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TOXICOLOGICAL PROFILE FOR 

TRICHLOROBENZENES 

 

 

 

 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry 

September 2010 
 

TRICHLOROBENZENES 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. 

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy. 

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TRICHLOROBENZENES iii 

UPDATE STATEMENT 

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

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch 

1600 Clifton Road NE 

Mailstop F-62 

Atlanta, Georgia 30333 

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TRICHLOROBENZENES iv 

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v 

FOREWORD 


This toxicological profile is prepared in accordance with goidelines developed by the Agency for Toxic 

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

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

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

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

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

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

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

The focus of the profiles is on health and toxicologic infonnation; therefore, each toxicological profile 

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

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

sigoificant human exposure and, where known, sigoificant health effects. The adequacy ofinfonnation to 

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

significance to protection ofpublic health are identified by ATSDR and EPA. 

Each profile includes the following: 

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

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

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

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

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

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

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

of exposure that may present significant risk ofadverse 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. We plan to 

revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series ofthe greatest use. 

Comments should be sent to: 

The Agency for Toxic Substances and Disease Registry 

Division ofToxicology and Environmental Medicine 

Applied Toxicology Branch 

Regolar Mailing Address: Physical Mailing Address: 

1600 Clifton Road, N .E. 4770 Buford Highway 

Mail Stop F -62 Building 106, 8th floor, MS F-62 

Atlanta, Georgia 30333 Chamblee, Georgia 30341 

Electronic Comments should be sent to: TPPublicComments(al.cdc.gov 
VI 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

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

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

authorities" ofthe statute. This includes the preparation of 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 Section 

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

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

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

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

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

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

This profile reflects ATSDR's assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staffs ofthe Centers for Disease Control and Prevention and other federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and is being made available for public review. Final responsibility for the contents and views expressed 

in this toxicological profile resides with ATSDR. 

f"'.. ~~Thomas R. Frieden, M.D., M.P .H. 

Administrator 

Agency for Toxic Substances and 

Disease Registry 
 

 

 

 

TRICHLOROBENZENES vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

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

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

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

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

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

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

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

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

the general health effects observed following exposure. 

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

and assesses the significance of toxicity data to human health. 

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

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

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

reported in this section. 

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

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

following exposure. 

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

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 

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

Section 3.7 Children’s Susceptibility 

Section 6.6 Exposures of Children 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

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

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

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

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

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

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

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TRICHLOROBENZENES 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, 25 Northwest Point Boulevard, Suite 700, Elk 

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

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TRICHLOROBENZENES ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Obaid Faroon, D.V.M., Ph.D. 

Sharon Wilbur, M.A. 

Annette Ashizawa, Ph.D.

Franco Scinicariello, M.D., M.P.H. 

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

Fernando Llados, Ph.D. 

Mario Citra, Ph.D. 

Amber Eade, Ph.D. 

Laura McIlroy, B.A. 

SRC, Inc., North Syracuse, NY 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

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

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

end points. 

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

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

profile, and makes recommendations for derivation of MRLs. 

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

consistency across profiles and adherence to instructions in the Guidance. 

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

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TRICHLOROBENZENES xi 

PEER REVIEW 

A peer review panel was assembled for trichlorobenzenes. The panel consisted of the following 

members: 

1.	 Ralph L. Kodell, Ph.D., Professor, Department of Biostistics, University of Arkansas for Medical 

Sciences, Little Rock, Arkansas; 

2.	 Richard J. Bull, Ph.D., President, MoBull Consulting, Richland Washington; and 

3.	 James E. Klaunig, Ph.D., Professor and Chair, Department of Environmental Health, School of 

Public Health, Indiana University at Bloomington, Indiana. 

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

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

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

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

and Liability Act, as amended. 

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

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

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

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

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

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

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TRICHLOROBENZENES xii 

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CONTENTS 

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

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

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

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

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

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

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

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

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

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

1.1 WHAT ARE TRICHLOROBENZENES?..................................................................................... 2 

1.2 WHAT HAPPENS TO TRICHLOROBENZENES WHEN THEY ENTER THE 

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

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

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

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

1.6 HOW CAN TRICHLOROBENZENES AFFECT CHILDREN?.................................................. 5 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 

TRICHLOROBENZENES?........................................................................................................... 5 

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

EXPOSED TO TRICHLOROBENZENES?.................................................................................. 6 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? ................................................................................................... 6 

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

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

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO 

TRICHLOROBENZENES IN THE UNITED STATES ............................................................... 9 

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

2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 13 

3. HEALTH EFFECTS.............................................................................................................................. 31 

3.1 INTRODUCTION........................................................................................................................ 31 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................... 31 

3.2.1 

3.2.1.1 

Inhalation Exposure ............................................................................................................ 32 

 Death............................................................................................................................... 32 

3.2.1.2 

3.2.1.3 

3.2.1.4 

3.2.1.5 

3.2.1.6 

3.2.1.7 

Systemic Effects.............................................................................................................. 32 

Immunological and Lymphoreticular Effects ................................................................. 49 

Neurological Effects ....................................................................................................... 50 

Reproductive Effects....................................................................................................... 50 

Developmental Effects.................................................................................................... 51 

 Cancer............................................................................................................................. 51 

3.2.2 

3.2.2.1 

Oral Exposure ..................................................................................................................... 51 

Death ............................................................................................................................... 51 

3.2.2.2 

3.2.2.3 

Systemic Effects.............................................................................................................. 52 

Immunological and Lymphoreticular Effects ................................................................. 90 

TRICHLOROBENZENES xiii 

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3.2.2.4 Neurological Effects ....................................................................................................... 90 

3.2.2.5 Reproductive Effects....................................................................................................... 91 

3.2.2.6 Developmental Effects.................................................................................................... 92 

3.2.2.7 Cancer ............................................................................................................................. 93 

3.2.3 Dermal Exposure................................................................................................................. 94 

3.2.3.1 Death ............................................................................................................................... 94 

3.2.3.2 Systemic Effects............................................................................................................ 100 

3.2.3.3 Immunological and Lymphoreticular Effects ............................................................... 106 

3.2.3.4 Neurological Effects ..................................................................................................... 106 

3.2.3.5 Reproductive Effects..................................................................................................... 106 

3.2.3.6 Developmental Effects.................................................................................................. 106 

3.2.3.7 Cancer ........................................................................................................................... 106 

3.3 GENOTOXICITY...................................................................................................................... 107 

3.4 TOXICOKINETICS................................................................................................................... 112 

3.4.1 Absorption......................................................................................................................... 113 

3.4.1.1 Inhalation Exposure ...................................................................................................... 113 

3.4.1.2 Oral Exposure ............................................................................................................... 113 

3.4.1.3 Dermal Exposure........................................................................................................... 115 

3.4.2 Distribution ....................................................................................................................... 115 

3.4.2.1 Inhalation Exposure ...................................................................................................... 115 

3.4.2.2 Oral Exposure ............................................................................................................... 115 

3.4.2.3 Dermal Exposure........................................................................................................... 117 

3.4.3 Metabolism ....................................................................................................................... 117 

3.4.4 Elimination and Excretion ................................................................................................ 121 

3.4.4.1 Inhalation Exposure ...................................................................................................... 122 

3.4.4.2 Oral Exposure ............................................................................................................... 122 

3.4.4.3 Dermal Exposure........................................................................................................... 124 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ......... 124 

3.5 MECHANISMS OF ACTION ................................................................................................... 125 

3.5.1 Pharmacokinetic Mechanisms........................................................................................... 125 

3.5.2 Mechanisms of Toxicity.................................................................................................... 128 

3.5.3 Animal-to-Human Extrapolations..................................................................................... 128 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS........................... 129 

3.7 CHILDREN’S SUSCEPTIBILITY............................................................................................ 130 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT..................................................................... 132 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Trichlorobenzenes....................... 133 

3.8.2 Biomarkers Used to Characterize Effects Caused by Trichlorobenzenes......................... 133 

3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 133 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE................................................ 134 

3.11 METHODS FOR REDUCING TOXIC EFFECTS ................................................................... 134 

3.11.1 Reducing Peak Absorption Following Exposure .............................................................. 134 

3.11.2 Reducing Body Burden..................................................................................................... 135 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects............................................ 135 

3.12 ADEQUACY OF THE DATABASE ........................................................................................ 135 

3.12.1 Existing Information on Health Effects of Trichlorobenzenes ......................................... 136 

3.12.2 Identification of Data Needs ............................................................................................. 136 

3.12.3 Ongoing Studies................................................................................................................ 148 

4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 149 

4.1 CHEMICAL IDENTITY ........................................................................................................... 149 

4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 149 

TRICHLOROBENZENES xiv 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL.......................................................... 153 

5.1 PRODUCTION .......................................................................................................................... 153 

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

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

5.4 DISPOSAL................................................................................................................................. 157 

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

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

6.2 RELEASES TO THE ENVIRONMENT................................................................................... 163 

6.2.1 Air ..................................................................................................................................... 164 

6.2.2 Water................................................................................................................................. 167 

6.2.3 Soil .................................................................................................................................... 168 

6.3 ENVIRONMENTAL FATE ...................................................................................................... 169 

6.3.1 Transport and Partitioning ................................................................................................ 169 

6.3.2 Transformation and Degradation ...................................................................................... 172 

6.3.2.1 Air ................................................................................................................................. 172 

6.3.2.2 Water............................................................................................................................. 172 

6.3.2.3 Sediment and Soil ......................................................................................................... 173 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT.................................. 174 

6.4.1 Air ..................................................................................................................................... 174 

6.4.2 Water................................................................................................................................. 174 

6.4.3 Sediment and Soil ............................................................................................................. 181 

6.4.4 Other Environmental Media.............................................................................................. 181 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE........................................ 183 

6.6 EXPOSURES OF CHILDREN.................................................................................................. 186 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 187 

6.8 ADEQUACY OF THE DATABASE ........................................................................................ 187 

6.8.1 Identification of Data Needs ............................................................................................. 187 

6.8.2 Ongoing Studies................................................................................................................ 190 

7. ANALYTICAL METHODS ............................................................................................................... 191 

7.1 BIOLOGICAL MATERIALS.................................................................................................... 191 

7.2 ENVIRONMENTAL SAMPLES .............................................................................................. 193 

7.3 ADEQUACY OF THE DATABASE ........................................................................................ 195 

7.3.1 Identification of Data Needs ............................................................................................. 195 

7.3.2 Ongoing Studies................................................................................................................ 196 

8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 197 

9. REFERENCES .................................................................................................................................... 205 

10. GLOSSARY ...................................................................................................................................... 221 

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 

TRICHLOROBENZENES xv 

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LIST OF FIGURES 

3-1. Levels of Significant Exposure to 1,2,4-Trichlorobenzene-Inhalation .............................................. 39 

3-2. Levels of Significant Exposure to 1,3,5-Trichlorobenzene-Inhalation............................................... 44 

3-3. Levels of Significant Exposure to 1,2,4-Trichlorobenzene-Oral........................................................ 67 

3-4. Levels of Significant Exposure to 1,2,3-Trichlorobenzene-Oral........................................................ 74 

3-5. Levels of Significant Exposure to 1,3,5-Trichlorobenzene-Oral........................................................ 80 

3-6. Hypothesized Metabolic Pathways for Trichlorobenzene Isomers Through Arene Oxide 

Intermediates.................................................................................................................................... 119 

3-7. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance.................................................................................................... 126 

3-8. Existing Information on Health Effects of 1,2,3-Trichlorobenzene ................................................. 137 

3-9. Existing Information on Health Effects of 1,2,4-Trichlorobenzene ................................................. 138 

3-10. Existing Information on Health Effects of 1,3,5-Trichlorobenzene ............................................... 139 

6-1. Frequency of NPL Sites with 1,2,3-Trichlorobenzene Contamination............................................. 160 

6-2. Frequency of NPL Sites with 1,2,4-Trichlorobenzene Contamination............................................. 161 

6-3. Frequency of NPL Sites with 1,3,5-Trichlorobenzene Contamination............................................. 162 

TRICHLOROBENZENES xvii 

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TRICHLOROBENZENES xix 

LIST OF TABLES 

2-1. Summary of End Points Modeled in 13-Week Studies ...................................................................... 23 

2-2. Incidence of Liver Lesions in Rats in a 104-Week Dietary Study ..................................................... 25 

3-1. Levels of Significant Exposure to 1,2,4-Trichlorobenzene-Inhalation ............................................. .34 

3-2. Levels of Significant Exposure to 1,3,5-Trichlorobenzene-Inhalation............................................... 42 

3-3. Levels of Significant Exposure to 1,2,4-Trichlorobenzene-Oral........................................................ 53 

3-4. Levels of Significant Exposure to 1,2,3-Trichlorobenzene-Oral........................................................ 70 

3-5. Levels of Significant Exposure to 1,3,5-Trichlorobenzene-Oral........................................................ 76 

3-6. Levels of Significant Exposure to 1,2,4-Trichlorobenzene-Dermal................................................... 95 

3-7. Levels of Significant Exposure to 1,2,3-Trichlorobenzene-Dermal................................................. 101 

3-8. Levels of Significant Exposure to 1,3,5-Trichlorobenzene-Dermal................................................. 102 

3-9. Genotoxicity of Trichlorobenzenes In Vitro..................................................................................... 108 

3-10. Genotoxicity of Trichlorobenzenes In Vivo.................................................................................... 111 

4-1. Chemical Identity of Trichlorobenzenes .......................................................................................... 150 

4-2. Physical and Chemical Properties of Trichlorobenzenes ................................................................. 151 

5-1. Facilities that Produce, Process, or Use 1,2,4-Trichlorobenzene ..................................................... 154 

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

1,2,4-Trichlorobenzene .................................................................................................................... 165 

6-2. Emissions of 1,2,4-Trichlorobenzene in 2005.................................................................................. 166 

6-3. Measured Bioconcentration Factors (BCF) of Trichlorobenzenes in Carp ...................................... 170 

6-4. 1,2,4-Trichlorobenzene Air Levels at Monitoring Stations Throughout the United States 

in 2008 ............................................................................................................................................. 175 

6-5. The Range and Mean Concentration of Trichlorobenzene Isomers in Sediment Samples 

Obtained From the Great Lakes ....................................................................................................... 182 

6-6. Trichlorobenzene Concentrations in Whole Vegetables .................................................................. 184 

7-1. Analytical Methods for Determining Trichlorobenzenes in Biological Samples............................. 192 

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7-2. Analytical Methods for Determining Trichlorobenzenes in Environmental Samples...................... 194 

8-1. Regulations and Guidelines Applicable to Trichlorobenzenes......................................................... 198 

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TRICHLOROBENZENES 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about trichlorobenzenes 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. 1,2,3-Trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene 

have been identified in 31, 187, and 4 of the 1,699 hazardous waste sites, respectively. Although the 

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

number of sites at which trichlorobenzenes 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 be harmful. 

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

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

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

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

If you are exposed to trichlorobenzenes, 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. 

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TRICHLOROBENZENES 2 

1. PUBLIC HEALTH STATEMENT 

1.1 WHAT ARE TRICHLOROBENZENES? 

Description Trichlorobenzenes are human-made compounds that occur in 

three different chemical forms. Although they have the same 

molecular weight and molecular formula, they differ structurally 

by where the chlorine atoms are attached to the benzene ring. 

Compounds like these are referred to as isomers. Drawings of 

the three different isomers are shown in Chapter 4. 

1,2,3-Trichlorobenzene and 1,3,5-trichlorobenzene are 

colorless solids, while 1,2,4-trichlorobenzene is a colorless 

liquid. 

Although the three isomers of trichlorobenzene are structurally 

similar, they each may have different chemical and toxicological 

properties. 

Uses Trichlorobenzenes have primarily been used as solvents and 

chemical intermediates to produce other compounds. In the 

past, mixed isomers of trichlorobenzene had been used for 

termite control, but this is not a current use. One of the isomers 

(1,2,4-trichlorobenzene) is produced in large quantities and is 

used as a solvent to dissolve such special materials as oils, 

waxes, resins, greases, and rubber. It is also frequently used 

to produce dyes and textiles. The other two isomers, 

1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene, are 

produced in lower quantities and have fewer uses. 

1.2 WHAT HAPPENS TO TRICHLOROBENZENES WHEN THEY ENTER THE 

ENVIRONMENT? 

Air Trichlorobenzenes are volatile substances and may therefore 

partition to air when released to the environment. The half-life 

(the time it takes for 50% of the compound to degrade) of 

trichlorobenzenes in air is about 1 month. 

Water Trichlorobenzenes have been detected in groundwater, 

drinking water, and surface water (rivers and lakes). 

Trichlorobenzenes have a tendency to evaporate over time 

from water, but can also adsorb to suspended solids and 

sediment in water. 

Soil and sediment Trichlorobenzenes evaporate from soils and are slowly broken 

down by microorganisms in soil and sediment. 

Animals and fish Trichlorobenzenes in water and soil may be absorbed or 

ingested by animals and fish. High levels of trichlorobenzenes 

are often detected in fish or other species living in 

contaminated waters because trichlorobenzenes can 

accumulate in fatty tissues. 

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TRICHLOROBENZENES 3 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO TRICHLOROBENZENES? 

Environmental exposure Monitoring data suggest that the general population may be 

exposed to trichlorobenzenes by inhaling air and through the 

ingestion of food and drinking water. Other substances that 

have been released into the environment, such as higher 

chlorinated benzenes, or the formerly used pesticide, lindane, 

can break down into trichlorobenzene. Therefore, if you live in 

an area where these products were used or disposed of 

(hazardous waste sites) you may potentially be exposed to 

trichlorobenzenes as well. 

Ingestion of food and fish Trichlorobenzenes have been identified in a variety of food 

items including vegetables, milk, eggs/meat, and oils produced 

from corn, soybeans, peanuts, walnuts, hazelnuts, and rape, 

sunflower, sesame, and poppy seeds. People who eat large 

quantities of fish from areas contaminated by trichlorobenzenes 

may have higher exposure to these substances since fish tend 

to accumulate trichlorobenzenes in their fatty tissues. 

Occupational exposure You can be exposed to trichlorobenzenes by inhalation and 

dermal contact with these substances if you are employed in an 

occupation where trichlorobenzenes are manufactured or used. 

According to the National Occupational Exposure Survey 

(NOES), workers employed in textile mill production and 

electric and electronic manufacturing tend to have the greatest 

potential exposure to trichlorobenzenes. 

1.4 HOW CAN TRICHLOROBENZENES ENTER AND LEAVE MY BODY? 

Enter the body There is not enough information to determine how much or how 

fast trichlorobenzenes can enter your body if you inhale vapors 

or contaminated air, if you swallow these chemicals, or if they 

get onto your skin. 

Studies in animals suggest that trichlorobenzenes can rapidly 

enter the body through the lungs and the gastrointestinal tract. 

Less is known about entering the body through the skin. 

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TRICHLOROBENZENES 4 

1. PUBLIC HEALTH STATEMENT 

Leave the body There is no information on how these compounds could leave 

the body in humans, but based on studies in animals, they 

probably leave principally in the urine. 

In animals, trichlorobenzenes are transformed in the body into 

other chemicals, which are eliminated in the urine, feces, and 

bile in a few days. 

Studies in animals suggest that trichlorobenzenes do not 

accumulate in the body of mammals, but accumulate in fish. 

1.5 HOW CAN TRICHLOROBENZENES AFFECT MY HEALTH? 

This section looks at studies concerning potential health effects in animal and human studies. 

Effects in humans There is virtually no information regarding health effects of 

trichlorobenzenes in humans other than reports of minimal eye 

and throat irritation in certain people exposed to vapors of 

1,2,4-trichlorobenzene and a report of a woman who developed 

a blood disorder due to prolonged inhalation of 

trichlorobenzenes from her husband’s work clothes. 

However, based on results from studies in animals, it is 

reasonable to predict that humans exposed to high amounts of 

trichlorobenzenes may develop liver problems. 

Laboratory animals Studies in animals indicate that oral administration of 

trichlorobenzenes for short or long periods produces mainly 

alterations in the liver and kidneys. 

Prolonged administration of 1,2,4-trichlorobenzene to rats did 

not affect their capacity to reproduce. 

Placing trichlorobenzenes on the skin or the eyes of animals 

produced transitory irritation. 

It should be noted that, in general, animals have been exposed 

to considerably higher amounts of trichlorobenzenes than the 

amounts that humans can encounter in the environment. 

Cancer There are no studies of cancer in humans exposed to 

trichlorobenzenes. 

Mice given 1,2,4-trichlorobenzene in the food for 2 years 

developed cancer of the liver. 

The EPA has stated that 1,2,4-trichlorobenzene is not 

classifiable as to human carcinogenicity. However, this was 

based on studies conducted prior to 1990; newer information 

has not been evaluated. 

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TRICHLOROBENZENES 5 

1. PUBLIC HEALTH STATEMENT 

1.6 HOW CAN TRICHLOROBENZENES AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

Effects in children There are no studies of children exposed to trichlorobenzenes. 

Laboratory animals For the most part, studies in rats and mice given 1,2,4-trichlorobenzene during pregnancy have not found adverse effects in 

their pups at birth or later during the growing period. However, 

a study in rats found lesions in the eyes of the pups. 

Breast milk Trichlorobenzenes have been found in human breast milk, 

which means that mothers can transfer these chemicals to their 

babies by nursing. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 

TRICHLOROBENZENES? 

Avoid sources of 

trichlorobenzenes 

Trichlorobenzenes do not have widespread use in consumer 

products that are readily available to the general public. 

However, 1,2,4-trichlorobenzene is often detected in air, water, 

and aquatic species such as fish. The highest levels are 

typically encountered near facilities that manufacture and use 

trichlorobenzenes and other chlorinated substances or 

hazardous waste sites at which these substances may have 

been disposed of. Avoiding these areas will reduce your risk of 

exposure to trichlorobenzenes and other chemicals. 

Avoiding high consumption of root crops and fish living in 

contaminated environments will reduce the risk of exposure. 

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TRICHLOROBENZENES	 6 

1. PUBLIC HEALTH STATEMENT 

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

TRICHLOROBENZENES? 

Detecting exposure Trichlorobenzenes can be measured in blood and body fat, but 

the tests used are not routinely available in the doctor’s office. 

There is not enough information to determine whether 

trichlorobenzenes detected in your body indicate that you have 

been exposed recently to a high amount or you are 

continuously exposed to lower amounts. 

Measuring exposure Detecting trichlorobenzenes in your body generally means that 

you were exposed to these compounds. However, detecting 

breakdown products of trichlorobenzenes may mean that you 

were exposed to trichlorobenzenes or that you were exposed to 

other chemicals that produce the same breakdown products. 

The presence of trichlorobenzenes in your body does not 

necessarily mean that you will suffer adverse health effects. 

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. These are levels of a toxic 

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

on levels that affect animals; they are then adjusted to levels that will help protect humans. Sometimes 

these not-to-exceed levels differ among federal organizations because they used different exposure times 

(an 8-hour workday or a 24-hour day), different animal studies, or other factors. 

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

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

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TRICHLOROBENZENES 7 

1. PUBLIC HEALTH STATEMENT 

Some regulations and recommendations for trichlorobenzenes include the following: 

Levels in drinking water set 

by EPA 

The EPA has determined that exposure to 1,2,4-trichlorobenzene and 1,3,5-trichlorobenzene in drinking water at 

concentrations of 0.1 and 0.6 milligrams per liter (mg/L), 

respectively, for 1 or 10 days is not expected to cause any 

adverse effects in a child. 

The EPA has determined that lifetime exposure to 0.07 mg/L 

1,2,4-trichlorobenzene and 0.04 mg/L 1,3,5-trichlorobenzene is 

not expected to cause any adverse effects. 

EPA established a maximum contaminant level (MCL) of 

0.07 mg/L for 1,2,4-trichlorobenzene in drinking water. 

Bottled water The FDA has determined that the concentration of 

1,2,4-trichlorobenzene in bottled drinking water should not 

exceed 0.7 mg/L. 

1.10 WHERE CAN I GET MORE INFORMATION? 

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

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

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

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

substances. 

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

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

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

to: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Environmental Medicine 

1600 Clifton Road NE 

Mailstop F-62 

Atlanta, GA 30333 

Fax: 1-770-488-4178 

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TRICHLOROBENZENES 8 

1. PUBLIC HEALTH STATEMENT 

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/ 

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TRICHLOROBENZENES 9 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO TRICHLOROBENZENES IN 

THE UNITED STATES 

The manufacture and use of trichlorobenzenes as solvents, chemical intermediates, and dye carriers 

(Rossberg et al. 2006) has led to their release into the environment. Trichlorobenzenes may also be 

released into the environment indirectly from the degradation of higher chlorinated benzenes 

(tetrachlorobenzene, pentachlorobenzene, and hexachlorobenzene) and the pesticide lindane 

(γ-hexachlorocyclohexane). They may also be present as a minor impurity in other chlorinated 

substances and are formed unintentionally during the combustion of organic materials when chlorine is 

present (for example during the incineration of wastes containing polyvinyl chloride). 

Trichlorobenzenes are volatile substances that are relatively persistent in the environment. They are 

expected to possess low mobility in soil and generally do not leach into groundwater except in the case of 

a large spill or their subsurface disposal at hazardous waste sites. Volatilization is considered an 

important environmental fate process in soils and water; however, their tendency to adsorb to soil and 

sediment may attenuate the rate of volatilization. In the atmosphere, trichlorobenzenes degrade through 

their reaction with photochemically-generated hydroxyl radicals. The half-life for this reaction in air is 

approximately 16–38 days. In soil and water, trichlorobenzenes degrade slowly under aerobic conditions 

but undergo reductive dechlorination resulting in the formation of mono- and dichlorobenzenes as 

degradation products under methanogenic conditions. 

1,2,4-Trichlorobenzene is one of 188 chemicals that is designated as a hazardous air pollutant (HAP) 

under the Clean Air Act. Monitoring data from 2008 indicate that average atmospheric levels in the 

United States are typically less than 1 part per billion by volume (<1 ppbv); however, maximum levels 

above 3 ppbv have been observed. In atmospheric samples, 1,2,3- and 1,3,5-trichlorobenzene are 

detected less frequently than 1,2,4-trichlorobenzene since they have fewer uses and subsequently fewer 

direct emissions. Trichlorobenzenes are detected infrequently in groundwater unless a large spill occurs 

to a soil surface. Both 1,2,3- and 1,2,4-trichlorobenzene were monitored for, but not detected in, aquifer 

samples in a comprehensive survey conducted by the U.S. Geological Survey (USGS) of volatile organic 

compounds in private and public groundwater wells used for drinking water. Neither isomer was detected 

in samples obtained from nearly 2,000 public and private wells across the United States. Municipal 

drinking water samples have occasionally been shown to contain low levels of trichlorobenzenes at the 

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TRICHLOROBENZENES 10 

2. RELEVANCE TO PUBLIC HEALTH 

parts per trillion levels. Trichlorobenzenes have been detected in fish and wildlife, particularly in the 

vicinity of chemical manufacturing plants that produce chlorinated substances. They have also been 

detected in various food items. Leafy vegetables, fruits, milk, and eggs/meat purchased at grocery stores 

in Canada contained trichlorobenzene levels of 0.11–0.40, 0.12–0.14, 0.14–1.2, and 0.70–0.74 μg/kg,

respectively. 

The general population is exposed to trichlorobenzene from inhalation of ambient air and ingestion of 

food and drinking water. In a European Union Risk Assessment Report for 1,2,4-trichlorobenzene, the 

total daily intake was calculated as 0.0715 mg/kg/day for the exposure scenario which yielded the highest 

estimated total daily intake for humans. The estimates suggest that the most important human intake 

routes are ingestion of root crops, fish, and drinking water. Occupational exposure may occur through 

inhalation and dermal exposure where trichlorobenzenes are produced or used. Chapter 7 provides details 

of analytical methods used to determine whether exposure to trichlorobenzenes has occurred; however, 

not enough data are available to determine what baseline levels are in human tissues. 

2.2 SUMMARY OF HEALTH EFFECTS 

There is very limited information regarding health effects in humans following exposure to 

trichlorobenzenes. A review of the literature indicates that an adult male who inhaled trichlorobenzene 

for several hours during the repair of a pump suffered massive hemoptysis (blood-stained sputum), and 

that some trichlorobenzene production workers developed chloroacne. There is also a case report of 

aplastic anemia in a woman with prolonged exposure through the soaking of her husband’s work clothes 

in trichlorobenzene. None of these reports provided exposure details or specified the isomer involved. 

Citing an unpublished source, the American Conference of Governmental Industrial Hygienists (ACGIH) 

stated that minimal eye and throat irritation could occur in some people exposed to 3–5 ppm 

1,2,4-trichlorobenzene. This information is insufficient to determine a clear target for trichlorobenzenes 

in humans. However, based on information from effects of other chlorinated benzenes in humans, and 

from limited information on the metabolism of 1,2,4-trichlorobenzene by microsomal preparations from 

human livers that indicated that cytochrome P-450 enzymes might be involved in the metabolism of 

trichlorobenzenes, it is reasonable to assume that excessive exposure to trichlorobenzenes could induce 

liver effects such as porphyria in humans. 

Studies have been conducted in animals exposed to trichlorobenzenes by the inhalation, oral, and dermal 

routes. 1,2,4-Trichlorobenzene has been the most extensively studied of the three trichlorobenzene 

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TRICHLOROBENZENES 11 

2. RELEVANCE TO PUBLIC HEALTH 

isomers. Repeated inhalation studies in multiple species exposed to up to 100 ppm 1,2,4-trichlorobenzene 

showed the liver to be a target, and rats appeared to be more sensitive than other species. Liver effects 

consisted mostly of increases in liver weight not accompanied by histological alterations. Exposure to 

30 or 100 ppm 1,2,4-trichlorobenzene also increased the urinary excretion of porphyrins in rats. No target 

could be identified for 1,3,5-trichlorobenzene in rats in the only 13-week inhalation study located for this 

isomer. No inhalation data were located for 1,2,3-trichlorobenzene. 

Trichlorobenzenes produced transitory irritation of the skin of animals when applied for short periods of 

time. As the duration of exposure increases, the severity of the effects also increases. Trichlorobenzenes 

also produced transitory eye irritation when instilled into the eyes of rabbits for short periods of time. 

Considerable more data are available in animals exposed orally to trichlorobenzenes. Significantly more 

information is available for 1,2,4-trichlorobenzene than for the other two isomers. Acute- , intermediate- , 

and chronic-duration studies showed that the liver and kidneys are targets for 1,2,4-trichlorobenzene in 

rats. The liver was also the target for 1,2,4-trichlorobenzene in mice in an intermediate-duration study. 

Liver changes included increases in the weight of the organ and histological alterations consisting of 

periportal cytoplasmic eosinophilia and anisokaryosis (variation in size) of hepatocellular nuclei in acuteduration studies in rats dosed with ≥150 mg/kg/day 1,2,4-trichlorobenzene or ≥300 mg/kg/day 1,2,3- or 

1,3,5-trichlorobenzene. Liver necrosis was reported in a 10-day study in rats dosed with 500 mg/kg/day 

1,2,4-trichlorobenzene. Moderate liver histopathology was reported in rats dosed with ≥49 mg/kg/day of 

the trichlorobenzene isomers for 90 days. Extending the duration of exposure to 1,2,4-trichlorobenzene to 

2 years resulted in increased incidences of various lesions including hepatocellular hypertrophy, focal 

cystic degeneration, and diffuse fatty change in rats. No chronic-duration studies were located with the 

other two trichlorobenzene isomers. 

In addition to inducing morphological alterations in the liver, 1,2,4-trichlorobenzene has been shown to 

be a potent inducer of phase I and phase II metabolic enzymes. In addition, in rats, 1,2,4-trichlorobenzene 

induces δ-aminolevulinic acid (ALA) synthetase, the rate-limiting enzyme in the biosynthesis of heme, 

which is consistent with the development of porphyria in rats administered 1,2,4-trichlorobenzene. 

Studies by Kato and coworkers have shown that both the induction of drug-metabolizing enzymes and 

ALA synthetase are not due to 1,2,4-trichlorobenzene itself but to its metabolite, 2,3,5-trichlorophenyl 

methyl sulfone. 

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TRICHLOROBENZENES 12 

2. RELEVANCE TO PUBLIC HEALTH 

Kidney lesions were observed in male rats dosed with 144 mg/kg/day 1,2,4-trichlorobenzene for 

13 weeks. The lesions consisted of dilated tubules, granular casts, hyaline droplets, and papillary mineral 

deposition. Also increased was the incidence or severity of interstitial nephritis and regenerative tubular 

epithelium. These lesions, particularly the hyaline droplets, are consistent with a α2μ-globulin 

nephropathy induced by a variety of organic chemicals in male rats. Increased incidences of transitional 

renal cell hyperplasia and renal papilla mineralization were reported in male rats dosed with 

66.5 mg/kg/day 1,2,4-trichlorobenzene for 104 weeks. This is also consistent with the occurrence of 

male-specific nephropathy. None of these lesions were seen in female rats or in mice. 1,3,5-Trichlorobenzene was also reported to induce renal lesions in rats in a 13-week study. The alterations were also 

consistent with the male-specific nephropathy and were characterized by eosinophilic inclusions, 

enlargement and anisokaryosis of the epithelial lining cells, and hyperplasia of renal tubular epithelial 

cells. 

Less clear than the effects on the liver and on the kidneys of male rats are reported alterations on the 

thyroid of rats induced by trichlorobenzenes. The three trichlorobenzene isomers reportedly induced mild 

histological changes in the thyroid from pregnant female rats administered the chemicals on gestation 

days (Gd) 6–15 and sacrificed on Gd 22. The alterations occurred with doses ≥300 mg/kg/day and were 

characterized as reductions in follicle size and increased epithelial height accompanied by cytoplasmic 

vacuolization. Similar findings were reported in rats dosed with 78–82 mg/kg/day trichlorobenzenes for 

13 weeks. However, neither study showed the data or provided quantitative analyses of the lesions that 

would have helped determine whether differences between dose groups were statistically significant. A 

13-week study in rats that used comparable doses and a 104-week study in rats that provided quantitative 

data did not report treatment-related histological alterations in the thyroid. Intermediate- and chronicduration studies in mice also did not report histological changes in the thyroid. None of these studies 

measured levels of thyroid hormones or thyrotrophin (TSH) in blood. 

1,2,4-Trichlorobenzene did not affect fertility in rats in a multi-generation reproductive study. None of 

the intermediate-duration oral, inhalation, or dermal studies conducted with trichlorobenzenes reported 

treatment-related histological alterations in the reproductive organs of male and female animals. Most 

studies that examined whether 1,2,4-trichlorobenzene is a developmental toxicant reported negative 

results. The only effects reported were the presence of microscopic alterations in the lenses of the eye of 

fetuses from rats treated with 150 mg/kg/day 1,2,4-trichlorobenzene on Gd 6–15 and sacrificed on Gd 22. 

However, no lesions were observed in fetuses from dams dosed with 75 or 300 mg/kg/day 1,2,4-trichlorobenzene. This lesion was also observed in fetuses from dams dosed with 150, 300, or 600 mg/kg/day 

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TRICHLOROBENZENES 13 

2. RELEVANCE TO PUBLIC HEALTH 

1,3,5-trichlorobenzene. Since no quantitative data were presented, it is not known whether the incidences 

were dose-related. The lesion was characterized as central areas of cellular disorientation and 

disaggregation with ballooning and granular degeneration. Another gestational exposure study reported 

retarded development of the fetuses from rats dosed with 360 mg/kg/day 1,2,4-trichlorobenzene on Gd 9– 

13 and sacrificed on Gd 14. This dose level was lethal to two out of nine dams and induced significant 

weight loss in dams that survived. In studies of pregnant mice dosed with 0 or 130 mg/kg/day 

1,2,4-trichlorobenzene on Gd 8–12, the chemical did not affect pup’s viability or growth or offspring’s 

locomotor activity or fertility to produce a second generation. 

1,2,4-Trichlorobenzene did not significantly increase the incidence of malignancies in rats fed a diet that 

provided up to 66.5 mg/kg/day to males or 81.4 mg/kg/day to females. However, it did increase the 

incidence of hepatocellular carcinoma in mice fed a diet that provided ≥100.6 mg/kg/day to males and 

≥127 mg/kg/day to females for 104 weeks. A dermal bioassay was also conducted with 1,2,4-trichlorobenzene in mice. Tumors developed in the lungs, kidneys, stomach, urinary bladder, mammary gland, 

and skin in both treated and control groups. Several limitations of this study rendered it inadequate for 

assessing the potential carcinogenicity of 1,2,4-trichlorobenzene following dermal exposure. EPA 

classified 1,2,4-trichlorobenzene in Group D: not classifiable as to human carcinogenicity, or as a 

chemical for which there is “Inadequate Information to Assess Carcinogenic Potential” according to the 

Guidelines for Carcinogen Risk Assessment. EPA’s classification was done in 1988 and was last revised 

in 1991. No cancer studies were available for 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene. 

2.3 MINIMAL RISK LEVELS (MRLs) 

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

trichlorobenzenes. An MRL is defined as an estimate of daily human exposure to a substance that is 

likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of 

exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of 

effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. 

MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can 

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

Appropriate methodology does not exist to develop MRLs for dermal exposure. 

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

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

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TRICHLOROBENZENES 14 

2. RELEVANCE TO PUBLIC HEALTH 

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 

1,2,4-Trichlorobenzene 

Acute-Duration MRL. No relevant human data were located for 1,2,4-trichlorobenzene. The only data 

in animals is that exposure of rats (2–4/sex) to ≥70 ppm for 6 hours caused lethargy and initial lacrimation

(Gage 1970), and that exposure of two rats to an average concentration of 293 ppm of 1,2,4-trichlorobenzene vapors 6 hours/day for 12 days did not cause gross or microscopic alterations in unspecified 

organs (E.I. Dupont 1971). This information is insufficient for MRL derivation. 

Intermediate-Duration MRL. No relevant human data were located. Several intermediate-duration 

studies in various species are available. Continuous exposure of cynomolgous monkeys (9 males/group), 

Sprague-Dawley rats (30 males/group) rats, or New Zealand rabbits (16 males/group) to 0, 25, 50, or 

100 ppm 1,2,4-trichlorobenzene vapors did not result in significant gross or microscopic appearance of 

the major organs at termination or in significant deviations in hematology or clinical chemistry tests 

conducted at various times during the study (Coate et al. 1977). Exposure-related histopathological 

changes characterized as mild (only qualitative descriptions were provided) were observed in the liver and 

kidneys from rats usually after 4 or 13 weeks of exposure, but not at week 26. Pulmonary function tests 

and operant behavior tests conducted in monkeys during the study were unremarkable. In another 

intermediate-duration study, exposure of Sprague-Dawley rats (20 males/group), beagle dogs 

(2 males/group), and New Zealand rabbits (4 males/group) to 0, 30, or 100 ppm 1,2,4-trichlorobenzene 

vapors 5 days/week for a total of 30 exposures did not result in gross or histological changes in any major 

tissues and organs, including the liver and kidneys (Kociba et al. 1981). Hematology and clinical 

chemistry tests also were unremarkable. The only significant changes in organ weights were an 11% 

increase in relative liver weight in rats and a 27–30% increase in absolute and relative liver weight in 

dogs. Increased urinary excretion of porphyrins was reported in exposed rats, which the investigators 

attributed to hepatic enzyme induction by 1,2,4-trichlorobenzene. In yet an additional intermediateduration earlier study, Alderley Park rats (2–4/sex/group) were exposed 6 hours/day to 20 ppm 

1,2,4-trichlorobenzene vapors for 20 exposures or to 70 or 200 ppm for 15 exposures (Gage 1970). 

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TRICHLOROBENZENES 15 

2. RELEVANCE TO PUBLIC HEALTH 

Exposure to 70 or 200 ppm 1,2,4-trichlorobenzene produced lacrimation and lethargy, presumably during 

exposures, although it was not explicitly stated, but did not induce histological alterations in the lung, 

liver, heart, intestines, adrenals, spleen, or thymus. Although there is suggestive evidence from some 

studies that the liver might be a target for 1,2,4-trichlorobenzene, inadequacies in the studies (no 

quantitative data, only a few animals tested) preclude derivation of an intermediate-duration inhalation 

MRL for this isomer. 

Chronic-Duration MRL. No chronic-duration inhalation studies were available in humans or animals for 

1,2,4-trichlorobenzene; therefore, a chronic-duration inhalation MRL was not derived for this isomer. 

1,2,3-Trichlorobenzene 

No inhalation studies in humans or in animals were located for 1,2,3-trichlorobenzene; therefore, no 

inhalation MRLs were derived for this compound. 

1,3,5-Trichlorobenzene 

Acute-Duration MRL. No pertinent information in humans was located for 1,3,5-trichlorobenzene. The 

only acute data in animals is that head-only exposure of Sprague-Dawley rats (8/sex) for 60 minutes to 

1,209 ppm 1,3,5-trichlorobenzene vapors appeared to cause some irritation around the eyes (Jorgenson et 

al. 1976). No clinical signs or mortality occurred during 14 days after the exposure, but exposed males 

and females weighed 44 and 60%, respectively, less than unexposed control rats. Gross necropsy did not 

reveal compound-related alterations. This information is inadequate for MRL derivation. 

Intermediate-Duration MRL. Only one intermediate-duration inhalation study was located for 

1,3,5-trichlorobenzene. In this study, male and female CD rats (20/sex/group) were exposed to 0, 1.3, 13, 

or 130 ppm 1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks (Sasmore et al. 1983). 

A dried red material was often seen on the faces of rats during exposures, including controls, although the 

incidence was noticeably higher in the 13 and 130 ppm groups. Exposure to 1,3,5-trichlorobenzene had 

no significant effect on body weight or on hematology or clinical chemistry tests conducted at 

termination. Methemoglobin was slightly higher at week 13 than at week 4, but according to the 

investigators, the values did not reach significant levels (data not shown). Urinalyses performed on 

samples collected on weeks 4 and 13 showed an apparent increase in porphyrins in male rats on week 13, 

but the large standard deviations rendered the differences with controls nonsignificant. Relative liver 

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TRICHLOROBENZENES 16 

2. RELEVANCE TO PUBLIC HEALTH 

weight was significantly increased (11%) in male rats on week 4 but not at termination. At termination, a 

total of 34 organs and tissues (not all specified) from the control and high-exposure group were examined 

microscopically, including the nasal passages. The only treatment-related histopathology was the 

presence of squamous metaplasia and hyperplasia in the respiratory epithelium of the nasal passages of 

three high-exposure rats (3/20); this incidence is not statistically significant from controls (0/20) as 

determined by the Fisher Exact Test. The lack of clear effects precludes the use of this study for MRL 

derivation. The study NOAELwas the highest exposure concentration tested, 130 ppm, but the true 

NOAEL may have been higher. 

Chronic-Duration MRL. No chronic-duration inhalation studies were available for 1,3,5-trichlorobenzene; therefore, a chronic-duration inhalation MRL was not derived for this isomer. 

Oral MRLs 

1,2,4-Trichlorobenzene 

Acute-Duration MRL. An acute-duration oral MRL was not derived for 1,2,4-trichlorobenzene due to 

inadequacies of the data base. No relevant human data were located. Other than acute lethality studies, 

the animal database consists of developmental studies in rats (Black et al. 1988; Kitchin and Ebron 1983) 

and mice (Chernoff and Kavlock 1983; Gray and Kavlock 1984; Gray et al. 1986) and two studies aimed 

mainly at evaluating the effects of 1,2,4-trichlorobenzene on porphyrin metabolism (Rimington and 

Ziegler 1963), liver weight, and liver microsomal enzymes (Carlson and Tardiff 1976). These studies 

identified the liver as a target for 1,2,4-trichlorobenzene. In the study by Black et al. (1988), microscopic 

examination of the major tissues and organs from the dams exposed on Gds 6–15 and sacrificed on Gd 22 

showed mild histological alterations in the liver and thyroid at doses of 300 mg/kg/day but not 

150 mg/kg/day. However, the investigators provided only qualitative descriptions of the histological 

changes; incidences of lesions were not provided. Hemoglobin and hematocrit were decreased 6–7% in 

rats dosed with ≥150 mg/kg/day 1,2,4-trichlorobenzene relative to controls. This difference is not 

considered biologically significant since the values in treated rats were within the normal range. Rats 

dosed with 300 mg/kg/day 1,2,4-trichlorobenzene showed an 11% increase in relative liver weight; the 

investigators stated that absolute weight of rats dosed with 300 mg/kg/day was significantly increased but 

did not provide the values for the control group, and therefore the magnitude of the increase cannot be 

assessed. There were no significant effects on number of pregnancies, fetal weight, litter size, number of 

resorptions and dead fetuses, or incidences of skeletal or visceral anomalies. The only developmental 

effect reported was the presence of microscopic lesions in the lenses of the eyes of fetuses from dams 

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TRICHLOROBENZENES 17 

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treated with 150 mg/kg/day 1,2,4-trichlorobenzene; no such lesions were reported in groups dosed with 

75 or 300 mg/kg/day. This study is inadequate for MRL derivation due to the lack of quantitative 

histology data, which precludes constructing dose-response relationships to determine points of departure 

for the MRL. 

In the other developmental study in rats, pregnant animals were administered 0, 36, 120, or 

360 mg/kg/day 1,2,4-trichlorobenzene on Gd 9–13 and were sacrificed on Gd 14 (Kitchin and Ebron 

1983). Rats that received the highest dose, 360 mg/kg/day, lost weight and had moderate hepatocellular 

hypertrophy (only the liver was examined microscopically); the no-observed-adverse-effect level 

(NOAEL) for these effects was 120 mg/kg/day. While doses of 360 mg/kg/day did not increase 

resorptions or cause significant embryolethality or teratogenicity, they significantly retarded fetal 

development as measured by reduced head length, crown-rump length, somite number, and protein 

content. These end points were evaluated only in dams administered 360 mg/kg/day 1,2,4-trichlorobenzene and controls, but not in groups dosed with 36 or 120 mg/kg/day 1,2,4-trichlorobenzene, which 

makes this study inadequate for MRL derivation because the NOAEL for weight loss and liver effects 

(120 mg/kg/day) may not be the NOAEL for retarded fetal development. 

In the developmental studies in mice, pregnant mice were administered 0 or 130 mg/kg 1,2,4-trichlorobenzene on Gd 8–12 (Chernoff and Kavlock 1983; Gray and Kavlock 1984; Gray et al. 1986). This 

treatment did not significantly affect offspring viability, reactive locomotor activity of the pups evaluated 

at various times up to 200 days of age, or reproductive performance of the offspring to produce a second 

generation. The use of only one dose level in these studies precludes constructing dose-response 

relationships for the end points measured. The lack of reported effects also precludes using this study for 

MRL derivation. 

Rimington and Ziegler (1963) reported increased liver microsomal enzyme activities, increased urinary 

excretion of porphyrins, and also elevated levels of porphyrins in the liver of rats following daily gavage 

doses of 500 mg/kg/day for 10 days. The limited scope and single dose level precludes considering this 

study for MRL derivation. Carlson and Tardiff (1976) administered 1,2,4-trichlorobenzene in doses of 0, 

10, 20, or 40 mg/kg/day to male rats by gavage in corn oil for 14 days. Sacrifices were conducted on 

day 15, and liver microsomal enzymes were analyzed. Blood was also collected for hemoglobin and 

hematocrit determinations. Sections of the liver were also prepared for histological examination. 

Administration of 1,2,4-trichlorobenzene resulted in dose-related increases in cytochrome c reductase, 

cytochrome P-450, glucuronyltransferase, EPN detoxification, and azoreductase. 1,2,4-Trichlorobenzene 

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TRICHLOROBENZENES 18 

2. RELEVANCE TO PUBLIC HEALTH 

induced a dose-related increase in relative liver weight (all doses, 15% at the lowest dose, 28% at the 

highest dose). There were no significant effects on hemoglobin concentration or hematocrit. No specific 

information regarding liver histopathology was provided. Because the Carlson and Tardiff (1976) study 

is of limited scope and provided no information regarding histology of the liver, it is considered 

inadequate for MRL derivation. 

