Toxicological
Profile
for
CHLOROBENZENE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-06
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TOXICOLOGICAL PROFILE FOR
CHLOROBENZENE
Prepared by:
Life Systems, Inc.
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990
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ii
DISCLAIMER
The use of company or product name(s) is for identification only
and does not imply endorsement by the Agency for Toxic Substances and
Disease Registry.
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iii
FOREWORD
The Superfund Amendments and Reauthorization Act (SARA) of 1986
(Public Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law directed the Agency for Toxic Substances and Disease
Registry (ATSDR) to prepare toxicological profiles for hazardous
substances which are most commonly found at facilities on the CERCLA
National Priorities List and which pose the most significant potential
threat to human health, as determined by ATSDR and the Environmental
Protection Agency (EPA). The lists of the 250 most significant hazardous
substances were published in the Federal Register on April 17, 1987, on
October 20, 1988, on October 26, 1989, and on October 17, 1990.
Section 104(i)(3) of CERCLA, as amended, directs the Administrator of
ATSDR to prepare a toxicological profile for each substance on the list.
Each profile must include the following content:
(A) An examination, summary, and interpretation of available
toxicological information and epidemiological evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute,
and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by CERCLA, as amended.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and adverse health effects information for the hazardous
substance being described. Each profile identifies and reviews the key
literature (that has been peer-reviewed) that describes a hazardous
substance's toxicological properties. Other pertinent literature is also
presented but 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.
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iv
Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the public health statement is
information concerning significant health effects associated with exposure
to the substance. The adequacy of information to determine a substance s
health effects is described. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program (NTP) of the Public Health Service, and EPA. The focus
of the profiles is on health and toxicological information; therefore, we
have included this information in the beginning of the document.
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 our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed
by scientists from ATSDR, the Centers for Disease Control, the NTP, and
other federal agencies. It-has also been reviewed by a panel of
nongovernment peer reviewers and is being made available for public
review. Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR.
Wi ., M.P.H.
Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS CHLOROBENZENE? 1
1.2 HOW MIGHT I BE EXPOSED TO CHLOROBENZENE? 1
1.3 HOW CAN CHLOROBENZENE ENTER AND LEAVE MY BODY? 2
1.4 HOW CAN CHLOROBENZENE AFFECT MY HEALTH? 2
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE
BEEN EXPOSED TO CHLOROBENZENE? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? 8
