an alternative BMR. The simplest model (linear) for 

continuous data was initially fit to the data; constant variance was selected (Table A-3). The model 

output indicated that constant variance was appropriate, but inadequate model mean fit was obtained 

(p-value <0.01). The more complex (polynomial, power, Hill) models were also fit to the liver weight 

data. The Hill model provided inadequate mean fit due to an insufficient number of dose groups (4, 

including controls), which resulted in insufficient (0) degrees of freedom. The 2-degree polynomial 

provided adequate mean fit and the power model provided marginally adequate mean fit as indicated by 

the p-values for mean fit (Table A-3). The 2-degree polynomial model was the best fitting model (the 

adequate model with the lowest Akaike’s Information Criteria [AIC]), predicting a BMC1sd and BMCL1sd 
 

 

Polynomial Model with 0.95 Confidence Level 

5.5 

5 

4.5 

4 

3.5 

Mean Response 

BMDL BMD

Polynomial 

0 100 200 300 400 500 

DICHLOROBENZENES A-9 

APPENDIX A 

(lower 95% confidence limit on the BMC1sd) of 119.91 and 92.45 ppm, respectively (Table A-3). A plot 

of observed and predicted relative liver weight from the 2-degree polynomial model is shown in 

Figure A-1. 

Table A-3. Model Predictions for Relative Liver Weight in F0 Male Rats Exposed 

to 1,4-Dichlorobenzene Vapors 6 Hours/Day for 15 Weeks 

Variance Mean fit BMC1sd BMCL1sd 

Model p-valuea p-valuea AIC (ppm) (ppm) 

Linearb, c 0.6877 0.00026 NA NA NA 

2-Degree polynomialb,c 0.6877 0.3926 -205.3345 119.907 92.4533 

Powerb

 0.9241 0.09954 -202.3525 129.587 100.477 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria. b

Constant variance assumed 

c

Restriction = non-negative 

BMC1sd = benchmark dose based on a benchmark response of 1 standard deviation from the control mean; 

BMCL1sd = lower confidence limit (95%) on the BMC1sd; NA = not applicable because model failed a goodness-of-fit 

test 

Figure A-1. Observed Liver Weights in Adult Male Rats Exposed 

to 1,4-Dichlorobenzene for 15 Weeks and Predicted Relative 

Liver Weights by the 2-Degree Polynomial Model* 

dose 

18:25 07/26 2006 

*BMD = BMC; BMDL=BMCL; BMC and BMCL (in ppm) are associated with a 1 standard deviation from the control 

mean. 
 

 

 

 

 

 

 

DICHLOROBENZENES A-10 

APPENDIX A 

The BMCL1sd of 92.45 ppm was duration-adjusted to 23 ppm, converted to a human equivalent 

concentration (HEC) of 23 ppm, and divided by an uncertainty factor of 100 to derive an MRL of 

0.2 ppm. 

Uncertainty Factors used in MRL derivation: 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Although the rat BMCL was adjusted to a HEC (see below), an uncertainty factor of 10 for extrapolation 

from animals to humans was still applied, because the HEC calculation was based on an assumption of 

equivalent blood-gas partition coefficients, and not on actual data. 

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: 

1,4-DCB exhibited the effects outside of the respiratory tract and consequently is treated as a 

category 3 gas for purposes of calculating the MRL. The HEC for extrarespiratory effects produced by a 

category 3 gas is calculated by multiplying the duration-adjusted BMCL1sd (BMCL1sd ADJ, see below) by 

the ratio of blood:gas partition coefficients (Hb/g) in animals and humans (EPA 1994k). Hb/g values were 

not available for 1,4-DCB in rats and humans. Using a default value of 1 for the ratio of partition 

coefficients, the BMCL1sd HEC becomes 23 ppm: 

BMCL1sd HEC	 = (BMCL1sd ADJ) x [(Hb/g)RAT / (Hb/g)HUMAN],
 

= 23 ppm x [1] = 23 ppm
 

Was a conversion used from intermittent to continuous exposure? The BMCL1sd of 92 ppm was durationadjusted for intermittent exposure, as follows (EPA 1994k): 

BMCL1sd ADJ = (BMCL1sd) (hours/24 hours) (days/7 days) 

= (92.45 ppm) (6 hours/24 hours) (7 days/7 days) 

= 23 ppm 

Other additional studies or pertinent information that lend support to this MRL: Supporting information 

on hepatic effects of intermediate-duration inhalation exposure to 1,4-DCB are available from a 

multispecies subchronic toxicity study in which rats, mice, guinea pigs, rabbits, and monkeys were 

exposed to 96 or 158 ppm for 7 hours/day, 5 days/week for 5–7 months (Hollingsworth et al. 1956). 

Some of these animals were also similarly exposed to 341 ppm for 6 months (rats and guinea pigs) or 

798 ppm for 23–69 exposures (rats, guinea pigs, and rabbits). The experiments with rabbits and monkeys 

exposed to levels of 96 or 158 ppm are limited by small numbers of animals (1–2/group). Hepatic effects 

included increased relative liver weight and slight histological alterations in rats at 158 ppm (not observed 

at 96 ppm), and more severe histopathology (e.g., cloudy swelling and necrosis) in guinea pigs at 

341 ppm, and in rats, guinea pigs, and rabbits at 798 ppm. Other findings in the animals exposed to 

798 ppm included eye irritation and frank signs of neurotoxicity (e.g., marked tremors). The hepatic 

histological changes observed in rats at 158 ppm (cloudy swelling, congestion, or granular degeneration) 

were considered of questionable significance and were not reported at 358 ppm, indicating that neither 

158 nor 358 ppm is a reliable LOAEL for liver pathology in rats in this study. The hepatic histological 

effects observed in the guinea pigs at 341 ppm appear have been more severe (fatty degeneration, focal 

necrosis, slight cirrhosis) than in rats, but only occurred in some of the animals (number not reported). 

Although this information suggests that 341 ppm is a LOAEL for liver histopathology in guinea pigs, 

confidence in this effect level is low due to imprecise and brief qualitative reporting of the results (a 
 

 

 

DICHLOROBENZENES A-11 

APPENDIX A 

general limitation of the study). The 798 ppm exposure concentration is a reliable LOAEL because this 

level clearly caused both liver histopathology (e.g., cloudy swelling and central necrosis) and overt signs 

of toxicity (e.g., marked tremors, eye irritation, and unconsciousness) in all three species. 

A chronic inhalation study was conducted in which rats and mice were exposed to 1,4-DCB in target 

concentrations of 0, 20, 75, or 300 ppm for 6 hours/day, 5 days/week for 104 weeks (Aiso et al. 2005b). 

Effects in the rats included nasal lesions at ≥75 ppm and increased liver weight at 300 ppm, and effects in 

the mice included increased liver weight and hepatocellular hypertrophy at 300 ppm. The 75 ppm 

NOAEL and 300 ppm LOAEL for liver effects in the chronic study are consistent with the 120 ppm 

NOAEL and 211 ppm LOAEL for liver effects in the intermediate-duration studies (Aiso et al. 2005a; Tyl 

and Neeper-Bradley 1989). The 75 ppm LOAEL for nasal lesions in rats indicates that these tissues are 

more sensitive than the liver following chronic exposure, and the nasal lesions were used as the basis for 

the chronic inhalation MRL for 1,4-DCB. Because nasal lesions were not found in the 13-week study, it 

appears that the lesions are late-developing effects of chronic exposure. The lack of nasal lesions in the 

13-week study therefore indicates that these are not critical effects of intermediate-duration exposure. 

The NOAEL/LOAEL approach to MRL derivation results in the same MRL as the 0.2 ppm value derived 

using the BMD approach. The 13-week study (Aiso et al. 2005a) and two-generation study (Tyl and 

Neeper-Bradley 1989) are consistent in identifying the liver as the most sensitive target of intermediate 

duration inhalation of 1,4-DCB and showing that hepatic effects increased in severity with increasing 

level of exposure. The 13-week study (Aiso et al. 2005a) identified a hepatic NOAEL of 120 ppm and a 

LOAEL of 270 ppm in rats (increased liver weight) and mice (increased liver weight, hepatocellular 

hypertrophy, and serum ALT). The two-generation study identified a hepatic NOAEL of 66 ppm and a 

LOAEL of 211 ppm in rats (increased liver weight). The 120 ppm NOAEL is the highest hepatic 

NOAEL below the lowest hepatic LOAEL of 211 ppm, indicating that it is an appropriate basis for MRL 

derivation using the NOAEL/LOAEL approach. Using the NOAEL of 120 ppm for liver effects in male 

mice (the more sensitive species and sex), the NOAEL was duration-adjusted for the intermittent 

experimental exposure, as follows: 

NOAELADJ	 = (NOAEL) (hours/24 hours) (days/7 days) 

= (120 ppm) (6/24) (5/7) 

= 21.4 ppm 

1,4-DCB exhibited the effects outside of the respiratory tract and consequently is treated as a 

category 3 gas for purposes of calculating the human equivalent concentration (HEC). The HEC for extra 

respiratory effects produced by a category 3 gas is calculated by multiplying the NOAELADJ by the ratio 

of blood:gas partition coefficients (Hb/g) in animals and humans (EPA 1994k). Hb/g values were not 

available for 1,4-DCB in rats, mice and humans. Using a default value of 1 for the ratio of partition 

coefficients, the NOAELHEC is 21.4 ppm, calculated as follows: 

NOAELHEC = (NOAELADJ) x [(Hb/g)MOUSE / (Hb/g)HUMAN],
 

= 21.4. ppm x [1] = 21.4 ppm 

The NOAELHEC was divided by the uncertainty factor of 100 to derive an MRL of 0.2 ppm. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

DICHLOROBENZENES A-12 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,4-Dichlorobenzene (1,4-DCB) 

CAS Numbers: 106-46-7 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 32 

Species: Rat 

Minimal Risk Level: [ ] mg/kg/day [0.01] ppm 

References: Aiso S, Takeuchi T, Arito H, et al. 2005b. Carcinogenicity and chronic toxicity in mice and 

rats exposed by inhalation to para-dichlorobenzene for two years. J Vet Med Sci 67(10):1019-1029. 

Japan Bioassay Research Center. 1995. Toxicology and carcinogenesis studies of p-dichlorobenzene in 

344/DuCrj rats and Crj:BDF1 mice. Two-year inhalation studies. Japan Industrial Safety and Health 

Association. Study carried under contract with the Ministry of Labour of Japan. 

Experimental design: Groups of 50 male and female F344/DuCrj rats and 50 male and female 

Crj:BDF1 mice were exposed to 1,4-DCB in target concentrations of 0, 20, 75, or 300 ppm for 

6 hours/day, 5 days/week for 104 weeks. Study end points included clinical signs and mortality, body 

weight (weekly for the first 13 weeks, and subsequently every 4 weeks), and hematology, blood 

biochemistry, and urinalysis indices (evaluated at end of study). Selected organ weight measurements 

(liver, kidneys, heart, lungs, spleen, adrenal, brain, testis, ovary) and comprehensive gross pathology and 

histology evaluations were performed on all animals at the end of the study or at time of unscheduled 

death. No interim pathology examinations were performed. 

Effects noted in study and corresponding doses: For the rats, the actual mean chamber concentrations 

were 0, 19.8, 74.8, or 298.4 ppm over the duration of the study. The number of rats surviving to 

scheduled termination was significantly (p<0.05) reduced at 300 ppm in males. Survival in the male rats 

was noticeably lower than controls beginning at approximately study week 80, and overall survival at 0, 

20, 75, and 300 ppm was 66% (33/50), 68% (34/50), 58% (29/50), and 36% (18/50), respectively. There 

were no exposure-related decreases in survival in the female rats, or effects on growth or food 

consumption in either sex. Changes in various hematological and blood biochemical indices (mean cell 

volume, total cholesterol, phospholipids, blood urea nitrogen, creatinine, and calcium in males; total 

protein, total bilirubin, blood urea nitrogen, and potassium in females) occurred at 300 ppm (Japan 

Bioassay Research Center 1995), but a lack of both numerical data and statistical analysis precludes 

interpretations of significance for these end points. Absolute and relative liver weights in both sexes and 

kidney weights in males were significantly increased at 300 ppm. Additional findings included 

histopathological changes in the nasal epithelia and kidneys. The nasal lesions mainly included increased 

incidences of eosinophilic changes (globules) in the olfactory epithelium (moderate or greater severity) in 

males at 300 ppm and females at ≥75 ppm. Incidences of this lesion at 0, 20, 75, and 300 ppm were 1/50, 

2/50, 2/50, and 7/50 in males, and 27/50, 29/50, 39/50, and 47/50 in females. The increases were 

statistically significant (p≤0.05, Fisher's Exact Test performed by ATSDR) at ≥75 ppm in females and 

300 ppm in males, and there was a trend of increasing response with increasing dose in both sexes 

(Cochran-Armitage test, performed by ATSDR). Other nasal lesions that were significantly increased at 

300 ppm were eosinophilic globules in the respiratory epithelium (11/50, 10/50, 14/50, 38/50) and 

respiratory metaplasia in the nasal gland (5/50, 4/50, 4/50, 33/50) in females at 300 ppm. Kidney lesions 

were increased only in male rats at 300 ppm and included significantly increased incidences of 
 

 

 

 

 

DICHLOROBENZENES A-13 

APPENDIX A 

mineralization of the renal papilla (0/50, 1/50, 0/50, 41/50) and in hyperplasia of the urothelium (7/50, 

8/50, 13/50, 32/50). 

For the mice, the actual mean chamber concentrations were 0, 19.9, 74.8, or 298.3 ppm over the duration 

of the study. Survival was significantly reduced in male mice at 300 ppm (due to an increase in liver 

tumor deaths), but comparable to controls in the females. Terminal body weight was significantly 

reduced at 300 ppm in males (11.5% less than controls, beginning at study week 80). Changes in various 

hematological and blood biochemical indices (total cholesterol, SGOT, SGPT, LDH, and AP in both 

sexes; platelet numbers, total protein, albumin, total cholesterol, blood urea nitrogen, and calcium in 

females) occurred at 300 ppm (Japan Bioassay Research Center 1995), but a lack of reported numerical 

data and results of statistical analysis precludes interpretation of these end points. Absolute and relative 

liver and kidney weights in both sexes were significantly increased at 300 ppm. Additional findings 

included histopathological changes in the nasal cavity, liver, and testes. The nasal lesions included 

significantly increased incidences of respiratory metaplasia in the nasal gland (moderate severity) in 

males at 75 ppm (9/49, 12/49, 18/50, 11/49) and olfactory epithelium (slight severity) in males at 75 ppm 

(23/49, 30/49, 37/50, 22/49) and females at 300 ppm (7/50, 6/50, 2/49, 20/50); the effects in the males 

were not dose-related (i.e., incidences were increased at 75 ppm but not at 300 ppm). The incidence of 

centrilobular hepatocellular hypertrophy was significantly increased in male mice at 300 ppm (0/49, 0/49, 

0/50, 34/49). Incidences of liver tumors were also increased at 300 ppm; these included hepatocellular 

carcinoma in males (12/49, 17/49, 16/50, 38/49) and females (2/50, 4/50, 2/49, 41/50), hepatocellular 

adenoma in females (2/50, 10/50, 6/49, 20/50), hepatoblastoma in males (0/49, 2/49, 0/50, 8/49) and 

females (0/50, 0/50, 0/49, 6/50), and histiocytic sarcoma in males (0/49, 3/49, 1/50, 6/49). Testicular 

mineralization was significantly increased in males at ≥75 ppm (27/49, 35/49, 42/50, 41/49) (Japan 

Bioassay Research Center 1995). The testicular mineralization was not considered to be a toxicologically 

significant effect (Aiso 2006) because (1) no signs of testicular toxicity were observed in mice exposed 

for 13 weeks (Aiso et al. 2005a), and (2) it was confined to the testicular capsules and testicular blood 

vessels and not observed in the testicular parenchyma, indicating that it is a finding commonly observed 

in aged mice independent of exposure to 1,4-DCB (Aiso 2006). 