•	 An MRL of 0.1 mg/kg/day has been derived for intermediate-duration oral exposure (15– 

364 days) to 1,2,4-trichlorobenzene. 

No relevant intermediate-duration studies in humans were located. The intermediate-duration oral 

database for 1,2,4-trichlorobenzene consists of two 3-month dietary studies in rats (CMA 1989; Côté et 

al. 1988), a 13-week dietary study in mice (Hiles 1989), two studies in rats aimed mainly at evaluating 

porphyrin metabolism and enzyme induction in the liver by 1,2,4-trichlorobenzene (Carlson and Tardiff 

1976; Rimington and Ziegler 1963), and a multi-generation reproductive study in rats (Robinson et al. 

1981). As a whole, these studies suggested that the liver and kidneys are targets for 1,2,4-trichlorobenzene and that male rats may be more sensitive than females. Administration of 730 mg/kg/day 

1,2,4-trichlorobenzene (only dose level tested) by gavage to male albino rats caused intense necrosis and 

fatty change in the liver (only organ examined) and increased urinary porphyrins (Rimington and Ziegler 

1963). Treatment of male albino rats via the diet with a much smaller dose, 40 mg/kg/day, increased 

relative liver weight (9–14%) and induced microsomal enzymes, but did not induce histological 

alterations in the liver (Carlson and Tardiff 1976). 

In the multi-generation study, doses of up to 33 mg/kg/day in males and 54 mg/kg/day in females (mean 

doses estimated by the investigators consumed by 83 days of age F0 generation of rats) did not affect 

fertility in the F0 or F1 generation or affect the time of vaginal opening in F2 females (Robinson et al. 

1981). Treatment with 1,2,4-trichlorobenzene did not affect neonates' weight, litter size, or viability 

during the pre-weaning period in any generation. Post-weaning growth of F1 rats was not affected by 

1,2,4-trichlorobenzene. Tests for locomotor activity in the F1 or F2 generation rats were unremarkable. 

Of the organs weighed in the study (which included the liver and kidneys), only the adrenals were 

affected by 1,2,4-trichlorobenzene. Absolute weight of the adrenals of F0 and F1 males and females were 

significantly increased relative to controls (11–12% in F0 and 4–6% in F1); no histological evaluation of 

the glands was conducted. No histological damage was found in the livers and kidneys. Results from 

blood chemistry tests in F0 and F1 rats did not reveal any treatment-related alterations. The significance 

of the increase in adrenals weight is unknown. EPA (IRIS 2010) states that a 1-month study was 

performed by the Agency in which five rats/group were dosed by gavage with 53 mg/kg/day 

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TRICHLOROBENZENES 19 

2. RELEVANCE TO PUBLIC HEALTH 

1,2,4-trichlorobenzene in corn oil. Microscopic examination of the adrenals from treated rats showed 

moderate vacuolization of the zona fasciculata; the control group showed only slight vacuolization. A 

14% increase in absolute adrenal gland weight and a 13% increase in relative adrenal weight were found. 

According to EPA (IRIS 2010, last revised 11/01/96), this study indicated that the increase in adrenal 

gland weight observed by Robinson et al. (1981) could be associated with vacuolization of the zona 

fasciculata. Since these observations are not supported by results from an acute-duration study (Black et 

al. 1988), two 3-month studies (CMA 1989; Côté et al. 1988), or a 104-week dietary study in rats, all of 

which conducted gross and microscopic evaluation of the adrenals from rats, the biological significance 

of the effects reported by Robinson et al. (1981) remains unclear. Since aside from the changes in 

adrenals weight, no adverse effect was identified in this multi-generation study, the study is considered 

inadequate for MRL derivation. 

In the 13-week study in mice, groups of B6C3F1 mice (10/sex/group) were administered a diet with 0, 

220, 3,850, or 7,700 ppm 1,2,4-trichlorobenzene (Hiles 1989). The diet provided doses of 0, 67, 850, or 

1,222 mg/kg/day to males and 0, 86, 1,183, or 1,345 mg/kg/day to females. End points monitored 

included clinical signs twice daily, and body weight and food consumption weekly. Hematology and 

clinical chemistry tests were conducted at initiation and during week 14. At termination, gross necropsy 

was conducted, selected organs were weighed, and selected tissues were examined microscopically. The 

lungs, liver, and kidneys from all groups were examined; other organs from only the control and highdose groups were examined. Ophthalmologic examinations were conducted at initiation and termination. 

One control female and one high-dose female were accidentally killed during the study. Final body 

weight was significantly reduced in high-dose males (9%) and females (8.3%). Cumulative body weight 

gain was significantly reduced in low-dose males (27%), high-dose males (40%), and high-dose females 

(33%); these changes were associated with significant reductions in food consumption throughout the 

study. Significant, treatment-related alterations occurred only in the liver from males dosed with 

≥850 mg/kg/day and females dosed with ≥1,183 mg/kg/day; the respective NOAELs were 67 and

86 mg/kg/day. The lesions consisted of hepatocellular cytomegaly with karyomegaly and hepatocellular 

atrophy and degeneration. The incidences in males and females were 0/10, 0/10, 10/10, and 10/10 and 

0/9, 0/10, 10/10, and 9/9, respectively. 

One of the 3-month studies in Sprague-Dawley rats that evaluated hematology, clinical chemistry, and 

histopathology of the major organ and tissues reported histological alterations in the liver, kidneys, and 

thyroid in the various dose groups (doses ranged from 0.07 to 82 mg/kg/day in males and from 0.11 to 

101 mg/kg/day in females) (Côté et al. 1988). However, the investigators provided only a qualitative 

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TRICHLOROBENZENES 20 

2. RELEVANCE TO PUBLIC HEALTH 

description of the results, such that dose-response relationships for the histological changes could not be 

constructed. In that study, high-dose males showed increases of 13 and 20% in absolute and relative liver 

weight, respectively, and of 31 and 36% in absolute and relative kidneys weight, respectively. 

Hematology and clinical chemistry tests were unremarkable. Because quantitative data regarding the 

histological effects were not presented, potential points of departure for the MRL could not be identified 

and the study is considered inadequate for MRL derivation. 

In the 3-month study conducted by CMA (1989), groups of Fisher-344 rats (10/sex/group) were fed a diet 

containing 0, 200, 600, or 1,800 ppm 1,2,4-trichlorobenzene for 14 weeks; this diet provided doses of 0, 

14.6, 45.6, or 133.7 mg/kg/day for males and 0, 17.0, 52.5, or 150.6 mg/kg/day for females. End points 

monitored included clinical signs (daily), physical examination (weekly), ophthalmology (initiation and 

termination), body weight and food consumption (weekly), hematology and clinical chemistry 

(termination), gross necropsy (all rats at termination), selected organ weights, and histopathology of all 

major organs and tissues of the control and high-dose group and liver and kidney of the low- and middose groups. Treatment with 1,2,4-trichlorobenzene did not affect survival rate. Clinical signs were 

limited to chromodacryorrhea and lacrimation, which occurred more frequently in treated groups, but 

without dose-response. The test for ocular abnormalities did not reveal compound-related effects. 

Administration of 1,2,4-trichlorobenzene did not significantly affect body weight or weight gain. Food 

consumption was significantly higher in the mid- and high-dose groups than in controls. Significant 

hematological alterations consisted of decreased mean erythrocyte count (5%), hemoglobin (7%), and 

hematocrit (5%) in males dosed with 133.7 mg/kg/day and decreased hemoglobin (4%) and hematocrit 

(4%) in females dosed with 150.6 mg/kg/day. These changes are within the normal range and are not 

considered biologically significant. Platelets were significantly increased (16%) in males dosed with 

133.7 mg/kg/day; the clinical significance of this finding is unclear; however, thrombocytosis is usually 

caused by a reaction to injury or inflammation. Significant clinical chemistry changes included elevated 

blood urea nitrogen (BUN) in high-dose males (12%) and females (20%), elevated total protein, albumin, 

and calcium in high-dose males, and lower serum aspartate aminotransferase (AST) activity in males 

dosed with 45.6 mg/kg/day (22%) and 133.7 mg/kg/day (28%). The elevated BUN was consistent with 

microscopic alterations in kidneys from male rats. The clinical significance of the alterations in protein 

and calcium were unclear and the lower transaminase activity was not considered of biological 

significance. Significant changes in organ weight included dose-related increases in absolute and relative 

liver weight in all treated male groups and in females dosed with 52.5 and 150.6 mg/kg/day, and 

increased absolute and relative kidney weight and absolute testes weight in males dosed with 

133.7 mg/kg/day. No compound-related gross lesions were observed. Histological alterations were 

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TRICHLOROBENZENES 21 

2. RELEVANCE TO PUBLIC HEALTH 

limited to the kidneys and liver. Kidney lesions were evident in males dosed with 45.6 and 

133.7 mg/kg/day and consisted of dilated tubules, granular casts, hyaline droplets, interstitial nephritis, 

and papillary mineral deposition. In the liver, centrilobular hepatocyte hypertrophy occurred in males 

dosed with 45.6 and 133.7 mg/kg/day (0/10, 0/10, 5/10, and 10/10) and in females dosed with 

150.6 mg/kg/day (0/10, 0/10, 0/10, and 10/10). Liver changes were more prominent in males than in 

females. 

Both the 14-week study in rats by CMA (1989) and the 13-week study in mice by Hiles (1989) evaluated 

a comprehensive number of end points and presented the results in a manner useful for establishing doseresponse relationships, and can potentially be used for MRL derivation. 

Data sets of centrilobular hepatocyte hypertrophy in male rats and relative liver weights in male and 

female rats (CMA 1989), as well as hepatocyte atrophy and degeneration in male mice (Hiles 1989) were 

analyzed using the benchmark dose (BMD) approach for MRL derivation. Data for renal effects in male 

rats were not considered for modeling due to the strong suggestive evidence that this may be a unique 

response of the male rat and not relevant for human risk assessment (EPA 1991). Specific indications that 

this may be the case include the increased incidences of hyaline droplets, granular casts, and tubule 

dilation, and the fact that none of these lesions occurred in female rats. In addition, since there is not 

enough evidence to dissociate the interstitial nephritis from the male-specific nephropathy, interstitial 

nephritis was also not considered for modeling. In support of this position is the fact that interstitial 

nephritis did not occur in female rats. 

Models in the EPA Benchmark Software (BMDS version 2.1) were fit to the data sets for centrilobular 

hepatocyte hypertrophy in male rats and relative liver weights in male and female rats from the CMA 

(1989) study, as well as hepatocyte atrophy and degeneration in male mice from the Hiles (1989) study. 

A benchmark response (BMR) of 10% was selected in the absence of data that would support a lower 

BMR. In accordance with EPA (2000a) guidance, BMDs and the lower-bound confidence limits on the 

BMDs (BMDLs) associated with an extra risk of 10% are calculated for all models. For continuous data, 

in the absence of a clear criteria as to what level of change in organ weight should be considered adverse, 

the BMR was defined as a change in mean body weight gain equal to 1 standard deviation from the 

control mean (EPA 2000a). Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), 

visual inspection of the dose-response curve, and scaled residual at the data point (except the control) 

closest to the predefined BMR. Among all of the models providing adequate fit to the data, the BMDL 

from the model with the lowest Akaike’s Information Criterion (AIC) is chosen. None of the models 

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TRICHLOROBENZENES 22 

2. RELEVANCE TO PUBLIC HEALTH 

could provide an adequate fit for relative liver weight in female rats, but the lowest dose, 17.0 mg/kg/day, 

was a NOAEL. A summary of the modeling results is presented in Table 2-1. 

Although Table 2-1 shows that the BMDL1SD of 9.41 mg/kg/day for relative liver weight would be a 

slightly more protective point of departure for MRL derivation than the BMDL10 of 14.35 mg/kg/day for 

hepatocyte hypertrophy in male rats, the latter is preferred as the point of departure on the basis of being a 

more biologically meaningful end point. The MRL is derived by dividing the BMDL10 of 

14.35 mg/kg/day for centrilobular hepatocyte hypertrophy by an uncertainty factor of 100 (10 for animal 

to human extrapolation and 10 for human variability). This yields an intermediate-duration oral MRL of 

0.1 mg/kg/day for 1,2,4-trichlorobenzene. Detailed information regarding the modeling of hepatocyte 

hypertrophy in male rats is presented in Appendix A. Note that rounding to one decimal place would give 

the same MRL if based on relative liver weight. 

•	 An MRL of 0.1 mg/kg/day has been derived for chronic-duration oral exposure (365 days or 

more) to 1,2,4-trichlorobenzene. 

No relevant chronic data in humans exposed orally to 1,2,4-trichlorobenzene were located, but there are 

104-week dietary bioassays in rats (Moore 1994a) and in mice (Moore 1994b). In the study in rats, 

groups of Fisher-344 rats (50/sex/group) were fed a diet containing 0, 100, 350, or 1,200 ppm 

1,2,4-trichlorobenzene for 104 weeks. The diet provided doses of 0, 5.6, 19.4, or 66.5 mg/kg/day 

1,2,4-trichlorobenzene to males and 0, 6.9, 23.5, or 81.4 mg/kg/day 1,2,4-trichlorobenzene to females. 

Parameters evaluated included mortality (twice daily), clinical signs, body weight and food consumption 

(weekly for 16 weeks and every 4 weeks thereafter), hematology (week 52 and 78 for cellular 

morphology and leukocyte differential, from control and high-dose groups), organ weight (at termination, 

brain, brainstem, liver, kidneys, testes, and epididymis), and gross necropsy and histological examination 

of all major organs and tissues at termination. Treatment with 1,2,4-trichlorobenzene resulted in a 

significant reduction in survival rate in males dosed with 66.5 mg/kg/day. Survival rate in the control, 

5.6, 19.4, and 66.5 mg/kg/day males at week 104 were 84, 80, 84, and 60% respectively. There were no 

distinct or pronounced compound-related differences in clinical signs between treated and control groups. 

Differences in body weight between treated and control rats were <10% throughout the study. Food 

consumption was decreased 4–7% in treated groups relative to controls during the study. The only 

statistically significant hematology findings were a decrease in basophiles at week 52 and monocytes at 

week 105 in males dosed with 66.5 mg/kg/day, which the investigators considered minor. No evidence of 

leukemia was noted. Gross necropsy at termination showed increased incidence of liver and kidney 

abnormalities in males dosed with 19.4 and 66.5 mg/kg/day and a slight increase in incidence of uterine 

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2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Summary of End Points Modeled in 13-Week Studies 

BMD1SD/BMD10 BMDL1SD/BMDL10 Best fitting 

End point (mg/kg/day) (mg/kg/day) model 

Relative liver weight (male rats)a 11.27 9.41 Linear 

Hepatocyte hypertrophy (male rats)a 33.09 14.35 Gamma 

Hepatocyte atrophy and degeneration (male mice)b 220.61 58.94 Gamma 

a

CMA 1989 

b

Hiles 1989 

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TRICHLOROBENZENES 24 

2. RELEVANCE TO PUBLIC HEALTH 

masses in treated females relative to controls; these changes were not discussed any further. Significant 

changes in organ weight were limited to an increase in absolute and relative liver weight in both male and 

female rats receiving the highest doses of 1,2,4-trichlorobenzene and a decrease in absolute and relative 

testes weight in males dosed with 5.6 and 19.4 mg/kg/day. Treatment-related histological alterations 

were restricted to the liver of males and females and to the kidneys of males and consisted of the 

following: hepatocellular hypertrophy, focal cystic degeneration, diffuse fatty change, transitional renal 

cell hyperplasia, and increased severity of chronic rat nephropathy in males. Incidences of liver lesions 

are presented in Table 2-2 (note that a smaller number of animals from the low-dose groups were 

examined for histopathology). 

The incidences of transitional cell hyperplasia in the kidneys of male rats were as follows: 2/50, 0/19, 

2/50, and 34/50 in males dosed with 0, 5.6, 19.4, and 66.5 mg/kg/day 1,2,4-trichlorobenzene, 

respectively. Since there is strong evidence from the 14-week study (CMA 1989) suggesting that the 

renal lesions in male rats may represent a male-specific response not relevant for MRL derivation and that 

renal cell hyperplasia reported in the 104-week study is a typical response seen in the male rat 

nephropathy, renal cell hyperplasia is not considered any further as a potential end point for MRL 

derivation. 

In the study in mice, groups of B6C3F1 mice (50/sex/group) were fed a diet containing 0, 150, 700, or 

3,200 ppm 1,2,4-trichlorobenzene for 104 weeks (Moore 1994b). The diet provided doses of 0, 21, 100.6, 

or 519.9 mg/kg/day 1,2,4-trichlorobenzene to males and 0, 26.3, 127, or 572.6 mg/kg/day 1,2,4-trichlorobenzene to females. End points monitored were the same as in the study in rats described above (Moore 

1994a). The liver was the target for 1,2,4-trichlorobenzene in mice. The most significant effect was an 

increase incidence of hepatocellular carcinoma in mid- and high-dose mice (8/50, 5/50, 27/50, and 50/50 

in males and 1/50, 1/50, 28/50, and 46/50 in females). Centrilobular hepatocytomegaly was also 

significantly increased in mid- and high-dose males (0/50, 0/50, 27/50, and 20/50). Since non-neoplastic 

effects were observed only at higher doses than in rats and carcinoma occurred at that same dose level, 

this study will not be considered any further for MRL derivation. 

Table 2-2 shows that: (1) diffuse fatty change was significantly increased in males and females only at 

the highest dose; (2) focal cystic degeneration occurred at lower incidence in the low- and mid-dose males 

compared to controls, and was significantly increased only at the highest dose; (3) hepatocellular 

hypertrophy in female rats occurred at increased frequency only at the highest dose; and (4) only 

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2. RELEVANCE TO PUBLIC HEALTH 

Table 2-2. Incidence of Liver Lesions in Rats in a 104-Week Dietary Study 

Males 

Dose (mg/kg/day) 0 5.6 19.4 66.5 

Hepatocellular hypertrophy 2/50 (4%) 1/26 (3.8%) 5/50 (10%) 30/50 (60%) 

Focal cystic degeneration 9/50 (18%) 3/26 (11.5%) 4/50 (8%) 19/50 (38%) 

Diffuse fatty change 5/50 (10%) 3/26 (11.5%) 5/50 (10%) 14/50 (28%) 

Females 

Dose (mg/kg/day) 0 6.9 23.5 81.4 

Hepatocellular hypertrophy 6/50 (12%) 5/25 (20%) 5/50 (10%) 37/50 (74%) 

Diffuse fatty change 15/50 (30%) 6/25 (24%) 21/50 (42%) 30/50 (60%) 

Source: Moore 1994a 

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TRICHLOROBENZENES 26 

2. RELEVANCE TO PUBLIC HEALTH 

hepatocellular hypertrophy in male rats exhibited dose-response characteristics. Based on these facts, 

only the hepatocellular hypertrophy in male rats was considered for MRL derivation. 

Models in the EPA Benchmark Software (BMDS version 2.1) were fit to the data set for hepatocellular 

hypertrophy in the liver of male rats. A BMR of 10% was selected in the absence of data that would 

support a lower BMR. In accordance with EPA (2000a) guidance, BMDs and BMDLs associated with an 

extra risk of 10% are calculated for all models. Adequate model fit is judged by three criteria: goodnessof-fit (p>0.1), visual inspection of the dose-response curve, and scaled residual at the data point (except 

the control) closest to the predefined BMR. Among all of the models providing adequate fit to the data, 

the BMDL from the model with the lowest AIC is chosen. The Multistage (2-degree) model provided the 

best fit for the data yielding a BMD10 of 23.25 mg/kg/day and a corresponding BMDL10 of 

13.33 mg/kg/day. 

The MRL is derived by dividing the BMDL10 of 13.33 mg/kg/day for hepatocellular hypertrophy in male 

rats by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). 

This yields a chronic-duration oral MRL of 0.1 mg/kg/day for 1,2,4-trichlorobenzene. Detailed 

information regarding the modeling of hepatocellular hypertrophy in male rats is presented in 

Appendix A. 

1,2,3-Trichlorobenzene 

Acute-Duration MRL. An acute-oral MRL for 1,2,3-trichlorobenzene was not derived due to inadequacy 

of the available data. No human data were located for 1,2,3-trichlorobenzene. Only one acute-duration 

oral animal study was located for 1,2,3-trichlorobenzene. In that study, pregnant Sprague-Dawley rats 

(14/group) were administered 0, 150, 300, or 600 mg/kg/day 1,2,3-trichlorobenzene by gavage in corn oil 

on Gd 6–15 (Black et al. 1988). The dams were sacrificed on Gd 22 and the uterus and ovaries were 

removed. Dams were reweighed and the internal organs were weighed. In addition, blood was collected 

for hematology and clinical chemistry tests. Fetuses were examined grossly for birth defects and skeletal 

and visceral anomalies. Fetuses were also preserved for histological examinations. The major organs and 

tissues from the dams were examined microscopically. There were no treatment-related deaths and no 

clinical signs, but mean body weight of the high-dose group tended to be lower (data not shown). Organ 

weights were not significantly affected. Hemoglobin was reduced in the 300 and 600 mg/kg/day groups 

(6–7%) and hematocrit was reduced (~6%) in the 600 mg/kg/day groups. Given the magnitude of these 

hematological changes, the effects are not considered biologically significant since the values are within 

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TRICHLOROBENZENES 27 

2. RELEVANCE TO PUBLIC HEALTH 

the normal range. No significant clinical chemistry effects were reported. Reported histological changes 

were limited to the kidneys, liver, and thyroid. However, the investigators provided only a qualitative 

description of the results; incidences of lesions were not provided. There were no significant effects on 

number of pregnancies, fetal weight, litter size, number of resorptions and dead fetuses, or incidences of 

skeletal or visceral anomalies. Histological examination of the fetuses did not reveal treatment-related 

alterations. The lack of a quantitative presentation of the results of the histological examination of the 

maternal tissues renders this study inadequate for MRL derivation because of the inability to inspect doseresponse relationships. 

Intermediate-Duration MRL. No intermediate-duration oral MRL was derived for 1,2,3-trichlorobenzene. No relevant human data were located. Only one intermediate-duration study was available for 

this compound (Côté et al. 1988). In that study, groups of Sprague-Dawley rats (10/sex/group) were fed a 

diet containing 0, 1, 10, 100, or 1,000 ppm 1,2,3-trichlorobenzene for 13 weeks. This diet provided doses 

of 0, 0.08, 0.78, 7.6, 78 mg/kg/day 12,3-trichlorobenzene to males and 0, 0.13, 1.3, 12, or 113 mg/kg/day 

to females. End points evaluated included body weight (weekly), food consumption (weeks 1, 4, 8, 12), 

urinalysis (weeks 4, 8, 12), and clinical signs (daily). At termination, the rats were necropsied and blood 

was collected for hematological and clinical chemistry testing. Hepatic microsomal aniline hydroxylase 

(AH), aminopyrine demethylase (APDM) activities, and liver protein content were also determined. Bone 

marrow from the femur was aspirated for cytological evaluation. All major tissues and organs were 

prepared for microscopic examination. There were no treatment-related deaths. Food consumption was 

not affected; body weight gain from high-dose males was reduced 10.2% relative to controls (only data 

for males shown). There were no significant alterations in hematology or clinical chemistry parameters, 

and urinalyses were unremarkable. No significant gross changes in tissues were reported. Statistically 

significant changes in organs weight were limited to increases in relative liver weight (14%) in males 

dosed with 78 mg/kg/day and in relative kidney weight in males dosed with 0.08 mg/kg/day (14%), 

0.78 mg/kg/day (14%), and 78 mg/kg/day (21%). 1,2,3-Trichlorobenzene had no significant effect on the 

hepatic mixed function oxidase activities measured. For the most part, compound-related histopathology 

was reported as mild and was limited to the liver and thyroid of generally high-dose rats and appeared to 

be more severe in males. However, the investigators provided only a qualitative description of the 

histological examinations; incidences of lesions were not presented. In the liver, most treated groups 

showed mild-to-moderate increases in cytoplasmic volume and anisokaryosis of hepatocytes, mostly in 

perivenous and midzone areas. High-dose rats showed mild aggregated basophilia as well as mild 

widespread midzonal vacuolization due to fatty infiltration. Changes in the thyroid consisted of reduction 

in follicular size, increased epithelial height from flattened cuboidal cells to columnar shape, and reduced 

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TRICHLOROBENZENES 28 

2. RELEVANCE TO PUBLIC HEALTH 

colloid density. Changes in the high-dose group varied from mild to moderate. The urinalyses were 

unremarkable. Since no dose-responses can be constructed with the histological data and since the 

increases in relative kidney weight in males were not accompanied by any histological changes, this study 

is considered inadequate for use as basis for MRL derivation. 

Chronic-Duration MRL. No chronic-duration oral data in humans or in animals were located for 

1,2,3-trichlorobenzene. Therefore, a chronic-duration oral MRL was not derived for this compound. 

1,3,5-Trichlorobenzene 

Acute-Duration MRL. No acute-duration oral MRL was derived for 1,3,5-trichlorobenzen due to 

inadequacies of the database. No relevant human data were located. The acute-duration oral database for 

1,3,5-trichlorobenzene in animals is limited to information regarding acute lethal doses (Côté et al. 1988; 

Jorgenson et al. 1976) and a developmental study in rats (Black et al. 1988). In the developmental study, 

pregnant Sprague-Dawley rats (14/group) were administered 0, 150, 300, or 600 mg/kg/day 

1,3,5-trichlorobenzene by gavage in corn oil on Gd 6–15. The dams were sacrificed on Gd 22 and the 

uterus and ovaries were removed. Dams were reweighed and the internal organs were also weighed. 

Blood was collected for hematology and clinical chemistry tests. Fetuses were examined grossly for birth 

defects and skeletal and visceral anomalies. Fetuses were also preserved for histological evaluations. 

The major organs and tissues from the dams were examined microscopically. There were no treatmentrelated deaths. There were no clinical signs, but mean maternal body weight gain in the high-dose group 

was 34% lower than controls. Food consumption data were not provided. Significant increases in 

relative liver weight were observed at 300 and 600 mg/kg/day (9 and 25%, respectively); the investigators 

also stated that absolute liver weights from rats in the 300 and 600 mg/kg/day groups were significantly 

increased but did not provide the values for the control group, and therefore, the magnitude of the changes 

cannot be assessed. Hemoglobin and hematocrit were reduced in the 600 mg/kg/day group (10–11%). 

This is not considered a biologically significant change since it is still within the normal range. Maternal 

histological changes were restricted to the kidneys, liver, and thyroid. However, only a qualitative 

description of the histological changes was provided; incidences of lesions were not presented. There 

were no significant effects on the number of pregnancies, fetal weight, litter size, number of resorptions 

and dead fetuses, or incidences of skeletal and visceral abnormalities. However, histological examination 

of the fetuses showed lesions in the lenses of the eyes of pups from all treated groups (150, 300, and 

600 mg/kg/day). These changes consisted of central areas of cellular disorientation and disaggregation 

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TRICHLOROBENZENES 29 

2. RELEVANCE TO PUBLIC HEALTH 

with ballooning and granular degeneration. The lack of quantitative histology data precludes the use of 

this study for MRL derivation. 

Intermediate-Duration MRL. An intermediate-duration oral MRL for 1,3,5-trichlorobenzene was not 

derived due to inadequacy of the database. No relevant human studies were located. Only one 

intermediate-duration oral study in animals was available for 1,3,5-trichlorobenzene. In that study, 

groups of Sprague-Dawley rats (10/sex/group) were fed a diet containing 0, 1, 10, 100, or 1,000 ppm 

1,3,5-trichlorobenzene for 13 weeks (Côté et al. 1988). This diet provided doses of 0, 0.08, 0.81, 7.7, and 

82 mg/kg/day for males and 0, 0.13, 1.5, 17, and 146 mg/kg/day for females. End points evaluated 

included body weight (weekly), food consumption (weeks 1, 4, 8, 12), urinalysis (weeks 4, 8, 12), and 

clinical signs (daily). At termination, the rats were necropsied and blood was collected for hematological 

and clinical chemistry testing. Hepatic microsomal AH, APDM activities, and liver protein content were 

also determined. Bone marrow from the femur was aspirated for cytological evaluation. All major 

tissues and organs were prepared for microscopic examination. Gross observations did not reveal any 

significant treatment-related alterations. Significant changes in organs weight were limited to an increase 

in relative liver weight in males dosed with 82 mg/kg/day (11%), an increase in absolute kidney weight in 

males dosed with 0.81 and 7.7 mg/kg/day (~20%), and increases in relative kidney weight in males dosed 

with 0.81 (14%), 7.7 (25%), and 82 mg/kg/day (14%). There were no significant alterations in 

hematology or clinical chemistry parameters. 1,3,5-Trichlorobenzene had no significant effect on AH and 

APDM activities. For the most part, compound-related histopathology was mild and was limited to the 

liver, thyroid, and kidneys, generally high-dose rats, and appeared to be more severe in males. However, 

the investigators only provided a qualitative description of the histological changes; incidences of lesions 

were not presented. In the liver, most treated groups showed mild-to-moderate increase in cytoplasmic 

volume and anisokaryosis of hepatocytes mostly in perivenous and midzone areas. High-dose rats 

showed aggregated basophilia as well as widespread midzonal vacuolization due to fatty infiltration. 

Changes in the thyroid consisted of reduction in follicular size, increased epithelial height from flattened 

cuboidal cells to columnar shape, and reduced colloid density. Changes in the high-dose group varied 

from mild to moderate. Changes in the kidneys were characterized by eosinophilic inclusion, 

enlargement and anisokariosis of the epithelial lining cells, and hyperplasia of renal tubular epithelial 

cells. Only the changes associated with the high-dose diet were considered to be biologically significant 

by the investigators. Since no dose-responses can be constructed with the histological data and increases 

in relative kidneys weights in males did not coincide with biologically significant histological changes, 

this study is inadequate for use as the basis for MRL derivation. 

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TRICHLOROBENZENES 30 

2. RELEVANCE TO PUBLIC HEALTH 

Chronic-Duration MRL. No chronic-duration oral data in humans or animals were located for 

1,3,5-trichlorobenzene; therefore, a chronic-duration oral MRL was not derived for this compound. 

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TRICHLOROBENZENES 31 

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 trichlorobenzenes. 

It contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

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TRICHLOROBENZENES 32 

3. HEALTH EFFECTS 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals or exposure levels below which no adverse 

effects have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or 

MRLs) may be of interest to health professionals and citizens alike. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

No studies were located regarding death in humans and/or animals after inhalation exposure to 

trichlorobenzenes. 

3.2.1.2 Systemic Effects 

There is very limited information regarding health effects in humans following exposure to 

trichlorobenzenes. A review of the literature indicates that an adult male who inhaled trichlorobenzene 

for several hours during the repair of a pump suffered massive hemoptysis, and that some 

trichlorobenzene production workers developed chloroacne (IPCS 1991). There is also a case report of 

aplastic anemia in a woman with prolonged exposure through the soaking of her husband’s work clothes 

in trichlorobenzene (Girard et al. 1969). None of these reports provided exposure details or specified the 

isomer involved. Citing an unpublished source, ACGIH (2001) states that minimal eye and throat 

irritation could occur in some people exposed to 3–5 ppm 1,2,4-trichlorobenzene. 

No information was located regarding systemic effects in animals following inhalation exposure to 

1,2,3-trichlorobenzene. 

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TRICHLOROBENZENES 33 

3. HEALTH EFFECTS 

The highest NOAEL values and all LOAEL values of 1,2,4-trichlorobenzene and 1,3,5-trichlorobenzene 

from each reliable study for systemic effects in each species and duration category are recorded in 

Tables 3-1 and 3-2 and plotted in Figures 3-1 and 3-2. 

Respiratory Effects. Continuous exposure of male cynomolgous monkeys to up to 100 ppm 

1,2,4-trichlorobenzene vapors for 26 weeks had no significant effect on results of pulmonary function 

tests (static compliance, diffusion capacity, distribution of ventilation, and lung volumes) conducted in 

anesthetized monkeys at termination (Coate et al. 1977). Measurements of mechanical properties of the 

lungs conducted in unanesthetized monkeys also were not significantly affected by exposure to 

1,2,4-trichlorobenzene. Histological examination of the lungs showed no treatment-related effects. 

Continuous exposure of male rats to up to 100 ppm 1,2,4-trichlorobenzene vapors for up to 26 weeks did 

not induce significant histological alterations in the lungs (Coate et al. 1977). Similar results were 

reported in rats exposed to up to 200 ppm 1,2,4-trichlorobenzene vapors 6 hours/day for 15 exposures 

(Gage 1970) or in male rats exposed 7 hours/day, 5 days/week to up to 100 ppm 1,2,4-trichlorobenzene 

vapors for a total of 30 exposures (Kociba et al. 1981). Two intermediate-duration studies in rabbits 

exposed to up to 100 ppm 1,2,4-trichlorobenzene vapors continuously (Coate et al. 1977) or intermittently 

(Kociba et al. 1981) also reported no significant alterations in the lungs upon microscopic examination. 

Similar results were reported in dogs following intermittent intermediate-duration exposure to up to 

100 ppm 1,2,4-trichlorobenzene (Kociba et al. 1981). The nasal mucosa was also examined in rats and 

rabbits in the Kociba et al. (1981) study. 

The only information regarding 1,3,5-trichlorobenzene is from a study in male and female CD rats in 

which the animals were exposed 6 hours/day, 5 days/week for 13 weeks (Sasmore et al. 1983). Exposure 

to up to 130 ppm 1,3,5-trichlorobenzene vapors did not induce significant histological alterations in the 

lungs, trachea, or nasal passages. 

Cardiovascular Effects. Continuous exposure of male monkeys, rats, or rabbits up to 100 ppm 

1,2,4-trichlorobenzene vapors for 26 weeks did not induce significant gross or microscopic alterations in 

the heart (Coate et al. 1977). Exposure of male rats, dogs, and rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors 7 hours/day, 5 days/week for a total of 30 exposures during a 40-day period did not 

induce significant gross or microscopic alterations in the heart or aorta (Kociba et al. 1981). 

***DRAFT FOR PUBLIC COMMENT*** 
12

100100100100100100100100

6

100100100100100100100100

***DRAFT FOR PUBLIC COMMENT***

Table 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

INTERMEDIATE EXPOSURE Systemic 

1 Monkey 26 wk 

24 h/d (Cynomolgus) 

2 Rat 26 wk 

24 h/d (SpragueDawley)

System 

Resp 

Cardio Hemato Hepatic Renal Dermal Ocular Bd Wt Resp 

Cardio Hemato Hepatic Renal Dermal Ocular Bd Wt 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

100 M Coate et al. 1977 

1,2,4-trichlorobenzene 

100 M 100 M 100 M 100 M 100 M 100 M 100 M 100 M Coate et al. 1977 

1,2,4-trichlorobenzene 

100 M 100 M 100 M 100 M 100 M 100 M 100 M 
15

10010010010010030

100

100100100100

***DRAFT FOR PUBLIC COMMENT***

Table 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

3 Rat 

(SpragueDawley) 

44 d 5 d/wk 7 h/d 

Resp 100 M Kociba et al. 1981 

1,2,4-trichlorobenzene 

Cardio 100 M Gastro 100 M Hemato 100 M Musc/skel Hepatic 

100 M 

30 M 100 M (increased relative liver 

weight) 

Renal 100 M 

Endocr 100 M Ocular 100 M Bd Wt 100 M 
9

100100100100100100100100

19

100100100100100100100100100100

***DRAFT FOR PUBLIC COMMENT***

Table 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

4 Rabbit 

(New Zealand) 

26 wk 24 h/d 

5 Rabbit 

(New Zealand) 

44 d 5 d/wk 7 h/d 

System 

Resp 

Cardio Hemato Hepatic Renal Dermal Ocular Bd Wt Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Ocular Bd Wt 

LOAEL 

NOAEL Less Serious Serious Reference 

(ppm) (ppm) (ppm) Chemical Form 

100 M Coate et al. 1977 

1,2,4-trichlorobenzene 

100 M 100 M 100 M 100 M 100 M 100 M 100 M 100 M Kociba et al. 1981 

1,2,4-trichlorobenzene 

100 M 100 M 100 M 100 M 100 M 100 M 100 M 100 M 100 M 
14

100

8

100

16

100

10

100

20

100

13

100

***DRAFT FOR PUBLIC COMMENT***

Table 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

Immuno/ Lymphoret 

6 Monkey 

(Cynomolgus) 

26 wk 24 h/d 100 M Coate et al. 1977 

1,2,4-trichlorobenzene 

7 Rat 

(SpragueDawley) 

26 wk 24 h/d 100 M Coate et al. 1977 

1,2,4-trichlorobenzene 

8 Rat 

(SpragueDawley) 

44 d 5 d/wk 7 h/d 

100 M Kociba et al. 1981 

1,2,4-trichlorobenzene 

9 Rabbit 

(New Zealand) 

26 wk 24 h/d 100 M Coate et al. 1977 

1,2,4-trichlorobenzene 

10 Rabbit 

(New Zealand) 

44 d 5 d/wk 7 h/d 

Neurological 

11 Monkey 

(Cynomolgus) 

26 wk 24 h/d 

100 M 100 M 

Kociba et al. 1981 1,2,4-trichlorobenzene Coate et al. 1977 1,2,4-trichlorobenzene 
7

100

17

100

11

100

21

100

18

100

22

100

***DRAFT FOR PUBLIC COMMENT***

Table 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

12 Rat 

(SpragueDawley) 

13 Rat 

(SpragueDawley) 

14 Rabbit 

(New Zealand) 

15 Rabbit 

(New Zealand) 

Reproductive 

16 Rat 

(SpragueDawley) 

17 Rabbit 

(New Zealand) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

26 wk 24 h/d 44 d 5 d/wk 7 h/d 

100 M 100 M 

Coate et al. 1977 1,2,4-trichlorobenzene Kociba et al. 1981 1,2,4-trichlorobenzene 

26 wk 24 h/d 44 d 5 d/wk 7 h/d 

100 M 100 M 

Coate et al. 1977 1,2,4-trichlorobenzene Kociba et al. 1981 1,2,4-trichlorobenzene 

44 d 5 d/wk 7 h/d 44 d 5 d/wk 7 h/d 

100 M 100 M 

Kociba et al. 1981 1,2,4-trichlorobenzene Kociba et al. 1981 1,2,4-trichlorobenzene 

a The number corresponds to entries in Figure 3-1. Bd Wt = body weight; (Cardio = cardiovascular; d = day(s); Endocr = endocrine; Gastro = gastrointestinal; Hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; M = male; Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s) 
Res

CarGaHeMu

ppm 

1000 

100 1k 2r 3r 4h 5h 1k 2r 3r 4h 5h 3r 5h 1k 2r 3r 4h 5h 3r 5h 

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

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

piratory 

diovascular 

strointestinal 

matological 

sculoskeletal 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation
	

Intermediate (15-364 days)
	

Systemic 

39
Hepatic 

Renal Endocrine Dermal Ocular 

ppm 

1000 

100 1k 2r 3r 4h 5h 1k 2r 3r 4h 5h 3r 5h 1k 2r 4h 1k 2r 3r 4h 5h 

3r 

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

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation (Continued)

Intermediate (15-364 days) 

Systemic 

40
Body W

ImmunoNeuroloReprod

ppm 

1000 

100 1k 2r 3r 4h 5h 6k 7r 8r 9h 10h 11k 12r 13r 14h 15h 16r 17h 

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

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

eight 

/Lymphor 

gical 

uctive 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-1 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Inhalation (Continued) 

Intermediate (15-364 days)
	

Systemic
	

41
106

1209

58

130130130130130130130130130

59

130

60

130

***DRAFT FOR PUBLIC COMMENT***

Table 3-2 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Inhalation 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Systemic 

1 Rat 

(SpragueDawley) 

1 hr 

System 

Bd Wt 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

Jorgenson et al. 1976 1,3,5-Trichlorobenzene 

1209 (44-60% less weight than 

controls 14 days after exposure) 

INTERMEDIATE EXPOSURE Systemic 

2 Rat 

(CD) 

13 wk 5 d/wk 6 h/d 

Resp 130 Sasmore et al. 1983 

1,3,5-Trichlorobenzene 

Cardio 130 Gastro 130 Hemato 130 Hepatic 130 Renal 130 Endocr 130 Ocular 130 

Immuno/ Lymphoret 

3 Rat 

(CD) 

13 wk 5 d/wk 6 h/d 

Bd Wt 130 

130 Sasmore et al. 1983 

1,3,5-Trichlorobenzene 

Neurological 

4 Rat 

(CD) 

13 wk 5 d/wk 6 h/d 

130 Sasmore et al. 1983 

1,3,5-Trichlorobenzene 
61

130

***DRAFT FOR PUBLIC COMMENT***

Table 3-2 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

Reproductive 

5 Rat 

(CD) 

13 wk 5 d/wk 6 h/d 

130 Sasmore et al. 1983 

1,3,5-Trichlorobenzene 

a The number corresponds to entries in Figure 3-2. Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; Gastro = gastrointestinal; Hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s) 
Body Weight 

Systemic 

ppm 

10000 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-2 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Inhalation 

Acute (≤14 days) 

1r 

1000 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

44
Respiratory 

Cardiovascular Gastrointestinal Hematological Hepatic Renal Endocrine Ocular Body Weight Immuno/Lymphor Neurological Reproductive 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

1000 

Figure 3-2 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Inhalation (Continued) 

Intermediate (15-364 days)
	

Systemic
	

ppm 

2r 2r 2r 2r 2r 2r 2r 2r 2r 3r 4r 5r 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

100 

45
 

 

 

 

 

 

TRICHLOROBENZENES 46 

3. HEALTH EFFECTS 

Exposure of rats to up to 130 ppm 1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks 

did not induce histological changes in the heart (Sasmore et al. 1983). 

Gastrointestinal Effects. Exposure of male rats, dogs, and rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors 7 hours/day, 5 days/week for a total of 30 exposures during a 40-day period did not 

induce significant gross or microscopic alterations in the gastrointestinal tract (Kociba et al. 1981). 

Similar results were reported for the gastrointestinal tract of rats exposed to up to 130 ppm 

1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks (Sasmore et al. 1983). 

Hematological Effects. Complete blood counts performed on male monkeys, rats, and rabbits 

exposed continuously to up to 100 ppm 1,2,4-trichlorobenzene vapors for up to 26 weeks did not show 

any significant exposure-related differences from controls (Coate et al. 1977). Kociba et al. (1981) 

reported no significant alterations in total red blood cells, total differential leukocytes, packed cell volume 

or hemoglobin concentration in blood samples from male rats, rabbits, and dogs following 30 intermittent 

exposures to up to 100 ppm 1,2,4-trichlorobenzene vapors. 

Exposure of rats to up to 130 ppm 1,3,5-trichlorobenzene 6 hours/day, 5 days/week for 13 weeks did not 

significantly alter blood cell counts and mean corpuscular values, differential counts, or platelet counts 

(Sasmore et al. 1983). Methemoglobin was slightly higher at 13 weeks than at 4 weeks, but values did 

not reach significant levels (data not shown). 

Musculoskeletal Effects. No significant alterations were reported in skeletal muscle from male rats, 

rabbits, and dogs following 30 intermittent exposures to up to 100 ppm 1,2,4-trichlorobenzene vapors 

(Kociba et al. 1981). 

In the 13-week inhalation study with 1,3,5-trichlorobenzene (Sasmore et al. 1983), there is no explicit 

indication that musculoskeletal tissues were examined, although the investigators stated that 34 specific 

organs and tissues from the control and the high-exposure groups (130 ppm) were examined 

microscopically. Therefore, it is reasonable to assume that evaluations were conducted and that no 

alterations were observed. 

Hepatic Effects. Continuous exposure of male monkeys or rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors for 26 weeks did not induce significant gross or microscopic alterations in the liver (Coate 

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TRICHLOROBENZENES 47 

3. HEALTH EFFECTS 

et al. 1977). However, exposure-related liver changes were described in rats (only qualitative description 

provided). The changes were characterized as mild and were seen in all exposed groups (25, 50, 

100 ppm) usually after 4 and 13 weeks but not at 26 weeks. Hepatocytomegaly occurred in all exposed 

groups but seemed more noticeable in the mid- and high-exposure groups. There was also a slight 

increase in the degree of vacuolization of hepatocytes in exposed rats that did not appear dose-related. 

Hepatocytomegaly was present in all exposed groups at 4 weeks and in the mid- and high-exposure 

groups at 13 weeks. Exposed rats also showed a slight increase in incidence of granuloma at 4 weeks, 

which did not appear to be dose-related. No histological alterations were reported in the liver from rats 

following 15 exposures to 200 ppm 1,2,4-trichlorobenzene each lasting 6 hours (Gage 1970). 

Changes in liver weight were reported in rats, dogs, and rabbits exposed to 100 ppm 1,2,4-trichlorobenzene vapors 7 hours/day, 5 days/week for a total of 30 exposures during a 44-day period (Kociba et al. 

1981). These changes were not accompanied by histological alterations or alterations in clinical 

chemistry tests for liver function. In rats, relative liver weight increased 11% relative to controls. 

Urinalyses conducted after 15 and 30 days of exposure showed statistically significant increased 

coproporphyrins and uroporphyrins in both the low- (30 ppm) and high-dose rats (100 ppm), which the 

investigators attributed to the ability of 1,2,4-trichlorobenzene to induce hepatic microsomal enzymes 

rather than to induce destruction of heme-containing cytochromes or inhibition of heme synthesis. In 

dogs, both absolute and relative liver weights were increased (27–30%). In rabbits, relative liver weight 

was decreased 16% relative to controls. Urinary porphyrins levels were not examined in dogs or rabbits. 

Exposure of rats to up to 130 ppm 1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks 

did not significantly affect liver weight or the gross or microscopic appearance of the liver (Sasmore et al. 

1983). Urinary porphyrin levels were elevated in males at 13 weeks, but large variability rendered the 

differences with controls nonsignificant. 

Renal Effects. Continuous exposure of male monkeys or rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors for 26 weeks did not induce significant gross or microscopic alterations in the kidneys 

(Coate et al. 1977). Male rats exposed in a similar manner showed kidney changes characterized as mild 

and present in all exposed groups usually after 4 and 13 weeks but not at 26 weeks of exposure (only a 

qualitative description was provided). Exposed male rats showed hyaline degeneration in the inner zone 

of the cortex, which appeared more severe at 4 weeks but was not dose-related; severity appeared 

increased at 13 weeks in high-dose rats. No histological alterations were reported in the kidneys from rats 

following 15 exposures to 200 ppm 1,2,4-trichlorobenzene each lasting 6 hours (Gage 1970), or in the 

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TRICHLOROBENZENES 48 

3. HEALTH EFFECTS 

kidneys from rats, rabbits, and dogs exposed to up to 100 ppm 1,2,4-trichlorobenzene vapors 7 hours/day, 

5 days/week for 30 exposures during a 44-day period (Kociba et al. 1981). 

Exposure of rats to up to 130 ppm 1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks 

did not result in significant gross or microscopic alterations in the kidneys (Sasmore et al. 1983). 

Endocrine Effects. Fifteen 6-hour exposures to up to 200 ppm 1,2,4-trichlorobenzene vapors did not 

induce significant gross or histological alterations in the adrenal glands from rats (Gage 1970). Exposure 

of rats, dogs, and rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors 7 hours/day, 5 days/week for a 

total of 30 exposures did not induce significant gross or microscopic alterations in the pituitary gland, 

adrenal gland, thyroid, or parathyroid (Kociba et al. 1981). 

In the 13-week study of rats exposed intermittently to up to 130 ppm 1,3,5-trichlorobenzene vapors, the 

investigators stated that 34 organs were examined in the control and high-dose groups but did not specify 

the organs (Sasmore et al. 1983). However, there is mention that hemosiderosis was noted in the thyroid 

gland, which, by the distribution and nature in the different groups, appeared unrelated to the treatment. 

