Toxicological Profile for

Chlorobenzene

October 2020
CHLOROBENZENE ii

DISCLAIMER

Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic 

Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human 

Services.
CHLOROBENZENE iii

FOREWORD

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

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

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

and republished as necessary.

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

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

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

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

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

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

begins with a relevance to public health discussion which would allow a public health professional to 

make a real-time determination of whether the presence of a particular substance in the environment 

poses a potential threat to human health. The adequacy of information to determine a substance's health 

effects is described in a health effects summary. Data needs that are of significance to the protection of 

public health are identified by ATSDR.

Each profile includes the following:

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

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

human exposure for the substance due to associated acute, intermediate, and chronic 

exposures;

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

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

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

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

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

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

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

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

peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have 

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

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

this toxicological profile resides with ATSDR.

Patrick N. Breysse, Ph.D., CIH

Director, National Center for Environmental Health and

Agency for Toxic Substances and Disease Registry

Centers for Disease Control and Prevention

Christopher M. Reh, Ph.D.

Associate Director

Agency for Toxic Substances and Disease Registry

Centers for Disease Control and Prevention
CHLOROBENZENE iv

*Legislative Background

The toxicological profiles are developed under the Comprehensive Environmental Response, 

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

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

authorities” of the statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that 

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

Section 104(i)(3) of CERCLA, 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 NPL, 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)(1)(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.
CHLOROBENZENE v

VERSION HISTORY

Date Description

October 2020 Final toxicological profile released

December 2019 Draft for public comment profile released

August 2013 Addendum to the toxicological profile released

December 1990 Final toxicological profile released
CHLOROBENZENE vi

CONTRIBUTORS & REVIEWERS

CHEMICAL MANAGER TEAM

Breanna Alman, MPH (Lead) David W. Wohlers, Ph.D.

G. Daniel Todd, Ph.D. Lisa Ingerman, Ph.D., DABT

Dennis Jones D.V.M. Jenny S. Crisman, B.S.

ATSDR, Office of Innovation and Analytics, 

Toxicology Section, Atlanta, GA

SRC, Inc., North Syracuse, NY

REVIEWERS

Interagency Minimal Risk Level Workgroup: 

Includes ATSDR; National Center for Environmental Health (NCEH); National Institute for 

Occupational Safety and Health (NIOSH); U.S. Environmental Protection Agency (EPA); National 

Toxicology Program (NTP).

Additional reviews for science and/or policy: 

ATSDR, Office of Community Health and Hazard Assessment; ATSDR, Office of Capacity 

Development and Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of 

Laboratory Science; NCEH, Division of Environmental Health Science and Practice; EPA.

PEER REVIEWERS

1. Dr. Ghulam Ahmad Shakeel Ansari, University of Texas Medical Branch at Galveston, 301 

University Boulevard, Galveston, Texas

2. Dr. Olen R. Brown, Professor Emeritus, 527 North Cedar Lake Drive West, Columbia, Missouri

3. Dr. Dale Hattis, Research Professor, George Perkins Marsh Institute, Clark University, 950 Main 

Street, Worcester, Massachusetts

4. Lisa M. Kamendulis, M.D., Director of Graduate Studies, Environmental and Occupational 

Health, School of Public Health, Indiana University, Bloomington, Indiana

These experts collectively have knowledge of toxicology, chemistry, and/or health effects. All reviewers 

were selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, 

Compensation, and Liability Act, as amended.

ATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the 

profile based on comments. The peer reviewers’ comments and responses to these comments are part of 

the administrative record for this compound.

The listing of peer reviewers should not be understood to imply their approval of the profile's final 

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

CONTENTS

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

FOREWORD...............................................................................................................................................iii

VERSION HISTORY...................................................................................................................................v

CONTRIBUTORS & REVIEWERS...........................................................................................................vi

CONTENTS................................................................................................................................................vii

LIST OF FIGURES .....................................................................................................................................ix

LIST OF TABLES........................................................................................................................................x

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................1

1.1 OVERVIEW AND U.S. EXPOSURES.........................................................................................1

1.2 SUMMARY OF HEALTH EFFECTS...........................................................................................1

1.3 MINIMAL RISK LEVELS (MRLs)..............................................................................................5

CHAPTER 2. HEALTH EFFECTS.............................................................................................................7

2.1 INTRODUCTION..........................................................................................................................7

2.2 DEATH ........................................................................................................................................23

2.3 BODY WEIGHT..........................................................................................................................23

2.4 RESPIRATORY ..........................................................................................................................23

2.5 CARDIOVASCULAR.................................................................................................................24

2.6 GASTROINTESTINAL...............................................................................................................24

2.7 HEMATOLOGICAL ...................................................................................................................24

2.8 MUSCULOSKELETAL..............................................................................................................24

2.9 HEPATIC.....................................................................................................................................25

2.10 RENAL ........................................................................................................................................25

2.11 DERMAL.....................................................................................................................................26

2.12 OCULAR .....................................................................................................................................26

2.13 ENDOCRINE...............................................................................................................................26

2.14 IMMUNOLOGICAL ...................................................................................................................26

2.15 NEUROLOGICAL.......................................................................................................................27

2.16 REPRODUCTIVE .......................................................................................................................28

2.17 DEVELOPMENTAL...................................................................................................................28

2.18 OTHER NONCANCER...............................................................................................................28

2.19 CANCER......................................................................................................................................28

2.20 GENOTOXICITY........................................................................................................................29

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL 

INTERACTIONS...............................................................................................................32

3.1 TOXICOKINETICS.....................................................................................................................32

3.1.1 Absorption.............................................................................................................................32

3.1.2 Distribution ...........................................................................................................................33

3.1.3 Metabolism............................................................................................................................33

3.1.4 Excretion ...............................................................................................................................35

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models.............38

3.1.6 Animal-to-Human Extrapolations.........................................................................................38

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.....39

3.3 BIOMARKERS OF EXPOSURE AND EFFECT.......................................................................39

3.3.1 Biomarkers of Exposure........................................................................................................40

3.3.2 Biomarkers of Effect.............................................................................................................41

3.4 INTERACTIONS WITH OTHER CHEMICALS .......................................................................41
CHLOROBENZENE viii

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................42

4.1 CHEMICAL IDENTITY .............................................................................................................42

4.2 PHYSICAL AND CHEMICAL PROPERTIES ..........................................................................42

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE........................................................................44

5.1 OVERVIEW ................................................................................................................................44

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ..................................................45

5.2.1 Production .............................................................................................................................45

5.2.2 Import/Export........................................................................................................................46

5.2.3 Use ........................................................................................................................................47

5.2.4 Disposal.................................................................................................................................47

5.3 RELEASES TO THE ENVIRONMENT.....................................................................................47

5.3.1 Air .........................................................................................................................................48

5.3.2 Water.....................................................................................................................................49

5.3.3 Soil ........................................................................................................................................50

5.4 ENVIRONMENTAL FATE ........................................................................................................50

5.4.1 Transport and Partitioning.....................................................................................................50

5.4.2 Transformation and Degradation ..........................................................................................50

5.5 LEVELS IN THE ENVIRONMENT...........................................................................................53

5.5.1 Air .........................................................................................................................................55

5.5.2 Water.....................................................................................................................................56

5.5.3 Sediment and Soil .................................................................................................................56

5.5.4 Other Media ..........................................................................................................................57

5.6 GENERAL POPULATION EXPOSURE....................................................................................57

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ................................................58

CHAPTER 6. ADEQUACY OF THE DATABASE.................................................................................59

6.1 Information on Health Effects......................................................................................................59

6.2 Identification of Data Needs ........................................................................................................59

6.3 Ongoing Studies...........................................................................................................................67

CHAPTER 7. REGULATIONS AND GUIDELINES ..............................................................................68

CHAPTER 8. REFERENCES ...................................................................................................................71

APPENDICES

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS ....................................................A-1

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR CHLOROBENZENE........................B-1

APPENDIX C. USER’S GUIDE.............................................................................................................C-1

APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS.......................................D-1

APPENDIX E. GLOSSARY ................................................................................................................... E-1

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ..................................................F-1
CHLOROBENZENE ix

LIST OF FIGURES

1-1. Health Effects Found in Animals Following Inhalation Exposure to Chlorobenzene..........................2

1-2. Health Effects Found in Animals Following Oral Exposure to Chlorobenzene...................................3

1-3. Summary of Sensitive Targets of Chlorobenzene – Inhalation ............................................................5

1-4. Summary of Sensitive Targets of Chlorobenzene – Oral .....................................................................6

2-1. Overview of the Number of Studies Examining Chlorobenzene Health Effects..................................9

2-2. Levels of Significant Exposure to Chlorobenzene – Inhalation .........................................................13

2-3. Levels of Significant Exposure to Chlorobenzene – Oral ..................................................................20

3-1. Mammalian Metabolism of Chlorobenzene to Phenols, Dihydrodiols, Catechols, and 

Glutathione Conjugates ......................................................................................................................34

5-1. Number of NPL Sites with Chlorobenzene Contamination................................................................44

6-1. Summary of Existing Health Effects Studies on Chlorobenzene By Route and Endpoint.................60
CHLOROBENZENE x

LIST OF TABLES

1-1. Minimal Risk Levels (MRLs) for Chlorobenzene................................................................................6

2-1. Levels of Significant Exposure to Chlorobenzene – Inhalation .........................................................10

2-2. Levels of Significant Exposure to Chlorobenzene – Oral ..................................................................15

2-3. Genotoxicity of Chlorobenzene In Vivo .............................................................................................29

2-4. Genotoxicity of Chlorobenzene In Vitro ............................................................................................30

4-1. Chemical Identity of Chlorobenzene ..................................................................................................42

4-2. Physical and Chemical Properties of Chlorobenzene.........................................................................42

5-1. Facilities that Produce, Process, or Use Chlorobenzene.....................................................................45

5-2. Releases to the Environment from Facilities that Produce, Process, or Use Chlorobenzene .............48

5-3. Lowest Limit of Detection Based on Standards.................................................................................54

5-4. Summary of Environmental Levels of Chlorobenzene.......................................................................54

5-5. Chlorobenzene Levels in Water, Soil, and Air of National Priorities List (NPL) Sites.....................55

7-1. Regulations and Guidelines Applicable to Chlorobenzene ................................................................68
CHLOROBENZENE 1

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH

1.1 OVERVIEW AND U.S. EXPOSURES

Chlorobenzene (C6H5Cl; CAS Number 108-90-7) is used as a solvent and as a chemical intermediate in 

industry, a portion of which is lost to the environment in water and air discharges. Chlorobenzene 

adsorbs moderately to soil and is biodegraded comparatively rapidly.

The most likely sources of potential exposure of the general population to chlorobenzene are from 

breathing air, drinking water, or eating food contaminated with chlorobenzene. However, chlorobenzene 

has been detected in only very small quantities in air, water, and limited food sources. In a study of urban 

volatile organic compound (VOC) concentrations in the United States between 1996 and 1997, the 

highest levels of chlorobenzene were <1 ppbv (<4.6 μg/m3

) at 13 monitoring stations (Mohamed et al. 

2002). The potential for toxic exposure to chlorobenzene via the water supply may be somewhat limited 

by the relatively low solubility of chlorobenzene in water, as evidenced by the fact that environmental 

levels of chlorobenzene in groundwater and surface water are generally in the low ppb range (e.g., Van 

Wijk et al. 2004; USGS 2006).

According to the results of the Centers for Disease Control and Prevention (CDC) National Health and 

Nutrition Examination Surveys conducted between 2003 and 2016, blood levels in the general public 

were undetectable at a limit of detection (LOD) of 0.011 ng/mL (CDC 2019).

1.2 SUMMARY OF HEALTH EFFECTS 

• Available data, mostly from animal studies, identify the liver, kidney, and nervous system as 

principal targets of chlorobenzene, as illustrated in Figures 1-1 and 1-2 for inhalation and oral 

exposure, respectively.

• Results from oral studies in rats and mice indicate that the immunological system may be a target 

of chlorobenzene toxicity; however, tests of immune function in chlorobenzene-treated animals 

have not been performed.

• Results from limited animal studies suggest possible chlorobenzene-induced hematological 

effects.

• It is not clear whether chlorobenzene may cause cancer in humans.
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1. RELEVANCE TO PUBLIC HEALTH

Figure 1-1. Health Effects Found in Animals Following Inhalation Exposure to 

Chlorobenzene
CHLOROBENZENE 3

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-2. Health Effects Found in Animals Following Oral Exposure to 

Chlorobenzene
CHLOROBENZENE 4

1. RELEVANCE TO PUBLIC HEALTH

Hematological Effects. Limited animal data suggest that chlorobenzene may exert adverse effects on red 

blood cell (RBC) parameters (NIOSH 1977) and cause leukopenia and lymphocytosis (Zub 1978). 

Decreases in hematocrit, hemoglobin, and/or RBC counts and changes in white blood cell (WBC) counts 

were noted in dogs administered chlorobenzene orally for 13 weeks (Monsanto Co. 1967a).

Hepatic Effects. Available information regarding the potential for chlorobenzene-induced hepatic effects 

in humans is limited to a single case report of severe liver necrosis in a suicidal male with a daily alcohol 

consumption of 200 g (Babany et al. 1991; Reygagne et al. 1992). The liver was identified as a target of 

chlorobenzene toxicity in laboratory animals following inhalation or oral exposure; effects included 

increased liver weight and histopathologic liver lesions (e.g., hepatocellular hypertrophy, vacuolation, 

degeneration/necrosis, bile duct hyperplasia) (Monsanto Co. 1967a, 1967b; Nair et al. 1987; NTP 1985).

Renal Effects. The kidney was identified as a target of chlorobenzene toxicity in laboratory animals 

following inhalation or oral exposure; effects included increased kidney weight and histopathologic 

kidney lesions (e.g., tubular dilatation, interstitial nephritis, degeneration/focal necrosis of proximal 

tubules, foci of regenerative epithelium) (Monsanto Co. 1967a; Nair et al. 1987; NTP 1985).

Immunological Effects. Results from 13-week studies of orally-exposed rats and mice suggest that 

chlorobenzene may affect the immune system; effects observed included myeloid and/or lymphoid 

depletion in bone marrow, spleen, and/or thymus (NTP 1985). However, no data were located regarding 

testing of immune function in animals exposed to chlorobenzene.

Neurological Effects. Case reports of humans demonstrated that chlorobenzene caused disturbances of 

the central nervous system, but there were no reports of changes in the structure of the brain or other parts 

of the nervous system. Neurological effects (e.g., headaches, dizziness, sleepiness) were observed in 

humans who inhaled vapors of chlorobenzene in the workplace for up to 2 years (Rozenbaum et al. 1947). 

However, quantitative exposure data were not available. Acute inhalation data from animals confirm the 

neurotoxicity of chlorobenzene at high exposure concentrations (Rozenbaum et al. 1947).

Cancer. No studies were found regarding the carcinogenicity of chlorobenzene in humans. In a chronic 

bioassay in animals, chlorobenzene (up to 120 mg/kg/day) did not produce increased tumor incidences in 

mice of either sex or in female rats (NTP 1985). High-dose (120 mg/kg/day) male rats exhibited 

statistically significantly increased incidence of neoplastic liver nodules. Based on available information 

from animal carcinogenicity studies and genotoxicity evaluations, the U.S. Environmental Protection 
CHLOROBENZENE 5

1. RELEVANCE TO PUBLIC HEALTH

Agency (EPA) (IRIS 2003) assigned chlorobenzene to group D (not classifiable as to human 

carcinogenicity).

1.3 MINIMAL RISK LEVELS (MRLs)

As presented in Figure 1-3, available data have identified the liver and kidney as sensitive targets of 

chlorobenzene toxicity following inhalation exposure. No inhalation MRLs were derived for 

chlorobenzene due to insufficient data (see Appendix A). As presented in Figure 1-4, available data have 

identified the liver and kidney as sensitive targets of chlorobenzene toxicity following oral exposure. The 

oral database was considered adequate for derivation of an intermediate-duration oral MRL for 

chlorobenzene. The MRL value is summarized in Table 1-1 and discussed in detail in Appendix A. The 

database was not considered adequate for derivation of acute- or chronic-duration oral MRLs (see 

Appendix A).

Figure 1-3. Summary of Sensitive Targets of Chlorobenzene – Inhalation

The liver and kidney are the most sensitive targets of chlorobenzene inhalation exposure.

Numbers in circles are the lowest LOAELs for all health effects in animals; no human data were identified.
CHLOROBENZENE 6

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-4. Summary of Sensitive Targets of Chlorobenzene – Oral

The liver is the most sensitive target of chlorobenzene oral exposure. 

Numbers in circles are the lowest LOAELs for all health effects in animals.

No reliable dose response data were available for humans.

Table 1-1. Minimal Risk Levels (MRLs) for Chlorobenzenea

Exposure 

duration MRL Critical effect Point of departure

Uncertainty and 

modifying factors Reference

Inhalation exposure (ppm)

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate 0.07 Bile duct 

hyperplasia

BMDL10: 9.59 mg/kg

(BMDLADJ: 6.85)

UF: 100 Monsanto Co. 

1967a

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information. 

ADJ = duration-adjusted; BMDL10 = 95% lower confidence limit on the benchmark dose with a benchmark response 

of 10% of extra risk; UF = uncertainty factor
CHLOROBENZENE 7

CHAPTER 2. HEALTH EFFECTS

2.1 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 chlorobenzene. 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. 

When available, mechanisms of action are discussed along with the health effects data; toxicokinetic 

mechanistic data are discussed in Section 3.1. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

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 by health effect. These data are discussed in terms of 

route of exposure (inhalation, oral, and dermal) and three exposure periods: acute (≤14 days), intermediate 

(15–364 days), and chronic (≥365 days).

As discussed in Appendix B, a literature search was conducted to identify relevant studies examining health 

effect endpoints. Figure 2-1 provides an overview of the database of studies in humans or experimental 

animals included in this chapter of the profile. These studies evaluate the potential health effects associated 

with inhalation, oral, or dermal exposure to chlorobenzene, but may not be inclusive of the entire body of 

literature. 

Animal inhalation studies are presented in Table 2-1 and Figure 2-2, and animal oral studies are presented 

in Table 2-2 and Figure 2-3; no dose-response dermal data were identified for chlorobenzene. 

Levels of significant exposure (LSEs) 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 endpoint should be 
CHLOROBENZENE 8

2. HEALTH EFFECTS

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 endpoints. 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 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. Levels of exposure to chlorobenzene associated with cancer (Cancer Effect 

Levels, CELs) are indicated in Table 2-2 and Figure 2-3. 

A User's Guide has been provided at the end of this profile (see Appendix C). This guide should aid in 

the interpretation of the tables and figures for LSEs and MRLs.

Human data regarding the potential health effects of chlorobenzene exposure are essentially limited to 

reports of clinical signs of neurotoxicity among occupationally-exposed workers and among volunteers 

exposed by inhalation.

As illustrated in Figure 2-1, available animal data suggest the following sensitive targets of chlorobenzene 

toxicity:

• Hepatic endpoint: Inhalation or oral exposure of animals to chlorobenzene resulted in hepatic 

effects such as liver weight increases and dose-related increased incidence and severity of 

histopathologic liver effects such as hepatocellular hypertrophy and degenerative and 

regenerative liver lesions.

• Renal endpoint: Inhalation or oral exposure of animals to chlorobenzene resulted in renal 

effects such as increased kidney weight and dose-related increased incidence and severity of 

histopathologic kidney effects such as tubular dilatation, interstitial nephritis, and degenerative 

and regenerative kidney lesions.

• Neurotoxicity endpoint: Occupational and voluntary inhalation exposure to chlorobenzene has 

been associated with clinical signs of neurotoxicity such as numbness, cyanosis, muscle spasms, 

drowsiness, headache, ocular pain, and sore throat. Neurotoxic signs in animals exposed to 

chlorobenzene by inhalation or gavage include ataxia, decreased activity, salivation, prostration, 

and narcosis.

• Immunological endpoint: Lymphoid depletion/necrosis in thymus and/or spleen, and myeloid 

depletion in bone marrow were reported among rats and/or mice in 13-week gavage studies.
CHLOROBENZENE 9 

2. HEALTH EFFECTS

Figure 2-1. Overview of the Number of Studies Examining Chlorobenzene Health Effects 

Most studies examined the potential body weight, hepatic, and renal effects of chlorobenzene

The majority of the studies examined inhalation or oral exposure in animals; limited data were identified for humans (counts represent the 

number of studies examining endpoint)

*Includes studies discussed in Chapter 2. A total of 22 studies (including those finding no effect) have examined toxicity; most studies examined multiple 

endpoints.
CHLOROBENZENE 10

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to Chlorobenzene – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

ACUTE EXPOSURE

1 Rat 

(SpragueDawley)

5 M, 5 F

30 minutes 2,990, 

5,850, 

7,970

BW, CS, GN, 

HP, LE, OW

Bd wt 7,970

Hepatic 7,970

Renal 7,970

Ocular 2,990 Squinting, lacrimation

Neuro 2,990 5,850 Ataxia, narcosis

Shell Oil Co. 1991

2 Mouse 2 hours LE Death 4,300 100% mortality

Rozenbaum et al. 1947

3 Rabbit 2 hours LE Death 537

Rozenbaum et al. 1947

4 Rat 

(Fischer 

344)

32–33 F

GDs 6–15

6 hours/day

0, 75, 

210, 590

BW, DX, FI, 

FX, LE, MX, 

OW, TG, WI

Bd wt 590

Develop 590

John et al. 1984

5 Rabbit 

(New 

Zealand 

white)

30 F

GDs 6–18

6 hours/day

0, 75, 

210, 590

BW, DX, FI, 

FX, LE, MX, 

OW, TG, WI

Bd wt 590

Develop 590

John et al. 1984

6 Rabbit

(New 

Zealand 

white)

30 F

GDs 6–18

6 hours/day

0, 10, 30, 

75, 590

BW, DX, FI, 

FX, LE, MX, 

OW, TG, WI

Bd wt 590

Develop 590

John et al. 1984
CHLOROBENZENE 11

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to Chlorobenzene – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

7 Guinea pig 

(Hartley 

albino)

5 M, 5 F

30 minutes 2,990, 

5,850, 

7,970

BW, CS, GN, 

HP, LE, OW

Bd wt 7,970

Hepatic 7,970

Renal 7,970

Ocular 2,990 Squinting, lacrimation

Neuro 2,990 5,850 Salivation, narcosis

Shell Oil Co. 1991

INTERMEDIATE EXPOSURE

8 Rat 

(SpragueDawley)

30 M, 30 F

2 

generations

18–20 weeks

per 

generation

6 hours/day

9, 50, 

150, 450 

BW, CS, FI, 

DX, GN, HP, 

LE, OF, OW

Bd wt 450

Hepatic 50 M

450 F

150 M Increased mean relative liver 

weight, increased incidence of 

hepatocellular hypertrophy in 

parental males

Renal 50 M

450 F

150 M Renal lesions including chronic 

interstitial nephritis and foci of 

regenerative epithelium in parental 

males

Repro 150 M

450 F

450 M Increased incidence of 

degeneration of testicular germinal 

epithelium in the absence of 

apparent effects on fertility

Develop 450

Nair et al. 1987 (data also reported in CMA 1986)

9 Rat 

(SpragueDawley)

32 M

Up to 

24 weeks

5 days/week

7 hours/day

0, 75, 

250

BC, BW, CS, 

EA, FI, GN, 

HE, HP, LE, 

OF, OW

Bd wt 250

Hemato 250

Hepatic 250

NIOSH 1977

10 Mouse

(Swiss)

5 M, 5 F

3 weeks

7 hours/day

0, 543 BW, CS, HE, 

LE

Death 543 5/10 mice died

Zub 1978
CHLOROBENZENE 12

2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to Chlorobenzene – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

11 Rabbit

(NS)

32 M

Up to 

24 weeks

5 days/week

7 hours/day

0, 75, 

250

BC, BW, CS, 

EA, FI, GN, 

HE, HP, LE, 

OF, OW

Bd wt 250

Hemato 250

Hepatic 250

NIOSH 1977

12 Dog

(beagle)

6 M, 6 F

6 months

5 days/week

6 hours/day

0, 173.8, 

349.8, 

453.2 

BC, BW, CS, 

EA, FI, GN, 

HE, HP, LE, 

OF, UR

Bd wt 453.2

Hemato 453.2

Hepatic 453.2

Renal 453.2

Monsanto Co. 1980

aThe number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in

Figure 2-2. Where such differences exist, only the levels of effect for the most sensitive gender are presented.