The results of this study indicate that moderate or severe eosinophilic changes in the nasal olfactory 

epithelium in female rats is the most sensitive toxic effect in the most sensitive species and sex. The 

NOAEL and LOAEL for these nasal lesions are 19.8 and 74.8 ppm, respectively. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMCL 

As discussed below, a BMCL10 of 9.51 ppm for increased incidences of nasal lesions in female rats is 

used as the point of departure for the MRL. 

BMD analysis was conducted using the incidences for eosinophilic changes of moderate or greater 

severity in the nasal olfactory epithelium in female rats and the actual exposure concentrations. The data 

that were modeled are shown in Table A-4. Data for other end points were not modeled because the 

effects occurred at higher concentrations (nasal lesions and hepatocellular hypertrophy in mice, kidney 

lesions in rats) or were not toxicologically significant (testicular mineralization in mice). All 

dichotomous models in the Benchmark Dose Software (version 1.3.2) were fit to the female rat nasal 

lesion incidence data. A 10% extra risk above the control incidence was selected as the BMR in the 

absence of a biological rationale for using an alternative BMR. As assessed by the chi-square goodnessof-fit statistic, all models provided adequate fits to the data (the quantal quadratic model was marginally 

adequate based on a chi-square p-value of 0.09 rather than the conventionally acceptable p-value of ≥0.1). 

The gamma, multistage, quantal linear, and Weibull models provided identical fit and were judged the 
DICHLOROBENZENES A-14 

APPENDIX A 

best-fitting models based on the lowest AIC value (Table A-5). These models each provided a 

benchmark concentration (BMC10) of 14.08 ppm and lower 95% confidence limit (BMCL10) of 9.51 ppm. 

A representative plot of the observed and predicted incidences of nasal lesions from the quantal linear 

model output is shown in Figure A-2. The BMCL10 of 9.51 ppm was duration-adjusted to 1.70 ppm, 

converted to a HEC of 0.27 ppm, and divided by an uncertainty factor of 30 to derive an MRL of 

0.01 ppm. 

Table A-4. Incidences of Nasal Lesions in Female Rats Exposed to 

1,4-Dichlorobenzene by Inhalation for 104 Weeks 

Exposure concentration (ppm) 0 19.8 74.8 298.4 

Nasal olfactory epithelial lesions (incidence)a

 27/50b 29/50 39/50c 47/50c
 

a

Lesions of moderate or greater severity. 

b

Significant trend of increasing response with increasing dose (Cochran-Armitage Test, performed by ATSDR). c

Significantly (p≤0.05) different from control value (Fisher’s Exact Test performed by ATSDR). 

Source: Aiso et al. 2005b 

Table A-5. Modeling Results for Incidences of Nasal Lesions in Female Rats 

Exposed to 1,4-Dichlorobenzene by Inhalation for 104 Weeks 

Model 

Gammab

Chi-square 

p-valuea 

0.70 

AIC 

217.13 

BMC10 (ppm) 

14.08 

BMCL10 (ppm) 

9.51 

Logistic 0.51 217.79 19.43 13.90 

Log-logisticc

Multi-staged

 0.74 

0.70 

218.52 

217.13 

15.45 

14.08 

4.12 

9.51 

Probit 0.42 218.21 22.17 16.70 

Log-probitc

 0.74 218.52 16.09 3.20 

Quantal linear 0.70 217.13 14.08 9.51 

Quantal quadratic 

Weibullb

0.09 

0.70 

221.36 

217.13 

67.38 

14.08 

53.07 

9.51 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria b

Restrict power >=1 

c

Slope restricted to >1

d

Restrict betas ≥0; Degree of polynomial=2 

AIC = Akaike’s Information Criteria; BMC10 = benchmark dose associated with a 10% extra risk; BMCL10 = lower 

confidence limit (95%) on the benchmark dose 
 

 

Figure A-2. Observed and Predicted Incidences of Nasal Lesions in Female Rats 

Exposed to 1,4-Dichlorobenzene for 104 Weeks* 

Quantal Linear Model with 0.95 Confidence Level 

1 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

BMDL BMD 

Quantal Linear 

0 50 100 150 200 250 300 

Fraction Affected 

 

DICHLOROBENZENES A-15 

APPENDIX A 

dose 

13:24 07/24 2006 

*BMD = BMC; BMDL = BMCL; BMC and BMCL (in ppm) are associated with a 10% extra risk. The quantal linear 

model plot in this figure is identical to the plots produced by the gamma, multistage, and Weibull models. 

Uncertainty Factors used in MRL derivation: 

[X] 3 for extrapolation from animals to humans 

[X] 10 for human variability 

A 3-fold uncertainty factor was used instead of a default 10-fold factor to extrapolate from rats to humans 

because the dosimetry adjustment (i.e., calculation of the human equivalent exposure for time and 

concentration [HEC]) addresses one of the two areas of uncertainty encompassed in an interspecies 

extrapolation factor. The dosimetric adjustment addresses the pharmacokinetic component of the 

extrapolation factor, but the pharmacodynamic area of uncertainty remains as a partial factor for 

interspecies uncertainty. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: For 

the nasal olfactory epithelium changes in female rats, 1,4-DCB was treated as a category 1 gas with 

effects in the extrathoracic region for purposes of calculating the HEC. Using EPA (1988, 1994b) 

reference values, the regional gas deposition ratio was calculated as follows (EPA 1994a): 
 

 

 

 

 

 

 

 

 

DICHLOROBENZENES A-16 

APPENDIX A 

RGDRET = [(VE/SAET)A/(VE/SAET)H] 

= (0.24 m3

/day/15cm2)/(20 m3/day/200cm2) 

= 0.16 

 where: RGDRET = regional gas deposition ratio in the extrathoracic region 

VE = minute volume in rats (VE)A or humans (VE)H 

 SAET = extrathoracic surface area in rats (SAET)A or humans (SAET)H 

The HEC was calculated by multiplying the rat BMCL10 ADJ by the RGDRET to yield a BMCL10 HEC of 

0.27 ppm, as follows: 

BMCL10 HEC = BMCL10 ADJ x RGDRET

 = 1.70 ppm x 0.16 

= 0.27 ppm 

Was a conversion used from intermittent to continuous exposure? The animal BMCL10 value of 

15.34 ppm was duration-adjusted for intermittent experimental exposure, as follows: 

BMCL10 ADJ = (BMCL10) (hours/24 hours) (days/7 days) 

= (9.51 ppm) (6 hours/24 hours) (5 days/7 days) 

= 1.70 ppm 

Other additional studies or pertinent information that lend support to this MRL: The only other 

information on the chronic inhalation toxicity of 1,4-DCB in animals is available from another study in 

rats and mice (Riley et al. 1980a, 1980b). In this study, rats of both sexes and female mice were exposed 

to 75 or 500 ppm of 1,4-DCB for 5 hours/day, 5 days/week for up to 76 weeks (rats) or 57 weeks (mice), 

followed by 32 weeks (rats) or 18–19 weeks (mice) without exposure. There were no exposure-related 

histopathological changes in the nasal cavity or other tissues in either species. Liver and kidney weights 

were increased in rats of both sexes at 500 ppm, but the toxicological significance is questionable due to 

the negative histopathology findings and the lack of related clinical chemistry effects. Evaluation of the 

mouse data is limited by reporting insufficiencies in the available summary of the study. 

A limited amount of information is available on the long-term toxicity of inhaled 1,4-DCB in humans. 

Periodic occupational health examinations of workers who were exposed to 1,4-DCB for an average of 

4.75 years (range 8 months to 25 years) showed no changes in standard blood and urine indices 

(Hollingsworth et al. 1956). The odor was found to be faint at 15–30 ppm and strong at 30–60 ppm. 

Painful irritation of the eyes and nose was usually experienced at 50–80 ppm, although the irritation 

threshold was higher (80–160 ppm) in workers acclimated to exposure. Concentrations above 160 ppm 

caused severe irritation and were considered intolerable to people not adapted to it. Occasional 

examination of the eyes showed no cataracts or any other lens changes. The odor and irritation properties 

were considered to be fairly good warning properties that should prevent excessive exposures, although 

the industrial experience indicated that it is possible for people to become sufficiently acclimated to 

tolerate high concentrations of the vapor. The data from this study are inadequate for chronic MRL 

derivation due to poor characterization of long-term exposure levels, insufficient investigation of systemic 

health end points, reporting and other study deficiencies. Although the available human information is 

insufficient for chronic MRL derivation, the human eye and nose irritation data are consistent with the 

nasal effects observed in the chronically exposed animals. 

The NOAEL/LOAEL approach to MRL derivation results in an MRL of 0.02 ppm, similar to the 

0.01 ppm value based on BMD analysis. Using the NOAEL of 19.8 ppm for moderate or severe changes 
 

 

 

 

 

 

DICHLOROBENZENES A-17 

APPENDIX A 

in the nasal olfactory epithelium in rats (Aiso et al. 2005b), the NOAEL was duration-adjusted for 

intermittent experimental exposure, as follows: 

NOAELADJ = (NOAEL) (hours/24 hours) (days/7 days) 

= (19.8 ppm) (6 hours/24 hours) (5 days/7 days) 

= 3.54 ppm 

A HEC was calculated using EPA (1994a) inhalation dosimetric adjustment methodology. For the 

olfactory epithelium changes in rats, 1,4-DCB was treated as a category 1 gas with effects in the 

extrathoracic region. Using EPA (1988, 1994b) reference values, the regional gas deposition ratio was 

calculated as follows: 

RGDRET = [(VE/SAET)A/(VE/SAET)H] 

= (0.24 m3

/day/15cm2)/(20 m3/day/200cm2) 

= 0.16 

 where: RGDRET = regional gas deposition ratio in the extrathoracic region 

VE = minute volume in rats (VE)A or humans (VE)H 

 SAET = extrathoracic surface area in rats (SAET)A or humans (SAET)H 

The rat NOAELADJ was multiplied by the RGDRET to yield a NOAELHEC of 0.57 ppm (3.54 ppm x 0.16), 

and the NOAELHEC was divided by the uncertainty factor of 30 to derive an MRL of 0.02 ppm. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

DICHLOROBENZENES A-18 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,2-Dichlorobenzene (1,2-DCB) 

CAS Numbers: 95-50-1 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 11 

Species: Rat 

Minimal Risk Level: [0.7] mg/kg/day [ ] ppm 

Reference: Robinson M, Bercz JP, Ringhand HP, et al. 1991. Ten and ninety-day toxicity studies of 

1,2-dichlorobenzene administered by oral gavage to Sprague-Dawley rats. Drug Chem Toxicol 

14(1&2):83-112. 

Experimental design: Groups of 10 male and 10 female Sprague-Dawley rats were administered 

1,2-DCB in corn oil by gavage in doses of 0, 37.5, 75, 150, or 300 mg/kg/day for 10 consecutive days. 

The doses were selected on the basis of a reported rat oral LD50 of 500 mg/kg. End points evaluated 

during the study included clinical signs, body weight, and food and water consumption. Evaluations at 

the end of the exposure period included hematology (five indices), serum chemistry (nine indices 

including AST, ALT, LDH, cholesterol, BUN, and creatinine), and selected organ weights (brain, liver, 

spleen, lungs, thymus, kidneys, adrenal glands, heart, and testes or ovaries). Histological examinations 

were performed on various tissues including liver, kidneys, urinary bladder, heart, skin, muscle, bone, 

respiratory tract (nasal cavity with turbinates, lungs), nervous system (brain, sciatic nerve), 

immunological (spleen, thymus, lymph nodes), gastrointestinal (duodenum, ileum, jejunum, salivary 

gland, colon, cecum, rectum), endocrine (adrenal glands, pancreas), and reproductive (testes, seminal 

vesicles, prostate, ovaries) in the high-dose and control groups. Target organs identified in the high-dose 

groups were also histologically evaluated at the lower dose levels. 

Effects noted in study and corresponding doses: No clinical signs or effects on survival were observed. 

Body weight gain was significantly reduced in the male rats at 300 mg/kg/day (final body weights were 

10.9% lower than controls), but not in females, and there were no exposure-related changes in food 

consumption in either sex. Statistically significant changes in organ weights predominantly occurred at 

300 mg/kg/day, including significantly decreased absolute spleen weight in both sexes, and decreased 

absolute heart, kidney, thymus, and testes weights in males. Liver weight (relative and absolute) was 

significantly increased in females at ≥150 mg/kg/day and in males at 300 mg/kg/day; compared to 

controls in the low- to high-dose females, absolute liver weights were 1.8, 9.0, 20.5, and 29.0% increased 

and relative liver weights were 6.8, 7.6, 21.7, and 34.5% increased. Clinical chemistry findings included 

significantly increased serum ALT in both sexes at 300 mg/kg/day and serum phosphorus in females at 

≥150 mg/kg/day. Serum cholesterol was significantly increased in females at ≥37.5 mg/kg/day, but the 

toxicological significance is unclear because values were similar at all dose levels and showed no doseresponse. Histopathological findings were limited to the liver and included necrosis that was slight in 

severity and significantly (p=0.04) increased in males at 300 mg/kg/day (4/10 compared to 0/10 in 

controls; incidences in the other dose groups were not reported, although the study authors indicated that 

target organs in the high-dose groups were histologically evaluated at the lower dose levels. Incidences 

of other hepatic lesions were not significantly increased, but included inflammation (characterized by 

lymphocyte and macrophage infiltrates) and degeneration of hepatocytes (characterized by varying 

degrees of fibrillar or vacuolated cytoplasm and swelling with intact cell membranes). Because 

incidences of histopathologic liver lesions were not reported for females, it is presumed that incidences in 
 

 

 

DICHLOROBENZENES A-19 

APPENDIX A 

the control and high-dose females were 0/10 and that the lower female dose groups were not assessed for 

liver lesions. This study identified a NOAEL of 75 mg/kg/day and LOAEL of 150 mg/kg/day for 

increased liver weight in female rats, as well as a LOAEL of 300 mg/kg/day for liver necrosis in male 

rats. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDL 

As discussed below, a BMDL1sd of 67.73 mg/kg/day for increased liver weight in female rats is used as 

the point of departure for the MRL. 

BMD analysis was conducted using the rat absolute liver weight data (Robinson et al. 1991) shown in 

Table A-6. The liver lesion data were not subjected to BMD analysis because incidences of liver necrosis 

were only reported for control and high-dose rats. Serum liver enzyme (ALT, AST, LDH) data were not 

subjected to BMD analysis because a statistically significant increase was noted only for serum ALT in 

the high-dose group of male rats and the magnitude of the increase (50% higher than the control serum 

ALT level) is not considered to be adverse. 