It seems reasonable to assume that other endocrine glands were also examined and that no alterations 

were observed. 

Dermal Effects. Continuous exposure of male monkeys, rats, and rabbits to up to 100 ppm 

1,2,4-trichlorobenzene vapors for 26 weeks did not induce significant gross or microscopic alterations in a 

section of abdominal skin that was examined (Coate et al. 1977). 

No relevant data were located regarding 1,3,5-trichlorobenzene. 

Ocular Effects. Gage (1970) reported that lacrimation occurred in rats initially during the 6-hour 

exposures to 70 ppm 1,2,4-trichlorobenzene but not during exposures to 20 ppm 1,2,4-trichlorobenzene. 

Continuous exposure of male monkeys, rats, or rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors 

for 26 weeks did not induce significant gross or microscopic alterations in the eyes (Coate et al. 1977). 

The eyes from rats, dogs, and rabbits were also examined in the intermediate-duration study by Kociba et 

al. (1981). In that study, exposure to up to 100 ppm 1,2,4-trichlorobenzene vapors did not induce 

alterations in the microscopic morphology of the eye. 

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TRICHLOROBENZENES 49 

3. HEALTH EFFECTS 

Body Weight Effects. Continuous exposure of male monkeys, rats, and rabbits to up to 100 ppm 

1,2,4-trichlorobenzene vapors for 26 weeks (Coate et al. 1977) or intermittent exposure of rats, dogs, and 

rabbits to up to 100 ppm for 44 days (Kociba et al. 1981) did not significantly alter body weight. Gage 

(1970) reported that rats exposed to 70 ppm 1,2,4-trichlorobenzene 6 hours/day for 15 exposures showed 

retarded weight gain, but no data were presented. 

Exposure of rats to 1,209 ppm 1,3,5-trichlorobenzene vapors for 60 minutes resulted in 44 and 60% less 

body weight gain in males and females, respectively, 14 days after exposure (Jorgenson et al. 1976). 

Body weight was not affected in rats exposed intermittently to up to 130 ppm 1,3,5-trichlorobenzene 

vapors for 13 weeks (Sasmore et al. 1983). 

Metabolic Effects. Intermittent exposure of rats to up to 130 ppm 1,3,5-trichlorobenzene vapors for 

13 weeks did not significantly affect serum electrolyte levels or electrolyte balance (Sasmore et al. 1983). 

No relevant data were located regarding 1,2,4-trichlorobenzene. 

3.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans after inhalation exposure to 

trichlorobenzenes. 

Continuous exposure of monkeys, rats, and rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors for 

26 weeks did not induce significant gross or microscopic changes in the spleen of the animals (Coate et 

al. 1977). Fifteen intermittent exposures (6 hours/day) of rats to up to 200 ppm 1,2,4-trichlorobenzene 

vapors also did not result in significant histological alterations in the spleen (Gage 1970). Similar 

experiments in rats, rabbits, and dogs exposed 7 hours/day, 5 days/week to up to 100 ppm 1,2,4-trichlorobenzene vapors for a total of 30 exposures during a 44-day period did not result in significant gross or 

microscopic alterations in the spleen, thymus, or lymph nodes (Kociba et al. 1981). 

No histological alterations were observed in lymphoreticular tissues from rats exposed to up to 130 ppm 

1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks (Sasmore et al. 1983). 

No relevant data were located regarding 1,2,3-trichlorobenzene. 

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TRICHLOROBENZENES 50 

3. HEALTH EFFECTS 

NOAELs for lymphoreticular effects of 1,2,4-trichlorobenzene and 1,3,5-trichlorobenzene are presented 

in Tables 3-1 and 3-2 and are plotted in Figures 3-1 and 3-2. 

3.2.1.4 Neurological Effects 

No studies were located regarding neurological effects in humans after inhalation exposure to 

trichlorobenzenes. 

Lethargy was reported in rats during 6-hour exposures to 70 ppm 1,2,4-trichlorobenzene vapors (Gage 

1970). No such effect was observed during exposures to 20 ppm. 

Continuous exposure of monkeys, rats, or rabbits to up to 100 ppm 1,2,4-trichlorobenzene vapors for 

26 weeks did not induce significant gross or microscopic changes in the brain and spinal cord (Coate et al. 

1977). Operant behavior tests conducted in the monkeys throughout the study showed no exposurerelated alterations. Similar lack of gross or histological alterations were reported in the brain, spinal cord, 

and peripheral nerves from rats, dogs, and rabbits exposed intermittently to up to 100 ppm 1,2,4-trichlorobenzene vapors during a 44-day period (Kociba et al. 1981). 

No histological alterations were observed in the brain and spinal cord from rats exposed to up to 130 ppm 

1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks (Sasmore et al. 1983). 

No relevant data were located regarding 1,2,3-trichlorobenzene. 

NOAELs and LOAELs for neurological effects are presented in Tables 3-1 and 3-2 and are plotted in 

Figures 3-1 and 3-2. 

3.2.1.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after inhalation exposure to 

trichlorobenzenes. 

No significant gross or histological alterations were reported in the reproductive organs from male rats, 

dogs, and rabbits exposed intermittently to up to 100 ppm 1,2,4-trichlorobenzene vapors for 44 days 

(Kociba et al. 1981). It should be noted, however, that absolute and relative testes weights were 

significantly increased (30 and 43%, respectively) in rabbits exposed to 100 ppm (but not 30 ppm). The 

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TRICHLOROBENZENES 51 

3. HEALTH EFFECTS 

investigators considered this change unrelated to the test material since, as indicated above, microscopic 

examination did not reveal any significant histological changes. 

No histological alterations were observed in the reproductive organs from male or female rats exposed to 

up to 130 ppm 1,3,5-trichlorobenzene vapors 6 hours/day, 5 days/week for 13 weeks (Sasmore et al. 

1983). 

No relevant data were located regarding 1,2,3-trichlorobenzene. 

NOAELs for reproductive effects are presented in Table 3-1 and are plotted in Figure 3-1. 

No studies were located regarding the following health effects in humans or animals after inhalation 

exposure to trichlorobenzenes: 

3.2.1.6 Developmental Effects 

3.2.1.7 Cancer 

3.2.2 Oral Exposure 

3.2.2.1 Death 

No studies were located regarding death in humans after oral exposure to trichlorobenzenes. 

Information regarding acute lethality is available for the three trichlorobenzene isomers. An LD50 of 

756 mg/kg was reported for 1,2,4-trichlorobenzene in CFE rats (Brown et al. 1969). In the same study, 

the investigators determined an oral LD50 of 766 mg/kg for 1,2,4-trichlorobenzene in C57BL/6N mice. In 

both species, lower doses caused depression of activity, while lethal doses induced extensor convulsions. 

Another study reported an LD50 of 880 mg/kg for 1,2,4-trichlorobenzene in Sprague-Dawley rats (Côté et 

al. 1988). In a developmental study, six out of six pregnant Sprague-Dawley rats died after 3 days of 

dosing with 1,200 mg/kg 1,2,4-trichlorobenzene (Kitchin and Ebron 1983). 

Without providing further details, Côté et al. (1988) reported that the oral LD50 for 1,2,3-trichlorobenzene 

in Sprague-Dawley rats was 1,830 mg/kg. In a brief report in which groups of two rats per group were 

administered 1,000 or 2,000 mg/kg 1,2,3-trichlorobenzene by gavage in corn oil, one rat in the high-dose 

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TRICHLOROBENZENES 52 

3. HEALTH EFFECTS 

group died within 2 days of dosing (Dow Chemical 1956). The investigators stated that slight pathology 

of the liver and spleen occurred, but no details were provided. 

An oral LD50 of 2,100 mg/kg was reported for 1,3,5-trichlorobenzene in Sprague-Dawley rats (Côté et al. 

1988). In another study, Jorgenson et al. (1976) reported LD50 values of 1,800 and 2,800 mg/kg for 

1,3,5-trichlorobenzene in male and female Sprague-Dawley rats, respectively. All deaths except one 

occurred between 21 and 96 hours after dosing. Clinical signs observed included rough hair coat, passive 

tremors, depression, and inactivity leading to prostration, persistent tremor, coma, and death; necropsy 

revealed no gross abnormalities. The corresponding oral LD50 values for 1,3,5-trichlorobenzene in male 

and female ICR mice were 3,350 and 3,402 mg/kg, respectively (Jorgenson et al. 1976). Clinical signs 

observed included rough hair coat, passive tremors, depression, inactivity, prostration, persistent tremors, 

coma, and death. Deaths occurred between 22 and 288 hours after dosing; necropsy revealed no gross 

abnormalities. Increased mortality rate was reported in male rats dosed with 66.5 mg/kg/day 

1,2,4-trichlorobenzene for 104 weeks (Moore 1994a). Similar results were reported in male and female 

mice dosed with 519.9 and 572.6 mg/kg/day 1,2,4-trichlorobenzene, respectively, for 104 weeks (Moore 

1994b). 

The limited data available suggest that 1,2,4-trichlorobenzene has a stronger acute toxicity than the other 

two isomers, and that rats may be more susceptible than mice. 

Lethal doses and LD50 values are presented in Tables 3-3, 3-4, and 3-5 and plotted in Figures 3-3, 3-4, and 

3-5. 

3.2.2.2 Systemic Effects 

No studies were located regarding systemic effects in humans after oral exposure to trichlorobenzenes. 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Tables 3-3, 3-4, and 3-5 and plotted in Figure 3-3, 3-4, and 

3-5. 

Respiratory Effects. No gross or microscopic alterations were observed in the lungs, bronchi, or 

trachea from rats administered up to 300 mg/kg/day 1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3- or 

1,3,5-trichlorobenzene on Gd 6–15 and sacrificed on Gd 22 (Black et al. 1988). In intermediate-duration 

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62

756

5

880

127

2250

28

1200

63

766

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

once (G) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

756 (LD50) 

Reference Chemical Form 

Brown et al.1969 1,2,4-trichlorobenzene 

2 Rat 

(SpragueDawley) 

once (G) 880 (LD50) Cote et al. 1988 1,2,4-trichlorobenzene 

3 Rat 

(NS) 

once (G) 2250 (lowest lethal dose) E.I. Dupont 1971 1,2,4-trichlorobenzene 

4 Rat 

(SpragueDawley) 

Gd 9-13 1 x/d (GO) 

1200 F (6/6 died after 3 days of 

dosing) 

Kitchin and Ebron 1983 1,2,4-trichlorobenzene 

5 Mouse 

(C57BL/6N) 

once (G) 766 (LD50) Brown et al.1969 1,2,4-trichlorobenzene 
43

300300300300300150

300

300300300300

84

40

10

128

450

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Systemic 

6 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

Resp 300 F Black et al. 1988 

1,2,4-trichlorobenzene 

Cardio 300 F 

Gastro 300 F Hemato 300 F Musc/skel Hepatic 

300 F 150 F 300 F (11% increase in relative 

liver weight) 

Renal 300 F Dermal 300 F Ocular 300 F Metab 300 F 

7 Rat 

(albino) 

14 d 1 x/d (GO) 

Hemato 40 M Carlson and Tardiff 197

1,2,4-trichlorobenzene 

Hepatic 10 M (15% increase in relative 

liver weight; increased phase I and phase II enzyme activity) 

8 Rat 

(NS) 

3 d 1 x/d (GO) 

Bd Wt 450 (4% weight loss in 3 

days) 

E.I. Dupont 1971 1,2,4-trichlorobenzene 
27

36

120

120

360

81

500500

80

130

44

300

45

300

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

9 Rat 

(SpragueDawley) 

Gd 9-13 1 x/d (GO) 

Hepatic 36 F 120 F (increased phase I and 

phase II metabolic enzyme activity) 

Kitchin and Ebron 1983 1,2,4-trichlorobenzene 

Bd Wt 120 F 360 F (17 grams lost, controls 

gained 37 grams) 

10 Rat 

(albino) 

10 d 1 x/d (G) 

Hepatic 500 M (intense necrosis and 

fatty change) 

Rimington and Ziegler 11,2,4-trichlorobenzene 

Bd Wt 500 M (weight loss) 

11 Mouse 

(CD-1) 

Gd 8-12 1 x/d (G) 

Bd Wt 130 F Chernoff and Kavlock 1

1,2,4-trichlorobenzene 

Immuno/ Lymphoret 

12 Rat 

(SpragueDawley) 

Neurological 

13 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) Gd 6-15 1 x/d (GO) 

300 F 300 F 

Black et al. 1988 1,2,4-trichlorobenzene Black et al. 1988 1,2,4-trichlorobenzene 
46

300

47

300

29

360

79

130

86

130

87

130

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Reproductive 

14 Rat 

(SpragueDawley) 

Developmental 

15 Rat 

(SpragueDawley) 

16 Rat 

(SpragueDawley) 

17 Mouse 

(CD-1) 

18 Mouse 

(CD-1) 

19 Mouse 

(CD-1) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Gd 6-15 1 x/d (GO) Gd 6-15 1 x/d (GO) 

300 F 300 

Black et al. 1988 1,2,4-trichlorobenzene Black et al. 1988 1,2,4-trichlorobenzene 

Gd 9-13 1 x/d (GO) 

360 F (retarded fetal 

development) 

Kitchin and Ebron 1983 1,2,4-trichlorobenzene 

Gd 8-12 1 x/d (G) Gd 8-12 1 x/d (GO) 

130 130 

Chernoff and Kavlock 11,2,4-trichlorobenzene Gray and Kavlock 1984 1,2,4-trichlorobenzene 

Gd 8-12 1 x/d (GO) 

130 Gray et al. 1986 

1,2,4-trichlorobenzene 
85

4020

40

40

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

INTERMEDIATE EXPOSURE 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Systemic 

20 Rat 

(albino) 

90 d 1 x/d (GO) 

Hemato 40 M Carlson and Tardiff 197

1,2,4-trichlorobenzene 

Hepatic 20 M 40 M (14% increase in relative 

liver weight after 30-day recovery period; increased phase I metabolic enzymes) 

Bd Wt 40 M 
112

150.6150.6150.6150.6150.614.6

45.6

45.6

133.7

150.6150.6150.6150.6

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) Exposure/

Duration/

a Frequency Key to Species (Route) Figure (Strain) System 

21 Rat 14 wk Resp ad lib (Fischer- 344) 

(F) 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Ocular Bd Wt Metab 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

CMA 1989 

150.6 F 

1,2,4-trichlorobenzene 

150.6 F 150.6 F 150.6 F 150.6 F 

b

14.6 M 45.6 M (increased liver weight, 

hepatocyte hypertrophy) 

45.6 M 133.7 M (increased kidney weight; 

dilated tubules, granular casts; interstitial nephritis; elevated BUN) 

150.6 F 150.6 F 150.6 F 150.6 F 
1

1011011011011017.8

82

7.8

82

101101101101

82

730730

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

22 Rat 

(SpragueDawley) 

13 wk ad lib (F) 

Resp 101 F Cote et al. 1988 

1,2,4-trichlorobenzene 

Cardio 101 F 

Gastro 101 F Hemato 101 F Musc/skel Hepatic 

101 F 

7.8 M 82 M (13-20% increased 

absolute and relative liver weight) 

Renal 7.8 M 82 M (31-36% increase 

absolute and relative kidney weight) 

Dermal 101 F Ocular 101 F Bd Wt 101 F Metab 101 F 

23 Rat 

(albino) 

15 d 1 x/d (G) 

Hepatic 730 M (intense necrosis and 

fatty change) 

Rimington and Ziegler 11,2,4-trichlorobenzene 

Bd Wt 730 M (weight loss) 
98

1345134513451345134567

850

1345134513451345

113

150.6

2

101

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Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

LOAEL 

System 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Ocular Metab 

NOAEL 

(mg/kg/day) 

1345 F 

1345 F1345 F1345 F1345 F

67 M

1345 F1345 F1345 F1345 F

150.6 F 

101 F 

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

850 M (hepatocyte hypertrophy, 

atrophy, vacuolar degeneration, necrosis; higher ALT and SDH activities) 

Reference Chemical Form 

Hiles 1989 1,2,4-trichlorobenzene CMA 1989 1,2,4-trichlorobenzene Cote et al. 1988 1,2,4-trichlorobenzene 

24 Mouse 

(B6C3F1) 

Immuno/ Lymphoret 

25 Rat 

(Fischer- 344) 

26 Rat 

(SpragueDawley) 

13 wk ad lib (F) 14 wk ad lib (F) 13 wk ad lib (F) 
99

1345

114

150.6

3

101

100

1345

115

133.7150.6

4

82101

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Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

27 Mouse 

(B6C3F1) 

13 wk ad lib (F) 

Neurological 

28 Rat 

(Fischer- 344) 

14 wk ad lib (F) 

1345 F 

150.6 F 

Hiles 1989 1,2,4-trichlorobenzene CMA 1989 1,2,4-trichlorobenzene 

29 Rat 

(SpragueDawley) 

13 wk ad lib (F) 

101 F Cote et al. 1988 

1,2,4-trichlorobenzene 

30 Mouse 

(B6C3F1) 

13 wk ad lib (F) 

Reproductive 

31 Rat 

(Fischer- 344) 

14 wk ad lib (F) 

1345 F 

133.7 M 

150.6 F 

Hiles 1989 1,2,4-trichlorobenzene CMA 1989 1,2,4-trichlorobenzene 

32 Rat 

(SpragueDawley) 

13 wk ad lib (F) 

82 M 

101 F 

Cote et al. 1988 1,2,4-trichlorobenzene 
70

3353.6

101

12221345

71

53.6

92

66.5

97

519.9572.6

***DRAFT FOR PUBLIC COMMENT***

Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

33 Rat 

(SpragueDawley) 

90 d ad lib (W) 

33 M 

53.6 F 

Robinson et al. 1981 1,2,4-trichlorobenzene 

34 Mouse 

(B6C3F1) 

13 wk ad lib (F) 

1222 M 1345 F 

Hiles 1989 1,2,4-trichlorobenzene 

Developmental 

35 Rat 

(SpragueDawley) 

90 d ad lib (W) 

53.6 F Robinson et al. 1981 

1,2,4-trichlorobenzene 

CHRONIC EXPOSURE Death 

36 Rat 

(Fischer- 344) 

104 wk ad lib (F) 

66.5 M (decreased survival) Moore 1994a 

1,2,4-trichlorobenzene 

37 Mouse 

(B6C3F1) 

104 wk ad lib (F) 

519.9 M (decreased survival) 572.6 F (decreased survival) 

Moore 1994b 1,2,4-trichlorobenzene 
88

81.481.481.481.481.419.4

66.5

19.4

66.5

81.481.481.481.4

***DRAFT FOR PUBLIC COMMENT***

Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Systemic 

38 Rat 

(Fischer- 344) 

104 wk ad lib (F) 

Resp 81.4 F Moore 1994a 

1,2,4-trichlorobenzene 

Cardio 81.4 F Gastro 81.4 F Hemato 81.4 F Musc/skel Hepatic 

81.4 F 

c

19.4 M 66.5 M (increased liver weight; 

hepatocellular hypertrophy) 

Renal 19.4 M 66.5 M (renal transitional cell 

hyperplasia) 

Endocr 81.4 F Dermal 81.4 F Ocular 81.4 F Bd Wt 81.4 F 
93

572.6572.6572.6572.6572.621

100.626.3

572.6572.6572.6572.6100.6

519.9

89

81.4

***DRAFT FOR PUBLIC COMMENT***

Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

39 Mouse 104 wk 

ad lib (B6C3F1) (F) 

Immuno/ Lymphoret 

40 Rat 104 wk 

ad lib (Fischer- 344) (F) 

System 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

572.6 F Moore 1994b 

1,2,4-trichlorobenzene 

572.6 F 572.6 F 572.6 F 572.6 F 

21 M 100.6 M (centrilobular 

hepatocytomegaly) 

26.3 F (increased absolute and 

relative liver weight) 

572.6 F 572.6 F 572.6 F 572.6 F 100.6 M 519.9 M (16% decreased final 

body weight) 

81.4 F Moore 1994a 

1,2,4-trichlorobenzene 
94

572.6

90

81.4

95

572.6

91

66.581.4

96

519.9572.6

***DRAFT FOR PUBLIC COMMENT***

Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

41 Mouse 

(B6C3F1) 

104 wk ad lib (F) 

572.6 F Moore 1994b 

1,2,4-trichlorobenzene 

Neurological 

42 Rat 

(Fischer- 344) 

104 wk ad lib (F) 

81.4 F Moore 1994a 

1,2,4-trichlorobenzene 

43 Mouse 

(B6C3F1) 

104 wk ad lib (F) 

572.6 F Moore 1994b 

1,2,4-trichlorobenzene 

Reproductive 

44 Rat 

(Fischer- 344) 

104 wk ad lib (F) 

66.5 M 81.4 F 

Moore 1994a 1,2,4-trichlorobenzene 

45 Mouse 

(B6C3F1) 

104 wk ad lib (F) 

519.9 M 

572.6 F 

Moore 1994b 1,2,4-trichlorobenzene 
117

100.6127

***DRAFT FOR PUBLIC COMMENT***

Table 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Cancer 

46 Mouse 

(B6C3F1) 

104 wk ad lib (F) 

100.6 M (CEL: hepatocellular 

carcinoma) 

Moore 1994b 1,2,4-trichlorobenzene 

127 F (CEL: hepatocellular 

carcinoma) 

a The number corresponds to entries in Figure 3-3. b Used to derive an intermediate-duration oral MRL of 0.1 mg/kg/day for 1,2,4-trichlorobenzene; the MRL was derived by dividing the BMDL10 by an uncertainty faanimal to human extrapolation and 10 for human variability). c Used to derive a chronic-duration oral MRL of 0.1 mg/kg/day for 1,2,4-trichlorobenzene; the MRL was derived by dividing the BMDL10 by an uncertainty factor of to human extrapolation and 10 for human variability). ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; gastrointestinal; Gd = gestation day; (GO) = gavage in oil; Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M metabolic; Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; (W) = drinking water; wk = week(s); x = time(s) 
Death 

I

mg/kg/day 

10000 

3r 

4r 

1000 

2r 

5m 1r 

10r 10r 8r 

9r 16r 

6r 6r 6r 6r 6r 6r 6r 6r 6r 6r 12r 13r 14r 15r 

6r 

11m 17m 18m 19m 9r 9r 

100 

7r 9r 

10 7r 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

Respiratory Cardiovascular 

Gastrointestinal 

Hematological 

Musculoskeletal 

Hepatic 

Renal 

Dermal 

Ocular 

Body Weight 

Metabolic 

mmuno/Lymphor 

Neurological 

Reproductive 

Developmental 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral
	

Acute (≤14 days)
	

Systemic 

67
Res

CarGasHeMusHepRenEndDerOcuBodMetImmNeuRepDev

mg/kg/day 

10000 

24m 24m 24m 24m 24m 24m 24m 24m 24m 27m 30m 34m 34m

1000 24m 23r 23r 

21r 21r 21r 21r 21r 21r 21r 21r 21r 25r 28r 31r 21r 31r 

100 22r 22r 22r 22r 22r 22r 22r 22r 22r 26r 29r 32r

22r 22r 32r

24m 

33r 35r 21r 21r 20r 20r 20r 33r 

20r 

21r
	

10
	 22r 22r 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

piratory 

diovascular 

trointestinal 

matological 

culoskeletal 

atic 

al 

ocrine 

mal 

lar 

y Weight 

abolic 

uno/Lymphor 

rological 

roductive 

elopmental 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (Continued)

Intermediate (15-364 days) 

Systemic 

68
Death 

RespiraCardiovGastroiHematoMusculHepaticRenal EndocriDermal Ocular Body WImmunNeuroloReprodCancer 

 

 

mg/kg/day 

1000 

37m 39m 39m 39m 39m 39m 39m 39m 39m 39m 41m 43m 45m 37m 39m 45m 

46m 

100 39m 39m 46m 

38r 38r 38r 38r 38r 38r 38r 38r 38r 40r 42r 44r 

36r 38r 38r 44r 

39m 

39m 38r 38r 

10 

1 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

0.1 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

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

tory ascular 

ntestinal 

logical 

oskeletal 

ne 

eight 

o/Lymphor 

gical 

uctive 

* 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-3 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Oral (Continued) 

Chronic (≥365 days)
	

Systemic
	

69
37

1830

107

2000

48

600600600600600150

300

600600600

83

780

***DRAFT FOR PUBLIC COMMENT***

Table 3-4 Levels of Significant Exposure to 1,2,3-Trichlorobenzene - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

once (F) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

1830 (LD50) 

Reference Chemical Form 

Cote et al. 1988 1,2,3-Trichlorobenzene 

2 Rat 

(NS) 

once (GO) 2000 (1 out of 2 rats died within two days of 

dosing) 

Dow Chemical 1956 1,2,3-Trichlorobenzene 

Systemic 

3 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

Resp 600 F Black et al. 1988 

1,2,3-Trichlorobenzene 

Cardio 600 F Gastro 600 F Hemato 600 F Musc/skel Hepatic 

600 F 150 F 300 F (14% increase in relative 

liver weight) 

Dermal 600 F Ocular 600 F Metab 600 F 

4 Rat 

(albino) 

7 d 1 x/d (G) 

Bd Wt 780 M (weight loss) Rimington and Ziegler 1

1,2,3-Trichlorobenzene 
49

600

50

600

51

600

52

600

***DRAFT FOR PUBLIC COMMENT***

Table 3-4 Levels of Significant Exposure to 1,2,3-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Immuno/ Lymphoret 

5 Rat 

(SpragueDawley) 

Neurological 

6 Rat 

(SpragueDawley) 

Reproductive 

7 Rat 

(SpragueDawley) 

Developmental 

8 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) Gd 6-15 1 x/d (GO) Gd 6-15 1 x/d (GO) Gd 6-15 1 x/d (GO) 

600 F 600 F 600 F 600 

Black et al. 1988 1,2,3-Trichlorobenzene Black et al. 1988 1,2,3-Trichlorobenzene Black et al. 1988 1,2,3-Trichlorobenzene Black et al. 1988 1,2,3-Trichlorobenzene 
33

1131131131131137.6

78

7.6

78

1131137.6

78

113

34

113

35

113

***DRAFT FOR PUBLIC COMMENT***

Table 3-4 Levels of Significant Exposure to 1,2,3-Trichlorobenzene - Oral (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

INTERMEDIATE EXPOSURE Systemic 

9 Rat 13 wk 

ad lib (SpragueDawley) (F) 

Immuno/ Lymphoret 

10 Rat 13 wk 

ad lib (SpragueDawley) (F) 

Neurological 

11 Rat 13 wk 

ad lib (SpragueDawley) (F) 

System 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Dermal Ocular Bd Wt Metab 

NOAEL 

(mg/kg/day) 

113 F 

113 F 113 F 113 F 113 F 

7.6 M 7.6 M 

113 F 113 F 

7.6 M 

113 F 113 F 113 F 

LOAEL 

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

78 M 14% increase in relative 

liver weight) 

78 M (21% increase in relative 

kidney weight) 

78 M (10.2% reduced body 

weight gain) 

Reference Chemical Form 

Cote et al. 1988 1,2,3-Trichlorobenzene Cote et al. 1988 1,2,3-Trichlorobenzene Cote et al. 1988 1,2,3-Trichlorobenzene 
36

78113

***DRAFT FOR PUBLIC COMMENT***

Table 3-4 Levels of Significant Exposure to 1,2,3-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Reproductive 

12 Rat 

(SpragueDawley) 

13 wk ad lib (F) 

78 M 

113 F 

Cote et al. 1988 1,2,3-Trichlorobenzene 

a The number corresponds to entries in Figure 3-4. ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); (F) = feed; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = gestation day; (oil; Hemato = hematological; Immuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M metabolic; Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; wk = week(s); x = time(s) 
Death 

RespiratorCardiovasGastrointeHematologMusculoskHepatic Dermal Ocular Body WeigMetabolic Immuno/LNeurologicReproductiDevelopm

mg/kg/day 

10000 

2r
	 1r
	

1000 

4r 

3r 3r 3r 3r 3r 3r 3r 3r 5r 6r 7r 8r 

3r 

3r 

100 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

y 

cular 

stinal 

ical 

eletal 

ht 

ymphor 

al 

ve 

ental 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-4 Levels of Significant Exposure to 1,2,3-Trichlorobenzene - Oral
	

Acute (≤14 days)
	

Systemic
	

74
Respir

CardioGastroiHematMusculHepatiDermalOcular Body MetaboImmunNeurolReprod

1000 

Renal 

mg/kg/day 

9r 9r 9r 9r 9r 9r 9r 9r 10r 11r 12r

100 

9r 9r 9r 12r 

10 

9r 9r 9r 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

atory 

vascular 

ntestinal 

ological 

oskeletal 

c 

Weight 

lic 

o/Lymphor 

ogical 

uctive 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-4 Levels of Significant Exposure to 1,2,3-Trichlorobenzene - Oral (Continued) 

Intermediate (15-364 days)
	

Systemic
	

75
42

2100

102

18002800

103

33503402

53

600600600600600300

600

600600300

600

600

***DRAFT FOR PUBLIC COMMENT***

Table 3-5 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(SpragueDawley) 

once (F) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

2100 (LD50) 

Reference Chemical Form 

Cote et al. 1988 1,3,5-Trichlorobenzene 

2 Rat 

(SpragueDawley) 

once (GO) 1800 M (LD50) 

2800 F (LD50) 

Jorgenson et al. 1976 1,3,5-Trichlorobenzene 

3 Mouse 

(ICR) 

once (GO) 3350 M (LD50) 

3402 F (LD50) 

Jorgenson et al. 1976 1,3,5-Trichlorobenzene 

Systemic 

4 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

Resp 600 F Black et al. 1988 

1,3,5-Trichlorobenzene 

Cardio 600 F Gastro 600 F Hemato 600 F Musc/skel Hepatic 

600 F 300 F 600 F (25% increase in relative 

liver weight) 

Dermal 600 F Ocular 600 F Bd Wt 300 F 600 F (34% reduced body 

weight gain) 

Metab 600 F 
54

600

56

600

55

600

57

150

***DRAFT FOR PUBLIC COMMENT***

Table 3-5 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Immuno/ Lymphoret 

5 Rat 

(SpragueDawley) 

Neurological 

6 Rat 

(SpragueDawley) 

Reproductive 

7 Rat 

(SpragueDawley) 

Developmental 

8 Rat 

(SpragueDawley) 

Gd 6-15 600 F Black et al. 1988 

1 x/d 

1,3,5-Trichlorobenzene (GO) 

Gd 6-15 600 F Black et al. 1988 

1 x/d 

1,3,5-Trichlorobenzene (GO) 

Gd 6-15 600 F Black et al. 1988 

1 x/d 

1,3,5-Trichlorobenzene (GO) 

Gd 6-15 150 (histological lesions in Black et al. 1988 1 x/d the lenses of pups) 1,3,5-Trichlorobenzene (GO) 
38

1461461461461467.7

82

0.81

7.7

146146146146

39

146

40

146

***DRAFT FOR PUBLIC COMMENT***

Table 3-5 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Oral (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

INTERMEDIATE EXPOSURE Systemic 

9 Rat 13 wk 

ad lib (SpragueDawley) (F) 

Immuno/ Lymphoret 

10 Rat 13 wk 

ad lib (SpragueDawley) (F) 

Neurological 

11 Rat 13 wk 

ad lib (SpragueDawley) (F) 

LOAEL 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Resp 146 F Cote et al. 1988 

1,3,5-Trichlorobenzene 

Cardio Gastro Hemato Musc/skel Hepatic 

146 F 146 F 146 F 146 F 

7.7 M 82 M 11% increase in relative 

liver weight) 

Renal 0.81 M 7.7 M 25% increase in relative 

kidney weight) 

Dermal Ocular Bd Wt Metab 

146 F 146 F 146 F 146 F 146 F Cote et al. 1988 

1,3,5-Trichlorobenzene 

146 F Cote et al. 1988 

1,3,5-Trichlorobenzene 
41

82146

***DRAFT FOR PUBLIC COMMENT***

Table 3-5 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Reproductive 

12 Rat 

(SpragueDawley) 

13 wk ad lib (F) 

82 M 

146 F 

Cote et al. 1988 1,3,5-Trichlorobenzene 

a The number corresponds to entries in Figure 3-5. ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); (F) = feed; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = gestation day; (oil; Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; Metab = metabolic; Musc/skel = musculoskelno-observed-adverse-effect level; Resp = respiratory; wk = week(s); x = time(s) 
De

ReCaGaHeMuHeDeOcBoMeImNeReDe

mg/kg/day 

10000 

3m 3m 

2r 

1r 

2r 

1000 

4r 4r 4r 4r 4r 4r 4r 4r 4r 4r 5r 6r 7r 

4r 4r 

8r 

100 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

ath 

spiratory 

rdiovascular 

strointestinal 

matological 

sculoskeletal 

patic 

rmal 

ular 

dy Weight 

tabolic 

muno/Lymphor 

urological 

productive 

velopmental 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-5 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Oral 

Acute (≤14 days) 

Systemic 

80
Respir

CardiGastrHemaMuscHepatiRenal DermOculaBody MetabImmuNeuroRepro

mg/kg/day 

1000 

9r 9r 9r 9r 9r 9r 9r 9r 9r 10r 11r 12r 

100 

9r 12r 

10 

9r 9r 

1 

9r 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

atory 

ovascular 

ointestinal 

tological 

uloskeletal 

c 

al 

r 

Weight 

olic 

no/Lymphor 

logical 

ductive 

TRICHLOROBENZENES ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS

Figure 3-5 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Oral (Continued) 

Intermediate (15-364 days)
	

Systemic 

81
 

 

 

 

 

 

 

 

TRICHLOROBENZENES 82 

3. HEALTH EFFECTS 

studies, there were also no significant histological alterations in the lungs, trachea, or bronchi from rats 

exposed via the diet to up to 101 mg/kg/day (Côté et al. 1988) or 150.6 mg/kg/day (CMA 1989) 

1,2,4-trichlorobenzene. A 13-week dietary study in mice reported no significant histological alterations in 

the lungs or trachea from animals dosed with up to 1,345 mg/kg/day 1,2,4-trichlorobenzene (Hiles 1989). 

Chronic-duration exposure to 1,2,4-trichlorobenzene also did not induce significant histological 

alterations in the lungs and trachea from rats dosed via the diet with up to 81.4 mg/kg/day 1,2,4-trichlorobenzene (Moore 1994a) or from mice dosed with up to 572.6 mg/kg/day 1,2,4-trichlorobenzene (Moore 

1994b). 

Black et al. (1988) also studied the 1,2,3- and 1,3,5- isomers and reported no significant effects in the 

lungs, bronchi, and trachea of pregnant rats dosed by gavage with up to 600 mg/kg/day of either isomer 

on Gd 6–15 and sacrificed on Gd 22. Similar results were reported in rats treated with up to 

113 mg/kg/day 1,2,3-trichlorobenzene or 146 mg/kg/day 1,3,5-trichlorobenzene in the diet for 13 weeks 

(Côté et al. 1988). 

Cardiovascular Effects. No significant gross or microscopic alterations were observed in the heart 

of rats dosed by gavage with up to 300 mg/kg/day 1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3- or 

1,3,5-trichlorobenzene on Gd 6–15 and sacrificed on Gd 22 (Black et al. 1988). Similar results were 

reported regarding the heart and aorta from rats treated with up to 101 mg/kg/day 1,2,4-trichlorobenzene, 

113 mg/kg/day 1,2,3-trichlorobenzene, or 146 mg/kg/day 1,3,5-trichlorobenzene in the diet for 13 weeks 

(Côté et al. 1988), or 150.6 mg/kg/day 1,2,4-trichlorobenzene for 14 weeks (CMA 1989). Treatment of 

mice with up to 1,345 mg/kg/day 1,2,4-trichlorobenzene for 13 weeks via the diet did not significantly 

alter the gross or microscopic appearance of the heart or aorta (Hiles 1989). Treatment of rats with up to 

81.4 mg/kg/day 1,2,4-trichlorobenzene or mice with up to 572.6 mg/kg/day 1,2,4-trichlorobenzene 

through the diet for 104 weeks did not induce gross or microscopic changes in the heart (Moore 1994a, 

1994b). 

Gastrointestinal Effects. No significant gross or microscopic alterations were reported in the 

gastrointestinal tract of rats dosed by gavage with up to 300 mg/kg/day 1,2,4-trichlorobenzene or 

600 mg/kg/day 1,2,3- or 1,3,5-trichlorobenzene on Gd 6–15 and sacrificed on Gd 22 (Black et al. 1988). 

Similar results were reported in rats treated with up to 101 mg/kg/day 1,2,4-trichlorobenzene, 

113 mg/kg/day 1,2,3-trichlorobenzene, or 146 mg/kg/day 1,3,5-trichlorobenzene in the diet for 13 weeks 

(Côté et al. 1988), or 150.6 mg/kg/day 1,2,4-trichlorobenzene for 14 weeks (CMA 1989). Examination of 

the gastrointestinal tract from mice dosed with up to 1,345 mg/kg/day 1,2,4-trichlorobenzene for 

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13 weeks via the diet did not reveal significant treatment-related gross or histological alterations (Hiles 

1989). No gross or histological alterations were reported in the gastrointestinal tract from rats or mice 

dosed via the diet with up to 81.4 or 572.6 mg/kg/day 1,2,4-trichlorobenzene, respectively for 104 weeks 

(Moore 1994a, 1994b). 

Hematological Effects. Changes in hematological parameters have been reported in some acute- and 

intermediate-duration studies. However, since the reductions in hemoglobin and hematocrit reported in 

some of these studies are within the normal range for these parameters, they are not listed as LOAELs in 

Table 3-2; instead, the highest doses tested are listed as NOAELs for hematological effects. 

Treatment of pregnant rats with 150 or 300 mg/kg/day 1,2,4-trichlorobenzene during Gd 6–15 resulted in 

reductions in hemoglobin (6–7%) and hematocrit (6%) (Black et al. 1988). In the same study, doses of 

300 and 600 mg/kg/day 1,2,3-trichlorobenzene reduced hemoglobin by 6–7% and doses of 

600 mg/kg/day reduced the hematocrit by approximately 6%. Rats treated with 600 mg/kg/day 

1,3,5-trichlorobenzene showed reduction in hemoglobin and hematocrit of approximately 10–11% (Black 

et al. 1988). In another acute-duration study in rats, doses of up to 40 mg/kg/day 1,2,4-trichlorobenzene 

by gavage for 14 days did not affect hemoglobin or hematocrit levels (Carlson and Tardiff 1976). 

Some intermediate-duration dietary studies have reported mild hematological changes following exposure 

to 1,2,4-trichlorobenzene. For example, treatment of male rats with 133.7 mg/kg/day, but not 

45.6 mg/kg/day, 1,2,4-trichlorobenzene in the diet for 14 weeks reduced mean erythrocyte count (5%), 

hemoglobin (1.2%), and hematocrit (6%) (CMA 1989). In female rats, doses of 150.6 mg/kg/day reduced 

hemoglobin and hematocrit by 3.6–4%. Platelets were increased in males dosed with 133.7 mg/kg/day. 

In a similar study, administration of doses of up to 82 mg/kg/day to male rats and 101 mg/kg/day to 

females did not alter hematological parameters (Côté et al. 1988). No significant hematological changes 

were observed in male mice dosed with up to 1,222 mg/kg/day 1,2,4-trichlorobenzene for 13 weeks (Hiles 

1989). In the same study, female mice dosed with 1,345 mg/kg/day 1,2,4-trichlorobenzene had lower (5– 

9%) hemoglobin, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin; since the 

these changes occurred only in females, the investigator (Hiles 1989) did not consider them to be 

treatment-related. 

Administration in the diet of up to 113 mg/kg/day 1,2,3-trichlorobenzene or 146 mg/kg/day 

1,3,5-trichlorobenzene to rats for 13 weeks did not alter hematological parameters (Côté et al. 1988). 

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In the chronic-duration oral studies with 1,2,4-trichlorobenzene, cellular morphology and leukocyte 

differential were monitored on weeks 52, 78, and at termination (Moore 1994a, 1994b). The results 

showed no significant treatment-related alterations in the parameters monitored in rats dosed through the 

diet with up to 81.4 mg/kg/day or in mice dosed with up to 572.6 mg/kg/day 1,2,4-trichlorobenzene. No 

evidence of leukemia was seen in either study. 

Musculoskeletal Effects. No significant gross or histological alterations were reported in skeletal 

muscle from pregnant rats dosed with up to 300 mg/kg/day 1,2,4-trichlorobenzene or 600 mg/kg/day 

1,2,3-trichlorobenzene or 1,3,5,-trichlorobenzene on Gd 6–15 and sacrificed on Gd 22 (Black et al. 1988). 

Similar results were reported in rats dosed via the diet with up to 150.6 mg/kg/day 1,2,4-trichlorobenzene, 

113 mg/kg/day 1,2,3-trichlorobenzene, or 146 mg/kg/day 1,3,5-trichlorobenzene for 3 months (CMA 

1989; Côté et al. 1988). An intermediate-duration dietary study in mice dosed with up to 1,345 

mg/kg/day 1,2,4-trichlorobenzene for 13 weeks also did not find morphological alterations in bone or 

skeletal muscle (Hiles 1989). Chronic-duration studies did not find morphological alterations in bone or 

skeletal muscle from rats or mice dosed with up to 81.4 or 572.6 mg/kg/day 1,2,4-trichlorobenzene via the 

diet, respectively, for 104 weeks (Moore 1994a, 1994b). 

Hepatic Effects. Acute-, intermediate-, and chronic-duration oral studies in animals indicate that the 

liver is a target for trichlorobenzenes. An acute-duration study with 1,2,4-trichlorobenzene described 

intense necrosis and fatty change in rats following administration of 500 mg/kg/day 1,2,4-trichlorobenzene by gavage for 10 days (Rimington and Ziegler 1963). In a 14-day gavage study in male rats, 

1,2,4-trichlorobenzene induced a dose-related increase in relative liver weight (all doses, 15.3% at 

10 mg/kg/day, 28.9% at 40 mg/kg/day) (Carlson and Tardiff 1976). Moderate hepatocellular hypertrophy 

was reported in the liver from pregnant rats following administration of 360 mg/kg/day for 4 days; the 

NOAEL for this effect was 120 mg/kg/day (Kitchin and Ebron 1983). In another developmental study, 

mild hepatic changes consisting of increased periportal cytoplasmic eosinophilia and mild anisokaryosis 

of hepatocellular nuclei were reported in pregnant rats dosed with 150 and 300 mg/kg/day 1,2,4-trichlorobenzene on Gd 6–15 (Black et al. 1988). The same was reported in pregnant rats dosed with 300 and 

600 mg/kg/day 1,2,3- or 1,3,5-trichlorobenzene. Because no quantitative histological data were presented 

in the latter study, this information is not listed in Tables 3-3, 3-4, and 3-5. Histological alterations in the 

liver were almost always accompanied by increases in liver weight. 

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In a 90-day study in male rats, gavage administration of 1,2,4-trichlorobenzene (10, 20, 40 mg/kg/day) 

increased relative liver weight 14% in high-dose rats after a 30-day recovery period; however, no 

significant histological alterations were seen in the liver (Carlson and Tardiff 1976). Dietary 

administration of ≥14.6 mg/kg/day 1,2,4-trichlorobenzene to male rats or ≥52.5 mg/kg/day to females for 

14 weeks induced dose-related increases in absolute and relative liver weights (CMA 1989). Microscopic 

examination of the liver revealed an increased incidence of centrilobular hepatocyte hypertrophy in male 

rats dosed with ≥45.6 mg/kg/day 1,2,4-trichlorobenzene and in female rats dosed with 150.6 mg/kg/day; 

the corresponding NOAELs were 14.6 and 52.5 mg/kg/day (CMA 1989). Centrilobular hepatocyte 

hypertrophy was used as the basis for derivation of an intermediate-duration oral MRL for 1,2,4-trichlorobenzene. An additional intermediate-duration dietary study reported significant increases in relative liver 

weight in male rats dosed with 78–82 mg/kg/day of each trichlorobenzene isomer (Côté et al. 1988). The 

investigators stated that most treated groups (doses ranged from approximately 0.1 to 140 mg/kg/day) 

showed mild-to-moderate increases in cytoplasmic volume and anisokaryosis of hepatocytes mostly in 

perivenous and midzone areas. High-dose rats showed aggregated basophilia as well as widespread 

midzonal vacuolation due to fatty infiltration. However, since only a qualitative description of the 

histological changes was provided, it is impossible to determine with certainty NOAELs or LOAELs for 

the lesions; therefore, they are not listed in Tables 3-3, 3-4, or 3-5, but the organ weight changes are. 

A significant increase in absolute and relative liver weight was reported in male mice dosed via the diet 

with ≥850 mg/kg/day 1,2,4-trichlorobenzene and female mice dosed with ≥1,183 mg/kg/day 

1,2,4-trichlorobenzene for 13 weeks (Hiles 1989). These changes in liver weight correlated with 

microscopic changes characterized by hepatocellular cytomegaly with karyomegaly and multinucleation 

complex with adjacent hepatocellular compression, atrophy, anisocytosis, vacuolar degeneration, and 

necrosis. The NOAELs for these alterations were 67 and 86 mg/kg/day in males and females, 

respectively. In addition, changes in clinical chemistry that were considered treatment-related consisted 

of higher total protein in mid-dose males (850 mg/kg/day) and high-dose males (1,222 mg/kg/day) and 

females (1,345 mg/kg/day), increased albumin and globulin in high-dose males and females, increased 

serum alanine aminotransferase (ALT) in mid-dose males and in high-dose males and females, and 

increased sorbitol dehydrogenase (SDH) in mid- and high-dose males and females. According to the 

investigators, the higher protein was probably caused by dehydration. 

In a 104-week dietary study with 1,2,4-trichlorobenzene in rats, doses of 66.5 mg/kg/day in males and 

81.4 mg/kg/day in females produced significant increases in absolute and relative liver weight at 

termination (Moore 1994a). The corresponding NOAELs were 19.4 and 23.5 mg/kg/day. Significant 

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increases in the incidence of liver lesions were reported in rats that received the highest doses, 

66.5 mg/kg/day in males and 81.4 mg/kg/day in females. The histological alterations consisted of 

hepatocyte hypertrophy, focal cystic degeneration, and diffuse fatty change. The increased incidence of 

hepatocyte hypertrophy in male rats served as the basis for derivation of a chronic-duration oral MRL for 

1,2,4-trichlorobenzene. In a similar study in mice, doses ≥21 mg/kg/day 1,2,4-trichlorobenzene induced a 

dose-related increase in absolute and relative liver weight in males, whereas doses ≥100.6 mg/kg/day

1,2,4-trichlorobenzene increased relative liver weight (Moore 1994b). In females, doses ≥26.3 mg/kg/day 

also increased absolute and relative liver weight. Histological examination of the liver showed a 

significant increase in the incidence of centrilobular hepatocytomegaly in males dosed with 

≥101 mg/kg/day 1,2,4-trichlorobenzene. The neoplastic effects in mice are described in Section 3.2.2.7, 

Cancer. 

In addition to inducing changes in liver weight and morphological alterations in the liver, 1,2,4-trichlorobenzene has been shown to be a potent inducer of phase I and phase II metabolic enzymes (Ariyoshi et al. 