1.8 WHERE CAN I GET MORE INFORMATION? 8
2. HEALTH EFFECTS 9
2.1 INTRODUCTION 9
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 9
2.2.1 Inhalation Exposure • 10
2.2.1.1 Death 10
2.2.1.2 Systemic Effects 10
2.2.1.3 Immunological Effects 15
2.2.1.4 Neurological Effects 15
2.2.1.5 Developmental Effects 15
2.2.1.6 Reproductive Effects 15
2.2.1.7 Genotoxic Effects 16
2.2.1.8 Cancer 16
2.2.2 Oral Exposure 16
2.2.2.1 Death 16
2.2.2.2 Systemic Effects 17
2.2.2.3 Immunological Effects 21
2.2.2.4 Neurological Effects 21
2.2.2.5 Developmental Effects 21
2.2.2.6 Reproductive Effects 22
2.2.2.7 Genotoxic Effects 22
2.2.2.8 Cancer 22
2.2.3 Dermal Exposure 22
2.2.3.1 Death 22
2.2.3.2 Systemic Effects 22
2.2.3.3 Immunological Effects 22
2.2.3.4 Neurological Effects 22
2.2.3.5 Developmental Effects 22
2.2.3.6 Reproductive Effects 23
2.2.3.7 Genotoxic Effects 23
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vi
2.2.3.8 Cancer 23
2.3 TOXICOKINETICS 23
2.3.1 Absorption 23
2.3.1.1 Inhalation Exposure 23
2.3.1.2 Oral Exposure 23
2.3.1.3 Dermal Exposure 23
2.3.2 Distribution 23
2.3.2.1 Inhalation Exposure 23
2.3.2.2 Oral Exposure 24
2.3.2.3 Dermal Exposure 24
2.3.3 Metabolism 24
2.3.4 Excretion 26
2.3.4.1 Inhalation Exposure 26
2.3.4.2 Oral Exposure 27
2.3.4.3 Dermal Exposure 27
2.4 RELEVANCE TO PUBLIC HEALTH 27
2.5 BIOMARKERS OF EXPOSURE AND EFFECT 31
2.5.1 Biomarkers Used to Identify and/or Quantify Exposure
to Chlorobenzene 33
2.5.2 Biomarkers Used to Characterize Effects Caused by
Chlorobenzene 33
2.6 INTERACTIONS WITH OTHER CHEMICALS 33
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 34
2.8 ADEQUACY OF THE DATABASE 34
2.8.1 Existing Information on Health Effects of
Chlorobenzene 34
2.8.2 Identification of Data Needs 35
2.8.3 On-going Studies 39
3. CHEMICAL AND PHYSICAL INFORMATION 41
3.1 CHEMICAL IDENTITY 41
3.2 PHYSICAL AND CHEMICAL PROPERTIES 41
4. PRODUCTION, IMPORT, USE, AND DISPOSAL 45
4.1 PRODUCTION 45
4.2 IMPORT 45
4.3 USE 45
4.4 DISPOSAL 46
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
5.2 RELEASES TO THE ENVIRONMENT ....
5.2.1 Air
5.2.2 Water
5.2.3 Soil
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
5.3.2 Transformation and Degradation
5.3.2.1 Air
5.3.2.2 Water
5.3.2.3 Soil
47
47
47
47
47
49
49
49
49
49
49
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vii
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 50
5.4.1 Air 50
5.4.2 Water 50
5.4.3 Soil 50
5.4.4 Other Media 50
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 50
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 51
5.7 ADEQUACY OF THE DATABASE 51
5.7.1 Identification of Data Needs 51
5.7.2 On-going studies 53
6. ANALYTICAL METHODS 55
6.1 BIOLOGICAL MATERIALS 55
6.2 ENVIRONMENTAL SAMPLES 56
6.3 ADEQUACY OF THE DATABASE 58
6.3.1 Identification of Data Needs 60
6.3.2 On-going Studies 61
7. REGULATIONS AND ADVISORIES 63
8. REFERENCES 67
9. GLOSSARY 83
APPENDIX 87
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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to Chlorobenzene -
Inhalation 13
2-2 Levels of Significant Exposure to Chlorobenzene - Oral 20
2-3 Metabolic Scheme for Chlorobenzene 25
2-4 Existing Information on Health Effects of Chlorobenzene 35
5-1 Frequency of Sites with Chlorobenzene Contamination 48
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xi
LIST OF TABLES
1-1 Human Health Effects from Breathing Chlorobenzene 4
1-2 Animal Health Effects from Breathing Chlorobenzene 5
1-3 Human Health Effects from Eating or Drinking Chlorobenzene 6
1-4 Animal Health Effects from Eating or Drinking Chlorobenzene .... 7
2-1 Levels of Significant Exposure to Chlorobenzene - Inhalation .... 11
2-2 Levels of Significant Exposure to Chlorobenzene - Oral 18
2-3 Genotoxicity of Chlorobenzene In Vivo 30
2-4 Genotoxicity of Chlorobenzene In Vitro 32
3-1 Chemical Identity of Chlorobenzene 42
3-2 Physical and Chemical Properties of Chlorobenzene 43
6-1 Analytical Methods for Determining Chlorobenzene in Biological
Materials 57
6-2 Analytical Methods for Determining Chlorobenzene in Environmental
Samples 59
7-1 Regulations and Guidelines Applicable to Chlorobenzene 64
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1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about
chlorobenzene and to emphasize the human health effects that may result
from exposure to it. The Environmental Protection Agency (EPA) has
identified 1,177 sites on its National Priorities List (NPL).
Chlorobenzene has been found at 97 of these sites. However, we do not
know how many of the 1,177 NPL sites have been evaluated for
chlorobenzene. As EPA evaluates more sites, the number of sites at
which chlorobenzene is found may change. The information is important
for you because chlorobenzene may cause harmful health effects and
because these sites are potential or actual sources of human exposure to
chlorobenzene.
When a chemical is released from a large area, such as an
industrial plant, or from a container, such as a drum or bottle, it
enters the environment as a chemical emission. This emission, which is
also called a release, does not always lead to exposure. You can be
exposed to a chemical only when you come into contact with the chemical.
You may be exposed to it in the environment by breathing, eating, or
drinking substances containing the chemical or from skin contact with
it.
If you are exposed to a hazardous substance such as chlorobenzene,
several factors will determine whether harmful health effects will occur
and what the type and severity of those health effects will be. These
factors include the dose (how much), the duration (how long), the route
or pathway by which you are exposed (breathing, eating, drinking, or
skin contact), the other chemicals to which you are exposed, and your
individual characteristics such as age, sex, nutritional status, family
traits, life style, and state of health.
1.1 WHAT IS CHLOROBENZENE?
Chlorobenzene is a colorless liquid with an almond-like odor. The
compound does not occur widely in nature, but is manufactured for use as
a solvent (a substance used to dissolve other substances) and is used in
the production of other chemicals. Chlorobenzene persists in soil
(several months), in air (3.5 days), and water (less than 1 day).
Additional information can be found in Chapters 3, 4, and 5.
1.2 HOW MIGHT I BE EXPOSED TO CHLOROBENZENE?
There is potential for humans to be exposed to chlorobenzene by
breathing contaminated air, by drinking water or eating food
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2
1. PUBLIC HEALTH STATEMENT
contaminated with chlorobenzene, or by getting chlorobenzene-
contaminated soil on the skin. These exposures are most likely to occur
in the workplace or in the vicinity of chemical waste sites.
Occupational exposure occurs primarily through breathing the
chemical. Personnel engaged in the production and handling of
chlorobenzene would be at greatest risk. Levels of chlorobenzene in the
air at several industrial sites during normal operations were found to
be below allowable federal standards.
Exposure in humans could occur in persons living or working in the
vicinity of hazardous waste sites if emissions to water, air, and soil
are not adequately controlled. Chlorobenzene has been found at 97 out
of 1,177 NPL hazardous waste sites in the United States. Thus, federal
and state surveys suggest that chlorobenzene is not a widespread
environmental contaminant. The chemical has not been detected in
surface water, although a few ground water systems have been found with
chlorobenzene levels in the parts per billion (ppb) range. Background
levels of less than 1 ppb were detected in air samples from urban and
suburban areas. No information of the occurrence of chlorobenzene in
food has been found. Additional information on the potential for human
exposure is presented in Chapter 5.
1.3 HOW CAN CHLOROBENZENE ENTER AND LEAVE MY BODY?
Chlorobenzene enters your body when you breathe in air containing
it, when you drink water or eat food containing it, or when it comes in
contact with your skin. Human exposure to contaminated water could
occur near hazardous waste sites where chlorobenzene is present.
Significant exposure to chlorobenzene is not expected to occur by
getting chlorobenzene contaminated soil on your skin. When
chlorobenzene enters your body, most of it is expelled from your lungs
in the air we breathe out and in urine. Additional information is
presented in Chapter 2.
1.4 HOW CAN CHLOROBENZENE AFFECT MY HEALTH?
Workers exposed to high levels of chlorobenzene complained of
headaches, numbness, sleepiness, nausea, and vomiting. However, it is
not known if chlorobenzene alone was responsible for these health
effects since the workers may have also been exposed to other chemicals
at the same time. Mild to severe depression of functions of parts of
the nervous system is a common response to exposure to a wide variety of
industrial solvents (a substance that dissolves other substances).
In animals, exposure to high concentrations of chlorobenzene
affects the brain, liver, and kidneys. Unconsciousness, tremors and
restlessness have been observed. The chemical can cause severe injury
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3
1. PUBLIC HEALTH STATEMENT
to the liver and kidneys. Data indicate that chlorobenzene does not
affect reproduction or cause birth defects. Studies in animals have
shown that chlorobenzene can produce liver nodules, providing some but
not clear evidence of cancer risk. Additional information on health
effects is presented in Chapter 2.
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Harm to human health from breathing, eating or drinking
chlorobenzene is not established (Tables 1-1 and 1-3). Tables 1-2 and
1-4 show the relationship between exposure to chlorobenzene and known
health effects in animals. A Minimal Risk Level (MRL) is included in
Table 1-3. The MRL was derived from animal data for long-term exposure,
as described in Chapter 2 and in Table 2-2. The MRL provides a basis
for comparison with levels that people might encounter either in the air
or in food or drinking water. If a person is exposed to chlorobenzene
at an amount below the MRL, it is not expected that harmful (noncancer)
health effects will occur. Because this level is based only on
information currently available, some uncertainty is always associated
with it. Also, because the method for deriving MRLs does not use any
information about cancer, a MRL does not imply anything about the
presence, absence, or level of risk for cancer. Further information on
the levels of chlorobenzene that have been observed to cause health
effects in animals is presented in Chapter 2.