BC = serum (blood) chemistry; Bd wt or BW = body weight; CS = clinical signs; EA = enzyme activity; Develop = developmental; DX = developmental toxicity; 

F = female(s); FI = food intake; FX = fetal toxicity; GD = gestation day(s); GN = gross necropsy; HE = hematology; Hemato = hematological; HP = histopathology; 

LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MX = maternal toxicity; Neuro = neurological; NOAEL = no-observed-adverse-effect 

level; NS = not specified; OF = organ function; OW = organ weight; Repro = reproductive; TG = teratogenicity; UR = urinalysis; WI = water intake
CHLOROBENZENE 13

2. HEALTH EFFECTS

Figure 2-2. Levels of Significant Exposure to Chlorobenzene – Inhalation

Acute (≤14 days)
CHLOROBENZENE 14

2. HEALTH EFFECTS

Figure 2-2. Levels of Significant Exposure to Chlorobenzene – Inhalation

Intermediate (15-364 days)
CHLOROBENZENE 15

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Chlorobenzene – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

ACUTE EXPOSURE

1 Rat 

(F344/N)

5 M, 5 F

Once

(GO)

250, 500, 

1,000, 2,000, 

4,000

CS, LE Death 4,000 3/5 males and 4/5 females 

died

Neuro 2,000 4,000 Prostration

NTP 1985 (data also reported in Kluwe et al. 1985)

2 Rat 

(albino)

22 F

GDs 6–15

1 time/day

(GO)

0, 100, 300 BW, CS, DX, 

FX, LE, MX, 

TG

Bd wt 300

Develop 300

Monsanto Co. 1977

3 Rat 

(F344/N)

5 M, 5 F

14 days

1 time/day

(GO)

0, 125, 250, 

500, 1,000, 

2,000

BW, CS, GN, 

LE

Death 1,000 5/5 males and 5/5 females 

died

Bd wt 500

Neuro 500 1,000 Prostration

NTP 1985 (data also reported in Kluwe et al. 1985)

4 Mouse 

(B6C3F1)

5 M, 5 F

Once

(GO)

250, 500, 

1,000, 2,000, 

4,000

CS, LE Death 1,000 M

2,000 F

5/5 males died

5/5 females died

NTP 1985 (data also reported in Kluwe et al. 1985)

5 Mouse 

(B6C3F1)

5 M, 5 F

14 days

1 time/day

(GO)

0, 30, 60, 

125, 250, 

500

BW, CS, GN, 

LE

Bd wt 500

NTP 1985 (data also reported in Kluwe et al. 1985)
CHLOROBENZENE 16

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Chlorobenzene – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

INTERMEDIATE EXPOSURE

6 Rat 

(F344/N)

10 M, 10 F

13 weeks

5 days/week

1 time/day

(GO)

0, 60, 125, 

250, 500, 

750

BC, BW, CS, 

GN, HE, HP, 

LE, OW, UR

Death 500 4/10 males and 

3/10 females died

Bd wt 125 M

250 F

250 M

500 F

12% lower mean final body 

weight

Hepatic 125 M

60 F

250 M

125 F

750 M, F Males: 24% increased 

mean relative liver weight 

at 250 mg/kg/day; hepatic 

degeneration/necrosis at 

750 mg/kg/day

Females: 19% increased 

mean relative liver weight 

at 125 mg/kg/day; hepatic 

degeneration/necrosis at 

750 mg/kg/day

Renal 250 500 750 F 13–15% increased mean 

relative kidney weight at 

500 mg/kg/day; renal 

necrosis/degeneration in 

females at 750 mg/kg/day

Immuno 500 750 Myeloid depletion in bone 

marrow, lymphoid depletion 

in spleen

NTP 1985 (data also reported in Kluwe et al. 1985)

7 Rat

(albino)

18 M, 18 F

3 months

1 time/day

(GO)

Controls 

(untreated), 

12.5, 50, 

100, 250

BC, BW, CS, 

FI, GN, HE, 

HP, LE, OF, 

OW, UR

Bd wt 250

Hemato 250

Hepatic 100 250 27–29% increased liver 

weight

Renal 100 250 13–14% increased kidney 

weight

Monsanto Co. 1967b
CHLOROBENZENE 17

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Chlorobenzene – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

8 Mouse 

(B6C3F1)

10 M, 10 F

13 weeks

5 days/week

1 time/day

(GO)

0, 60, 125, 

250, 500, 

750

BC, BW, CS, 

GN, HE, HP, 

LE, OW, UR

Death 250 5/9 males and 4/10 females 

died

Bd wt 125 M

250 F

250 M

500 F

15–20% lower mean final 

body weight at lethal dose 

levels

Hepatic 60 M

125 F

125 M 250 M, F At 125 mg/kg/day: 14% 

increased mean relative 

liver weight in males

At 250 mg/kg/day: 29–35% 

increased mean relative 

liver weight and hepatic 

necrosis/degeneration

Renal 125 250 Renal 

necrosis/degeneration

Immuno 125 250 Males: lymphoid 

depletion/necrosis in 

thymus and spleen; 

myeloid depletion in bone 

marrow

Females: lymphoid 

depletion/necrosis in 

spleen

NTP 1985 (data also reported in Kluwe et al. 1985)

9 Dog 

(beagle)

4 M, 4 F

13 weeks

5 days/week

1 time/day

(C)

0, 28, 55, 

280

BC, BW, CS, 

FI, GN, HE, 

HP, LE, OF, 

OW, UR

Death 280 2/4 dogs of each sex died

Bd wt 55 280 Emaciation, weight loss at 

lethal dose

Hemato 55 280 Males: decreased 

hematocrit, hemoglobin, 

RBCs; increased 

lymphocytes

Females: decreased 

hemoglobin, RBCs, total 

WBCs
CHLOROBENZENE 18

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Chlorobenzene – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Hepatic 28b M

55 F

55 M 280 At 55 mg/kg/day: 22% 

increased liver weight in 

males; bile duct 

hyperplasia (2/4) males

At 280 mg/kg/day:

increased liver weight (56% 

in males, 77% in females); 

degenerative liver lesions 

in most males and females

(BMDL10 of 9.59 mg/kg)

Renal 55 280 Increased kidney weight 

(62% in males, 87% in 

females); degenerative 

kidney lesions in most 

males and females

Monsanto Co. 1967a

CHRONIC EXPOSURE

10 Rat 

(F344/N)

50 M, 50 F

103 weeks

5 days/week

1 time/day

(GO)

0, 60, 120 BW, CS, GN, 

HP, LE

Death 120 Decreased survival

Bd wt 120

Hepatic 120

Renal 120

Cancer 120 CEL: neoplastic liver 

nodules

NTP 1985 (data also reported in Kluwe et al. 1985)
CHLOROBENZENE 19

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Chlorobenzene – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

11 Mouse 

(B6C3F1)

50 M, 50 F

103 weeks

5 days/week

1 time/day

(GO)

Males: 0, 30, 

60

Females: 0, 

60,120

BW, CS, GN, 

HP, LE

Bd wt 60 M

120 F

Hepatic 60 M

120 F

Renal 60 M

120 F

NTP 1985 (data also reported in Kluwe et al. 1985)

aThe number corresponds to entries in Figure 2-3; differences in levels of health effects and cancer effects between male and females are not indicated in

Figure 2-3. Where such differences exist, only the levels of effect for the most sensitive gender are presented. bUsed to derive an intermediate-duration oral MRL of 0.07 mg/kg/day; based on a BMDL10 of 9.59 mg/kg, adjusted to continuous duration exposure (BMDLADJ of 

6.85 mg/kg/day) and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability).

BC = serum (blood) chemistry; Bd wt or BW = body weight; (C) = capsule; CEL = cancer effect level; CS = clinical signs; Develop = developmental; 

DX = developmental toxicity; F = female(s); FI = food intake; FX = fetal toxicity; (GO) = gavage in oil; GN = gross necropsy; HE = hematology; 

Hemato = hematological; HP = histopathology; Immuno = immunological; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); 

MX = maternal toxicity; Neuro = neurological; NOAEL = no-observed-adverse-effect level; OF = organ function; OW = organ weight; RBC = red blood cell; 

TG = teratogenicity; UR = urinalysis; WBC = white blood cell
CHLOROBENZENE 20

2. HEALTH EFFECTS

Figure 2-3. Levels of Significant Exposure to Chlorobenzene – Oral

Acute (≤14 days)
CHLOROBENZENE 21

2. HEALTH EFFECTS

Figure 2-3. Levels of Significant Exposure to Chlorobenzene – Oral

Intermediate (15-364 days)
CHLOROBENZENE 22

2. HEALTH EFFECTS

Figure 2-3. Levels of Significant Exposure to Chlorobenzene – Oral

Chronic (≥365 days)
CHLOROBENZENE 23

2. HEALTH EFFECTS

2.2 DEATH

There have been no documented human deaths from chlorobenzene exposure.

The acute lethality of chlorobenzene is relatively low in animals. Single exposure of mice to 

chlorobenzene vapor at 4,300 ppm for 2 hours resulted in 100% mortality (Rozenbaum et al. 1947). 

Rabbits died 2 weeks after a 2-hour inhalation exposure at approximately 537 ppm (Rozenbaum et al. 

1947). In a 3-week study of mice exposed to chlorobenzene vapor for 7 hours/day at 543 ppm, death was 

reported in 5/10 mice (Zub 1978). Death occurred in 3/5 male and 4/5 female rats within 2–3 days 

following a single gavage dose at 4,000 mg/kg; similar exposure of mice resulted in 100% mortality of 

males at 1,000 mg/kg and females at 2,000 mg/kg (NTP 1985). In a 14-day repeated-dose study of rats, 

gavage exposure at doses ≥1,000 mg/kg resulted in 100% lethality (NTP 1985). In 13-week repeateddose studies, survival was reduced in male and female rats gavaged at doses ≥500 and male and female 

mice gavaged at doses ≥250 mg/kg/day (NTP 1985). In a 13-week oral study of dogs, ingestion of 

chlorobenzene at 280 mg/kg/day resulted in death of 2/4 dogs of each sex (Monsanto Co. 1967a). In a 

2-year oral rat study, survival of males at 120 mg/kg/day was significantly lower than that of vehicle 

controls (NTP 1985).

2.3 BODY WEIGHT

No exposure-related effects on body weight were observed in laboratory animals repeatedly exposed to 

chlorobenzene vapor at concentrations as high as 250–590 ppm (NIOSH 1977; John et al. 1984; 

Monsanto Co. 1980; Nair et al. 1987). In a 13-week gavage study, chlorobenzene exposure of male and 

female rats and mice at 250 mg/kg/day (males) and 500 mg/kg/day (females) resulted in 12–20% 

depressed mean final body weight (NTP 1985). Dogs, which were exposed for 13 weeks to 

chlorobenzene by daily capsule, exhibited emaciation and weight loss at a lethal dose of 280 mg/kg/day

(Monsanto Co. 1967a).

2.4 RESPIRATORY

Available information regarding chlorobenzene-induced respiratory effects is limited to observations of 

nose rubbing behavior among guinea pigs exposed to chlorobenzene vapor for 30 minutes at a 

concentration as low as 2,990 ppm (Shell Oil Co. 1991).
CHLOROBENZENE 24

2. HEALTH EFFECTS

Chlorobenzene has been used as a model VOC in several in vitro studies to investigate possible 

mechanisms of lung inflammation (Feltens et al. 2010; Fischäder et al. 2008; Lehmann et al. 2008; RöderStolinski et al. 2008).

2.5 CARDIOVASCULAR

No studies were located regarding cardiovascular effects in humans or laboratory animals exposed to 

chlorobenzene.

2.6 GASTROINTESTINAL

No studies were located regarding gastrointestinal effects in humans or laboratory animals exposed to 

chlorobenzene.

2.7 HEMATOLOGICAL

Information regarding the potential for inhaled chlorobenzene to cause hematological effects is limited. 

In studies of rats and rabbits exposed to chlorobenzene vapor for 7 hours/day, 5 days/week, for up to 

24 weeks at concentrations of 75 or 250 ppm, NIOSH (1977) reported exposure concentration-related

effects on RBC parameters (primarily an increase in reticulocyte count). Other hematological parameters 

(RBC count, hemoglobins, hematocrit, and WBC count) were variable and were comparable to controls at 

the end of the test. Zub (1978) reported slight leukopenia and lymphocytosis in mice exposed to 

chlorobenzene for 7 hours/day for 3 months at 21.7 ppm, and similar effects in mice similarly exposed for 

up to 3 weeks at 543 ppm (Zub 1978). However, limited details in the study report and lack of supportive 

evidence from other animal studies preclude meaningful evaluation of chlorobenzene-induced 

hematological effects following inhalation exposure. Monsanto Co. (1967a) reported changes in selected 

blood parameters in dogs receiving chlorobenzene in daily capsule at 280 mg/kg/day for 13 weeks. Highdose males exhibited decreases in hematocrit, hemoglobin, and RBCs, and increased lymphocytes; highdose females exhibited decreased in hemoglobin, RBCs, and total WBCs.

2.8 MUSCULOSKELETAL

No studies were located regarding musculoskeletal effects in humans or laboratory animals exposed to 

chlorobenzene.
CHLOROBENZENE 25

2. HEALTH EFFECTS

2.9 HEPATIC

Available information regarding the potential for chlorobenzene to cause adverse liver effects in humans 

is limited to a single case report in which ingestion of 140 mL of 90% chlorobenzene by a suicidal 

40-year-old, 58-kg, male with a daily alcohol intake of 200 g resulted in severe liver necrosis (Babany et 

al. 1991; Reygagne et al. 1992). Although daily alcohol consumption was estimated at approximately 

200 g, the patient had no history of chronic liver disease. Serum aspartate aminotransferase (AST) and 

alanine aminotransferase (ALT) levels on the third day after chlorobenzene ingestion were 345 and 

201 times, respectively, the upper limit of normal. Liver biopsy revealed centrilobular and mediolobular 

necrosis.

Results from animal studies identify the liver as a target of chlorobenzene toxicity. In a 2-generation 

inhalation study of rats, repeated inhalation exposure to chlorobenzene vapor at 150 ppm resulted in 

statistically significantly increased mean relative liver weight and increased incidence of hepatocellular 

hypertrophy of parental males (incidence data not included in the study report) (Nair et al. 1987). In 

several studies that employed repeated gavage exposure to chlorobenzene for up to 3 months, increased 

liver weight was reported in rats at doses as low as 100–250 mg/kg/day (Monsanto Co. 1967b; NTP 

1985), mice at 125 mg/kg/day (NTP 1985), and male dogs at 55 mg/kg/day (Monsanto Co. 1967a). Two 

of four male dogs treated at 55 mg/kg/day exhibited bile duct hyperplasia (a lesion not observed in control 

dogs); bile duct hyperplasia was noted in 4/4 male and 3/4 female dogs dosed at 280 mg/kg/day 

(Monsanto Co. 1967a). Hepatic degeneration/necrosis were observed in rats treated at 750 mg/kg/day and 

mice treated at 250 mg/kg/day (NTP 1985). There were no apparent exposure-related hepatic effects 

among rats or mice administered chlorobenzene by gavage for up to 2 years at doses as high as 60–

120 mg/kg/day (NTP 1985).

2.10 RENAL

Available animal data implicate the kidney as a target of chlorobenzene toxicity. Nair et al. (1987) 

reported tubular dilatation with eosinophilic material, interstitial nephritis, and foci of regenerative 

epithelium in 2 generations of parental male rats exposed to chlorobenzene vapor at concentrations 

≥150 ppm. In 3-month repeated-dose gavage studies of rats and mice (NTP 1985), increased kidney 

weight was observed at doses ≥500 mg/kg/day. Histopathologic kidney lesions (degeneration/focal 

necrosis of the proximal tubules) were observed in rats at 750 mg/kg/day and in mice at doses 

≥250 mg/kg/day (NTP 1985). Kidney lesions (e.g., tubule dilatation, epithelial degeneration, vacuolation) 

were observed in dogs treated with chlorobenzene in capsules for 13 weeks at 280 mg/kg/day (Monsanto 
CHLOROBENZENE 26

2. HEALTH EFFECTS

Co. 1967a). There were no indications of exposure-related kidney effects in rats or mice administered 

chlorobenzene by gavage for up to 2 years at doses as high as 60–120 mg/kg/day (NTP 1985).

2.11 DERMAL

Limited information was located regarding chlorobenzene-induced dermal effects. There were no signs 

of dermal sensitization in a guinea pig dermal sensitization assay in which chlorobenzene was applied via 

intradermal injection (induction at 1% chlorobenzene), followed by topical induction of a 50% solution 

and two challenge dermal applications of a 25% solution (Miles Inc. 1984).

2.12 OCULAR

Limited information was located regarding chlorobenzene-induced ocular effects. Lacrimation and 

squinting behavior was observed among rats and guinea pigs exposed to chlorobenzene vapor for 

30 minutes at concentrations ≥2,990 ppm (Shell Oil Co. 1991). Mild to moderate corneal opacity, iritis, 

redness, chemosis, and discharge were among the effects observed in the eyes of rabbits following ocular 

instillation of chlorobenzene (Zeneca Specialties 1982).

2.13 ENDOCRINE

No studies were located regarding endocrine effects in humans or laboratory animals exposed to 

chlorobenzene.

2.14 IMMUNOLOGICAL

Histological studies in mice and rats suggest that chlorobenzene has immunotoxic properties. In a 

13-week oral study of rats, gavage exposure at 750 mg/kg/day resulted in myeloid depletion in bone 

marrow and lymphoid depletion in the spleen (NTP 1985). Similar exposure of mice at doses 

≥250 mg/kg/day resulted in lymphoid depletion/necrosis in the thymus and spleen and myeloid depletion 

in bone marrow of males and lymphoid depletion/necrosis in the spleen of females (NTP 1985). Since no 

human data were located regarding immunotoxic effects and no animal studies that evaluated immune 

function are available, firm conclusions cannot be made concerning the potential for chlorobenzene to 

affect the immune system in humans.
CHLOROBENZENE 27

2. HEALTH EFFECTS

2.15 NEUROLOGICAL

Chlorobenzene affects the central nervous system. Humans occupationally exposed to chlorobenzene 

intermittently for up to 2 years displayed signs of neurotoxicity including numbness, cyanosis (from 

depression of respiratory center), hyperesthesia, and muscle spasms (Rozenbaum et al. 1947). Specific

exposure levels and histopathologic data were not provided in the study report. When four volunteers 

were exposed via inhalation to 60.2 ppm chlorobenzene for 7 hours during a study of urinary metabolites 

in exposed workers, all complained of disagreeable odor and drowsiness, three complained of headache, 

two of throbbing pain in eyes, and one of sore throat (Ogata et al. 1991). A test of critical flicker fusion 

frequency was also conducted. The critical flicker fusion rate is the frequency at which an intermittent 

light stimulus is perceived as continuous; the test is used to evaluate the rate of perceptual temporal 

processing capacity. The mean flicker-fusion value declined 3.1 cycles/second in exposed subjects, 

compared to controls (Ogata et al. 1991).

Neurological effects of chlorobenzene have also been reported in animals following inhalation. Acute 

inhalation exposure produced muscle spasms followed by narcosis in rabbits exposed to 1,090 ppm 

chlorobenzene for >2 hours (Rozenbaum et al. 1947). Ataxia and narcosis were observed in rats exposed 

to chlorobenzene vapor for 30 minutes at concentrations ≥5,850 ppm; most rats displayed these effects 

within 25 minutes following initiation of exposure, but they recovered rapidly after removal from the test 

chamber (Shell Oil Co. 1991). At an exposure concentration of 7,970 ppm, tremors were observed as 

well. In addition to the narcotic effects observed in the rats, similarly-exposed guinea pigs also exhibited 

salivation at 7,970 ppm.

There is a paucity of data on the effects of chlorobenzene in humans following oral exposure. A 2-yearold male swallowed 5–10 cc of a stain remover, which consisted almost entirely of chlorobenzene. He 

became unconscious, did not respond to skin stimuli, showed muscle spasms, and became cyanotic. The 

odor of chlorobenzene could be detected in his urine and exhaled air; however, the child recovered 

uneventfully (Reich 1934).

Available information regarding the potential for chlorobenzene to cause neurological effects following 

oral exposure in laboratory animals is limited to findings of decreased activity and prostration among rats 

administered chlorobenzene by gavage once at 4,000 mg/kg/day or repeatedly for 14 days at 

1,000 mg/kg/day; these doses were also lethal (NTP 1985).
CHLOROBENZENE 28

2. HEALTH EFFECTS

2.16 REPRODUCTIVE

No studies were located regarding reproductive effects in humans exposed to chlorobenzene.

Limited information is available regarding the potential for chlorobenzene-induced reproductive effects in 

laboratory animals. In a two-generation study of rats intermittently exposed to chlorobenzene vapor from 

at least 10 weeks prior to mating through lactation of their progeny, increased incidences of degenerative 

testicular changes were observed in males of both generations (6/30 versus 1/30 among controls; 

p=0.051) exposed at 450 ppm (Nair et al. 1987). The toxicological significance of this finding is unclear 

because mean mating, pregnancy, and male fertility indices for both F0 and F1 generations were 

comparable for all groups.

2.17 DEVELOPMENTAL

No studies were located regarding developmental effects in humans exposed to chlorobenzene.

Limited information is available regarding the potential for chlorobenzene-induced developmental effects 

in laboratory animals. No indications of chlorobenzene exposure-related developmental effects were 

observed in studies of rats and rabbits exposed to chlorobenzene vapor for 6 hours/day at concentrations 

as high as 590 ppm during gestation days 6–15 (rats) or 6–18 (rabbits) (John et al. 1984). No indications 

of exposure-related developmental effects were observed in a study of rats administered chlorobenzene by 

daily gavage at doses up to 300 mg/kg/day during gestation days 6–15 (Monsanto Co. 1977).

2.18 OTHER NONCANCER

No studies were located regarding other noncancer effects.

2.19 CANCER

In a chronic oral bioassay in rats and mice (NTP 1985), there was no evidence for carcinogenicity in 

either sex of mice or in female rats administered chlorobenzene in corn oil by gavage at dose levels up to

120 mg/kg/day. Increased tumor frequencies were not seen in female rats or in male or female mice. 