1975a, 1975b; Carlson and Tardiff 1976; Kato and Kimura 2002; Kato et al. 1988, 1993; Kitchin and 

Ebron 1983). For example, administration of ≥10 mg/kg/day 1,2,4-trichlorobenzene to rats by gavage for 

14 days resulted in dose-related increases in cytochrome c reductase, cytochrome P-450, 

glucuronyltransferase, EPN detoxification, and azoreductase (Carlson and Tardiff 1976). Extending the 

dosing period to 90 days resulted in smaller increases in enzyme activities, except for 

glucuronyltransferase activity, which was reduced relative to controls (Carlson and Tardiff 1976). In rats, 

1,2,4-trichlorobenzene also induced ALA synthetase, the rate-limiting enzyme in the biosynthesis of 

heme, which is consistent with the development of porphyria in rats administered 1,2,4- trichlorobenzene 

(Rimington and Ziegler 1963). For example, doses of 250–500 mg/kg/day significantly increased the 

urinary excretion of coproporphyrin and, to a smaller extent, the excretion of uroporphyrins. Liver 

uroporphyrin was also increased by 1,2,4-trichlorobenzene; liver coproporphyrin and protoporphyrin were 

increased in rats showing marked porphyrinuria. Studies by Kato and coworkers (Kato and Kimura 2002; 

Kato et al. 1988, 1993) have shown that both the induction of drug-metabolizing enzymes and ALA 

synthetase are not due to 1,2,4-trichlorobenzene itself but its metabolite 2,3,5-trichlorophenyl methyl 

sulfone. Further information on the mechanism of porphyria can be found in Section 3.5, Mechanisms of 

Action. 

Renal Effects. No gross or microscopic alterations were reported in the kidneys from pregnant rats 

dosed on Gd 6–15 with up to 300 mg/kg/day 1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene and sacrificed on Gd 22 (Black et al. 1988). 

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In a 13-week dietary study in rats with trichlorobenzenes, the three isomers increased relative kidney 

weight in male rats in doses ranging between 78 and 82 mg/kg/day (no data on females were presented), 

but only 1,3,5-trichlorobenzene reportedly induced morphological alterations in the kidneys (Côté et al. 

1988). The changes were characterized by eosinophilic inclusion, enlargement and anisokariosis of the 

epithelial lining cells, and hyperplasia of renal tubular epithelial cells. Only the changes associated with 

the highest dose levels, 78–82 mg/kg/day, were considered to be biologically significant by the 

investigators. Since only a qualitative description of the histology was provided, NOAELs and LOAELs 

for histological changes are not presented in Tables 3-3, 3-4, and 3-5, but the organ weight changes are. 

In a 14-week dietary study with 1,2,4-trichlorobenzene in rats, doses ≥45.6 mg/kg/day in males and 

≥52.5 mg/kg/day in females significantly increased relative kidney weight, but morphological alterations 

were seen only in high-dose males (133.7 mg/kg/day) and consisted of dilated tubules, granular casts, 

hyaline droplets, and interstitial nephritis (CMA 1989). BUN was also significantly elevated in high-dose 

males and females (150.6 mg/kg/day). Mice administered up to 1,345 mg/kg/day 1,2,4-trichlorobenzene 

via the diet for 13 weeks did not show significant gross or microscopic alterations in the kidneys (Hiles 

1989). 

In the 104-week dietary studies with 1,2,4-trichlorobenzene in rats and mice, kidney alterations were 

reported only in rats (Moore 1994a). Gross necropsy at termination showed increases incidence of kidney 

abnormalities in mid- (19.4 mg/kg/day) and high-dose (66.5 mg/kg/day) males. Microscopically, there 

was an increased incidence in marked renal papilla mineralization in high-dose males and in transitional 

renal cell hyperplasia, also in males; only the latter effect showed dose-response. In addition, there was 

an increase in severity of chronic nephropathy in males. In mice, there were no significant gross or 

microscopic alterations in the kidneys following dosing with up to 572.6 mg/kg/day 1,2,4-trichlorobenzene (Moore 1994b). 

Endocrine Effects. The only relevant information from acute-duration exposures is that from the 

study by Black et al. (1988) in which pregnant rats were administered trichlorobenzenes by gavage on 

Gd 6–15 and were sacrificed on Gd 22. No significant gross or microscopic alterations were reported in 

the pituitary, parathyroid, adrenals, or pancreas from dams following doses of up to 300 mg/kg/day 

1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene. However, 

mild thyroid histopathology was reported in rats dosed with ≥300 mg/kg/day of each isomer; the NOAEL 

in each case was 150 mg/kg/day. The alterations were described as reduction of follicle size and 

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increased epithelial height accompanied by cytoplasmic vacuolization. Since no quantitative data were 

presented, NOAELs and LOAELs for thyroid effects are not presented in Tables 3-3, 3-4, and 3-5. 

Côté et al. (1988) examined the same organs in a 13-week study in Sprague-Dawley rats and reported 

similar results. Morphological alterations were limited to the thyroid and were described as mild and 

appeared to be more severe in males. Reported changes consisted of reduction in follicular size, increased 

epithelial height from flattened cuboidal cells to columnar shape, and reduced colloid density. Changes in 

the high-dose groups (78–82 mg/kg/day) varied from mild to moderate. Since no quantitative data were 

presented, NOAELs and LOAELs for histological alterations in the thyroid are not listed in Tables 3-3, 

3-4, and 3-5. In contrast, CMA (1989) did not find significant histological alterations in the thyroid from 

Fisher-344 rats dosed with up to 150.6 mg/kg/day 1,2,4-trichlorobenzene in the diet for 14 weeks. 

Whether this can be attributed to differences in sensitivity between rat strains is unknown. No significant 

alterations were reported in endocrine glands from mice dosed via the diet with up to 1,345 mg/kg/day 

1,2,4-trichlorobenzene for 13 weeks (Hiles 1989) or from rats or mice dosed with up to 81.4 or 

572.6 mg/kg/day 1,2,4-trichlorobenzene, respectively, for 104 weeks (Moore 1994a, 1994b). 

Dermal Effects. None of the studies that examined the skin of animals following oral administration 

of trichlorobenzenes reported treatment-related gross or microscopic alterations. These include the acute 

developmental study by Black et al. (1988) (300 mg/kg/day 1,2,4-trichlorobenzene; 600 mg/kg/day 

1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene), a 13-week dietary study (Côté et al. 1988) (78– 

82 mg/kg/day), and 104-week dietary studies with 1,2,4-trichlorobenzene in rats (Moore 1994a) 

(81.4 mg/kg/day) and mice (Moore 1994b) (572.6 mg/kg/day). 

Ocular Effects. Examination of the eyes of animals exposed orally to trichlorobenzenes did not show 

treatment-related gross or histological alterations. These include the acute developmental study by Black 

et al. (1988; 300 mg/kg/day 1,2,4-trichlorobenzene; 600 mg/kg/day 1,2,3-trichlorobenzene and 

1,3,5-trichlorobenzene), 3-month dietary studies in rats (Côté et al. 1988; 78–82 mg/kg/day, and CMA 

1989; 150.6 mg/kg/day), a 13-week dietary study with 1,2,4-trichlorobenzene in mice (Hiles 1989; 

1,345 mg/kg/day), and 104-week dietary studies with 1,2,4-trichlorobenzene in rats (Moore 1994a; 

81.4 mg/kg/day) and mice (Moore 1994b; 572.6 mg/kg/day). 

Body Weight Effects. Almost all studies of trichlorobenzenes monitored body weight of the animals. 

Pregnant rats administered 300 mg/kg/day 1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3-trichlorobenzene on Gd 6–15 gained less weight than controls, but quantitative data for these isomers were not 

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provided (Black et al. 1988). However, administration of 600 mg/kg/day 1,3,5-trichlorobenzene resulted 

in a reduction in weight gain of 34% relative to controls on Gd 22 (Black et al. 1988). In another 

developmental study, doses of 360 mg/kg/day 1,2,4-trichlorobenzene on Gd 9–13 induced weight loss; 

120 mg/kg/day had no significant effect (Kitchin and Ebron 1983). Weight loss was also reported in a 

study in rats dosed by gavage with 500 mg/kg/day 1,2,4-trichlorobenzene for 10 days or with 

780 mg/kg/day 1,2,3-trichlorobenzene for 7 day (Rimington and Ziegler 1963). None of these studies 

provided information on food consumption. 

Fifteen days of dosing with 730 mg/kg/day 1,2,4-trichlorobenzene by gavage resulted in loss of appetite 

and weight loss in rats (Rimington and Ziegler 1963). Neither food consumption nor weight gain was 

significantly affected in rats dosed vai the diet with up to 101 mg/kg/day 1,2,4-trichlorobenzene or 

146 mg/kg/day 1,3,5-trichlorobenzene for 13 weeks (Côté et al. 1988). Similar results were reported in 

rats dosed through the diet with up to 150.6 mg/kg/day 1,2,4-trichlorobenzene for 14 weeks (CMA 

1989). Male rats treated with 78 mg/kg/day 1,2,3-trichlorobenzene for 13 weeks gained 10.2% less 

weight than controls (Côté et al. 1988); the NOAEL was 7.6 mg/kg/day. Final body weight was 

significantly reduced in male mice dosed with 1,222 mg/kg/day 1,2,4-trichlorobenzene (9%) and in 

female mice dosed via the diet with 1,345 mg/kg/day 1,2,4-trichlorobenzene (8.3%) for 13 weeks (Hiles 

1989). Cumulative body weight gain was significantly reduced in males dosed with 67 mg/kg/day 

1,2,4-trichlorobenzene (27%), in males dosed with 1,222 mg/kg/day 1,2,4-trichlorobenzene (40%), and in 

females dosed with 1,345 mg/kg/day 1,2,4-trichlorobenzene (33%); these changes were associated with 

significant reductions in food consumption throughout the study. 

Final body weight of rats dosed through the diet with up to 81.4 mg/kg/day 1,2,4-trichlorobenzene for 

104 weeks was not significantly different than controls (Moore 1994a). Final body weight of male mice 

dosed with 519.9 mg/kg/day 1,2,4-trichlorobenzene in the diet for 104 weeks was 16% lower than 

controls; food consumption in this group was reduced during the first 52 weeks of the study (Moore 

1994b). Final body weight was not significantly affected in female mice dosed with up to 

572.6 mg/kg/day 1,2,4-trichlorobenzene. The NOAEL for body weight changes in male mice was 

100.6 mg/kg/day. 

Metabolic Effects. Administration of up to 300 mg/kg/day 1,2,4-trichlorobenzene or up to 

600 mg/kg/day 1,2,3- or 1,3,5-trichlorobenzene to pregnant rats on Gd 6–15 did not significantly alter the 

concentration of electrolytes or glucose in blood (Black et al. 1988). 

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None of the intermediate-duration studies with trichlorobenzenes reported adverse metabolic effects. 

Treatment of rats with dietary doses of up to 150.6 mg/kg/day or mice with up to 1,345 mg/kg/day 

1,2,4-trichlorobenzene for 3 months had no significant effect on serum electrolyte or glucose levels 

(CMA 1989; Côté et al. 1988; Hiles 1989). Similar results were reported in rats dosed via the diet with 

up to 113 mg/kg/day 1,2,3-trichlorobenzene or 146 mg/kg/day 1,3,5-trichlorobenzene (Côté et al. 1988). 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological and lymphoreticular effects in humans after oral 

exposure to trichlorobenzenes. 

Information from studies in animals is limited to evaluations of the gross and microscopic morphology of 

lymphoreticular organs and tissues. In pregnant rats that were exposed to up to 300 mg/kg/day 

1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene on Gd 6– 

15, there were no significant morphological changes in the spleen or thymus on Gd 22 (Black et al. 1988). 

Intermediate-duration studies showed that exposure of rats to up to 150.6 mg/kg/day 1,2,4-trichlorobenzene, 113 mg/kg/day 1,2,3-trichlorobenzene, or 146 mg/kg/day 1,3,5-trichlorobenzene, or mice to up 

to 1,345 mg/kg/day 1,2,4-trichlorobenzene in the diet for 3 months did not alter the gross or microscopic 

morphology of the spleen, thymus, or lymph nodes (CMA 1989; Côté et al. 1988). Similar results were 

reported in rats and mice dosed with up to 81.4 and 572.6 mg/kg/day 1,2,4-trichlorobenzene, respectively, 

in the diet for 104 weeks (Moore 1994a, 1994b). 

These values are presented as NOAELs for lymphoreticular effects in Table 3-3, 3-4, and 3-5 and are 

plotted in Figures 3-3, 3-4, and 3-5. 

3.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans after oral exposure to 

trichlorobenzenes. 

No gross or histological alterations were observed in the brain and peripheral nerves from rats exposed to 

up to 300 mg/kg/day 1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene on Gd 6–15 and sacrificed on Gd 22 (Black et al. 1988). 

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Côté et al. (1988) examined the brain, spinal cord, and sciatic nerve from rats following a 13-week 

exposure period via the diet to doses of up to 101 mg/kg/day 1,2,4-trichlorobenzene, 113 mg/kg/day 

1,2,3-trichlorobenzene, or 146 mg/kg/day 1,3,5-trichlorobenzene and reported no significant gross or 

microscopic alterations in those tissues. Similar results were reported in rats dosed via the diet with up to 

150.6 mg/kg/day 1,2,4-trichlorobenzene for 14 weeks (CMA 1989) and in mice dosed with up to 

1,345 mg/kg/day 1,2,4-trichlorobenzene for 13 weeks (Hiles 1989). Dietary exposure of rats and mice to 

up to 81.4 and 572.6 mg/kg/day 1,2,4-trichlorobenzene, respectively, in the diet for 104 weeks also did 

not induce histological alterations in the brain, spinal cord, or sciatic nerve (Moore 1994a, 1994b). 

The NOAELs for morphological changes in the central and peripheral nervous systems are listed in 

Tables 3-3, 3-4, and 3-5 and are plotted in Figures 3-3, 3-4, and 3-5. 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after oral exposure to 

trichlorobenzenes. 

Examination of the ovaries and uteri from rats dosed by gavage with up to 300 mg/kg/day 1,2,4-trichlorobenzene or 600 mg/kg/day 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene on Gd 6–15 and sacrificed on 

Gd 22 did not show significant gross or microscopic alterations (Black et al. 1988). 

No treatment-related morphological alterations were reported in the reproductive organs from male or 

female rats dosed via the diet with 1,2,4-trichlorobenzene (82 mg/kg/day males, 101 mg/kg/day females), 

1,2,3-trichlorobenzene (78 mg/kg/day males, 113 mg/kg/day females), or 1,3,5-trichlorobenzene 

(82 mg/kg/day males, 146 mg/kg/day females) for 13 weeks (Côté et al. 1988). No alterations were noted 

in the reproductive organs from male and female rats dosed via the diet with up to 133.7 and 

150.6 mg/kg/day 1,2,4-trichlorobenzene, respectively, for 14 weeks (CMA 1989) or male and female 

mice dosed with up to 1,222 and 1,345 mg/kg/day, respectively, for 13 weeks (Hiles 1989). 

Two-year dietary studies with 1,2,4-trichlorobenzene in rats (66.5 mg/kg/day males, 81.4 mg/kg/day 

females) and mice (519.9 mg/kg/day males, 572.6 mg/kg/day females) also did not find gross or 

microscopic alterations in the reproductive organs (Moore 1994a, 1994b). 

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TRICHLOROBENZENES 92 

3. HEALTH EFFECTS 

Robinson et al. (1981) conducted a multi-generation reproductive study in rats in which the F0 and F1 

generations were exposed to 1,2,4-trichlorobenzene via the mother’s milk until weaning and then directly 

through their drinking water. At approximately 90 days of age in the F0 and F1 generations, the rats were 

mated to produce the subsequent generation. The results showed that treatment of males and females 

with up to 33 or 53.6 mg/kg/day 1,2,4-trichlorobenzene, respectively, did not affect fertility. The doses 

correspond to the intake of test material by the F0 generation at 83 days of age and were estimated by the 

investigators. 

The NOAELs for reproductive organs histology and the NOAEL for fertility from Robinson et al. (1981) 

are presented in Tables 3-3, 3-4, and 3-5 and are plotted in Figures 3-3, 3-4, and 3-5. 

3.2.2.6 Developmental Effects 

No studies were located regarding developmental effects in humans after oral exposure to 

trichlorobenzenes. 

Black et al. (1988) examined the developmental effects of trichlorobenzenes in Sprague-Dawley rats. 

Rats were administered 0, 75, 150, or 300 mg/kg/day 1,2,4-trichlorobenzene or 0, 150, 300, or 

600 mg/kg/day 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene by gavage in corn oil on Gd 6–15. Dams 

were sacrificed on Gd 22, and the uterus and ovaries were removed. Fetuses were examined grossly for 

birth defects and were also examined for skeletal and visceral anomalies. Also, entire fetuses were fixed, 

stained, and examined microscopically. Gestational exposure to the trichlorobenzenes did not 

significantly alter the number of pregnancies, fetal weight, litter size, resorptions, or dead fetuses, or the 

incidences of skeletal and visceral anomalies. However, fetuses from the 150 mg/kg/day 1,2,4-trichlorobenzene group and all groups exposed to 1,3,5-trichlorobenzene showed histological alterations in the 

lenses of the eye consisting of central areas of cellular disorientation and disaggregation with ballooning 

and granular degeneration. The investigators stated that autolysis and incomplete preservation made 

examination of other fetal tissues difficult, but there did not appear to be any significant treatment-related 

changes. In an additional study, pregnant rats were dosed with 0 or 360 mg/kg/day 1,2,4-trichlorobenzene on Gd 9–13 and were sacrificed on Gd 14 (Kitchin and Ebron 1983). Treatment did not increase 

resorptions or induce significant embryolethality or teratogenicity; however, it significantly retarded 

development as measured by reduced head length, crown-rump length, somite number, and protein 

content. It should be noted that dams administered 360 mg/kg/day 1,2,4-trichlorobenzene lost 

considerable body weight, which probably contributed to the delayed development of the offspring. 

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TRICHLOROBENZENES 93 

3. HEALTH EFFECTS 

A series of studies were conducted with 1,2,4-trichlorobenzene in which pregnant mice were administered 

0 or 130 mg/kg/day 1,2,4-trichlorobenzene by gavage on Gd 8–12 (Chernoff and Kavlock 1983; Gray and 

Kavlock 1984; Gray et al. 1986). Treatment with 1,2,4-trichlorobenzene had no significant effect on 

average litter weight, pup viability, or growth. Testing of the pups in a figure 8 maze for reactive 

locomotor activity levels on postnatal days 22, 58, and 200 showed no significant differences between 

pups from treated groups and controls. Examination of female pups at age 30 days showed no significant 

effect on percent vaginal patency. Breeding of the F1 pups resulted in no significant effects on percent 

pregnant, age at parturition, F2 litter size, or abnormalities in the F2 generation. Necropsy of F1 males at 

about 250 days of age showed no significant effects on body weight and weight of the liver, testes, 

seminal vesicles, or right kidneys. 

In the multi-generation reproductive study conducted by Robinson et al. (1981), treatment with 

1,2,4-trichlorobenzene did not affect neonates' weight, litter size, or viability during the pre-weaning 

period in any generation. In addition, there were no treatment-related effects on locomotor activity in the 

F1 or F2 generation rats. Of the organs weighed in the pups (liver, lungs, heart, kidneys, adrenals, and 

gonads, as well as seminal vesicles in males), only the adrenals were affected by 1,2,4-trichlorobenzene. 

Absolute weight of the adrenals of high-dose F0 and F1 males and females were significantly increased 

relative to controls (7–12%), although with no clear dose-response relationship. Microscopic examination 

of liver and kidneys from F1 rats showed no histological damage. Results from blood chemistry tests in 

F0 and F1 rats did not reveal any treatment-related alterations. The dose levels of 1,2,4-trichlorobenzene 

at which the increase in adrenal weight were observed in F0 males and females were estimated by the 

investigators to be 33 and 53.6 mg/kg/day, respectively. 

NOAELs and LOAELs for developmental effects are presented in Tables 3-3, 3-4, and 3-5 and are plotted 

in Figure 3-3, 3-4, and 3-5. 

3.2.2.7 Cancer 

Two long-term bioassays are available for 1,2,4-trichlorobenzene. Groups of F-344 rats (50/sex/group) 

were fed a diet containing 0, 100, 350, or 1,200 ppm 1,2,4-trichlorobenzene for 104 weeks (Moore 

1994a). The diet provided doses of 0, 5.6, 19.4, or 66.5 mg/kg/day to males and 0, 6.9, 23.5, or 

81.4 mg/kg/day to females. In the study in mice, groups of B6C3F1 mice (50/sex/group) were fed a diet 

containing 0, 150, 700, or 3,200 ppm 1,2,4-trichlorobenzene (98.9% pure) for 104 weeks (Moore 1994b). 

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TRICHLOROBENZENES 94 

3. HEALTH EFFECTS 

The diet provided doses of 0, 21, 100.6, or 519.9 mg/kg/day to males and 0, 26.3, 127, or 

572.6 mg/kg/day to females. Parameters evaluated in both studies included mortality (twice daily), 

clinical signs, body weight, and food consumption (weekly for 16 weeks and every 4 weeks thereafter), 

hematology (week 52 and 78 for cellular morphology and leukocyte differential, from control and highdose groups), organ weight (at termination, brain, brainstem, liver, kidneys, testes, and epididymis), and 

necropsy and histopathology findings (at termination, all major organs and tissues). 

There was no evidence of treatment-related increases in the incidences of neoplasia in rats. In mice, 

treatment with 1,2,4-trichlorobenzene resulted in significant early mortality in both high-dose male and 

female groups. Percent survival on week 105 was 90, 88, 82, and 10% in males and 78, 76, 84, and 0% in 

females from the control, low-, mid-, and high-dose mice, respectively. Histological examination of 

tissue and organs from both unscheduled deaths and terminal sacrifice showed significantly increased 

incidence of hepatocellular carcinoma in mid- and high-dose groups (males: 8/50, 5/50, 27/50, and 50/50; 

females: 1/50, 1/50, 28/50, and 46/50). Neoplasms in other organs showed comparable incidences 

between the control and treated groups. 

EPA classified 1,2,4-trichlorobenzene in Group D: not classifiable as to human carcinogenicity (IRIS 

2010), or as a chemical for which there is “Inadequate Information to Assess Carcinogenic Potential” 

according to the Guidelines for Carcinogen Risk Assessment (EPA 2005a). EPA’s classification was 

done in 1988 and was last revised in 1991. 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding death in humans after dermal exposure to trichlorobenzenes. 

A dermal LD50 of 6,139 mg/kg was reported for 1,2,4-trichlorobenzene in Sprague-Dawley rats (Brown et 

al. 1969). This value is presented in Table 3-6. The investigators noted that low doses caused depression 

of activity, whereas lethal doses induced extensor convulsions, and that all deaths occurred within 5 days 

of exposure. Dermal LD50 values of 300 and 305 mg/kg were estimated for 1,2,4-trichlorobenzene in 

mice applied doses ranging from 122 to 769 mg/kg (Yamamoto et al. 1978). During the 7-day 

observation period, no deaths occurred in the group dosed with 122 mg/kg 1,2,4-trichlorobenzene. No 

information was located regarding 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene. 

***DRAFT FOR PUBLIC COMMENT*** 
64 mg/kg

122

mg/kgmg/kg

123

mg/kg mg/kg

124

%volume

110

ml

65

ml

***DRAFT FOR PUBLIC COMMENT*** Table 3-6 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Dermal Species (Strain) Exposure/ Duration/ Frequency (Route) ACUTE EXPOSURE Death 

(SpragueDawley) Rat 

(NS) once 

System NOAEL Less Serious 

LOAEL 

6139 B 

mg/kg 

Serious 

(LD50) 

Reference Chemical Form 

Brown et al.1969 1,2,4-trichlorobenzene 

(CD-1) Mouse once 

300 M 

mg/kg 

(LD50) Yamamoto et al. 1978 

1,2,4-trichlorobenzene 

Systemic 

(CD-1) Mouse once Hepatic 591 B 

mg/kg 

305 F 

mg/kg 

769 B 

mg/kg 

(LD50) (liver congestion and necrosis) 

Yamamoto et al. 1978 1,2,4-trichlorobenzene 

(CD-1) Mouse once Dermal 70 B 

%volume 

(erythema) Yamamoto et al. 1978 

1,2,4-trichlorobenzene 

(albino) Gn Pig 3 wk Dermal 0.05 M 

mL 

(moderate to severe skin 

irritation in older guinea pigs) 

E.I. Dupont 1971 1,2,4-trichlorobenzene 

(NS) Rabbit 3 d 

6 hr/d Dermal 2 B 

mL 

(spongiosis, acanthosis, parakeratosis) 

Brown et al.1969 1,2,4-trichlorobenzene 
111

ml 

68

ml/day 

67

ml/day

ml/day

66

ml/day

***DRAFT FOR PUBLIC COMMENT*** Table 3-6 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Dermal (continued) Exposure/ LOAEL Duration/ Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Immuno/ Lymphoret 

(albino) Gn Pig 3 wk 0.05 M 

mL 

E.I. Dupont 1971 1,2,4-trichlorobenzene 

INTERMEDIATE EXPOSURE 

Death 

(NS) Gn Pig 3 wk 

5 d/wk 1 x/d 6 hr/d 

0.5 B 

mL/day 

(death of unspecified number of g. pigs) 

Brown et al.1969 1,2,4-trichlorobenzene 

Systemic 

(NS) Gn Pig 3 wk 

5 d/wk 1 x/d 6 hr/d 

Hepatic 0.5 B 

mL/day 

(necrotic foci in the liver) Brown et al.1969 

1,2,4-trichlorobenzene 

Dermal 0.5 B 

mL/day 

(spongiosis, acanthosis, parakeratosis) 

(NS) Rabbit 3 wk 

5 d/wk 1 x/d 6 hr/d 

Dermal 1 B 

mL/day 

(spongiosis, acanthosis, parakeratosis) 

Brown et al.1969 1,2,4-trichlorobenzene 
74 mg/kg 

mg/kgmg/kg

mg/kg

mg/kg

***DRAFT FOR PUBLIC COMMENT*** Table 3-6 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Dermal (continued) Exposure/ LOAEL Duration/ Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

(New Zealand) Rabbit 13 wk 

3 x/wk Cardio 97 B 

mg/kg 

Powers et al. 1975 1,2,4-trichlorobenzene 

Hepatic 97 B 

mg/kg 

Renal 97 B 

mg/kg 

Dermal 4.8 B 

mg/kg 

(slight skin redness and scaling with desquamation) 

Bd Wt 97 B 

mg/kg 
118 mg/kg 

mg/kgmg/kgmg/kgmg/kgmg/kgmg/kgmg/kg

mg/kg

mg/kgmg/kg

***DRAFT FOR PUBLIC COMMENT*** Table 3-6 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Dermal (continued) Exposure/ LOAEL Duration/ Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Rabbit 4 wk Resp Rao et al. 1982 

450 B (New 5 d/wk 

1,2,4-trichlorobenzene Zealand) 1 x/d mg/kg 

Cardio 450 B 

mg/kg 

Gastro 450 B 

mg/kg 

Hemato 450 B 

mg/kg 

Musc/skel 450 B 

mg/kg 

Hepatic 450 B 

mg/kg 

Renal 450 B 

mg/kg 

Endocr 450 B 

mg/kg 

Dermal 30 B 

mg/kg 

(slight gross and histological damage at application site) 

Ocular 450 B 

mg/kg 

Bd Wt 450 B 

mg/kg 
69

%volume

75 mg/kg 119 mg/kg 121 mg/kg 125

%volume

%volume

***DRAFT FOR PUBLIC COMMENT*** Table 3-6 Levels of Significant Exposure to 1,2,4-Trichlorobenzene - Dermal (continued) Exposure/ LOAEL Duration/ Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Immuno/ Lymphoret 

(NS) Gn Pig 3 wk 

3 d/wk 0.1 

%volume 

Brown et al.1969 1,2,4-trichlorobenzene 

(New Zealand) Rabbit 13 wk 

3 x/wk 97 B 

mg/kg 

Powers et al. 1975 1,2,4-trichlorobenzene 

(New Zealand) Rabbit 4 wk 

5 d/wk 1 x/d 

450 B 

mg/kg 

Rao et al. 1982 1,2,4-trichlorobenzene 

Reproductive 

(New Zealand) Rabbit 4 wk 

5 d/wk 1 x/d 

CHRONIC EXPOSURE 

Systemic 

(CD-1) Mouse 104 wk 

2 x/wk Dermal 

450 B 

mg/kg 

30 B 

%volume 

(keratinization of epidermis, inflammation) 

Rao et al. 1982 1,2,4-trichlorobenzene 

Yamamoto et al. 1982 1,2,4-trichlorobenzene 

Bd Wt 60 B 

%volume 

B = both; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Gn Pig = guinea pig; Hemato = hemhour(s); Immuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; Musc/skel = NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; wk = week(s); x = time(s) 
 

 

 

 

 

 

 

 

TRICHLOROBENZENES 100 

3. HEALTH EFFECTS 

Application of 0.5 mL of undiluted 1,2,4-trichlorobenzene to a shaven area of the back of guinea pigs 

6 hours/day, 5 days/week for 3 weeks resulted in the death of an unspecified number of guinea pigs; the 

time of death was also not specified (Brown et al. 1969). 

3.2.3.2 Systemic Effects 

The highest NOAEL values and all LOAEL values from each study for systemic effects in each species 

and duration category are recorded in Tables 3-6, 3-7, and 3-8. 

No studies were located regarding systemic effects in humans after dermal exposure to trichlorobenzenes. 

Respiratory Effects. Application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the 

back skin of rabbits in doses of up to 450 mg/kg 5 days/week for 4 weeks did not induce histological 

alterations in the respiratory tract including the nasal turbinates (Rao et al. 1982). 

Cardiovascular Effects. No histological alterations were observed in the heart from rabbits 

administered 0.2 mL of a 100% solution of technical-grade 1,2,4-trichlorobenzene (97 mg/kg) to the ear 

3 times/week for 13 weeks (Powers et al. 1975). Similar results were reported in rabbits following 

application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin in doses of up to 

450 mg/kg, 5 days/week for 4 weeks (Rao et al. 1982). 

Gastrointestinal Effects. Application of technical-grade 1,2,4-trichlorobenzene to a shaved area of 

the back skin of rabbits in doses of up to 450 mg/kg 5 days/week for 4 weeks did not induce histological 

alterations in the gastrointestinal tract, including the nasal turbinates (Rao et al. 1982). 

Hematological Effects. No treatment-related hematological alterations were reported in rabbits 

following application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin in doses 

of up to 450 mg/kg, 5 days/week for 4 weeks (Rao et al. 1982). 

Musculoskeletal Effects. Histological examination of skeletal and bone from rabbits administered 

technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin in doses of up to 450 mg/kg, 

5 days/week for 4 weeks did not show treatment-related effects (Rao et al. 1982). 

***DRAFT FOR PUBLIC COMMENT*** 
108

%volume

109

%volume

***DRAFT FOR PUBLIC COMMENT***

Table 3-7 Levels of Significant Exposure to 1,2,3-Trichlorobenzene - Dermal 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Systemic 

(NS) Rabbit once 

System 

Ocular 

NOAEL Less Serious 

10 (slight conjunctival 

irritation and trace of corneal injury) 

%volume 

LOAEL 

Serious 

Reference Chemical Form 

Dow Chemical 1956 1,2,3-Trichlorobenzene 

(NS) Rabbit 7 d 

1 x/d Dermal 100 

%volume 

(slight reddening of the skin to slight exfoliation after 7 applications) 

Dow Chemical 1956 1,2,3-Trichlorobenzene 

d = day(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; NS = not specified; x = time(s) 
104 mg

105 mg131

%volume

***DRAFT FOR PUBLIC COMMENT***

Table 3-8 Levels of Significant Exposure to 1,3,5-Trichlorobenzene - Dermal 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Systemic 

(New Zealand) Rabbit once 

System 

Dermal 

NOAEL Less Serious 

500 (mild skin irritation) 

mg 

LOAEL 

Serious 

Reference Chemical Form 

Jorgenson et al. 1976 1,3,5-Trichlorobenzene 

(New Zealand) Rabbit once Ocular 100 

mg 

(mild, transitory eye irritation) 

Jorgenson et al. 1976 1,3,5-Trichlorobenzene 

Immuno/ Lymphoret 

(Hartley) Gn Pig once 0.1 M 

%volume 

Jorgenson et al. 1976 1,3,5-Trichlorobenzene 

LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level 
 

 

 

 

 

TRICHLOROBENZENES 103 

3. HEALTH EFFECTS 

Hepatic Effects. In an acute lethality study in mice applied single doses of 1,2,4-trichlorobenzene 

ranging from 123 to 769 mg/kg onto the skin, mice that survived the highest dose showed congestion and 

necrosis of the liver (Yamamoto et al. 1978). Guinea pigs that died following application of 0.5 mL of 

undiluted 1,2,4-trichlorobenzene to a shaven area of the back for 6 hours/day, 5 days/week for 3 weeks 

showed necrotic foci in the liver (Brown et al. 1969). 

No histological alterations were observed in the liver from rabbits administered 0.2 mL of a 100% 

solution of technical-grade 1,2,4-trichlorobenzene (97 mg/kg) to the ear 3 times/week for 13 weeks 

(Powers et al. 1975). Application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the back 

skin of rabbits in doses of up to 450 mg/kg, 5 days/week for 4 weeks did not induce histological 

alterations in the liver; grossly, however, the liver of rabbits treated with 450 mg/kg did show slight pallor 

(Rao et al. 1982). 

Renal Effects. No histological alterations were reported in the kidneys from rabbits applied 0.2 mL of 

a 100% solution of technical-grade 1,2,4-trichlorobenzene (97 mg/kg) to the ear 3 times/week for 

13 weeks (Powers et al. 1975). No histological alterations were reported in the kidneys from rabbits 

following application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin in doses 

of up to 450 mg/kg, 5 days/week for 4 weeks (Rao et al. 1982). However, urinalysis revealed a slight but 

significant increase in urinary coproporphyrin in high-dose males on day 24 of the study, which was 

considered only a slight or questionable effect of treatment. 

Endocrine Effects. Microscopic examination of the pituitary gland, pancreas, adrenal gland, and 

thyroid and parathyroid glands from rabbits administered technical-grade 1,2,4-trichlorobenzene to a 

shaved area of the back skin in doses of up to 450 mg/kg, 5 days/week for 4 weeks showed no significant 

treatment-related alterations (Rao et al. 1982). 

Dermal Effects. Application of 1,2,4-trichlorobenzene in concentrations of 70–100% to the skin of 

mice produced erythema, but histological examination of the skin showed no remarkable change 

(Yamamoto et al. 1978). Application of 0.05 mL of a 75% solution of 1,2,4-trichlorobenzene to the 

shaved intact shoulder of guinea pigs for 24 hours produced no to mild irritation in young animals, but 

moderate to severe irritation in older guinea pigs (E.I. DuPont 1971). In a repeated treatment study, 1 mL 

of undiluted 1,2,4-trichlorobenzene was applied in a patch of lint to the shaved skin of rabbits for 6 hours 

during 3 consecutive days (Brown et al. 1969). Seven days after the first application, histological 

examination of the skin showed spongiosis, acanthosis, and parakeratosis. 

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TRICHLOROBENZENES 104 

3. HEALTH EFFECTS 

Repeated applications of a 10% solution of 1,2,3-trichlorobenzene to the abraded belly of rabbits caused 

questionable irritation and edema that healed normally (Dow Chemical 1956). When the solution was 

applied to intact skin, essentially no response was observed except for slight exfoliation after six 

applications. Application of undiluted 1,2,3-trichlorobenzene to the intact skin induced slight reddening 

to slight exfoliation after seven applications. However, in the abraded area, the undiluted chemical 

produced moderate reddening of the skin, slight edema, and trace of necrosis; healing was described as 

ordinary (Dow Chemical 1956). 

In a study with 1,3,5-trichlorobenzene, 500 mg of the chemical was applied to the abraded or intact skin 

of six rabbits (Jorgenson et al. 1976). The test sites were covered and 24 hours later, the excess 

compound was removed and the sites were scored for erythema and edema. All treated rabbits showed 

erythema and edema at the 24-hour reading, and only three rabbits showed erythema at the 72-hour 

reading. The chemical was considered mildly irritating. 

Intermittent application of 0.5 mL of undiluted 1,2,4-trichlorobenzene to guinea pigs or 1 mL to rabbits 

for 3 weeks produced spongiosis, acanthosis, and parakeratosis in both species (Brown et al. 1969). 

Rabbits applied 0.2 mL of a 5% solution of technical-grade 1,2,4-trichlorobenzene (4.8 mg/kg) onto the 

ventral surface of the ear 3 times/week for 13 weeks showed slight redness with slight scaling and 

desquamation that did not increase in severity after 39 exposures (Powers et al. 1975). Rabbits applied 

25 or 100% solutions (24 or 97 mg/kg) showed moderate to severe irritation characterized by slight to 

severe erythema, severe scaling, desquamation and encrustation with slight enlargement of the follicles, 

some hair loss, and scarring. There was no evidence of acne form dermatitis. 

A study was conducted in rabbits in which the animals were applied technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin in doses of 0, 30, 150, or 450 mg/kg, 5 days/week for 4 weeks 

(Rao et al. 1982). At termination, the skin of all treated rabbits showed localized effects considered slight 

at the low- and mid-dose levels and moderate at the high-dose level. The effects consisted of an area 

where regrowing fur was matted by a white bran-like scale, slight thickening of the skin, fissures which 

progressed to erosions and shallow ulcers, and erythema. Increasing dose increased the affected area. 

Microscopically, the skin site showed changes including inflammation, focal erosion and ulcers, and 

accumulation of inflammatory cells with varying degrees of exudation. Some rabbits showed slight 

superficial edema with slight fibrosis. 

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TRICHLOROBENZENES 105 

3. HEALTH EFFECTS 

Painting 0.03 mL of a 30% solution of 1,2,4-trichlorobenzene 2 times/week for 2 years induced 

thickening and keratinization of the epidermis followed by inflammation (Yamamoto et al. 1982). 

Ocular Effects. Instillation of a 10% solution of 1,2,3-trichlorobenzene to the eyes of rabbits followed 

by washing with water produced marked pain, slight conjunctival irritation, and trace of corneal injury 

(Dow Chemical 1956). The corneal injury almost completely healed in 24 hours, and irritation almost 

completely healed in 48 hours. In the unwashed eye, there was marked pain, conjunctival irritation and 

no corneal injury; complete healing occurred in 24 hours. In unwashed eyes instilled with undiluted 

1,2,3-trichlorobenzene, there was a trace of pain, slight conjunctival irritation, and no corneal injury; 

healing occurred in 48 hours. The same was found in the washed eye, but healing occurred in 24 hours. 

In a study with 1,3,5-trichlorobenzene, an amount of 100 mg of the chemical was applied into the eyes of 

rabbits (Jorgenson et al. 1976). Some rabbits had the compound washed out at 30 seconds or 5 minutes 

after application, or did not have the compound washed out. The eye was graded for ocular lesions at 24, 

48, 72, and 96 hours. There was no corneal damage in rabbits that underwent washing, but minor damage 

was observed in the no-wash group. The cornea returned to normal within 3 days. Occasional 

circumcorneal injection was seen in some rabbits, but all effects on the iris disappeared by posttreatment 

day 4. Conjunctival responses occurred in all treated rabbits and generally involved varying degrees of 

redness, chemosis, and discharge. The eyes of the rabbits in the 30-second wash group returned to normal 

within 24 hours, but the 5-minute wash group was not normal until day 3, and the no-wash group did not 

return to normal until day 7. The investigators concluded that 1,3,5-trichlorobenzene produced mild 

transitory eye irritation. 

Histological examination of the eyes from rabbits administered technical-grade 1,2,4-trichlorobenzene to 

a shaved area of the back skin in doses of up to 450 mg/kg, 5 days/week for 4 weeks showed no 

significant treatment-related alterations (Rao et al. 1982). 

Body Weight Effects. Application of 0.2 mL of a 100% solution of technical-grade 1,2,4-trichlorobenzene (97 mg/kg) to the ear of rabbits 3 times/week for 13 weeks did not affect body weight (Powers et 

al. 1975). Application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin of 

rabbits in doses of up to 450 mg/kg, 5 days/week for 4 weeks did not significantly affect body weight 

(Rao et al. 1982). 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

TRICHLOROBENZENES 106 

3. HEALTH EFFECTS 

3.2.3.3 Immunological and Lymphoreticular Effects 

No histological alterations were reported in the spleen from rabbits administered 0.2 mL of a 100% 

solution of technical-grade 1,2,4-trichlorobenzene (97 mg/kg) to the ear 3 times/week for 13 weeks 

(Powers et al. 1975). Similar results were reported for the spleen, thymus, and lymph nodes from rabbits 

following application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin in doses 

of up to 450 mg/kg, 5 days/week for 4 weeks (Rao et al. 1982). 

Tests for skin sensitization conducted with 1,2,4-trichlorobenzene or 1,3,5-trichlorobenzene in guinea 

pigs were negative (Brown et al. 1969; E.I. DuPont 1971; Jorgenson et al. 1976). 

3.2.3.4 Neurological Effects 

Microscopic examination of the brain, spinal cord, and peripheral nerve from rabbits applied technicalgrade 1,2,4-trichlorobenzene onto a shaved area of the back skin in doses of up to 450 mg/kg, 

5 days/week for 4 weeks showed no significant treatment-related alterations (Rao et al. 1982). 

3.2.3.5 Reproductive Effects 

Application of technical-grade 1,2,4-trichlorobenzene to a shaved area of the back skin of male and 

female rabbits in doses of up to 450 mg/kg, 5 days/week for 4 weeks did not induce gross or microscopic 

alterations in the reproductive organs (Rao et al. 1982). 

3.2.3.6 Developmental Effects 

No studies were located that assessed developmental effects in humans or animals following dermal 

exposure to trichlorobenzenes. 

3.2.3.7 Cancer 

A 2-year cancer study was conducted with 1,2,4-trichlorobenzene in mice (Yamamoto et al. 1982). 

Groups of Slc:ddY mice (75/sex/group) were painted with 0.03 mL of a 30 or 60% solution of 

1,2,4-trichlorobenzene 2 times/week for 104 weeks. There was high mortality both in the treated and 

control groups, beginning on week 30. At week 83, <10% of treated females and <15% of treated males 

survived. The main causes of death were respiratory infections, amyloidosis, and tumors. Histological 

alterations in tissues appeared more prevalent in the high-dose group, but the number of mice examined 

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was not indicated. Tumors developed in the lungs, kidneys, stomach, urinary bladder, mammary gland, 

and skin in both treated and control groups. There was no indication of the time to first tumor appearance 

or whether the tumors were all found in different animals or were multiple tumors in the same animal. 

Skin tumors were classified as squamous cell carcinoma, papilloma, and fibroma. This study is 

inadequate for assessing the potential carcinogenicity of 1,2,4-trichlorobenzene following dermal 

exposure. 

3.3 GENOTOXICITY 

For the most part, genotoxicity data for trichlorobenzenes have provided negative evidence of 

mutagenicity in in vitro tests with prokaryotic organisms (i.e., Salmonella typhimurium) and positive 

evidence of deoxyribonucleic acid (DNA) damage at concentrations that were generally also cytotoxic in 

mammalian cell systems in vitro. In vivo studies suggest that trichlorobenzenes are clastogenic. The role, 

if any, that these effects may play in the liver carcinogenicity of 1,2,4-trichlorobenzene in mice (Moore 

1994b) is unknown. Tables 3-9 and 3-10 provide a summary of genotoxicity data for these test systems. 

In vitro Exposure Studies. As shown in Table 3-9, in vitro assays of gene mutation in various strains of 

S. typhimurium provided mostly negative results, regardless of the presence or absence of metabolic 

activation in the incubation medium (Ethyl Corp. 1975; Haworth et al. 1983; Jorgenson et al. 1976; Kubo 

et al. 2002; Lawlor et al. 1979; Nohmi et al. 1985; Ono et al. 1992; Schoeny et al. 1979). 

Studies with mammalian cell systems in vitro assessed mainly clastogenicity, cytotoxicity, and DNA 

damage, and for the most part, yielded positive results. A series of experiments conducted by Fratello et 

al. (1997) showed 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene to induce DNA damage as assessed 

by detecting loss of DNA fragment by means of cytofluorimetric analysis. Since the preparations used 

(Chinese hamster V79 cells) were devoid of cytochrome P-450 activity, the DNA damage was attributed 

to the parent compound rather than to a toxic metabolite. 1,3,5-Trichlorobenzene was considerably less 

cytotoxic than the other two isomers (Fratello et al. 1997). A similar study also found 1,2,4-trichlorobenzene to be cytotoxic in Chinese hamster ovary cells by inhibiting protein and DNA synthesis (Garret 

and Lewtas 1983). 1,2,4-Trichlorobenzene produced positive results in tests for cytotoxicity in rat 

hepatocytes and was positive in a transformation assay in rat liver epithelial (ARL) cells in the absence of 

metabolic activation, but at concentrations that were toxic to the cells (Shimada et al. 1983). Conversely, 

in an hepatocyte primary culture (HPC)/DNA repair assay conducted by Shimada et al. (1983), 

1,2,4-trichlorobenzene was not genotoxic to rat hepatocytes in the absence of metabolic activation. 