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED
TO CHLOROBENZENE?
Exposure to chlorobenzene can be determined by measuring the
chemical or its metabolite in urine, exhaled air, blood, and body fat.
Tests are not routinely available at the doctor's office. Specific
tests are available that can determine if exposure is currently
occurring or has occurred very recently, but not whether exposure
occurred in the past. Further, levels in the various media stated above
do not predict adverse health effects. Additional information on how
chlorobenzene can be measured in exposed humans is given in Chapters 2
and 6.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing Chlorobenzene*
Short-term Exposure
(less than or equal to 14 days)
T.evels
i n
Air
Length of Exposure
Description of Effects
The health effects result-
ing from short-term
exposure of humans to
air containing specific
levels of chlorobenzene
are not known.
Long-term Exposure
(greater than 14 days)
Levels
i n
Air
Length of Exposure
Description of Effects
The health effects result-
ing from long-term
exposure of humans to
air containing specific
levels of chlorobenzene
are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Chlorobenzene
Short-term Exposure
(less than or equal to 14 days)
Levels in Air
(ppm)
Lenpth of Exposure
DescriDtion of Effects*
537
2 hours
Death in rabbits.
Long-term Exposure
(greater than 14 days)
Levels in Air
(ppm)
Leneth of Exposure
DescriDtion of Effects*
75
24 weeks
Liver and kidney damage
in rats and rabbits.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking Chlorobenzene
Short-term Exposure
(less than or equal to 14 days)
T.sngth of Exposure
Description of Effects
The health effects result-
ing from short-terra
exposure of humans to
food containing specific
levels of chlorobenzene
are not known.
Levels
in Water
The health effects result-
ing from short-term
exposure of humans to
water containing specific
levels of chlorobenzene
are not known.
Long-term Exposure
(greater than 14 days)
l.f;npth of Exposure
Description of Effects
15
91 days
Minimal Risk Level (based
on animal studies; see
Section 1.5 for discus-
sion) .
T.eve Is
in Water
The health effects result-
ing from long-term
exposure of animals to
water containing specific
levels of chlorobenzene
are not known.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal
Health Effects from Eating
or Drinking Chlorobenzene
Short-term Exposure
(less than or equal to 14
days)
Levels in Food CppnO
Lenpth of Exposure
Description of Effects*
7,692 - 20,000
1-14 days
Death in mice and rats.
Levels in Water
The health effects of
short-term exposure of
animals to water con-
taining specific levels
of chlorobenzene are
not known.
Long-term Exposure
(greater than 14 days)
Levels in Food (cDml
Length of Exposure
Description of Effects*
1,923 - 5,000
91 days
Liver and kidney damage
in mice. Liver injury
rats.
1,923
13 weeks
Injury to organs of the
immune system in mice.
1,923
13 weeks
Death in mice.
Levels in Water
The health effects result-
ing from long-term
exposure of animals to
water containing specific
levels of chlorobenzene
are not known.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The Federal Government has developed regulatory standards and
advisories to protect individuals from potential health effects of
chlorobenzene in the environment. The Environmental Protection Agency
has proposed that the maximum level of chlorobenzene in drinking water
be 0.1 parts per million (ppm). For short-term exposures to drinking
water, EPA has recommended that drinking water levels not exceed 2 ppm
for up to ten days. The Occupational Safety and Health Administration
(OSHA) has established a legally enforceable maximum limit of 75 ppm of
chlorobenzene in workplace air for an 8 hour/day, 40-hour work week.
Additional information regarding federal and state regulations is
presented in Chapter 7.
1.8 WHERE CAN I GET MORE INFORMATION?
If you have any more questions or concerns not covered here, please
contact your State Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
This agency can also give you information on the location of the
nearest
occupational and environmental health clinics. Such clinics
specialize in recognizing, evaluating, and treating illnesses that
result from exposure to hazardous substances.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
chlorobenzene. Its purpose is to present levels of significant exposure
for chlorobenzene based on toxicological studies, epidemiological
investigations, and environmental exposure data. This information is
presented to provide public health officials, physicians, toxicologists,
and other interested individuals and groups with (1) an overall
perspective of the toxicology of chlorobenzene and (2) a depiction of
significant exposure levels associated with various adverse health
effects.
2.2. DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section
are organized first by route of exposure -- inhalation, oral, and
dermal -- and then by health effect -- death, systemic, immunological,
neurological, developmental, reproductive, genotoxic, and carcinogenic
effects. These data are discussed in terms of three exposure periods --
acute, intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-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.
These distinctions are intended to help the users of the document
identify the levels of exposure at which adverse health effects start to
appear, determine whether or not the intensity of the effects varies
with dose and/or duration, and place into perspective the possible
significance of these effects to human health.
The significance of the exposure levels shown on the tables and
graphs may differ depending on the user's perspective. For example,
physicians concerned with the interpretation of clinical findings in
exposed persons or with the identification of persons with the potential
to develop such disease may be interested in levels of exposure
associated with "serious effects". Public health officials and project
managers concerned with response actions at Superfund sites may want
information on levels of exposure associated with more subtle effects in
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10
2. HEALTH EFFECTS
humans or animals (LOAELs) or exposure levels below which no adverse
effects (NOAELs) have been observed. Estimates of levels posing minimal
risk to humans (minimal risk levels, MRLs) a re of interest to health
professionals and citizens alike.
Estimates of exposure levels posing minimal risk to humans (MRLs)
have been made, where data were believed reliable, for the most
sensitive noncancer end point for each exposure duration. MRLs include
adjustments to reflect human variability and, where appropriate, the
uncertainty of extrapolating from laboratory animal data to humans.
Although methods have been established to derive these levels (Barnes
et al. 1987; EPA 1989a), uncertainties are associated with the
techniques.
2.2.1 Inhalation Exposure
2.2.1.1 Death
No studies were located regarding lethality in humans following
inhalation exposure to chlorobenzene.