Male rats showed a significant (p<0.05) increase in the incidence of neoplastic nodules of the liver in the 

120 mg/kg/day dose group, but no increases were found at lower doses. While progression from nodules 

to carcinomas is a well-characterized phenomenon, existing data are inadequate to characterize the 
CHLOROBENZENE 29

2. HEALTH EFFECTS

carcinogenic potential of chlorobenzene in humans. EPA (IRIS 2003) assigned chlorobenzene to class D 

(not classifiable as to human carcinogenicity), based on lack of human data, inadequate animal data, and 

predominantly negative genetic toxicity data in bacterial, yeast, and mouse lymphoma cells.

2.20 GENOTOXICITY

No studies were located regarding the genotoxic effects of chlorobenzene in humans. The potential 

genotoxicity of chlorobenzene has been evaluated in several in vivo studies (Table 2-3) and a greater 

number of in vitro assays (Table 2-4). Collectively, the results indicate that chlorobenzene is not likely to 

act as a mutagen; however, in vivo results indicate that chlorobenzene may induce other genotoxic effects. 

However, as shown in Figure 3-1, chlorobenzene undergoes CYP450 catalyzed oxidation to form the 

3,4- and 2,3-epoxides of chlorobenzene. Both epoxides can be formed in liver and lung (and other tissues 

such as kidney and adrenal cortex) and are capable of covalently binding to deoxyribonucleic acid 

(DNA), ribonucleic acid (RNA), and proteins.

Table 2-3. Genotoxicity of Chlorobenzene In Vivo

Species (exposure route) Endpoint Results Reference

Drosophila:

Male germ cells (airborne 

exposure)

Sex-linked recessive lethal 

mutations

– Bioassay Systems Corp. 1982

Mammalian cells:

Rat bone marrow 

(intraperitoneal injection)

Chromosomal aberrations + Siddiqui et al. 2006

Mouse bone marrow 

(intraperitoneal injection)

Chromosomal aberrations + Mohtashumipur et al. 1987

Rat bone marrow 

(intraperitoneal injection)

Micronuclei + Siddiqui et al. 2006

Mouse bone marrow 

(intraperitoneal injection)

Micronuclei + Mohtashumipur et al. 1987

Mouse bone marrow 

(intraperitoneal injection)

Micronuclei – Shelby and Witt 1995

Mouse bone marrow 

(intraperitoneal injection)

Micronuclei – Shelby et al. 1993

Mouse peripheral lymphocytes 

(intraperitoneal injection)

DNA damage + Vaghef and Hellman 1995

Mouse bone marrow 

(intraperitoneal injection)

DNA damage – Vaghef and Hellman 1995

+ = positive result; – = negative result; DNA = deoxyribonucleic acid
CHLOROBENZENE 30

2. HEALTH EFFECTS

Table 2-4. Genotoxicity of Chlorobenzene In Vitro

Species (test system) Endpoint

Results

With activation Without activation Reference

Prokaryotic organisms:

Salmonella typhimurium 

TA98, TA100, TA1535, 

TA1537, TA1538

Gene mutation – – E.I. DuPont 1977

S. typhimurium TA98, 

TA100, TA1535, TA1537

Gene mutation – – Haworth et al. 1983; 

NTP 1985

S. typhimurium TA98, 

TA100, TA1535, TA1537, 

TA1538

Gene mutation – – Monsanto Co. 

1976a, 1976b

S. typhimurium TA98, 

TA100, TA1535, TA1537, 

TA1538

Gene mutation – – Shimizu et al. 1983

Saccharomyces 

cerevisiae D4

Gene mutation – – Monsanto Co. 

1976a, 1976b

Eukaryotic organisms:

Aspergillus nidulans Gene mutation – No data Prasad 1970

Mammalian cells:

Mouse L5178Y 

lymphoma cells

Gene mutation + +/– McGregor et al. 

1988

Mouse L5178Y 

lymphoma cells

Gene mutation – – Monsanto Co. 

1976c

Rat liver epithelial cells Cell 

transformation

No data + Shimada et al. 1983

Rat hepatocytes DNA repair No data – Shimada et al. 1983

Chinese hamster ovary 

cells

Chromosomal 

aberrations

– – Bioassay Systems 

Corp. 1982

Chinese hamster ovary 

cells

Chromosomal 

aberrations

– – Loveday et al. 1989

Chinese hamster ovary 

cells

Sister chromatid 

exchange

– + Loveday et al. 1989

+ = positive result; – = negative result; +/– = inconclusive results; DNA = deoxyribonucleic acid

Chlorobenzene did not induce sex-linked recessive lethal mutations in male Drosophila germ cells 

(Bioassay Systems Corp. 1982). Chlorobenzene induced chromosomal aberrations and micronuclei in 

bone marrow cells in two assays that employed intraperitoneal injection of chlorobenzene into rats and 

mice (Mohtashumipur et al. 1987; Siddiqui et al. 2006), but did not induce micronuclei in mouse bone 

marrow cells in other similarly-designed studies (Shelby and Witt 1995; Shelby et al. 1993). Vaghef and 

Hellman (1995) reported DNA damage in peripheral lymphocytes from mice following intraperitoneal 
CHLOROBENZENE 31

2. HEALTH EFFECTS

injection of chlorobenzene for 3 days at 750 mg/kg/day, but no evidence of DNA damage to bone marrow 

cells.

Chlorobenzene did not induce gene mutations either in the presence or absence of exogenous metabolic 

activation in bacterial assays that employed multiple strains of Salmonella typhimurium (E.I. DuPont 

1977; Haworth et al. 1983 [also reported in NTP 1985]; Monsanto Co. 1976a, 1976c; Shimizu et al. 1983) 

or the D4 strain of Saccharomyces cerevisiae (Monsanto Co. 1976a, 1976b). Chlorobenzene did not 

induce gene mutations in the fungus Aspergillus nidulans in the presence of exogenous metabolic 

activation (Prasad 1970). Positive results for chlorobenzene-induced gene mutations in mouse L5178Y 

lymphoma cells in the presence and absence of exogenous metabolic activation were obtained in one 

study (McGregor et al. 1988), but not in another study (Monsanto Co. 1976c). Chlorobenzene induced 

cell transformation in rat liver epithelial cells, but did not induce DNA repair in rat hepatocytes (Shimada 

et al. 1983). In Chinese hamster ovary cells, negative results were obtained for chromosomal aberrations 

in the presence and absence of exogenous metabolic activation (Bioassay Systems Corp. 1982; Loveday 

et al. 1989), but positive results were obtained for sister chromatic exchange in the absence of exogenous 

metabolic activation (Loveday et al. 1989).
CHLOROBENZENE 32

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, 

BIOMARKERS, CHEMICAL INTERACTIONS

3.1 TOXICOKINETICS 

• Chlorobenzene is readily absorbed from the respiratory and gastrointestinal tracts.

• Chlorobenzene is widely distributed in the blood, but may accumulate to some extent in adipose 

tissue due to its lipophilicity.

• Most chlorobenzene is metabolized via a chlorobenzene 3,4-epoxide pathway to ultimate urinary 

glucuronide or sulfate conjugates.

• Urinary excretion of chlorobenzene metabolites is the major route of excretion.

3.1.1 Absorption 

Limited information was located regarding absorption of inhaled chlorobenzene. Absorption from the 

respiratory tract of two workers exposed to airborne chlorobenzene concentrations in the range of 0.5–

0.84 ppm was estimated to have been 70% (Ogata and Shimada 1983). In other human studies that 

involved occupational exposure to chlorobenzene, the detection of chlorobenzene metabolites in blood 

and urine provides unquantified demonstration that chlorobenzene is absorbed from the respiratory tract 

(Knecht and Woitowitz 2000; Kumagai and Matsunaga 1994; Kusters and Lauwerys 1990; Ogata et al. 

1991; Yoshida et al. 1986). Rats were reported to readily absorb 14C-labeled chlorobenzene at airborne 

concentrations up to 700 ppm (Sullivan et al. 1983). Shimada (1981, 1988) evaluated distribution and 

urinary excretion of chlorobenzene and its metabolites in laboratory animals exposed to chlorobenzene by 

inhalation, thus demonstrating that inhaled chlorobenzene is absorbed.

Chlorobenzene is readily absorbed from the gastrointestinal tract. Ogata and Shimada (1983) reported at 

least 31% absorption of chlorobenzene orally administered to a single volunteer. In the same study, rats 

administered chlorobenzene absorbed at least 18% of the administered dose. Lindsay Smith et al. (1972) 

administered [14C]chlorobenzene to two rabbits orally at approximately 500 mg/rabbit, twice per day for 

4 days and measured radioactivity in urine and feces of both rabbits and tissues of one rabbit. Recovered 

radioactivity was 19.6% in the urine, 1.05–1.55% in the feces, and 0.05% in tissues; thus, approximately 

20% of the administered dose was absorbed. The absorption of orally-administered chlorobenzene from 

the gastrointestinal tract was demonstrated in a variety of oral animal studies that were designed to 

evaluate chlorobenzene metabolites in urine (e.g., Azouz et al. 1952; Gillham and Young 1968; Krewet et 

al. 1989; Parke and Williams 1953; Lindsay Smith et al. 1950, 1972; Spencer and Williams 1950).
CHLOROBENZENE 33

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

3.1.2 Distribution 

Limited information was located regarding distribution of absorbed chlorobenzene in humans. Knecht 

and Woitowitz (2000) exposed eight volunteers to Germany’s maximum workplace concentration (MAK) 

of 10 ppm chlorobenzene 8 hours/day for 5 days. There was no apparent tendency for chlorobenzene or 

its metabolites to accumulate in blood or urine with prolonged exposure. Blood levels reached a steady 

state (mean, 197.0±9.7 μg/L) after the first hour of exposure. The mean concentration of chlorobenzene 

in blood in five subjects exposed during physical exercise (75 W, 10 minutes/hour on a bicycle) was 

217 μg/L. The mean chlorobenzene blood concentrations were 133 μg/L in two subjects exposed during 

mild exercise (50 W, 10 minutes/hour on a bicycle) and 78 μg/L in one subject exposed while at rest.

Studies in laboratory animals indicate that chlorobenzene is widely distributed and may accumulate in 

adipose tissue (Shimada 1988; Sullivan et al. 1983). Accumulation in adipose tissue is related to the 

lipophilicity of chlorobenzene and likely depends on the species-specific lipid distribution in various 

organs.

3.1.3 Metabolism 

A proposed metabolic pathway of chlorobenzene (Chadwick et al. 1984) is shown in Figure 3-1. The 

numbers 1–16 in Figure 3-1 correspond to the numbers in the following text that presents the various 

metabolic processes.

According to the proposed metabolic pathway, chlorobenzene undergoes CYP450 catalyzed oxidation to 

form chemically-reactive chlorobenzene 3,4-epoxide (1), relatively nontoxic chlorobenzene 2,3-epoxide 

(2) to a lesser extent, and 3 chlorophenol (3). Both epoxides can be formed in liver and lung (and other 

tissues such as kidney and adrenal cortex) and are capable of covalently binding to DNA, RNA, and 

proteins. The chlorobenzene epoxides can be further metabolized by three separate pathways. One 

pathway for 3,4- and 2,3-chlorobenzene epoxides involves the GSH transferase-catalyzed formation of 

glutathione conjugates of 4-chlorophenyl (4) and 2-chlorophenyl (5), respectively, followed by 

conversion to mercapturic acid derivatives. Another metabolic pathway for the 3,4- and 2,3-epoxides is 

the enzymatic (epoxide hydrase) conversion to 3,4-dihydro-3,4-dihydroxychlorobenzene (6 and 7, 

respectively) which is enzymatically converted to chlorocatechol (8) or chlorophenol (9). Both 

chlorocatechol and chlorophenol can form glucuronide and sulfate conjugates (10 and 11, respectively). 
CHLOROBENZENE 34

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Figure 3-1. Mammalian Metabolism of Chlorobenzene to Phenols, Dihydrodiols, 

Catechols, and Glutathione Conjugates

Source: Chadwick et al. 1984; reprinted from Pesticide Biochemistry and Physiology 21:148-161 (1984) 

with permission from Elsevier.

OH Cl

Cl

H

OH

OH

H

OH

OH

OH

Cl

Cl Cl

OH

Cl

2-Chlorophenol

OH

Cl

4-Chlorophenol

O

Cl

Chlorobenzene

2,3-epoxide

O

Cl

Chlorobenzene

3,4-epoxide

SG

Cl

2-Chlorophenyl

GSH conjugate

SG

Cl

4-Chlorophenyl

GSH conjugate

Chlorobenzene 3-Chlorophenol

Glucuronide and sulfate

conjugates

Glucuronide and sulfate

conjugates

Hydrolysis Hydrolysis

Chlorocatechol Chlorophenol

Glucuronide and sulfate

conjugates

3,4-Dihydro-3,4-

dihydroxychlorobenzenes

GSH transferase GSH transferase Epoxide hydrase

1 2

3

4 7 5

6

8 9

10 11

12

13

16 14 15
CHLOROBENZENE 35

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

The 3,4- and 2-3-epoxides can also undergo hydrolysis to form 4-chlorophenol (12) and 2-chlorophenol 

(13), respectively. The chlorophenols (4-chlorophenol, 3-chlorophenol, and 2-chlorophenol) can form 

glucuronide and sulfate conjugates (14, 15, and 16, respectively).

Chlorobenzene metabolites that have been detected in the urine of a variety of animal species include 2-, 

3-, and 4-chlorophenyl-mercapturic acid, chlorophenols and chlorocatechols and their glucuronide and 

sulfate conjugates, and 3,4-dihydro-3,4-dihydroxychlorobenzene. Chlorocatechol and 2-chlorophenylmercapturic acid were detected in the urine of humans who received chlorobenzene orally or by 

inhalation (Ogata and Shimada 1983). Chlorobenzene metabolites that have been detected in the urine of 

chlorobenzene-exposed humans include 4-chlorocatechol, 4-chlorophenol, and 2-chlorophenylmercapturic acid (Kusters and Lauwerys 1990; Ogata and Shimada 1983; Ogata et al. 1991; Yoshida et al. 

1986).

Cytochrome P-450 2E1 is the main enzyme involved in the oxidation of chlorobenzene in mice, rats, and 

humans. Cytochrome P-450 3A also appears to play a role in the generation of reactive metabolites in 

mice, rats, and humans. It is important to note, however, that, compared to mice and rats, the rate of 

metabolism of chlorobenzene to soluble metabolites is higher in humans, and the formation of covalently 

bound products is lower (Nedelcheva et al. 1998). In addition, there is up to a 10-fold difference in the 

rate of metabolism of chlorobenzene in different human livers. There are also significant species and sex 

differences in the metabolism of chlorobenzene with markedly higher rates of oxidation in male mice than 

in male rats and female mice.

Co-treatment of rats with chlorobenzene and an epoxide hydrase inhibitor (cyclohexane oxide) resulted in 

decreases in chlorobenzene metabolism and its necrotic toxicity on the liver, suggesting that the 

metabolism of chlorobenzene is partially responsible for its liver toxicity (Oesch et al. 1973).

3.1.4 Excretion 

Knecht and Woitowitz (2000) exposed eight volunteers to Germany’s MAK of 10 ppm chlorobenzene 

8 hours/day for 5 days. Half-lives of elimination of chlorobenzene from blood were 53 minutes in the 

first hour after cessation of exposure and 150 minutes thereafter. The major urinary metabolite of 

chlorobenzene was 4-chlorocatechol (74%), with the remainder comprised of chlorophenol isomers of 

which 4-chlorophenol (13%) was the most abundant. Urinary 4-chlorophenol was useful as a biomarker 
CHLOROBENZENE 36

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

of exposure due to its half-life of approximately 12 hours. The elimination half-life of urinary 

4-chlorocatechol was 6.4 hours (Knecht and Woitowitz 2000).

Ogata and Shimada (1983) reported that in two workers exposed by inhalation to 0.84 and 0.5 ppm of 

chlorobenzene, the excretion of 4-chlorophenylmercapturic acid was markedly lower than that of 

4-chlorocatechol. Ogata and Shimada (1983) also assayed the urinary metabolites of chlorobenzene of a 

57-year-old male volunteer given an oral dose of 0.3 mmol/kg of chlorobenzene. Two urinary 

metabolites, 4-chlorophenylmercapturic acid and 4-chlorocatechol, were detected. As in the case of 

inhalation exposure, the excretion of 4-chlorophenylmercapturic acid was reported to be markedly lower 

than that of 4-chlorocatechol. However, the ratio of mercapturic-acid to 4-chlorocatechol in the urine of 

human subject receiving oral chlorobenzene was similar to that of the two workers inhaling 

chlorobenzene.

Linear correlations between urinary 4-chlorocatechol excretion and airborne exposure of workers to 

chlorobenzene were established by Yoshida et al. (1986) after monitoring end-of-shift urinary metabolites 

in healthy male workers in two chemical factories where chlorobenzene was used as a solvent. The 

primary urinary metabolites were 4-chlorocatechol (mean 76.9%) and 4-chlorophenol (mean 12.4%). In 

factories A and B, average chlorobenzene concentrations in air were 3.16 ppm (range 1.72–5.78 ppm) and 

3.14 ppm (range 2.68–3.68 ppm), respectively. These levels of exposure in factories A and B 

corresponded, respectively, to mean 4-chlorocatechol levels of 0.362 μmoles/mg creatinine (range 0.166–

0.787 μmoles/mg creatinine) and 0.482 μmoles/mg creatinine (range 0.354–0.655 μmoles/mg creatinine) 

in urine (Yoshida et al. 1986).

Assessing 44 maintenance workers in a diphenylmethane 4,4'-diisocyanate plant for chlorobenzene 

exposure, Kusters and Lauwerys (1990) also found that the main urinary metabolites at the end of shift 

were 4-chlorophenol and 4-chlorocatechol, with the latter being 3 times more abundant than the former. 

The time-weighted average exposure to chlorobenzene in air (mean 1.2 ppm, range 0.05–106 ppm) was 

less than the current German MAK value of 10 ppm established in 1995. More than 80% of the 

metabolites were eliminated within 16 hours after the end of exposure, and there was no tendency for an 

increase in concentration during the working week.

Ogata et al. (1991) reported that, in order of abundance, the main urinary metabolites of chlorobenzene in 

exposed workers were 4-chlorocatechol and 2-chlorophenylmercapturic acid. The concentrations of 

chlorobenzene in blood and metabolites in urine (e.g., 4-chlorocatechol, approximately 26% of exposure) 
CHLOROBENZENE 37

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

were both proportional to the concentration of chlorobenzene in air. The molar ratio of urinary 

chlorocatechol to inhaled chlorobenzene was estimated to be approximately 26%, and the mean slope of 

regression line for chlorobenzene in air versus blood was 4.6±1.15 μg/L for 1 ppm chlorobenzene. The 

measured biological half-time of 4-chlorocatechol was 2.9 hours.

Rats were exposed to 14C-chlorobenzene vapor at concentrations of 100, 400, and 700 ppm for 8 hours 

(Sullivan et al. 1983). The plasma concentration-time profile for chlorobenzene on cessation of exposure, 

as estimated by respiratory elimination of radioactivity, indicated a two-compartment elimination. 

Increase in exposure by a factor of 7 (100–700 ppm) increased the total uptake of radioactivity by a factor 

of about 13. This increase in body burden was associated with a decrease in total body clearance, as 

indicated by an approximate 4-fold increase in the half-life of the central compartment. The proportion of 

the dose excreted via the lungs (which may be presumed to be largely, if not entirely, unchanged 

chlorobenzene) increased nonlinearly and the proportion eliminated by hepatic metabolism decreased. 

Increase in the dose of chlorobenzene was associated with a decrease in the proportion cleared as the 

mercapturic acid derivative. Of interest, the half-life of chlorobenzene was shorter at the 700 ppm 

exposure level when the animals were subjected to repeated exposure daily for 5 days, as compared with 

that of the single 700 ppm exposure animals, raising the possibility of induction of metabolic clearance. 

In agreement with this possibility, the proportion cleared by metabolism in the multi-exposed animals was 

increased, and the proportion excreted unchanged via the lung was decreased, as compared with the 

700 ppm-single exposure animals.

In the repeated-dose oral study of rabbits administered [14C]chlorobenzene (Lindsay Smith et al. 1972), 

total recovery of radioactivity from the urine was approximately 20% of the administered dose. The 

contributions of the various metabolites in the urine were 33.88% for ethereal sulfates, 33.57% for 

glucuronides, 23.8% for mercapturic acids, 4.17% for diphenols, 2.84% for monophenols, and 0.57% for 

3,4-dihydro-3,4-dihydroxychlorobenzene. It was concluded that the remaining radiolabel was excreted in 

the expired air. The major urinary metabolites were 4-chlorophenylmercapturic acid and conjugates of 

4-chlorocatechol. Other identified urinary metabolites included quinol, 3-chlorocatechol, and 2- and 

3-chlorophenylmercapturic acid. Ogata and Shimada (1983) reported that the primary urinary metabolite 

in rats was 4-chlorophenylmercapturic acid and that 4-chlorocatechol was a minor metabolite.
CHLOROBENZENE 38

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

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. 

Thrall et al. (2004) developed a rat PBPK model for chlorobenzene in air using metabolic data derived 

from groups of F344 male rats exposed to chlorobenzene levels ranging from 82 to 6,750 ppm in air. 

Physiological values (e.g., breathing rate, organ volumes, etc.) were taken from the literature, and 

partition coefficients were determined from in vitro experiments with rat tissues and blood samples. The 

finished model was evaluated by using it to predict the chlorobenzene levels in exhaled breath of rats 

exposed by corn oil gavage (127 mg/kg) or intraperitoneal injection (131 mg/kg).

A PBPK model was developed to estimate the amount of 19 different VOCs that a nursing infant would 

receive from its occupationally-exposed mother (Fisher et al. 1997). In a simulation of a lactating woman 

exposed to the threshold limit value (TLV) concentration of chlorobenzene in air at the workplace, the 

amount of chlorobenzene transferred to a nursing infant from mother’s milk was calculated to be 

0.229 mg for a 10-kg infant.

3.1.6 Animal-to-Human Extrapolations 

A number of differences between humans and various laboratory animal species preclude meaningful 

extrapolation from animals to humans. Compared to mice and rats, the rate of metabolism of 

chlorobenzene to soluble metabolites is higher in humans, and the formation of covalently bound products 

is lower (Nedelcheva et al. 1998). In addition, there is up to a 10-fold difference in the rate of metabolism 

of chlorobenzene in different human livers. There are also significant species and sex differences in the 

metabolism of chlorobenzene with markedly higher rates of oxidation in male mice than in male rats and 

female mice.
CHLOROBENZENE 39

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans. 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. Children may be more or less susceptible than adults to health 

effects from exposure to hazardous substances and the relationship may change with developmental age. 

This section also discusses unusually susceptible populations. A susceptible population may exhibit 

different or enhanced responses to certain chemicals than most persons exposed to the same level of these 

chemicals in the environment. Factors involved with increased susceptibility may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters can reduce detoxification or excretion or compromise organ function. 

Populations at greater exposure risk to unusually high exposure levels to chlorobenzene are discussed in 

Section 5.7, Populations with Potentially High Exposures.

No information was located regarding potential differences in susceptibility to chlorobenzene.

3.3 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as biomarkers of exposure, biomarkers of effect, and biomarkers of susceptibility 

(NAS/NRC 1989).

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. Biomarkers of 

exposure to chlorobenzene are discussed in Section 3.3.1. The National Report on Human Exposure to 

Environmental Chemicals provides an ongoing assessment of the exposure of a generalizable sample of 

the U.S. population to environmental chemicals using biomonitoring (see http://www.cdc.gov/

exposurereport/). If available, biomonitoring data for chlorobenzene from this report are discussed in 

Section 5.6, General Population Exposure. 
CHLOROBENZENE 40

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that (depending on magnitude) can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effect caused 

by chlorobenzene are discussed in Section 3.3.2.