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Table 3-9. Genotoxicity of Trichlorobenzenes In Vitro 

Results 

With Without 

Species (test system) Compound End point activation activation Reference 

Prokaryotic organisms: 

Salmonella 

typhimurium, TA98, 

TA100, TA1535, 

TA1537 

1,2,3-TCB Gene mutation – – Haworth et al. 1983 

S. typhimurium, TA98, 

TA100 

1,2,3-TCB Gene mutation – – Kubo et al. 2002 

S. typhimurium, TA98, 

TA100, TA2637 

1,2,3-TCB Gene mutation – – Nohmi et al. 1985 

S. typhimurium, 

TA1535/pSK1002 

1,2,3-TCB Gene mutation – – Ono et al. 1992 

S. typhimurium, TA98, 

TA100, TA1535, 

TA1537 

1,2,4-TCB Gene mutation – – Haworth et al. 1983 

S. typhimurium, TA98, 

TA100 

1,2,4-TCB Gene mutation – – Kubo et al. 2002 

S. typhimurium, TA98, 

TA100, TA2637 

1,2,4-TCB Gene mutation – – Nohmi et al. 1985 

S. typhimurium, 

TA1535/pSK1002 

1,2,4-TCB Gene mutation – + Ono et al. 1992 

S. typhimurium, TA98, 

TA100, TA1535, 

TA1537 

1,2,4-TCB Gene mutation, 

microsomal 

assay 

– – Schoeny et al. 1979 

S. typhimurium, TA98, 

TA100, TA1535, 

TA1537, TA1538 

1,2,4-TCB Gene mutation – – Ethyl Corp. 1975 

Saccharomyces 

cerevisiae D3 

1,2,4-TCB Gene mutation, 

mitotic 

– – Ethyl Corp. 1975 

recombination 

assay 

S. typhimurium, TA98, 

TA100, TA1535, 

TA1537 

1,3,5-TCB Gene mutation – – Haworth et al. 1983 

S. typhimurium, TA98, 

TA100, TA2637 

1,3,5-TCB Gene mutation – – Nohmi et al. 1985 

S. typhimurium, 

TA1535/pSK1002 

1,3,5-TCB Gene mutation – – Ono et al. 1992 

S. typhimurium, TA98, 

TA100, TA1535, 

TA1537, TA1538 

1,3,5-TCB Gene Mutation – – Jorgenson et al. 1976 

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Table 3-9. Genotoxicity of Trichlorobenzenes In Vitro 

Results 

With Without 

Species (test system) Compound End point activation activation Reference 

Escherichia coli, 1,3,5-TCB Reverse gene – – Jorgenson et al. 1976 

WP2uvrA- mutation 

E. coli, W3110 and 1,3,5-TCB DNA repair No data – Jorgenson et al. 1976 

p3478 assay 

Bacillus subtilis, H17 1,3,5-TCB DNA repair No data – Jorgenson et al. 1976 

and M45 assay 

S. cerevisiae D3 1,3,5-TCB Mitotic (+) (+) Jorgenson et al. 1976 

recombination 

Mammalian cells: 

Chinese hamster lung 1,2,3-TCB Chromosomal – – McElroy et al. 2003 

(CHL) cells aberrations 

Chinese hamster ovary 1,2,3-TCB Chromosomal – – McElroy et al. 2003 

(CHO) cells aberrations 

Chinese hamster V79 1,2,3-TCB Cytotoxicity, No data + Fratello et al. 1997 

cells neutral red 

uptake assay 

Chinese hamster V79 1,2,3-TCB Cell replication No data + Fratello et al. 1997 

cells (Colony 

forming ability) 

Chinese hamster V79 1,2,3-TCB DNA damage No data + Fratello et al. 1997 

cells 

Chinese hamster V79 1,2,4-TCB Cytotoxicity, No data + Fratello et al. 1997 

cells neutral red 

uptake assay 

Chinese hamster V79 1,2,4-TCB Cell replication No data + Fratello et al. 1997 

cells (Colony 

forming ability) 

Chinese hamster V79 1,2,4-TCB DNA damage No data + Fratello et al. 1997 

cells 

CHO cells 1,2,4-TCB Cytotoxicity No data + Garrett and Lewtas 

1983 

Rat hepatocyte (male 1,2,4-TCB Gene mutation, No data – Shimada et al. 1983 

F344 Fischer) HPC/DNA 

repair assay 

Rat hepatocyte (male 1,2,4-TCB Cytotoxicity No data + Shimada et al. 1983 

F344 Fischer) 

Rat liver epithelial 1,2,4-TCB Gene mutation, No data + Shimada et al. 1983 

(ARL) cells (male F344 Transformation 

Fischer) Assay 

Chinese hamster V79 1,3,5-TCB Cytotoxicity, No data (+) Fratello et al. 1997 

cells neutral red 

uptake assay 

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Table 3-9. Genotoxicity of Trichlorobenzenes In Vitro 

Results 

With Without 

Species (test system) Compound End point activation activation Reference 

Chinese hamster V79 1,3,5-TCB Cell replication No data (+) Fratello et al. 1997 

cells (Colony 

forming ability) 

Chinese hamster V79 1,3,5-TCB DNA damage No data (+) Fratello et al. 1997 

cells 

+ = positive result; (+) = weakly positive result; C = negative result; DNA = deoxyribonucleic acid; HPC = hepatocyte 

primary culture; TCB = trichlorobenzene 

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Table 3-10. Genotoxicity of Trichlorobenzenes In Vivo 

Species (test system) Compound End point Results Reference 

Mouse (male NMR, 1,2,3-TCB Chromosomal aberrations, + Mohtashamipur et al. 1987 

5/dose) micronucleus assay 

Mouse (male Swiss 1,2,3-TCB Chromosomal aberrations, + Parrini et al. 1990 

CD-1) micronucleous assay 

Mouse (male NMR, 1,2,4-TCB Chromosomal aberrations, + Mohtashamipur et al. 1987 

5/dose) micronucleus assay 

Mouse (male Swiss 1,2,4-TCB Chromosomal aberrations, + Parrini et al. 1990 

CD-1) micronucleous assay 

Mouse (male NMR, 1,3,5-TCB Chromosomal aberrations, + Mohtashamipur et al. 1987 

5/dose) micronucleus assay 

Mouse (male Swiss 1,3,5-TCB Chromosomal aberrations, + Parrini et al. 1990 

CD-1) micronucleous assay 

Drosophila 1,3,5-TCB Gene mutation, sex-linked – Zimmering et al. 1985 

melanogaster recessive lethal test 

+ = positive result; – = negative result; TCB = trichlorobenzene 

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1,2,4-Trichlorobenzene did not induce chromosomal aberrations in Chinese hamster lung (CHL) or ovary 

(CHO) cells in assays conducted with and without metabolic activation (McElroy et al. 2003). 

In vivo Exposure Studies. There were few studies available for review that examined the potential in 

vivo genotoxicity of trichlorobenzenes; however, as seen in Table 3-10, the results of the available studies 

were mostly positive. Intraperitoneal administration of either one of the trichlorobenzene isomers to male 

NMRI mice in doses ranging from 210 to 1,700 mg/kg resulted in dose-related increases in micronuclei in 

polychromatic erythrocytes of the femoral bone marrow 30 hours after the first of two injections 

(Mohtashamipur et al. 1987). A similar study in male Swiss CD1 mice also reported increases in 

micronuclei frequency in the femoral bone marrow 6 hours after a second intraperitoneal injection of 

500–650 mg/kg of either one of the trichlorobenzene isomers (Parrini et al. 1990). There were no 

significant differences among the trichlorobenzenes in either study. In a sex-linked recessive lethal test, 

1,3,5-trichlorobenzene was negative for mutagenesis in Drosophila melanogaster (Zimmering et al. 

1985). 

3.4 TOXICOKINETICS 

Results from studies of orally exposed animals indicate that trichlorobenzene isomers are rapidly and 

extensively absorbed, widely distributed, and quickly eliminated. Urinary excretion of radiolabeled 

1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene has illustrated that at least 50–80% of the administered 

radioactivity is absorbed and excreted in rats within 24 hours of dose administration. Urinary elimination 

of metabolites is the major route of elimination, with fecal elimination representing a minor pathway. In 

bile duct-cannulated rats, significant enterohepatic circulation of metabolites has been demonstrated. 

Results from rat studies indicate that, once absorbed, all three isomers are widely distributed throughout 

the body and are detectable in tissue within 0.5 hours of dosing. Tissues with the highest peak 

concentrations following oral administration included fat, skin, liver, kidneys, bladder, and the 

gastrointestinal tract. Identification of metabolites in urine, feces, and bile following exposure of rabbits, 

rats, and monkeys to the individual isomers indicates that the parent compounds are metabolized to 

phenolic compounds through arene oxide intermediates, which are conjugated to glutathione, glucuronic 

acid, or sulfates before elimination in the urine, feces, or bile. Some evidence is available suggesting that 

conjugation with glutathione predominates in rats, whereas glucuronidation predominates in monkeys. 

Enzymes involved in the proposed metabolic schemes for each isomer have not been definitively 

identified. However, the initial formation of arene oxides and phenols is likely to be catalyzed by 

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cytochrome P450 (CYP) oxygenases. The relevance of the animal toxicokinetic information for humans 

has not been established because, as indicated below, there are no human data. 

Studies describing the absorption, distribution, metabolism, and elimination of 1,2,3-, 1,2,4-, and 

1,3,5-trichlorobenzene following oral exposure in humans, as well as inhalation and dermal exposure in 

humans and animals, are not available. 

3.4.1 Absorption 

No information was located regarding absorption of trichlorobenzenes in humans following any route of 

exposure. 

3.4.1.1 Inhalation Exposure 

Quantitative data on the absorption of trichlorobenzenes following inhalation exposure are not available 

for animals. However, indirect evidence that 1,2,4-trichlorobenzene is absorbed through inhalation can 

be inferred from minor liver effects in rats following inhalation exposure (Kociba et al. 1981). 

3.4.1.2 Oral Exposure 

Evidence from elimination studies in animals indicate that trichlorobenzene isomers are rapidly and 

extensively absorbed through the gastrointestinal tract in animals. 

1,2,3-Trichlorobenzene. Radiolabeled 1,2,3-trichlorobenzene has been detected in both the urine and 

feces of rats following oral exposure. Specifically, 92% of administered radioactivity was eliminated 

through the urine and feces within 24 hours of administration of a single 10 mg/kg gavage dose of 

14C-labeled 1,2,3-trichlorobenzene to male Sprague-Dawley rats (Chu et al. 1987). Overall excretion 

increased to 95% at 48 hours post ingestion. The percentage of the administered radioactivity in urine 

alone accounted for 56 and 59% of the total ingested dose at 24 and 48 hours, respectively. Therefore, 

assuming that none of the radioactivity excreted in the feces was absorbed, at least 59% of the 

administered dose was absorbed. These results are also consistent with as much as 95% of the 

administered dose may have been absorbed if all radiolabeled material excreted in the feces had first been 

absorbed and excreted through the biliary system. 

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1,2,4-Trichlorobenzene. Within 7 days after receiving a dose of 50 mg/kg of 14C-labeled 1,2,4-trichlorobenzene, male Wistar rats excreted 66 and 17% of the radioactivity in urine and feces, respectively, 

suggesting that at least 66% of the administered dose was absorbed (Tanaka et al. 1986). Radioactivity in 

expired air accounted for 2.1% of the absorbed dose. Excretion in all three excreta reached a peak on day 

3, indicating rapid absorption and elimination. Measurements of biliary excretion for 4 days in bilecannulated rats showed that radioactivity in bile accounted for 45% of the administered dose (Tanaka et 

al. 1986). Bakke et al. (1992) reported that >60% of a 21 mg/kg dose of 14C-1,2,4-trichlorobenzene was 

excreted in bile, while 21% was excreted in the urine of bile-cannulated male Sprague-Dawley rats within 

24 hours. Findings from this study indicate an 81% absorption rate following oral exposure to 

1,2,4-trichlorobenzene. In control non-cannulated rats, 70 and 9% of the radioactivity was excreted 

within 24 hours in urine and feces, respectively (Bakke et al. 1992). Following 7 consecutive days of oral 

dosing of male Sprague-Dawley rats with 181.5 mg/kg/day 14C-1,2,4-trichlorobenzene, radioactivity in 

urine was still detectable 21 days after the first oral administration; total radioactivity detected in urine 

accounted for approximately 72% of the administered dose (Smith and Carlson 1980). Radioactivity in 

the feces was not detectable past day 15 and accounted for only 4% of the administered dose. Thus, 

between 72 and 76% of the administered dose was absorbed in this study. 

14C-Labeled material was excreted by both monkeys and rats following oral exposure to a 10 mg/kg dose 

of 14C-labeled 1,2,4-trichlorobenzene. By 24 hours after dosing, female Rhesus monkeys had excreted 

about 40% of the administered radioactivity in the urine and <1% in the feces. Male albino rats, however, 

excreted 84% of the administered radioactivity in the urine and 11% in the feces by 24 hours. With 

intravenous administration of 10 mg/kg 14C-labeled 1,2,4-trichlorobenzene, monkeys eliminated about 

22% of the administered radioactivity in urine within 24 hours (none was detected in feces), whereas 

radioactivity in 24-hour urine and feces in rats accounted for 78 and 7% of the administered dose, 

respectively (Lingg et al. 1982). These data suggest that differences in elimination rates between rats and 

monkeys may be due to species differences in metabolic rate or elimination rate, rather than absorption 

rate. 

1,3,5-Trichlorobenzene. The excretion of radioactivity derived from 1,3,5-trichlorobenzene in both the 

urine and feces of rats has also been monitored following oral exposure. Within 24 hours of a single 

10 mg/kg dose of 14C-labeled 1,3,5-trichlorobenzene to male Sprague-Dawley rats, 82% of radioactivity 

was eliminated through the urine and feces (Chu et al. 1987). Overall excretion increased to 89% at 

48 hours post ingestion. The percentage of administered radioactivity in urine accounted for 47 and 50% 

at 24 and 48 hours, respectively. Thus, assuming that none of the radioactivity excreted in the feces was 

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absorbed, at least 50% of the administered dose was absorbed. These results are also consistent with as 

much as 89% of the administered dose may have been absorbed if all radiolabeled material excreted in the 

feces had first been absorbed and excreted through the biliary system. 

3.4.1.3 Dermal Exposure 

No quantitative data were located on the absorption of trichlorobenzenes following dermal exposure of 

animals. Theoretical predictive models based on chemical and physical properties, however, have 

indicated that 1,2,4-trichlorobenzene has a significant potential for dermal absorption (FiserovaBergerova et al. 1990). Specifically, the findings of this study suggest that dermal exposure to 

1,2,4-trichlorobenzene is expected to raise the biological levels of this isomer 30% above those occurring 

during inhalation exposure to threshold limit values. 1,2,4-Trichlorobenzene absorption can also be 

inferred from evidence of systemic toxicity in animals following dermal exposure (Brown et al. 1969; 

Yamamoto et al. 1978). 

3.4.2 Distribution 

1,2,3- and 1,3,5-Trichlorobenzene were detected in autopsies of Canadian citizens at median levels of 

1.9 and 1.1 ng/g, respectively, and at maximum levels of 9.1 and 3.7 ng/g, respectively (Mes 1992). 

Levels were below the detection limits in blood samples. 1,2,4-Trichlorobenzene was detected in human 

follicular fluid at a mean concentration of 214 pg/mL for patients undergoing in vitro fertilization in 

Canada (Younglai et al. 2002). Trichlorobenzenes detected in the general population are the result of 

inhalation of ambient air and ingestion of food and drinking water contaminated with trichlorobenzenes. 

No specific information was located regarding distribution of trichlorobenzenes in children. 

3.4.2.1 Inhalation Exposure 

No data on the distribution of trichlorobenzenes following inhalation exposure were located for animals. 

3.4.2.2 Oral Exposure 

Trichlorobenzene isomers are readily distributed throughout bodily tissues in animals. However, the level 

of distribution and length of retention vary between isomers. Several studies have been conducted with 

14C-labeled trichlorobenzenes. It should be noted that generally in these studies no distinction can be 

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made between parent compound, metabolites, and recycled carbon incorporated into body 

macromolecules. 

1,2,3-Trichlorobenzene. Radioactivity was present in the blood and tissues of male Sprague-Dawley rats 

0.5 hours following gavage administration of 10 mg/kg 14C-labeled 1,2,3-trichlorobenzene (Chu et al. 

1987). Tissue concentrations peaked at 24 hours with very high concentrations appearing in the 

gastrointestinal tract (2,180 ppb), liver (277 ppb), fat (1,920 ppb), kidney (399 ppb), and bladder 

(284 ppb). Seven days after dosing, radioactivity in the brain, muscle, testes, and seminal vesicles were 

no longer detectible. Radioactivity was nearly undetectable in the liver, fat, and skin by 56 days after 

dosing (Chu et al. 1987). Chu et al. (1987) reported gas chromatography (GC) data that indicated that 

most of the radioactivity in skin, liver, and fat was the parent compound, whereas that in muscle and 

kidney was predominantly more polar metabolites. 

1,2,4-Trichlorobenzene. Radioactivity was found in the blood and tissues of male Sprague-Dawley rats 

0.5 hours after oral dosing with 10 mg/kg 14C-labeled 1,2,4-trichlorobenzene (Chu et al. 1987). Levels 

peaked around 4 hours and declined thereafter. High concentrations remained present in the bladder 

(1,280 ppb), kidney (1,160 ppb), fat (4,260 ppb), skin (243 ppb), liver (680 ppb), and adrenal glands 

(850 ppb) at 24 hours. Seven days after dosing, radioactivity was no longer detectable in the brain, 

spleen, muscle, testes, seminal vesicles, epididymis, or prostate. Most tissues showed levels of 

radioactivity barely distinguishable from background levels 28 days after dosing (<10 ppb except adrenals 

with 40 ppb) (Chu et al. 1987). Sprague-Dawley rats given a daily oral dose of 181.5 mg/kg 14C-labeled 

1,2,4-trichlorobenzene for 7 consecutive days showed the highest initial concentration of radioactivity in 

the adrenal glands (Smith and Carlson 1980). This level declined rapidly and no radioactivity could be 

detected 11 days after dosing. Abdominal fat had the highest concentrations on day 1 (2,033 dpm/g) and 

maintained detectable concentrations (~20% of day 1 level) through the remainder of the 16-day 

observation period. The liver also maintained detectable concentrations (1,075 dpm/g on day 1 and 

317 dpm/g on day 19) throughout the entire observation period (Smith and Carlson 1980). High levels of 

radioactivity were found in adipose tissue and skin (81 and 15% of administered dose, respectively) 

12 hours following administration of a single 50 mg/kg oral dose of 14C-labeled 1,2,4-trichlorobenzene to 

male Wistar rats. Radioactivity was also detectable in muscle and intestine at this time (~8 and 5% of 

administered dose). By 168 days after dosing, radioactivity was virtually undetectable in all examined 

tissues (Tanaka et al. 1986). 

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1,3,5-Trichlorobenzene. An early study by Parke and Williams (1960) indicated a wide distribution of 

1,3,5-trichlorobenzene following a 500 mg/kg dose in rabbits. Specifically, 13% of the administered dose 

was detected in the feces, 23% in the gut, 5% in the pelt, 5% in the depot fat, and 22% in the carcass 

8 days after administration. A later study revealed radioactivity in the blood and tissues 0.5 hours after 

oral dosing of male Sprague-Dawley rats with 10 mg/kg of 14C-labeled 1,3,5-trichlorobenzene (Chu et al. 

1987). As with the other isomers, levels of radioactivity peaked at 1 day after administration. The peak 

concentrations in tissues with the highest concentrations showed the following order: fat (8,960 ppb) 

> gastrointestinal tract > salivary gland > adrenal ≈ bladder > liver > kidney > pancreas > epididymis

> prostate > skin > lung > seminal vesicle (410 ppb). Peak tissue concentrations were generally higher 

following administration of 1,3,5-trichlorobenzene compared with 1,2,3- and 1,2,4-trichlorobenzene (Chu 

et al. 1987). Chu et al. (1987) reported GC data that indicated that most of the radioactivity in skin, liver, 

and fat was the parent compound, whereas that in muscle and kidney was predominantly more polar 

metabolites. Côté et al. (1988) found an accumulation of trichlorobenzene isomers in the fat and liver of 

rats, indicating that 1,3,5-trichlorobenzene accumulated at a higher level in these tissues than 1,2,4- and 

1,2,3-trichlorobenzene when presented at 1,000 ppm in food for 13 weeks. The levels of isomer in the fat 

(15.5–76 ppm in males; 7.8–49 ppm in females) were one order of magnitude higher than those found in 

the liver (1.4–4.3 ppm in males; 0.73–1.9 ppm in females). 

Trichlorobenzenes have been identified in human breast milk; therefore, infants may also be potentially 

exposed through breast feeding (see Section 6.6, Exposures of Children). 

3.4.2.3 Dermal Exposure 

Quantitative data on the distribution of trichlorobenzenes following dermal exposure were not located for 

humans or animals. 

3.4.3 Metabolism 

There is no information regarding the metabolism of trichlorobenzenes in humans following exposure by 

any route or regarding the metabolism of trichlorobenzenes in animals following inhalation or dermal 

exposure. Several studies have examined and identified urinary metabolites following oral, 

intraperitoneal, or intravenous exposure of rabbits (Jondorf et al. 1955; Kohli et al. 1976; Parke and 

Williams 1960), rats (Bakke et al. 1992; Lingg et al. 1982), and monkeys (Lingg et al. 1982). Identified 

metabolites are consistent with the initial formation of phenolic intermediates (indicative of arene oxide 

intermediates), which become conjugated with glutathione or glucuronic acid prior to excretion in the 

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urine or bile. A comparison of rat and monkey urinary metabolites indicated that glutathione conjugation 

was the predominant pathway in rats, whereas glucuronidation was predominant in monkeys (Lingg et al. 

1982). Figure 3-6 diagrams hypothesized metabolic pathways of trichlorobenzene isomers. To date, 

enzymes involved in the proposed steps have not been definitively established, but based on analogy to 

benzene and other halogenated benzenes, cytochrome P450 isozymes likely catalyze the initial formation 

of phenols through arene oxides. 

1,2,3-Trichlorobenzene. Jondorf et al. (1955) identified urinary metabolites of all three isomers in 

Chinchilla rabbits given a single oral 500 mg/kg dose. Spectrophotometric analysis indicated that 

1,2,3-trichlorobenzene was the most rapidly metabolized of the three isomers. This isomer was mostly 

metabolized to 2,3,4-trichlorophenol, but lesser amounts of 3,4,5-trichlorophenol and 3,4,5-trichlorocatechol were also detected. Of the administered dose, 62% was excreted in urine as oxygen conjugates 

containing glucuronic and sulphuric acids within 5 days. Major metabolite excretions rose to a maximum 

on the first day after dosing and were no longer detectable in rabbit urine after 5 days. 

Kohli et al. (1976) identified urinary metabolites of trichlorobenzene isomers following a single 60– 

75 mg/kg intraperitoneal injection in male rabbits, finding similar results as those reported by Jondorf et 

al. (1955). Specifically, GC and mass spectrometry (MS) revealed the major metabolite of 

1,2,3-trichlorobenzene to be 2,3,4-trichlorophenol with 2,3,6- and 3,4,5-trichlorophenol appearing at 

lower levels. 

1,2,4-Trichlorobenzene. The only relevant information regarding metabolism of 1,2,4-trichlorobenzene 

in humans is that incubation of 1,2,4-trichlorobenzene with microsomes derived from cell lines 

expressing human CYP1A1, CYP1A2, CYP3A4, CYP2E1, and CYP2D6 showed that CYP2E1had the 

highest enzymatic activity towards the chemical (Bogaards et al. 1995). The investigators also reported 

that in microsomal preparations from 22 human livers, CYP2E1 was the major enzyme involved in the 

formation of 2,3,5-trichlorophenol and 2,3,4-trichlorophenol from 1,2,4-trichlorobenzene, whereas 

CYP3A4 was responsible for the formation of 2,3,6-trichlorophenol. 

In Chinchilla rabbits given a single 500 mg/kg dose by gavage, 1,2,4-tricholorobenzene was primarily 

metabolized to 2,4,5- and 2,3,5-trichlorophenol, with 5-day urinary metabolites of the isomer consisting 

of 38% glucuronic and sulphuric acid conjugates (Jondorf et al. 1955). Similar findings were obtained in 

a study examining urinary metabolites of trichlorobenzene isomers following a single 60–75 mg/kg 

intraperitoneal injection in male rabbits (Kohli et al. 1976). This study indicated that the primary 

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Cl 

Cl 

OH 

Cl 

Cl

O 

Cl 2,3,6-TCP 

Cl Cl 

O 

2,3,4-TCBO Cl Cl 

HO Cl 

Cl 

Cl 1,2,3-TCB Cl 

Cl 2,3,4-TCP 

Cl 

3,4,5-TCBO 

Cl 

Cl 

OH Cl

3,4,5-TCP 

Cl 

OH 

Cl Cl Cl Cl

Cl 

O 2,4,6-TCP 

OH 

Cl Cl Cl Cl 

1,3,5-TCB 1,3,5-TCBO 

Cl Cl 

Cl 2,3,5-TCP 

Cl 

Cl 

O 

2,3,5-TCBO 

Cl 

O 

Cl Cl

Cl Cl Cl

HO 

Cl Cl Cl

2,4,5-TCBO 2,4,5-TCP 1,2,4-TCB 

Cl 

Cl 

Cl 

O 

3,4,6-TCBO 

- Glutathione and glucuronide

 conjugation (rabbit) 

- Glutathione conjugation (rat) 

- Glucuronide conjugation (monkey) 

TRICHLOROBENZENES 119 

3. HEALTH EFFECTS 

Figure 3-6. Hypothesized Metabolic Pathways for Trichlorobenzene Isomers 

Through Arene Oxide Intermediates 

TCB = trichlorobenzene; TCBO = trichlorobenzene oxide; TCP = trichlorophenol 

Source: Adapted from Kohli et al. (1976), with information from Bakke et al. (1992), Lingg et al. (1982), and Parke 

and Williams (1960). 

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metabolites of 1,2,4-trichlorobenzene were 2,3,5- and 2,4,5-trichlorophenol, while those of 

1,3,5-trichlorobenzene were 2,3,5- and 2,4,6-trichlorophenol. 

Further studies of 1,2,4-trichlorobenzene metabolism monitored urinary metabolites from rats and 

monkeys following oral or intravenous administration of single 10 mg/kg doses (Lingg et al. 1982). 

Although this study revealed similar metabolites as those previously observed in rabbits, some speciesspecific differences in conjugated metabolites were apparent. In rats, 60–62% of the urinary metabolites 

consisted of the mercapturic acids 2,3,5- and 2,4,5-N-acetyl-S-(trichlorophenyl)-L-cysteine 24 hours after 

dose administration. This finding suggests that conjugation with glutathione is the major metabolic 

pathway and that arene oxides, such as 3,4,6-trichlorobenzene oxide, are likely reactive metabolic 

intermediates in rats. In the urine of monkeys, isomeric glucuronides of 3,4,6-trichloro-3,5 cyclohexadiene accounted for between 48 and 61% of urinary metabolites. Sulfur-containing metabolites were 

not found in the urine of monkeys following oral dosing with 10 mg/kg, indicating that conjugation of 

metabolic intermediates to glucuronic acid, not glutathione conjugation, is important in the monkey. 

A later study in bile-duct cannulated male Sprague-Dawley rats reported that over 60% of a 21 mg/kg oral 

dose of 14C-1,2,4-trichlorobenzene was excreted in bile, while 21 and 2% were excreted in the urine and 

feces, respectively, within 24 hours (Bakke et al. 1992). In intact rats, about 70 and 9% of the 

administered dose were excreted in the urine and feces, respectively, within 24 hours. In urine from 

cannulated rats, the major identified metabolites were consistent with catabolism following glutathione 

conjugation of phenolic intermediates. S-(trichlorophenyl)-N-(acetyl) cysteine was the major urinary 

metabolite identified; S-(dichloro-hydroxyphenol)-N-(acetyl) cysteine (another mercapturic acid), 

trichlorothiophenol, and trichlorophenol were present at lesser concentrations. Only trace levels of 

glucuronides and sulphate esters were detected. Bile showed a wider range of metabolites consistent with 

catabolism of glutathione conjugates and relatively more trichlorothiophenol compared with urine. A 

single 3.5 mg intraperitoneal injection of 14C-2,4,5-trichlorothiophenol resulted in excretion of 17% of the 

administered dose as S-glucuronide and 36% as S-(methylsulphonyl-dichlorophenyl)-mercapturic acid, 

metabolites not found in the excrement of rats dosed with 1,2,4-trichlorobenzene. These findings led to 

the suggestion that trichlorothiophenols are not major intermediates or end-products of enzymatic 

metabolism of trichlorobenzene in rats, but were formed from enterohepatic circulation via intestinal 

flora. This was later confirmed by Kato et al. (1993) who suggested that the formation of methylsulfonyl 

metabolites of 1,2,4-trichlorobenzene involves the initial biliary secretion of 1,2,4-trichlorobenzene 

metabolites into the intestinal tract, followed by metabolism by intestinal microflora and the absorption of 

secondary metabolites into the systemic circulation. 

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The metabolism of 1,2,4-trichlorobenzene in vitro has also been investigated. Incubation of 

1,2,4-trichlorobenzene with liver microsomes from male rats pretreated with dexamethasone (DEX) 

showed the formation of trichlorohydroquinone in addition to various trichlorophenols (Den Besten et al. 

1991). Trichlorohydroquinone, which appeared to be formed as a result of secondary metabolism, was 

found to covalently interact with microsomal protein. Both the conversion and the covalent binding of 

1,2,4-trichlorobenzene were mediated by cytochrome P-450 as shown by the dependence on the presence 

of NADPH and the inhibitory action of metyrapone. The addition of glutathione reduced the covalent 

binding almost completely through the formation of water soluble conjugates. Pretreatment of the rats 

with different inducers resulted in preferential formation of different trichlorophenols. Induction with 

DEX resulted in preferential formation of 2,3,6-trichlorophenol, whereas other inducers preferentially 

produced 2,4,5-trichlorophenol. 2,4,6-Trichlorophenol was a minor metabolite in all microsomal 

suspensions, whereas 2,3,4-trichlorophenol and 2,3,5-trichlorophenol were formed only in trace amounts. 

Adding DNA to the microsomal suspension resulted in covalent binding of 1,2,4-trichlorophenol with the 

DNA, although to a much lesser extent than with proteins. 

1,3,5-Trichlorobenzene. Following oral administration of a 500 mg/kg dose of 1,3,5-trichlorobenzene in 

Chinchilla rabbits, only one phenol was detected in the urine (2,4,6-trichlorophenol), and only 23% of the 

administered dose was excreted as conjugates of glucuronic and sulfuric acids within 5 days (Jondorf et 

al. 1955). A subsequent study by Parke and Williams (1960) further detailed the metabolism of 

1,3,5-trichlorobenzene in Chinchilla rabbits given a single 500 mg/kg dose by gavage. Within the first 

3 days after dosing, 2,4,6-trichlorophenol and some minor monochlorophenols were excreted in the urine. 

2,4,6-Trichlorophenol continued to be excreted from days 4 through 9 with the addition of 4-chlorophenol 

elimination. The principal urinary metabolites identified in urine collected from male rabbits following 

an intraperitoneal injection of 300 mg 1,3,5-trichlorobenzene were 2,3,5- and 2,4,6-trichlorophenol (Kohli 

et al. 1976). A third more polar metabolite was identified, but insufficient material was available to 

determine the structure of the compound by MS. 

3.4.4 Elimination and Excretion 

No information was located regarding elimination and excretion of trichlorobenzenes in humans 

following any route of exposure. 

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3.4.4.1 Inhalation Exposure 

No data were found on the elimination and excretion of trichlorobenzenes following inhalation exposure 

in animals. 

3.4.4.2 Oral Exposure 

All three isomers of trichlorobenzene have been shown to be rapidly and efficiently eliminated following 

oral exposure, principally via metabolites in the urine in rabbits (Jondorf et al. 1955) and rats (Bakke et al. 

1992; Chu et al. 1987), although enterohepatic biliary circulation has been demonstrated in bilecannulated rats (Bakke et al. 1992). 

1,2,3-Trichlorobenzene. Jondorf et al. (1955) illustrated the rapid elimination of 1,2,3-trichlorobenzene 

in Chinchilla rabbits administered a 500 mg/kg oral dose. Five days after dosing, 78% of the 

administered dose had been excreted as trichlorophenols and 62% as oxygen conjugates in urine, with no 

trace of the isomer found in feces. In rats, 92% of 14C-labeled 1,2,3-trichlorobenzene was eliminated 

through the urine and feces within 24 hours of a single 10 mg/kg gavage dose (Chu et al. 1987). Overall 

excretion increased to 95% at 48 hours post ingestion. The percentage of the radiolabeled 1,2,3-isomer in 

urine alone accounted for 56 and 59% at 24 and 48 hours, respectively. Data for radioactivity in tissues 

measured at 0.5, 1, 2, and 4 hours and 1, 2, 7, 14, 28, and 56 days after dose administration were fit to a 

two-compartment elimination model; estimated half-lives were 9.2 and 145 hours for the first and second 

compartments, respectively. 

1,2,4-Trichlorobenzene. Chinchilla rabbits excreted 42% of a single 500 mg/kg oral dose of 

1,2,4-trichlorobenzene as trichlorophenols 5 days after administration (Jondorf et al. 1955). This same 

study also noted that 38% of the administered dose was excreted in the urine as oxygen conjugates during 

the same time frame. A later study in rats dosed with 50 mg/kg 14C-labeled 1,2,4-trichlorobenzene 

revealed 66 and 17% excretion of radioactivity in urine and feces, respectively, 7 days post administration 

(Tanaka et al. 1986). Radioactivity in expired air consisted of 2.1% of the absorbed dose. Excretion in 

all three excreta reached a peak on day 3. Biliary excretion accounted for 45% of the radioactivity. The 

authors considered the enterohepatic circulation of trichlorobenzene metabolites in the body as a possible 

explanation for the difference in biliary and fecal excretion rates. Bakke et al. (1992) reported that >60% 

of a 21 mg/kg dose of 14C-1,2,4-trichlorobenzene was excreted in bile, while 21% was excreted in the 

urine of bile-cannulated Sprague-Dawley rats within 24 hours. In control rats without bile cannulation, 

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70 and 9% of the administered radioactivity was excreted within 24 hours in the urine and feces, 

respectively (Bakke et al. 1992). 

Following a longer period of exposure, 181.5 mg/kg/day of 14C-labeled 1,2,4-trichlorobenzene for 

7 consecutive days, Smith and Carlson (1980) found that the urinary and fecal excretion of the isomerderived radioactivity in Sprague-Dawley rats peaked during the first 3 days of dosing and declined rapidly 

thereafter. Radioactivity in the feces was not detectable past day 15 and accounted for only 4% of the 

administered dose. Urinary excretion, however, displayed detectable radioactivity 21 days after the first 

oral administration. Radioactivity in the urine accounted for approximately 72% of the administered 

dose. 

Showing variations between species, Lingg et al. (1982) measured excretion rates in both monkeys and 

rats given a 10 mg/kg oral dose of 14C-labeled 1,2,4-trichlorobenzene. By 24 hours after dosing, monkeys 

had excreted 40% of the administered dose in the urine. Less than 1% was found in the feces. Rats 

excreted 84% of the oral dose via the urine by 24 hours; 11% was found in feces. Following intravenous 

administration of 10 mg/kg 14C-labeled 1,2,4-trichlorobenzene, monkeys eliminated about 22% of the 

administered radioactivity in urine and none in the feces 24 hours after exposure. Rats, on the other hand, 

excreted 78 and 7% of the administered dose in urine and feces at 24 hours, respectively. Regardless of 

the route of exposure, rats excreted radioactivity at a rate roughly 2–3 times faster than monkeys 

following administration of 14C-labeled 1,2,4-trichlorobenzene. 

1,3,5-Trichlorobenzene. In Chinchilla rabbits dosed with a single 500 mg/kg dose by gavage, 9% of the 

administered dose was excreted as trichlorophenols in the urine during the 5 days after dosing (Jondorf et 

al. 1955), while 23% was excreted as oxygen conjugates. A follow-up study indicated that only 4 and 

14% of a 500 mg/kg dose were eliminated as phenols 8 and 9 days after dosing, respectively (Parke and 

Williams 1960). A much higher level of excretion, 82% of 14C-labeled 1,3,5-trichlorobenzene, was found 

in the urine and feces of Sprague-Dawley rats within 24 hours of a single 10-mg/kg gavage dose (Chu et 

al. 1987). Overall excretion increased to 89% at 48 hours post ingestion. The percentage of the 

radiolabeled 1,3,5-isomer in urine alone accounted for 47 and 50% at 24 and 48 hours, respectively. Data 

for radioactivity in tissues measured at 1, 2, 7, 14, 28, and 56 days after dose administration were fit to a 

two-compartment elimination model; estimated half-lives were 8 and 67.5 hours for the first and second 

compartments, respectively (Chu et al. 1987). 

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3.4.4.3 Dermal Exposure 

No data on the elimination and excretion of trichlorobenzenes following dermal exposure were located for 

animals. 

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 endpoints. 

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 et al. 

1987; Andersen and Krishnan 1994). 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 parametrization, (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. 

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The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-7 shows a conceptualized representation of a PBPK model. 

If PBPK models for trichlorobenzenes 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. 

No PBPK/PD models have been developed for trichlorobenzenes. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Studies in animals indicate that trichlorobenzenes are rapidly and efficiently absorbed through the 

gastrointestinal tract. However, the specific mechanisms by which this occurs have not been evaluated. 

Given that they are fairly soluble in lipids, it is reasonable to assume that absorption will occur through 

passive diffusion. No specific information was located regarding mechanisms of inhalation or dermal 

absorption. In addition, no relevant information was located regarding mechanisms of transport of 

trichlorobenzenes (or metabolites) in the blood, distribution to tissues, or storage in tissues. 

The role of metabolism on the liver effects of 1,2,4-trichlorobenzene, specifically enzyme induction and 

alterations in heme metabolism, has been examined by Kato and coworkers (Kato and Kimura 2002; Kato 

et al. 1988, 1993). Intraperitoneal injection of the metabolite 2,3,5-trichlorophenyl methyl sulfone to 

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Figure 3-7. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance 

Inhaled chemical Exhaled chemical 

Ingestion 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 

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male Wistar rats resulted in significant increases in the activities of aminopyrine N-demethylase and 

cytochrome P-450 content in liver microsomes, reaching a maximum at 48–72 hours after the injection 

(Kato et al. 1993). Significant increases in aniline hydroxylase and cytochrome b5 contents were also 

observed at 12–120 hours and 24–120 hours, respectively. The rise and fall in enzyme activities 

correlated with the rise and fall of the hepatic concentration of 2,3,5-trichlorophenyl methyl sulfone rather 

than with the hepatic concentration of 1,2,4-trichlorobenzene. This was consistent with the estimated 

elimination half-lives from the liver of 5.2 hours and 37.8 hours for 1,2,4-trichlorobenzene and 

2,3,5-trichlorophenyl methyl sulfone, respectively. In this study, 2,4,5-trichlorophenyl methyl sulfone 

was found to be a weaker inducer, although an earlier study had shown 2,4,5-trichlorophenyl methyl 

sulfone to induce a component of the microsomal electron transport system and also uridine diphosphateglucuronyltransferase, a phase II metabolic enzyme (Kato et al. 1988). Overall, these findings strongly 

suggest that the inducing effect of 1,2,4-trichlorobenzene on liver microsomal drug-metabolizing 

enzymes is not due to the parent compound, but to its methysulfonyl metabolite 2,4,5-trichlorophenyl 

methyl sulfone. 

1,2,4-Trichlorobenzene has been shown to induce ALA synthetase, the rate-limiting enzyme in the 

biosynthesis of heme (Ariyoshi et al. 1975a, 1975b) and also heme oxygenase, the rate-limiting enzyme in 

the degradation of heme (Kato and Kimura 2002). Administration of 1,2,4-trichlorobenzene or 

2,3,5-trichlorophenyl methyl sulfone to male Wistar rats resulted in significant increases in ALA 

synthetase activity, but only 1,2,4-trichlorobenzene induced heme oxygenase (Kato and Kimura 2002). In 

both cases, there were significant increases in the contents of cytochrome P-450, which paralleled 

increases in total heme content. In rats with reduced liver glutathione levels by pretreatment with 

buthionine-(S,R)-sulfoximine (BSO) and dosed with 1,2,4-trichlorobenzene, 2,3,5-trichlorophenyl methyl 

sulfone was present in the liver at much lower concentrations than in rats not pretreated with BSO. In 

addition, 1,2,4-trichlorobenzene did not induce ALA synthetase in BSO-treated rats, but 2,3,5-trichlorophenyl methyl sulfone did, suggesting that the induction of ALA synthetase in rats dosed with 

1,2,4-trichlorobenzene is not due to 1,2,4-trichlorobenzene, but to 2,3,5-trichlorophenyl methyl sulfone. 

Kato and Kimura (2002) suggested that the prolonged induction of ALA synthetase by 2,3,5-trichlorophenyl methyl sulfone results in excess heme biosynthesis, which overrides the destruction of heme that 

results from the induction of heme oxygenase by 1,2,4-trichlorobenzene or a metabolite other than 

2,3,5-trichlorophenyl methyl sulfone. This is consistent with the induction of porphyria in rats dosed with 

1,2,4-trichlorobenzene (i.e., Rimington and Ziegler 1963). 

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No studies were located that examined the effect of dose on metabolism or excretion pathways of 

trichlorobenzenes. 

3.5.2 Mechanisms of Toxicity 

The toxicity of trichlorobenzenes does not appear to be route-dependent, and the liver appears to be the 

main target regardless of the duration of exposure. 

The mechanism(s) of liver toxicity induced by trichlorobenzenes has not been elucidated, but it probably 

involves arene oxide intermediates which form during the initial transformation to trichlorophenols. As 

mentioned above, 1,2,4-trichlorobenzene, and presumably the other isomers, induce a number of drugmetabolizing enzymes in the liver of rats which will affect the biotransformation of other chemicals. 

Whether or not this will result in increased toxicity of other xenobiotics will depend on whether the 

toxicity of the other chemical is due to the parent compound or to a metabolite. Also, as mentioned 

above, exposure to 1,2,4-trichlorobenzene induced porphyria in rats by inducing ALA synthetase and thus 

increasing heme production. Trichlorobenzenes and other chlorinated benzenes induce nephropathy in 

the male rat by a mechanism that involves a series of events beginning with an excessive accumulation of 

hyaline droplets. This appears to be unique to the male rat and is not relevant for human risk assessment. 

A study of 1,2,4-trichlorobenzene with liver microsomes from male rats in vitro reported the formation of 

trichlorohydroquinone as a result of secondary metabolism (Den Besten et al. 1991). Trichlorohydroquinone was found to covalently interact with microsomal protein and with added DNA. Whether 

or not this plays a role in the in vivo toxicity of 1,2,4-trichlorobenzene is unknown. 

3.5.3 Animal-to-Human Extrapolations 

There is virtually no information on health effects of trichlorobenzenes in humans, so the animal species 

that is the most appropriate model for human exposure is not known. The liver is the target for 

trichlorobenzenes in animals, and rats appear to be more sensitive than other species. Based on 

information from effects of other chlorinated benzenes in humans, and from limited information on the 

metabolism of 1,2,4-trichlorobenzene by microsomal preparations from human livers that indicated that 

cytochrome P-450 enzymes might be involved in the metabolism of trichlorobenzenes, it is reasonable to 

assume that excessive exposure to trichlorobenzenes could induce liver effects such as porphyria in 

humans. 

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3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC) which in 

1998 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 terms endocrine modulators have 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 1997). Stated differently, such compounds may cause toxicities that are mediated through 

the neuroendocrine axis. As a result, these chemicals may play a role in altering, for example, metabolic, 

sexual, immune, and neurobehavioral function. Such chemicals are also thought to be involved in 

inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; Giwercman et al. 

1993; Hoel et al. 1992). 

There is no evidence from the reproductive and developmental studies, summarized in Sections 3.2.2.5 

and 3.2.2.6, respectively, that suggests that trichlorobenzenes affect the neuroendocrine axis. 

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The only relevant information that was located regarding in vitro tests is that 1,2,4-trichlorobenzene and 

1,2,3-trichlorobenzene tested negative for estrogenic activity in a reporter gene expression assay using 

yeast cells (Nishihara et al. 2000). A substance was considered positive when its activity was more than 

10% of the activity of 10-7M 17β-estradiol. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

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sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

No studies were located that described health effects in children following exposure to trichlorobenzenes. 

Also, no studies were located that compared the health effects of these compounds in young and adult 

animals to ascertain potential age-related differences in susceptibility. 

Standard developmental toxicity studies in animals do not suggest that trichlorobenzenes are embryotoxic 

or teratogenic or that they alter the development of young animals. The only effects reported in a study 

with 1,2,4-trichlorobenzene in rats were the presence of microscopic alterations in the lenses of the eye of 

fetuses from dams treated with 150 mg/kg/day 1,2,4-trichlorobenzene on Gd 6–15 and sacrificed on 

Gd 22 (Black et al. 1988). However, no lesions were observed in fetuses from dams dosed with 

300 mg/kg/day 1,2,4-trichlorobenzene. This lesion was also observed in fetuses from dams dosed with 

150, 300, or 600 mg/kg/day 1,3,5-trichlorobenzene; however, since no quantitative data were presented, it 

is not known whether the incidences were dose-related. Another gestational exposure study reported 

retarded development of the fetuses from rats dosed with 360 mg/kg/day 1,2,4-trichlorobenzene on Gd 9– 

13 and sacrificed on Gd 14 (Kitchin and Ebron 1983). This dose level was lethal to two out nine dams 

and induced significant weight loss in dams that survived, which may have contributed to the delayed 

development of the fetuses. In studies of pregnant mice dosed with 0 or 130 mg/kg/day 1,2,4-trichlorobenzene on Gd 8–12, the chemical did not affect pup’s viability or growth, or offspring’s locomotor 

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activity or fertility to produce a second generation (Chernoff and Kavlock 1983; Gray and Kavlock 1984; 

Gray et al. 1986). 

Trichlorobenzenes have been identified in breast milk; therefore, infants may also be potentially exposed 

through breast feeding (see Section 6.6, Exposures of Children). No information was located regarding 

the pharmacokinetics of these compounds in children, regarding biomarkers of exposure or effect for 

these compounds in children, or regarding interactions with other chemicals in children. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself, substance-specific metabolites in 

readily obtainable body fluid(s), 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 exposures 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 trichlorobenzenes are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

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capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by trichlorobenzenes 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 Trichlorobenzenes 

Trichlorobenzenes have been detected in blood (Bristol et al. 1982; Mes 1992; Pellizzari et al. 1985a), 

adipose tissue (Mes 1992), and exhaled breath (Pellizzari et al. 1985b) and their presence in the body can 

be used as biomarkers of exposure to trichlorobenzenes. However, metabolites of trichlorobenzenes, such 

as trichlorophenols, cannot be used as specific biomarkers for exposure to trichlorobenzenes because they 

can also be generated from the metabolism of other chlorinated compounds such as the pesticide lindane 

(Agency for Toxic Substances and Disease Registry 2005). 

3.8.2 Biomarkers Used to Characterize Effects Caused by Trichlorobenzenes 

No specific biomarker of effects could be identified from the very limited information regarding humans 

exposed to trichlorobenzenes (see Section 3.2.1.2, Systemic Effects). Based on the existing information 

regarding the effects of trichlorobenzenes in animals, it is difficult to envision a health condition that 

could be attributed solely to exposure to trichlorobenzenes. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

No studies were located regarding interactions among trichlorobenzenes and limited data were found 

regarding interactions between trichlorobenzenes and other chemicals. Since trichlorobenzenes are 

inducers of liver microsomal enzymes (Ariyoshi et al. 1975a, 1975b; Carlson and Tardiff 1976; Kato and 

Kimura 2002; Kato et al. 1988, 1993; Kitchin and Ebron 1983), they will affect the metabolism of other 

compounds. For example, gavage administration of 1,2,4-trichlorobenzene at 600 mg/kg/day to rats for 

14 days significantly decreased hexobarbital sleeping time (Carlson and Tardiff 1976). In another study, 

1,2,4-trichlorobenzene increased the LD50 values for malathion, malaoxon, parathion, and paraoxon in 

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mice (Townsend and Carlson 1981). In the same study, 1,2,4-trichlorobenzene protected against the 

decrease in brain cholinesterase induced by malathion, but not against reductions in liver, plasma, or RBC 

cholinesterase. The protection afforded by 1,2,4-trichlorobenzene correlated well with increased 

carboxylesterase activity. These examples can be considered inhibitory types of interactions. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to trichlorobenzenes than will most 

persons exposed to the same level of trichlorobenzenes 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 may result in reduced detoxification or excretion of trichlorobenzenes, or compromised 

function of organs affected by trichlorobenzenes. Populations who are at greater risk due to their 

unusually high exposure to trichlorobenzenes are discussed in Section 6.7, Populations with Potentially 

High Exposures. 

A specific target for trichlorobenzene toxicity in humans exposed to these compounds has not been 

identified, but it is reasonable to assume that the liver could be a main target based on studies in animals. 

Therefore, individuals with compromised liver function may represent a susceptible population. No 

information was located regarding whether or not children represent a group unusually susceptible to 

trichlorobenzenes. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to trichlorobenzenes. 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 trichlorobenzenes. 

When specific exposures have occurred, poison control centers and medical toxicologists should be 

consulted for medical advice. No texts were identified that provide specific information about treatment 

following exposures to trichlorobenzenes. 

3.11.1 Reducing Peak Absorption Following Exposure 

The following information has been extracted from HSDB (2010). Methods for reducing peak absorption 

of trichlorobenzenes include gut dilution with water or milk and eye irrigation with water or sterile saline. 

Activated charcoal is not recommended, as it may promote vomiting and make endoscopic evaluation 

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difficult. If exposure occurs via the dermal route, contaminated clothing should be removed and affected 

areas should be washed with soap. Exposure to fresh air or oxygen treatment is recommended to reduce 

absorption after inhalation exposure to trichlorobenzenes. 

3.11.2 Reducing Body Burden 

No information was located regarding reducing body burden of trichlorobenzenes following exposure to 

these chemicals. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Studies in animals indicate that isomers of trichlorobenzene enhance xenobiotic metabolism via the 

induction of numerous hepatic drug-metabolizing enzymes including cytochromes c and P-450, 

glucuronyltransferase, glutathione S-transferase, and microsomal proteins (Ariyoshi et al. 1975a, 1975b; 

Kato and Kimura 2002; Kato et al. 1988, 1993). Also induced by 1,2,4-trichlorobenzene is ALA 

synthetase, the rate-limiting enzyme in heme biosynthesis (Ariyoshi et al. 1975a, 1975b), which is the 

cause of hepatic porphyria in rats treated with 1,2,4-trichlorobenzene (Rimington and Ziegler 1963). 