Table A-6. Absolute Liver Weights in Rats Orally Exposed to 

1,2-Dichlorobenzene for 10 Days 

Dose (mg/kg/day) 

Effect Sex 0 37.5 75 150 300 

Absolute liver M 9.8±0.70a 10.30±0.94 9.90±0.62 10.21±1.29 11.00±0.83b 

weight (g) 

F 

n=10 

6.00±0.45 

n=10 

6.11±0.33 

n=10 

6.54±0.70 

n=10 

7.23±0.62b 

n=10 

7.74±0.41b 

n=10 n=10 n=10 n=10 n=10 

a

Mean ± standard deviation 

b

Significantly (p≤0.05) different from control value 

Source: Robinson et al. 1991 

All continuous variable models in the EPA Benchmark Dose Software (Version 1.3.2) were fit to the 

absolute liver weight data from male and female rats. One standard deviation increase from the control 

mean value was selected as the BMR in the absence of a biological rationale for using an alternative 

BMR. The modeling results are shown in Table A-7. Constant variance was assumed; the assumption 

was considered appropriate based on p-values >0.1 for the test of homogeneous variance. The linear, 

2-degree polynomial, power, and Hill models provided adequate mean fit to the male rat liver weight 

data, as determined by p-values >0.1 for the test of mean fit. The linear model was determined to the 

best-fitting model (lowest AIC among all adequate model outputs) for the male rat liver weight data and 

provided a BMD1sd of 249.04 mg/kg/day and a BMDL1sd of 158.55 mg/kg/day. For the female liver 

weight data, the linear and Hill models provided adequate mean fit (p-values >0.1). The linear model was 

the best-fitting model (lowest AIC) for the female rat liver weight data and provided a BMD1sd of 

84.67 mg/kg/day and a BMDL1sd of 67.73 mg/kg/day. Among the best-fitting model results for absolute 

liver weight in the male and female rats, the lowest (linear model-generated) BMDL1sd of 

67.73 mg/kg/day for increased absolute liver weight in female rats is selected as the point of departure for 

deriving the MRL. The BMDL1sd of 67.73 mg/kg/day was divided by an uncertainty factor of 100 to 

derive an MRL of 0.7 mg/kg/day. 
 

 

Linear Model with 0.95 Confidence Level 

8 

7.5 

7 

6.5 

6 

5.5 

Mean Response 

BMDL BMD 

Linear 

0 50 100 150 200 250 300 

DICHLOROBENZENES A-20 

APPENDIX A 

Table A-7. Model Predictions for Increased Absolute Liver Weight in Rats Orally
 

Exposed to 1,2-Dichlorobenzene for 10 Days 

Variance Mean fit BMD1sd BMDL1sd 

Model p-valuea p-valuea AIC (mg/kg/day) (mg/kg/day) 

Males 

 Linearb

 0.15 0.48 41.40 249.04 158.55 

Polynomialb,c,d 0.15 0.38 42.87 274.93 164.78 

Powerb,e 0.15 0.38 44.86 281.79 164.87 

Hillb,f 0.15 0.17 46.80 180.01 No value 

Females 

 Linearb

 0.12 0.19 -11.85 84.67 67.73 

Polynomialb,c,d, 0.12 0.09 -11.85 84.67 67.73 

Powerb,e 0.12 0.09 -7.85 84.67 67.73 

Hillb,f 0.12 0.84 -10.55 71.51 43.18 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria b

Constant variance assumed 

c

Restriction = non-negative 

d

2-degree polynomial 

e

Restrict power >=1 

f

Restrict n>1 

g

Non-homogeneous variance assumed 

AIC = Akaike’s Information Criteria; BMD1sd = benchmark dose associated with one standard deviation increase 

above control mean; BMDL = lower confidence limit (95%) on the benchmark dose 

Figure A-3. Observed and Predicted Mean Absolute Liver Weight in Female Rats 

Orally Exposed to 1,2-Dichlorobenzene for 10 Days* 

dose 

14:10 08/01 2006 

*The BMD and BMDL (in mg/kg/day) represent a 1 standard deviation increase in mean absolute liver weight from 

the control mean. 
 

 

DICHLOROBENZENES A-21 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[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? Not applicable. 

(gavage study) 

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: Information on effects of 

acute oral exposure to sublethal doses of 1,2-DCB essentially consists of findings in three systemic 

toxicity studies in rats and mice and one developmental toxicity study in rats (NTP 1985; Rimington and 

Ziegler 1963; Robinson et al. 1991; Ruddick et al. 1983). These studies administered the compound by 

gavage and collectively identify the liver as the most sensitive target. Severe liver damage, characterized 

by intense necrosis and fatty changes as well as porphyria, occurred in rats administered 455 mg/kg/day 

for 15 consecutive days (Rimington and Ziegler 1963). Rats that were exposed to 300 mg/kg/day for 

10 consecutive days had hepatic effects that included necrosis and increased serum ALT (Robinson et al. 

1991). Hepatocellular degeneration and necrosis occurred in mice that were exposed to 250 or 

500 mg/kg/day for 14 consecutive days (NTP 1985). The 15-day rat and 14-day mouse studies are 

limited by small numbers of animals (3–5 per dose) and lack of a NOAEL due a single dose level 

(Rimington and Ziegler 1963) or lack of histopathology evaluations at doses lower than the LOAEL (NTP 

1985). The 10-day study (Robinson et al. 1991) is the most appropriate basis for MRL derivation because 

it is well designed, included four dose levels, and provides dose-response data for several hepatic end 

points. 

The NOAEL/LOAEL approach to MRL derivation results in an MRL similar to the 0.7 mg/kg/day value 

based on BMD analysis. Using the 75 mg/kg/day NOAEL for increased liver weight (Robinson et al. 

1991) and the uncertainty factor of 100, the NOAEL/LOAEL approach yields an MRL of 0.8 mg/kg/day. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

 

DICHLOROBENZENES A-22 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,2-Dichlorobenzenes (1,2-DCB) 

CAS Numbers: 95-50-1 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 17 

Species: Rat 

Minimal Risk Level: [0.6] mg/kg/day [ ] ppm 

Reference: NTP. 1985. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene 

(o-dichlorobenzene) (CAS No. 95-50-1) in F344/N rats and B6C3F1 mice (gavage studies). Research 

Triangle Park, NC: National Toxicology Program. NTP TR 255. NIH Publication No. 86-2511. 

Experimental design: Groups of 10 male and 10 female F344/N rats and 10 male and 10 female 

B6C3F1 mice were administered 1,2-DCB (>99% pure) in corn oil by gavage in doses of 0, 30, 60, 125, 

250, or 500 mg/kg on 5 days/week for 13 weeks. Evaluations included clinical signs, body weight, food 

consumption, hematology, clinical chemistry, urine volume, urine uroporphyrins and coproporphyrins, 

liver porphyrins, organ weights, and necropsies in all groups of animals. Complete histological 

examinations were performed on all control and high-dose animals; histology exams in lower dose groups 

were limited to liver, kidneys and thymus at 125 and 250 mg/kg/day. 

Effects noted in study and corresponding doses: Effects in the rats included necrosis of individual 

hepatocytes at ≥250 mg/kg/day and centrilobular degeneration at 500 mg/kg/day; total incidences of these 

lesions at 0, 125, 250, and 500 mg/kg/day were 0/10, 1/10, 4/9, and 8/10 in males, and 0/10, 3/10, 5/10, 

and 7/8 in females. Relative liver weights were significantly increased at 125, 250, and 500 mg/kg/day in 

the males (8, 17, and 45% higher than controls) and females (8, 15, and 30%); increased relative liver 

weights were not seen at lower doses in either sex. There were no increases in serum levels of liver 

enzymes [ALT, AP, or GGPT] at any dose in either sex. Serum cholesterol was significantly increased in 

males at ≥30 mg/kg/day (50.0, 17.6, 26.5, 70.6, and 109% higher than controls in the low- to high-dose 

groups, not significant at 60 mg/kg/day) and females at ≥125 mg/kg/day (12.2, 12.2, 32.6, 26.5, and 

51.0%). Although increases in serum cholesterol were observed at levels as low as 30 mg/kg/day, the 

toxicological significance is unclear because there was no clear dose-response unless the increase at 

30 mg/kg/day is considered to be outlying. Urinary concentrations of uroporphyrin and coproporphyrin 

were 3–5 times higher than controls in the 500 mg/kg/day males and females, but this increase was not 

considered indicative of porphyria because total porphyrin concentration in the liver was not altered at 

any dose level and no pigmentation indicative of porphyria was observed by ultraviolet light at necropsy. 

The increases in relative liver weight and liver lesions seen in both sexes at 125 mg/kg/day are believed to 

represent the beginning of adverse hepatic effects, and are thus designated a minimal LOAEL for this 

study. The NOAEL is therefore 60 mg/kg/day. 

In the mice, no compound-related histopathological changes were observed in either sex at 0 and 

125 mg/kg/day, or in females at 250 mg/kg/day. Lesions that were significantly increased included 

necrosis of individual hepatocytes, hepatocellular degeneration and/or pigment deposition in 4/10 males 

at 250 mg/kg/day, and centrilobular necrosis, necrosis of individual hepatocytes, and/or hepatocellular 

degeneration in 9/10 males and 9/10 females at 500 mg/kg/day. Relative liver weights were significantly 

increased at 500 mg/kg/day in both sexes, but there were no exposure-related changes in serum levels of 

ALT, AP, or GGPT in either sex at any dose (no other clinical chemistry indices were examined in the 
 

 

 

DICHLOROBENZENES A-23 

APPENDIX A 

mice). Based on the liver lesion data, the NOAEL and LOAEL in mice are 125 and 250 mg/kg/day, 

respectively. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDL 

As discussed below, a BMDL1sd of 89.27 mg/kg/day for increased relative liver weight in female rats is 

used as the point of departure for the MRL. 

Benchmark dose analysis was conducted using the male and female rat and male mouse liver lesion 

incidence data summarized in Table A-8. Dichotomous models available in the EPA Benchmark Dose 

Software were fit to data for incidences of liver lesions (single cell necrosis, centrilobular necrosis, and/or 

hepatocellular degeneration) in male and female rats (combined) and male mice. Because there were no 

apparent differences in sensitivity to 1,2-DCB among the male and female rats, the liver lesion data were 

combined to increase the statistical power for BMD analysis. For each data set (combined incidences in 

male and female rats and incidences in male mice), the Chi-square p-value and AIC were used to select 

the best fitting model from which BMDs and their lower 95% confidence limits (BMDLs) were 

calculated, using a BMR of 10% extra risk. 

Table A-8. Incidences of Liver Lesions in Rats and Mice Orally Exposed to 

1,2-Dichlorobenzene for 13 Weeks 

Lesions: Individual cell or focal necrosis; Dose (mg/kg/day) 

centrilobular degeneration in high-dose group 0 30 60 125 250 500 

Male rat 0/10 ND ND 1/10 4/9a 8/10a 

Female rat 0/10 ND ND 3/10 5/10a 7/8a 

Combined (male and female) 0/20 ND ND 4/20a 9/19b

 15/18b 

Male mouse 0/10 ND ND 0/10 4/10a 9/10a 

a

Significantly (p<0.05) different from control; Fisher Exact Test performed by ATSDR b

Significantly (p<0.01) different from control; Fisher Exact Test performed by ATSDR 

ND = no histological examinations conducted in this group 

Source: NTP 1985 

All models provided adequate fit to liver lesion data for male and female rats combined (Table A-9). The 

best-fitting model (lowest AIC) was the quantal quadratic model, which provided a BMD10 of 

108.71 mg/kg/day and a BMDL10 of 92.08 mg/kg/day. The log-probit model was determined to be the 

best-fitting model for the male mouse data and provided a BMD10 of 176.05 mg/kg/day and BMDL10 of 

114.58 mg/kg/day. 
DICHLOROBENZENES A-24 

APPENDIX A 

Table A-9. BMD Model Results of Incidence Data for Liver Lesions in Male and 

Female Rats (Combined) and Male Mice Exposed to 1,2-Dichlorobenzene 

for 13 Weeks 

Chi-square BMD10 BMDL10 

Model p-valuea AIC (mg/kg/day) (mg/kg/day) 

Male and female rats combined 

Gammab

 0.99 66.53 81.08 31.38 

 Logistic 0.34 69.78 112.08 81.57 

 Log Logisticc

 0.94 66.64 89.36 39.14 

Multi-staged

 0.99 66.55 66.22 31.31 

Probit 0.38 69.33 106.79 78.36 

Log-probitc

 0.94 66.64 92.42 54.15 

 Quantal-linear 0.67 66.20 38.18 27.93 

 Quantal-quadratic 0.64 66.02 108.71 92.08 

Weibull 0.99 66.52 75.28 31.39 

Male mice 

Gammab

 0.75 24.78 172.36 102.08 

 Logistic 0.44 26.24 168.53 106.72 

 Log-logisticc

 0.81 24.62 175.35 110.25 

Multi-staged

 0.48 24.57 116.66 63.82 

Probit 0.48 25.93 167.39 102.39 

Log-probitc

 0.86 24.42 176.05 114.58 

 Quantal-linear 0.14 30.41 44.73 28.59 

 Quantal-quadratic 0.69 24.57 116.66 91.67 

 Weibull 0.61 25.46 158.84 86.28 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria b

Restrict power >=1 

c

Slope restricted to >1

d

Restrict betas >=0; lowest degree polynomial (2-degree) with an adequate fit 

AIC = Akaike’s Information Criteria; BMD10 = benchmark dose based on a benchmark response of 10%; BMDL10 = 

lower confidence limit (95%) on the BMD10 

BMD analysis was also conducted using the relative liver weight data for male and female rats shown in 

Table A-10). Continuous variable models in the EPA Benchmark Dose Software were fit to the liver 

weight data, and one standard deviation from the control mean was selected as the BMR in the absence of 

a biological rationale for using a different BMR. For the male rat relative liver weight data, results of 

model runs using constant variance indicated that non-homogeneous variance was more appropriate. 

However, selection of non-homogeneous variance resulted in inadequate mean fits (p-value <0.04) from 

the linear, polynomial, and power models, and the Hill model would not generate an output. For the 

relative liver weight data of the female rats, constant variance was appropriate (p-value >0.1) and 

adequate mean fits were obtained from the linear, polynomial, and power models (Table A-11). The Hill 

model would not generate an output for the female relative liver weight data. Among the adequate mean 

fits, the linear model provided the lowest AIC and was therefore selected as the best-fitting model for the 
DICHLOROBENZENES A-25 

APPENDIX A 

female rat relative liver weight data (Table A-11, Figure A-4), which resulted in a BMD1sd of 

108.15 mg/kg/day and a BMDL1sd of 89.27 mg/kg/day. 