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 3.2, Children and Other Populations that are Unusually Susceptible.

3.3.1 Biomarkers of Exposure

Levels of chlorobenzene and its metabolites have been measured in blood, urine, and exhaled air. Levels 

of 0.05–17 mg/L in the blood and 25–120 μg/L in the urine were detected in samples from residents 

living near a former toxic chemical dump, while trace amounts were found in exhaled air (Barkley et al. 

1980). Yoshida et al. (1986) demonstrated linear correlations between urinary 4-chlorocatechol excretion 

and airborne exposure of workers to chlorobenzene. These authors suggested that the former might be an 

effective biomarker of exposure in humans.

Kumagai and Matsunaga (1994, 1995) also found that the major urinary metabolites of chlorobenzene in 

humans, including 4-chlorocatechol (especially) and 4-chlorophenol, are good biomarkers of recent 

exposure in workers. The slopes of the regression line for urinary metabolite concentration versus 

inhalation exposure concentration do appear to vary somewhat between studies, probably because of 

differences in workloads (active versus at rest) and patterns of exposure (acute versus chronic). 

Nevertheless, controlled chamber studies with workers have demonstrated that the concentrations of both 

major urinary metabolites of chlorobenzene correlate well with workers’ 8-hour time-weighted average 

exposure to chlorobenzene and reflect variations in workplace exposure to chlorobenzene (Kumagai and 

Matsunaga 1995).
CHLOROBENZENE 41

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

In an occupational study by Knecht and Woitowitz (2000), the major urinary metabolite of chlorobenzene 

was 4-chlorocatechol (74%). The remainder consisted of chlorophenol isomers of which 4-chlorophenol 

(13%) was the most abundant. In spite of its being <20% as abundant as 4-chlorocatechol, urinary 

4-chlorophenol was still considered to be potentially useful as a biomarker of exposure due to its longer 

half-life (approximately 12 hours). The elimination half-life of urinary 4-chlorocatechol was 6.4 hours.

3.3.2 Biomarkers of Effect

There are no known biomarkers of effect that are specific to chlorobenzene exposure.

3.4 INTERACTIONS WITH OTHER CHEMICALS 

In an attempt to identify the proposed epoxide intermediate of chlorobenzene, Oesch et al. (1973) coadministered the epoxide hydrase inhibitor, cyclohexane oxide, together with chlorobenzene to rats. 

Instead of increasing the toxicity of chlorobenzene as expected, through the inhibition of epoxide hydrase, 

cyclohexane oxide actually decreased the metabolism of chlorobenzene and its necrotic toxicity on the 

liver, suggesting that the metabolism of chlorobenzene is partially responsible for its liver toxicity.

In a mechanistic rat study, a chlorobenzene oral dose of 0.04 mL/180 g (approximately 246 mg/kg) 

caused extensive liver necrosis in rats pretreated with phenobarbital, but little or none in rats that were 

that were not pretreated with phenobarbital (Brodie et al. 1971). In another study, the severity of 

chlorobenzene-induced necrosis was decreased by pretreatment with the microsomal enzyme inhibitor,

SKF 525A. The authors concluded that reactive metabolites of chlorobenzene that were formed in the 

liver may have subsequently reacted with tissue macromolecules (Brodie et al. 1971). 
CHLOROBENZENE 42

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY

Data pertaining to the chemical identity of chlorobenzene are listed in Table 4-1.

Table 4-1. Chemical Identity of Chlorobenzene

Characteristic Information Reference

Chemical name Chlorobenzene NLM 2020

Synonym(s) and registered 

trade name(s)

Monochlorobenzene; Benzene chloride; Phenylchloride; 

MCB; Chlorobenzol; Caswell no. 183A

NLM 2020

Chemical formula C6H5Cl NLM 2020

Chemical structure NLM 2020

CAS Registry Number 108-90-7 NLM 2020

CAS = Chemical Abstracts Service 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

The odor threshold for chlorobenzene in humans has been reported to be as low as 0.21 ppm or 

0.97 mg/m3 (Leonardos et al. 1969). However, others have reported its “almond-like odor” to be “barely 

perceptible” at 60 ppm (Von Burg 1981; Willhite and Book 1990). The physical and chemical properties 

of chlorobenzene are presented in Table 4-2.

Table 4-2. Physical and Chemical Properties of Chlorobenzene

Property Information Reference

Molecular weight 112.56 Weast 1985

Color Colorless Verschueren 1983

Physical state Liquid Verschueren 1983

Melting point -45.6°C Weast 1985

Boiling point 132°C Weast 1985

Density at 20°C 1.1058 Weast 1985

Odor Aromatic, almond-like Sax and Lewis 1987

Cl
CHLOROBENZENE 43

4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Chlorobenzene

Property Information Reference

Odor threshold: Conflicting data Leonardos et al. 1969

Water 0.050 mg/L Verschueren 1983

Air 1–8 mg/m3 Verschueren 1983

Solubility:

Water at 20°C 500 mg/L Verschueren 1983

Organic solvents Soluble in alcohol, ether, benzene Weast 1985

Partition coefficients:

Log Kow 2.84 Verschueren 1983

Log Koc 2.52 EPA 1982

Vapor pressure at 20°C 8.8 mmHg Verschueren 1983

Henry's law constant at 25°C 3.58x10-3 atm-m3/mol EPA 1982

Autoignition temperature 637°C Sax and Lewis 1987

Flashpoint 29.4°C Sax and Lewis 1987

Flammability limits 1.8–9.6% Sax and Lewis 1987

Conversion factors 1 ppm=4.7 mg/m3

1 mg/m3=0.22 ppm

Verschueren 1983

Explosive limits 1.3-11 vol% in air) NIOSH 2015
CHLOROBENZENE 44

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW 

Chlorobenzene has been identified in at least 491 of the 1,867 hazardous waste sites that have been 

proposed for inclusion on the EPA National Priorities List (NPL) (ATSDR 2019). However, the number 

of sites in which chlorobenzene has been evaluated is not known. The number of sites in each state is 

shown in Figure 5-1. Of these sites, 490 are located within the United States, and 1 is located in Puerto 

Rico (not shown).

Figure 5-1. Number of NPL Sites with Chlorobenzene Contamination

• The most likely sources of potential exposure of the general population to chlorobenzene are from 

breathing air, drinking water, or eating food that contains chlorobenzene.

• Chlorobenzene has been detected in only very small quantities in air, water, and limited food 

sources.

• Chlorobenzene degrades rapidly in air, water, and soil; it is not expected to bioconcentrate.
CHLOROBENZENE 45

5. POTENTIAL FOR HUMAN EXPOSURE

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2.1 Production

Production of chlorobenzene in the United States declined by nearly 60%, from the peak production 

volume of 274,000,000 kg in 1960 to 112,000,000 kg in 1987. This decline is attributed primarily to the

replacement of chlorobenzene by cumene in phenol production and the cessation of DDT production in 

the United States. In addition, pesticide production using chlorobenzene as an intermediate has declined

and no major new uses have been found for chlorobenzene in recent years. Therefore, the decline in 

chlorobenzene production is expected to continue (EPA 1980a; Hughes et al. 1983; USITC 1988).

In the 1980s, chlorobenzene was produced by three United States chemical companies: Monsanto 

Chemical Company, Sauget, Illinois; PPG Industries, Inc., Natrium, West Virginia; and Standard 

Chlorine Chemical Co., Inc., Delaware City, Delaware. Production capacity for chlorobenzene at these

plants remained constant after 1985, although it appeared that actual production declined slightly after 

1985 (Hughes et al. 1983; SRI 1985, 1986, 1987, 1988; USITC 1988).

Chlorobenzene is produced commercially by the chlorination of benzene in the presence of a catalyst 

(e.g., ferric chloride, aluminum chloride, or stannic chloride). This process yields a mixture of

chlorobenzene, dichlorobenzenes, and higher analogs, which are distilled and crystallized to obtain pure 

products (EPA 1985; Hughes et al. 1983).

The Hazardous Substance Data Bank (HSDB) listed the following figures for U.S. production capacity (in 

lbs/year): 368 million in 1990; 371 million in 1993; 370 million in 1996; 358 million in 1999; and 

205 million in 2004; and 52.7 million in 2014 (NLM 2020). Table 5-1 summarizes information on U.S. 

companies that manufactured or used chlorobenzene in 2018 (TRI18 2020).

Table 5-1. Facilities that Produce, Process, or Use Chlorobenzene

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

AL 1 10,000 99,999 6, 7

AR 4 100 999,999 7, 12

CA 1 100,000 999,999 7, 11

CO 1 10,000 99,999 6, 10
CHLOROBENZENE 46

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. Facilities that Produce, Process, or Use Chlorobenzene

Statea

Number of 

facilities

Minimum 

amount on site 

in poundsb

Maximum 

amount on site 

in poundsb Activities and usesc

GA 1 1,000,000 9,999,999 1, 2, 3, 6, 11

IA 2 100,000 999,999 7, 10

IL 1 1,000 9,999 12

IN 3 100 99,999 9, 12, 14

KS 3 100 999 12

KY 3 10,000 999,999 1, 3, 6, 7, 9

LA 10 0 9,999,999 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13

MI 3 0 999,999 1, 5, 6, 10, 11, 13, 14

MO 3 1,000 99,999 10, 12

NE 1 100,000 999,999 9, 12

NY 2 100 99,999 10, 12

OH 6 1,000 9,999,999 9, 10, 12, 14

PA 1 1,000 9,999 12

SC 1 0 0 0

TN 2 10,000 99,999 1, 5, 6, 10, 13

TX 16 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14

UT 1 100,000 999,999 12

WI 3 0 999,999 6, 7, 12

aPost office state abbreviations used.

bAmounts on site reported by facilities in each state.

cActivities/Uses:

1. Produce

2. Import

3. Used Processing

4. Sale/Distribution

5. Byproduct

6. Reactant

7. Formulation Component

8. Article Component

9. Repackaging

10. Chemical Processing Aid

11. Manufacture Aid

12. Ancillary

13. Manufacture Impurity

14. Process Impurity

Source: TRI18 2020 (Data are from 2018)

5.2.2 Import/Export

Import and export data for chlorobenzene are not readily available. Estimates indicated that both imports 

and exports were negligible in the late 1970s and early 1980s (Hughes et al. 1983).

From 2002 to 2003, U.S. exports of chlorobenzene declined from 3.5 million to 1.5 million pounds

annually. Imports remained negligible during that time period (NLM 2020; Kirschner 2004).

Current data regarding import and export of chlorobenzene were not located.
CHLOROBENZENE 47

5. POTENTIAL FOR HUMAN EXPOSURE

5.2.3 Use

Historically, the primary uses of chlorobenzene were as a solvent for pesticide formulations, diisocyanate 

manufacture, degreasing automobile parts, and for the production of nitrochlorobenzene and diphenyl 

oxide. Solvent uses accounted for about 37% of chlorobenzene consumption in the United States in 1981, 

nitrochlorobenzene production for 33%, and diphenyl oxide and phenylphenol production for 16% of 

consumption. Chlorobenzene has also been used in silicone resin production and as an intermediate in the

synthesis of other halogenated organics, including DDT (Hughes et al. 1983). Recent data regarding 

chlorobenzene uses were not located.

5.2.4 Disposal

Because chlorobenzene is listed as a hazardous substance, disposal of waste chlorobenzene is controlled 

by a number of federal regulations. Spent solvent wastes, which may include chlorobenzene, are 

prohibited from land disposal, except under specific conditions. Land disposal restrictions (treatment 

standards) are proposed for other wastes containing chlorobenzene. Wastes containing chlorobenzene 

may be disposed of by liquid injection, rotary kiln, or fluidized bed incineration (EPA 1988, 1989). Since 

chlorobenzene is a volatile compound and is used extensively as a solvent, large quantities are released to 

the air. Some estimates indicate that 30–50% of the annual production of chlorobenzene is released to the 

atmosphere, while <0.1% is found in wastewater and <1% is disposed of on land (EPA 1985).

5.3 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ ≥10 full-time employees; if 

their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 1081, and 

1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the purpose of 

generating electricity for distribution in commerce), 4931 (limited to facilities that combust coal and/or 

oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to facilities that 

combust coal and/or oil for the purpose of generating electricity for distribution in commerce), 4953 

(limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 5169, 5171, and 

7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities primarily engaged in 

solvents recovery services on a contract or fee basis); and if their facility produces, imports, or processes 
CHLOROBENZENE 48

5. POTENTIAL FOR HUMAN EXPOSURE

≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI chemical in a calendar 

year (EPA 2005).

5.3.1 Air 

Estimated releases of 546,112 pounds (~248 metric tons) of chlorobenzene to the atmosphere from 

69 domestic manufacturing and processing facilities in 2018, accounted for about 77.94% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI18 2020). These releases are 

summarized in Table 5-2.

Table 5-2. Releases to the Environment from Facilities that Produce, Process, or 

Use Chlorobenzenea

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek On- and off-site

AL 1 10 0 0 0 0 10 0 10 

AR 4 780 0 0 14 76 780 90 870 

CA 1 324 0 0 0 0 324 0 324 

CO 1 32 0 0 0 0 32 0 32 

GA 1 61,167 0 0 4,564 0 61,167 4,564 65,731 

IL 1 1 0 0 13 0 1 13 14 

IN 3 164 0 0 580 0 164 580 744 

IA 2 800 0 0 0 0 800 0 800 

KS 3 1 0 0 0 0 1 0 1 

KY 3 533 9 0 0 0 542 0 542 

LA 10 206,072 250 130,000 241 207 336,322 448 336,770 

MI 3 930 25 0 9 0 955 9 964 

MO 3 281 0 0 0 643 281 643 924 

NE 1 10 0 0 12 0 10 12 22 

NY 2 65 1 0 0 0 65 1 67 

OH 6 236,342 360 0 5,683 0 236,452 5,932 242,384 

PA 1 64 0 0 0 0 64 0 64 

SC 1 0 0 0 0 0 0 0 0 

TN 2 422 74 0 20 0 516 0 516 

TX 16 30,170 42 9 11,638 85 41,544 400 41,944 

UT 1 3 0 0 0 0 3 0 3 
CHLOROBENZENE 49

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-2. Releases to the Environment from Facilities that Produce, Process, or 

Use Chlorobenzenea

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek On- and off-site

WI 3 7,942 0 0 0 0 7,942 0 7,942 

Total 69 546,112 762 130,009 22,773 1,011 687,974 12,694 700,668 

aThe 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. bData in TRI are maximum amounts released by each facility.

cPost office state abbreviations are used.

dNumber of reporting facilities.

eThe sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, wastewater treatment-(metals only), and publicly owned treatment works (POTWs) (metal 

and metal compounds).

gClass I wells, Class II-V wells, and underground injection. hResource Conservation and Recovery Act (RCRA) subtitle C landfills; other onsite 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. kTotal amount of chemical transferred off-site, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI18 2020 (Data are from 2018)

5.3.2 Water 

Estimated releases of 762 pounds (~0.35 metric tons) of chlorobenzene to surface water from 69 domestic 

manufacturing and processing facilities in 2018, accounted for about 0.11% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI18 2020). These releases are 

summarized in Table 5-2.

The principal source of chlorobenzene in water is release from chemical manufacturing facilities. Dow 

Chemical Company estimated that 0.1% of its annual production entered waters (EPA 1980b). EPA

(1979) found chlorobenzene in 6/63 industrial effluent in concentrations up to 100 μg/L. Based on 

1,338 samples collected from about 1980 to 1983, the medium concentration of chlorobenzene in waste 

effluent was <3 ppb and was detected in 54 samples. The total amount released to the environment was 

not reported (Staples et al. 1985). Chlorobenzene has been detected in both surface and groundwater 

samples at hazardous waste sites.
CHLOROBENZENE 50

5. POTENTIAL FOR HUMAN EXPOSURE

5.3.3 Soil 

Estimated releases of 22,773 pounds (~10.3 metric tons) of chlorobenzene to soil from 69 domestic 

manufacturing and processing facilities in 2018, accounted for about 0.03% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI18 2020). Estimated releases of 

130,009 pounds (~55 metric tons) of chlorobenzene via underground injection from 69 domestic 

manufacturing and processing facilities in 2018, accounted for about 18.56% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI18 2020). These releases are 

summarized in Table 5-2.

5.4 ENVIRONMENTAL FATE 

5.4.1 Transport and Partitioning 

The air, undoubtedly, plays a large role in the environmental transport and degradation of chlorobenzene, 

although studies addressing this aspect were not found. Chlorobenzene is volatile and has only moderate 

solubility in water (500 mg/L). Chlorobenzene was observed to evaporate (>99%) from an unaerated 

aqueous solution in 72 hours (Garrison and Hill 1972). Chlorobenzene is considered sufficiently volatile 

and toxic to pose inhalation risk via vapor intrusion from soil and groundwater (EPA 2018a).

5.4.2 Transformation and Degradation 

Under hypoxic conditions in groundwater, shifts in the bacterial community may occur as a result of 

syntrophic interactions rather than competitive interactions, facilitating the degradation of chlorobenzene 

(Kiesel et al. 2007). Syntrophy occurs when one organism lives off the product of another organism, 

rather than the organism itself.

Air. Physical constants for chlorobenzene, especially its vapor pressure and water solubility, indicate 

that the air is an important, and perhaps the dominant, medium for the transport and transformation of

chlorobenzene. As an aromatic molecule with strong ultraviolet-absorption, chlorobenzene has a half-life 

of 20–40 hours under simulated atmospheric conditions (Dilling et al. 1976). This appears to be

confirmed by the large difference between chlorobenzene measurements in urban air (3,000 ng/m3

[0.66 ppb]) and in rural air (not detected) in 1982 (EPA 1983).
CHLOROBENZENE 51

5. POTENTIAL FOR HUMAN EXPOSURE

Water. Biodegradation in a wastewater inoculum was studied by Tabak et al. (1981). Among 

57 environmental pollutants tested, chlorobenzene at 5 mg/L (5 ppm) was among the more rapidly 

biodegraded substances, with 89% degradation in a week and 100% after adaptation. Biodegradation is

therefore a major degradation process in oxygenated waters, while evaporation will play an additional 

role in surface waters.

Few data are available from the field, but evaporation, hydrolysis, and microbial degradation, in that 

order, are likely to be the major fates of chlorobenzene discharged to water.

Bioconcentration of chlorobenzene does not appear to be a significant process in aquatic environments. 

However, bioconcentration factors for chlorobenzene do increase somewhat in phytoplankton as 

temperature increases between 4.5 and 27.6°C (Koelmans and Sanchez 1994).

Oxygen appears to be required for the initial activation of chlorobenzene and the fission of the aromatic 

ring, although it can be partially replaced by nitrate (Nestler et al. 2007).

Metabolic dechlorination of chlorobenzenes seems to proceed fastest under methanogenic conditions 

(Adrian and Görisch 2002; Ramanand et al. 1993). While the negative changes in Gibbs free energy 

associated with all 20 possible dechlorination reactions of chlorobenzenes are large enough to be coupled 

to adenine triphosphate (ATP) generation, not all of those reactions have been observed in laboratory 

systems, and the extent to which any of them occurs in nature remains unknown (Adrian and Görisch 

2002).

The potential for anaerobic degradation has also been studied in contaminated groundwater plumes, 

where oxygen levels are generally lower than they are outside the plume. In a study of three North 

Central Florida landfills, Hallbourg et al. (1992) found that due to the high water table, anaerobic 

degradation predominated. In a contaminated aquifer in Bitterfeld, Germany, the decreases of 

chlorobenzene concentrations at the horizontal fringes of the plume and at shallower depths were 

accompanied by changes in isotopic composition (i.e., enrichment in 13C) that suggested the in situ

anaerobic degradation of chlorobenzene was occurring, albeit slowly (Kaschl et al. 2005). Since the 

known aerobic pathway initiated by dioxygenases in chlorobenzene-degrading strains (Ralstonia sp. DSM 

8910, Acidovorax facilis UFZ B517, Rhodococcus erythropolis UFZ B528, and Pseudomonas verinii

UFZ B547) did not result in isotopic fractionation, it was concluded that a novel anaerobic pathway 

resulting in isotopic fractionation was the predominant process of chlorobenzene degradation in this 
CHLOROBENZENE 52

5. POTENTIAL FOR HUMAN EXPOSURE

aquifer. Chlorobenzene contamination of this aquifer was the likely result of its proximity to a site where 

lindane had been formerly produced; chlorobenzene was measured at up to 30 ppm. The anaerobic 

microbial degradation of [13C6]-chlorobenzene was confirmed by Nijenhuis et al. (2007). In a constructed 

wetland designed to treat contaminated groundwater, Braeckevelt et al. (2007a) observed an isotope shift 

that was higher than expected for aerobic chlorobenzene degradation and concluded that an anaerobic 

degradation pathway must be making a significant contribution to the overall degradation. Natural 

attenuation of 13C-labeled chlorobenzene in this constructed wetland was indicated by: (1) detection of 

13C-labeled (i.e., reductively dechlorinated) benzene; (2) incorporation of chlorobenzene-derived 

radiolabel (

13C) into bacterial fatty acids; and (3) a systematic correlation between decreasing 

chlorobenzene concentration and significant enrichment in 13C with increasing distance from the source of 

contamination (Braeckevelt et al. 2007b).

Sediment and Soil. Biodegradation of chlorobenzene is rapid, leaving no detectable residues after 

1 or 2 weeks. Adaptation is also rapid (Tabak et al. 1981).

Evaporation and microbial degradation, in that order, are likely to be the major fates of chlorobenzene in 

soils. However, very few data are available from the field. Most relevant information comes from 

laboratory studies on amended soils and strains of soil bacteria isolated from contaminated water, soil, or 

sediments.

Under aerobic conditions, all 15 volatile and semivolatile organic compounds (including chlorobenzene) 

in a soil-applied mixture disappeared rapidly during a 7-day observation period due to abiotic factors 

(Anderson et al. 1991). Feidieker et al. (1995) documented the aerobic degradation of chlorobenzene 

with mixed bacterial cultures. Complete metabolism of chlorinated benzenes is not a feature that is 

generally found in aerobic bacteria. However, at chlorobenzene-contaminated sites, indigenous bacteria 

populations appear able to evolve the capacity for natural attenuation of chlorobenzene (Van der Meer et 

al. 1998). Pseudomonas putida MST that was previously isolated in the presence of α-methylstyrene was 

shown to regioselectively hydroxylate chlorobenzene to 3-chlorocatechol, and 2- and 4-chlorophenol to 

3- and 4-chlorocatechol, respectively (Bestetti et al. 1992). Inoculation of a soil slurry with Pseudomonas 

aeruginosa (105 microbes/g soil) led to rapid and complete degradation of 0.8 mM chlorobenzene within 

30 hours (Brunsbach and Reineke 1994). Indigenous soil microbes also degraded chlorobenzene, but the 

higher chlorobenzenes persisted.
CHLOROBENZENE 53

5. POTENTIAL FOR HUMAN EXPOSURE

Chlorobenzene contamination of soil stimulates the growth of indigenous, chlorobenzene metabolizing 

bacteria. The latter may even out-compete inoculated strains of Pseudomonas (Nishino et al. 1994).