The acute lethality of chlorobenzene is relatively low in animals
Exposure to concentrations of 20 mg/L (4,100 ppm) for 2 hours resulted"
in 100% mortality in mice (Rozenbaum et al. 194/). Rabbits died 2 weeks
after chlorobenzene exposure to concentrations of about 537 ppm
(Rozenbaum et al. 1947).
The highest NOAEL values and all reliable LOAEL values for death in
each species and duration category are recorded in Table 2-1 and plotted
in Figure 2-1.
2.2.1.2 Systemic Effects
No studies were located regarding effects on the respiratory
cardiovascular, gastrointestinal, hematological, musculoskeletal
hepatic, renal, and dermal/ocular systems in humans following inhalatio
exposure to chlorobenzene.
As shown in Table 2-1 and Figure 2-1, animal studies indicate that
chlorobenzene induces injury to the liver and kidneys following
intermediate and chronic inhalation exposures.
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TABLE 2-1. Levels of Significant Exposure to Chlorobenzene - Tnhalatlan
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Duration Effect (ppm) (ppm) (ppm) Reference
ACUTE EXPOSURE
Death
1 Rabbit
2 Mouse
Developmental
3 Rat
4 Rabbit
INTERMEDIATE EXPOSURE
Systemic
5 Rat
6 Rat
7 Rabbit
2 hr
2 hr
10 d
Gd6-15
6hr/d
13 d
Gd6-18
6hr/d
120 d
Sd/wk
7hr/d
120 d
5d/vrk
7hr/d
120 d
5d/wk
7hr/d
537
4300
590
590
Renal
Hepatic
Hepatic
75a (micro, lesions)
75a (deer. SGOT)
75a (deer. LDH)
Rozenbaum 1947
Rozenbaum 1947
John et a!. 1984
John et al. 1984
Dilley 1977
Dilley 1977
Dilley 1977
SC
M
>
n
X
•*1
M
a
H
00
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TABLE 2-1 (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Duration Effect (ppm) (ppm) (pp«) Reference
CHRONIC EXPOSURE
Systemic
8 Rat
9 Rat
2 gen Hepatic 50 150 (hypertrophy)
7d/vk
6hr/d
2 gen Renal
7d/vk
6hr/d
50 150 (micro, changes)
Nair et al. 1987
Nair et ai 1987
Reproduct ive
10 Rat
2 gen
7 d / vk
6hr / d
Nair et a. 198?
H ~
— NJ
^Presented in Tabic
LQAEL « 1 ovest-observes-adverse-effect level; KOAEL - r.o-cbserved-acverse-ef£ect .eve., pprr, = parts per r.il.ion:
LC10C ¦ lethal concentration, I C 0 £ aniiaa.s exposed: d - cav; C-c ges:a;.or. cay; wk - veek ; cec: ¦ decrease; SSOT
glutamic oxaloacetic t ransaicinase ; micro » microscopic ; « lactate dehydrogenase; ger. = generation
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ACUTE INTERMEDIATE CHRONIC
(£14 Days) (15-364 Days) (>365 Days)
Systemic Systemic
(ppm)
10,000 i—
^ ^ ^ 8r 39r
Ol°r
a
ra
>
5
a
w
•*1
•*1
m
o
H
M
08r 09r
10
Key
r Rat 9 LOAEL for serious effects (animals)
m Mouse
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14
2. HEALTH EFFECTS
Hematological. Based on a small number of studies, chlorobenzene
may cause hematological changes. There were dose and time-related
effects on red blood cell parameters, primarily an increase in
reticulocyte count which increased in rats but not in rabbits exposed to
vapors of chlorobenzene at concentrations ;> 75 ppm for 24 weeks (Dilley
1977). Other hematological parameters (red blood cell count
hemoglobins, hematocrit, and white blood cell count) were variable and
were comparable to controls at the end of the test. Slight leukopenia
and lymphocytosis occurred in mice exposed to chlorobenzene (0 1 me/L')
for 3 months (Zub 1978) . In the absence of more detailed experimental
data and information on compound purity, it is not certain if the
effects in mice were compound-related. Further, these effects have not
been confirmed at comparable doses in other species. Thus, it appears
that hematological effects may not be sensitive indicators of
chlorobenzene toxicity.
Hepatic Effects. No data were found that severe liver damage
results from acute exposure to chlorobenzene vapor. Treatment-related
congestion of the liver was observed in male rats and to a lesser degree
in male rabbits exposed for 24 weeks to * 75 ppm (Dilley 1977) Focal
hemorrhages and foci of perivascular lymphocytes were observed
Decreased levels of serum enzymes (lactate dehydrogenase [LDHl'and serum
glutamic-oxaloacetic transaminase [SCOT]) were observed at the end of
the treatment period; the significance of this response is not clear
Nair et al. (1987) reported liver hypertrophy and increased liver
weights in male rats exposed to chlorobenzene vapors daily at 150 and
450 ppm for two generations. Overall, data suggest liver toxicity mav
be an area of concern for chlorobenzene exposure in humans.
The highest NOAEL values and all reliable LOAEL values for liver
toxicity in each species and duration category are recorded in Table 2 1
and plotted in Figure 2-1.
Renal Effects, a small number of studies demonstrates that the
kidney is also a target organ following chlorobenzene exposure and that
the effects occur at levels comparable to those causing liver effects
Nair et al. (1987) reported tubular dilatation with eosinophilic
material, interstitial nephritis and foci of regenerative epithelium in
male rats exposed to vapors of chlorobenzene at 150 and 450 ppm for two
generations. There was also treatment-related congestion of the kidneys
in rabbits exposed to chlorobenzene at concentrations * 75 ppm in
animals sacrificed at 5 weeks of a 24 week treatment period (Dilley
1977). Interstitial foci of lymphocytes were evident. Overall, data
suggest that this effect may also be an area of concern for
chlorobenzene exposure in humans.
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15
2. HEALTH EFFECTS
The highest NOAEL values and all reliable LOAEL values for renal
toxicity in each species and duration category are recorded in Table 2-1
and plotted in Figure 2-1.
2.2.1.3 Immunological Effects
No studies were located regarding the immunological effects in
humans or animals following inhalation exposure to chlorobenzene.
2.2.1.A Neurological Effects
Chlorobenzene affects the central nervous system. Humans occupa-
tionally exposed to chlorobenzene intermittently for up to 2 years at
levels above current federal limits 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 have not been provided.
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 5 mg/L chlorobenzene
(1,090 ppm) or greater for 2 hours (Rozenbaum et al. 1947).