Table A-10. Relative Liver Weight Data for Male and Female Rats Orally Exposed 

to 1,2-Dichlorobenzene for 13 Weeks 

Mean measured exposure concentration (ppm) 

0 30 60 125 250 500 

Males 

 Group size 9 9 10 9 9 10 

 Relative liver weighta

 3.18 3.28 3.10 3.43b 3.72b 4.61b

 Standard deviation 0.20 0.22 0.15 0.22 0.29 0.47 

Females 

 Group size 10 10 10 10 10 8 

 Relative liver weighta

 2.90 2.98 2.92 3.13b 3.33b 3.78b

 Standard deviation 0.20 0.15 0.16 0.20 0.18 0.30 

a

Mean value 

b

Significantly different (p<0.05) from control group 

Source: NTP 1985 

Table A-11. Model Predictions for Relative Liver Weight in Female Rats Orally 

Exposed to 1,2-Dichlorobenzene for 13 Weeks 

Variance Mean fit 

Model p-valuea p-valuea

 AIC BMD1sd (ppm) BMDL1sd (ppm) 

Linearb 0.338 0.719 -129.0910 108.15 89.27 

2-Degree polynomialb,c 0.338 0.559 -127.1169 112.34 89.34 

Powerb,d 0.338 0.5679 -125.1600 116.96 89.47 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria. b

Constant variance assumed 

c

Restriction = non-negative 

d

Power restricted to >=1 

AIC = Akaike’s Information Criteria; BMD1sd = benchmark dose based on a benchmark response of 1 standard 

deviation from the control mean; BMDL1sd = lower confidence limit (95%) on the BMD1sd 
 

 

Figure A-4. Observed and Predicted Mean Relative Liver Weights in Female Rats 

Orally Exposed to 1,2-Dichlorobenzene for 13 Weeks* 

Linear Model with 0.95 Confidence Level 

Mean Response 

4 

3.8 

3.6 

3.4 

3.2 

3 

2.8 

BMDL BMD 

Linear 

0 100 200 300 400 500 

 

DICHLOROBENZENES A-26 

APPENDIX A 

dose 

18:07 08/01 2006 

*BMD and BMDL (in mg/kg/day) are associated with a benchmark response of 1 standard deviation increase above 

the control mean 

The BMDL1sd of 89.27 mg/kg/day from the best-fitting modeling results of the female rat relative liver 

weight data is lower than the BMDL10 of 92.08 mg/kg/day from the best-fitting modeling results of liver 

lesion incidences in the male and female rats combined and the BMDL10 of 114.58 mg/kg/day from the 

best-fitting model results of liver lesion incidences in the male mice. Therefore, the BMDL1sd of 

89.27 mg/kg/day for increased relative liver weight in the female rats is selected as the point of departure 

for the MRL. The BMDL1sd of 89.27 mg/kg/day was duration-adjusted to 63.76 mg/kg/day and divided 

by an uncertainty factor of 100 to yield an MRL of 0.6 mg/kg/day. 

Uncertainty Factors used in MRL derivation: 

[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? Not applicable 

(gavage study). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 
 

 

 

DICHLOROBENZENES A-27 

APPENDIX A 

Was a conversion used from intermittent to continuous exposure? The BMDL1sd of 89.27 mg/kg/day was 

duration-adjusted for intermittent exposure, as follows (EPA 1994k): 

BMDL1sd ADJ = (BMDL1sd) (days/7 days) 

= (89.27 mg/kg/day) (5 days/7 days) 

= 63.76 mg/kg/day 

Other additional studies or pertinent information that lend support to this MRL: Information on effects of 

intermediate-duration oral exposure to 1,2-DCB are available from three intermediate studies in rats and 

mice identifying the liver as the most sensitive target of toxicity (Hollingsworth et al. 1958; NTP 1985; 

Robinson et al. 1991). Incidences of degenerative liver lesions were significantly increased in rats and 

mice exposed to ≥250 mg/kg/day, 5 days/week for 13 weeks (NTP 1985), 376 mg/kg/day, 5 days/week 

for 192 days (Hollingsworth et al. 1958; NTP 1985), and 400 mg/kg/day for 90 consecutive days 

(Robinson et al. 1991). Necrotic lesions also occurred in several rats at 125 mg/kg/day (1/10 males, 

3/10 females) in the NTP (1985) study, but the increase was not statistically significant. Other hepatic 

findings in rats exposed to lower doses (125–188 mg/kg/day for >13 weeks) in these studies included 

small increases in relative liver weight and serum levels of ALT, cholesterol, and serum protein, and 

decreases in serum triglycerides. Increased serum ALT is an inconsistent finding because it was induced 

in rats exposed to >100 mg/kg/day for 90 days (Robinson et al. 1991), but not in rats exposed to 

≥125 mg/kg/day for 13 weeks (NTP 1985). Additionally, the increase in serum ALT was not doserelated, and serum levels of other liver-associated enzymes were not increased in either the Robinson et 

al. (1991) study (AST, LDH, and AP) or the NTP (1985) study (AP and gamma-glutamyltranspeptidase 

[GGTP]). The lowest LOAEL is 125 mg/kg/day, which is a minimal LOAEL for increased liver weight 

in rats in the NTP (1985) study; the corresponding NOAEL is 60 mg/kg/day. 

The NOAEL/LOAEL approach to MRL derivation results in a lower MRL than the 0.6 mg/kg/day value 

based on benchmark dose analysis. Using the 60 mg/kg/day NOAEL for increased liver weight in rats 

(NTP 1985), the NOAEL is duration-adjusted to 42.9 mg/kg/day (60 mg/kg/day x 5 days/7 days) and 

divided by the uncertainty factor of 100 to yield an MRL of 0.4 mg/kg/day. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

 

DICHLOROBENZENES A-28 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,2-Dichlorobenzene (1,2-DCB) 

CAS Numbers: 95-50-1 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 31 

Species: Mouse 

Minimal Risk Level: [0.3] mg/kg/day [ ] ppm 

Reference: NTP. 1985. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene 

(o-dichlorobenzene) (CAS No. 95-50-1) in F344/N rats and B6C3F1 mice (gavage studies). Research 

Triangle Park, NC: National Toxicology Program. NTP TR 255. NIH Publication No. 86-2511. 

Experimental design: Groups of 50 male and 50 female F344/N rats and 50 male and 50 female 

B6C3F1 mice were administered 1,2-DCB (>99% pure) in corn oil by gavage in doses of 0, 60, or 

120 mg/kg on 5 days/week for 103 weeks. Evaluations included clinical signs, body weight, and gross 

observations in all groups of animals. Complete histological examinations were performed on all 

animals, and included evaluations of at least 30 tissues. 

Effects noted in study and corresponding doses: Survival was significantly reduced in high-dose male 

rats, relative to control male rats, but not in the low-dose group or in any group of female rats. Mean 

body weights of high-dose male rats were slightly, but not statistically significantly, lower than those of 

controls throughout the study; the mean body weights of low-dose males were comparable to those of 

controls, and exposed female rats had higher body weights than controls. No changes in clinical signs 

were reported for either sex of rats. No increases in gross observations were reported on necropsy, and no 

changes in nonneoplastic lesions were seen in the liver, kidney, bone marrow, spleen, thymus, or other 

organs or tissues in exposed rats. 

In the mice, no statistically significant differences in survival were seen in either sex at any dose level. 

Mean body weights were similar to controls for all treated groups of male and female mice. In male 

mice, there was a dose-related increase in the incidence of renal tubular regeneration (controls: 8/48; low 

dose: 12/50; high dose: 17/49); the increase was statistically significant (Fisher’s Exact Test, performed 

by ATSDR) in the high-dose group. No other increases were observed in nonneoplastic lesions of the 

liver, bone marrow, spleen, or any other evaluated organ or tissue. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDL 

As discussed below, a BMDL10 of 43.04 mg/kg/day for increased incidences of renal tubular regeneration 

in male mice is used as the point of departure for the MRL. 

BMD analysis was conducted using the kidney lesion incidence data summarized in Table A-12. All 

dichotomous models in the Benchmark Dose Software (version 1.3.2) were fit to the male mouse 

incidence data for renal tubule regeneration. A 10% extra risk above the control incidence was selected 

as the BMR in the absence of a biological rationale for using an alternative BMR. The modeling results 

are shown in Table A-13. The gamma, log-logistic, and Weibull models outputs failed to provide Chi­
 

 

 

DICHLOROBENZENES A-29 

APPENDIX A 

square p-values for goodness of fit statistic (Chi-square = 0; degrees of freedom = 0) and were therefore 

not considered for selection of a point of departure. The other models (logistic, multistage, probit, logprobit, quantal-linear, and quantal-quadratic) provided adequate fits to the data (Chi-square p-values 

≥0.1). The logistic model was the best-fitting model for the renal tubule regeneration incidence data, 

based on the lowest AIC, and provided a BMD10 of 62.96 mg/kg/day and a BMDL10 of 43.04 mg/kg/day 

(Table A-13, Figure A-5). The BMDL10 of 43.04 mg/kg/day was duration-adjusted to 30.74 mg/kg/day 

and divided by an uncertainty factor of 100 to yield an MRL of 0.3 mg/kg/day. 

Table A-12. Incidences of Kidney Lesions in Male Mice Orally Exposed to 

1,2-Dichlorobenzene for 103 Weeks 

Dose (mg/kg/day) 

Lesion: Regeneration of kidney tubule cells 0 60 120 

Incidence/group size 8/48 12/50 17/49a 

a

Significantly (p<0.05) different from control; Fisher Exact Test performed by ATSDR 

Source: NTP 1985 

Table A-13. BMD Modeling of Incidence Data for Kidney Lesions in Male Mice 

Exposed to 1,2-Dichlorobenzene for 103 Weeks 

Chi-square BMD10 BMDL10 

Model p-value AIC (mg/kg/day) (mg/kg/day) 

Gammaa NA 167.62 65.92 29.80 

Logistic 

Log-logisticb 

0.94 

NA 

165.63 

167.62 

62.96 

65.85 

43.04 

26.33 

Multi-stagec 0.77 165.71 53.90 29.58 

Probit 0.91 165.64 61.60 41.20 

Log-probitb 0.84 165.67 72.33 46.85 

Quantal-linear 0.77 165.71 53.90 29.58 

Quantal-quadratic 0.74 165.73 79.20 57.20 

Weibull NA 167.62 66.03 29.80 

a

Restrict power >=1 

b

Slope restricted to >1 

c

Restrict betas >=0; lowest degree polynomial (1-degree) providing adequate fit 

AIC = Akaike’s Information Criteria; BMD10 = benchmark dose associated with 10% extra risk; BMDL10 = lower 

confidence limit (95%) on the benchmark dose; NA = Chi-square p-value not applicable (Chi-square = 0; degrees of 

freedom = 0) 
 

 

Figure A-5. Observed and Predicted Incidences of Kidney Lesions in Male Mice 

Exposed to 1,2-Dichlorobenzene for 103 Weeks* 

Logistic Model with 0.95 Confidence Level 

Fraction Affected 

0.5 

0.4 

0.3 

0.2 

0.1 

BMDL BMD 

Logistic 

0 20 40 60 80 100 120 

 

 

DICHLOROBENZENES A-30 

APPENDIX A 

dose 

14:08 07/21 2006 

*BMD and BMDL (in mg/kg/day) are associated with a 10% extra risk. 

Source: NTP 1985 

Uncertainty Factors used in MRL derivation: 

[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? Not applicable 

(gavage study). 

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? The BMDL10 of 43.04 mg/kg/day was 

duration-adjusted for intermittent exposure, as follows (EPA 1994k): 

BMDL10 ADJ = (BMDL10) (days/7 days) 

= (43.04 mg/kg/day) (5 days/7 days) 

= 30.74 mg/kg/day 

Other additional studies or pertinent information that lend support to this MRL: No other studies were 

located that evaluated effects on renal tissues following chronic oral exposure to 1,2-DCB. 
DICHLOROBENZENES A-31 

APPENDIX A 

The NOAEL/LOAEL approach to MRL derivation results in a similar chronic-duration oral MRL value 

as the benchmark dose approach. Using the NOAEL of 60 mg/kg/day for increased incidence of renal 

tubular regeneration, the NOAEL is duration-adjusted to 43 mg/kg/day (60 mg/kg/day x 5 days/7 days) 

and divided by the uncertainty factor of 100 to yield an MRL of 0.4 mg/kg/day. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

DICHLOROBENZENES A-32 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,3-Dichlorobenzene (1,3-DCB) 

CAS Numbers: 541-73-1 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 2 

Species: Rat 

Minimal Risk Level: [0.4] mg/kg/day [ ] ppm 

Reference: McCauley PT, Robinson M, Daniel FB, et al. 1995. Toxicity studies of 1,3-dichlorobenzene 

in Sprague-Dawley rats. Drug Chem Toxicol 18(2 & 3):201-221. 

Experimental design: Groups of 10 male and 10 female Sprague-Dawley rats were administered 

1,3-DCB in gavage doses of 0, 37, 147, 368, or 735 mg/kg/day in corn oil for 10 consecutive days. End 

points evaluated during the study included clinical signs, survival, body weight, and food and water 

consumption. At the end of the study, blood was collected for hematology and serum chemistry analyses 

(erythrocytes, leukocytes, hemoglobin, hematocrit, mean corpuscular volume, glucose, BUN, creatinine, 

AP, AST, ALT, cholesterol, LDH, and calcium levels), and selected organs were weighed (brain, liver, 

spleen, lungs with lower half of trachea, thymus, kidneys, adrenal glands, heart, and gonads). Gross 

pathology was evaluated in all animals, and comprehensive histological examinations were performed in 

the high dose and control groups; histology in the lower dose groups was limited to the liver. 

Inflammatory and degenerative lesions were graded on a relative scale from one to four depending on the 

severity (minimal, mild, moderate, or marked). 

Effects noted in study and corresponding doses: No compound-related deaths or overt clinical signs were 

observed. Body weight was significantly reduced in both sexes at 735 mg/kg/day (20 and 13% lower 

than controls in males and females, respectively). Food consumption was significantly decreased at 

735 mg/kg/day in males (12%, normalized by body weight), and water consumption was significantly 

increased (8–13%) in females at ≥735 mg/kg/day. The hematological evaluation showed 8% decreased 

MCV in females at 735 mg/kg/day. The clinical chemistry analyses showed statistically significant 

changes in several indices, but serum cholesterol was the only end point that had values that exceeded the 

reference range. Serum cholesterol was significantly increased in females at 368 and 735 mg/kg/day 

(94 and 63% higher than controls, respectively), as well as in males at 368 and 735 mg/kg/day (79 and 

84% higher than controls, respectively). Relative liver weight was significantly increased in males at 

≥147 mg/kg/day and females at ≥368 mg/kg/day; increases in the males were 9.1, 31.3, 50.63, and 32.5% 

higher than controls in the low- to high-dose groups. Other significant changes in relative organ weight 

included decreased spleen weight in females at ≥368 mg/kg/day and in males at 735 mg/kg/day, 

decreased thymus weight in both sexes at 735 mg/kg/day, and decreased testes weight in males at 

735 mg/kg/day. Absolute organ weights were not reported. Histological changes primarily occurred in 

the liver, particularly centrilobular hepatocellular degeneration at ≥368 mg/kg/day. This lesion was 

characterized by varying degrees of cytoplasmic vacuolization and swelling with intact membranes, and 

occurred in the 368 and 735 mg/kg/day groups in 2/10 and 9/10 males, respectively, and in 6/10 and 

10/10 females, respectively; incidences in the other groups were not reported, but are presumed to be 

0/10. Other hepatic alterations included hepatocellular necrosis that was sporadically noted in the 147, 

368, and 735 mg/kg/day groups. This change was usually minimal to mild, and tended to increase in 

incidence and severity in the males in a dose-related manner; however, incidences were not reported. The 

only other reported histological change was atrophy of the thymus, characterized by loss of normal 
DICHLOROBENZENES A-33 

APPENDIX A 

differentiation between medulla and cortex. The thymic atrophy was observed in 2/10 males (both 

marked in severity) and 2/9 females (both mild in severity) at 735 mg/kg/day; this change was not 

observed in controls, and the other dosed groups were not examined. The 147 mg/kg/day dose is a 

LOAEL based on the >30% increase in relative liver weight in male rats. The NOAEL for increased liver 

weight is 37 mg/kg/day. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDL 

As discussed below, a BMDL1sd of 36.32 mg/kg/day for increased liver weight in female rats is used as 

the point of departure for the MRL. 