Studies suggest that both the induction of hepatic microsomal drug-metabolizing enzymes and ALA 

synthetase may not be mediated directly by 1,2,4-trichlorobenzene, but by its metabolite 2,3,5-trichlorophenyl methyl sulfone (Kato and Kimura 2002; Kato et al. 1988, 1993). Since 2,3,5-trichlorophenyl 

methyl sulfone results from the conjugation of glutathione with a 1,2,4-trichlorobenzene hydroxyl 

derivative, theoretically, reducing glutathione levels would prevent, at least in part, the effects of 

1,2,4-trichlorobenzene. 

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 trichlorobenzenes 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 trichlorobenzenes. 

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 

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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 Trichlorobenzenes 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

1,2,3- ,1,2,4-, and 1,3,5-trichlorobenzenes are summarized in Figures 3-8, 3-9, and 3-10, respectively. 

The purpose of these figures is to illustrate the existing information concerning the health effects of 

trichlorobenzene. Each dot in the figures 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. 

There is virtually no information regarding health effects in humans exposed to trichlorobenzenes. 

Information is available regarding health effects in animals exposed orally and dermally to each one of 

the three trichlorobenzene isomers and exposed by inhalation to 1,2,4-trichlorobenzene and 

1,3,5-trichlorobenzene. 1,2,4-Trichlorobenzene has been the most widely studied of the three isomers. 

Chronic-duration studies in animals are available only for 1,2,4-trichlorobenzene and only via the oral 

route of exposure. Studies in animals showed that the liver is a target for trichlorobenzene toxicity, 

particularly in rats. The kidney was also affected in male rats, but this effect appears to be a unique 

response of male rats to exposure to a variety of organic chemicals and not relevant to humans. 

1,2,4-Trichlorobenzene was evaluated for carcinogenicity in rats and mice; this isomer induced malignant 

liver tumors in mice. Trichlorobenzenes induced transitory skin and eye irritation when applied onto the 

skin or instilled into the eyes of animals. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. No acute-duration studies were located in humans exposed by inhalation 

to trichlorobenzenes that could be used for derivation of an acute-duration MRL for this route. A review 

of the literature indicates that an adult male who inhaled trichlorobenzene for several hours during the 

repair of a pump suffered massive hemoptysis, and that some trichlorobenzene production workers 

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Figure 3-8. Existing Information on Health Effects of 1,2,3-Trichlorobenzene 

Inhalation 

Oral 

Dermal 

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 

Existing Studies 

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Figure 3-9. Existing Information on Health Effects of 1,2,4-Trichlorobenzene 

Inhalation 

Oral 

Dermal 

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 

Existing Studies 

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Figure 3-10. Existing Information on Health Effects of 1,3,5-Trichlorobenzene 

Inhalation 

Oral 

Dermal 

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 

Existing Studies 

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developed chloroacne (IPCS 1991). Citing an unpublished source, ACGIH (2001) stated that minimal 

eye and throat irritation could occur in some people exposed to 3–5 ppm 1,2,4-trichlorobenzene. No 

relevant inhalation studies were located of animals exposed to 1,2,4-trichlorobenzene or 1,3,5-trichlorobenzene, and no information was located for 1,2,3-trichlorobenzene. A decision to conduct studies in 

animals for possible derivation of acute-duration inhalation MRLs for trichlorobenzenes has to be made 

after evaluating the likelihood that exposure to high concentrations of these chemicals for short periods of 

time will occur. No information was located regarding oral toxicity of trichlorobenzenes in humans. 

Aside from studies that provided information on lethal doses of trichlorobenzenes in animals (Brown et 

al. 1969; Côté et al. 1988; Jorgenson et al. 1976), there are few studies available that examined the effects 

of acute oral exposure to these compounds. A developmental study in rats exposed to the three 

trichlorobenzene isomers during Gd 6–15 conducted histological evaluations of tissues and organs from 

the dams sacrificed on Gd 22 (Black et al. 1988). The liver and possibly the thyroid appeared to be 

targets for trichlorobenzenes; however, no quantitative data were presented, so NOAELs or LOAELs 

could not be defined and the study could not be used for MRL derivation. A 14-day gavage study with 

1,2,4-trichlorobenzene in rats by Carlson and Tardiff (1976) identified the liver as a target for this isomer 

based on increases in liver weight and enzyme induction, but did not provide data regarding 

histopathology of the liver; therefore, it was considered inadequate for MRL derivation. While additional 

studies that provide adequate data for establishing dose-response relationships for acute exposure to the 

trichlorobenzenes would be valuable, particularly for liver effects, it is unlikely that acute oral exposure to 

high amounts of trichlorobenzenes will occur in humans. Studies in animals are available indicating that 

trichlorobenzenes are mild to moderate skin and eye irritants (Brown et al. 1969; Dow Chemical 1956; 

E.I. Dupont 1971; Jorgenson et al. 1976; Yamamoto et al. 1978). Additional acute-duration dermal 

studies do not seem necessary at this time. 

Intermediate-Duration Exposure. No studies were located regarding health effects in humans 

exposed to trichlorobenzenes for intermediate duration periods by any route of exposure. Intermediateduration inhalation studies in animals are available for 1,2,4-trichlorobenzene in various animal species 

(Coate et al. 1977; Gage 1970; Kociba et al. 1981) and for 1,3,5-trichlorobenzene in rats (Sasmore et al. 

1983). The results showed that exposure to up to 100 ppm 1,2,4-trichlorobenzene for up to 26 weeks or 

130 ppm 1,3,5-trichlorobenzene for 13 weeks had no significant effect on hematological and clinical 

chemistry tests or on histological appearance of tissues and organs. Although there is suggestive evidence 

from some studies that the liver might be a target for 1,2,4-trichlorobenzene, inadequacies in the studies 

(no quantitative data, too few animals) precluded derivation of an intermediate-duration inhalation MRL 

for this isomer. No intermediate-duration inhalation study for 1,2,3-trichlorobenzenes was located; 

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however, there is no reason to believe that the results would have been different than those obtained for 

1,2,4-trichlorobenzene or 1,3,5-trichlorobenzene. It should be noted that the exposure levels used in the 

animal studies are several orders of magnitude higher than those monitored in outdoor air in the United 

States in 2008 (EPA 2010a; see Section 6.4, Levels Monitored or Estimated in the Environment). 

Additional inhalation studies in animals do not seem necessary at this time. Wide-scope intermediateduration oral studies in animals are available for 1,2,4-trichlorobenzene in rats (CMA 1989; Côté et al. 

1988) and mice (Hiles 1989) and for 1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene in rats (Côté et al. 

1988). These studies identified the liver as the main target for trichlorobenzenes. Kidney effects were 

also reported in male rats, but this response was characterized by hyaline droplet accumulation and was 

unique to the male and considered not relevant for human risk assessment. The studies by CMA (1989) 

in rats and Hiles (1989) in mice provided quantitative histological data, and the former was used to derive 

an intermediate-oral MRL for 1,2,4-trichlorobenzene. The study with 1,2,3-trichlorobenzene and 

1,3,5-trichlorobenzene in rats (Côté et al. 1988) reported quantitative changes in liver weight and 

histological alterations in the liver and thyroid in treated groups of rats. However, quantitative 

histological data were not provided and, therefore, NOAELs and LOAELs for histological alterations 

could not be defined; thus, the study was considered inadequate for derivation of intermediate-duration 

oral MRLs for 1,2,3- and 1,3,5-trichlorobenzene. Additional studies that provide quantitative histological 

data would be valuable to define better points of departure for MRL derivation than organ weight. 

Intermediate-duration dermal studies are available for 1,2,4-trichlorobenzene (Brown et al. 1969; Powers 

et al. 1975; Rao et al. 1982). For the most part, effects were limited to the site of application of the 

chemical. Additional dermal studies with 1,2,4-trichlorobenzene do not seem necessary. Although no 

intermediate-dermal studies were located for 1,2,3-trichlorobenzene or 1,3,5-trichlorobenzene, it is 

unclear what key new information such studies would provide. 

Chronic-Duration Exposure and Cancer. No studies were located regarding health effects in 

humans exposed chronically to trichlorobenzenes. Health evaluations of workers exposed to 

trichlorobenzenes may have been conducted, but none were identified in the literature reviewed. No 

chronic-duration inhalation animal studies are available for trichlorobenzenes. Since chlorobenzenes 

have been detected in outdoor air from cities in the United States (EPA 2010a), the general population is 

exposed to these chemicals by inhalation. However, as mentioned above, the exposure levels monitored 

in that study were several orders of magnitude lower than those used in intermediate-duration inhalation 

studies in animals which did not induce significant health effects. Therefore, the value of conducting 

chronic-duration inhalation studies with exposure concentrations around environmental levels is 

questionable. There are chronic-duration oral studies with 1,2,4-trichlorobenzene in rats (Moore 1994a) 

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and mice (Moore 1994b). These studies reported adverse histological effects in the liver from rats and 

mice and also renal lesions in male rats. The liver effects in rats served as basis for the derivation of a 

chronic-duration oral MRL for 1,2,4-trichlorobenzene. 

There are no studies of cancer in humans exposed to trichlorobenzenes. Both the chronic-duration oral 

study with 1,2,4-trichlorobenzene in rats (Moore 1994a) and mice (Moore 1994b) evaluated the animals 

for tumors and reported that 1,2,4-trichlorobenzene increased the incidence of hepatocellular carcinoma in 

both male and female mice. Additional cancer studies for this isomer do not appear necessary, but oral 

toxicity/carcinogenicity studies for 1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene seem warranted 

since the general population is exposed to these isomers through the consumption of fish and other foods 

(see Section 6.4.4, Other Environmental Media). 

Genotoxicity. Trichlorobenzenes were not mutagenic in in vitro tests with prokaryotic organisms with 

or without metabolic activation (Haworth et al. 1983; Jorgenson et al. 1976; Kubo et al. 2002; Nohmi et 

al. 1985; Ono et al. 1992; Schoeny et al. 1979). It is unclear what key information additional studies 

would provide. 1,2,3-Trichlorobenzene and 1,2,4-trichlorobenzene were cytotoxic to mammalian cells in 

studies conducted in Chinese hamster V79 cells in vitro, a system that lacks metabolic activation capacity, 

indicating that the effect was due to the parent compound (Fratello et al. 1997). Other studies in vitro 

with mammalian cells also showed 1,2,4-trichlorobenzene to be cytotoxic (Garrett and Lewtas 1983; 

Shimada et al. 1983). Fratello et al. (1997) suggested that the toxicity of these chemicals was related to 

their ability to penetrate/perturbate the cellular membranes, but further studies examining this issue would 

be valuable. Limited studies of the genotoxicity of trichlorobenzenes in vivo, mostly micronuclei assays, 

indicate that these compounds are clastogenic (Mohtashamipur et al. 1987; Parrini et al. 1990). Studies 

that evaluate whether metabolites of trichlorobenzenes, such as methylsulfones, thought to be responsible 

for the induction of drug-metabolizing enzymes and alterations in heme metabolism (Kato and Kimura 

2002; Kato et al. 1993) could provide insight into the mechanism of action of trichlorobenzenes. 

Reproductive Toxicity. There is no information regarding reproductive effects in humans exposed to 

trichlorobenzenes. A multi-generation reproductive study in rats exposed to 1,2,4-trichlorobenzene in the 

drinking water is available (Robinson et al. 1981). In that study, 1,2,4-trichlorobenzene did not affect 

fertility. None of the intermediate-duration oral, inhalation, or dermal studies or the chronic-duration oral 

studies conducted with trichlorobenzenes reported treatment-related histological alterations in the 

reproductive organs of male and female animals (Black et al. 1988; CMA 1989; Coate et al. 1977; Côté et 

al. 1988; Hiles 1989; Kociba et al. 1981; Moore 1994a, 1994b; Rao et al. 1982; Sasmore et al. 1983). 

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Additional studies with 1,2,4-trichlorobenzene or multi-generation studies with 1,2,3-trichlorobenzene or 

1,3,5-trichlorobenzene do not seem warranted at this time. 

Developmental Toxicity. No information was located regarding developmental effects in humans 

exposed to trichlorobenzenes. The three trichlorobenzene isomers have been tested for potential 

developmental toxicity in rats (Black et al. 1988; Kitchin and Ebron 1983; Robinson et al. 1981); 

1,2,4-trichlorobenzene has also been tested in mice (Chernoff and Kavlock 1983; Gray and Kavlock 

1984; Gray et al. 1986). In all these studies, 1,2,4-trichlorobenzene was administered by oral gavage 

during pregnancy. Kitchin and Ebron (1983) reported retarded development of the fetuses from rats 

dosed with 360 mg/kg/day 1,2,4-trichlorobenzene; this dose level also induced significant weight loss in 

the dams, which may have contributed to the slower fetal development. In the studies in pregnant mice 

dosed with up to 130 mg/kg/day 1,2,4-trichlorobenzene on Gd 8–12, the chemical did not affect pup’s 

viability or growth, or offspring’s locomotor activity or fertility to produce a second generation. In the 

study by Black et al. (1988) with the three trichlorobenzene isomers, the only significant effect reported 

was the presence of microscopic alterations in the lenses of the eye of fetuses from rats treated with 

150 mg/kg/day; no lesions were observed in fetuses from dams dosed with 75 or 300 mg/kg/day 

1,2,4-trichlorobenzene. This lesion was not observed in fetuses from dams dosed with 150, 300, or 

600 mg/kg/day 1,2,3-trichlorobenzene, but occurred in fetuses from dams administered 150, 300, or 

600 mg/kg/day 1,3,5-trichlorobenzene; however, because no quantitative data were presented, it is not 

known whether the incidences were dose-related. It seems important to try to duplicate these findings 

and/or test a different animal species, and to also perform quantitative analyses of the results to obtain 

dose-response relationships. Since the toxicity of trichlorobenzenes does not seem to be route-dependent, 

developmental studies by the inhalation and dermal routes do not appear necessary. 

Immunotoxicity. No information was located regarding immunological effects in humans exposed to 

trichlorobenzenes. The information available from studies in animals is limited to results of evaluations 

of the gross and microscopic morphology of lymphoreticular organs and tissues in some inhalation, oral, 

and dermal studies conducted with trichlorobenzenes (Black et al. 1988; CMA 1989; Coate et al. 1977; 

Côté et al. 1988; Hiles 1989; Kociba et al. 1981; Moore 1994a, 1994b; Powers et al. 1975; Rao et al. 

1982; Sasmore et al. 1983). For the most part, no significant alterations have been reported. Tests for 

skin sensitization conducted with 1,2,4-trichlorobenzene or 1,3,5-trichlorobenzene in guinea pigs were 

negative (Brown et al. 1969; E.I. DuPont 1971; Jorgenson et al. 1976). No studies were located that 

examined immunocompetence in animals exposed to trichlorobenzenes. Since it is not uncommon to find 

that subtle changes in immunological parameters occur at exposure levels or doses of chemicals lower 

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than (sometimes much lower) those that produce systemic toxicity, it would be useful to conduct 

screening studies (Tier I) to assess, for example, cell-mediated and humoral-mediated immunity in 

rodents exposed to trichlorobenzenes. 

Neurotoxicity. No studies were located regarding neurological effects in humans exposed to 

trichlorobenzenes. Tremors and convulsions were reported in rats and mice administered lethal doses of 

1,2,4-trichlorobenzene or 1,3,5-trichlorobenzene (Brown et al. 1969; Jorgenson et al. 1976). Several 

inhalation, oral, and dermal intermediate- and chronic-duration studies in animals examined the gross and 

microscopic appearance of the brain, spinal cord, and peripheral nerve and reported no significant 

alterations (Black et al. 1988; CMA 1989; Coate et al. 1977; Côté et al. 1988; Hiles 1989; Kociba et al. 

1981; Moore 1994a, 1994b; Rao et al. 1982; Sasmore et al. 1983). One intermediate-duration inhalation 

study in monkeys exposed to 1,2,4-trichlorobenzene conducted operant behavior tests in the animals 

throughout the exposure period and reported no exposure-related alterations (Coate et al. 1977). The data 

available suggest that the nervous system is not a sensitive target for trichlorobenzenes, but there has not 

been extensive testing of neurological parameters in animals during prolonged exposure to 

trichlorobenzenes. 

Epidemiological and Human Dosimetry Studies. No epidemiological studies were identified for 

trichlorobenzenes. It is likely that health evaluations of workers exposed to 1,2,4-trichlorobenzene during 

the production of this chemical have been conducted at some point, but no data were located in the 

literature available for review. Studies in animals indicate that the main target for trichlorobenzenes is the 

liver. Therefore, should a population be identified as being exposed to high levels of trichlorobenzenes, 

liver function should be monitored with the appropriate tests. 

Biomarkers of Exposure and Effect. 

Exposure. A biomarker of exposure is an exogenous substance, or its metabolite(s) or the product of the 

interaction between a xenobiotic agent and some target molecule or cell that is measured within a 

compartment of an organism (e.g., measurement of the parent compound or its metabolite(s), NA adducts, 

etc.). 

Body burdens of trichlorobenzenes do not necessarily indicate that exposure to trichlorobenzenes 

occurred or is occurring because they can also be generated in the body from the metabolism of higher 

chlorinated benzenes such as tetrachlorobenzenes, pentachlorobenzene, hexachlorobenzene, or the 

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pesticide lindane. Studies of the metabolism of trichlorobenzenes in workers exposed solely to 

trichlorobenzenes are needed to elucidate a metabolite profile which might include a metabolite that is not 

produced following exposures to other chlorinated benzenes. This would allow the differentiation 

between exposures to trichlorobenzenes from exposures to other chlorinated benzenes. 

Effect. For the purpose of this data need, a biomarker of effect is a measurable biochemical, 

physiological, or other alteration within an organism that, depending on the magnitude, can be recognized 

as an established or potential health impairment or disease. 

There is virtually no information regarding health effects of trichlorobenzenes in humans, so no specific 

effect of exposure has been identified. Studies in animals have identified the liver as the main target for 

trichlorobenzenes toxicity. Even if this were the case in humans exposed to trichlorobenzenes, similar 

liver alterations can be produced by exposure to many other chemicals. Health evaluations of 

trichlorobenzene workers may provide useful information regarding health effects that may be specific to 

exposure to these substances. 

Absorption, Distribution, Metabolism, and Excretion. There is virtually no information 

regarding toxicokinetics of trichlorobenzenes in humans. Studies in animals have shown that 

trichlorobenzenes are readily absorbed through the gastrointestinal tract following oral exposure (Bakke 

et al. 1992; Chu et al. 1987; Tanaka et al. 1986), but no information is available regarding absorption 

through the lungs or the skin. Since trichlorobenzenes are present in outdoor air in cities in the United 

States (EPA 2010a), absorption studies in animals exposed by inhalation would provide useful 

information. 

Radioactivity derived from the labeled trichlorobenzenes was found widely distributed in tissues of rats 

and rabbits following administration of single doses of 14C-trichlorobenzenes (Chu et al. 1987; Parke and 

Williams 1960). Elimination half-lives of 1,2,4-trichlorobenzene from the blood, liver, and kidneys from 

male rats given a single intraperitoneal injection of the chemical were 5.8, 5.2, and 6.2 hours, respectively 

(Kato et al. 1993). Elimination half-lives for the other isomers are not available. While short-term 

studies showed that trichlorobenzenes did not accumulate in tissues, information from repeated-dosing 

studies is lacking. One 13-week dietary study reported that 1,3,5-trichlorobenzene accumulated at higher 

levels in fat and liver from rats than 1,2,3-trichlorobenzene or 1,2,4-trichlorobenzene; the levels in fat 

were one order of magnitude higher than those measured in the liver (Côté et al. 1988). 

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The only relevant information regarding metabolism of trichlorobenzenes in humans is that in microsomal 

preparations from human livers, CYP2E1 was the major enzyme in the formation of 2,3,4-trichlorophenol 

and 2,3,5-trichlorophenol, while CYP3A4 was responsible for the formation of 2,3,6-trichlorophenol 

(Bogaards et al. 1995). The metabolism of trichlorobenzenes in animals exposed orally and parenterally 

has been fairly well studied, but no information is available following inhalation or dermal exposure. The 

specific enzymes involved in the initial formation of phenolic intermediates are not known, but probably 

involve cytochrome P-450 isozymes. The role of metabolism in the toxicity of 1,2,4-trichlorobenzene has 

been studied (Kato and Kimura 2002; Kato et al. 1993), but no information is available for the other two 

trichlorobenzene isomers. A study in which 1,2,4-trichlorobenzene was incubated in vitro with 

microsomes isolated from the liver of male rats reported the formation of quinone metabolites, which 

bound covalently with microsomal protein and with exogenously added DNA (Den Besten et al. 1991). 

Further studies are needed to examine whether this can also occur in vivo and to determine the role that 

these metabolites may play in the toxicity of trichlorobenzenes. 

Data are available on the elimination and excretion of metabolites of the three trichlorobenzene isomers 

following single or short-term oral exposure to these chemicals (Chu et al. 1987; Jondorf et al. 1955; 

Lingg et al. 1982; Parke and Williams 1960; Tanaka et al. 1986). Further information regarding route of 

excretion in relation to increasing dose levels in single dose studies and in relation to duration of exposure 

would be useful. 

Comparative Toxicokinetics. There are no data regarding toxicokinetics of trichlorobenzenes in 

humans. Studies in animals have reported qualitative differences in metabolite production and disposition 

between species. For example, glutathione conjugation was the predominant pathway in rats, whereas 

glucuronidation was predominant in monkeys (Lingg et al. 1982). The same study also showed that rats 

excreted 1,2,4-trichlorobenzene-derived radioactivity in the urine 2–3 times faster than monkeys. 

However, since there are no toxicokinetic data in humans, the animal species that is the most appropriate 

model for humans is unknown. Analyses of the urine of workers exposed to trichlorobenzenes would 

provide valuable information. 

Methods for Reducing Toxic Effects. No specific methods for the mitigation of effects of acute 

exposure to trichlorobenzenes were located other than measures to support vital functions. No 

information was located concerning mitigation of effects of lower-level or longer-term exposure to 

trichlorobenzenes. This, in part, may reflect the fact that no population has been identified as having been 

subjected or currently undergoing exposure to excessive amounts of trichlorobenzenes. Therefore, it is 

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difficult to design studies or methods for reducing toxic effects if no significant health effects have been 

reported to date. 

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. 

It is not known whether children are more or less susceptible to the effects of exposure to 

trichlorobenzenes than adults because there are no studies that specifically addressed this question. There 

is no information on whether the developmental process is altered in humans exposed to trichlorobenzenes. For the most part, studies in rats and mice did not show trichlorobenzenes to be embryotoxic or 

teratogenic (Black et al. 1988; Chernoff and Kavlock 1983; Gray and Kavlock 1984; Gray et al. 1986; 

Kitchin and Ebron 1983). However, Black et al. (1988) reported lesions in the lenses of the eye of fetuses 

from rats dosed with 1,2,4-trichlorobenzene and 1,3,5-trichlorobenzene on Gd 6–15 and sacrificed on 

Gd 22. Since no quantitative data were shown, the shape of the dose-response relationship could not be 

verified. Replication of these results would be useful. The information available does not suggest that 

trichlorobenzenes have endocrine-disrupting ability, but this issue has not been systematically studied. 

There are no data to evaluate whether pharmacokinetics of trichlorobenzenes in children are different 

from adults. There is no information on whether trichlorobenzenes can cross the placenta, but they have 

been detected in human breast milk, so they could be transferred to newborns (Mes et al. 1993; Newsome 

et al. 1995). There are no data to permit an evaluation of whether metabolism of trichlorobenzenes is 

different in children than in adults. 

Research into the development of sensitive and specific biomarkers of exposures and effects for 

trichlorobenzenes would be valuable for both adults and children. There are no data on the interactions of 

trichlorobenzenes with other chemicals in children. There are no pediatric-specific methods to reduce 

peak absorption, body burdens, or to interfere with the mechanisms of action of trichlorobenzenes. Based 

on the information available, it is reasonable to assume that the supportive methods recommended for 

maintaining vital functions in adults will also be applicable to children. 

Child health data needs relating to exposure are discussed in 6.8.1, Identification of Data Needs: 

Exposures of Children. 

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3.12.3 Ongoing Studies 

No ongoing studies were identified for trichlorobenzenes in the FEDRIP (2010) database. 

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4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

There are three possible isomers for trichlorobenzene: 1,2,3-trichlorobenzene; 1,2,4-trichlorobenzene; 

and 1,3,5-trichlorobenzene. The chemical identity of each isomer is shown in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Trichlorobenzenes are relatively volatile, hydrophobic substances. The physical and chemical properties 

of each isomer are shown in Table 4-2. 

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Table 4-1. Chemical Identity of Trichlorobenzenesa 

Characteristic 1,2,3-Trichlorobenzene 1,2,4-Trichlorobenzene 1,3,5-Trichlorobenzene 

Synonym(s) Benzene, 1,2,3-trichloro-; Benzene, 1,2,4-trichloro-; Benzene, 1,3,5-trichloro-; 

vic-trichlorobenzene; unsym-Trichlorobenzene; s-Trichlorobenzene; symAI3-15516 AI3-07775; 1,2,4-Tricloro- Trichlorobenzene 

benceno (Spanish) 

Chemical formula C6H3Cl3 C6H3Cl3 C6H3Cl3 

Chemical structure 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl 

Cl Cl 

Cl 

Identification numbers: 

CAS registry 87-61-6 120-82-1 108-70-3 

RTECS No data DC2100000b No data 

EPA hazardous waste No data No data No data 

EPA/OPP pesticide No data No data No data 

Code 

OHM/TADS No data No data No data 

DOT/UN/NA/IMDG No data No data No data 

shipping 

HSDB 1502 1105 132 

EINECS No data 204-428-0c No data 

NCI No data No data No data 

a

All information from HSDB 2010, unless otherwise noted.

b

NIOSH 1994. c

European Communities 2003. 

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Table 4-2. Physical and Chemical Properties of Trichlorobenzenesa 

Property 1,2,3-Trichlorobenzene 1,2,4-Trichlorobenzene 1,3,5-Trichlorobenzene 

Molecular weight 181.45 181.45 181.45 

Physical 

description 

Platelets from alcohol Colorless liquid White crystals 

Melting point 51.3 °C 16.92 °C 62.8 °C 

Boiling point 

Density 

218.5 °C 

1.4533 g/cm3 at 25 °C 

213.5 °C 

1.459 g/cm3 at 20 °C 

208 °C 

1.456 g/cm3 at 20 °C 

Odor No data Aromatic odor No data 

Solubility: 

Water 18 mg/L at 25 °C 49 mg/L at 25 °C 6.01 mg/L at 25 °C 

Organic 

solvent(s) 

Slightly soluble in ethanol; 

very soluble in ether and 

benzene. Freely soluble in 

carbon disulfide 

Sparingly soluble in alcohol; 

miscible with ether, 

benzene, petroleum ether, 

carbon disulfide 

Sparingly soluble in alcohol; 

freely soluble in ether, 

benzene, petroleum ether, 

carbon disulfide, glacial 

acetic acid 

Partition coefficients: 

Log Kow 4.05 4.02 4.19 

Log Koc 

Henry’s Law 

constant 

3.21–3.90 

1.25x10-3 atm-m3/mol 

3.10–4.03 

1.42x10-3 atm-m3/mol 

2.80–3.82 

1.89x10-3 atm-m3/mol 

Vapor pressure 0.21 mm Hg at 25 °C 0.46 mm Hg at 25 °C 0.24 mm Hg at 25 °C 

Autoignition 

temperature 

No data 571 °C No data 

Flashpoint 112.7 °C 105 °C 107 °C 

Flammability 

limits in air 

Conversion 

factorsb 

No data 

1 mg/m3=0.13 ppm 

Lower flammable limit: 

2.5% by volume at 302 °F 

(150 °C). Upper flammable 

limit: 6.6% by volume at 

302 °F (150 °C) 

1 mg/m3=0.13 ppm 

No data 

1 mg/m3=0.13 ppm 

Explosive limits No data 2.5–6.6 % volume (at 

150 °C) 

No data 

a

All information from HSDB 2010, unless otherwise noted.

b

Verschueren 2001 

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5.1 PRODUCTION 

No information is available in the Toxics Release Inventory (TRI) database on facilities that manufacture 

or process 1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene because this chemical is not required to be 

reported under Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of 

the Superfund Amendments and Reauthorization Act of 1986) (EPA 1998c). 

Table 5-1 lists the facilities in each state that manufacture or process 1,2,4-trichlorobenzene, the intended 

use, and the range of maximum amounts of trichlorobenzenes that are stored on site. The data listed in 

Table 5-1 are derived from the Toxics Release Inventory (TRI08 2010). These data should be used with 

caution, however, since only certain types of facilities are required to report (EPA 2005b). Therefore, this 

is not an exhaustive list. 

Chlorobenzenes are prepared industrially by reacting liquid benzene with gaseous chlorine in the presence 

of a Lewis acid catalyst such as ferric chloride (Rossberg et al. 2006). The reaction is carried out at 

moderate temperature and atmospheric pressure. Generally, mixtures of isomers and compounds with 

varying degrees of chlorination are obtained, because any given chlorobenzene can react further until 

hexachlorobenzene is ultimately produced. 1,2,3-Trichlorobenzene and 1,2,4-trichlorobenzene are 

formed in minor quantities in the production of monochlorobenzene and dichlorobenzene; however, 

trichlorobenzenes become the primary product if the chlorine input is increased to about 3 moles of 

chlorine per mole of benzene (Rossberg et al. 2006). 1,2,4-Trichlorobenzene can be obtained more 

directly via chlorination of 1,4-dichlorobenzene. 

An additional method employed to produce 1,2,4- and 1,2,3-trichlorobenzene is based on the dehydrohalogenation of 1,2,3,4,5,6-hexachlorocyclohexane. By reacting hexachlorocyclohexane with aqueous 

alkali or alkaline earth solutions, ammonia, or other catalysts in the temperature range of 90–250 °C, 

trichlorobenzene is produced. The yield is generally high, ranging between 80 and 99%, with the mixture 

consisting of 70–85% 1,2,4- trichlorobenzene and 13–30% 1,2,3-trichlorobenzene (Rossberg et al. 2006). 

1,3,5-Trichlorobenzene is usually only produced in minor quantities during the chlorination of liquid 

benzene; however, it can be produced by Sandmeyer reaction on 3,5-dichloroaniline or by reacting 

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Table 5-1. Facilities that Produce, Process, or Use 1,2,4-Trichlorobenzene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 10 0 999,999 0, 2, 3, 4, 0, 6, 7, 0, 0, 10, 11, 12, 0, 0 

AR 4 100 99,999 0, 0, 0, 0, 0, 0, 7, 0, 0, 0, 0, 12, 0, 0 

AZ 3 1,000 9,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 12, 0, 0 

CA 13 100 999,999 0, 0, 0, 4, 0, 0, 7, 8, 9, 10, 11, 12, 0, 0 

CT 1 1,000 9,999 1, 0, 3, 0, 0, 0, 7, 0, 0, 0, 11, 0, 0, 0 

DE 5 1,000,000 49,999,999 1, 2, 3, 4, 0, 0, 7, 0, 0, 0, 0, 0, 0, 0 

FL 4 1,000 99,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 10, 11, 12, 0, 0 

GA 10 0 99,999 0, 0, 0, 0, 0, 6, 7, 0, 0, 10, 11, 0, 0, 0 

IL 5 1,000 99,999 1, 0, 0, 0, 5, 0, 0, 0, 0, 10, 0, 12, 0, 0 

IN 7 100 999,999 0, 2, 3, 0, 0, 0, 7, 0, 9, 0, 11, 12, 0, 0 

KS 5 0 499,999,999 0, 0, 0, 0, 0, 0, 0, 0, 9, 0, 0, 12, 0, 0 

KY 9 1,000 999,999 1, 0, 3, 0, 5, 6, 0, 0, 9, 10, 0, 12, 0, 0 

LA 8 0 999,999 1, 0, 0, 0, 5, 6, 0, 0, 0, 0, 0, 12, 0, 0 

MI 4 0 99,999 0, 0, 0, 0, 0, 0, 0, 8, 0, 10, 0, 12, 0, 0 

MO 3 0 99,999 0, 0, 0, 0, 0, 0, 0, 0, 9, 0, 0, 12, 0, 0 

MS 3 0 999,999 1, 0, 0, 0, 5, 0, 0, 0, 0, 0, 0, 12, 0, 0 

NC 25 100 999,999 1, 2, 3, 4, 0, 6, 7, 8, 0, 10, 11, 12, 0, 0 

NE 3 1,000 999,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 0, 0 

NJ 5 1,000 99,999 0, 0, 0, 0, 0, 0, 7, 0, 9, 0, 11, 12, 0, 0 

NY 3 1,000 99,999 0, 0, 0, 0, 0, 0, 0, 0, 9, 10, 0, 12, 13, 0 

OH 13 0 49,999,999 0, 0, 0, 0, 0, 0, 7, 8, 9, 10, 11, 12, 0, 0 

OK 5 100 9,999,999 1, 0, 0, 0, 0, 0, 0, 0, 0, 10, 0, 12, 13, 0 

OR 1 100,000 999,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 0, 0 

PA 14 0 9,999,999 1, 2, 3, 0, 5, 0, 7, 0, 9, 10, 0, 12, 13, 0 

PR 2 1,000 9,999 0, 0, 0, 0, 0, 0, 7, 0, 0, 10, 0, 0, 0, 0 

RI 3 1,000 99,999 0, 2, 0, 0, 0, 0, 0, 0, 9, 10, 0, 12, 13, 0 

SC 11 1,000 99,999 0, 2, 3, 0, 0, 6, 7, 8, 9, 10, 0, 12, 0, 0 

SD 1 10,000 99,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 12, 0, 0 

TN 2 10,000 999,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 10, 0, 12, 0, 0 

TX 21 0 49,999,999 1, 2, 3, 0, 5, 6, 7, 0, 9, 10, 11, 12, 0, 0 

UT 3 100 99,999 0, 0, 0, 0, 0, 0, 7, 8, 0, 0, 11, 12, 0, 0 

VA 6 0 99,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 10, 11, 12, 0, 0 

WA 3 1,000 999,999 0, 0, 0, 0, 0, 0, 7, 0, 0, 0, 0, 12, 0, 0 

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Table 5-1. Facilities that Produce, Process, or Use 1,2,4-Trichlorobenzene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

WI 1 1,000 9,999 0, 0, 0, 0, 0, 0, 0, 0, 0, 10, 0, 0, 0, 0 

WV 3 10,000 9,999,999 1, 0, 0, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI08 2010 (Data are from 2008) 

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benzene-1,3,5-trisulfonic acid derivatives with phosgene (Rossberg et al. 2006). It can also be produced 

by diazotization of 2,4,6-trichloroaniline, followed by treatment with a reducing agent such as 

hypophosphorous acid (O’Neil et al. 2006). 

The EPA Inventory Update Reporting rule requires chemical companies to submit data for compounds 

manufactured or imported in quantities of ≥25,000 pounds at a single site during a calendar year. For

fiscal year 2005, three companies (Ashland Incorporated, BASF Corporation, and PPG Industries, Inc.) 

reported either manufacturing or importing quantities of 1,2,4-trichlorobenzene in quantities of 

>25,000 pounds (EPA 2010b, 2010f). Two of these corporations (Ashland Incorporated and BASF 

Corporation) also imported 1,2,3-trichlorobenzene. No data were located for 1,3,5-trichlorobenzene. 

5.2 IMPORT/EXPORT 

Non-confidential data obtained from the EPA Inventory Update Reporting rule indicated that 

<500,000 pounds of 1,2,3-trichlorobenzene were imported into the United States in 2005 and 1– 

<10 million pounds of 1,2,4-trichlorobenzene were imported in 2005 (EPA 2010b, 2010f). No export 

volumes were located. 

5.3 USE 

Trichlorobenzenes have primarily been used as solvents and chemical intermediates. In the past, mixed 

isomers of trichlorobenzene had been used for termite control in soil; however, there are currently no 

registered uses of trichlorobenzenes as a pesticide (HSDB 2010). 1,2,4-Trichlorobenzene is currently 

used in solvents in chemical reactions and to dissolve special materials such as oils, waxes, resins, 

greases, and rubber (Rossberg et al. 2006). It is used as a dye carrier and in the production of dyes 

(Rossberg et al. 2006). Other uses are associated with textile auxiliaries and as a dielectric liquid (a 

substance that conducts little or no electricity). 1,2,4-Trichlorobenzene is also one of the most important 

solvents used for extracting fullerenes from soot (Beer et al. 1997). 1,2,3-Trichlorobenzene is used as an 

intermediate for the manufacture of pesticides (through the production of 2,3,4-trichloronitrobenzene), 

and as an intermediate in several fine chemical products and particularly herbicides, pigments, and dyes 

(Euro Chlor 2002). There is some use of 1,3,5-trichlorobenzene but only as a chemical intermediate and 

in low quantities (Euro Chlor 2002). In Europe, 1,2,4-trichlorobenzene, has also been used in anticorrosives paint or rust removing agents and as an additive in polish and maintenance products; however, 

most of these uses have been discontinued (European Communities 2003). Other former uses of 

trichlorobenzene include use of the substance in degreasing agents, septic tanks and drain cleaners, wood 

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preservatives, and abrasive formulations (European Communities 2003). Approximately 7,000 metric 

tons were produced in Europe in 1994–1995 with approximately 75–90% exported (European 

Communities 2003). 

5.4 DISPOSAL 

The preferred method of disposal of trichlorobenzene is incineration, preferably after mixing with another 

combustible fuel (HSDB 2010). Care must be exercised to assure complete combustion to prevent the 

formation of phosgene. An alkali scrubber is necessary to remove the halo acids produced. Powdered 

activated carbon treatment (PACT) is used with the activated sludge for waste water treatment of 

trichlorobenzene (HSDB 2010). Primary treatment consists of neutralization with lime and settling 

followed by combined powdered activated carbon-activated sludge for secondary/tertiary treatment. 

Primary sludge consisting of metal salts and unreacted lime is dewatered before disposal in a lined 

landfill. Powdered activated carbon and return powdered activated carbon treatment sludge are added to 

the primary effluent as it is fed to aeration tanks. Treated effluent is discharged after first passing through 

a settling lagoon. Consistency and efficiency of removal varies greatly with reported ranges from 44% 

for 1,2-dichlorobenzene to 99% for a number of volatile organic compounds. For 1,2,4-trichlorobenzene, 

66% was removed. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

1,2,3-Trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene have been identified in 31, 

187, and 4 of the 1,699 hazardous waste sites that have been proposed for inclusion on the EPA National 

Priorities List (NPL) (HazDat 2007). However, the number of sites evaluated for trichlorobenzenes is not 

known. The frequency of these sites can be seen in Figures 6-1, 6-2, and 6-3. 

Trichlorobenzenes can be released to the environment from their production and use as solvents, dye 

carriers and chemical intermediates (Rossberg et al. 2006). They are also formed unintentionally during 

the combustion of organic materials when chlorine is present and from the degradation of higher 

chlorinated benzenes, such as tetrachlorobenzene, pentachlorobenzene, and hexachlorobenzene, or the 

degradation of the pesticide, lindane (γ-hexachlorocyclohexane). Since trichlorobenzenes are minor 

impurities in mono- and dichlorobenzene; their production and use may also result in the release of 

trichlorobenzenes to the environment. At one time, mixed isomers of trichlorobenzene were used for the 

control of termites around the foundations of buildings, which also led to their direct release into the 

environment. Trichlorobenzenes are volatile substances; consequently, they partition to the atmosphere 

and are frequently detected in ambient air samples. In addition to being detected in air, trichlorobenzenes 

have been identified in water, soil, sediment, plants, fish, animals, and food samples. It is often difficult 

to determine whether levels monitored in environmental samples arise from the direct release of 

trichlorobenzenes or their unintentional formation from other processes. 

1,2,4-Trichlorobenzene is one of 188 chemicals that is designated as a hazardous air pollutant (HAP) 

under the Clean Air Act. Monitoring data from 2008 indicate that average atmospheric levels in the 

United States are typically <1 ppbv; however, maximum levels >3 ppbv have been observed (EPA 

2010a). In the atmosphere, trichlorobenzenes exist primarily in the vapor phase. Vapor-phase 

trichlorobenzenes are removed from air by reacting with photochemically produced hydroxyl radicals. 

The half-life for this reaction is approximately 16–38 days, suggesting that they are susceptible to longrange atmospheric transport. 

Trichlorobenzenes volatilize from water surfaces; however, they also tend to adsorb to suspended solids 

in the water column and partition to sediment, which attenuates the rate at which volatilization occurs. 

The rate of hydrolysis and biodegradation is generally considered slow under environmental conditions. 

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Figure 6-1. Frequency of NPL Sites with 1,2,3-Trichlorobenzene Contamination 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-2. Frequency of NPL Sites with 1,2,4-Trichlorobenzene Contamination 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-3. Frequency of NPL Sites with 1,3,5-Trichlorobenzene Contamination 

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These substances have the potential to bioconcentrate in fish and other aquatic species. Trichlorobenzenes have been detected in surface water, groundwater, and drinking water sources near hazardous 

waste sites or industrialized areas that produce chlorinated substances. Levels are typically in the parts 

per trillion (ng/L) range in surface water and drinking water, but vary based on location and emission 

sources. Trichlorobenzenes have low mobility in soil and typically do not leach into groundwater unless 

there is a large spill to a soil surface. 1,2,3-Trichlorobenzene and 1,2,4-trichlorobenzene were not 

detected in an analyses of groundwater samples collected at about 2,400 domestic wells and about 

1,100 public wells in a monitoring program conducted by the United States Geological Survey (USGS) to 

assess groundwater quality in major aquifers in the United States (USGS 2006). However, 

1,2,4-trichlorobenzene was detected in groundwater in the ppm range at superfund sites where chlorinated 

substances were used and disposed of (Carmichael et al. 1999; EPA 1976). 

Volatilization is expected to be an important environmental fate process for trichlorobenzenes released to 

soil; however, adsorption may reduce the rate at which trichlorobenzenes evaporate from soil surfaces. 

Trichlorobenzenes biodegrade slowly in soils under aerobic conditions, but undergo reductive 

dechlorination under methanogenic conditions, yielding lower chlorinated species (monochlorobenzene 

and dichlorobenzenes). 

Exposure of the general population to trichlorobenzenes is possible through inhalation of ambient air and 

ingestion of contaminated food and water. The average daily intake (AVDI) of 1,2,4-trichlorobenzene 

was estimated to range from 3.34x10-5 to 0.0715 mg/kg/day, with ingestion of root crops, fish, and 

drinking water identified as the primary exposure routes (European Communities 2003). Occupational 

exposure to trichlorobenzenes is possible through inhalation and dermal contact at workplaces where 

these substances are manufactured and used. 

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 2005b). 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 

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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 2005b). 

6.2.1 Air 

Estimated releases of 30,373 pounds (~13.8 metric tons) of 1,2,4-trichlorobenzene to the atmosphere from 

17 domestic manufacturing and processing facilities in 2008, accounted for about 83% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI08 2010). These releases are 

summarized in Table 6-1. There is no information on releases of 1,2,3-trichlorobenzene and 

1,3,5-trichlorobenzene to the atmosphere from manufacturing and processing facilities because these 

releases are not required to be reported (EPA 1998c). 

Section 112 of the Clean Air Act (CAA) lists 1,2,4-trichlorobenzene as one of 188 hazardous air 

pollutants (HAPs) known to cause or suspected of causing cancer or other serious human health effects or 

ecosystem damage (EPA 2000b). EPA's National Emission Inventory (NEI) database contains detailed 

information about sources that emit criteria air pollutants and their precursors, and HAPs for the 

50 United States, Washington DC, Puerto Rico, and the U.S. Virgin Islands (prior to 1999, criteria 

pollutant emission estimates were maintained in the National Emission Trends [NET] database and HAP 

emission estimates were maintained in the National Toxics Inventory [NTI] database). The NEI database 

derives emission data from several sources including state and local environmental agencies, the TRI 

database, computer models for on-road and off-road emissions, and databases related to EPA's Maximum 

Achievable Control Technology (MACT) programs to reduce emissions of hazardous air pollutants. 

Table 6-2 provides emissions data for 1,2,4-trichlorobenzene obtained from the NEI in 2005. The total 

emissions of 1,2,4-trichlorobenzene in 2005 are significantly lower than total emissions from previous 

years. According to the National-Scale Air Toxic Assessment that used data from the NEI, total 

emissions of 1,2,4-trichlorobenzene were approximately 264 tons in 2002. Using composite data from 

the NTI database from 1990 to 1993, it was estimated that the annual emissions of 1,2,4-trichlorobenzene 

in the United States was nearly 6,000 tons per year during that time frame (EPA 2000b). 

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

Use 1,2,4-Trichlorobenzenea 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

AL 2 150 0 0 0 0 150 0 150 

FL 1 21,503 0 0 0 0 21,503 0 21,503 

GA 1 0 0 0 0 0 0 0 0 

KY 1 0 0 0 0 0 0 0 0 

LA 2 1 0 0 20 0 1 20 21 

OH 2 6,573 0 0 46 39 6,573 85 6,658 

PA 3 37 0 0 30 0 37 30 67 

TN 1 0 0 0 0 0 0 0 0 

TX 3 363 0 6,200 1 0 6,563 1 6,564 

WV 1 1,747 0 0 0 0 1,747 0 1,747 

Total 17 30,373 0 6,200 97 39 36,573 136 36,709 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number. b

Data in TRI are maximum amounts released by each facility. c

Post office state abbreviations are used. d

Number of reporting facilities. e

The sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal 

and metal compounds). g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs. 

RF = reporting facilities; UI = underground injection 

Source: TRI08 2010 (Data are from 2008) 

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Table 6-2. Emissions of 1,2,4-Trichlorobenzene in 2005 

Emission category Type of source Annual emissions (tons) 

Fuel combustion, commercial/institutional Point 0.00 

Surface coating, industrial Point 3.61 

Industrial process, pulp and paper Point 161.96 

Graphic arts Nonpoint 0.06 

Industrial process, storage and transfer Nonpoint 6.33 

Industrial process, storage and transfer Point 0.22 

Industrial process, cement manufacturing Point 0.00 

Industrial process, not elsewhere classified Nonpoint 0.11 

Solvent, not elsewhere classified Point 0.32 

Industrial process, chemical manufacturing Point 17.94 

Waste disposal, open burning Nonpoint 0.88 

Fuel comb, electric utility Point 0.57 

Waste disposal Point 2.87 

Waste disposal Nonpoint 4.87 

Industrial process, petroleum refineries Point 0.00 

Bulk gasoline terminals Point 0.00 

Industrial process, chemical manufacturing Nonpoint 0.05 

Industrial process, not elsewhere classified Point 19.71 

Industrial process, oil and gas production Point 0.00 

Industrial process-metals Point 0.00 

Graphic arts Point 0.02 

Fuel comb-industrial boilers, internal combustion engine Point 1.28 

Total 220.79 

Source: EPA 2010c 

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Trichlorobenzenes are also indirectly released to air from combustion processes, such as those that might 

occur at hazardous waste incinerators. The European Union Risk Assessment for 1,2,4-Trichlorobenzene 

(European Communities 2003) summarized several combustion experiments, which resulted in the 

formation of trichlorobenzenes. Plastic waste, including polyethylene and polyvinyl chloride (PVC), was 

burned in a laboratory scale rotary kiln simulator. Combustion at temperatures exceeding 1,066 °C and 

excess air resulted in the formation of dichlorobenzenes, trichlorobenzenes, pentachlorobenzene, and 

hexachlorobenzene when polyethylene and PVC were burned together. No chlorinated aromatics were 

formed, when polyethylene was burned alone. No higher chlorinated (>2) benzenes were formed, when 

PVC was burned alone (European Communities 2003). 