2.2.1.5 Developmental Effects
No studies were located regarding developmental effects in humans
following inhalation exposure to chlorobenzene.
In rats and rabbits, inhalation of chlorobenzene vapors at
concentrations up to 590 ppm during periods of major organogenesis did
not produce structural malformations (John et al. 1984). This value has
been presented in Table 2-1 and plotted in Figure 2-1. The highest dose
resulted in maternal toxicity, as indicated by elevation of liver
weights (both species) and decreased food consumption and body weight
gain (rats only).
2.2.1.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following inhalation exposure to chlorobenzene.
In a two-generation study in rats, chlorobenzene in concentrations
up to 450 ppm did not adversely affect reproductive performance or
fertility (Nair et al. 1987). This value has been presented in
Table 2-1 and plotted in Figure 2-1. A slight increase was observed in
the incidence of degenerative testicular changes (unilateral and
bilateral) in high-dose (450 ppm) males (F0 and Fi generations) and the
Fx mid-dose (150 ppm) males. The significance of this finding is
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16
2. HEALTH EFFECTS
unclear since the mean mating, pregnancy, and male fertility indices for
both F0 and Fx generations were comparable for all groups and the
incidences of testicular lesion were identical in F0 and Fx animals.
2.2.1.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans or
animals following inhalation exposure to chlorobenzene.
2.2.1.8 Cancer
No studies were located regarding carcinogenic effects in humans or
animals following inhalation exposure to chlorobenzene.
2.2.2 Oral Exposure
2.2.2.1 Death
No studies were located regarding lethality in humans following
oral exposure to chlorobenzene.
Animal studies show that chlorobenzene is lethal following acute,
intermediate, and chronic oral exposures. Death occurred within 2 to
3 days after a single exposure to 4,000 mg/kg in corn oil by gavage in
rats of both sexes, and in mice after a single exposure to 1,000 mg/kg
(NTP 1985). Necropsy or histological examination was not performed. In
a 14-day repeated-dose gavage study in rats, administration of
* 1,000 mg/kg was lethal to all rats by the end of the study (NTP 1985).
This dose has been converted to an equivalent concentration of
20,000 ppm in food for presentation in Table 1-4. Survival was reduced
in rats of both sexes exposed to i 500 mg/kg/day and * 250 mg/kg/day in
mice following intermediate-duration exposure (NTP 1985). The dose of
250 mg/kg/day has been converted to an equivalent concentration of
1,923 ppm in food for presentation in Table 1-4. Clinical signs of
toxicity were not observed in mice and rats but histopathologic
examination revealed dose-related chemical-induced changes to the liver,
kidney, bone marrow, spleen, and thymus. Liver and kidney weights
increased in mice and rats, while spleen weights decreased. In chronic
oral studies, male rat survival at 120 mg/kg (2,400 ppm) was
significantly lower than that of vehicle controls (NTP 1985); however,
no compound-induced toxic lesions responsible for this reduction in
survival were observed.
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17
2. HEALTH EFFECTS
The highest NOAEL values and all reliable LOAEL values for death in
each species and duration category are recorded in Table 2-2 and plotted
in Figure 2-2.
2.2.2.2 Systemic Effects
No studies in humans were located regarding the effects on the
respiratory, cardiovascular, gastrointestinal, hematological,
musculoskeletal, hepatic, renal, and dermal/ocular systems following
oral exposure to chlorobenzene. The following sections describe effects
observed in animals.
Hepatic Effects. Animal studies indicate that the liver is
susceptible to injury by chlorobenzene following oral exposure. Typical
signs include: increased serum enzymes, altered liver weights,
degeneration, necrosis, and interference with porphyrin metabolism. In
acute studies (5 days), effects on porphyrin metabolism occurred at
1,140 mg/kg/day by gavage (Rimington and Ziegler 1963). Intermediate
and long-term exposure studies in rats and mice reported organ weight
increases at 100 (Hazleton 1967) and 125 mg/kg/day (NTP 1985), while
organ weight increases and microscopic lesions were detected at
2 250 mg/kg/day by the same route (NTP 1985). Focal hepatocytic
necrosis and degenerative changes in the centrilobular hepatocytes were
observed in mice. These effects were most apparent in the 2 500 mg/kg
dose group in rats. The dose of 250 mg/kg/day has been converted to
equivalent concentrations of 1,923 ppm (in mice) and 5,000 ppm (in rats)
in food for presentation in Table 1-4. No effects were observed at
60 mg/kg/day. Based on this value, an intermediate oral MRL of
0.4 mg/kg/day was calculated as described in the footnote in Table 2-2.
This MRL has been converted to an equivalent concentration in food
(15 ppm) for presentation in Table 1-3.
Renal Effects. Animal studies demonstrate that chlorobenzene can
cause injury to the kidney at doses comparable to those which cause
liver effects. In a 90-day study, degeneration or focal necrosis of the
proximal tubules was observed at 2 250 mg/kg in mice and 2 500 mg/kg in
rats (NTP 1985). Repeated doses of 2 100 mg/kg/day for 90 to 99 days
(Hazleton 1967) caused an increase in kidney weights.
-------
TABLE 2-2. Levels of Signifleant: Exposure t o Chlorobenzene - Oral
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Se rious Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference
ACUTE EXPOSURE
Death
1
Rat
Rat
Systemic
5 Rat
Neurological
6 Rat
(G) 14 d
lx/d
(G) 1 d
lx/d
Mouse (G) 14 d
lx/d
Mouse (G) 1 d
lx/d
7 Rat
INTERMEDIATE EXPOSURE
Death
(G) 5 d
(G) 1 d
lx/d
(G) 14 d
lx/d
8
Rat
(G) 91 d
5d/vk
9 Mouse (G) 91 d
5d/vk
Systemic
10 Rat
(G) 91 d
5d/wk
Hepatic
Hepatic
500
250
500
250
125
60c 125 (incr. wt. and
serum enzymes)
1000a
4000
1000c
1140 (necrosis)
NTP 1985
NTP 1985
NTP 1985
NTP 1985
Ridington and
Ziegler 1963
4000 (prostration) NTP 1985
1000 (prostration) NTP 1985
NTP 1985
NTP 1985
250d (necrosis) NTP 1985
•X
w
>
5
a
pi
*rj
~n
o
H
cn
-------
TABLE 2-2 (Continued)
Exposure LQAEL (Effect)
Figure Frequency/ NOAEL Less Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day)
Serious
(mg/kg/day)
Reference
11
12
Mouse
Mouse
(G) 91 d
5d/vk
(G) 91 d
5d/wk
Renal
Hepatic
125
60 125 (incr. vt.)