BMD analysis was conducted on hepatic effects data in the male and female rats of the McCauley et al. 

(1995) study. The liver effects data modeled included the incidences of hepatocellular degeneration, 

absolute liver weights, and mean serum cholesterol levels shown in Table A-14. 

Table A-14. Liver Effects Observed in Rats Orally Exposed to 

1,3-Dichlorobenzene for 10 Days 

Dose (mg/kg/day) 

Effects Sex 0 37 147 368 735 

Centrilobular M 0/10a 0/10a 0/10a 2/10 9/10b 

hepatocellular 

degeneration 

F 0/10a

 0/10a 0/10a 6/10b 10/10b 

Absolute liver M 11.04±1.00 12.06±1.56 14.5±2.30b 16.63±1.62b 14.63±2.26b 

weight (g) n=10 n=10 n=9 n=10 n=9 

F 7.68±0.75 8.12±0.77 9.18±0.99 11.90±1.19b 12.66±2.55b 

n=10 n=10 n=9 n=10 n=9 

Mean serum M 63.0±10.2 63.6±3.7 92.4±20.9 112.5±16.3b 116.0±49.6b 

cholesterol n=10 n=10 n=10 n=9 n=10 

(mg/dL) F 64.8±12.2 73.3±10.8 87.9±13.8 125.4±27.0b 105.7±16.6b 

n=8 n=10 n=9 n=10 n=9 

a

Incidences of centrilobular hepatocellular degeneration were not reported for the 0, 37, and 147 mg/kg/day dose 

groups, but are assumed to be 0/10 each because the lesion was only reported present in the two highest dose 

groups. 

b

Significantly (p≤0.05) different from control value. 

Source: McCauley et al. 1995 

All dichotomous variable models available in the EPA Benchmark Dose Software (Version 1.3.2) were fit 

to the incidence data for hepatocellular degeneration in male and female rats. A BMR of 10% extra risk 

was selected in the absence of a biological rationale for selecting an alternative BMR. The modeling 

results are shown in Table A-15. All dichotomous models provided adequate fit to the male and female 

hepatocellular degeneration incidence data, as determined by Chi-square p-values >0.1 (Table A-15). 

The log-probit model was determined to be the best-fitting (lowest AIC) model for the male data and 

provided a BMD10 of 319.18 mg/kg/day and a BMDL10 of 207.86 mg/kg/day. The log-logistic model was 

determined to be the best-fitting (lowest AIC) model for the female data and provided a BMD10 of 

318.46 mg/kg/day and a BMDL10 of 159.37 mg/kg/day. 
DICHLOROBENZENES A-34 

APPENDIX A 

Table A-15. Modeling Results for Incidences of Centrilobular 

Degeneration in Male and Female Rats Orally Exposed to 

1,3-Dichlorobenzene for 10 Days 

Chi-square 

Model p-valuea AIC BMD10 (mg/kg/day) BMDL10 (mg/kg/day) 

Males 

Gammab

 0.9997 20.53 314.37 196.42 

 Logistic 0.9386 21.15 322.99 215.61 

 Log-logisticc

 0.9992 20.55 317.16 206.86 

Multi-staged

 0.9895 20.72 305.72 156.48 

Probit 0.9787 20.81 316.14 205.06 

Log-probitc

 1.0000 20.51 319.18 207.86 

 Quantal linear 0.1153 28.95 82.93 51.49 

 Quantal quadratic 0.7150 21.46 190.83 148.00 

 Weibullb

 0.9918 20.69 306.04 182.80 

Females 

Gammab

 1.00 15.48 251.73 145.75 

 Logistic 1.00 17.46 338.16 167.41 

 Log-logisticc

 1.00 15.46 318.46 159.37 

Multi-staged

 0.97 15.92 216.50 124.71 

Probit 1.00 17.46 310.54 153.36 

Log-probitc

 1.00 17.46 303.18 153.81 

 Quantal linear 0.13 28.04 45.74 29.88 

 Quantal quadratic 0.75 19.06 128.58 99.32 

 Weibullb

 1.00 17.46 313.61 138.53 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria b

Restrict power >=1 

c

Slope restricted to >1

d

Restrict betas ≥0; Degree of polynomial=2 

AIC = Akaike’s Information Criteria; BMD10 = benchmark dose associated with a 10% extra risk; BMDL10 = lower 

confidence limit (95%) on the benchmark dose 

All continuous variable models in the EPA Benchmark Dose Software (Version 1.3.2) were fit to the 

mean absolute liver weight data and mean serum cholesterol level data from the male and female rats. A 

BMR of 1 standard deviation increase above the control mean was selected in the absence of a biological 

rationale for using an alternative BMR. None of the available models provided adequate mean fit to the 

male rat absolute liver weight data or the female rat serum cholesterol data, based on p-values <0.01 for 

mean fit. Modeling of the male rat serum cholesterol data resulted in failed tests for both constant and 

non-homogeneous variance. 

For the female rat absolute liver weight data, results of testing for constant and non-homogeneous 

variance indicated that a non-homogeneous variance assumption was appropriate. The modeling results 

are shown in Table A-16. Based on this assumption, the linear, 2-degree polynomial, and Hill models 

provided adequate mean fit to the female rat absolute liver weight data. The power model provided a 

p-value of 0.093, which was considered adequate, although a p-value >0.1 is the conventional goodness­
DICHLOROBENZENES A-35 

APPENDIX A 

of-fit standard. Although the Hill model provided adequate mean fit, it failed to determine a BMDL and 

was rejected from further consideration for selection of a point of departure for deriving an acute-duration 

oral MRL. The best-fitting model for the female rat absolute liver weight data was the 2-degree 

polynomial model (lowest AIC), which provided a BMD1sd of 51.83 mg/kg/day and a BMDL1sd of 

36.32 mg/kg/day. 

In summary, BMD analysis of liver effects in the male and female rats of the principal study (McCauley 

et al. 1995) resulted in a BMDL10 of 207.86 mg/kg/day for hepatocellular degeneration in male rats (bestfitting [log-probit] model), a BMDL10 of 159.37 mg/kg/day for hepatocellular degeneration in female rats 

(best-fitting [log-probit] model), and a BMDL1sd of 36.32 mg/kg/day for absolute liver weight changes in 

female rats (best-fitting [2-degree polynomial] model). Using a conservative approach, the BMDL1sd of 

36.32 mg/kg/day for absolute liver weight changes in female rats (Table A-16, Figure A-6) is selected as 

the point of departure for deriving an MRL. The BMDL1sd of 36.32 mg/kg/day was divided by an 

uncertainty factor of 100 to derive an MRL of 0.4 mg/kg/day. 

Table A-16. Modeling Results for Absolute Liver Weight Data in Female Rats 

Orally Exposed to 1,3-Dichlorobenzene for 10 Days 

Model 

Linearb,c

Variance 

p-valuea 

0.0002 

Mean fit 

p-valuea 

NA NA 

AIC 

BMD1sd 

(mg/kg/day) 

NA 

BMDL1sd 

(mg/kg/day) 

NA 

Linearc,d 0.36 0.15 68.39 76.09 55.09 

Polynomialc,e

Powerd,f

 0.36 

0.29 

0.62 

0.093 

66.046 

70.39 

51.83 

76.08 

36.32 

55.09 

Hilld,g 0.36 0.37 67.87 78.40 No value 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria. b

Constant variance assumed 

c

Restriction = non-negative 

d

Non-homogeneous variance assumed 

e

Lowest degree polynomial (2-degree) providing adequate fit 

f

Restrict power >=1 

g

Restrict n>1 

AIC = Akaike’s Information Criteria; BMD1sd = benchmark dose associated with one standard deviation increase 

above control mean; BMDL1sd = lower confidence limit (95%) on the BMD1sd; F= BMDL computation failed due to 

bad completion code in Optimization routine; NA = not applicable, as model does not provide adequate fit 
 

 

Figure A-6. Observed and Predicted Liver Weights in Female Rats Exposed to Mean Response 

1,3-Dichlorobenzene for 10 Days* 

Polynomial Model with 0.95 Confidence Level 

15 

14 

13 

12 

11 

10 

9 

8 

7 

BMDL BMD 

Polynomial 

0 100 200 300 400 500 600 700 800 

 

DICHLOROBENZENES A-36 

APPENDIX A 

dose 

15:04 07/28 2006 

*BMD and BMDL (in mg/kg/day) are for a 1 standard deviation increase above the control mean. 

Uncertainty Factors used in MRL derivation: 

[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? Not applicable 

(gavage study). 

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: No additional acuteduration studies of 1,3-DCB were located. 

The NOAEL/LOAEL approach to MRL derivation results in same MRL as the 0.4 mg/kg/day value 

derived using the benchmark dose approach. Using the 37 mg/kg/day NOAEL for increased liver weight 

and the uncertainty factor of 100, the NOAEL/LOAEL approach yields an MRL of 0.4 mg/kg/day. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

 

 

DICHLOROBENZENES A-37 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,3-Dichlorobenzene (1,3-DCB) 

CAS Numbers: 541-73-1 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 7 

Species: Rat 

Minimal Risk Level: [0.02] mg/kg/day [ ] ppm 

Reference: McCauley PT, Robinson M, Daniel FB, et al. 1995. Toxicity studies of 1,3-dichlorobenzene 

in Sprague-Dawley rats. Drug Chem Toxicol 18(2 & 3):201-221. 

Experimental design: Groups of 10 male and 10 female Sprague-Dawley rats were administered 

1,3-DCB in gavage doses of 0, 9, 37, 147, or 588 mg/kg/day in corn oil for 90 consecutive days 

(McCauley et al. 1995). End points evaluated during the study included clinical signs and mortality, body 

weight, and food and water consumption. At end of the exposure period, blood was collected for 

hematology and serum chemistry analyses (erythrocytes, leukocytes, hemoglobin, hematocrit, mean 

corpuscular volume, glucose, BUN, creatinine, AP, AST, ALT, cholesterol, LDH, and calcium levels), 

selected organs were weighed (brain, liver, spleen, lungs with lower half of trachea, thymus, kidneys, 

adrenal glands, heart, and gonads), and gross pathology was assessed. Histological examinations were 

performed on all tissues that were examined grossly in all high-dose rats and in one-half of control rats, as 

well as in the liver, thyroid, and pituitary glands from all animals in the 9, 37, and 147 mg/kg/day dose 

groups. Inflammatory and degenerative lesions were graded on a relative scale from one to four 

depending on the severity (minimal, mild, moderate, or marked). 

Effects noted in study and corresponding doses: No compound-related deaths or overt clinical signs were 

observed. Body weight was reduced in both sexes at 588 mg/kg/day (24 and 10% lower than controls in 

males and females, respectively). The decreased weight gain was progressive throughout the exposure 

period and occurred despite increased food and water consumption in the same groups. Other effects 

included increased relative kidney weight in males at ≥147 mg/kg/day and in females at 588 mg/kg/day, 

but there were no renal histopathological changes in any of the exposed animals. Hematological 

alterations consisted of significant increases in leukocyte levels in males at 147 mg/kg/day and in females 

at 588 mg/kg/day, and erythrocyte levels in males at 588 mg/kg/day. Histopathology and serum 

chemistry findings indicated that the thyroid, pituitary, and liver were the most sensitive targets of 

toxicity, as discussed below. The lowest LOAEL is 9 mg/kg/day, which is the lowest tested dose and a 

minimal LOAEL for thyroid and liver effects. 

Thyroid effects included significantly (p≤0.05) increased incidences of reduced colloidal density in 

follicles that exceeded normal variability in male rats at ≥9 mg/kg/day and in female rats at 

≥37 mg/kg/day (control to high dose group incidences of 2/10, 8/10, 10/10, 8/9, and 8/8 in males, and 

1/10, 5/10, 8/10, 8/10, and 8/9 in females). Depletion of colloid density in the thyroid was characterized 

by decreased follicular size with scant colloid and follicles lined by cells that were cuboidal to columnar. 

The severity of the colloid density depletion generally ranged from mild to moderate, increased with dose 

level, and was greater in males than females. Incidences of male rats with thyroid colloidal density 

depletion of moderate or marked severity were significantly increased at ≥147 mg/kg/day (0/10, 0/10, 

2/10, 5/9, and 6/8). The 9 mg/kg/day dose is considered to be a minimal LOAEL for thyroid effects 
 

 

DICHLOROBENZENES A-38 

APPENDIX A 

because the morphological alterations (reduced colloidal density in follicles) are unlikely to be associated 

with functional changes in the thyroid. 

Pituitary effects included significantly (p≤0.05) increased incidences of cytoplasmic vacuolization in the 

pars distalis in male rats at ≥147 mg/kg/day (2/10, 6/10, 6/10, 10/10, 7/7). The vacuoles were variably 

sized, irregularly shaped, and often poorly defined, and the severity of the lesions (i.e., number of cells 

containing vacuoles) ranged from minimal to mild and generally increased with increasing dose level. 

Incidences of male rats with pituitary cytoplasmic vacuolization of moderate or marked severity were 

significantly increased at 588 mg/kg/day (1/10, 0/10, 2/10, 3/9, and 7/7). The pituitary lesion was 

reported to be similar to "castration cells" found in gonadectomized rats and considered to be an indicator 

of gonadal deficiency. No compound-related pituitary lesions were observed in female rats. Serum 

cholesterol was significantly increased in males at ≥9 mg/kg/day and in females at ≥37 mg/kg/day in a 

dose-related manner, and serum calcium was significantly increased in both sexes at ≥37 mg/kg/day. The 

investigators suggested that these serum chemistry changes might reflect a disruption of hormonal 

feedback mechanisms, or target organ effects on the pituitary, hypothalamus, and/or other endocrine 

organs. Based on the increased incidences of cytoplasmic vacuolation, the LOAEL for pituitary effects is 

147 mg/kg/day. 

Hepatic effects occurred in both sexes at 147 and 588 mg/kg/day, including significantly increased 

relative liver weight and incidences of liver lesions. Absolute organ weights were not reported. Liver 

lesions were characterized by inflammation, hepatocellular alterations (eosinophilic homogeneous 

inclusions), and hepatocellular necrosis. Liver lesions that were significantly (p≤0.05) increased included 

hepatocellular cytoplasmic alterations of minimal to mild severity in males at ≥147 mg/kg/day (1/10, 

2/10, 1/10, 6/10, 7/9) and in females at 588 mg/kg/day (0/10, 2/10, 0/10, 1/10, 7/9), and necrotic 

hepatocyte foci of minimal severity at 588 mg/kg/day in both males (1/10, 2/10, 1/10, 2/10, 5/9) and 

females (0/10, 0/10, 0/10, 3/10, 5/9). Other statistically significant liver-associated effects included 

significantly increased serum AST levels (90–100% higher than controls) in males at ≥9 mg/kg/day and 

in females at ≥37 mg/kg/day. Serum cholesterol levels were significantly increased in males at 

≥9 mg/kg/day and in females at ≥37 mg/kg/day, but might be pituitary-related, as indicated above. Serum 

LDH levels were reduced in males at ≥9 mg/kg/day and BUN levels were reduced in both sexes at 

588 mg/kg/day, but the biological significance of decreases in these indices is unclear. The 9 mg/kg/day 

dose is considered to be a minimal LOAEL for liver effects because the main effect, increased serum 

AST, showed no clear dose-response and was only accompanied by necrotic liver lesions at a much 

higher dose (588 mg/kg/day). 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDL 

As discussed below, a BMDL10 of 2.1 mg/kg/day for increased incidences of pituitary lesions is used as 

the basis for the MRL. 