1,2,4-Trichlorobenzene was detected in air samples at nine current or former NPL hazardous waste sites 

where it was detected in some environmental media (HazDat 2007). The other two isomers, 

1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene, were not detected in air samples at any of the current 

or former NPL hazardous waste sites. 

6.2.2 Water 

There were no estimated releases of 1,2,4-trichlorobenzene to surface water from facilities required to 

report to the TRI (TRI08 2010). There is no information on releases of 1,2,3-trichlorobenzene and 

1,3,5-trichlorobenzene to the water from manufacturing and processing facilities because these releases 

are not required to be reported (EPA 1998c). 

1,2,3-Trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene were detected in waste water 

effluents from treatment plants located along the Niagara River and Grand River in Western, New York at 

mean concentrations of 2, 11, and 0.3 ng/L, respectively (Oliver and Nicol 1982). 1,2,4-Trichlorobenzene 

was detected in the industrial effluents of 10 out of 114 industrial sites monitored in the Rhône-Alpes 

region in France in 1993 (European Communities 2003). Measured levels in these effluents ranged from 

9 μg/L (paint manufacturing plant) to 6,150 μg/L (textile dying facility). 

1,2,3-Trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene were detected in groundwater 

samples at 20, 114, and 2 current or former NPL hazardous waste sites, respectively, where they were 

detected in some environmental media (HazDat 2007). 1,2,4-Trichlorobenzene was detected in surface 

water samples at 18 NPL hazardous waste sites where it was detected in some environmental media 

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(HazDat 2007). The other two isomers, 1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene, were not 

detected in surface water samples at any of the NPL hazardous waste sites. 

6.2.3 Soil 

Estimated releases of 97 pounds of 1,2,4-trichlorobenzene to soils from 17 domestic manufacturing and 

processing facilities in 2008, accounted for <1% of the estimated total environmental releases from 

facilities required to report to the TRI (TRI08 2010). An additional 6,200 pounds (~2.8 metric tons), 

constituting about 17% of the total environmental emissions, were released via underground injection 

(TRI08 2010). These releases are summarized in Table 6-1. There is no information on releases of 

1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene to the soil from manufacturing and processing facilities 

because these releases are not required to be reported (EPA 1998c). 

The reductive dechlorination of highly chlorinated benzenes, such as tetrachlorobenzene, pentachlorobenzene, and hexachlorobenzene, results in the formation of trichlorobenzenes in soils and sediment. In 

addition, the degradation of the pesticide, lindane, has also been demonstrated to result in the formation of 

1,2,4-trichlorobenzene (Bharati et al. 1998; Nagpal and Paknikar 2006). Hexachlorobenzene was 

dechlorinated to tri- and dichlorobenzenes in anaerobic sewage sludge within a three-week incubation 

period (Fathepure et al. 1988). Greater than 90% of the added hexachlorobenzene was recovered as 

1,3,5-trichlorobenzene, and there was no evidence for further dechlorination of 1,3,5-trichlorobenzene 

The former use of trichlorobenzenes as a soil treatment to control termite damage around the foundation 

of buildings also released these compounds directly to the environment; however, the quantitative amount 

released from this former use is unknown. 

1,2,3-Trichlorobenzene, 1,2,4-trichlorobenzene and 1,3,5-trichlorobenzene were detected in soil samples 

at 17, 125, and 1 current or former NPL hazardous waste sites, respectively where they were detected in 

some environmental media (HazDat 2007). 1,2,3-Trichlorobenzene was detected in sediment samples at 

1 NPL site and 1,2,4-trichlorobenzene was detected in sediment samples at 34 NPL sites. 

1,3,5-Trichlorobenzene was not detected in sediment samples at any of the current or former NPL 

hazardous waste sites. 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

All three isomers of trichlorobenzene possess vapor pressures and Henry’s Law constants (see Table 4-2) 

that suggest a tendency for these compounds to partition into the atmosphere where they will exist 

predominantly in the vapor phase. In the atmosphere, trichlorobenzenes have fairly long half-lives and 

therefore, may be subject to long-range atmospheric transport. 

Trichlorobenzenes are expected to possess low mobility in soil given their soil adsorption coefficients. 

The soil adsorption coefficient (Koc) measured in the upper horizon (0–28 cm depth) of a sandy forest soil 

obtained from North Carolina (91% sand, 8.4% silt, 0.6% clay) was 2,850 (Njoroge et al. 1998). The Koc 

value of 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene have been also 

reported as 1,622 (log Koc 3.21), 10,715 (log Koc 4.03), and 4,898 (log Koc 3.69), respectively (Beck et al. 

1995). 

Laboratory and field studies demonstrated that volatilization is an important environmental fate process 

for trichlorobenzenes released to surface water (Wakeham et al. 1983a, 1983b). Volatilization half-lives 

ranged from approximately 11 days (summer-time conditions) to 22 days (spring-time conditions) for 

1,2,4-trichlorobenzene in mesocosm experiments used to simulate ecosystem conditions of Narragansett 

Bay, Rhode Island (Wakeham et al. 1983a). Trichlorobenzenes are hydrophobic substances that are 

expected to adsorb to suspended solids and sediment in natural waters. Using water and sediment from 

the Niagara River, the sediment-water adsorption coefficient of 1,2,4-trichlorobenzene was measured to 

range from 63,096 to 199,526 (log Koc 4.8–5.3) (Oliver 1987). Other studies have also indicated that 

trichlorobenzenes adsorb strongly to sediment in the water column. Jonker and Smedes (2000) measured 

the log Koc values of 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene as 5.79, 

6.12, and 5.96, respectively, using water and sediment (0–30 cm depth) from Lake Ketelmeer, the 

Netherlands. The log Koc values were reported as 5.56 (1,2,3-trichlorobenzene), 5.50 (1,2,4-trichlorobenzene), and 5.36 (1,3,5-trichlorobenzene) using sediment from a deeper (40–120 cm) layer. The rate of 

adsorption to sediment as well as the extent to which adsorption takes place within the water column may 

attenuate the rate of volatilization of trichlorobenzenes under environmental conditions. 

Trichlorobenzenes have been shown to bioconcentrate in fish. The measured bioconcentration factors 

(BCF) of 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene measured at different 

concentrations in carp over a 6-week incubation period are provided in Table 6-3 (NITE 2002). The 

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Table 6-3. Measured Bioconcentration Factors (BCF) of Trichlorobenzenes in 

Carp 

Isomer BCF range in carp 

1,2,3-Trichlorobenzene 350–980 (concentration 100 μg/L); 130–1,200 (concentration 10 μg/L) 

1,2,4-Trichlorobenzene 420–1,140 (concentration 100 μg/L); 120–1,320 (concentration 10 μg/L) 

1,3,5-Trichlorobenzene 620–1,620 (concentration 100 μg/L); 150–1,700 (concentration 10 μg/L) 

Source: NITE 2002 

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mean BCF values of 1,2,4-trichlorobenzene measured in rainbow trout maintained in a flow-through 

aquarium at initial concentrations of 3.2 and 52 ng/L, were 1,300 and 3,200, respectively, over an 

exposure period exceeding 100 days (Oliver and Niimi 1983). The mean BCF values of 1,3,5-trichlorobenzene using initial concentrations of 2.3 and 45 ng/L were measured as 1,800 and 4,100, respectively 

(Oliver and Niimi 1983). American flagfish (Jordanella floridae) exposed to 3.8 μg/L (3,800 ng/L) of

1,2,4-trichlorobenzene for 28 days followed by a depuration period of 5–7 days, had a whole-body BCF 

of 2,026 and the metabolic half-life was estimated to be 1.21 days (European Communities 2003). Spot 

fish (Leiostomus xanthurus) were placed in aquariums containing 10 μg/L (10,000 ng/L) 1,2,4-trichlorobenzene and fed either shrimp exposed to 1,2,4-trichlorobenzene or non contaminated shrimp over a 

28-day exposure period (Heitmuller and Clark 1989). Uptake was determined to occur primarily through 

the gills rather than accumulation from food. BCF values of 69–135 measured for these fish suggest only 

modest bioconcentration of 1,2,4-trichlorobenzene and the rapid rate of depuration (half-life of 0.2 days) 

appeared to be responsible for the lack of accumulation in these fish. 

A field study measured the bioaccumulation factor (BAF) of 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene in four aquatic species (mummichog, blue crabs, gulf menhaden and Atlantic croaker) living in 

an effluent/cooling water canal receiving discharge from a chemical manufacturing plant in the Bayou 

d’Inde, Louisiana (Burkhard et al. 1997). The lipid-normalized log BAFs for the three species of fish 

ranged from approximately 4.64 to 4.80 for 1,2,3-trichlorobenzene and 4.68 to 4.86 for 1,2,4-trichlorobenzene (Burkhard et al. 1997). The log BAF for blue crabs were 4.63 and 4.62 for 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene, respectively. These values were found to be consistent with 

measurements made for trichlorobenzenes in Atlantic croaker, spotted sea trout, blue crabs, and blue 

catfish obtained from another sampling location of in the Bayou d’Inde (Pereira et al. 1988). 

In general, whole-body BCF and BAF values that are >5,000 suggest a high potential for a chemical 

substance to bioaccumulate under typical environmental conditions, while values <1,000 suggest a much 

lower potential. Given the range of BCF and BAF values for the trichlorobenzenes, the weight of 

evidence suggests that these substances may bioconcentrate and bioaccumulate to some extent in the 

environment, but do not possess the same high degree of bioaccumulation potential as higher chlorinated 

substances such as hexachlorobenzene. 

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6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Trichlorobenzenes released to the atmosphere will degrade by reacting with photochemically generated 

hydroxyl radicals. Degradation by reaction with other common atmospheric oxidants such as nitrate 

radicals or ozone, and degradation by direct sunlight photolysis are not expected to be important 

environmental fate pathways. Second-order hydroxyl radical rate constants were estimated using a 

quantitative structure estimation method (Meylan and Howard 1993). Using these estimated rate 

constants and assuming a 12-hour hydroxyl radical concentration of 1.5x106 hydroxyl radicals per cubic 

cm of air, estimated half-lives for 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene are 38, 38, and 16 days, respectively. 

6.3.2.2 Water 

Trichlorobenzenes are expected to biodegrade slowly in water. The rate of aerobic biodegradation of 

chlorinated aromatic substances decreases as the degree of chlorination on the benzene ring increases. 

Standardized screening methods used to characterize the capability of rapid mineralization of a substance 

have determined that trichlorobenzenes and higher chlorinated benzenes are not readily biodegradable 

under aerobic conditions. A mixture of trichlorobenzene isomers present at 100 mg/L achieved 0% of its 

theoretical biochemical oxygen demand (BOD) using an activated sludge inoculum at 30 mg/L and the 

modified MITI test (OECD 301C) over a 28-day incubation period (NITE 2002). 

The degradation pattern of 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene was studied using 

methanogenic water-sediment slurries obtained from nine eutrophic ponds and slow moving streams 

(Peijnenburg et al. 1992). The degradation pattern was bi-phasic in each water-sediment slurry with an 

initial half-life range of 62–212 days for 1,2,4-trichlorobenzene and 63–323 days for 1,2,3-trichlorobenzene after a characteristic lag period of approximately 4–8 weeks. 

1,2,3-, 1,2,4-, and 1,3,5-Trichlorobenzene were shown to undergo photoreductive dechlorination in water 

with the presence of a photosensitizing agent, suggesting that photolysis in sunlit surface waters 

containing natural photosensitizers may be an important environmental fate process (Choudhry et al. 

1986). Hydrolysis is not expected to be an important environmental fate process for the trichlorobenzene 

isomers. The hydrolysis half-life of 1,2,4-trichlorobenzene at pH 7 and 25 °C was reported as 3.4 years 

(USGS 1998). 

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6.3.2.3 Sediment and Soil 

Degradation of highly chlorinated benzenes is generally slow under aerobic conditions but occurs under 

methanogenic conditions by reductive dechlorination, yielding lower chlorinated benzenes. 

1,2,4-Trichlorobenzene was completely degraded within 4 days using a methanogenic microbial culture 

isolated from sediment obtained from polluted regions of the Rhine River, Lake Ketelmeer, and an 

anaerobic waste water treatment plant located in the Netherlands (Middeldorp et al. 1997). 1,4-Dichlorobenzene and monochlorobenzene were observed as the main biodegradation byproducts. The degradation 

of trichlorobenzenes was studied using sediment obtained from the Rhine River and a municipal water 

treatment facility in the Netherlands (Bosma et al. 1996). 1,2,4-Trichlorobenzene was partially degraded 

under aerobic conditions, but only after a long lag time. 1,3,5-Trichlorobenzene and 1,2,3-trichlorobenzene were not degraded under aerobic conditions. Under methanogenic conditions, degradation to 

mono- and dichlorobenzenes were observed for all three isomers after a 2-month lag period. All three 

isomers of trichlorobenzene were biodegraded by an acclimated anaerobic sediment slurry using sediment 

and water from the Tsurumi River, Japan (Masunaga et al. 1996). The first-order biodegradation rate 

constants for 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene were 0.0299/days, 0.017/days, and 0.0198/days, 

respectively; corresponding to half-lives were about 23 days (1,2,3-trichlorobenzene), 41 days 

(1,2,4-trichlorobenzene), and 35 days (1,3,5-trichlorobenzene). 

The biodegradation rate of 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene were studied in a Nixon 

sandy loam under aerobic conditions (Marinucci and Bartha 1979). It was determined that the 

trichlorobenzenes became increasingly toxic to soil microorganisms at concentrations exceeding 50 μg/g 

soil and that mineralization proceeded at very slow rates (approximately 0.35 nanomoles/day/20 g soil for 

1,2,3-trichlorobenzene and 1.0 nanomoles per day per 20 grams of soil for 1,2,4-trichlorobenzene). 

Primary degradation products of 1,2,3-trichlorobenzene were identified as 3,4,5-trichlorophenol and 

2,4- and 2,6-dichlorophenol. The primary degradation products of 1,2,4-trichlorobenzene were 2,4-, 2,5-, 

and 3,4-dichlorophenol. 1,2,4-Trichlorobenzene was not significantly biodegraded in soil slurries using a 

silty loam soil containing 8% organic matter or a loamy sand soil containing 2.6% organic matter over the 

course of a 30-day incubation period (Brunsbach and Reineke 1994). Trichlorobenzene isomers were 

extensively degraded under aerobic conditions by enriched microbial cultures that were isolated from 

contaminated soil samples obtained from a location heavily polluted with electrical transformer fluids 

(Adebusoye et al. 2007). Both 1,2,3- and 1,3,5-trichlorobenzene were degraded 91% over the course of a 

202-hour incubation period using two strains of bacteria isolated from the contaminated soil. 

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6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to trichlorobenzenes depends in part on the 

reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of trichlorobenzenes 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 trichlorobenzenes 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 trichlorobenzenes in a variety of environmental media are detailed in Chapter 7 

(Analytical Methods). 

6.4.1 Air 

The Air Quality System (AQS) database is EPA's repository of criteria air pollutant and hazardous air 

pollutants monitoring data. Detailed air monitoring data for 1,2,4-trichlorobenzene in various cities in the 

United States for 2008 are shown in Table 6-4. Data for other years are available as zipped Microsoft 

Access database files that may be accessed directly from the EPA website. In general, the average 

concentration of 1,2,4-trichlorobenzene in outdoor air is <1 ppbv for the majority of the U.S. locations 

sampled. Maximum concentrations >3 ppbv were identified at three U.S. cities (Davie, Florida; 

Hollywood, Florida; Tulsa, Oklahoma). The mean and median daily concentrations of 1,2,4-trichlorobenzene in outdoor air samples in the United States had previously been reported as 0.172 and 

0.100 ppbv, respectively (Shah and Singh 1988). Grosjean (1991) reported a maximum concentration of 

1,2,4-trichlorobenzene of 0.34 ppbv in measurements of air quality of cities in California. Indoor air 

concentrations of 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene were reported as <1 μg/m3 (<0.13 ppbv) at 

unspecified locations (Brown et al. 1994). Unspecified isomers of trichlorobenzene were reportedly 

identified in indoor air at two buildings in the United States at a mean concentration of 0.065 ppbv (Otson 

and Fellin 1992). In a survey of 300 Dutch homes, 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene were 

measured in indoor air at maximum levels of 28, 33, and 5 μg/m3 (3.6, 4.3, and 0.65 ppbv), respectively 

(Otson and Fellin 1992). 

6.4.2 Water 

1,2,4-Trichlorobenzene was detected at mean concentrations of 0.6 and 0.2 ng/L in Lake Ontario and 

Lake Huron, respectively, in surface water samples collected between April and November of 1980 

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Table 6-4. 1,2,4-Trichlorobenzene Air Levels at Monitoring Stations Throughout 

the United States in 2008a 

Number of Mean concentration 

observations (ppbv) City State 

23 0.09 Phoenix Arizona 

39 0.103 Phoenix Arizona 

46 0.09 Grand Junction Colorado 

16 0.12 Washington District of Columbia 

32 1.232 Davie Florida 

11 0.09 Davie Florida 

16 1.125 Pompano Beach Florida 

25 1.294 Hollywood Florida 

23 0.817 Not specified Florida 

12 0.09 Not specified Florida 

42 0.205 Tampa Florida 

45 0.206 Plant City Florida 

19 0.497 Tallahassee Florida 

38 0.22 Winter Park Florida 

46 0.203 Saint Petersburg Florida 

45 0.213 Pinellas Park Florida 

14 0.06 Milledgeville Georgia 

11 0.07 Macon Georgia 

13 0.06 Savannah Georgia 

14 0.06 Douglas Georgia 

14 0.06 Not specified Georgia 

29 0.06 Decatur Georgia 

14 0.06 Decatur Georgia 

15 0.06 Rome Georgia 

15 0.06 Not specified Georgia 

15 0.06 Not specified Georgia 

10 0.06 Brunswick Georgia 

19 0.06 Gainesville Georgia 

12 0.06 Warner Robins Georgia 

13 0.06 Valdosta Georgia 

13 0.06 Columbus Georgia 

15 0.06 Not specified Georgia 

12 0.06 Augusta Georgia 

5 0.45 Not specified Idaho 

7 0.45 Boise City (corporate name for) Idaho 

6 0.45 Nampa Idaho 

5 0.45 Not specified Idaho 

42 0.092 Schiller Park Illinois 

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Table 6-4. 1,2,4-Trichlorobenzene Air Levels at Monitoring Stations Throughout 

the United States in 2008a 

Number of Mean concentration 

observations (ppbv) City State 

49 0.09 Northbrook Illinois 

5 0.09 Northbrook Illinois 

4 0.05 Clarksville Indiana 

51 0.05 Gary Indiana 

13 0.05 East Chicago Indiana 

14 0.05 Whiting Indiana 

16 0.05 Hammond Indiana 

15 0.05 Indianapolis (remainder) Indiana 

16 0.05 Indianapolis Indiana 

15 0.05 Indianapolis (remainder) Indiana 

16 0.05 Ogden Dunes (Wickliffe) Indiana 

14 0.05 Lafayette Indiana 

14 0.05 Evansville Indiana 

25 0.38 Cedar Rapids Iowa 

17 0.329 Des Moines Iowa 

25 0.4 Davenport Iowa 

28 0.12 Essex Maryland 

30 0.12 Beltsville Maryland 

30 0.12 Baltimore Maryland 

31 0.12 Baltimore Maryland 

30 0.506 Sault Ste. Marie Michigan 

5 0.09 Dearborn Michigan 

44 0.01 Rosemount Minnesota 

45 0.01 Inver Grove Heights Minnesota 

48 0.01 Rosemount Minnesota 

48 0.01 Rosemount Minnesota 

50 0.01 Apple Valley Minnesota 

46 0.01 Richfield Minnesota 

49 0.01 Minneapolis Minnesota 

46 0.01 Minneapolis Minnesota 

46 0.01 Minneapolis Minnesota 

50 0.01 Minneapolis Minnesota 

46 0.01 Minneapolis Minnesota 

45 0.01 St. Louis Park Minnesota 

49 0.01 St. Paul Minnesota 

31 0.01 St. Paul Minnesota 

41 0.01 Duluth Minnesota 

46 0.01 St. Paul Park Minnesota 

29 0.01 St. Paul Park Minnesota 

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Table 6-4. 1,2,4-Trichlorobenzene Air Levels at Monitoring Stations Throughout 

the United States in 2008a 

Number of Mean concentration 

observations (ppbv) City State 

47 0.01 Newport Minnesota 

29 0.01 Bayport Minnesota 

50 0.01 Bayport Minnesota 

10 0.09 Gulfport Mississippi 

12 0.09 Tupelo Mississippi 

46 0.09 St. Louis Missouri 

34 0.09 Camden New Jersey 

43 0.09 North Brunswick Township New Jersey 

44 0.09 Chester New Jersey 

41 0.09 Elizabeth New Jersey 

45 0.05 New York New York 

46 0.11 New York New York 

41 0.08 Lackawanna New York 

39 0.05 Tonawanda New York 

43 0.05 Tonawanda New York 

37 0.05 Tonawanda New York 

46 0.05 Tonawanda New York 

28 0.05 Tonawanda New York 

29 0.05 Not specified New York 

40 0.05 Not specified New York 

45 0.1 New York New York 

45 0.06 Rochester New York 

31 0.07 New York New York 

39 0.07 Niagara Falls New York 

42 0.16 New York New York 

30 0.06 Troy New York 

39 0.09 Troy New York 

39 0.06 Troy New York 

44 0.12 New York New York 

44 0.08 New York New York 

24 0.32 Asheville North Carolina 

26 0.3 Not specified North Carolina 

12 0.37 Charlotte North Carolina 

26 0.33 Candor North Carolina 

24 0.39 Not specified North Carolina 

24 0.36 Not specified North Carolina 

22 0.33 Raleigh North Carolina 

16 0.47 Middletown Ohio 

15 0.38 Cleveland Ohio 

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Table 6-4. 1,2,4-Trichlorobenzene Air Levels at Monitoring Stations Throughout 

the United States in 2008a 

Number of Mean concentration 

observations (ppbv) City State 

14 0.39 Cleveland Ohio 

15 0.38 Cleveland Ohio 

13 0.39 Cleveland Ohio 

22 0.44 Columbus Ohio 

23 0.46 Steubenville Ohio 

22 0.46 Marietta Ohio 

14 0.09 Not specified Oklahoma 

41 0.09 Tulsa Oklahoma 

5 0.09 Tulsa Oklahoma 

43 0.167 Tulsa Oklahoma 

4 0.09 Tulsa Oklahoma 

44 0.093 Tulsa Oklahoma 

6 0.09 Tulsa Oklahoma 

30 0.06 Not specified Pennsylvania 

24 0.06 Not specified Pennsylvania 

18 0.06 Not specified Pennsylvania 

18 0.06 Chester Pennsylvania 

17 0.06 Marcus Hook Pennsylvania 

22 0.06 Erie Pennsylvania 

31 0.12 Lancaster Pennsylvania 

26 0.06 Lancaster Pennsylvania 

26 0.06 West Norriton Pennsylvania 

32 0.06 Collegeville Pennsylvania 

29 0.07 Philadelphia Pennsylvania 

30 0.09 Philadelphia Pennsylvania 

30 0.1 Philadelphia Pennsylvania 

28 0.07 Philadelphia Pennsylvania 

30 0.05 Philadelphia Pennsylvania 

17 0.06 Not specified Pennsylvania 

31 0.05 Not specified South Carolina 

31 0.05 Not specified South Carolina 

45 0.09 Not specified South Dakota 

46 0.09 Sioux Falls South Dakota 

45 0.09 Loudon Tennessee 

4 0.09 Loudon Tennessee 

45 0.09 Loudon Tennessee 

5 0.09 Loudon Tennessee 

17 0.09 Memphis Tennessee 

47 0.09 Bountiful Utah 

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Table 6-4. 1,2,4-Trichlorobenzene Air Levels at Monitoring Stations Throughout 

the United States in 2008a 

Number of Mean concentration 

observations (ppbv) City State 

34 0.214 Underhill (town of) Vermont 

18 0.214 Burlington Vermont 

18 0.214 Burlington Vermont 

18 0.214 Rutland Vermont 

18 0.214 Brattleboro (town of) Vermont 

15 0.12 Franconia Virginia 

16 0.12 Not specified Virginia 

16 0.12 Virginia Beach Virginia 

46 0.09 Seattle Washington 

4 0.09 Seattle Washington 

Source: EPA 2010a 

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(Oliver and Nicol 1982). 1,2,3-Trichlorobenzene and 1,3,5-trichlorobenzene were also detected in Lake 

Ontario at mean concentrations of 0.1 ng/L; however, neither isomer was detected in surface water 

obtained from Lake Huron. All three isomers of trichlorobenzene were detected in certain locations of 

the Niagara River. 1,2,3-Trichlorobenzene was identified in three of four sampling locations at 

concentrations ranging from 2 to 38 ng/L; 1,2,4-trichlorobenzene was identified at four out of four 

sampling locations at levels ranging from 0.1 to 107 ng/L; and 1,3,5-trichlorobenzene was detected in 

three out of four sampling locations at levels ranging from 1 to 8 ng/L (Oliver and Nicol 1982). 

1,2,3-Trichlorobenzene and 1,2,4-trichlorobenzene were detected at concentrations of 12 and 40 ng/L, 

respectively, in surface water obtained from the Bayou d’Inde, Louisiana near an industrial plant that 

produced trichloroethylene and perchloroethylene (Pereira et al. 1988). In surface water obtained from 

the Niagara River at Niagara on the Lake, 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene were detected at 

levels of 1.8, 6.4, and 0.7 ng/L, respectively (Fox et al. 1983). During the same sampling period, 

1,2,4-trichlorobenzene was detected in Fort Erie water samples at a concentration of 0.1 ng/L. Neither 

1,2,3- nor 1,3,5-trichlorobenzene were detected at this location. 

Both 1,2,3- and 1,2,4-trichlorobenzene were monitored for, but not detected in, aquifer samples in a 

comprehensive survey conducted by the USGS of volatile organic compounds in private and public 

groundwater wells used for drinking water (USGS 2006). Neither isomer was detected in samples 

obtained from nearly 2,000 public and private wells across the United States. However, 1,2,3-trichlorobenzene was detected in 2 of 19 groundwater wells two years after a polychlorinated biphenyls/ 

trichlorobenzene spill of transformer fluid near Kingston, Tennessee at concentrations of 0.18 and 

0.097 mg/L (EPA 1976). 1,2,4-Trichlorobenzene was detected at levels ranging from 4.43 to 5.02 mg/L 

in groundwater at the Ciba-Geigy Toms River, New Jersey Superfund site, a location that manufactured 

dyes, pigments, resins, and epoxy additives from 1952 to 1990 (Carmichael et al. 1999). 

1,2,3- and 1,2,4-Trichlorobenzene were detected at mean concentrations of 0.1 and 2 ng/L from municipal 

drinking water samples obtained from three cities in the Lake Ontario region (Oliver and Nicol 1982). 

Samples were obtained prior to and immediately after chlorine treatment, and no increase in the levels of 

trichlorobenzene and other chlorobenzenes were observed following chlorination. 1,3,5-Trichlorobenzene was monitored for, but not detected in drinking water at these locations. 1,2,3-Trichlorobenzene 

was detected at a level of approximately 100 ng/L in chlorinated drinking water samples from 2 out of 

10 Canadian water treatment plants (Otson et al. 1986). 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.3 Sediment and Soil 

Chlorobenzenes, including trichlorobenzenes are widespread in Western, New York, particularly in the 

Niagara Falls region. 1,2,3-Trichlorobenzene was detected in soil samples at mean concentrations of 

0.19, 0.54, 0.42, 0.17, and 0.16 ng/g at five locations in Erie County, New York, including the Love 

Canal area (Ding et al. 1992). 1,2,4-Trichlorobenzene was detected at mean concentrations of 0.96, 2.53, 

1.80, 1.00, and 0.48 ng/g in soils at the same five locations. 1,2,4-Trichlorobenzene levels in soil samples 

in the Toms River Superfund site in New Jersey ranged from below detection limits to 440 ng/g 

(Carmichael et al. 1999). 

Trichlorobenzenes were detected in surficial sediment samples obtained from four of the Great Lakes 

during sampling conducted between April and November of 1980 (Oliver and Nicol 1982). The results 

are summarized in Table 6-5. The substantial concentrations of trichlorobenzenes (and other chlorinated 

substances) observed in the sediment samples obtained from Lake Ontario in comparison to the levels in 

the other lakes were attributed to the large amount of waste disposal sites and chemical manufacturing 

plants along the Niagara River leading into Lake Ontario. Suspended solids obtained from the Niagara 

River contained 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene at levels of 5.4–38, 33–210, and 1.5–23 ng/g, 

respectively (Fox et al. 1983). 1,2,3-, 1,2,4-, and 1,3,5-Trichlorobenzene were detected at concentrations 

of 9.6, 306.0, and 83.0 μg/kg (ng/g), respectively, in bottom sediment obtained from the Bayou d’Inde,

Louisiana near an industrial plant that produced trichloroethylene and perchloroethylene (Pereira et al. 

1988). 

1,2,4-Trichlorobenzene was detected in stream bed sediment samples obtained at 1 out of 517 sites in 

20 major river basins in the continental United States sampled from August 1992 to September 1995 

(Lopes and Furlong 2001). The maximum concentration was reported as 68 μg/kg (ng/g).

6.4.4 Other Environmental Media 

Trichlorobenzenes have been detected in a variety of environmental media including plants, fish, animals, 

and foods. 1,2,4-Trichlorobenzene was identified, not quantified, in various plant material grown in an 

Illinois coal refuse reclamation site (Webber et al. 1994) and was also present in plants at an average 

concentration of 0.002 mg/kg in localities contaminated by agrochemical and communal waste 

(Veningerova et al. 1997). 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. The Range and Mean Concentration of Trichlorobenzene Isomers in 

Sediment Samples Obtained From the Great Lakes 

Isomer 

Lake Superior 

(ng/g) 

Lake Heron 

(ng/g) 

Lake Erie 

(ng/g) 

Lake Ontario 

(ng/g) 

1,2,3-Trichlorobenzene ND–1.0 (range); 

0.2 (mean) 

0.1–1 (range); 

0.3 (mean) 

0.1–1 (range); 

0.4 (mean) 

1–16 (range); 

7 (mean) 

1,2,4-Trichlorobenzene 0.1–4 (range); 

1 (mean) 

1–26 (range); 

6 (mean) 

1–9 (range); 

3 (mean) 

20–220 (range); 

94 (mean) 

1,3,5-Trichlorobenzene ND–0.4; 

0.2 (mean) 

ND–4 (range); 

0.7 (mean) 

0.1–5 (range); 

1 (mean) 

7–250 (range); 

60 (mean) 

ND = Not detected 

Source: Oliver and Nicol 1982 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Catfish obtained from the Bayou d’Inde, Louisiana near an industrial plant that produced 

trichloroethylene and perchloroethylene had levels of 1,3,5-trichlorobenzene, 1,2,4-trichlorobenzene, and 

1,2,3-trichlorobenzene of 480, 3,900, and 770 ng/g, respectively (Pereira et al. 1988). The levels 

decreased to 250 ng/g (1,3,5-trichlorobenzene), 1,900 ng/g (1,2,4-trichlorobenzene), and 370 ng/g 

(1,2,3-trichlorobenzene) in catfish obtained 1 mile downstream from the plant. Atlantic croakers, blue 

crabs, and spotted sea trout obtained 1 mile downstream from the plant had levels of 1,3,5-trichlorobenzene, 1,2,4-trichlorobenzene, and 1,2,3-trichlorobenzene of 50–420, 140–3,200, and 20–710 ng/g, 

respectively (Pereira et al. 1988). 1,2,3-Trichlorobenzene, 1,2,4-trichlorobenzene, and 1,3,5-trichlorobenzene were detected in trout from Lake Superior, Lake Huron, Lake Erie, Lake Ontario, and the 

Niagara River (Oliver and Nicol 1982). Levels of 1,2,3-trichlorobenzene ranged from 0.1 to 1 ng/g, 

levels of 1,2,4-trichlorobenzene ranged from 0.5 to 5 ng/g, and levels of 1,3,5-trichlorobenzene ranged 

from 0.1 to 4 ng/g. In each case, the highest levels were obtained from trout in Lake Ontario or the 

Niagara River. 1,3,5-Trichlorobenzene and 1,2,4-trichlorobenzene were also detected in trout caught near 

the Niagara River mouth in Lake Ontario at levels of 1.0 and 3.7 ng/g, respectively (Fox et al. 1983). 

Hoekstra et al. (2003) measured the levels of persistent chlorinated substances in muscle and liver tissue 

of Arctic foxes obtained from Holman, Canada, Arviat, Canada, and Barrow, Alaska. Total 

chlorobenzene levels (1,2-dichlorobenzene, 1,4-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, 1,3,5-trichlorobenzene, pentachlorobenzene, and hexachlorobenzene) ranged from 4.4 to 

17.6 ng/g in muscle tissue and 4.2 to 12 ng/g in liver tissue. 

Trichlorobenzene isomers were detected in nine different vegetables collected from supermarkets in Great 

Britain (Wang and Jones 1994). The results of this study are summarized in Table 6-6. Peattie et al. 

(1984) identified isomers of trichlorobenzene in seed oils produced from corn, soybean, rape, sunflower, 

peanut, sesame, walnut, hazelnut, and poppy. 1,2,3-, 1,2,4-, and 1,3,5-Trichlorobenzene were detected in 

various foods purchased at grocery stores in Ontario, Canada (Davies 1988). Leafy vegetables, fruits, 

milk, and eggs/meat contained trichlorobenzene levels of 0.11–0.40, 0.12–0.14, 0.14–1.2, and 0.70– 

0.74 μg/kg, respectively. These results suggest that ingestion of some foods may be a significant source

of trichlorobenzene exposure to the general population. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The general population is exposed to trichlorobenzene from inhalation of ambient air and ingestion of 

food and drinking water (see Sections 6.4.1–6.4.4 for background environmental levels). In a European 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Trichlorobenzene Concentrations in Whole Vegetables 

1,2,3-Trichlorobenzene 1,2,4-Trichlorobenzene 1,3,5-Trichlorobenzene 

Vegetable (μg/kg) (μg/kg) (μg/kg) 

Carrots ND ND ND 

Potato 0.0484 0.0038 0.010 

Cabbage ND 0.0068 0.0225 

Cauliflower ND 0.0309 ND 

Lettuce ND 0.0027 0.0030 

Onion 0.0490 ND 0.0363 

Beans ND ND ND 

Peas ND 0.0342 0.117 

Tomatoes 0.0440 ND ND 

ND = not detected 

Source: Wang and Jones 1994 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Union Risk Assessment Report, four different exposure scenarios were developed to estimate the average 

daily intake of 1,2,4-trichlorobenzene. The total daily intake was 0.0715 mg/kg/day for the exposure 

scenario, which yielded the highest estimated total daily intake for humans (European Communities 

2003). The estimates suggest that the most important human intake routes are ingestion of root crops, 

fish, and drinking water. Davies (1988) used the concentration of trichlorobenzene residues in food items 

purchased in Ontario, Canada and estimated an annual dietary intake of approximately 147 μg/year

(0.402 μg/day) for all three combined isomers. MacLeod and Mackay (1999) estimated the daily intake 

of 1,2,4-trichlorobenzene for residents in Southern Ontario, Canada as 0.3 μg/day, with the greatest 

contribution arising from inhalation of ambient air (75.4% of the total exposure) followed by ingestion of 

meat (14.3%), milk (6.4%), and eggs (2.5%). 

Trichlorobenzenes have been detected in human body burden studies. In autopsies of Canadian citizens, 

1,2,3- and 1,3,5-trichlorobenzene were detected in biopsy fatty tissue at median levels of 1.9 and 1.1 ng/g, 

respectively, and at maximum levels of 9.1 and 3.7 ng/g, respectively (Mes 1992). Levels were below the 

detection limits in blood samples. 1,2,4-Trichlorobenzene was detected in human follicular fluid at a 

mean concentration of 214 pg/mL for patients undergoing in vitro fertilization in Canada (Younglai et al. 

2002). 1,2,4-Trichlorobenzene was detected in follicular fluid in over 50% of the patients tested. It was 

also identified, but not quantified in human female serum obtained at the time of oocyte retrieval for in 

vitro fertilization (Younglai et al. 2002). 

Occupational exposure to trichlorobenzenes arises from inhalation and dermal contact with these 

compounds at workplaces where they are produced and used. According to the National Occupational 

Exposure Study (NOES) conducted by NIOSH from 1981 to 1983, an estimated 691 workers (all 

employed in the textile mill trade) were potentially exposed to 1,2,3-trichlorobenzene in the workplace 

(NIOSH 1990a, 1990b). In addition, 4,033 workers, including 1,463 female employees, were potentially 

exposed to 1,2,4-trichlorobenzene (NIOSH 1990a, 1990b). The NOES database does not contain 

information on the frequency, concentration, or duration of occupational exposure to any of the chemicals 

listed. The survey provides only estimates of the numbers of workers for whom potential exposure in the 

workplace is an issue. Data from the EPA Inventory Update Reporting database indicate that 

>1,000 workers can be reasonably expected to have some form of exposure to 1,2,4-trichlorobenzene and 

between 100 and 999 workers are expected to be exposed to 1,2,3-trichlorobenzene in the United States 

(EPA 2010b, 2010f). However, this database does not indicate the level of exposure or the primary 

exposure route for these workers. Levels of 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene in the 

breathing zone at different locations of a chemical warehouse located in Michigan ranged from 0.03 to 

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TRICHLOROBENZENES 186 

6. POTENTIAL FOR HUMAN EXPOSURE 

0.06 ppmv and 0.57 to 1.4 ppmv, respectively (Dow Chemical 1981). The highest levels were observed 

in locations where trichlorobenzenes and trichloroethane were being packaged into drums. The NIOSH 

ceiling limit (concentration not to be exceeded at any time during the work day) is 5 ppmv (37 mg/m3

) for 

1,2,4-trichlorobenzene (NIOSH 2005). 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Children are exposed to trichlorobenzenes by the same means that adults are: inhalation of ambient air, 

and ingestion of contaminated food and drinking water. Trichlorobenzenes have also been identified in 

breast milk; therefore, infants may also be potentially exposed through breast feeding. The mean, 

median, and maximum concentrations of 1,2,3-trichlorobenzene from 412 breast milk samples obtained 

from different provinces in Canada in 1986 were 0.98, 0.49, and 18.33 ng/g, respectively, for whole milk 

samples and 38.7, 15.3, and 466.3 ng/g, respectively, in milk fat (Mes et al. 1993). Only maximum levels 

of 1,2,4-trichlorobenzene and 1,3,5-trichlorobenzene were reported. The maximum levels of 

1,2,4-trichlorobenzene in whole milk and milk fat were 17.40 and 4490.9 ng/g, respectively. The 

maximum levels of 1,3,5-trichlorobenzene in whole milk and milk fat were 5.18 and 128.2 ng/g, 

respectively. The mean concentrations of 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene in whole milk 

obtained from 497 breast milk samples in Canada collected in 1992 were reported as 0.07, 0.11, and 

0.04 ng/g, respectively (Newsome et al. 1995). The mean concentrations in milk fat were 2.79 ng/g for 

1,2,3-trichlorobenzene, 3.81 ng/g for 1,2,4-trichlorobenzene, and 1.40 ng/g for 1,3,5-trichlorobenzene. 

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No studies were located that expressed the level of trichlorobenzenes or its metabolites in amniotic fluid, 

meconium, cord blood, or neonatal blood. Children are unlikely to be exposed to trichlorobenzenes from 

their parents clothing or playing on the ground (soil, carpeting, etc.) due to the volatility of these 

substances. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

High levels of trichlorobenzenes have been identified in soil and water samples in heavily industrialized 

areas or at superfund sites. Populations residing near these locations may be exposed to higher levels of 

trichlorobenzenes than the general population. In addition, certain food items have been shown to contain 

high levels of trichlorobenzenes, in particular fish and root crops. Individuals who consume large 

amounts of these products may have higher exposures to trichlorobenzenes as compared to the general 

population. 

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 trichlorobenzenes 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 trichlorobenzenes. 

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 necessary for 

characterizing the environmental fate of all three isomers of trichlorobenzene have been measured or can 

be adequately estimated. No data needs have been identified. 

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Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2008, became available in February of 2010. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Data are available through the U.S. EPA Inventory Update Reporting system regarding the levels of 

trichlorobenzenes that are either manufactured or imported in quantities of ≥25,000 pounds at a single site

during a calendar year. Data are available for 1,2,4-trichlorobenzene and 1,2,3-trichlorobenzene. No data 

are available for 1,3,5-trichlorobenzene. Trichlorobenzenes appear to have no significant uses in 

household products in which the general population may be exposed, but have been identified in food. 

Sufficient use and disposal data exists for the trichlorobenzenes (HSDB 2010; Rossberg et al. 2006); 

however, a data need exists to determine the quantity of trichlorobenzenes that may have been exported. 

A data need also exists to estimate the amount of trichlorobenzenes released to the environment from both 

direct emissions and indirect releases via the degradation of higher chlorinated benzenes and lindane. 

Environmental Fate. Trichlorobenzenes are volatile substances that tend to partition to air and 

sediment when released to the environment and are generally slow to degrade in the environment 

(European Communities 2003; Peijnenburg et al. 1992;USGS 1998). Sufficient data exists to characterize 

the transport and environmental fate of trichlorobenzenes and consequently no data needs are identified. 

Bioavailability from Environmental Media. Studies characterizing the ADME (Absorption, 

Distribution, Metabolism, and Elimination) of 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene following oral 

exposure in humans are not available. In addition no ADME, data are available for inhalation and dermal 

exposure in humans and animals. A data need to determine the bioavailability of trichlorobenzenes from 

environmental media exists. 

Food Chain Bioaccumulation. Trichlorobenzenes have the potential to bioconcentrate and 

bioaccumulate in the environment and have been quantified in fish (Burkhard et al. 1997; Pereira et al. 

1988), animals (Hoekstra et al. 2003) and food crops (Wang and Jones 1994). No data needs are 

identified. 

Exposure Levels in Environmental Media. Monitoring data are available for trichlorobenzenes in 

air (EPA 2010a; Grosjean 1991; Shah and Singh 1988), water (Carmichael et al. 1999; Fox et al. 1983; 

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TRICHLOROBENZENES 189 

6. POTENTIAL FOR HUMAN EXPOSURE 

Oliver and Nicol 1982; Pereira et al. 1988), soil and sediment (Carmichael et al. 1999; Fox et al. 1983; 

Pereira et al. 1988), plants (Veningerova et al. 1997; Webber et al. 1994) and food (Davies 1988; Wang 

and Jones 1994). Human intakes have been estimated from environmental media (European 

Communities 2003; MacLeod and Mackay 1999). Reliable monitoring data for the levels of 

trichlorobenzenes in contaminated media at hazardous waste sites are needed so that the information 

obtained on levels of trichlorobenzenes in the environment can be used in combination with the known 

body burden of trichlorobenzenes to assess the potential risk of adverse health effects in populations 

living in the vicinity of hazardous waste sites. 

Exposure Levels in Humans. Limited studies have shown that trichlorobenzenes have been 

detected in human blood (Mes 1992), adipose tissue (Mes 1992), follicular fluid (Younglai et al. 2002), 

and breast milk (Mes et al. 1993) in Canada. Additional studies on exposure levels to the U.S. population 

are needed. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Children are exposed to trichlorobenzenes by the same routes that affect 

adults. Trichlorobenzenes have been detected in breast milk samples collected from Canadian females 

(Mes et al. 1993; Newsome et al. 1995). A data need exists to determine current trichlorobenzene 

residues and their sources in breast milk of members of the U.S. general population and whether children 

differ in weight-adjusted intakes of trichlorobenzenes as compared to adult populations. 

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 trichlorobenzene 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. 

Few populations are expected to have high exposures to trichlorobenzenes. Persons residing near 

hazardous waste sites where chlorinated substances are disposed of may be subject to higher levels of 

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TRICHLOROBENZENES 190 

6. POTENTIAL FOR HUMAN EXPOSURE 

trichlorobenzene than the general population. In addition, certain food items have been shown to contain 

high levels of trichlorobenzenes, in particular fish and root crops. Individuals who consume large 

amounts of these products may have higher exposures to trichlorobenzenes as compared to the general 

population. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2010) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. 

Researchers at Rutgers University are studying the adsorption/desorption kinetics of 1,3,5-trichlorobenzene in 11 different solid materials including a peat, a topsoil, a sediment, three humic acids extracted 

from the peat, the topsoil, and the sediment, a coal sample, a black carbon material, a silica gel, kaolinite, 

and bentonite. 

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TRICHLOROBENZENES 191 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring trichlorobenzenes, their metabolites, and other biomarkers of exposure and 

effect to trichlorobenzenes. 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 

Trichlorobenzenes are typically analyzed for in blood, adipose tissue, and breath samples using gas 

chromatographic (GC) analysis. Detection limits are typically in the ng/g range. Representative methods 

are summarized in Table 7-1. For analytes such as trichlorobenzenes, electron capture detection (ECD) is 

often employed since it is highly sensitive to halogenated compounds and is less costly than mass 

spectrometer (MS) detection systems. However, the specific identification of a compound is determined 

only by its retention time, which can be subject to shifts or to interference from other non-targeted 

compounds. GC using a quadrupole mass spectrometer operating in either the select ion monitoring 

(SIM) mode or the SCAN mode allows for positive identification of the compound. 

Blood or tissue samples are typically prepared by homogenizing and extracting the sample using a solvent 

such as benzene or acetone, followed by centrifugation and filtration (Mes 1992). In order to eliminate 

potential interferences from the sample matrix, cleanup and fractionation of the filtrate is accomplished 

with a Florisil® column using hexane as the eluting solvent prior to introduction to the GC. Average 

recoveries of the trichlorobenzenes from fortified adipose tissue or blood have been reported to exceed 

75% (Bristol et al. 1982; Mes 1992). Alternatively, a purge-and-trap method can be employed in which 

blood samples are warmed while passing an inert gas over the heated samples (Pellizari et al. 1985a). 

Trichlorobenzene vapors are trapped onto an adsorbent polymeric resin (Tenax®) and released by thermal 

desorption, followed by analysis with GC/MS or GC/ECD. 

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TRICHLOROBENZENES 192 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Trichlorobenzenes in Biological 

Samples 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Blood Blood samples were 

homogenized with 

benzene, centrifuged, and 

filtered 

GC/ECD 

and GC/MS 

1.17 ng/g 

(1,2,3-TCB); 

4.02 ng/g 

(1,3,5-TCB) 

75–90 Mes 1992 

Blood Trichlorobenzenes are 

volatilized from blood by 

warming the sample and 

collecting in Tenax 

cartridges 

GC/MS 3 ng/L 80 Pellizzari et al. 

1985a 

Blood Samples of whole blood 

were extracted with 

hexane, centrifuged, and 

analyzed by GC/ECD and 

GC/MS 

GC/ECD 

and GC/MS 

0.33–0.55 ng/g 77.2–93.4 

(1,3,5-TCB); 

80.4–88.4 

(1,2,3-TCB) 

Bristol et al. 1982 

Adipose 

tissue 

Blood samples were 

homogenized with 

benzene, centrifuged, and 

filtered with glass wool 

GC/ECD 

and GC/MS 

1.68 ng/g 

(1,2,3-TCB); 

0.90 ng/g 

(1,3,5-TCB) 

79–95 Mes 1992 

Breath Collection on Tenax 

tubes, dried using calcium 

sulfate and desorb to GC 

GC/MS No data No data Pellizzari et al. 

1985b 

inlet 

ECD = electron capture detector; GC = gas chromatography; MS = mass spectrometry; TCB = trichlorobenzene 

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TRICHLOROBENZENES 193 

7. ANALYTICAL METHODS 

Trichlorobenzenes can be analyzed in human breath by collecting exhaled air samples onto a Tenax® GC 

cartridge, followed by drying with calcium sulfate and thermal desorption to a GC/MS (Pellizari et al. 