250e (necrosis,
tub. degen.)
250e (necrosis,
degenerat ion)
NTP 1985
NTP 1985
I mtjun o 1 o g i c a 1
13 Mouse
(G) 91 d
5d/wk
250 (thymic necrosis, NTP 1985
splenic depletion)
CHRONIC EXPOSURE
Death
14 Mouse
Systemic
15 Rat
(G) 103 vk
5d/wk
lx/d
(G)
103 wk
5d/wk
lx/d
Hepatic
120
60
120 (necrosis)
NTP 1985
NTP 1985
32
m
>
r
H
X
-n
w
o
H
aConverted to an equivalent concentration of 20,000 ppm in food for presentation in Table 1-4.
^Converted to an equivalent concentration of 7692 ppm in food for presentation in Table 1-4.
cUsed to derive intermediate oral MRL of 0.4 mg/kg/day; dose adjusted for intermittent exposure and divided by an uncertainty
factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). This MRL has been converted to an
equivalent concentration in food (15 ppm) for presentation in Table 1-3.
^Converted to an equivalent concentration of 5000 ppm in food for presentation in Table 1-4.
®Converted to an equivalent concentration of 1923 ppm in food for presentation in Table 1-4.
LOAEL * lowest-observed-adverse-effect level; NOAEL - no-observed-adverse-effect level; mg « milligram; kg « kilogram; (G) —
gavage; d = day; lx « one time; wk = week; incr = increase; wt = weight; tub = tubular; degen = degeneration.
-------
ACUTE INTERMEDIATE CHRONIC
fc14 Days) (15-364 Days) fe365 Days)
/
^ Jr
(mg/Kg/day) ^ ^ ^
10,000
1,000
100 -
10
0.1
•2r #6»
•* •»
1. °"
Oa
rd>
&
»" CJ3l0r
Key
&
#15f
O'Sf
r Rat • LOAEL tor serious effects (animals) | Minimal risk
m Mouse 3 LOAEL for less serious effects (animals) J/ level for
O NOAEL (animals) e,fec,s other
The number next to each point corresponds to entries in Table 2-2. cancer
>
1-^
rr
vn
'-n
m
r-v
•-4
00
ho
o
FIGURE 2-2. Levels of Significant Exposure to Chlorobenzene - Oral
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21
2. HEALTH EFFECTS
The highest NOAEL values and all reliable LOAEL values for renal
effects in each species and duration category are recorded in Table 2-2
and plotted in Figure 2-2.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in humans
following oral exposure to chlorobenzene.
Histological studies in mice and rats suggest that chlorobenzene
has immunotoxic properties. Mice exposed to chlorobenzene at
2 250 mg/kg/day by gavage for 13 weeks showed thymic necrosis and
lymphoid or myeloid depletion of bone marrow, spleen, or thymus (NTP
1985). While histopathologic evidence suggests that chlorobenzene is
immunotoxic, a NOAEL cannot be established in this study since immune
function tests were not conducted. A LOAEL of 250 mg/kg/day was
determined (NTP 1935). This value has been presented in Table 2-2.
Since there are no human data on immunotoxic effects and animal data are
sparse, firm conclusions can not be made concerning the potential for
chlorobenzene to affect the immune system in humans following oral
exposure.
2.2.2.4 Neurological Effects
There is a paucity of data on the effects of chlorobenzene in
humans following oral exposure. A two-year-old male swallowed 5 to
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).
No studies were located regarding neurological effects in animals
following oral exposure. In the absence of dose-response data in humans
and the lack of animal evidence, the potential for chlorobenzene to
produce effects on the nervous system cannot be quantitatively
determined.
2.2.2.5 Developmental Effects
No studies were located regarding the developmental effects in
humans following oral exposure to chlorobenzene.
Limited data in animals suggest that chlorobenzene is not
teratogenic. Rats were administered chlorobenzene (100 or 300 mg/kg) in
corn oil by gavage from days 6-15 of gestation (IBT 1977). Fetal
weight, external anomalies, and skeletal and soft tissue abnormalities
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22
2. HEALTH EFFECTS
did not differ from control animals in any of the measured parameters.
Further, data on maternal weight and behavioral effects did not reveal
evidence for dose-related effects.
2.2.2.6 Reproductive Effects
No studies were located regarding the reproductive effects in
humans or animals following oral exposure to chlorobenzene.
2.2.2.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans or in
vivo studies in animals following oral exposure to chlorobenzene.
2.2.2.8 Cancer
No studies were located regarding carcinogenic effects in humans
following oral exposure to chlorobenzene.
In a chronic oral bioassay in rats and mice (NTP 1985) , there was
no evidence for carcinogenicity in both sexes of mice or 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 dose
levels. While progression from nodules to carcinomas is a well
characterized phenomenon, existing data are inadequate to characterize
the carcinogenic potential of chlorobenzene in humans. On the basis of
these data, the EPA has classified chlorobenzene as a class D carcinogen
(i.e., inadequate evidence of carcinogenicity In humans and animals)
(EPA 1987c).
2.2.3 Dermal Exposure
No studies were located regarding the following effects in humans
or animals following dermal exposure to chlorobenzene.
2.2.3.1 Death
2.2.3.2 Systemic Effects
2.2.3.3 Immunological Effects
2.2.3.4 Neurological Effects
2.2.3.5 Developmental Effects
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23
2. HEALTH EFFECTS
2.2.3.6 Reproductive Effects
2.2.3.7 Genotoxic Effects
2.2.3.8 Cancer
2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
Ogata and Shimada (1983) reported that in two workers exposed to
0.84 and 0.5 ppm of chlorobenzene, the amount absorbed was 38% and 45%,
respectively of the administered dose. It should be noted that the
percent recovery reported in this study did not take into consideration
elimination that occurred during the night nor of expired chlorobenzene.
Sullivan et al. (1983) reported that rats readily absorbed 14C-labeled
chlorobenzene vapor at concentrations up to 700 ppm.
2.3.1.2 Oral Exposure
Chlorobenzene is absorbed from the gastrointestinal tract. In a
study with a single human volunteer, Ogata and Shimada (1983) reported
that at least 31% of administered chlorobenzene was absorbed. In the
same study, rats administered chlorobenzene absorbed at least 18% of the
administered dose. Similar results were reported by Lindsay-Smith
et al. (1972), who observed that in rabbits administered lftC-labeled
chlorobenzene, at least 22% of the administered chlorobenzene was
absorbed.