Benchmark dose analysis was conducted using the thyroid and pituitary lesion incidence data and serum 

AST and cholesterol levels summarized in Table A-17. 
 

 

 

DICHLOROBENZENES A-39 

APPENDIX A 

Table A-17. Thyroid, Pituitary and Liver Effects in Rats Orally Exposed to 

1,3-Dichlorobenzene for 90 Days 

Dose (mg/kg/day) 

Effect Sex 0 9 37 147 588 

Thyroid, reduced follicular M 2/10 8/10a 10/10a 8/9a 8/8a 

colloidal density 

Pituitary, cytoplasmic M 2/10 6/10 6/10 10/10a 7/7a 

vacuolation in pars distalis 

Serum AST (U/L) M 43.7 ± 37.7 87.6 ± 24.7a 109.8 ± 9.5 88.0 ± 23.3a 82.8 ± 13.8a 

(mean ± SD) (n=10) (n=10) (n=10) (n=10) (n=8) 

Serum cholesterol (mg/dL) M 73.5 ± 1.4 96.6 ± 1.7a 111.1 ± 1.6a 157.9 ± 2.5a 89.5 ± 1.5a 

(mean ± SD) (n=10) (n=10) (n=10) (n=10) (n=8) 

Serum cholesterol (mg/dL) F 68.2 ± 1.7 85.0 ± 3.0 108.4 ± 2.2a 158.9 ± 1.8a 152.6 ± 2.6a 

(mean ± SD) (n=10) (n=10) (n=10) (n=10) (n=9) 

a

Significantly (p≤0.05) different from control 

Source: McCauley et al. 1995 

Continuous variable models (linear, polynomial, power, and Hill) in the EPA Benchmark Dose Software 

(Version 1.3.2) were fit to the serum AST levels in the male rats and the serum cholesterol levels in the 

male and female rats. One standard deviation change from the control mean was selected as the BMR for 

each data set in the absence of a biological rationale for an alternative BMR. Initial modeling results 

using constant variance indicated that modeling should be performed using non-homogeneous variance. 

However, modeling results using non-homogeneous variance for each of the continuous variable models 

resulted in inadequate mean fit to the serum AST and cholesterol data, as indicated by p-values 

<0.0001 for mean fit. 

Dichotomous variable models available in the EPA Benchmark Dose Software were fit to the male rat 

incidence data for: (1) reduced follicular colloidal density in the thyroid, and (2) cytoplasmic vacuolation 

in the pars distalis of the pituitary. For each variable, AIC was used to select the best-fitting model from 

which BMDs and BMDLs were calculated, using a BMR of 10% extra risk. For the thyroid incidence 

data, none of the available dichotomous variable models provided adequate fit as indicated by chi-square 

goodness of fit p-values ≤0.002. For the pituitary cytoplasmic vacuolation incidence data, all of the 

models provided adequate fit as indicated by chi-square goodness of fit p-values >0.1 (Table A-18). The 

probit model provided the lowest AIC (43.442). However, a nearly identical AIC value (43.467) was 

provided by each of three other models (gamma, quantal-linear, and Weibull). Because the BMD10 of 

4.08 mg/kg/day and associated BMDL10 of 2.10 mg/kg/day from the gamma, quantal-linear, and Weibull 

models are lower than those from the probit model (BMD10 = 7.79 mg/kg/day; BMDL10 = 

4.46 mg/kg/day), a conservative health protective approach was taken and the lower BMDL10 of 

2.10 mg/kg/day was selected as the point of departure for deriving the MRL (Table A-18, Figure A-7). 

The BMDL10 of 2.1 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolation from 

animals to humans, and 10 for human variability) to derive an MRL of 0.02 mg/kg/day. 
Fra

ctio

n

Affe

cte

d

 

Gamma Multi-Hit Model with 0.95 Confidence Level 

1 

0.8 

0.6 

0.4 

0.2
 

0
 

16:28 11/21 2002 

BMDLBMD 

Gamma Multi-Hit 

0 100 200 300 400 500 600 

dose 

DICHLOROBENZENES A-40 

APPENDIX A 

Table A-18. BMD Modeling Results of Incidence Data for Pituitary Lesions in 

Male Rats Exposed to 1,3-Dichlorobenzene for 90 Days 

Chi-square BMD10 BMDL10 

Model p-valuea AIC (mg/kg/day) (mg/kg/day) 

Probit 0.4823 43.442 7.79 4.46 

Gammab 0.4887 43.467 4.08 2.1 

Quantal-linear 

Weibullb 

0.4887 

0.4887 

43.467 

43.467 

4.08 

4.08 

2.1 

2.1 

Logistic 0.4639 43.58 7.49 4.29 

Quantal-quadratic 

Log-probitc 

Multi-staged 

Log-logisticc 

0.376 

0.3154 

0.3061 

0.2190 

44.122 

44.674 

45.350 

46.518 

17.11 

7.33 

5.21 

2.34 

10.10 

3.29 

2.28 

0.66 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria b

Restrict power >=1 

c

Slope restricted to >1

d

Restrict betas ≥0; Degree of polynomial=2 

Figure A-7. Observed Incidences for Pituitary Lesions in Male Rats and 

Incidences Predicted by the Gamma Model*
 

*BMD and BMDL (in mg/kg/day) are associated with a benchmark response of 10% extra risk. The gamma model 

plot in this figure is identical to plots produced by the quantal-linear and Weibull models. 

Uncertainty Factors used in MRL derivation: 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 
 

 

DICHLOROBENZENES A-41 

APPENDIX A 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

(gavage study) 

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: No additional 

intermediate-duration studies of 1,3-DCB were located. 

The NOAEL/LOAEL approach to MRL derivation provides support to the MRL of 0.02 mg/kg/day based 

on the BMD analysis of pituitary lesions. The lowest tested dose of 9 mg/kg/day is considered a minimal 

LOAEL for thyroid lesions and increases in serum AST. Using the minimal LOAEL of 9 mg/kg/day and 

an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for extrapolation from animals to 

humans, and 10 for human variability), the NOAEL/LOAEL approach yields an MRL of 0.03 mg/kg/day. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

DICHLOROBENZENES A-42 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,4-Dichlorobenzene (1,4-DCB) 

CAS Numbers: 106-46-7 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 44 

Species: Dog 

Minimal Risk Level: [0.07] mg/kg/day [ ] ppm 

References: Naylor MW, Stout LD. 1996. One year study of p-dichlorobenzene administered orally via 

capsule to beagle dogs. Environmental Health Laboratory, Monsanto Company, St. Louis, MO. Study 

No. ML-94-210, March 25, 1996. MRID# 43988802. Unpublished. 

EPA. 1996b. Data Evaluation Record (DER) for p-dichlorobenzene – chronic oral toxicity in dogs 

(MRID# 439888-01 and -02) for Section 6 (a) (2) and reregistration need. U.S. Environmental Protection 

Agency, Office of Prevention, Pesticides and Toxic Substances. 

Experimental design: Groups of five male and five female beagle dogs were orally administered 

1,4-DCB by capsule in dose levels of 0, 10, 50, or 75 mg/kg/day for 1 year. Based on the summarized 

design of a 4-week dose range-finding study, it is presumed that dosing was 5 days/week. The 

75 mg/kg/day dose is a time-weighted average level reflecting dose decreases at the beginning of the 

study in response to unexpected severe toxicity. An initial high dose of 150 mg/kg/day was adjusted to 

100 mg/kg/day for males during week 3, and a further decrease to 75 mg/kg/day was made for both sexes 

at the beginning of week 6. Both high dose males and females were untreated during weeks 4 and 5 to 

allow for recovery. End points evaluated throughout the study included clinical observations (daily), 

body weight (weekly), and food consumption (weekly). Ophthalmoscopic examinations were performed 

prior to study start and just prior to study completion. Hematology (11 indices, including activated partial 

thromboplastin time), clinical chemistry (18 indices, including ALT, AST, GGTP, AP, and creatinine 

phosphokinase), and urinalysis (10 indices) were performed at month 6 and study completion. Organ 

weights, gross pathology, and histology were evaluated at study completion. 

Effects noted in study and corresponding doses: Mortality occurred the first 25 days of the study before 

dose reduction; exposure to 150 mg/kg/day caused one male dog to be sacrificed in extremis on day 12, 

one male death on day 25, and one female death on day 24. A control male died on day 83, but all other 

dogs survived to the end of the study. Treatment-related clinical signs were primarily limited to severely 

affected high-dose dogs and the control male that died; these included hypoactivity, dehydration, 

decreased defecation, blood-like fecal color, emesis, emaciation, and/or pale oral mucosa. There were no 

significant group differences in mean body weight at the end of the study. Body weight gain was 

significantly reduced during the first month of the study, but recovered following dose reduction and 

adjustment of food availability. A mild anemia was observed at month 6 (significantly reduced red blood 

cells in females and HCT in males) at 75 mg/kg/day, but resolved by the end of the study. The mild 

anemia correlated with histologic findings of bone marrow erythroid hyperplasia in females, and splenic 

excessive hematopoiesis and megakaryocyte proliferation in both sexes, indicating a compensatory 

response to the earlier anemia. Hepatic effects occurred after 6 and 12 months at ≥50 mg/kg/day in both 

sexes as shown by changes in liver enzymes, increased liver weight, and/or histopathology. Effects on 

serum enzyme levels included significantly increased AP in males at 50 mg/kg/day at months 6 and 

12 (731 and 620% higher than controls, respectively), females at 50 mg/kg/day at months 6 and 
 

 

DICHLOROBENZENES A-43 

APPENDIX A 

12 (525 and 330% higher), and females at 75 mg/kg/day at months 6 and 12 months (761 and 680% 

higher). Serum AP levels were not statistically significantly increased in the 75 mg/kg/day males at 

months 6 or 12, but only 3 animals were evaluated in this dose group. Other clinical chemistry findings 

included significantly increased ALT in females at 75 mg/kg/day at month 12 (253% higher than 

controls), increased GGTP in females at 75 mg/kg/day at months 6 and 12 (131 and 161% higher), and 

decreased albumin in males at 50 and 75 mg/kg/day at month 6 (16 and 18% lower than controls) and 

females at 75 mg/kg/day at month 6 (19% lower). Absolute and relative liver weights were significantly 

increased (40–70% higher than controls) in both sexes at 50 and 75 mg/kg/day (except absolute liver 

weight in 50 mg/kg/day males). Hepatic lesions included hepatocellular hypertrophy (diffuse or 

multifocal in all males and females at 50 and 75 mg/kg/day and one female at 10 mg/kg/day), 

hepatocellular pigment deposition (two males and one female each at 50 and 75 mg/kg/day), bile 

duct/ductule hyperplasia (one male and one female at 75 mg/kg/day), and hepatic portal inflammation 

(periportal accumulation of neutrophils in one male at 50 mg/kg/day and two males at 75 mg/kg/day). 

Kidney effects included collecting duct epithelial vacuolation in one male at 75 mg/kg/day and at all dose 

levels in females (one each at 10 and 50 mg/kg/day and two at 75 mg/kg/day). The renal lesion was 

considered to be a possible effect of treatment at ≥50 mg/kg/day, because it was accompanied by 

increased relative kidney weight in females at ≥50 mg/kg/day and grossly observed renal discoloration in 

two females at 75 mg/kg/day. 

The highest NOAEL and lowest LOAEL are 10 and 50 mg/kg/day, respectively, based on the increases in 

serum AP at 6 months. This serum enzyme change is a sufficient indication of intermediate-duration 

hepatotoxicity because the increases were similar in magnitude to those that were observed after 1 year 

and associated with increased liver weight and liver lesions; the latter effects likely developed earlier in 

the study but could not be detected due to the lack of organ weight and histology examinations at 

6 months. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDL 

As discussed below, a BMDL1sd of 10 mg/kg/day for increased serum AP is used as the basis for the 

MRL. 

BMD analysis was conducted using the Naylor and Stout (1996) data for changes in serum AP in female 

dogs administered 1,4-DCB orally for 6 months, as shown in Table A-19. A BMR of 1 standard 

deviation change from the control mean was selected in the absence of a biological rationale for using an 

alternative BMR. Mean serum AP levels in the female dogs exhibited a dose-response relationship and 

were significantly higher in the 50 and 75 mg/kg/day groups, relative to controls. Although significantly 

increased mean serum AP levels were noted in the 50 mg/kg/day male dogs, the increase was not 

significant in the 75 mg/kg/day males; only three males in this dose group were available for the 

assessment of serum AP levels. Therefore, the male serum AP data were not modeled. The simplest 

model (linear) for continuous data from the EPA Benchmark Dose Software (Version 1.3.2) was initially 

fit to the female serum AP data; constant variance was selected. As shown in Table A-20, the linear 

model output indicated inadequate fit for constant variance (as indicated by a p-value <0.01 for the test of 

constant variance) and a model run using nonhomogeneous variance was suggested. However, using 

nonhomogeneous variance, inadequate model mean fit was obtained (p-value <0.01 for model mean fit) 

(see Table A-20). The more complex (polynomial, power, Hill) models were also fit to the serum AP 

data. The Hill model provided inadequate mean fit due to an insufficient number of dose groups (4, 

including controls), which resulted in insufficient (0) degrees of freedom. Both the polynomial and 

power models provided adequate mean fit (Table A-20). Following conventional protocol for selection of 

the point of departure (the adequate model with the lowest AIC [Akaike’s Information Criteria]), the 
 

 

DICHLOROBENZENES A-44 

APPENDIX A 

BMDL1sd of 9.97 mg/kg/day (lower 95% confidence limit on the BMD1sd of 12.48 mg/kg/day) was 

selected as the point of departure for deriving an intermediate-duration oral MRL for 1,4-DCB (see 

Table A-20, Figure A-8). The BMDL1sd of 9.97 mg/kg/day was duration-adjusted to 7 mg/kg/day and 

divided by an uncertainty factor of 100 to derive an MRL of 0.07 mg/kg/day. 