1985b). Detection limits and recoveries for trichlorobenzene were not reported; however, the detection 

limit and quantification limit for m-dichlorobenzene was 0.27 and 1.37 μg/m3

, respectively, suggesting 

that similar limits will be observed for trichlorobenzenes (Pellizari et al. 1985b). 

7.2 ENVIRONMENTAL SAMPLES 

Methods are available for determining the level of trichlorobenzenes in a variety of environmental 

matrices. A summary of representative methods is shown in Table 7-2. Validated methods, approved by 

EPA and NIOSH, are available for air, water, soil, and sediment. GC using ECD or GC/MS is the most 

widely used analytical technique for identifying and quantifying trichlorobenzenes in environmental 

matrices. 

NIOSH Method 5517 summarizes a method to analyze ambient air for the presence of trichlorobenzenes. 

Air samples are collected by a sampling pump at a flow rate between 0.01 and 0.2 L/minute for a total 

sample size of 3–12 L, and adsorption occurs onto a charcoal tube or Tenax® GC cartridge. 

Identification and quantification is accomplished using GC/ECD following ultrasonic desorption from the 

charcoal or Tenax® cartridge (NIOSH 1994). EPA Method TO-14 is similar to the previously described 

NIOSH method; however, collection of ambient air samples is performed using specially prepared 

passivated stainless steel canisters rather than adsorbant tubes. The collection of ambient air samples in 

these canisters provides a number of advantages as compared to the adsorbant tubes including: 

(1) convenient integration of ambient samples over a specific time period (e.g., 24 hours); (2) remote 

sampling and central analysis; (3) ease of storing and shipping samples; (4) unattended sample collection; 

(5) analysis of samples from multiple sites with one analytical system; (6) collection of sufficient sample 

volume to allow assessment of measurement precision and/or analysis of samples by several analytical 

systems; and (7) storage stability for many volatile organic compounds (VOCs) over periods of up to 

30 days (EPA 1999). Detection limits for trichlorobenzenes in ambient air are typically in the low ppbv 

range. 

Trichlorobenzenes in water, soil, and sediment are typically analyzed by GC/MS or GC/ECD after 

extraction from the environmental matrix. EPA Method 8260B is used to quantitatively analyze a variety 

of VOCs, including trichlorobenzenes, with GC/MS. Analysis can be performed on contaminated 

groundwater and surface water, aqueous sludges, caustic liquors, acid liquors, waste solvents, oily wastes, 

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TRICHLOROBENZENES 194 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Trichlorobenzenes in 

Environmental Samples 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Air Collection at flow rate of GC/ECD 0.002 mg/m3 No data NIOSH 1994 

0.01 and 0.2 L/minute (NIOSH 

onto sorbent tubes and method 5517) 

desorb with hexane 

Air Collection in passivated GC/ECD or ppbv level No data EPA 1999 

stainless steel canisters GC/MS (Method 

TO-14) 

Groundwater Closed-system purge- GC/MS 0.03– >100 EPA 1996b 

and surface and-trap process 0.04 μg/La (Method 

water, aqueous 8260B) 

sludges 

Water and waste Continuous liquid-liquid GC/ECD 39 ng/L No data EPA 1994 

samples extraction or separatory (1,2,3-TCB); (Method 8121) 

funnel extraction using 130 ng/L 

methylene chloride (1,2,4-TCB); 

12 ng/L 

(1,3,5-TCB) 

Groundwater Continuous liquid-liquid 

extraction or separatory 

GC/MS 10 μg/L >70% EPA 2007 

(Method 

funnel extraction using 8270D) 

methylene chloride 

Soil and Soxhlet Extraction using GC/ECD No data 96% EPA 1994 

sediment methylene (1,2,3-TCB); (Method 8121) 

chloride/acetone (1:1) 59% 

as the extraction solvent (1,2,4-TCB); 

or ultrasonic extraction 102% 

with GPC cleanup (1,3,5-TCB) 

Soil and 

sediment 

Closed-system purgeand-trap process GC/MS 0.44 μg/kg 11.4–75.4 EPA 1996b 

(Method 

8260B) 

Sediment Soxhlet Extraction using 

dichloromethane. 

GC/MS 50 μg/kg No data Lopes and 

Furlong 2001 

Cleanup with GPC 

Fruit and Homogenize in a GC/ECD 0.007– 76.5–125 Wang and 

vegetables blender followed by 

Soxhlet extraction using 

0.01 μg/kg (1,2,3-TCB); 

76.0–85.5 

Jones 1994 

hexane/acetone (2:1) (1,2,4-TCB); 

77.0–80.2 

(1,3,5-TCB) 

a

Value is dependent upon the GC column used and isomer measured. 

ECD = electron capture detector; GC = gas chromatography; GPC = gel permeation chromatography; MS = mass 

spectrometry; TCB = trichlorobenzene 

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TRICHLOROBENZENES 195 

7. ANALYTICAL METHODS 

mousses, tars, fibrous wastes, polymeric emulsions, filter cakes, spent carbons, spent catalysts, soils, and 

sediments (EPA 1996b). Purge-and-trap methods such as EPA Method 5035 are usually employed in 

conjunction with Method 8260B for sample preparation. Detection limits in water and waste samples are 

generally <1 ppb for trichlorobenzenes; however, the actual value depends upon the specific isomer and 

GC column used for the analysis. Detection limits in soil and sediment are also <1 ppb. Wang and Jones 

(1994) described an analytical method using GC/ECD to analyze levels of trichlorobenzenes in fruits and 

vegetables. Soxhlet extraction using a hexane/acetone (2:1) solvent mixture followed by cleanup using a 

Florisil® column was used for the sample preparation. Recoveries in fortified samples exceeded 75% for 

each isomer, and detection limits in the sub-ppb range were reported. 

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 trichlorobenzenes 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 trichlorobenzenes. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. There are no unique biomarkers of exposure for trichlorobenzenes other than the parent 

compound. Methods are available that can detect trichlorobenzenes in blood (Bristol et al. 1982; Mes 

1992; Pellizzari et al. 1985a), adipose tissue (Mes 1992), and exhaled breath (Pellizzari et al. 1985b). No 

data needs are identified. Trichlorobenzenes detected in humans may arise from direct exposure to the 

parent compound, but may also arise from the metabolism of other chlorinated compounds such as 

tetrachlorobenzenes, pentachlorobenzene, or hexachlorobenzene. 

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TRICHLOROBENZENES 196 

7. ANALYTICAL METHODS 

Effect. There are no unique biomarkers of effect for trichlorobenzenes. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Trichlorobenzene levels in air, water, and food are of most concern for human health. Methods 

are available to determine levels of trichlorobenzene in air (EPA 1999; NIOSH 1994), water (EPA 

1996b), soil (EPA 1996b), sediment (EPA 1996b), and foods (Wang and Jones 1994). These methods are 

sensitive enough to detect trichlorobenzene levels in environmental matrices that may be a concern to 

human health. No data needs are identified. 

7.3.2 Ongoing Studies 

The Environmental Health Laboratory Sciences Division of the National Center for Environmental 

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of 

trichlorobenzenes and other volatile organic compounds in blood. These methods use purge and trap 

methodology, high-resolution gas chromatography, and magnetic sector mass spectrometry, which give 

detection limits in the low parts per trillion (ppt) range. 

No ongoing studies pertaining to analytical methods for trichlorobenzenes were identified in a search of 

the Federal Research in Progress database (FEDRIP 2010). 

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TRICHLOROBENZENES 197 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

The international and national regulations, advisories, and guidelines regarding trichlorobenzenes in air, 

water, and other media are summarized in Table 8-1. 

ATSDR has derived an intermediate-duration oral MRL of 0.1 mg/kg/day for 1,2,4-trichlorobenzene 

based on an increased incidence of centrilobular hepatocyte hypertrophy in male rats administered 

1,2,4-trichlorobenzene in the diet for 13 weeks (CMA 1989). The MRL was derived using BMD 

modeling of incidence data for hepatocyte hypertrophy in male rats. The predicted dose associated with a 

10% extra risk (BMD10) for hepatocyte hypertrophy was 33.09 mg/kg/day; the lower 95% confidence 

limit on this dose (BMDL10) was 14.35 mg/kg/day. An uncertainty factor of 100 was used (10 for animal 

to human extrapolation and 10 for human variability). 

ATSDR has derived a chronic-duration oral MRL of 0.1 mg/kg/day for 1,2,4-trichlorobenzene based on 

an increased incidence of hepatocellular hypertrophy in male rats administered 1,2,4-trichlorobenzene in 

the diet for 104 weeks (Moore 1994a). The MRL was derived using BMD modeling of incidence data for 

hepatocellular hypertrophy in male rats. The predicted dose associated with a 10% extra risk (BMD10) for 

hepatocellular hypertrophy was 23.25 mg/kg/day; the lower 95% confidence limit on this dose (BMDL10) 

was 13.33 mg/kg/day. An uncertainty factor of 100 was used (10 for animal to human extrapolation and 

10 for human variability). 

EPA (IRIS 2010) has established an oral reference dose (RfD) for 1,2,4-trichlorobenzene of 

0.01 mg/kg/day based on a NOAEL of 14.8 mg/kg/day for increased adrenal weights in rats exposed to 

1,2,4-trichlorobenzene in drinking water (Robinson et al. 1981). The uncertainty factor used in this 

assessment was 1,000 (10 for extrapolation from laboratory studies, 10 for the protection of sensitive 

human subpopulations, and 10 to account for a lack of chronic studies). EPA’s assessment was 

conducted in 1991. 

EPA has not derived an inhalation reference concentration (RfC) for trichlorobenzenes. 

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TRICHLOROBENZENES 198 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Trichlorobenzenes 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No IARC 2009 

WHO Air quality guidelines No WHO 2000 

Drinking water quality guidelines Noa WHO 2006 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) No ACGIH 2009 

STEL (15-minute TWA) 

1,2,4-Trichlorobenzene 5 ppmb 

TLV-basis (critical effect) Eye and upper 

respiratory tract 

irritation 

AIHA ERPGs No AIHA 2010 

EPA AEGLs No EPA 2010c 

Hazardous air pollutant EPA 2006b 

42 USC 7412 

1,2,4-Trichlorobenzene Yes 

Regulated toxic substances and 

threshold quantities for accidental 

release prevention 

No EPA 2009j 

40 CFR 68.130 

Second AEGL chemical priority list EPA 2010d 

1,2,4-Trichlorobenzene Yesc 

NIOSH REL (10-hour TWA) 

1,2,4-Trichlorobenzene 5 ppm (40 mg/m3)

b 

NIOSH 2005 

Target organs 

Category of pesticide 

Eyes, skin, respiratory 

system, liver, 

reproductive system 

Group IIId NIOSH 1992 

OSHA PEL (8-hour TWA) for general industry No OSHA 2009 

29 CFR 1910.1000, 

Table Z-1 

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TRICHLOROBENZENES 199 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Trichlorobenzenes 

Agency Description	 Information Reference 

NATIONAL (cont.) 

DOE TEELs 

TEEL-0e 

1,2,3-Trichlorobenzene 5 mg/m3 DOE 2010a 

1,2,4-Trichlorobenzene 0.25 ppm (1.5 mg/m3) DOE 2010b 

PAC-1f 

1,2,3-Trichlorobenzene 15 mg/m3 

1,2,4-Trichlorobenzene 0.75 ppm (5 mg/m3) 

PAC-2g 

1,2,3-Trichlorobenzene 25 mg/m3 

1,2,4-Trichlorobenzene 5 ppm (35 mg/m3) 

PAC-3h 

1,2,3-Trichlorobenzene 500 mg/m3 

1,2,4-Trichlorobenzene 40 ppm (300 mg/m3) 

b. Water 

EPA Designated as hazardous substances in No EPA 2009c 

accordance with Section 311(b)(2)(A) of 40 CFR 116.4 

the Clean Water Act 

EPA	 Drinking water contaminant candidate No EPA 1998a 

list 63 FR 10274 

Drinking water standards and health EPA 2009d 

advisories 

1-Day health advisory for a 10-kg 

child 

1,2,4-Trichlorobenzene 0.1 mg/L 

1,3,5-Trichlorobenzene 0.6 mg/L 

10-Day health advisory for a 10-kg 

child 

1,2,4-Trichlorobenzene 0.1 mg/L 

1,3,5-Trichlorobenzene 0.6 mg/L 

DWEL 

1,2,4-Trichlorobenzene 0.35 mg/L 

1,3,5-Trichlorobenzene 0.2 mg/L 

Lifetime 

1,2,4-Trichlorobenzene 0.07 mg/L 

1,3,5-Trichlorobenzene 0.04 mg/L 

10-4 Cancer risk	 No 

Master Testing List	 Yesi EPA 1996a 

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TRICHLOROBENZENES 200 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Trichlorobenzenes 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA National primary drinking water 

standards (1,2,4-trichlorobenzene) 

EPA 2009e 

MCL 0.07 mg/L 

Potential health effects from longterm exposure above the MCL Changes in adrenal 

glands 

Common sources of 

1,2,4-Trichlorobenzene in drinking 

water 

Discharge from textile 

finishing factories 

Public health goal 0.07 mg/L 

National recommended water quality 

criteria (1,2,4-trichlorobenzene) 

Yes EPA 2006a 

Human health for the consumption of 

Water + organism 35 μg/L 

Organism only 70 μg/L 

Reportable quantities of hazardous 

substances designated pursuant to 

Section 311 of the Clean Water Act 

No EPA 2009l 

40 CFR 117.3 

Groundwater monitoring list Yes EPA 2009a 

40 CFR 264, 

Appendix IX 

c. Food 

FDA Bottled drinking water FDA 2010a 

21 CFR 165.110 

1,2,4-Trichlorobenzene 0.07 mg/L 

EAFUS No FDA 2010b 

d. Other 

ACGIH Carcinogenicity classification No ACGIH 2009 

EPA Carcinogenicity classification 

1,2,4-trichlorobenzene Dj 

IRIS 2010 

RfC No 

RfD 

1,2,4-Trichlorobenzene 0.01 mg/kg/day 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous 

substance (1,2,4-trichlorobenzene) 

Yesk EPA 2009g 

40 CFR 302.4 

Reportable quantity 100 pounds 

Effective date of toxic chemical 

release reporting 

EPA 2009i 

40 CFR 372.65 

1,2,4-Trichlorobenzene 1/1/1987 

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TRICHLOROBENZENES 201 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Trichlorobenzenes 

Agency Description	 Information Reference 

NATIONAL (cont.) 

Extremely hazardous substances No EPA 2009h 

and its threshold planning quantity 40 CFR 355, 

Appendix A 

EPA	 TSCA chemical lists and reporting No EPA 2009b 

periods 40 CFR 712.30 

TSCA health and safety data reporting EPA 2009m 

Effective date 40 CFR 716.120 

1,2,3-Trichlorobenzene 10/04/1982 

1,2,4-Trichlorobenzene 10/04/1982 

1,3,5-Trichlorobenzene 10/04/1982 

Sunset date 

1,2,3-Trichlorobenzene 10/04/1992 

1,2,4-Trichlorobenzene 10/04/1992 

1,3,5-Trichlorobenzene 10/04/1992 

RCRA waste minimization PBT priority Yes EPA 1998b 

chemical list (1,2,4-trichlorobenzene) 63 FR 60332 

EPA	 Standards of performance for EPA 2009f 

equipment leaks of VOC in the 40 CFR 60 

synthetic organic chemicals Subpart VV 

manufacturing industry 

Trichlorobenzenes Yes 

Organic hazardous air pollutant EPA 2009k 

40 CFR 63, Table 2 

to Subpart F 

1,2,4-Trichlorobenzene Yes 

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TRICHLOROBENZENES 202 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Trichlorobenzenes 

Agency Description Information Reference 

NATIONAL (cont.) 

NTP Carcinogenicity classification No NTP 2005 

a

Guideline value not established because total trichlorobenzenes occur in drinking water at concentrations below 

those at which toxic effects may occur, and health-based value would exceed lowest reported odor threshold (WHO 

2006).

b

Ceiling: the concentration should not be exceeded during any part of the working exposure. c

Trichlorobenzenes are included on the list of 371 priority chemicals that are acutely toxic and represent the selection 

of chemicals for AEGL development by the NAC/AEGL committee during the next several years.

d

Group III pesticides pose minimal risk of adverse acute effects even at relatively high doses. e

TEEL-0 is the threshold concentration below which most people will experience no adverse health effects. f

PAC-1 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the 

general population, including susceptible individuals, could experience discomfort, irritation, or certain asymptomatic, 

nonsensory effects. However, these effects are not disabling and are transient and reversible upon cessation of 

exposure.

g

PAC-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that 

the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting, 

adverse health effects or an impaired ability to escape.

h

PAC-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that 

the general population, including susceptible individuals, could experience life-threatening health effects or death. i

1,2,4-Trichlorobenzene was originally recommended to the MTL by the TSCA Interagency Testing Committee in 

1990 and was removed in 1994 because the TSCA Section 4 Final Rule-Making testing program was completed. 

1,2,4-Trichlorobenzene was again recommended to the MTL in 1995 by the Organization for Economic Cooperation 

and Development (OECD) and by the U.S. EPA Office of Air and Radiation (OAR). The OECD chemical testing 

program is currently underway by a voluntary testing agreement and the testing needs include SIDS screening data 

for health effects, environmental effects, and environmental fate and exposure. The OAR chemical testing action 

development is currently underway and the testing needs for health effects include acute toxicity, neurotoxicity, 

developmental toxicity and immunotoxicity.

j

D: not classifiable as to human carcinogenicity based on a dermal exposure study in mice that was found 

inadequate for drawing conclusions as to carcinogenicity in humans.

k

Designated CERCLA hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act and Section 112 of 

the Clean Air Act. 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels; 

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response, 

Compensation, and Liability Act; CFR = Code of Federal Regulations; DOE = Department of Energy; 

DWEL = drinking water equivalent level; EAFUS = Everything Added to Food in the United States; 

EPA = Environmental Protection Agency; ERPG = emergency response planning guidelines; FDA = Food and Drug 

Administration; IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System; 

MCL = maximum contaminant level; MCLG = maximum contaminant level goal; MTL = Master Testing List; 

NAC = National Advisory Committee; NIOSH = National Institute for Occupational Safety and Health; NTP = National 

Toxicology Program; OSHA = Occupational Safety and Health Administration; PAC = protective action criteria; 

PBT = persistent, bioaccumulative, and toxic; PEL = permissible exposure limit; RCRA = Resource Conservation and 

Recovery Act; REL = recommended exposure limit; RfC = inhalation reference concentration; RfD = oral reference 

dose; SIDS = Screening Information Data Sets; STEL = short-term expsoure limit; TEEL = temporary emergency 

exposure limits; TLV = threshold limit values; TSCA = Toxic Substances Control Act; TWA = time-weighted average; 

USC = United States Code; VOC = volatile organic compound; VTA = Voluntary Testing Agreement; WHO = World 

Health Organization 

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TRICHLOROBENZENES 203 

8. REGULATIONS AND ADVISORIES 

EPA has designated 1,2,4-trichlorobenzene as a hazardous air pollutant (HAP) under the Clean Air Act 

(CAA) (EPA 2006b). 1,2,4-Trichlorobenzene is on the list of chemicals appearing in “Toxic Chemicals 

Subject to Section 313 of the Emergency Planning and Community Right-to-Know Act of 1986" and has 

been assigned a reportable quantity (RQ) limit of 100 pounds (EPA 2009g). The RQ represents the 

amount of a designated hazardous substance which, when released to the environment, must be reported 

to the appropriate authority. 

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TRICHLOROBENZENES 205 

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*Agency for Toxic Substances and Disease Registry. 2005. Toxicological profile for 

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* Cited in text 

+ Cited in supplemental document 

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*den Besten C, Smink MC, de Vries EJ, et al. 1991. Metabolic activation of 1,2,4-trichlorobenzene and 

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+*Dow Chemical. 1956. Results of range finding toxicological tests on 1,2,3-trichlorobenzene. Dow 

Chemical Company. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

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*Dow Chemical. 1981. Comprehensive industrial hygiene survey for the Michigan division organic 

chemicals production department distribution center and warehouse, and buildings, March, 1979, to 

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under TSCA Section 8D. EPA Document No. 878214804. OTS0206686. 

+*E.I. Dupont. 1971. Primary skin irritation and sensitization tests on guinea pigs. E.I. Dupont de 

Nemours & Co Inc. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

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*EPA. 1976. Follow-up study of the distribution and fate of polychlorinated biphenyls and benzenes in 

soil and ground water samples after an accidental spill of transformer fluid. Atlanta, GA: U.S. 

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*EPA. 1990. Interim methods for development of inhalation reference concentrations. Washington, DC: 

U.S. Environmental Protection Agency. Office of Health and Environmental Assessment, Office of 

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*EPA. 1991. Alpha 2u-globulin: Association with chemically induced renal toxicity and neoplasia in the 

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*EPA. 1994. Method 8121: Chlorinated hydrocarbons by gas chromatography: Capillary column 

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*EPA. 1998a. Announcement of the drinking water contaminant candidate list. U.S. Environmental 

Protection Agency. Fed Regist 63(40):10274-10287. http://www.gpoaccess.gov/fr/index.html. June 17, 

2010. 

*EPA. 1998b. Notice of availability of draft RCRA waste minimization PBT chemical list. U.S. 

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*EPA. 1998c. Automated Form R for Windows: User’s guide (RY97). Washington, DC: U.S. 

Environmental Protection Agency. Office of Pollution Prevention and Toxics. 

*EPA. 1999. Compendium of methods for the determination of toxic organic compounds in ambient air. 

Second edition. Compendium method TO-14A. Determination of volatile organic compounds (VOCs) in 

ambient air using specially prepared canisters with subsequent analysis by gas chromatography. 

Cincinnati, OH: U.S. Environmental Protection Agency. EPA625R96010b. 

*EPA. 2000a. Benchmark dose technical guidance document. Washinton, DC: Environmental 

Protection Agency. EPA600R000-01. http://www.epa.gov/ncea/pdfs/bmds/BMDExternal_10_13_2000.pdf. October 21, 2010. 

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*EPA. 2006b. Title 42-The public health and welfare. Chapter 85-Air pollution prevention and control. 

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TRICHLOROBENZENES 221 

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. 

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TRICHLOROBENZENES 222 

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. 

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TRICHLOROBENZENES 223 

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. 

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TRICHLOROBENZENES 224 

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. 

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TRICHLOROBENZENES 225 

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. 

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TRICHLOROBENZENES 226 

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. 

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TRICHLOROBENZENES 227 

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. 

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TRICHLOROBENZENES 228 

10. GLOSSARY 

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TRICHLOROBENZENES A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

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TRICHLOROBENZENES A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-62, Atlanta, Georgia 30333. 

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TRICHLOROBENZENES A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,2,4-Trichlorobenzene 

CAS Number: 120-82-1 

Date: September 2010 

Profile Status: Final Pre-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 21 

Species: Rat 

Minimal Risk Level: 0.1 [x] mg/kg/day [ ] ppm 

Reference: CMA. 1989. A three month dietary range-finding study of 1,2,4-trichlorobenzene in rats 

final report with letter dated 2/2/89 from Chemical Manufacturers Association. Chemical Manufacturers 

Association. Submitted to the U.S. Environmental Protection Agency under TSCA Section 4. EPA 

Document No. 40-98201006. OTS0523023. 

Experimental design: Groups of Fisher-344 rats (10/sex/group) were fed a diet containing 0, 200, 600, or 

1,800 ppm 1,2,4-trichlorobenzene for 14 weeks; this diet provided doses of 0, 14.6, 45.6, or 

133.7 mg/kg/day for males and 0, 17, 52.5, or 150.6 mg/kg/day for females. These doses were calculated 

by dividing the sum of the weekly doses provided by the investigators by 14 weeks. End points 

monitored included clinical signs (daily), physical examination (weekly), ophthalmology (initiation and 

termination), body weight and food consumption (weekly), hematology and clinical chemistry 

(termination), gross necropsy (all rats at termination), selected organ weights, and histopathology of all 

major organs and tissues of the control and high-dose group and liver and kidney of the low- and middose groups. 

Effect noted in study and corresponding doses: Treatment with 1,2,4-trichlorobenzene did not affect 

survival rate. Clinical signs were limited to chromodacryorrhea and lacrimation, which occurred more 

frequently in treated groups, but without dose-response. The test for ocular abnormalities did not reveal 

compound-related effects. Administration of 1,2,4-trichlorobenzene did not significantly affect body 

weight or weight gain. Food consumption was significantly higher in the mid- and high-dose groups than 

in controls. Hematological alterations consisted of decreased mean erythrocyte count (5%), hemoglobin 

(7%), and hematocrit (5%) in males dosed with 133.7 mg/kg/day and decreased hemoglobin (4%) and 

hematocrit (4%) in females dosed with 150.6 mg/kg/day. These changes are within the normal range and 

are not considered biologically significant. Platelets were significantly increased (16%) in males dosed 

with 133.7 mg/kg/day; the toxicological significance of this finding is unclear. Significant clinical 

chemistry changes included elevated BUN in high-dose males (12%) and females (20%), elevated total 

protein, albumin, and calcium in high-dose males, and lower serum AST activity in males dosed with 

45.6 mg/kg/day (22%) and 133.7 mg/kg/day (28%). The elevated BUN was consistent with microscopic 

alterations in kidneys from male rats. The clinical significance of the alterations in protein and calcium 

were unclear and the lower transaminase activity was not considered of biological significance. 

Significant changes in organ weight included dose-related increases in absolute and relative liver weight 

in all male groups and in mid- and high-dose females, and increased absolute and relative kidneys weight 

and absolute testes weight in males dosed with 133.7 mg/kg/day. No compound-related gross lesions 

were observed. Histopathological alterations were limited to the kidneys and liver. Kidney lesions were 

evident in males dosed with 45.6 and 133.7 mg/kg/day and consisted of dilated tubules, granular casts, 

hyaline droplets, interstitial nephritis, and papillary mineral deposition. In the liver, centrilobular 

hepatocyte hypertrophy occurred in males dosed with 45.6 and 133.7 mg/kg/day (0/10, 0/10, 5/10, and 

10/10) and in females dosed with 150.6 mg/kg/day (0/10, 0/10, 0/10, and 10/10). Hepatocyte hypertrophy 

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TRICHLOROBENZENES A-4 

APPENDIX A 

was the probable cause of the increases in liver weight. Liver changes were more prominent in males 

than in females. 

Data for renal effects in male rats were not considered for MRL derivation due to the strong possibility 

that this may be a unique response of the male rat and not relevant for quantitative risk assessment (EPA 

1991). Specific indications that this may be the case include the increased incidences of hyaline droplets, 

granular casts, and tubule dilation, and the fact that none of these lesions occurred in female rats. In 

addition, since there is not enough evidence to dissociate the interstitial nephritis from the male-specific 

nephropathy, interstitial nephritis was also not considered for modeling. In support of this position is the 

fact that interstitial nephritis did not occur in female rats. 

Dose and end point used for MRL derivation: BMDL10 of 14.35 mg/kg/day for centrilobular hepatocyte 

hypertrophy in male rats. 

[ ] NOAEL [ ] LOAEL [ X ] BMDL10 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Yes, done by the 

investigators. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: The liver was also a 

target in an additional 3-month study in rats and in a 13-week study in mice. The study in SpragueDawley rats evaluated hematology, clinical chemistry and histopathology of the major organ and tissues, 

and reported histological alterations in the liver, kidneys, and thyroid in the various dose groups (doses 

ranged from 0.07 to 82 mg/kg/day in males and from 0.11 to 101 mg/kg/day in females) (Côté et al. 

1988). However, the investigators provided only a qualitative description of the results regarding 

histopathology. In that study, high-dose males showed increases of 13 and 20% in absolute and relative 

liver weight, respectively, and of 31 and 36% in absolute and relative kidneys weight, respectively. 

Hematology and clinical chemistry tests were unremarkable. In the 13-week study in mice, groups of 

B6C3F1 mice (10/sex/group) were administered a diet that provided doses of 0, 67, 850, or 

1,222 mg/kg/day to males and 0, 86, 1,183, or 1,345 mg/kg/day to females (Hiles 1989). End points 

monitored included clinical signs twice daily and body weight and food consumption weekly. 

Hematology and clinical chemistry tests were conducted at initiation and during week 14. At termination, 

gross necropsy was conducted, selected organs were weighed, and selected tissues were examined 

microscopically. The lungs, liver, and kidneys from all groups were examined; other organs from only 

the control and high-dose group were examined. Final body weight was significantly reduced in highdose males (9%) and females (8.3%). Cumulative body weight gain was significantly reduced in lowdose males (27%), high-dose males (40%) and high-dose females (33%); these changes were associated 

with significant reductions in food consumption throughout the study. Ophthalmologic examinations 

were conducted at initiation and termination. Significant, treatment-related alterations occurred only in 

the liver from males dosed with ≥850 mg/kg/day and females dosed with ≥1,183 mg/kg/day; the

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TRICHLOROBENZENES A-5 

APPENDIX A 

respective NOAELs were 67 and 86 mg/kg/day. The lesions consisted of hepatocellular cytomegaly with 

karyomegaly and hepatocellular atrophy and degeneration. The incidences in males and females were 

0/10, 0/10, 10/10, and 10/10 and 0/9, 0/10, 10/10, and 9/9, respectively (one control female and one highdose female were accidentally killed during the study). 

Agency Contacts (Chemical Managers): Obaid Faroon, D.V.M., Ph.D. 

BENCHMARK MODELING OF HEPATOCELLULAR HYPERTROPHY IN MALE RATS 

Models in the EPA Benchmark Software (BMDS version 2.1) were fit to the incidence data for 

centrilobular hepatocyte hypertrophy in male rats from the CMA (1989) study. Only incidences in males 

were modeled (0/10, 0/10, 5/10, 10/10); incidences in females (0/10, 0/10, 0/10, 10/10) were judged not 

amenable for benchmark analysis. A BMR of 10% was selected in the absence of data that would support 

a lower BMR. In accordance with EPA (2000a) guidance, BMDs and BMDLs associated with an extra 

risk of 10% are calculated for all models. Adequate model fit is judged by three criteria: goodness-of-fit 

(p>0.1), visual inspection of the dose-response curve, and scaled residual at the data point (except the 

control) closest to the predefined benchmark response (BMR). Among all of the models providing 

adequate fit to the data, the BMDL from the model with the lowest AIC is chosen. The Gamma model 

was selected for MRL derivation (Table A-1). 

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TRICHLOROBENZENES A-6 

APPENDIX A 

Table A-1. Model Predictions for the Incidence of Centrilobular Hepatocyte 

Hypertrophy in Male Rats Exposed to 1,2,4-Trichlorobenzene 

Model 

Gammab,c 

χ2 Goodness of fit 

p-valuea 

1.00 

AIC 

15.86 

BMD10 

(mg/kg/day) 

33.09 

BMDL10 

(mg/kg/day) 

14.35 

Logistic 

Log-Logisticd 

Log-Probitd 

Multistage (1-degree)e 

1.00 

1.00 

1.00 

0.26 

17.86 

17.86 

17.86 

23.05 

41.94 

40.29 

35.74 

6.43 

18.95 

16.74 

16.04 

4.04 

Multistage (2-degree) 0.85 17.29 18.59 8.90 

Multistage (3-degree) 0.97 16.31 24.71 10.07 

Probit 1.00 17.86 38.66 17.28 

Weibullb 1.00 17.86 37.74 13.40 

Quantal-Linear 0.26 23.05 6.43 4.04 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Power restricted to ≥1.
	 c

Best-fitting model. Among models with adequate fit, the model with the lowest AIC was selected (Gamma). d

Slope restricted to ≥1.
	 e

Betas restricted to ≥0.
	

AIC = Akaike’s Information Criterion; BMD = maximum likelihood estimate of the dose associated with the selected 

benchmark response; BMDL = 95% lower confidence limit on the BMD 

Source: CMA 1989 

The dose-response curve is shown in Figure A-1. 

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TRICHLOROBENZENES A-7 

APPENDIX A 

Figure A-1. Fit of Gamma Model to Data on 1,2,4-Trichlorobenzene, Incidence of 

Centrilobular Hepatocyte Hypertrophy in Male Rats

Gamma Multi-Hit Model with 0.95 Confidence Level 

0

 0.2

 0.4

 0.6

 0.8

 1

 0 20 40 60 80 100 120 140 

Fraction Affected 

BMDL BMD 

Gamma Multi-Hit 

dose 

15:35 07/02 2010 

Source: CMA 1989 

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TRICHLOROBENZENES A-8 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 1,2,4-Trichlorobenzene 

CAS Number: 120-82-1 

Date: September 2010 

Profile Status: Final Pre-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 38 

Species: Rat 

Minimal Risk Level: 0.1 [x] mg/kg/day [ ] ppm 

Reference: Moore MR. 1994a. Final report (6 copies), 104-week dietary carcinogenicity study with 

1,2,4-trichlorobenzene in rats, with cover letter dated 6/15/94. Chemical Manufacturers Association. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 4. EPA Document No. 

OPPTS-44612. OTS0558832. 

Experimental design: Groups of Fisher-344 rats (50/sex/group) were fed a diet containing 0, 100, 350, or 

1,200 ppm 1,2,4-trichlorobenzene for 104 weeks. The diet provided doses of 0, 5.6, 19.4, or 

66.5 mg/kg/day 1,2,4-trichlorobenzene to males and 0, 6.9, 23.5, or 81.4 mg/kg/day 1,2,4-trichlorobenzene to females. Parameters evaluated included mortality (twice daily), clinical signs, body weight 

and food consumption (weekly for 16 weeks and every 4 weeks thereafter), hematology (week 52 and 

78 for cellular morphology and leukocyte differential, from control and high-dose groups), organ weight 

(at termination, brain, brainstem, liver, kidneys, testes and epididymis), and gross necropsy and 

histological examination of all major organs and tissues at termination. 

Effect noted in study and corresponding doses: Treatment with 1,2,4-trichlorobenzene resulted in a 

significant reduction in survival rate in males dosed with 66.5 mg/kg/day. Survival rate in the control, 

5.6, 19.4, and 66.5 mg/kg/day males at week 104 were 84, 80, 84, and 60% respectively. There were no 

distinct or pronounced compound-related differences in clinical signs between treated and control groups. 

Differences in body weight between treated and control rats were <10% throughout the study. Food 

consumption was decreased 4–7% in treated groups relative to controls during the study. The only 

statistically significant hematology findings were a decrease in basophiles at week 52 and monocytes at 

week 105 in males dosed with 66.5 mg/kg/day, which the investigators considered minor. No evidence of 

leukemia was noted. Gross necropsy at termination showed increased incidence of liver and kidney 

abnormalities in males dosed with 19.4 and 66.5 mg/kg/day and a slight increase in incidence of uterine 

masses in treated females relative to controls; these changes were not discussed any further. Significant 

changes in organ weight were limited to an increase in absolute and relative liver weight in both male and 

female rats receiving the highest doses of 1,2,4-trichlorobenzene and a decrease in absolute and relative 

testes weight in males dosed with 5.6 and 19.4 mg/kg/day. Treatment-related histological alterations 

were restricted to the liver of males and females and to the kidneys of males and consisted of the 

following: hepatocellular hypertrophy (which probably caused the increase in liver weight), focal cystic 

degeneration, diffuse fatty change, transitional renal cell hyperplasia, and increased severity of chronic rat 

nephropathy in males. Incidences of liver lesions are presented in Table A-2 (note that a smaller number 

of animals from the low-dose groups were examined for histopathology). 

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TRICHLOROBENZENES A-9 

APPENDIX A 

Table A-2. Incidence of Liver Lesions in Rats in a 104-Week Dietary Study 

Males 

Dose (mg/kg/day) 0 5.6 19.4 66.5 

Hepatocellular hypertrophy 2/50(4%) 1/26(3.8%) 5/50(10%) 30/50(60%) 

Focal cystic degeneration 9/50(18%) 3/26(11.5%) 4/50(8%) 19/50(38%) 

Diffuse fatty change 5/50(10%) 3/26(11.5%) 5/50(10%) 14/50(28%) 

Females 

Dose (mg/kg/day) 0 6.9 23.5 81.4 

Hepatocellular hypertrophy 6/50(12%) 5/25(20%) 5/50(10%) 37/50(74%) 

Diffuse fatty change 15/50(30%) 6/25(24%) 21/50(42%) 30/50(60%) 

Source: Moore 1994a 

The incidences of transitional cell hyperplasia in the kidneys of male rats were as follows: 0/50, 0/19, 

2/50, and 34/50 in males dosed with 0, 5.6, 19.4, and 66.5 mg/kg/day 1,2,4-trichlorobenzene, 

respectively. Since there is strong evidence from the 14-week study (CMA 1989) suggesting that the 

renal lesions in male rats may represent a male-specific response not relevant for MRL derivation, and 

that the renal cell hyperplasia reported in the 104-week study is a typical response seen in the male rat 

nephropathy, renal cell hyperplasia was not considered as a potential end point for MRL derivation. 

Table A-2 shows that: (1) diffuse fatty change was significantly increased in males and females only at 

the highest dose; (2) focal cystic degeneration occurred at lower incidence in the low- and mid-dose males 

compared to controls, and was significantly increased only at the highest dose; (3) hepatocellular 

hypertrophy in female rats occurred at increased frequency only at the highest dose; and (4) only 

hepatocellular hypertrophy in male rats exhibited dose-response characteristics. Based on these facts, 

only the hepatocellular hypertrophy in male rats was considered for MRL derivation. 

Dose and end point used for MRL derivation: BMDL10 of 13.33 mg/kg/day for hepatocellular 

hypertrophy in male rats. 

[ ] NOAEL [ ] LOAEL [ X ] BMDL10 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Yes, done by the 

investigators. 

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: Treatment of B6C3F1 

mice with 1,2,4-trichlorobenzene in the diet for 104 weeks produced hepatocellular carcinoma (Moore 

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TRICHLOROBENZENES A-10 

APPENDIX A 

1994b). Two intermediate-duration studies in rats and one in mice also suggested that the liver is a target 

for 1,2,4-trichlorobenzene (CMA 1989; Côté et al. 1988; Hiles 1989). 

Agency Contacts (Chemical Managers): Obaid Faroon, D.V.M., Ph.D. 

BENCHMARK MODELING OF HEPATOCELLULAR HYPERTROPHY IN MALE RATS 

Models in the EPA Benchmark Software (BMDS version 2.1) were fit to the data set for hepatocellular 

hypertrophy in the liver of male rats. A BMR of 10% was selected in the absence of data that would 

support a lower BMR. In accordance with EPA (2000a) guidance, BMDs and BMDLs associated with an 

extra risk of 10% are calculated for all models. Adequate model fit is judged by three criteria: goodnessof-fit (p>0.1), visual inspection of the dose-response curve, and scaled residual at the data point (except 

the control) closest to the predefined BMR. Among all of the models providing adequate fit to the data, 

the BMDL from the model with the lowest AIC is chosen. Details of the modeling are presented below in 

Table A-3 and Figure A-2. 

Table A-3. Model Predictions for the Incidence of Hepatocellular Hypertrophy in 

Male Rats 

Model 

Gammab 

χ2 Goodness 

of fit p-valuea 

0.92 

AIC 

131.09 

BMD10 

(mg/kg/day) 

23.40 

BMDL10 

(mg/kg/day) 

13.76 

Logistic 

Log-Logisticc 

Log-Probitc 

Multistage (1-degree)d 

Multistage (2-degree)d,e 

Multistage (3-degree)d 

0.95 

0.91 

0.96 

0.06 

0.98 

0.87 

129.18 

131.10 

131.08 

135.48 

129.12 

131.11 

25.44 

23.34 

22.72 

10.13 

23.25 

23.94 

20.54 

14.03 

14.39 

7.62 

13.33 

13.02 

Probit 0.92 129.24 22.92 18.65 

Weibullb 0.88 131.11 23.95 13.62 

Quantal-Linear 0.06 135.48 10.13 7.62 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Power restricted to ≥1.
	 c

Slope restricted to ≥1.
	 d

Betas restricted to ≥0.
	 e

Best-fitting model. Among models with adequate fit, the model with the lowest AIC was selected (Multistage 

2-degree model). 

AIC = Akaike’s Information Criterion; BMD = maximum likelihood estimate of the dose/concentration associated with 

the selected benchmark response; BMDL = 95% lower confidence limit on the BMD 

Source: Moore 1994a 

In accordance with the selection criteria mentioned above, the Multistage (2-degree) model was selected 

for MRL derivation. The dose-response curve is shown in Figure A-2. 

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TRICHLOROBENZENES A-11 

APPENDIX A 

Figure A-2. Fit of Multistage (2-degree) Model to Data on 1,2,4-Trichlorobenzene, 

Incidence of Hepatocellular Hypertrophy in Male Rats

Multistage Model with 0.95 Confidence Level 

0

 0.1

 0.2

 0.3

 0.4

 0.5

 0.6

 0.7

 0.8

 0 10 20 30 40 50 60 70 

Fraction Affected 

BMDL BMD

Multistage 

dose 

16:13 06/17 2010 

Source: Moore 1994a 

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TRICHLOROBENZENES A-12 

APPENDIX A 

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TRICHLOROBENZENES 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 

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TRICHLOROBENZENES 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. 

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TRICHLOROBENZENES 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, 

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TRICHLOROBENZENES 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. 

***DRAFT FOR PUBLIC COMMENT*** 
TRICHLOROBENZENES 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. 

***DRAFT FOR PUBLIC COMMENT*** 
SAMPLE

***DRAFT FOR PUBLIC COMMENT*** 

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) 

figurea Species duration System (ppm) (ppm) Re

2 3 4 

→ INTERMEDIATE EXPOSURE 

5 6 7 8 9 10 

→ Systemic ↓ ↓ ↓ ↓ ↓ ↓

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

→ 5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple W

5 d/wk organs) 7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

12 → a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 
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TRICHLOROBENZENES B-8 

APPENDIX B 

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TRICHLOROBENZENES C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

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TRICHLOROBENZENES C-2 

APPENDIX C 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

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TRICHLOROBENZENES C-3 

APPENDIX C 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

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TRICHLOROBENZENES C-4 

APPENDIX C 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

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 

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TRICHLOROBENZENES 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 

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TRICHLOROBENZENES C-6 

APPENDIX C 

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TRICHLOROBENZENES D-1 

APPENDIX D. INDEX 

absorbed dose............................................................................................................................ 114, 122, 133 

adipose tissue .................................................................................................... 116, 133, 189, 191, 192, 195 

adrenal gland................................................................................................................. 19, 48, 103, 116, 200 

adrenals ............................................................................................................................. 15, 18, 87, 93, 116 

adsorption.......................................................................................................................... 163, 169, 190, 193 

aerobic................................................................................................................................... 9, 163, 172, 173 

alanine aminotransferase (see ALT) ........................................................................................................... 85 

ALT (see alanine aminotransferase) ........................................................................................................... 85 

ambient air .......................................................................................... 10, 115, 159, 163, 183, 185, 186, 193 

anaerobic........................................................................................................................................... 168, 173 

anemia................................................................................................................................................... 10, 32 

aspartate aminotransferase (see AST)......................................................................................................... 20 

AST (see aspartate aminotransferase)......................................................................................................... 20 

bioaccumulation........................................................................................................................................ 171 

bioavailability ........................................................................................................................................... 188 

bioconcentration factor ............................................................................................................................. 169 

biodegradation........................................................................................................................... 159, 172, 173 

biomarker .......................................................................................... 132, 133, 144, 145, 147, 191, 195, 196 

blood cell count........................................................................................................................................... 46 

body weight effects ....................................................................................................................... 49, 88, 105 

breast milk............................................................................................................. 5, 117, 132, 147, 186, 189 

cancer ...................................................................................................................... 4, 13, 106, 131, 142, 164 

carcinogenic .......................................................................................................................................... 13, 31 

carcinogenicity.................................................................................................. 4, 13, 94, 107, 136, 142, 202 

carcinoma........................................................................................................................ 13, 24, 94, 107, 142 

cardiovascular effects.................................................................................................................... 33, 82, 100 

cholinesterase............................................................................................................................................ 134 

chromosomal aberrations .......................................................................................................................... 112 

death............................................................................................................ 31, 32, 51, 52, 94, 100, 106, 202 

deoxyribonucleic acid (see DNA)..................................................................................................... 107, 110 

dermal effects................................................................................................................................ 48, 88, 103 

developmental effects ............................................................................................. 51, 92, 93, 106, 143, 147 

DNA (see deoxyribonucleic acid)............................................................. 107, 109, 110, 121, 128, 133, 146 

elimination rate ......................................................................................................................................... 114 

endocrine............................................................................................................................... 48, 88, 129, 147 

endocrine effects ........................................................................................................................... 48, 87, 103 

erythema............................................................................................................................................ 103, 104 

estrogenic .................................................................................................................................................. 130 

fetal tissue ................................................................................................................................................... 92 

fetus........................................................................................................................................................... 130 

gastrointestinal effects .................................................................................................................. 46, 82, 100 

general population........................................... 3, 10, 115, 132, 141, 142, 163, 183, 187, 188, 189, 190, 202 

genotoxic............................................................................................................................................. 31, 107 

genotoxicity............................................................................................................................... 107, 112, 142 

groundwater .............................................................................................................. 2, 9, 163, 167, 180, 193 

half-life...................................................................................................................... 2, 9, 132, 159, 171, 172 

hematological effects .................................................................................................................... 46, 83, 100 

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TRICHLOROBENZENES D-2 

APPENDIX D 

hepatic effects ............................................................................................................................... 46, 84, 103 

hydrolysis.......................................................................................................................................... 159, 172 

hydroxyl radical ............................................................................................................................ 9, 159, 172 

immunological ........................................................................................................................ 31, 49, 90, 143 

immunological effects......................................................................................................................... 49, 143 

Kow ............................................................................................................................................................ 151 

LD50......................................................................................................................................... 51, 52, 94, 133 

leukemia................................................................................................................................................ 22, 84 

lymphoreticular....................................................................................................................... 49, 50, 90, 143 

metabolic effects ............................................................................................................................. 49, 89, 90 

micronuclei ....................................................................................................................................... 112, 142 

milk ....................................................................................................... 3, 5, 10, 92, 134, 183, 185, 186, 189 

musculoskeletal effects ................................................................................................................. 46, 84, 100 

neonatal..................................................................................................................................................... 187 

neoplastic .............................................................................................................................................. 24, 86 

neurobehavioral......................................................................................................................................... 129 

neurological effects............................................................................................................... 50, 90, 106, 144 

ocular effects................................................................................................................................. 48, 88, 105 

pharmacodynamic ..................................................................................................................................... 124 

pharmacokinetic................................................................................................ 124, 125, 126, 130, 132, 147 

photolysis.................................................................................................................................................. 172 

placenta ..................................................................................................................................................... 147 

porphyria................................................................................................................. 10, 11, 86, 127, 128, 135 

rate constant ...................................................................................................................................... 172, 173 

renal effects............................................................................................................................. 21, 47, 86, 103 

reproductive effects......................................................................................................... 50, 51, 91, 106, 142 

respiratory effects.......................................................................................................................... 33, 52, 100 

retention ............................................................................................................................................ 115, 191 

systemic effects............................................................................................................... 32, 33, 52, 100, 133 

T3................................................................................................................................................................ 34 

thyroid................................................................................. 12, 16, 19, 27, 28, 29, 48, 87, 88, 103, 140, 141 

toxicokinetic........................................................................................................................ 31, 113, 145, 146 

tremors ........................................................................................................................................................ 52 

tumors ....................................................................................................................................... 106, 136, 142 

vapor phase ....................................................................................................................................... 159, 169 

vapor pressure ........................................................................................................................................... 169 

volatility .................................................................................................................................................... 187 

volatilization ................................................................................................................................. 9, 159, 169 

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