In an in vitro study, Nowak et al. (1996) demonstrated the total reductive dechlorination of 

chlorobenzenes by a methanogenic culture enriched from Saale River sediment. Dechlorination of 

chlorobenzene to benzene was also observed in these cultures. However, the amount of benzene formed 

was extremely low and the reaction occurred only in the presence of higher chlorinated benzenes (Nowak 

et al. 1996). Presumably, this was a co-metabolic process (i.e., one in which the metabolism of 

chlorobenzene occurred without benefit to the organism), but was co-incident with the metabolism of the 

substrate on which the microbe actually depended for energy production. Such reactions are useful in 

bioremediation because they can proceed at concentrations far below those required to support the 

organism (Hazen 2009).

As previously documented in the field for pesticides and other contaminants, the residue of chlorobenzene 

in soil that is not volatilized or metabolized tends to bind more tightly to soil with time, a phenomenon 

known as “aging” (Sharer et al. 2003). As a result, degradation occurs at lower rates and to a lesser 

extent, even though chlorobenzene-degrading bacteria still have access to sorbed chlorobenzene in aged 

wetland soils (Lee et al. 2009).

The reductive dechlorination of chlorobenzenes in an anaerobic estuarine sediment followed first-order 

reaction kinetics, with rate constants ranging from 0.0016 to 0.0389 day-1 or half-lives between 17 and 

433 days (Kochany and Boltob 1992; Masunaga et al. 1996). From the detected intermediates, it was 

apparent that the removal of chlorine atoms occurred at all possible positions on the aromatic ring, but 

removal followed a thermodynamically favored order (i.e., a chlorine atom flanked on both sides by 

another > one of two adjacent chlorine atoms > a chlorine with no adjacent chlorine atoms) (e.g., the 

dechlorination of chlorobenzene) (Masunaga et al. 1996).

Other Media. No studies on the transformation or degradation of chlorobenzene in food or other 

media were located.

5.5 LEVELS IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to chlorobenzene depends, in part, on the 

reliability of supporting analytical data from environmental samples and biological specimens. 
CHLOROBENZENE 54

5. POTENTIAL FOR HUMAN EXPOSURE

Concentrations of chlorobenzene 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 chlorobenzene 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.

Table 5-3 shows the lowest limit of detections that are achieved by analytical analysis in environmental 

media. An overview summary of the range of concentrations detected in environmental media is 

presented in Table 5-4.

Table 5-3. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Air 0.47 ppt Krost et al. 1982

Drinking water 0.01 μg/L (ppb) NEMI 2019

Surface water and groundwater 0.003 μg/L (ppb) NEMI 2019

Soil 0.003 μg/L (ppb) NEMI 2019

Sediment 0.002 ng/mL (ppb) Wolska et al. 2003

Whole blood 0.011 ng/mL (ppb) CDC 2018

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.

Table 5-4. Summary of Environmental Levels of Chlorobenzene

Media Low High For more information

Outdoor air (ppbv) <0.05 0.50 Section 5.5.1

Surface water (ppb) <0.01 10 Section 5.5.2

Ground water (ppb) <1 <5 Section 5.5.2

Drinking water (ppb) No data Section 5.5.2

Food (ppb) <2 13 Section 5.5.4

Soil (ppb) <5 (median value) Section 5.5.3

Detections of chlorobenzene in air, water, and soil at NPL sites are summarized in Table 5-5.
CHLOROBENZENE 55

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-5. Chlorobenzene Levels in Water, Soil, and Air of National Priorities List 

(NPL) Sites

Medium Mediana

Geometric 

meana

Geometric 

standard 

deviationa

Number of 

quantitative 

measurements NPL sites

Water (ppb) 38 73.5 23.4 215 127

Soil (ppb) 1,550 1,780 84.9 92 64

Air (ppbv) 1.92 2.66 35.2 28 19

aConcentrations found in ATSDR site documents from 1981 to 2019 for 1,867 NPL sites (ATSDR 2019). Maximum 

concentrations were abstracted for types of environmental media for which exposure is likely. Pathways do not 

necessarily involve exposure or levels of concern.

5.5.1 Air 

Air samples at 56 localities in the United States in 1982 showed mean chlorobenzene concentrations of 

0.24 ppb (EPA 1983). The highest concentration measured concentrations were in urban and suburban 

areas; the median concentration in these areas were 0.33 ppb. Chlorobenzene was not detectable in rural 

and remote areas. The median concentration at the sites of production was 0.03 ppb. EPA (1981) 

measured average concentrations of chlorobenzene of 0.309, 0.240, and 0.290 ppb in Houston, Texas, St. 

Louis, Missouri, and Denver, Colorado, respectively, with a calculated residence time of 13 days. Data 

collected from three urban sites in New Jersey from 1981 to 1982 contained mean chlorobenzene 

concentrations of ranging from 0.07 to 0.22 ppb (Harkov et al. 1987). A study of New Jersey waste sites 

found similar air levels of chlorobenzene (mean values of 0.05–0.80 ppb) (Harkov et al. 1985). However, 

air levels found by another study performed for the EPA (1978) were an order of magnitude lower, with 

only the air over a waste site approaching the mean urban concentrations reported above. 

Ambient air outside homes of "Old Love Canal" (Niagara Falls, New York) contained chlorobenzene 

ranging from not detectable at four sites to traces at four sites and 120 ng/m3 (0.026 ppb) at one site 

(Barkley et al. 1980). Corresponding indoor air concentrations of chlorobenzene were not detected at six 

sites and ranged from 60–600 ng/m3 (0.0013–0.13 ppb) at the remaining three sites (Barkley et al. 1980). 

In an air sampling study in West Virginia (Cohen et al. 1989), chlorobenzene was not detected in outdoor 

air samples; however, corresponding indoor air concentrations of chlorobenzene were reported at mean, 

median, and maximum values of 16.5, 5.62, and 72.22 μg/m3

, respectively (3.62, 1.23, and 15.8 ppb), in 

63% of homes evaluated.
CHLOROBENZENE 56

5. POTENTIAL FOR HUMAN EXPOSURE

5.5.2 Water 

Historically, chlorobenzene was found in U.S. rivers at levels up to and exceeding 10 μg/L (10 ppb) (EPA 

1976; Sheldon and Hites 1978). Private wells near a hazardous waste site contained as much as 41 μg/L 

(41 ppb) (Clark et al. 1982) and tap water at Love Canal contained concentrations ranging from 10 to 

60 ng/L (0.01–0.06 ppb) (Barkley et al. 1980). Of 2,401 groundwater samples from domestic wells and 

1,096 samples from public wells in a survey in the United States, >90% of the chlorobenzene 

concentrations were <1 ppb and none were as high as 5 ppb (USGS 2006).

Chlorobenzene was not detected in thousands of surface water and groundwater samples collected across 

the United States from 2016 to 2020 (WQP 2020). The highest concentration of chlorobenzene in landfill 

leachate samples collected during this time period was 6.09 ppb (WQP 2020). Chlorobenzene was not 

found in the limited number of storm water samples reported (WQP 2020). 

A risk assessment on chlorobenzene for the marine environment (the North Sea area) was conducted in 

which “risk” was indicated by the ratio of predicted environmental concentration (PEC) to the predicted 

no-effect concentration (PNEC) (set to 32 μg/L [ppb]) for the marine aquatic environment (Van Wijk et 

al. 2004). Since monitoring data indicated that chlorobenzene in surface waters was below the detection 

limits of 0.1, 0.2, and 0.5 μg/L (ppb), the worst-case PEC was assumed to be 0.5 μg/L (ppb), yielding a 

PEC/PNEC of at least 60, without even taking into account dilution of chlorobenzene-containing surface 

waters in the sea. The authors concluded that chlorobenzene is not a toxic, persistent, or bioaccumulating 

substance, and that current use of the compound posed no unacceptable risk to the aquatic environment 

(Van Wijk et al. 2004).

5.5.3 Sediment and Soil 

Staples et al. (1985) reported that the median concentration of chlorobenzene in the United States was 

estimated to be <5 ppb dry sediments. In more than 3,000 sediment data points compiled from Storage 

and Retrieval (STORET) Data Warehouse and the National Water Information System (NWIS), 

chlorobenzene was not detected in over 82%, was reported at less than the detection limit in about 18%,

and was found above the detection limit in about 0.4% (WQP 2020).
CHLOROBENZENE 57

5. POTENTIAL FOR HUMAN EXPOSURE

5.5.4 Other Media 

A national survey of the United States indicated that chlorobenzene was below detection limits in milk 

supplies (Schaum et al. 2003). VOCs were analyzed in 70 food types over a 5-year period, of the 

41 types reported, chlorobenzene was identified in nine (cheddar cheese, chocolate cake with frosting, 

carbonated cola beverage, chocolate chip cookies, sour cream, French fries, cheese and pepperoni pizza, 

sugar cookies, cake doughnuts with icing) at concentrations ranging from 2 to 13 ppb (Fleming-Jones and 

Smith 2003). 

5.6 GENERAL POPULATION EXPOSURE 

Chlorobenzene was found in 96% of human adipose tissue samples from all regions of the United States 

at levels ranging from 1 to 9 ng/g (EPA 1986). At Love Canal, Niagara Falls, chlorobenzene was 

detected in the breath of one of nine people evaluated for exposure and in the urine of six of nine persons 

at concentrations ranging from 20 to 120 ng/L (Barkley et al. 1980).

Personal sampling at chemical companies (NIOSH 1981) indicated that chlorobenzene levels, measured 

at up to 4 ppm in workplace air did not exceed the American Conference of Governmental Industrial 

Hygienists (ACGIH) and Occupational Safety and Health Administration (OSHA) permissible limit of 

75 ppm.

According to the results of the National Health and Nutrition Examination Survey (NHANES), 

chlorobenzene was undetectable in blood samples of every age group, gender, race, and ethnicity studied 

in the survey years between 2003 and 2016 (CDC 2019). The detection limit was 0.011 ng/mL.

Vapor intrusion may also be a potential source of chlorobenzene exposure, as vapor intrusion has been 

observed for several VOCs with similar properties. EPA’s compilation of six studies of background 

indoor air concentrations found a 0–8% detection rate for chlorobenzene in 1,050 U.S. resident samples 

between 1997 and 2004 (EPA 2011). The background medians ranged from <0.01 to <0.92 μg/m3 and 

the maximum values ranged from 0.04 to 9.7 μg/m3

. ATSDR extracted environmental data from 

135 ATSDR reports evaluating the vapor intrusion pathway at 121 sites published between 1994 and 

2009 (Burk and Zarus 2013). The levels of chlorobenzene did not exceed comparisons values 

(concentrations used by ATSDR to identify contaminants requiring further evaluation).
CHLOROBENZENE 58

5. POTENTIAL FOR HUMAN EXPOSURE

Chlorobenzene in water is expected to volatilize; thus, there is potential for inhalation exposure during 

showering and bathing. ATSDR’s three-compartment Shower and Household-Use Exposure (SHOWER) 

model predicts air concentrations in the shower stall, bathroom, and main house throughout the day by 

estimating the contribution from showering or bathing and the contribution from other water sources in 

the house, such as the dishwasher, clothes washer, and faucets. This information, along with human 

activity patterns, is used to calculate a daily time-weighted average exposure concentration via inhalation 

exposure and from dermal uptake from skin contact. ATSDR’s SHOWER model is available by sending 

a request to showermodel@cdc.gov. 

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Occupational settings provide the greatest potential for high exposures to chlorobenzene. Data from the 

National Occupational Exposure Survey (NOES), conducted by the National Institute for Occupational 

Safety and Health (NIOSH) from 1980 to 1983, indicated that 18,050 workers, including 3,881 women, in 

912 plants spanning 35 occupations were potentially exposed to chlorobenzene in the workplace (NIOSH 

2018a). Since chlorobenzene is a volatile compound and is used extensively as a solvent, large quantities 

may be released to the workplace air. Other populations that might be exposed include persons living 

near industrial facilities where chlorobenzene emissions are not properly controlled.
CHLOROBENZENE 59

CHAPTER 6. 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 chlorobenzene 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 adverse health effects (and techniques for developing methods to 

determine such health effects) of chlorobenzene.

Data needs are defined as substance-specific informational needs that, if met, would reduce the 

uncertainties of human health risk 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. 

6.1 Information on Health Effects

Studies evaluating the health effects of inhalation, oral, and dermal exposure of humans and animals to 

chlorobenzene that are discussed in Chapter 2 are summarized in Figure 6-1. The purpose of this figure is 

to illustrate the information concerning the health effects of chlorobenzene. The number of human and 

animal studies examining each endpoint is indicated regardless of whether an effect was found and the 

quality of the study or studies. 

6.2 Identification of Data Needs 

Missing information in Figure 6-1 should not 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 (ATSDR 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.
CHLOROBENZENE 60

6. ADEQUACY OF THE DATABASE

Figure 6-1. Summary of Existing Health Effects Studies on Chlorobenzene By 

Route and Endpoint* 

Potential body weight, liver, and kidney effects were the most studied endpoints 

The majority of the studies examined inhalation or oral exposure in animals; limited data were identified 

for humans (counts represent studies examining endpoint)

*Includes studies discussed in Chapter 2; many studies examined more than 

one endpoint. The number of studies include those finding no effect. No 

dermal studies in humans or animals were located.
CHLOROBENZENE 61

6. ADEQUACY OF THE DATABASE

Acute-Duration MRLs. No information is available on the health effects of acute-duration exposure of 

humans to chlorobenzene by any route of exposure. Limited studies that evaluated the health effects of 

acute-duration inhalation or oral exposure to chlorobenzene found adverse effects only at exposure levels

that also caused lethality (Monsanto Co. 1977; NTP 1985; Rozenbaum et al. 1947; Shell Oil Co. 1991). 

Since data on health effects in humans are not available and animal data are mostly limited to lethality, 

data are not sufficient to derive acute-duration MRLs. Further studies would be useful to identify target 

tissues and threshold levels for health effects that may exist.

Intermediate-Duration MRLs. No studies are available in humans on the health effects of 

intermediate-duration exposure to chlorobenzene by any route. Available animal studies identify the 

nervous system, liver, and kidneys as targets of chlorobenzene toxicity. Oral data were considered 

adequate to derive an intermediate-duration oral MRL for chlorobenzene. Additional animal studies 

could be designed to provide useful information to serve as the basis for deriving an intermediate-duration 

inhalation MRL for chlorobenzene.

Chronic-Duration MRLs. Limited studies are available on the health effects in humans chronically 

exposed to chlorobenzene via inhalation and suggest that the nervous system is a target tissue. Specific 

exposure data were not provided. No information is available on effects of chlorobenzene in humans 

following chronic oral exposure. No information is available regarding health effects of chlorobenzene in 

animals following chronic-duration inhalation exposure. One 2-year oral toxicity and carcinogenicity 

study of rats gavaged with chlorobenzene at 60 or 120 mg/kg/day reported decreased survival and 

increased incidences of neoplastic liver lesions at 120 mg/kg/day in the absence of other signs of 

exposure-related adverse effects (NTP 1985). There were no signs of adverse effects in mice similarly 

treated at 30 or 60 mg/kg/day (males) or 60 or 120 mg/kg/day (females) (NTP 1985). No nonlethal or

nonneoplastic effects were observed in rats or mice following chronic-duration oral exposures at doses 

resulting in adverse nonneoplastic effects in animals following intermediate-duration exposures. Results 

from intermediate-duration oral exposure to chlorobenzene indicate that dogs are more sensitive than rats 

or mice to chlorobenzene-induced adverse liver and kidney effects. The absence of chronic-duration oral 

data for dogs precludes derivation of a chronic-duration oral MRL for chlorobenzene. A well-designed 

chronic-duration oral study in dogs could potentially serve as the basis for deriving a chronic-duration 

oral MRL for chlorobenzene.
CHLOROBENZENE 62

6. ADEQUACY OF THE DATABASE

Health Effects. 

Hematological Effects. No data were located regarding the potential for chlorobenzeneinduced renal effects in humans. Limited animal data are available. One study reported 

concentration-related effects on RBC parameters (primarily an increase in reticulocyte count) in 

rats and rabbits repeatedly exposed to chlorobenzene by inhalation (NIOSH 1977). Slight 

leukopenia and lymphocytosis were reported in mice repeatedly exposed by inhalation; however, 

limited details were included in the study report (Zub 1978). Additional studies could be 

designed to evaluate hematological effects in animals exposed to chlorobenzene.

Hepatic Effects. Available information regarding the potential for chlorobenzene-induced 

hepatic effects in humans is limited to a single case report (Babany et al. 1991; Reygagne et al. 

1992). The liver was identified as a target of chlorobenzene toxicity in laboratory animals 

following inhalation or oral exposure (Monsanto Co. 1967a, 1967b; Nair et al. 1987; NTP 1985). 

No further animal studies are considered necessary.

Renal Effects. No data were located regarding the potential for chlorobenzene-induced renal 

effects in humans. The kidney was identified as a target of chlorobenzene toxicity in laboratory 

animals following inhalation or oral exposure (Monsanto Co. 1967a; Nair et al. 1987; NTP 1985). 

No further animal studies are considered necessary.

Immunotoxicity. No data were located regarding the potential immunotoxicity of 

chlorobenzene in humans. Histological examination of organs and tissues of the immunological 

system in orally-treated rats and mice resulted in some evidence for the immunotoxicity of 

chlorobenzene (NTP 1985). Immune function tests would provide a better assessment of 

potential immunotoxic effects.

Neurotoxicity. Limited data in humans indicate that exposure to chlorobenzene via inhalation 

and oral exposures can result in effects on the nervous system. Results from one acute-duration 

(30-minute exposure) inhalation study of rats and guinea pigs demonstrate the neurotoxicity of 

inhaled chlorobenzene at very high concentrations (≥2,990 ppm) (Shell Oil Co. 1991). Oral 

studies in animals could be designed to evaluate the potential neurotoxicity of chlorobenzene by 

this exposure route. However, it is not likely that oral exposure to chlorobenzene would cause 

neurological effects at environmentally-relevant exposure levels.
CHLOROBENZENE 63

6. ADEQUACY OF THE DATABASE

Reproductive Toxicity. No studies were located regarding the potential reproductive toxicity 

of chlorobenzene in humans. In a 2-generation oral toxicity study of rats (Nair et al. 1987), 

chlorobenzene gavage exposure of parental males for 18–20 weeks at 450 mg/kg/day resulted in 

increased incidence of testicular germinal epithelial degeneration, but no evidence of impaired 

reproductive function. There was no evidence of adverse reproductive effects among 

chlorobenzene-treated parental females of either generation at doses as high as 450 mg/kg/day. 

Additional animal studies (including another animal species) could provide additional 

information regarding the potential for chlorobenzene-induced reproductive effects.

Developmental Toxicity. No data were located regarding the potential developmental toxicity 

of chlorobenzene in humans. Chlorobenzene did not affect the developing fetus following 

inhalation exposure of rats or rabbits (John et al. 1984) or oral exposure of rats (Monsanto Co. 

1977). Additional studies, particularly in other species, could provide useful information for 

evaluating the potential of chlorobenzene to induce developmental effects in humans.

Cancer. No studies were found in humans regarding the carcinogenicity of chlorobenzene.

Epidemiological studies would be useful to assess potential risk to people who may be 

occupationally exposed to chlorobenzene or people who live near hazardous waste sites where 

chlorobenzene may be present. There was no evidence for carcinogenicity in male or female

mice or in female rats following oral exposure to chlorobenzene. However, an increased 

incidence of neoplastic liver nodules was observed in male rats. Based on available information 

from animal carcinogenicity studies and genotoxicity evaluations, EPA (IRIS 2003) assigned 

chlorobenzene to group D (not classifiable as to human carcinogenicity). An additional animal 

study could be designed to further assess the potential carcinogenicity of chlorobenzene. 

Although available human and animal data have not provided convincing evidence regarding the 

carcinogenicity of chlorobenzene, additional mechanistic studies should be designed to evaluate 

possible genotoxic mechanisms of carcinogenicity because chlorobenzene metabolism results in 

the formation of epoxides that can react with DNA, RNA, and proteins. Any in vitro assays 

should be performed using human microsomes due to interspecies differences in chlorobenzene 

metabolism.

Epidemiology and Human Dosimetry Studies. No epidemiological studies have been conducted 

to evaluate the adverse health effects of chlorobenzene. Existing studies are limited to case reports of
CHLOROBENZENE 64

6. ADEQUACY OF THE DATABASE

occupational exposures in which the nervous system was identified as a target tissue following chronic 

inhalation of chlorobenzene. Reliable exposure data were not reported. Additional studies that provide 

quantitative exposure data would be useful in evaluating potential noncancer and cancer risk in humans 

exposed to chlorobenzene.

Biomarkers of Exposure and Effect. Parent chlorobenzene and metabolites can be detected in 

biological tissues and fluids. However, existing methods may not be useful for evaluating the general 

population as opposed to industrial situations where preexposure levels are established prior to known 

chlorobenzene exposure. The overall reliability of these biomarkers are further reduced since data are not

available on the half-life of chlorobenzene in various biological media.

Central nervous system injury is a common effect associated with exposure to chlorobenzene vapor in 

humans. Studies in animals suggest that chlorobenzene can also result in damage to the liver and kidneys. 

Since similar effects occur with exposure to other chemicals, additional studies are needed to identify 

more specific biomarkers by which to monitor populations living near hazardous waste sites.

Absorption, Distribution, Metabolism, and Excretion. The toxicokinetics of chlorobenzene have 

not been evaluated to any great extent in humans. Limited studies suggest that chlorobenzene can be

absorbed following inhalation and oral exposures, but no data were located regarding absorption 

following dermal exposure. Based on absorption characteristics of benzene and the high lipid solubility 

of chlorobenzene, absorption may be significant depending on conditions. Additional studies are needed 

to determine absorption rates following exposure by all routes.

Data are also sparse on the distribution of chlorobenzene. No information is available regarding 

distribution of chlorobenzene in humans by inhalation, oral, or dermal exposure. Limited animal data 

suggest preferential distribution to adipose tissue in rats via inhalation. The kidneys and liver also 

showed significant amounts of chlorobenzene and rats that received multiple doses exhibited higher tissue 

burdens than rats exposed only once.

The metabolic transformation of chlorobenzene has been evaluated in humans and animals. Principal 

metabolites have been determined, but quantities and ratios differ among species. Additional studies 

would be useful to determine if these differences affect the toxicity of chlorobenzene.
CHLOROBENZENE 65

6. ADEQUACY OF THE DATABASE

There are limited data on the excretion of chlorobenzene. In humans exposed via the inhalation and oral 

routes, chlorobenzene and its metabolites were detected in urine and there were differences in excretion 

patterns via the two routes. Chlorobenzene and its metabolites were also detected in exhaled air of rats 

following inhalation and in exhaled air and urine of rabbits after oral exposure. The urinary metabolite 

profile appeared to be dose dependent and there were changes in excretion patterns due to multiple versus 

single exposures. No data on excretion following dermal exposure are available. Additional studies 

would be useful in determining the significance of these differences with regard to risk associated with

different routes of exposure.

Comparative Toxicokinetics. Although existing studies regarding toxicokinetics of chlorobenzene in 

humans are limited, available data provide some understanding of the absorption, metabolism, and 

excretion following inhalation and oral exposures. Since studies on distribution of chlorobenzene are 

lacking, quantitative data correlating human exposure and tissue accumulation would be useful. In 

animals, quantitative data on absorption, distribution, metabolism, and excretion are very limited in extent 

and quality. Additional studies using a variety of species and including PBPK modeling would be useful 

in determining the most suitable animal model for assessing human risk.

Children’s Susceptibility. No data were located to suggest age-related differences in susceptibility to 

chlorobenzene toxicity. Studies are needed to assess the susceptibility of children to chlorobenzene 

toxicity and to evaluate potential differences in sensitive endpoints. 