Table A-19. Serum Alkaline Phosphatase Levels in Female Dogs Orally Exposed 

to 1,4-Dichlorobenzene for 6 Months 

Mean serum AP level in IU/L 

Dose (mg/kg/day) Group size (percent of control mean) 

0 5 175.80 ± 50.05a 

--

10 5 176.00 ± 64.50 

(100) 

50 5 1098.20b ± 425.85 

(625) 

75 4 1513.50c ± 855.31 

(861) 

a

Standard deviation 

b

Significantly different (p<0.01) from control group 

c

Significantly different (p<0.05) from control group 

Source: Naylor and Stout 1996 

Table A-20. Model Predictions for Changes in Serum Alkaline 

Phosphatase Levels in Female Dogs Orally Exposed
 

to 1,4-Dichlorobenzene for 6 Months 

Variance Mean fit BMD1sd BMDL1sd 

Model 

Linearb,c 

p-valuea 

<0.01 

p-valuea 

NA NA 

AIC (mg/kg/day) 

NA 

(mg/kg/day) 

NA 

Linearc,d NA <0.01 NA NA NA 

2-Degree 

polynomialc,d 

Power d

0.776 

0.774 

0.13 

0.14 

220.61 

222.59 

12.48 

12.00 

9.97 

6.62 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria. b

Constant variance assumed 

c

Restriction = non-negative 

d

Nonhomogeneous variance assumed 

BMD1sd = benchmark dose based on a benchmark response of 1 standard deviation above the control mean; 

BMDL1sd = lower confidence limit (95%) on the BMD1sd; NA = not applicable because model failed a goodness-offit test 
 

 

Polynomial Model with 0.95 Confidence Level 

Mean Response 

3000 

2500 

2000 

1500 

1000 

500 

0 BMDL BMD

Polynomial 

0 10 20 30 40 50 60 70 80 

 

 

 

DICHLOROBENZENES A-45 

APPENDIX A 

Figure A-8. Changes in Serum Alkaline Phosphatase Levels in Female Dogs 

Orally Exposed to 1,4-Dichlorobenzene for 6 Months* 

dose 

17:43 06/29 2006 

*BMD and BMDL (in mg/kg/day) are associated with a benchmark response of 1 standard deviation above the control 

mean. 

Uncertainty Factors used in MRL derivation: 

[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? Not applicable 

(capsule study). 

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? The BMDL1sd of 10 mg/kg/day was 

adjusted to a continuous exposure scenario as follows: 

 BMDL1sd ADJ = (BMDL1sd) (5days/7 days) 

= (10 mg/kg/day) (5 days/7 days) 

= 7 mg/kg/day 

Other additional studies or pertinent information that lend support to this MRL: The NOAEL/LOAEL 

approach to MRL derivation results in the same intermediate-duration oral MRL value as the benchmark 

dose approach. Using the NOAEL of 10 mg/kg/day for increased serum AP in dogs (Naylor and Stout 

1996), the NOAEL is duration-adjusted to 7 mg/kg/day (10 mg/kg/day x 5 days/7 days) and divided by 

the uncertainty factor of 100 to yield an MRL of 0.07 mg/kg/day. 

Information on the systemic toxicity of intermediate-duration oral exposure to 1,4-DCB is available from 

a number of studies conducted in rodents, mainly rats and mice, as well as the MRL study in dogs. Liver 
DICHLOROBENZENES A-46 

APPENDIX A 

and kidney effects are the most consistently observed, best characterized, and most sensitive findings in 

these studies. The lowest observed adverse effect level is for liver toxicity in dogs, although reproductive 

and developmental studies in rats indicate that offspring are particularly sensitive to 1,4-DCB toxicity 

during the postnatal pre-weaning period. 

Hepatic effects induced by intermediate-duration oral exposures to 1,4-DCB ranged from increased liver 

weight and hepatocyte enlargement to hepatocellular degeneration, lesions, necrosis, and tumors in rats, 

mice, rabbits, and dogs. Increases in serum levels of enzymes and alterations in other end points (e.g., 

serum cholesterol and triglycerides) indicative of hepatocellular damage or liver dysfunction have also 

been induced. Increased liver weight is the most sensitive hepatic end point in subchronic studies in rats, 

observed at doses as low as 150 mg/kg/day for 4–13 weeks and 188 mg/kg/day for 192 days 

(Hollingsworth et al. 1956; Lake et al. 1997; Umemura et al. 1998). There was no indication of early 

liver damage in rats exposed to 150 mg/kg/day for 4 weeks using an immunohistochemical marker of 

centrilobular hepatocyte injury (Umemura et al. 1998), and increases in liver porphyrins in rats exposed to 

50–200 mg/kg/day for 120 days were not considered to be toxicologically significant (Carlson 1977). 

Hepatocellular hypertrophy and decreased serum triglycerides occurred in rats exposed to 

≥300 mg/kg/day for 13 weeks (NTP 1987; Lake et al. 1997). Higher dose levels of 1,4-DCB induced 

degenerative liver lesions in rats exposed to 376 mg/kg/day for 192 days (slight cirrhosis and focal 

necrosis) (Hollingsworth et al. 1956) or 1,200 mg/kg/day for 13 weeks (hepatocyte degeneration and 

necrosis) (NTP 1987). In mice, hepatocellular degeneration was induced at doses ≥600 mg/kg/day for 

13 weeks (NTP 1987), and rabbits had cloudy swelling and minimal focal necrosis in the liver after 

exposure to 500 mg/kg/day for 367 days (Hollingsworth et al. 1956). Dogs are more sensitive to hepatic 

effects of 1,4-DCB than the other species based on increases in serum enzymes following exposure to 

doses as low as 50 mg/kg/day for 6 months in the MRL study (Naylor and Stout 1996). 

Kidney effects, including collecting duct epithelial vacuolation, are additional effects of 1,4-DCB in the 

dogs exposed to ≥50 mg/kg/day for 1 year in the MRL study (Naylor and Stout 1996). Renal changes, 

including hyaline droplet accumulation, increased kidney weights, and tubular lesions, are 

characteristically observed effects of subchronic and chronic oral exposure to 1,4-DCB in male rats at 

doses >75 mg/kg/day (Bomhard et al. 1988; Lake et al. 1997; NTP 1987). These findings were not 

considered for MRL derivation because there is a scientific consensus that they are related to the 

α2μ-globulin nephropathy syndrome, which is specific to male rats and not relevant to humans. 

Subchronic studies in female rats found increased kidney weight, but no indications of nephrotoxic action 

(i.e., no histopathology or effects on urinary indices of renal function), following exposure to 

>188 mg/kg/day for 192 days or 600 mg/kg/day for 13 weeks (Bomhard et al. 1988; Hollingsworth et al. 

1956). 

Developmental toxicity studies provide no indications that 1,4-DCB is teratogenic in rats at oral doses as 

high as 1,000 mg/kg/day during gestation, although fetotoxicity occurred at maternally toxic levels 

>500 mg/kg/day (Giavini et al. 1986; Ruddick et al. 1983). Decreased maternal weight gain and 

increased incidences of extra ribs, a skeletal variation attributable to the maternal toxicity, occurred in rats 

at gestational dose levels >500 mg/kg/day, but not at 250 mg/kg/day (Giavini et al. 1986). In a 

2-generation study, reproductive and developmental toxicity were evaluated in male and female rats that 

were orally exposed to 30, 90, or 270 mg/kg/day of 1,4-DCB (Bornatowicz et al. 1994). No effects on 

mating and fertility indices were observed at any level, although toxicity occurred in the offspring at 

doses >90 mg/kg/day. Effects at >90 mg/kg/day included reduced birth weight in F1 pups and increased 

total number of deaths from birth to postnatal day 4 in F1 and F2 pups, clinical manifestations of dry and 

scaly skin (until approximately postnatal day 7) and tail constriction with occasional partial tail loss 

(during postnatal days 4–21) in F1 and F2 pups, reduced neurobehavioral performance (draw-up reflex 

evaluated at weaning) in F2 pups, and increased relative liver weight in adult F1 males. No exposure­
DICHLOROBENZENES A-47 

APPENDIX A 

related changes were found at 30 mg/kg/day, indicating that this is the NOAEL for reproductive and 

developmental toxicity in rats. 

As indicated above, liver, kidney, and perinatal developmental toxicity are main effects of concern for 

intermediate-duration oral exposure to 1,4-DCB in animals. The dog is the most sensitive tested species, 

as liver effects were induced by exposure to doses as low as 50 mg/kg/day for 6 months (Naylor and Stout 

1996), which are below subchronic LOAELs of approximately 150–200 mg/kg/day for liver and kidney 

effects in rats and mice. The two-generation study in rats demonstrates that oral exposure to 1,4-DCB can 

cause perinatal developmental toxicity, including reduced birth weight and neonatal survival in F1 and 

F2 pups, at doses >90 mg/kg/day (Bornatowicz et al. 1994). Although this finding indicates that perinatal 

developmental toxicity is an additional sensitive end point for 1,4-DCB exposure, the hepatotoxicity 

induced in dogs at the 50 mg/kg/day dose level (Naylor and Stout 1996) is a more appropriate basis for 

MRL derivation. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

 

 

 

 

 

DICHLOROBENZENES A-48 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,4-Dichlorobenzene (1,4-DCB) 

CAS Numbers: 106-46-7 

Date: August 2006 

Profile Status: Post-Public, Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 61 

Species: Dog 

Minimal Risk Level: [0.07] mg/kg/day [ ] ppm 

References: Naylor MW, Stout LD. 1996. One year study of p-dichlorobenzene administered orally via 

capsule to beagle dogs. Environmental Health Laboratory, Monsanto Company, St. Louis, MO. Study 

No. ML-94-210, March 25, 1996. MRID# 43988802. Unpublished. 

EPA. 1996b. Data Evaluation Record (DER) for p-dichlorobenzene – chronic oral toxicity in dogs 

(MRID# 439888-01 and -02) for Section 6 (a) (2) and reregistration need. U.S. Environmental Protection 

Agency, Office of Prevention, Pesticides and Toxic Substances. 

Experimental design: Groups of five male and five female beagle dogs were orally administered 

1,4-DCB by capsule in dose levels of 0, 10, 50, or 75 mg/kg/day for 1 year. Based on the summarized 

design of a 4-week dose range-finding study, it is presumed that dosing was 5 days/week. The 

75 mg/kg/day dose is a time-weighted average level reflecting dose decreases at the beginning of the 

study in response to unexpected severe toxicity. An initial high dose of 150 mg/kg/day was adjusted to 

100 mg/kg/day for males during week 3, and a further decrease to 75 mg/kg/day was made for both sexes 

at the beginning of week 6. Both high-dose males and females were untreated during weeks 4 and 5 to 

allow for recovery. End points evaluated throughout the study included clinical observations (daily), 

body weight (weekly), and food consumption (weekly). Ophthalmoscopic examinations were performed 

prior to study start and just prior to study completion. Hematology (11 indices, including activated partial 

thromboplastin time), clinical chemistry (18 indices, including ALT, AST, GGTP, AP, and creatinine 

phosphokinase), and urinalysis (10 indices) were performed at month 6 and study completion (month 12). 

Organ weights, gross pathology, and histology were evaluated at month 12. 

Effects noted in study and corresponding doses: Mortality occurred the first 25 days of the study before 

dose reduction; exposure to 150 mg/kg/day caused one male dog to be sacrificed in extremis on day 12, 

one male death on day 25, and one female death on day 24. A control male died on day 83, but all other 

dogs survived to the end of the study. Treatment-related clinical signs were primarily limited to severely 

affected high-dose dogs and the control male that died; these included hypoactivity, dehydration, 

decreased defecation, blood-like fecal color, emesis, emaciation, and/or pale oral mucosa. There were no 

significant group differences in mean body weight at the end of the study. Body weight gain was 

significantly reduced during the first month of the study, but recovered following dose reduction and 

adjustment of food availability. A mild anemia was observed at month 6 (significantly reduced red blood 

cells in females and HCT in males) at 75 mg/kg/day, but resolved by the end of the study. The mild 

anemia correlated with histologic findings of bone marrow erythroid hyperplasia in females, and splenic 

excessive hematopoiesis and megakaryocyte proliferation in both sexes, indicating a compensatory 

response to the earlier anemia. Hepatic effects occurred at ≥50 mg/kg/day in both sexes as shown by 

changes in liver enzymes, increased liver weight, and histopathology. Effects on serum enzyme levels 

included significantly increased AP in males at 50 mg/kg/day at months 6 and 12 (731 and 620% higher 

than controls, respectively), females at 50 mg/kg/day at months 6 and 12 (525 and 330% higher), and 
 

 

DICHLOROBENZENES A-49 

APPENDIX A 

females at 75 mg/kg/day at months 6 and 12 months (761 and 680% higher). Serum AP was also 

increased in males at 75 mg/kg/day after 6 and 12 months, but the changes were not statistically 

significant, possibly due to a reduced group size of 3 males at 75 mg/kg/day. Other clinical chemistry 

findings included significantly increased ALT in females at 75 mg/kg/day at month 12 (253% higher than 

controls), increased GGTP in females at 75 mg/kg/day at months 6 and 12 (131 and 161% higher), and 

decreased albumin in males at 50 and 75 mg/kg/day at month 6 (16 and 18% lower than controls) and 

females at 75 mg/kg/day at month 6 (19% lower). Absolute and relative liver weights were significantly 

increased (40-70% higher than controls) in both sexes at 50 and 75 mg/kg/day (except absolute liver 

weight in 50 mg/kg/day males). Hepatocellular hypertrophy (diffuse or multifocal) occurred in all males 

and females at 50 and 75 mg/kg/day and in one female at 10 mg/kg/day. The study authors (Naylor and 

Stout 1996) considered the hepatocellular hypertrophy (multifocal) in the single 10 mg/kg/day female dog 

to be an adaptive response to a xenobiotic agent rather than a direct treatment-related effect. Other liver 

lesions considered to be treatment-related included hepatocellular pigment deposition (two males and one 

female each at 50 and 75 mg/kg/day), bile duct/ductule hyperplasia (one male and one female at 

75 mg/kg/day), and hepatic portal inflammation (periportal accumulation of neutrophils in one male at 

50 mg/kg/day and two males at 75 mg/kg/day). Kidney effects included collecting duct epithelial 

vacuolation in one male at 75 mg/kg/day and at all dose levels in females (one each at 10 and 

50 mg/kg/day and two at 75 mg/kg/day). The renal lesion was considered to be a possible effect of 

treatment at ≥50 mg/kg/day, because it was accompanied by increased relative kidney weight in females 

at ≥50 mg/kg/day and grossly observed renal discoloration in two females at 75 mg/kg/day. The highest 

NOAEL and lowest LOAEL are 10 and 50 mg/kg/day, respectively, based on the hepatic effects 

(increased liver weight, changes in liver enzymes, and histopathology). 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] BMDL 

As discussed below, a BMDL1sd of 10 mg/kg/day for increased serum AP is used as the basis for the 

MRL. 