2.3.1.3 Dermal Exposure
No studies were located regarding dermal exposure to chlorobenzene
in humans or animals.
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
No studies were located regarding distribution after inhalation
exposure of chlorobenzene in humans.
Sullivan et al. (1983) reported the distribution of UC-labeled
chlorobenzene vapor in rat tissues following single or multiple 8-hour
exposures. Some rats were maintained for 48 hours for urine collection.
Others were sacrificed immediately or 16 hours after exposure for
analysis of tissue radioactivity. The radioactivity in all tissues,
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24
2. HEALTH EFFECTS
except for fat, increased in proportion to the increase in exposure
concentration. The amount of the radiolabel in adipose tissue increased
8 to 10 times when the concentration was increased from 100 to 400 ppm
and 3 to 5 times from 400 to 700 ppm. Tissue levels of radioactivity
following a single exposure were highest in epididymal and perirenal fat
(16.4 and 15.3 micromoles per gram, respectively) after the 700 ppm
exposure. These values were not exceeded in animals following multiple
exposures. However, multi-exposed rats exhibited higher tissue burdens
48 hours after the last exposure, than rats exposed only once. The
preferential distribution of chlorobenzene to the adipose tissue
reflects the lipophilic nature (log octanol/water partition coefficient-
2.84 (Verschueren 1983)) of this compound. The longevity of
radioactivity in fat tissue was not determined.
2.3.2.2 Oral Exposure
No studies were located regarding the distribution of chlorobenzene
after oral exposure in humans or animals.
2.3.2.3 Dermal Exposure
No studies were located regarding the distribution of chlorobenzene
after dermal exposure in humans or animals.
2.3.3 Metabolism
The proposed metabolic pathway (adapted from Ogata and Shimada
1983) of chlorobenzene is shown in Figure 2-3. The main metabolites of
chlorobenzene are p-chlorophenylmercapturic acid and 4-chlorocatechol.
The in vitro metabolites of chlorobenzene are o-chlorophenol,
m-chlorophenol, and p-chlorophenol; the proportions differ according to
the source of the mono-oxygenase system and its state of purity
(Selander et al. 1975). The o- and p-chlorophenols result from
isomerization of the intermediate 3- and 4-chlorobenzene oxides,
respectively. The formation of m-chlorophenol appears to occur via a
direct oxidative pathway (Oesch et al. 1973). In vitro conjugation of
the arene oxide with glutathione or hydration is not a significant
pathway (Selander et al. 1975).
Ogata and Shimada (1983) examined the urinary metabolites of
chlorobenzene in human subjects. An oral dose of 0.3 mmol/kg
chlorobenzene was given to a 57-year-old male subject. Metabolites were
also assayed in 2 workers exposed via inhalation of either 0.84 or
0.5 ppm of chlorobenzene. They reported the occurrence of
4-chlorocatechol and p-chlorophenylmercapturic acid in the urine of
humans who received chlorobenzene orally or by inhalation.
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25
2. HEALTH EFFECTS
transition
CI
monochloro-
monochloro
benzene
4-chlorobenzen-
1,2-epoxide
Cl~^ y*~OH
4-chlorophend
-~ conjugate
OH
OH
-H,
>CI
OH
OH
4-chlorocatechot
3,4-dihydro-3,4-dihydroxy-
chloro binzene
_/A?H
a-V X-H
glutathione
conjugation
>——/ c
SG
* c,hQ-
-> conjugate
SCH2CHCOOH
&
I
NHCOCH,
p- chlorophenylmercapturlc acid
FIGURE 2-3. Metabolic Scheme for Chlorobenzene
Source: Adapted from Ogata and Shimada 1983.
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26
2. HEALTH EFFECTS
Ogata and Shimada (1983) also examined the urinary metabolites of
chlorobenzene in rats, mice, and rabbits. Rats were given oral doses of
0.3 mmol/kg, while all three species received intraperitoneal injections
of 0.5, 1.0, or 2.0 raraol/kg. Urinary p-chlorophenylmercapturic acid,
and 4-chlorocatechol, after hydrolysis of its conjugate, were reported.
Lindsay-Smith et a1. (1972) reported that the major metabolites of
chlorobenzene in the rabbit are p-chlorophenylmercapturic acid and
conjugates of 4-chlorocatechol. Other urinary metabolites included
quinol, 3-chlorocatechol, and o- and m-chlorophenylmercapturic acids.
Oesch et al. (1973) studied the metabolism of chlorobenzene in rats
administered chlorobenzene by intraperitoneal injection. Thirty-three
percent of the administered dose was excreted in the urine, with
p-chlorophenol as the major metabolite. Other metabolites included
4-chlorocatechol, o-chlorophenol, and m-chlorophenol.
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
Rats were exposed to uC-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 seven
(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 four 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 treatment 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.
Ogata and Shimada (1983) reported that in two workers exposed to
0.84 and 0.5 ppm of chlorobenzene, the excretion of
p-chlorophenylmercapturic acid was markedly lower than that of
4-chlorocatechol. However, the ratio of mercapturic- acid to
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27
2. HEALTH EFFECTS
4-chlorocatechol in the urine of human subjects receiving chlorobenzene
orally was similar to that of workers inhaling chlorobenzene.
2.3.4.2 Oral Exposure
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,
p-chlorophenylmercapturic acid and 4-chlorocatechol, were detected. As
in the case of inhalation exposure, the excretion of p-chlorophenylmer-
capturic 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 subjects receiving oral
chlorobenzene was similar to that of workers inhaling chlorobenzene.
Lindsay-Smith et al. (1972) reported that rabbits administered
1AC-labeled chlorobenzene excreted 22% of the radiolabel in the urine.
The authors concluded that the remaining radiolabel was excreted in the
expired air. Ogata and Shimada (1983) reported that in rats the primary
urinary metabolite was p-chlorophenylmercapturic acid and that
4-chloroatechol was a minor metabolite.
2.3.4.3 Dermal Exposure
No studies were located concerning excretion of chlorobenzene in
animals or man after dermal exposure.