Physical and Chemical Properties. Physical and chemical properties of chlorobenzene have been 

adequately evaluated.

Production, Import/Export, Use, Release, and Disposal. Data indicate that chlorobenzene 

production has declined dramatically over the past two decades, but current quantitative data on use 

(especially solvent uses) and disposal practices would be helpful in evaluating the effect of current 

industrial practices on environmental levels of chlorobenzene.

Environmental Fate. Information on biodegradation in soil under aerobic conditions exists, but 

degradation products were not identified. Anaerobic biodegradation, as might occur in river bottoms and 

in Superfund sites, has not been studied and would be valuable. Emissions from waste lagoons have been 

modelled and measured in bench-top experiments and are measured as part of many Superfund Remedial

Investigation/Feasibility studies, but those were not located.
CHLOROBENZENE 66

6. ADEQUACY OF THE DATABASE

Bioavailability from Environmental Media. Chlorobenzene is absorbed primarily following 

inhalation of contaminated air. There is also some potential for exposure from water and soil. 

Chlorobenzene has been detected at low levels in surface water, groundwater, drinking water, and food. 

Since chlorobenzene binds tightly to soil particles, skin contact with, or ingestion of, contaminated soil 

may be an important source of exposure, particularly in children living near hazardous waste sites. 

Additional studies would be useful to determine if soil-bound chlorobenzene is bioavailable. There is 

also potential for inhalation exposure via vapor intrusion from soil and groundwater and during 

showering.

Food Chain Bioaccumulation. No information is available regarding biomagnification within 

aquatic or terrestrial food chains. Additional studies would be useful in assessing potential for human 

exposure to chlorobenzene.

Exposure Levels in Environmental Media. There are studies on concentrations of chlorobenzene 

in air and water, but many of the samples measured had low levels or did not have detectable levels. 

Additional studies using more sensitive analytical methods would be useful for measuring low levels of 

chlorobenzene in environmental media.

Exposure Levels in Humans. Chlorobenzene can be measured in blood, urine, and exhaled air. A 

survey of the general population (NHANES) did not find detectable levels of chlorobenzene in blood 

samples. Chlorobenzene is used in various occupational settings; however, there are limited 

biomonitoring data of populations potentially exposed to high levels of chlorobenzene. Additional 

studies are needed to evaluate occupational populations. 

Exposures of Children. No data were located to suggest age-related differences in potential exposure 

to children. Studies are needed to evaluate potential exposure risks that are unique to children. 

Analytical Methods. As noted previously, many environmental samples have undetectable levels of 

chlorobenzene. Additional studies to evaluate analytical methods with lower detection limits would be 

useful. 
CHLOROBENZENE 67

6. ADEQUACY OF THE DATABASE

6.3 Ongoing Studies 

No ongoing studies were identified in the National Institutes of Health (NIH) RePORTER (2020) 

database. 
CHLOROBENZENE 68

CHAPTER 7. REGULATIONS AND GUIDELINES

Pertinent international and national regulations, advisories, and guidelines regarding chlorobenzene in air, 

water, and other media are summarized in Table 7-1. This table is not an exhaustive list, and current 

regulations should be verified by referring to the appropriate regulatory agency.

ATSDR develops MRLs, which are substance-specific guidelines intended to serve as screening levels by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. See Section 1.3 and Appendix A for detailed information on 

the MRLs for chlorobenzene.

Table 7-1. Regulations and Guidelines Applicable to Chlorobenzene

Agency Description Information Reference

Air

EPA RfC Not evaluated IRIS 2003

Provisional Peer Reviewed Toxicity Value EPA 2006

Provisional chronic RfC 5x10-2 mg/m3 (0.01 ppm)

Provisional subchronic RfC 5x10-1 mg/m3 (0.1 ppm)

WHO Air quality guidelines Not listed WHO 2010

Water & Food

EPA Drinking water standards and health 

advisories 

EPA 2018b

1-Day health advisory (10-kg child) 4 mg/L

10-Day health advisory (10-kg child) 4 mg/L

DWEL 0.7 mg/L

Lifetime health advisory 0.1 mg/L

10-4 Cancer risk No data

National primary drinking water regulations EPA 2009

MCL 0.1 mg/L

PHG 0.1 mg/L

RfD 2x10-2 mg/kg/day EPA 2018b; IRIS 

2003

Provisional Peer Reviewed Toxicity Value EPA 2006

Provisional subchronic RfD 7x10-2 mg/kg/day

WHO Drinking water quality guidelines Guideline value not 

established

WHO 2017

FDA Substances Added to Fooda Not listed FDA 2020

Allowable level in bottled water 0.1 mg/L FDA 2017
CHLOROBENZENE 69

7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Chlorobenzene

Agency Description Information Reference

Cancer

HHS Carcinogenicity classification No data NTP 2016

EPA Carcinogenicity classification Db IRIS 2003

IARC Carcinogenicity classification No data IARC 2020

Occupational

OSHA PEL (8-hour TWA) for general industry, 

shipyards and construction

75 ppm (350 mg/m3) OSHA 2019a, 

2019b, 2019c

NIOSH REL (up to 10-hour TWA) No datac NIOSH 2019

IDLH 1,000 ppm NIOSH 1994

Emergency Criteria

EPA AEGLs-air EPA 2018c

AEGL 1d

10-minute 10 ppm

30-minute 10 ppm

60-minute 10 ppm

4-hour 10 ppm

8-hour 10 ppm

AEGL 2d

10-minute 430 ppm

30-minute 300 ppm

60-minute 150 ppm

4-hour 150 ppm

8-hour 150 ppm

AEGL 3d

10-minute 1,100 ppm

30-minute 800 ppm

60-minute 400 ppm

4-hour 400 ppm

8-hour 400 ppm

DOE PACs-air DOE 2018a

PAC-1e 10 ppm

PAC-2e 150 ppm

PAC-3e 400 ppm

bThe Substances Added to Food inventory replaces EAFUS and contains the following types of ingredients: food and 

color additives listed in FDA regulations, flavoring substances evaluated by FEMA or JECFA, GRAS substances 

listed in FDA regulations, substances approved for specific uses in food prior to September 6, 1958, substances that 

are listed in FDA regulations as prohibited in food, delisted color additives, and some substances "no longer FEMA 

GRAS."

bGroup D: not classifiable as to human carcinogenicity.

cAfter reviewing available published literature, NIOSH provided comments to OSHA on August 1, 1988, regarding

the "Proposed Rule on Air Contaminants" (29 CFR 1910, Docket No. H-020). In these comments, NIOSH 

questioned whether proposed PELs for certain chemicals including chlorobenzene (TWA 75 ppm) were adequate to 

protect workers from recognized health hazards (NIOSH 2018b).
CHLOROBENZENE 70

7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Chlorobenzene

Agency Description Information Reference

dDefinitions of AEGL terminology are available from U.S. Environmental Protection Agency (EPA 2018d). eDefinitions of PAC terminology are available from U.S. Department of Energy (DOE 2018b).

AEGL = acute exposure guideline levels; 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; FDA = Food and Drug Administration; FEMA = Flavor and Extract 

Manufacturers Association of the United States; GRAS = generally recognized as safe; HHS = Department of Health 

and Human Services; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or 

health concentrations; IRIS = Integrated Risk Information System; JECFA = Joint FAO/WHO Expert Committee on 

Food Additives; MCL = maximum contaminant level; NIOSH = National Institute for Occupational Safety and Health; 

NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; PAC = protective 

action criteria; PEL = permissible exposure limit; PHG = public health goal; REL = recommended exposure limit; 

RfC = inhalation reference concentration; RfD = oral reference dose; TWA = time-weighted average; WHO = World 

Health Organization
CHLOROBENZENE 71

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International. 489. 

SRI. 1986. Directory of chemical producers: United States of America. Menlo Park, CA: SRI 

International. 549. 

SRI. 1987. Directory of chemical producers: United States of America. Menlo Park, CA: SRI 

International. 532-533. 

SRI. 1988. Directory of chemical producers: United States of America. Menlo Park, CA: SRI 

International. 526. 

Staples CA, Werner AF, Hoogheem TJ. 1985. Assessment of priority pollutant concentrations in the 

United States using STORET database. Environ Toxicol Chem 4(2):131-142. 

http://doi.org/10.1002/etc.5620040202. 

Sullivan TM, Born CS, Carlson GP, et al. 1983. The pharmacokinetics of inhaled chlorobenzene in the 

rat. Toxicol Appl Pharmacol 71(2):194-203. http://doi.org/10.1016/0041-008x(83)90336-8. 

Tabak HH, Quave SA, Mashni CI, et al. 1981. Biodegradability studies with organic priority pollutant 

compounds. Water Pollut Control 53:1503-1518. 

Thrall KD, Woodstock AD, Kania MR. 2004. Development of a physiologically based pharmacokinetic 

model for chlorobenzene in F-344 rats. J Toxicol Environ Health 67(7):525-536. 

http://doi.org/10.1080/15287390490425731. 

TRI18. 2020. TRI explorer: Providing access to EPA’s toxics release inventory data. Washington, DC: 

U.S. Environmental Protection Agency. http://www.epa.gov/triexplorer/. May 21, 2020. 

USGS. 2006. The quality of our nation’s waters-volatile organic compounds in the nation’s ground 

water and drinking-water supply wells. Reston, VA: U.S. Geological Survey. Circular 1292. 

https://pubs.usgs.gov/circ/circ1292/pdf/circular1292.pdf. July 21, 2020. 

USITC. 1988. Synthetic organic chemicals: United States production and sales, 1987. Washington, DC: 

U.S. International Trade Commission. USITC Publication 2118. 

Vaghef H, Hellman B. 1995. Demonstration of chlorobenzene-induced DNA damage in mouse 

lymphocytes using the single cell gel electrophoresis assay. Toxicology 96(1):19-28. 

http://doi.org/10.1016/0300-483x(94)02910-m. 

van der Meer JR, Werlen C, Nishino SF, et al. 1998. Evolution of a pathway for chlorobenzene 

metabolism leads to natural attenuation in contaminated groundwater. Appl Environ Microbiol 

64(11):4185-4193. http://doi.org/10.1128/AEM.64.11.4185-4193.1998. 

Van Wijk D, Thompson RS, De Rooij C, et al. 2004. Monochlorobenzene marine risk assessment with 

special reference to the Osparcom Region: North Sea. Environ Monit Assess 97(1-3):69-86. 

http://doi.org/10.1023/B:EMAS.0000033042.01768.3f. 

Verschueren K. 1983. Chlorobenzene. In: Handbook of environmental data on organic chemicals. 2nd

ed. New York, NY: Van Nostrand Reinhold Company, 356-359, 712-717. 

Von Burg H. 1981. Toxicology updates - chlorobenzene. J Appl Toxicol 1(1):50-51. 
CHLOROBENZENE 80

8. REFERENCES

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Press, Inc., C-109, C-114. 

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Organization. http://www.euro.who.int/__data/assets/pdf_file/0009/128169/e94535.pdf. April 25, 

2012. 

WHO. 2017. Guidelines for drinking-water quality. Fourth edition incorporating the first addendum. 

Geneva, Switzerland: World Health Organization. 

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2017. 

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chlorobenzenes in sediments. J Chromatogr Sci 41(2):53-56. 

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https://www.waterqualitydata.us/portal/#characteristicName=Chlorobenzene&mimeType=csv. May 

28, 2020. 

Yoshida M, Sunaga M, Hara I. 1986. Urinary metabolite levels in workers exposed to chlorobenzene. 

Ind Health 24:255-258. http://doi.org/10.2486/indhealth.24.255. 

Zeneca Specialties. 1982. Eye irritation classification on monochlorobenzene in rabbits with cover letter 

dated 05/06/94. Zeneca Specialties. Submitted to the U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS0557374. 86940000964. 

https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0557374.xhtml. May 28, 2020. 

Zub M. 1978. Reactivity of the white blood cell system to toxic action of benzene and its derivatives. 

Acta Biol Crac 21:163-174. 
CHLOROBENZENE A-1

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS

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 route and duration of exposure. MRLs are based on

noncancer health effects only; cancer effects are not considered. 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 NOAEL/uncertainty factor approach. They are 

below levels that might cause adverse health effects in the people most sensitive to such chemicalinduced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic 

(≥365 days) 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 substance-induced endpoint 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 

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.
CHLOROBENZENE A-2

APPENDIX A

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Office of Innovation and Analytics, Toxicology Section, 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 MRLs. For additional information regarding MRLs, please contact the Office of Innovation 

and Analytics, Toxicology Section, Agency for Toxic Substances and Disease Registry, 1600 Clifton 

Road NE, Mailstop S102-1, Atlanta, Georgia 30329-4027.
CHLOROBENZENE A-3

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Chlorobenzene

CAS Numbers: 108-90-7

Date: October 2020

Profile Status: Final

Route: Inhalation

Duration: Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL.

Rationale for Not Deriving an MRL: Available information regarding adverse effects following acuteduration inhalation exposure to chlorobenzene is limited to evaluations of lethality (Rozenbaum et al. 

1947), developmental toxicity studies of rats and rabbits in which no adverse effects were observed at 

exposure concentrations as high as 590 ppm (John et al. 1984), and a study that evaluated effects of a 

single 30-minute exposure at 2,990–7,970 ppm (Shell Oil Co. 1991).

Agency Contacts (Chemical Managers): Breanna Alman, MPH
CHLOROBENZENE A-4

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Chlorobenzene

CAS Numbers: 108-90-7

Date: October 2020

Profile Status: Final

Route: Inhalation

Duration: Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL.

Rationale for Not Deriving an MRL: Available information regarding the effects of intermediateduration inhalation exposure to chlorobenzene is limited. Chlorobenzene exposure-related liver effects 

(increased liver weight and increased incidence of hepatocellular hypertrophy) and kidney effects (renal 

lesions including chronic interstitial nephritis and foci of regenerative epithelium) were reported for two 

generations of parental male (but not female) rats repeatedly exposed to chlorobenzene vapor at 150 ppm 

(NOAEL of 50 ppm) for 18–20 weeks (Nair et al. 1987). NIOSH (1977) reported significantly increased 

relative liver and kidney weights 31 and 13%, respectively, greater than controls) among rats (but not 

rabbits) repeatedly exposed to chlorobenzene vapor for up to 24 weeks at 250 ppm; however, there were 

no increased incidences of exposure-related histopathological liver or kidney lesions. Similar exposure of 

rabbits resulted in no significant changes in liver or kidney weight and no evidence of exposure-related 

increased incidence of histopathological liver or kidney lesions. No effects on liver or kidney were noted 

among dogs repeatedly exposed to chlorobenzene vapor at concentrations as high as 453.2 ppm for up to 

6 months (Monsanto Co. 1980). No data were located to support the findings of liver and kidney effects 

in the 2-generation study of rats (Nair et al. 1987) at exposure levels as low as 150 ppm. No intermediateduration inhalation MRL was derived for chlorobenzene because intermediate-duration inhalation studies 

of rats and rabbits (NIOSH 1977) and dogs (Monsanto Co. 1980) did not identify effects on liver or 

kidney at exposure levels approximately 2–3 times higher than the LOAEL of 150 ppm for parental male 

rats of the 2-generation study (Nair et al. 1987).

Agency Contacts (Chemical Managers): Breanna Alman, MPH
CHLOROBENZENE A-5

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Chlorobenzene

CAS Numbers: 108-90-7

Date: October 2020

Profile Status: Final

Route: Inhalation

Duration: Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL.

Rationale for Not Deriving an MRL: No exposure-response human or animal data are available for the 

chronic-duration inhalation exposure to chlorobenzene.

Agency Contacts (Chemical Managers): Breanna Alman, MPH
CHLOROBENZENE A-6

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Chlorobenzene

CAS Numbers: 108-90-7

Date: October 2020

Profile Status: Final

Route: Oral

Duration: Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL.

Rationale for Not Deriving an MRL: Limited studies that evaluated the effects of acute-duration oral 

exposure to chlorobenzene found adverse effects only at doses that also caused lethality (Monsanto Co. 

1977; NTP 1985).

Agency Contacts (Chemical Managers): Breanna Alman, MPH
CHLOROBENZENE A-7

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Chlorobenzene

CAS Numbers: 108-90-7

Date: October 2020

Profile Status: Final

Route: Oral

Duration: Intermediate

MRL 0.07 mg/kg/day

Critical Effect: Hepatic effect; bile duct hyperplasia

Reference: Monsanto Co. 1967a

Point of Departure: BMDL10 of 9.59 mg/kg (BMDLADJ of 6.85 mg/kg/day)

Uncertainty Factor: 100

LSE Graph Key: 9

Species: Dog

MRL Summary: An intermediate-duration oral MRL of 0.07 mg/kg/day was derived for chlorobenzene 

based on dose-related hepatic changes (bile duct hyperplasia) in dogs treated orally (via capsule) with 

chlorobenzene 5 days/week for 13 weeks (Monsanto Co. 1967a). The MRL is based on a BMDL10 of 

9.59 mg/kg, which was adjusted to continuous duration exposure to a BMDLADJ of 6.85 mg/kg/day and 

divided by a total uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for 

human variability). 1967a

Selection of the Critical Effect: There are no intermediate-duration oral studies in humans. Several 

intermediate-duration oral studies are available for rats or mice treated with chlorobenzene by gavage 

(Monsanto Co. 1967b; NTP 1985) or dogs treated via capsule (Monsanto Co. 1967a). NOAELs and 

LOAELs identified in these studies are summarized in Table A-1. The effects observed at the lowest 

LOAEL (55 mg/kg/day for liver and kidney effects in dogs) were considered to represent the critical 

effects for deriving an intermediate-duration oral MRL for chlorobenzene.

Table A-1. Intermediate-Duration Oral NOAELs and LOAELs for Chlorobenzene

Species 

(dosing)

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Body weight

Rat (GO, 

5 days/week)

125 250 12% lower mean final body weight in 

males

NTP 1985

Mouse (GO, 

5 days/week)

125 250 15–20% lower mean final body weight NTP 1985

Dog (C, 

5 days/week)

55 280 Emaciation, weight loss at lethal dose Monsanto 

Co.1967a

Rat (GO, 

7 days/week)

250 Monsanto Co. 

1967b

Hematological

Dog (C, 

5 days/week)

55 280 Low hemogram, increased numbers of 

immature WBCs

Monsanto Co.

1967a

Rat (GO, 

7 days/week)

250 Monsanto Co. 

1967b
CHLOROBENZENE A-8

APPENDIX A

Table A-1. Intermediate-Duration Oral NOAELs and LOAELs for Chlorobenzene

Species 

(dosing)

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Hepatic

Dog (C, 

5 days/week)

28 55 22% increased liver weight, bile duct 

hyperplasia (2/4 males)

Monsanto Co.

1967a

Rat (GO, 

5 days/week)

60 125 19% increased liver weight in females 

(LOAEL of 250 mg/kg in males) 

NTP 1985

Mouse (GO, 

5 days/week)

60 125 14% increased liver weight in males

250 Hepatic necrosis/degeneration in NTP 1985

males and females

Rat (GO, 

7 days/week)

100 250 27–29% increased mean relative liver 

weight

Monsanto Co. 

1967b

Renal

Rat (GO) 100 250 13–14% increased kidney weight Monsanto Co. 

1967b

Mouse (GO, 

5 days/week)

125 250 Renal necrosis/degeneration NTP 1985

Dog (C, 

5 days/week)

55 280 Increased kidney weight; tubule 

dilatation, vacuolation, epithelial 

degeneration

Monsanto Co.

1967a

Rat (GO, 

5 days/week)

250 500 13–15% increased kidney weight NTP 1985

Immunological

Mouse (GO, 

5 days/week)

125 250 Lymphoid depletion/necrosis in thymus 

and spleen; myeloid depletion in bone 

marrow in males; lymphoid 

depletion/necrosis in spleen in females

NTP 1985

Rat (GO, 

5 days/week)

500 750 Myeloid depletion in bone marrow, 

lymphoid depletion in spleen 

NTP 1985

C = capsule administration; GO = gavage in oil; LOAEL = lowest-observed-adverse-effect-level; NOAEL = noobserved-adverse-effect level; WBC = white blood cell

Selection of the Principal Study: The study of Monsanto Co. (1967a) was selected as the principal study 

for deriving an intermediate-duration oral MRL for chlorobenzene because it identified the lowest 

LOAEL of 55 mg/kg/day for increases in liver and kidney weight and increased incidences of 

histopathologic liver and kidney lesions in chlorobenzene-treated dogs (see Table A-1).

Summary of the Principal Study: 

Monsanto Co. 1967a. 13-Week oral administration- dogs. Monochlorobenzene final report. Monsanto 

Company. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS0200587. 877800212. 8DHQ10780212. 

Groups of beagle dogs (4/sex/group) were treated with chlorobenzene orally (in capsule) at 0, 0.025, 0.05, 

or 0.25 mL/kg/day (0, 28, 55, and 280 mg/kg/day, respectively, based on a density of 1.1058 g/mL for 

chlorobenzene), 5 days/week for 13 weeks. Dogs were monitored for survival, clinical signs, food intake, 
CHLOROBENZENE A-9

APPENDIX A

and body weight. At study initiation and 1 and 3 months, blood was collected for clinical chemistry and 

hematology and urine was collected for urinalysis. At death or terminal sacrifice, all animals were 

subjected to gross pathological examination; organ or tissues weighed included heart, liver, spleen, 

kidneys, testes, thyroid, and adrenals. Selected tissues were processed for histopathologic examination.

All dogs in control, 28, and 55 mg/kg/day groups survived to terminal sacrifice. Four of eight dogs dosed 

at 280 mg/kg/day died or were sacrificed moribund (between weeks 3 and 5). Decedents exhibited 

decreased appetite, decreased activity, anorexia, and body weight loss. There were no clear signs of 

exposure-related body weight effects at 28 and 55 mg/kg/day dose levels. Other effects observed at 

280 mg/kg/day included liver and kidney effects (56–77% increased mean relative liver weight, 62–87% 

increased mean relative kidney weight, increased incidences of pathologic liver and kidney lesions), 

increased adrenal weight, alterations in selected hematological parameters (low hemogram, increased 

numbers of immature WBCs), increases in selected serum chemistry parameters (low blood sugar; 

increased alkaline phosphatase, ALT, total bilirubin, and total cholesterol), increased urinary acetone and 

bilirubin, and death. The small numbers of animals (4/sex/group) limit the power to determine dose 

levels resulting in statistically significant changes in liver and kidney lesion incidences. However, as 

shown in Table A-2, the high-dose level (280 mg/kg/day) is an adverse effect level for liver effects in 

males (87% increased mean relative liver weight and centrilobular degeneration and bile duct hyperplasia 

in 4/4 high-dose males; no incidences in controls) and females (62% increased mean relative liver weight 

and centrilobular degeneration in 3/4 high-dose females; no incidences in controls). Bile duct hyperplasia 

was noted in 2/4 male dogs and 1/4 female dogs in the 55 mg/kg/day dose group (4/4 males and 

3/4 females in the 280 mg/kg/day dose group, compared to no incidences among control or 28 mg/kg/day 

groups of males or females). The incidences of bile duct hyperplasia in the 55 mg/kg/day group of male 

dogs is considered to represent a LOAEL for chlorobenzene-induced liver effects. Furthermore, after 

combining sexes, the bile duct hyperplasia exhibited a dose-response characteristic (incidences of 3/8 and 

7/8 at 55 and 280 mg/kg/day, respectively). The 28 mg/kg/day dose level is considered a NOAEL for 

liver effects and the 280 mg/kg/day dose level is considered a serious LOAEL for multiple degenerative 

liver effects (e.g., centrilobular degeneration, vacuolation, bile duct hyperplasia). As shown in Table A-3, 

the 280 mg/kg/day dose level represents a LOAEL for increased incidences of kidney lesions (e.g., 

significantly increased incidences of tubule dilatation, vacuolation, epithelial degeneration in combined 

sexes). The smaller number and nature of the reported histopathologic kidney lesions at the low- and 

mid-dose levels (28 and 55 mg/kg/day) and/or lack of dose-response characteristics suggest that the middose (55 mg/kg/day) represents a NOAEL for kidney effects.