BMD analysis was performed on serum AP level and relative liver weight data for the female dogs 

exposed to 1,4-DCB for 1 year. The incidences of hepatocellular hypertrophy in the females (0/5, 1/5, 

5/5, and 5/5 at 0, 10, 50, and 75 mg/kg/day) and males (0/5, 0/5, 5/5, and 5/5) are inappropriate for BMD 

modeling due to actual or effective responses of 0% in the control and low dose groups and 100% in the 

higher dose groups. The response in the low-dose female dog is effectively 0% because the authors 

implied that the hypertrophy in this single animal was not a hepatotoxic response. The incidences of the 

other liver lesions were not subjected to BMD analysis due to the low numbers of responders and group 

sizes. The data that were modeled are shown in Table A-21; the modeling results are shown in 

Table A-22. 
DICHLOROBENZENES A-50 

APPENDIX A 

Table A-21. Selected Liver Effects in Female Dogs Orally Exposed to 

1,4-Dichlorobenzene for 12 Months 

Dose 

(mg/kg/day) 

Group 

size 

Mean serum AP in IU/L 

(percent of control mean) 

Mean relative liver weight in percent 

(percent of control mean) 

0 5 173.40±55.09a 2.71±0.17a 

-- --

10 5 181.80±69.22 3.05±0.83 

(105) (113) 

50 5 745.80c

±329.53 4.20c±0.47 

75 4 

(430) 

1351.75b

±652.46 

(155) 

4.61c±0.70 

(780) (170) 

a

Standard deviation 

b

Significantly different (p<0.05) from control group 

c

Significantly different (p<0.01) from control group 

Source: Naylor and Stout 1996 

Table A-22. Model Predictions for Changes in Serum Alkaline 

Phosphatase Levels in Female Dogs Orally Exposed to 

1,4-Dichlorobenzene for 12 Months 

Model 

Linearb, c

Variance 

p-valuea 

<0.01 

Mean fit 

p-valuea 

0.42 

AIC 

NA 

BMDlsd 

(mg/kg/day) 

NA 

BMDLlsd 

(mg/kg/day) 

NA 

Linearc, d 0.94 <0.01 NA NA NA 

2-Degree 

polynomialc, d 

Powerd

0.94 

0.94 

0.65 

0.65 

215.12 

217.11 

15.40 

14.85 

12.32 

7.42 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria b

Constant variance assumed 

c

Restriction = non-negative 

d

Nonhomogeneous variance assumed 

AIC = Akaike’s Information Criteria; BMD1sd = benchmark dose based on a benchmark response of 1 standard 

deviation above the control mean; BMDL1sd = lower confidence limit (95%) on the BMD1sd; NA = not applicable 

because model failed a goodness-of-fit test 

For the relative liver weight data, the simplest continuous variable model (linear) from the EPA 

Benchmark Dose Software (Version 1.3.2) was initially fit; constant variance was assumed. A BMR of 

1 standard deviation above the control mean was selected in the absence of a biological rationale for using 

an alternative BMR. The model output indicated that a non-homogeneous variance was more appropriate 

for the data set (as indicated by a p-value <0.01 for the test for constant variance). However, using nonhomogeneous variance, inadequately modeled variance resulted (p-value <0.01). Similar inadequate 

results were obtained using the more complex polynomial and power models. The Hill model provided 

inadequate mean fit due to insufficient (0) degrees of freedom. Therefore, the relative liver weight data 

were judged to be unsuitable for benchmark dose analysis due to inadequate modeling of variance. 
 

 

 

 

DICHLOROBENZENES A-51 

APPENDIX A 

For the serum AP data, the simplest continuous variable model (linear) was initially fit; constant variance 

was assumed. A BMR of 1 standard deviation above the control mean was selected in the absence of a 

biological rationale for an alternative BMR. The model output indicated that a non-homogeneous 

variance was more appropriate for the data set (as indicated by a p-value <0.01 for the test for constant 

variance). However, using non-homogeneous variance, inadequate model mean fit was obtained (p-value 

<0.01). The more complex (polynomial, power, and Hill) models for continuous data were also fit to the 

serum AP data. The Hill model provided inadequate mean fit due to insufficient degrees (0) of freedom. 

Adequate mean fit was obtained with both the 2-degree polynomial and power models. Following 

conventional protocol for selection of the point of departure (the adequate model with the lowest AIC, the 

BMDL1sd of 12.32 mg/kg/day (lower 95% confidence limit on the BMD1sd of 15.40 mg/kg/day) was 

selected as the point of departure for deriving the chronic-duration oral MRL (see Table A-22, 

Figure A-9). The BMDL1sd of 12.32 mg/kg/day was rounded to one significant figure (10 mg/kg/day), 

duration adjusted to 7 mg/kg/day, and divided by an uncertainty factor of 100 to derive an MRL of 

0.07 mg/kg/day. 

Figure A-9. Changes in Serum Alkaline Phosphatase Levels in Female Dogs 

Orally Exposed to 1,4-Dichlorobenzene for 12 Months*
 

Polynomial Model with 0.95 Confidence Level 

2500 

2000 

1500 

1000 

500 

0 

Mean Response 

BMDL BMD 

Polynomial 

0 10 20 30 40 50 60 70 80 

dose 

11:54 06/30 2006 

*BMD and BMDL (in mg/kg/day) are associated with 1 standard deviation above the control mean. 

Uncertainty Factors used in MRL derivation: 

[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? Not applicable 

(capsule study). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 
 

 

DICHLOROBENZENES A-52 

APPENDIX A 

Was a conversion used from intermittent to continuous exposure? The BMDL1sd of 10 mg/kg/day was 

adjusted to a continuous exposure scenario as follows: 

 BMDL1sd ADJ = (BMDL1sd) (5days/7 days) 

= (10 mg/kg/day) (5/7) 

= 7 mg/kg/day 

Other additional studies or pertinent information that lend support to this MRL: The NOAEL/LOAEL 

approach to MRL derivation results in the same chronic-duration oral MRL value as the benchmark dose 

approach. Using the NOAEL of 10 mg/kg/day for increased serum AP and other liver effects in dogs 

(Naylor and Stout 1996), the NOAEL is duration-adjusted to 7 mg/kg/day (10 mg/kg/day x 5 days/7 days) 

and divided by the uncertainty factor of 100 to yield an MRL of 0.07 mg/kg/day. 

Additional information on the chronic oral effects of 1,4-DCB is available from one study each in rats, 

mice, and rabbits. Observed effects included nephropathy in rats (including tubular degeneration and 

atrophy in females) exposed to ≥150 mg/kg/day on 5 days/week for 103 weeks (NTP 1987), 

hepatocellular degeneration and nephropathy in mice exposed to ≥300 mg/kg/day on 5 days/week for 

103 weeks (NTP 1987), and cloudy swelling and minimal focal necrosis in rabbits exposed to 

500 mg/kg/day in 263 doses in 367 days (Hollingsworth et al. 1956). The lowest chronic LOAEL in 

these studies was 150 mg/kg/day for kidney effects in female rats (NTP 1987). Liver and kidney effects 

were induced in dogs in the principal study (Naylor and Stout 1996) at doses below the LOAELs in the 

other species. 

Agency Contact (Chemical Manager): Malcolm Williams, DVM, Ph.D. 
 

 

DICHLOROBENZENES 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 
 

 

 

DICHLOROBENZENES B-2 

APPENDIX B 

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. 

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. 
DICHLOROBENZENES 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, 
DICHLOROBENZENES B-4 

APPENDIX B 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "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. 
DICHLOROBENZENES 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. 
 B-6 

1 

SAMPLE 

→ 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) Reference 

2 → INTERMEDIATE EXPOSURE 

5 

3 → Systemic ↓

18 Rat 

→ 4 

CHRONIC EXPOSURE Cancer38 Rat 39 Rat 40 Mouse 

6 7 8 

↓ ↓ ↓13 wk Resp 3b 

5 d/wk6 hr/d18 mo5 d/wk7 hr/d89–104 wk 5 d/wk6 hr/d79–103 wk 5 d/wk6 hr/d 

9

↓

10 (hyperplasia) 

11↓20 (CEL, multiple

organs) 

10 (CEL, lung tumors, 

nasal tumors) 

10 (CEL, lung tumors, 

hemangiosarcomas) 

10

↓

Nitschke et al. 1981 Wong et al. 1982 NTP 1982 NTP 1982 

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 exposure and divided 

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

DICHLOROBENZENES 

APPENDIX B 
DICHLOROBENZENES B-7 

APPENDIX B 
DICHLOROBENZENES B-8 

APPENDIX B 

This page is intentionally blank. 
DICHLOROBENZENES 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 
 

 

DICHLOROBENZENES C-2 

APPENDIX C 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 
 

 

DICHLOROBENZENES C-3 

APPENDIX C 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 
DICHLOROBENZENES C-4 

APPENDIX C 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
DICHLOROBENZENES 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 
DICHLOROBENZENES C-6 

APPENDIX C 

This page is intentionally blank. 
 

 

 

 

DICHLOROBENZENES D-1 

APPENDIX D. INDEX 

absorbed dose............................................................................................................................ 232, 237, 253 

adenocarcinomas........................................................................................................................... 18, 20, 192 

adipose tissue ...............12, 203, 204, 205, 207, 209, 222, 231, 233, 252, 312, 313, 318, 320, 324, 330, 336 

adrenal gland..................................................................................................... 17, 35, 40, 42, 176, 190, 192
 

adrenals .....................................................................................................................................................175 

adsorption.................................................................................................................................. 284, 329, 335 

aerobic....................................................................................................................................... 289, 291, 293 

alanine aminotransferase (see ALT) ................................................................................................... 14, 163 

ALT (see alanine aminotransferase) ............................ 14, 26, 27, 28, 29, 35, 36, 37, 38, 40, 42, 48, 50, 87, 

 160, 161, 162, 163, 164, 165, 169, 223 

ambient air .......................................................................................................... 12, 271, 289, 298, 299, 312
 

anaerobic........................................................................................................................................... 289, 293 

anemia........................................................................... 6, 26, 50, 84, 85, 156, 158, 225, 230, 235, 245, 251 

aspartate aminotransferase (see AST).........................................................................................................16 

AST (see aspartate amino transferase)............................... 16, 26, 27, 28, 35, 36, 37, 40, 42, 44, 48, 50, 87, 

 161, 162, 163, 164, 169 

bioaccumulation.......................................................................................................... 11, 271, 285, 286, 323 

bioconcentration factor ..................................................................................................................... 285, 286 

biodegradation..................................................................................................... 11, 271, 289, 291, 293, 323
 

biomarker .......................................................................................................................... 232, 233, 234, 252 

biomarkers ........................................................................................................ 232, 233, 234, 254, 327, 336
 

blood cell count..................................................................................................................... 24, 84, 157, 158 

body weight effects ............................................................................................................. 93, 179, 180, 245 

breast milk....................15, 202, 203, 204, 205, 207, 222, 231, 233, 252, 254, 315, 316, 318, 321, 324, 325 

cancer ............................................................................ 5, 6, 13, 15, 100, 101, 193, 224, 229, 246, 247, 341 

carcinogen....................................................................................................................... 6, 18, 341, 344, 345 

carcinogenic .............................................. 6, 13, 18, 20, 21, 53, 54, 190, 191, 192, 201, 243, 247, 341, 345 

carcinogenicity.................................................................... 6, 13, 15, 18, 101, 246, 247, 248, 252, 341, 345 

carcinoma.............................................................................................................. 20, 33, 101, 191, 192, 193 

cardiovascular ............................................................................................................................. 82, 153, 154 

cardiovascular effects.................................................................................................................. 82, 153, 154 

chromosomal aberrations .................................................................................................................. 195, 202 

clearance ...................................................................................................................................................216 

death.......................................................................... 32, 50, 53, 77, 102, 151, 152, 178, 193, 194, 239, 243 

deoxyribonucleic acid (see DNA)............................................................................................. 196, 199, 200 

dermal effects.......................................................................................................... 91, 92, 95, 177, 178, 230 

DNA (see deoxyribonucleic acid)...................................... 45, 164, 165, 167, 169, 172, 195, 196, 197, 198, 

199, 200, 201, 207, 231, 232 

endocrine..................................................... 15, 16, 36, 43, 91, 174, 175, 176, 226, 227, 228, 230, 244, 246 

endocrine effects ................................................................................................... 15, 91, 163, 174, 175, 176 

estrogen receptor.......................................................................................................................................227 

estrogenic ..................................................................................................................................................227 

fetal tissue .................................................................................................................................................188 

fetus........................................................................................................................................... 228, 231, 320 

follicle stimulating hormone (see FSH) ....................................................................................................186 

FSH (see follicle stimulating hormone) .................................................................................... 186, 188, 235
 
 

 

DICHLOROBENZENES D-2 

APPENDIX D 

gastrointestinal effects ................................................................................................................ 83, 155, 156 

general population......................................................... 11, 80, 232, 236, 271, 311, 312, 318, 320, 321, 324 

genotoxic............................................................................................. 53, 195, 200, 202, 231, 243, 320, 325 

genotoxicity....................................................................................................... 193, 195, 200, 201, 248, 320
 

groundwater .................................................. 2, 251, 278, 282, 285, 291, 302, 305, 306, 307, 320, 321, 323 

half-life...................................................................................................................... 232, 284, 289, 291, 293 

hematological effects .............................................................................................. 27, 84, 85, 156, 157, 224 

hematopoietic.................................................................................................................. 17, 27, 85, 183, 250
 

hepatic effects ............................ 14, 15, 16, 18, 26, 28, 35, 38, 47, 51, 86, 87, 88, 159, 160, 161, 162, 163, 

 165, 167, 168, 169, 170, 175, 233, 234, 238 

hydrolysis.............................................................................................................. 12, 16, 202, 203, 291, 293 

hydroxyl radical .................................................................................................................. 11, 271, 289, 323 

immune system .........................................................................................................................................250 

immunological .......................................................................... 36, 53, 95, 96, 182, 183, 184, 244, 246, 250 

immunological effects................................................................................................................. 95, 182, 184 

Kow .................................................................................................................................................... 285, 323 

LD50....................................................................................... 16, 35, 102, 151, 194, 202, 206, 222, 234, 244 

leukemia....................................................................................................................................................192 

lymphoreticular................................................................................................................................. 182, 183 

micronuclei ...............................................................................................................................................201 

milk ..................................................................................................... 12, 231, 310, 315, 318, 329, 330, 336 

musculoskeletal effects ......................................................................................................... 85, 86, 158, 159 

neonatal....................................................................................................... 48, 230, 231, 250, 254, 316, 324 

neoplastic .......................................................................................................................................... 101, 248 

neurobehavioral............................................................................................... 17, 20, 47, 189, 227, 230, 250 

neurodevelopmental.......................................................................................................................... 236, 249 

nuclear............................................................................................................................. 27, 28, 87, 157, 225 

octanol-water partition coefficient............................................................................................................285 

ocular effects............................................................................................................................... 92, 178, 179 

partition coefficients ................................................................................................................... 30, 219, 220 

pharmacodynamic.....................................................................................................................................216 

pharmacokinetic.......................................................................................... 34, 216, 217, 218, 225, 228, 254 

photolysis .......................................................................................................................................... 291, 293 

placenta ................................................................................................................................... 7, 12, 231, 254 

rate constant ...................................................................................................................... 219, 220, 221, 291 

renal effects............................................................................................... 45, 89, 90, 91, 170, 171, 174, 248 

retention ............................................................................................................................................ 291, 335 

salivation............................................................................................................................................... 17, 29 

sarcoma ............................................................................................................................................... 33, 101 

serum glutamic oxaloacetic transaminase (see SGOT)...............................................................................33 

serum glutamic pyruvic transaminase (see SGPT) .....................................................................................33 

SGOT (see serum glutamic oxaloacetic transaminase)...............................................................................33 

SGPT (see serum glutamic pyruvic transaminase) .....................................................................................33 

solubility ...................................................................................................................................................223 

thyroid....................................... 6, 15, 17, 42, 43, 44, 91, 174, 175, 176, 187, 188, 192, 227, 236, 244, 245 

toxicokinetic........................................................................................ 53, 194, 231, 244, 246, 248, 252, 254 

tremors ............................................................................................................................ 17, 29, 97, 184, 251 

tumors ....................................................................... 18, 20, 33, 46, 101, 152, 190, 191, 192, 193, 246, 248 

volatilization ............................................................................................. 284, 285, 288, 289, 291, 293, 323 

weanlings .................................................................................................................................... 28, 186, 189