Table A-2. Liver Lesion Incidences in Male and Female Dogs Administered

Chlorobenzene in Capsules 5 days/week for 13 Weeksa

Effect

Chlorobenzene dose (mg/kg)

0 28 55 280

Male Female Male Female Male Female Male Female

Parenchymal 

irregularity

3/4 

(1)

2/4 

(1)

3/4

(1)

Chronic hepatitis 1/4 

(1)

Portal fibrosis 1/4 

(1)

1/4 

(1)

Stromal infiltration 1/4 

(1)

2/4 

(1)

1/4 

(1)
CHLOROBENZENE A-10

APPENDIX A

Table A-2. Liver Lesion Incidences in Male and Female Dogs Administered

Chlorobenzene in Capsules 5 days/week for 13 Weeksa

Effect

Chlorobenzene dose (mg/kg)

0 28 55 280

Male Female Male Female Male Female Male Female

Focal leukocyte 

infiltration

2/4 

(1)

1/4 

(1)

Pigment deposition 1/4 

(1)

1/4 

(1)

2/4 

(1–2)

Extramedullary 

blood production

1/4 

(1)

1/4 

(1)

Centrilobular 

degeneration

4/4b

(3)

4/4b 

(1–3)

Vacuolation 1/4 

(1)

3/4 

(2–4)

3/4 

(1–3)

Bile duct 

hyperplasia

2/4

(1)

1/4 

(1)

4/4b

(+/0–4)

3/4 

(1)

Cytologic changes 1/4 

(1)

2/4 

(2–3)

2/4 

(1–2)

Cloudy swelling 2/4 

(1–3)

1/4 

(1)

Cholangitis 1/4 

(2)

1/4 

(1)

Bile stasis 2/4 

(1–3)

2/4 

(3)

aNumbers in parentheses denote relative severity of lesion (4 represents highest degree of severity).

bSignificantly different from control incidence (p<0.05).

Source: Monsanto Co. 1967a

Table A-3. Kidney Lesion Incidences in Male and Female Dogs Administered 

Chlorobenzene in Capsules 5 days/week for 13 Weeksa

Effect

Chlorobenzene dose (mg/kg)

0 28 55 280

Male Female Male Female Male Female Male Female

Pelvic epithelial 

irregularity

1/4 

(2)

2/4 

(1–2)

Terminal proximal tubule 

swelling

3/4 

(2)

3/4

(1–3)

3/4

(3)

1/4

(3)

1/4

(1)

Terminal proximal tubule 

vacuolation

1/4 

(1)

2/4 

(4)
CHLOROBENZENE A-11

APPENDIX A

Table A-3. Kidney Lesion Incidences in Male and Female Dogs Administered 

Chlorobenzene in Capsules 5 days/week for 13 Weeksa

Effect

Chlorobenzene dose (mg/kg)

0 28 55 280

Male Female Male Female Male Female Male Female

Tubule dilatation 1/4

(1)

1/4

(1)

2/4 

(1–2)

2/4 

(2)

Tubule epithelial 

degeneration

1/4 

(1)

1/4 

(2)

3/4 

(1–3)

Proximal convoluted 

tubule swelling

1/4 

(1)

1/4 

(1)

Proximal convoluted 

tubule vacuolation

1/4

(1)

1/4 

(1)

3/4 

(2–3)

Glomerular swelling 1/4 

(2)

Glomerulosclerosis 1/4 

(1)

1/4 

(1)

4/4 

(1)

1/4 

(1)

3/4 

(1)

1/4 

(1)

Chronic pyelitis 2/4

(2–3)

1/4 

(1)

1/4 

(2)

Intraluminal foreign 

matter

1/4 

(1)

Epithelial pigment 

deposition

2/4 

(2–3)

1/4 

(+/0)

aNumbers in parentheses denote relative severity of lesion (4 represents highest degree of severity).

Source: Monsanto Co. 1967a

Selection of the Point of Departure: Among available rat, mouse, and dog studies that employed 

intermediate-duration oral exposure, the lowest LOAEL is 55 mg/kg/day for liver effects in the dogs; the 

corresponding NOAEL is 28 mg/kg/day. Because the study employed only four dogs/sex/group, results 

for each sex were combined for each reported liver lesion type. The dataset for bile duct hyperplasia for 

combined sexes (see Table A-4) was considered adequate for benchmark dose (BMD) analysis. The data 

were fit to all available dichotomous models in EPA’s Benchmark Dose Software (BMDS, version 3.12) 

using the extra risk option. A benchmark response (BMR) of 10% over the control incidence was used. 

Adequate model fit was judged by four criteria: goodness-of-fit statistics (p-value >0.1), scaled residual at 

the data point (except the control) closest to the predefined BMR, BMDL that is not 10 times lower than 

the lowest non-zero dose, and visual inspection of the dose-response curve.

Table A-4. Dataset for Benchmark Dose Analysis of Bile Duct Hyperplasia 

Incidences in Male and Female Dogs Administered Chlorobenzene in 

Capsule for 13 Weeksa

Chlorobenzene dose (mg/kg/day)

Control 28 55 280

Males 0/4 0/4 2/4 (1) 4/4b

Females 0/4 0/4 1/4 (1) 3/4 (1)
CHLOROBENZENE A-12

APPENDIX A

Table A-4. Dataset for Benchmark Dose Analysis of Bile Duct Hyperplasia 

Incidences in Male and Female Dogs Administered Chlorobenzene in 

Capsule for 13 Weeksa

Chlorobenzene dose (mg/kg/day)

Control 28 55 280

Males and females (combined) 0/8 0/8 3/8 (1) 7/8b (+/0–4)

aNumbers in parentheses denote relative severity of lesion (4 represents highest degree of severity). bSignificantly different from control incidence (p<0.05).

Source: Monsanto Co. 1967a

The model predictions are presented in Table A-5. Among all models providing adequate fit to the data, 

the lowest BMDL (Multistage 1-degree model) was selected as the point of departure because the 

difference between the BMDLs estimated from these models was >3-fold.

Table A-5. Results from BMD Analysis of Bile Duct Hyperplasia Incidence in Male 

and Female Dogs Administered Chlorobenzene in Capsule 

5 Days/Week for 13 Weeks (Monsanto Co. 1967a)

Model

BMD10

(mg/kg)

BMDL10

(mg/kg) p-Valuea AIC

Scaled residualsb

Dose near 

BMD

Control 

group

Dichotomous Hill 47.04 20.44 0.959 22.62 3.00x10-3 -3.49x10-4

Gammac 29.15 10.37 0.182 25.05 -9.13x10-1 -3.49x10-4

Log-Logisticd 31.35 11.08 0.507 22.57 -8.40x10-1 -3.49x10-4

Multistage Degree 3e 23.07 9.96 0.165 25.43 -1.05 -3.49x10-4

Multistage Degree 2e 23.07 9.96 0.165 25.43 -1.05 -3.55x10-4

Multistage Degree 1e,f 16.41 9.59 0.593 21.81 -1.26 -3.49x10-4

Weibullc 26.73 10.20 0.176 25.20 -9.73x10-1 -3.71x10-4

Logistic 54.72 30.85 0.118 25.77 1.61 -7.80x10-1

Log-Probit 32.93 12.70 0.523 22.41 -7.74x10-1 -3.49x10-4

Probit 52.18 31.71 0.123 25.55 1.64 -7.21x10-1

aValues <0.1 fail to meet adequate fit

bScaled residuals for dose group near the BMD and for the control dose group cPower restricted to ≥1.

dSlope restricted to ≥1.

eBetas restricted to ≥0.

f

Recommended model. All models provided adequate fit to the data. BMDLs for models providing adequate fit were 

not sufficiently close (differed by >3-fold). Therefore, the model with lowest BMDL was selected (1-degree 

Multistage).

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure dose associated with the 

selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denote benchmark 

response: i.e., 10 = exposure dose associated with a 10% relative deviation from control)
CHLOROBENZENE A-13

APPENDIX A

BMD modeling was also conducted on selected kidney lesion data (tubule dilatation, tubule epithelial 

degeneration, and proximal convoluted tubule vacuolation) for combined sexes (see Table A-6) because 

they exhibited some evidence of dose-response characteristics and statistically significantly increased 

incidences for these lesions were observed at the highest dose (280 mg/kg/day). Each dataset was fit to 

all available dichotomous models in EPA’s BMDS (version 3.1.2) using the BMD approach described for 

the liver lesion data above.

Table A-6. Dataset for Benchmark Dose Analysis of Selected Kidney Lesion in 

Male and Female Dogs Administered Chlorobenzene in Capsule in 13 Weeks

Chlorobenzene dose (mg/kg)

Control 28 55 280

Tubule dilatation

Males 0/4 0/4 1/4 2/4

Females 0/4 0/4 1/4 2/4

Males and females combined 0/8 0/8 2/8 4/8a

Tubule epithelial degeneration

Males 0/4 0/4 1/4 1/4

Females 0/4 0/4 0/4 3/4

Males and females combined 0/8 0/8 1/8 4/8a

Proximal convoluted tubule vacuolation

Males 0/4 0/4 0/4 1/4

Females 0/4 0/4 1/4 3/4

Males and females combined 0/8 0/8 1/8 4/8a

aSignificantly different from control incidence (p<0.05).

All models provided adequate fit to each dataset for kidney lesions. The model results for tubule 

dilatation are presented in Table A-7. Most models provided adequate fit to the incidence data. The 

estimated BMDLs varied by greater than 3-fold, thus, the model with the lowest BMDL was selected 

(Log-Logistic model). The model for tubule dilatation estimated a BMD10 of 37.71 mg/kg and BMDL10

of 14.07 mg/kg. The incidence data for proximal convoluted tubule vacuolation and tubule epithelial 

degeneration were the same. The results of the BMD modeling for these two endpoints are presented in 

Table A-8. All models provided adequate fit and the Log-Probit model was selected because it had the 

lowest BMDL value. This model estimated a BMD10 of 61.67 mg/kg and BMDL10 of 13.99 mg/kg.
CHLOROBENZENE A-14

APPENDIX A

Table A-7. Results from BMD Analysis of Renal Tubule Dilatation Incidence in 

Male and Female Dogs Administered Chlorobenzene in Capsule 5 Days/Week 

for 13 Weeks (Monsanto Co. 1967a)

Model

BMD10a

(mg/kg)

BMDL10a

(mg/kg) p-Valueb AIC

Scaled residualsc

Dose near 

BMD

Control 

group

Dichotomous Hill 48.55 16.15 0.999 24.09 3.92x10-3 -3.49x10-4

Gammad 38.94 21.00 0.682 24.03 -7.93x10-1 -3.49x10-4

Log-Logistice,f 37.71 14.07 0.511 25.91 -7.94x10-1 -3.49x10-4

Multistage Degree 3g 38.94 21.00 0.682 24.03 -7.93x10-1 -3.49x10-4

Multistage Degree 2g 38.94 21.00 0.682 24.03 -7.93x10-1 -3.49x10-4

Multistage Degree 1g 38.94 21.00 0.682 24.03 -7.93x10-1 -3.49x10-4

Weibulld 38.94 21.00 0.682 24.03 -7.93x10-1 -3.49x10-4

Logistic 104.66 63.17 0.190 27.86 1.48 -6.94x10-1

Log-Probit 0.531 25.77 -7.40x10-1 -3.49x10-4

Probit 95.50 58.90 0.199 27.70 1.47 -6.54x10-1

aBMD and BMDL values for models that do not provide adequate are not included in this table. bValues <0.1 fail to meet adequate fit. cScaled residuals for dose group near the BMD and for the control dose group. dPower restricted to ≥1. eSlope restricted to ≥1.

f

Recommended model. BMDLs for models providing adequate fit were not sufficiently close (differed by >3-fold). 

Therefore, the model with lowest BMDL was selected (Log-Logistic).

gBetas restricted to ≥0.

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure dose associated with the 

selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denote benchmark 

response: i.e., 10 = exposure dose associated with a 10% relative deviation from control)
CHLOROBENZENE A-15

APPENDIX A

Table A-8. Results from BMD Analysis of Renal Proximal Tubule Vacuolation and 

Tubule Epithelial Degeneration Incidences in Male and Female Dogs 

Administered Chlorobenzene in Capsule 5 Days/Week for 13 Weeks (Monsanto 

Co. 1967a)

Model

BMD10a

(mg/kg)

BMDL10a

(mg/kg) p-Valueb AIC

Scaled residualsc

Dose near 

BMD

Control 

group

Dichotomous Hill 53.67 20.27 1.000 21.12 8.67x10-4 -3.49x10-4

Gammad 65.97 25.36 0.480 23.83 4.88x10-1 -3.55x10-4

Log-Logistice 63.81 19.73 0.497 23.80 4.51x10-1 -3.56x10-4

Multistage Degree 3f 67.37 25.06 0.461 23.94 4.74x10-1 -3.52x10-4

Multistage Degree 2f 67.37 25.06 0.762 21.94 4.74x10-1 -3.49x10-4

Multistage Degree 1f 47.59 24.41 0.904 20.17 9.19x10-2 -3.49x10-4

Weibulld 66.14 25.28 0.476 23.86 4.80x10-1 -3.49x10-4

Logistic 127.20 75.54 0.497 22.78 9.37x10-1 -4.60x10-1

Log-Probitg 61.67 13.99 0.534 23.68 4.23x10-1 -8.93x10-3

Probit 114.82 69.29 0.522 22.65 9.10x10-1 -4.21x10-1

aBMD and BMDL values for models that do not provide adequate are not included in this table. bValues <0.1 fail to meet adequate fit. cScaled residuals for dose group near the BMD and for the control dose group. dPower restricted to ≥1.

eSlope restricted to ≥1.

f

Betas restricted to ≥0.

gRecommended model. BMDLs for models providing adequate fit were not sufficiently close (differed by >3-fold). 

Therefore, the model with lowest BMDL was selected (Log-Probit).

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure dose associated with the 

selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denote benchmark 

response: i.e., 10 = exposure dose associated with a 10% relative deviation from control)

A comparison of the BMD values for the liver and kidney endpoint was made:

• BMD10 of 16.41 mg/kg for bile duct hyperplasia (BMDL10 of 9.59 mg/kg),

• BMD10 of 37.71 mg/kg for renal tubular dilation (BMDL10 of 14.07 mg/kg), and 

• BMD10 of 61.67 mg/kg for proximal convoluted tubule vacuolation and tubule epithelial 

degeneration (BMDL10 of 13.99 mg/kg)

The bile duct hyperplasia had the lowest BMD10 and was selected as the critical effect. The BMDL10 of 

9.59 mg/kg for this endpoint was selected as the POD for the MRL. This BMDL10 was estimated using 

the 1-degree Multistage model, which is presented in Figure A-1. 
CHLOROBENZENE A-16

APPENDIX A

Figure A-1. Fit of 1-Degree Multistage Model for Bile Duct Hyperplasia in Male 

and Female Dogs Administered Chlorobenzene 5 Days/Week for 13 Weeks 

(Monsanto Co. 1967a) 

Intermittent Exposure: The BMDL10 of 9.59 mg/kg/day was adjusted for intermittent exposure 

(5 days/7 days) resulting in adjusted value of 6.85 mg/kg/day.

BMDLADJ = 9.59 mg/kg x (5 days/7 days) = 6.85 mg/kg/day

Uncertainty Factor: The BMDLADJ was divided by a total uncertainty factor (UF) of 100:

• 10 for extrapolation from animals to humans

• 10 for human variability

MRL = BMDLADJ ÷ UFs

6.85 mg/kg/day ÷ (10 x 10) = 0.0685 mg/kg/day≈0.07 mg/kg/day

Other Additional Studies or Pertinent Information that Lend Support: As shown in Table A-1, liver 

and kidney effects were observed in rats and mice treated orally with chlorobenzene for intermediateduration periods (Monsanto Co. 1967b; NTP 1985).

Agency Contacts (Chemical Managers): Breanna Alman, MPH

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 50 100 150 200 250

Response

Dose (mg/kg)

Estimated Probability

Response at BMD

Linear Extrapolation

Data

BMD

BMDL
CHLOROBENZENE A-17

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Chlorobenzene

CAS Numbers: 108-90-7

Date: October 2020

Profile Status: Final

Route: Oral

Duration: Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL.

Rationale for Not Deriving an MRL: One 2-year oral toxicity and carcinogenicity study of rats gavaged

with chlorobenzene at 60 or 120 mg/kg/day reported decreased survival and increased incidences of 

neoplastic liver lesions at 120 mg/kg/day in the absence of other signs of exposure-related adverse effects 

(NTP 1985). There were no signs of adverse effects in mice similarly treated at 30 or 60 mg/kg/day 

(males) or 60 or 120 mg/kg/day (females) (NTP 1985). No nonlethal and nonneoplastic effects were 

observed in the rats or mice following chronic-duration oral exposures at doses resulting in adverse 

nonneoplastic effects in animals following intermediate-duration exposures. Therefore, no chronicduration oral MRL was derived for chlorobenzene.

Agency Contacts (Chemical Managers): Breanna Alman, MPH
CHLOROBENZENE B-1

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR 

CHLOROBENZENE

The objective of the toxicological profile is to evaluate the potential for human exposure and the potential 

health hazards associated with inhalation, oral, or dermal/ocular exposure to chlorobenzene. 

B.1 LITERATURE SEARCH AND SCREEN 

A literature search and screen was conducted to identify studies examining health effects, toxicokinetics, 

mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical 

properties, production, use, environmental fate, environmental releases, and environmental and biological 

monitoring data for chlorobenzene. ATSDR primarily focused on peer-reviewed articles without 

publication date or language restrictions. Non-peer-reviewed studies that were considered relevant to the 

assessment of the health effects of chlorobenzene have undergone peer review by at least three ATSDRselected experts who have been screened for conflict of interest. The inclusion criteria used to identify 

relevant studies examining the health effects of chlorobenzene are presented in Table B-1.

Table B-1. Inclusion Criteria for the Literature Search and Screen

Health Effects

Species

Human

Laboratory mammals

Route of exposure

Inhalation

Oral

Dermal (or ocular)

Parenteral (these studies will be considered supporting data)

Health outcome

Death

Systemic effects

Body weight effects 

Respiratory effects

Cardiovascular effects

Gastrointestinal effects

Hematological effects

Musculoskeletal effects

Hepatic effects

Renal effects

Dermal effects

Ocular effects

Endocrine effects

Immunological effects

Neurological effects

Reproductive effects

Developmental effects
CHLOROBENZENE B-2

APPENDIX B

Table B-1. Inclusion Criteria for the Literature Search and Screen

Other noncancer effects

Cancer

Toxicokinetics

Absorption

Distribution

Metabolism

Excretion

PBPK models

Biomarkers

Biomarkers of exposure

Biomarkers of effect

Interactions with other chemicals

Potential for human exposure

Releases to the environment

Air

Water

Soil

Environmental fate

Transport and partitioning

Transformation and degradation

Environmental monitoring

Air

Water

Sediment and soil

Other media

Biomonitoring

General populations

Occupation populations

B.1.1 Literature Search

The current literature search was intended to update the draft toxicological profile for chlorobenzene

released for public comment in 2019; thus, the literature search was restricted to studies published 

between April 2016 and April 2020. The following main databases were searched in April 2020:

• PubMed 

• National Technical Reports Library (NTRL)

• Scientific and Technical Information Network’s TOXCENTER

The search strategy used the chemical names, Chemical Abstracts Service (CAS) numbers, 

synonyms, Medical Subject Headings (MeSH) headings, and keywords for chlorobenzene. The 

query strings used for the literature search are presented in Table B-2. 
CHLOROBENZENE B-3

APPENDIX B

The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS), 

NTP website, and National Institute of Health Research Portfolio Online Reporting Tools Expenditures 

and Results (NIH RePORTER) databases using the queries presented in Table B-3. Additional databases 

were searched in the creation of various tables and figures, such as the TRI Explorer, the Substance 

Priority List (SPL) resource page, and other items as needed. Regulations applicable to chlorobenzene 

were identified by searching international and U.S. agency websites and documents.

Review articles were identified and used for the purpose of providing background information and 

identifying additional references. ATSDR also identified reports from the grey literature, which included 

unpublished research reports, technical reports from government agencies, conference proceedings and 

abstracts, and theses and dissertations. 

Table B-2. Database Query Strings

Database

search date Query string

PubMed

04/2020 ((108-90-7[rn] OR "chlorobenzene"[nm]) OR (("Benzene chloride"[tw] OR "Benzene, 

chloro-"[tw] OR "Chlorbenzene"[tw] OR "Chlorbenzol"[tw] OR "Chlorobenzene"[tw] OR 

"Chlorobenzene, mono-"[tw] OR "Chlorobenzine"[tw] OR "Chlorobenzol"[tw] OR "I P 

Carrier T 40"[tw] OR "IP Carrier T 40"[tw] OR "Monochlorbenzene"[tw] OR 

"Monochlorobenzene"[tw] OR "Monochlorobenzenes"[tw] OR "Phenyl chloride"[tw] OR 

"Tetrosin SP"[tw]) AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] OR chlorobenzenes/ai OR 

ci[sh] OR bl[sh] OR cf[sh] OR ur[sh] OR "pharmacology"[sh:noexp] OR "environmental 

exposure"[mh] OR "endocrine system"[mh] OR "hormones, hormone substitutes, and 

hormone antagonists"[mh] OR "endocrine disruptors"[mh] OR "Computational biology"[mh] 

OR "Medical Informatics"[mh] OR Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR 

Proteome[mh] OR Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene 

expression"[mh] OR Phenotype[mh] OR genetics[mh] OR genotype[mh] OR 

Transcriptome[mh] OR ("Systems Biology"[mh] AND ("Environmental Exposure"[mh] OR 

"Epidemiological Monitoring"[mh] OR analysis[sh])) OR "Transcription, Genetic "[mh] OR 

"Reverse transcription"[mh] OR "Transcriptional activation"[mh] OR "Transcription 

factors"[mh] OR ("biosynthesis"[sh] AND (RNA[mh] OR DNA[mh])) OR "RNA, 

Messenger"[mh] OR "RNA, Transfer"[mh] OR "peptide biosynthesis"[mh] OR "protein 

biosynthesis"[mh] OR "Reverse Transcriptase Polymerase Chain Reaction"[mh] OR "Base 

Sequence"[mh] OR "Trans-activators"[mh] OR "Gene Expression Profiling"[mh] OR 

cancer[sb] OR toxicokinetics[mh:noexp] OR (me[sh] AND ("humans"[mh] OR 

"animals"[mh])))) OR (("Benzene chloride"[tw] OR "Benzene, chloro-"[tw] OR 

"Chlorbenzene"[tw] OR "Chlorbenzol"[tw] OR "Chlorobenzene"[tw] OR "Chlorobenzene, 

mono-"[tw] OR "Chlorobenzine"[tw] OR "Chlorobenzol"[tw] OR "I P Carrier T 40"[tw] OR "IP 

Carrier T 40"[tw] OR "Monochlorbenzene"[tw] OR "Monochlorobenzene"[tw] OR 

"Monochlorobenzenes"[tw] OR "Phenyl chloride"[tw] OR "Tetrosin SP"[tw]) NOT 

medline[sb])) AND (2017/04/01:3000[mhda] OR 2017/04/01:3000[crdt] OR 

2017/04/01:3000[edat] OR 2016/04/01:3000[dp])

NTRL

04/2020 "Benzene chloride" OR "Benzene, chloro-" OR "Chlorbenzene" OR "Chlorbenzol" OR 

"Chlorobenzene" OR "Chlorobenzene, mono-" OR "Chlorobenzine" OR "Chlorobenzol" OR 

"I P Carrier T 40" OR "IP Carrier T 40" OR "Monochlorbenzene" OR "Monochlorobenzene" 

OR "Monochlorobenzenes" OR "Phenyl chloride" OR "Tetrosin SP"

Toxcenter

04/2020 FILE 'TOXCENTER' ENTERED AT 09:15:35 ON 29 APR 2020

L1 9299 SEA FILE=TOXCENTER 108-90-7 
CHLOROBENZENE B-4

APPENDIX B

Table B-2. Database Query Strings

Database

search date Query string

L2 7919 SEA FILE=TOXCENTER L1 NOT PATENT/DT 

L3 510 SEA FILE=TOXCENTER L2 AND ED>=20170401 

L4 717 SEA FILE=TOXCENTER L2 AND PY>2015 

L5 741 SEA FILE=TOXCENTER L3 OR L4 

 ACT TOXQUERY/Q

 ---------

L6 QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR 

 BIOMARKER? OR NEUROLOG?) 

L7 QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR 

EPIDEMIOLOGY/ST,CT,

 IT) 

L8 QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR 

 LC(W)50) 

L9 QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT 

L10 QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?) 

L11 QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?) 

L12 QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS 

OR 

 DIETARY OR DRINKING(W)WATER?) 

L13 QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR 

PERMISSIBLE))

L14 QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?) 

L15 QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? 

OR 

 OVUM?) 

L16 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?) 

L17 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR 

 TERATOGEN?) 

L18 QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR 

SPERMAS? OR 

 SPERMATOB? OR SPERMATOC? OR SPERMATOG?) 

L19 QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR 

SPERMATOX? OR 

 SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?) 

L20 QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR 

DEVELOPMENTAL?) 

L21 QUE (ENDOCRIN? AND DISRUPT?) 

L22 QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR 

INFANT?) 

L23 QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?)

L24 QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?) 

L25 QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? 

OR 

 NEOPLAS?) 

L26 QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR 

CARCINOM?)

L27 QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR 

GENETIC(W)TOXIC?) 

L28 QUE (NEPHROTOX? OR HEPATOTOX?) 
CHLOROBENZENE B-5

APPENDIX B

Table B-2. Database Query Strings

Database

search date Query string

L29 QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?) 

L30 QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?) 

L31 QUE L6 OR L7 OR L8 OR L9 OR L10 OR L11 OR L12 OR L13 OR L14 OR 

 L15 OR L16 OR L17 OR L18 OR L19 OR L20 OR L21 OR L22 OR L23 OR 

 L24 OR L25 OR L26 OR L27 OR L28 OR L29 OR L30 

L32 QUE (RAT OR RATS OR MOUSE OR MICE OR GUINEA(W)PIG? OR 

MURIDAE 

 OR DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR 

SWINE 

 OR PORCINE OR MONKEY? OR MACAQUE?) 

L33 QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR 

LAGOMORPHA 

 OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE) 

L34 QUE L31 OR L32 OR L33 

L35 QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL? 

OR 

 PRIMATES OR PRIMATE?) 

L36 QUE L34 OR L35 

 ---------

L37 242 SEA FILE=TOXCENTER L5 AND L36 

L38 7 SEA FILE=TOXCENTER L37 AND MEDLINE/FS 

L39 235 SEA FILE=TOXCENTER L37 NOT MEDLINE/FS 

L40 236 DUP REM L38 L39 (6 DUPLICATES REMOVED)

 ANSWERS '1-236' FROM FILE TOXCENTER

L*** DEL 7 S L37 AND MEDLINE/FS

L*** DEL 7 S L37 AND MEDLINE/FS

L41 7 SEA FILE=TOXCENTER L40 

L*** DEL 235 S L37 NOT MEDLINE/FS

L*** DEL 235 S L37 NOT MEDLINE/FS

L42 229 SEA FILE=TOXCENTER L40 

L43 229 SEA FILE=TOXCENTER (L41 OR L42) NOT MEDLINE/FS 

 D SCAN L43

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

TSCATS via 

ChemView

04/2020 Compounds searched: 108-90-7

NTP

04/2020 108-90-7

"Benzene chloride" "Chlorobenzene" "Monochlorobenzene" "Phenyl chloride" 

"Benzene, chloro-" "Chlorbenzene" "Chlorbenzol" "Chlorobenzene, mono-" 

"Chlorobenzine" "Chlorobenzol" "I P Carrier T 40" "IP Carrier T 40" 

"Monochlorbenzene" "Monochlorobenzenes" "Tetrosin SP"

NIH RePORTER

05/2020 Search Criteria: Text Search: "Benzene chloride" OR "Benzene, chloro-" OR 

"Chlorbenzene" OR "Chlorbenzol" OR "Chlorobenzene" OR "Chlorobenzene, mono-" 
CHLOROBENZENE B-6

APPENDIX B

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

OR "Chlorobenzine" OR "Chlorobenzol" OR "I P Carrier T 40" OR "IP Carrier T 40" OR 

"Monochlorbenzene" OR "Monochlorobenzene" OR "Monochlorobenzenes" OR 

"Phenyl chloride" OR "Tetrosin SP" (Advanced), Search in: Projects AdminIC: All, 

Fiscal Year: Active Projects

Other Identified throughout the assessment process

The 2020 results were: 

• Number of records identified from PubMed, NTRL, and TOXCENTER (after duplicate 

removal): 486

• Number of records identified from other strategies: 38

• Total number of records to undergo literature screening: 524

B.1.2 Literature Screening

A two-step process was used to screen the literature search to identify relevant studies on chlorobenzene: 

• Title and abstract screen

• Full text screen

Title and Abstract Screen. Within the reference library, titles and abstracts were screened manually for 

relevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to the 

second step of the literature screening process. Studies were excluded when the title and abstract clearly 

indicated that the study was not relevant to the toxicological profile. 

• Number of titles and abstracts screened: 524

• Number of studies considered relevant and moved to the next step: 39

Full Text Screen. The second step in the literature screening process was a full text review of individual 

studies considered relevant in the title and abstract screen step. Each study was reviewed to determine 

whether it was relevant for inclusion in the toxicological profile. 

• Number of studies undergoing full text review: 39

• Number of studies cited in the pre-public draft of the toxicological profile: 127

• Total number of studies cited in the profile: 164

A summary of the results of the literature search and screening is presented in Figure B-1.
CHLOROBENZENE B-7

APPENDIX B

Figure B-1. April 2020 Literature Search Results and Screen for Chlorobenzene
CHLOROBENZENE C-1

APPENDIX C. USER'S GUIDE

Chapter 1. Relevance to Public Health

This chapter provides an overview of U.S. exposures, a summary of health effects based on evaluations of 

existing toxicologic, epidemiologic, and toxicokinetic information, and an overview of the minimal risk 

levels. This is designed to present interpretive, weight-of-evidence discussions for human health 

endpoints 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?

Minimal Risk Levels (MRLs)

Where sufficient toxicologic information is available, ATSDR derives MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans.

MRLs should help physicians and public health officials determine the safety of a community living near 

a hazardous substance 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. 

Section 1.2, Summary of Health Effects, contains basic information known about the substance. Other 

sections, such as Section 3.2 Children and Other Populations that are Unusually Susceptible and 

Section 3.4 Interactions with Other Substances, 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 endpoint 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 endpoint 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 

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 
CHLOROBENZENE C-2

APPENDIX C

substance-specific MRL are provided in the footnotes of the levels of significant exposure (LSE) tables

that are provided in Chapter 2. Detailed discussions of the MRLs are presented in Appendix A.

Chapter 2. 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 and MRLs to humans for noncancer 

endpoints. The LSE tables and figures can be used 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 tables and figures follow. The numbers in the left column of the legends correspond to 

the numbers in the example table and figure.

TABLE LEGEND

See Sample LSE Table (page C-5)

(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 figures are limited to the inhalation and oral routes. Not 

all substances will have data on each route of exposure and will not, therefore, have all five of the 

tables and figures. Profiles with more than one chemical may have more LSE tables and figures.

(2) Exposure period. Three exposure periods—acute (<15 days), intermediate (15–364 days), and 

chronic (≥365 days)—are presented within each relevant route of exposure. In this example, two 

oral studies of chronic-duration exposure are 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) Figure key. 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 51 identified NOAELs and less serious LOAELs (also see the three

"51R" data points in sample LSE Figure 2-X).

(4) Species (strain) No./group. The test species (and strain), whether animal or human, are identified 

in this column. The column also contains information on the number of subjects and sex per 

group. Chapter 1, Relevance to Public Health, covers the relevance of animal data to human 

toxicity and Section 3.1, 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.

(5) Exposure parameters/doses. The duration of the study and exposure regimens are provided in 

these columns. This permits comparison of NOAELs and LOAELs from different studies. In 

this case (key number 51), rats were orally exposed to “Chemical X” via feed for 2 years. For a 
CHLOROBENZENE C-3

APPENDIX C

more complete review of the dosing regimen, refer to the appropriate sections of the text or the 

original reference paper (i.e., Aida et al. 1992).

(6) Parameters monitored. This column lists the parameters used to assess health effects. Parameters 

monitored could include serum (blood) chemistry (BC), behavioral (BH), biochemical changes 

(BI), body weight (BW), clinical signs (CS), developmental toxicity (DX), enzyme activity (EA), 

food intake (FI), fetal toxicity (FX), gross necropsy (GN), hematology (HE), histopathology 

(HP), lethality (LE), maternal toxicity (MX), organ function (OF), ophthalmology (OP), organ 

weight (OW), teratogenicity (TG), urinalysis (UR), and water intake (WI).

(7) Endpoint. This column lists the endpoint examined. The major categories of health endpoints 

included in LSE tables and figures are death, body weight, respiratory, cardiovascular, 

gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, ocular, endocrine, 

immunological, neurological, reproductive, developmental, other noncancer, and cancer. "Other

noncancer" refers to any effect (e.g., alterations in blood glucose levels) not covered in these 

systems. In the example of key number 51, three endpoints (body weight, hematological, and 

hepatic) were investigated.

(8) NOAEL. A NOAEL is the highest exposure level at which no adverse effects were seen in the 

organ system studied. The body weight effect reported in key number 51 is a NOAEL at

25.5 mg/kg/day. NOAELs are not reported for cancer and death; with the exception of these two 

endpoints, this field is left blank if no NOAEL was identified in the study.

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused an adverse 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 endpoint used to 

quantify the adverse effect accompanies the LOAEL. Key number 51 reports a less serious 

LOAEL of 6.1 mg/kg/day for the hepatic system, which was used to derive a chronic exposure, 

oral MRL of 0.008 mg/kg/day (see footnote "c"). MRLs are not derived from serious LOAELs. 

A cancer effect level (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. If no LOAEL/CEL values were identified in the 

study, this field is left blank.

(10) Reference. The complete reference citation is provided in Chapter 8 of the profile.

(11) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. For example, footnote "c" indicates that the LOAEL of 6.1 mg/kg/day in key 

number 51 was used to derive an oral MRL of 0.008 mg/kg/day.

FIGURE LEGEND

See Sample LSE Figure (page C-6)

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 chronic exposure period are illustrated.
CHLOROBENZENE C-4

APPENDIX C

(14) Endpoint. These are the categories of health effects for which reliable quantitative data exist. 

The same health effect endpoints 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) LOAEL. In this example, the half-shaded circle that is designated 51R identifies a LOAEL 

critical endpoint in the rat upon which a chronic oral exposure MRL is based. The key number 

51 corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 6.1 mg/kg/day (see entry 51 in the sample LSE table) to 

the MRL of 0.008 mg/kg/day (see footnote "c" in the sample LSE table).

(17) CEL. Key number 59R is one of studies for which CELs were derived. The diamond symbol 

refers to a CEL for the test species (rat). The number 59 corresponds to the entry in the LSE 

table.

(18) Key to LSE figure. The key provides the abbreviations and symbols used in the figure.
CHLOROBENZENE

C-5

APPENDIX C
CHLOROBENZENE

C-6

APPENDIX C
CHLOROBENZENE D-1

APPENDIX D. 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 may find the following information helpful for fast 

answers to often-asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Relevance to Public Health: The Relevance to Public Health Section provides an overview 

of exposure and health effects and evaluates, interprets, and assesses the significance of toxicity 

data to human health. A table listing minimal risk levels (MRLs) is also included in this chapter.

Chapter 2: Health Effects: Specific health effects identified in both human and animal studies are 

reported by type of health effect (e.g., death, hepatic, renal, immune, reproductive), route of 

exposure (e.g., inhalation, oral, dermal), and length of exposure (e.g., acute, intermediate, and 

chronic). 

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

setting. 

Pediatrics: 

Section 3.2 Children and Other Populations that are Unusually Susceptible

Section 3.3 Biomarkers of Exposure and Effect

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) 

Internet: http://www.atsdr.cdc.gov

The following additional materials are available online:

Case Studies in Environmental Medicine are self-instructional publications designed to increase primary 

health care providers’ knowledge of a hazardous substance in the environment and to aid in the 

evaluation of potentially exposed patients (see https://www.atsdr.cdc.gov/csem/csem.html). 

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 (see https://www.atsdr.cdc.gov/MHMI/index.asp). 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 (ToxFAQsTM) provide answers to frequently asked questions about toxic substances (see 

https://www.atsdr.cdc.gov/toxfaqs/Index.asp).
CHLOROBENZENE D-2

APPENDIX D

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 • Web Page: 

https://www.cdc.gov/nceh/.

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, 395 E Street, S.W., Suite 9200, 

Patriots Plaza Building, Washington, DC 20201 • Phone: 202-245-0625 or 1-800-CDC-INFO 

(800-232-4636) • Web Page: https://www.cdc.gov/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 • Web Page: 

https://www.niehs.nih.gov/.

Clinical Resources (Publicly Available Information)

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 • Web Page: 

http://www.acoem.org/.

The American College of Medical Toxicology (ACMT) is a nonprofit association of physicians with 

recognized expertise in medical toxicology. Contact: ACMT, 10645 North Tatum Boulevard, 

Suite 200-111, Phoenix AZ 85028 • Phone: 844-226-8333 • FAX: 844-226-8333 • Web Page: 

http://www.acmt.net.

The Pediatric Environmental Health Specialty Units (PEHSUs) is an interconnected system of specialists 

who respond to questions from public health professionals, clinicians, policy makers, and the 

public about the impact of environmental factors on the health of children and reproductive-aged 

adults. Contact information for regional centers can be found at http://pehsu.net/findhelp.html.

The American Association of Poison Control Centers (AAPCC) provide support on the prevention and 

treatment of poison exposures. Contact: AAPCC, 515 King Street, Suite 510, Alexandria VA 

22314 • Phone: 701-894-1858 • Poison Help Line: 1-800-222-1222 • Web Page: 

http://www.aapcc.org/.
CHLOROBENZENE E-1

APPENDIX E. GLOSSARY

Absorption—The process by which a substance crosses biological membranes and enters systemic 

circulation. Absorption can also refer to 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, 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) or Benchmark Concentration (BMC)—is the dose/concentration 

corresponding to a specific response level estimate using a statistical dose-response model applied to 

either experimental toxicology or epidemiology data. For example, a BMD10 would be the dose 

corresponding to a 10% benchmark response (BMR). The BMD is determined by modeling the doseresponse curve in the region of the dose-response relationship where biologically observable data are 

feasible. The BMDL or BMCL is the 95% lower confidence limit on the BMD or BMC. 

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—Indicators signaling events in biologic systems or samples, typically classified as markers 

of exposure, effect, and susceptibility.

Cancer Effect Level (CEL)—The lowest dose of a 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-control study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without the outcome.

Case Report—A report that describes a single individual with a particular disease or exposure. These 

reports may suggest some potential topics for scientific research, but are not actual research studies.

Case Series—Reports that describe the experience of a small number of individuals with the same 

disease or exposure. These reports may suggest potential topics for scientific research, but are not actual 

research studies.
CHLOROBENZENE E-2

APPENDIX E

Ceiling Value—A concentration that must not be exceeded.

Chronic Exposure—Exposure to a chemical for ≥365 days, as specified in the Toxicological Profiles.

Clastogen—A substance that causes breaks in chromosomes resulting in addition, deletion, or 

rearrangement of parts of the chromosome.

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, and who are disease-free at start of follow-up. Often, at 

least one exposed group is compared to one unexposed group, while in other cohorts, exposure is a 

continuous variable and analyses are directed towards analyzing an exposure-response coefficient.

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 a specific point in time.

Data Needs—Substance-specific informational needs that, if met, would reduce the uncertainties of 

human health risk 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 response or amount of the response.

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 

effect occurs. Effects include malformations and variations, altered growth, and in utero death.

Epidemiology—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. 

Excretion—The process by which metabolic waste products are removed from the body.

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.

Health Advisory—An estimate of acceptable drinking water levels for a chemical substance derived by 

EPA and 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.

Immediately Dangerous to Life or Health (IDLH)—A condition that poses a threat of life or health, or 

conditions that pose an immediate threat of severe exposure to contaminants that are likely to have 

adverse cumulative or delayed effects on health.
CHLOROBENZENE E-3

APPENDIX E

Immunotoxicity—Adverse effect on the functioning of the immune system that may result from 

exposure to chemical substances. 

Incidence—The ratio of new cases 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.

Metabolism—Process in which chemical substances are biotransformed in the body that could result in 

less toxic and/or readily excreted compounds or produce a biologically active intermediate.

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.
CHLOROBENZENE E-4

APPENDIX E

Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease in 

a specific population.

Mortality—Death; the 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, which are changes 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 

hazardous substance.

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. Although effects may be produced at this dose, 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 odds ratio that is greater than 1 is considered to indicate greater risk of 

disease in the exposed group compared to the unexposed group.

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

regulatory limit on the amount or concentration of a substance not to be exceeded in workplace air 

averaged over any 8-hour work 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 (insects or other organisms harmful to cultivated plants or animals).

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 

endpoints. 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. 
CHLOROBENZENE E-5

APPENDIX E

Physiologically Based Pharmacokinetic (PBPK) Model—A type of physiologically based doseresponse model that is 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, including 

tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly 

membrane permeabilities. The models also utilize biochemical information, such as blood:air 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 a group is followed over time and the pertinent 

observations are made on events occurring after the start of the study. 

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 RfC is expressed in units of mg/m3 or ppm.

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily oral exposure of the human population to a potential hazard that is likely to be without risk of 

deleterious noncancer health effects during a lifetime. The oral RfD is expressed in units of mg/kg/day. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). RQs are 

(1) ≥1 pound 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 hazardous substance. The toxicity may be directed to the reproductive organs and/or 

the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual 

behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the 

integrity of this system.

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort.

Risk—The possibility or chance that some adverse effect will result from a given exposure to a hazardous 

substance.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing health 

condition, or an inborn or inherited characteristic that is associated with an increased occurrence of 

disease or other health-related event or condition.
CHLOROBENZENE E-6

APPENDIX E

Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to the 

risk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of disease 

in the exposed group compared to the unexposed group.

Short-Term Exposure Limit (STEL)—A STEL is a 15-minute TWA exposure that should not be 

exceeded at any time during a workday. 

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 it is believed that nearly all workers may be repeatedly 

exposed, day after day, for a working lifetime without adverse effect. The TLV may be expressed as a 

Time-Weighted Average (TLV-TWA), as a Short-Term Exposure Limit (TLV-STEL), or as a ceiling 

limit (TLV-C).

Time-Weighted Average (TWA)—An average exposure within a given time period. 

Toxicokinetic—The absorption, distribution, metabolism, and elimination of toxic compounds in the 

living organism.

Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases and 

pollution prevention activities reported by industrial and federal facilities. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL),

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 substance that is foreign to the biological system.
CHLOROBENZENE F-1

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

AAPCC American Association of Poison Control Centers

ACGIH American Conference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ACMT American College of Medical Toxicology

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AEGL Acute Exposure Guideline Level

AIC Akaike’s information criterion 

AIHA American Industrial Hygiene Association 

ALT alanine aminotransferase

AOEC Association of Occupational and Environmental Clinics

AP alkaline phosphatase

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

AWQC Ambient Water Quality Criteria

BCF bioconcentration factor

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

BUN blood urea nitrogen 

C centigrade

CAA Clean Air Act

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

cm centimeter

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DWEL drinking water exposure level

EAFUS Everything Added to Food in the United States

ECG/EKG electrocardiogram

EEG electroencephalogram

EPA Environmental Protection Agency

ERPG emergency response planning guidelines 

F Fahrenheit

F1 first-filial generation

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FR Federal Register
CHLOROBENZENE F-2

APPENDIX F

FSH follicle stimulating hormone

g gram

GC gas chromatography

gd gestational day

GGT γ-glutamyl transferase 

GRAS generally recognized as safe

HEC human equivalent concentration 

HED human equivalent dose 

HHS Department of Health and Human Services 

HPLC high-performance liquid chromatography

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer

IDLH immediately dangerous to life and health

IRIS Integrated Risk Information System 

Kd adsorption ratio

kg kilogram

kkg kilokilogram; 1 kilokilogram is equivalent to 1,000 kilograms and 1 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 Level of Significant Exposure

LT50 lethal time, 50% kill

m meter

mCi millicurie

MCL maximum contaminant level

MCLG maximum contaminant level goal

MF modifying factor

mg milligram

mL milliliter

mm millimeter

mmHg millimeters of mercury

mmol millimole

MRL Minimal Risk Level

MS mass spectrometry

MSHA Mine Safety and Health Administration

Mt metric ton

NAAQS National Ambient Air Quality Standard

NAS National Academy of Science

NCEH National Center for Environmental Health

ND not detected

ng nanogram

NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences
CHLOROBENZENE F-3

APPENDIX F

NIOSH National Institute for Occupational Safety and Health

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-observed-adverse-effect level

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NTP National Toxicology Program

OR odds ratio

OSHA Occupational Safety and Health Administration

PAC Protective Action Criteria

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PEHSU Pediatric Environmental Health Specialty Unit

PEL permissible exposure limit

PEL-C permissible exposure limit-ceiling value

pg picogram

PND postnatal day

POD point of departure

ppb parts per billion

ppbv parts per billion by volume

ppm parts per million

ppt parts per trillion

REL recommended exposure level/limit

REL-C recommended exposure level-ceiling value

RfC reference concentration

RfD reference dose

RNA ribonucleic acid

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SD standard deviation

SE standard error

SGOT serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)

SGPT serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)

SIC standard industrial classification

SMR standardized mortality ratio

sRBC sheep red blood cell

STEL short term exposure limit

TLV threshold limit value

TLV-C threshold limit value-ceiling value

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

USNRC U.S. Nuclear Regulatory Commission
CHLOROBENZENE

F-4

APPENDIX F

VOC volatile organic compound

WBC white blood cell

WHO World Health Organization > 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