2.4 RELEVANCE TO PUBLIC HEALTH
Inhalation studies in humans and animals and oral studies in
animals demonstrate that chlorobenzene can affect the central nervous
system, liver, and kidneys. Chlorobenzene did not affect the developing
fetus, was not genotoxic, and did not affect reproduction. Data has not
provided clear evidence that chlorobenzene causes cancer in animals.
Existing data are considered inadequate to derive human minimal risk
levels for acute and chronic exposures.
Death. No case studies of human fatalities have been reported
following exposure to chlorobenzene by inhalation, ingestion, or dermal
contact. Death has been reported in animals at high doses for brief
periods of exposure. Rabbits died within 2 weeks after removal from
exposure at approximately 537 ppm (Rozenbaum et al. 1947). The cause of
death has been attributed to central nervous system depression resulting
in respiratory failure. Animal data suggest that lethality may not be a
concern for humans unless the exposure level is very high.
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28
2. HEALTH EFFECTS
Systemic Effects. No studies were located regarding effects on the
respiratory, cardiovascular, gastrointestinal, hematological,
musculoskeletal, or dermal/ocular systems in humans or animals by any
route of exposure to chlorobenzene.
Hepatic Effects. No studies were located demonstrating that
chlorobenzene causes hepatic toxicity in humans by any route of
exposure. Acute and intermediate exposures in animals demonstrated that
chlorobenzene causes changes in liver weights and enzyme levels,
degeneration, necrosis, and alterations in microsomal enzymes. These
effects were first evident during acute exposure (5 days) at
1,140 mg/kg/day by gavage (Rimington and Ziegler 1963) and intermediate
exposure (5 days/wk for 24 weeks) at 75 ppm via inhalation (Dilley
1977). Similar effects were also observed following ingestion of
^ 250 mg chlorobenzene/kg/day for 91 days. The precise mechanism for
liver damage is not known; however, direct binding of chlorobenzene
metabolites to cellular protein may be involved (Reid et al. 1973; Reid
and Krishna 1973). There were differential sensitivities in animal
species tested which may be due to differences in metabolism. Based on
animal studies, liver toxicity may be an area of concern in humans.
Renal Effects. No studies were located demonstrating that
chlorobenzene causes renal effects in humans by any route of exposure.
Intermediate studies in animals showed effects on the kidney at doses
comparable to those causing liver effects. Typical signs included
tubular degeneration and necrosis as well as changes in organ weight.
Changes in organ weights with accompanying histopathology occurred at
£ 250 mg/kg/day (90 days) (Kluwe et al. 1985). The precise mechanism of
kidney damage is not clear. However, necrosis was associated with
covalent binding of substantial amounts of radiolabeled chlorobenzene to
kidney protein in intraperitoneal studies (Reid 1973). This study also
reported that autoradiograms revealed that most of the covalently bound
material was localized within necrotic tubular cells (Reid 1973). Based
on animal studies, renal toxicity may be an area of concern in humans.
Immunological Effects. Histopathologic evaluations in animals
suggest that chlorobenzene may be immunotoxic; however, direct tests of
immune function have not been performed. In the absence of functional
assessment, the potential for chlorobenzene to affect the immune system
in humans can not be determined.
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 and other
parts of the nervous system. Effects were observed in humans who
inhaled vapors of chlorobenzene in the workplace for up to 2 years
(Rozenbaum et al. 1947). Effects included headaches, dizziness, and
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29
2. HEALTH EFFECTS
sleepiness. Unconsciousness, lack of response to skin stimuli, and
muscle spasms were noted following accidental ingestion. While there is
qualitative evidence for central nervous system effects in humans, a
quantitative assessment can not be made since exposure levels were not
reported. Because work practices have changed significantly since these
studies, it is reasonable to assume that exposure levels in this study
were higher than current permissible federal exposure levels. Acute
studies in animals confirm that chlorobenzene is potentially neurotoxic.
These effects appear to be the result of narcotic effects of
chlorobenzene on the central nervous system, Acute inhalation exposure
produced narcosis preceded by muscle spasms in rabbits at 1,090 ppm
(Rozenbaum et al. 1947).
Developmental Effects. No studies were found regarding the
developmental toxicity of chlorobenzene in humans. In inhalation and
oral exposure studies, the animals did not demonstrate significant
developmental toxicity when compared with untreated controls. Negative
responses in two animal species suggest that developmental toxicity may
not be an area of concern for chlorobenzene.
Reproductive Effects. No studies were found regarding the
reproductive toxicity of chlorobenzene in humans. In a two-generation
inhalation study, chlorobenzene did not adversely affect various
reproductive parameters in rats (Nair et al. 1987). While results of
this study suggest reproductive toxicity may not be an area of concern
to humans, other considerations are warranted before firm conclusions
can be made regarding risk to humans. The slight increase in the
occurrence of degeneration of the germinal epithelium of the testes
provides some evidence for further consideration. Also, the study did
not provide histopathological data on other organs related to
reproductive functions (i.e., epididymis, vas deferens, accessory sex
glands, and pituitary). While the authors reported no treatment-related
impairment of fertility, it should be noted that fertility assessments
in test animals are limited by their insensitivity as measures of
reproductive injury in humans.
Genotoxic Effects. No studies were located regarding the genotoxic
effects of chlorobenzene in humans. No in vivo animal assays were
found, except the micronuclear test in mice which was moderately
positive (Mohtashamipur et al. 1987) (Table 2-3). Furthermore, in vitro
tests employing bacterial and yeast assay systems with and without
metabolic activation were negative (Haworth et al. 1983; NTP 1985;
Prasad 1970). Chlorobenzene induced transformation in adult rat liver
epithelial cells but was not genotoxic to hepatocytes (Shimada et al.
1983). Since transformations may occur through nongenotoxic mechanisms,
results do not necessarily indicate that chlorobenzene is potentially
genotoxic. Results of in vitro assays for chlorobenzene are presented
-------
TABLE 2-3. Genotoxicity of Qilorobenxene In Vivo
Exposure
End Point Species (Test System) Route Results Reference
Mammalian systems:
Chromosomal Mouse (micronuclear) IP + Mohtashumipur
et al. 1987
IP ¦ intraperitoneal; + * positive result.
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31
2. HEALTH EFFECTS
in Table 2-4. Existing data suggest that genotoxicity may not be an
area of concern for chlorobenzene exposure in humans.
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 both sexes or in female rats (NTP 1985). It was
noted, however, that male rats showed a statistically significant
increase in neoplastic nodules at the highest dose level tested. While
there is strong evidence for neoplastic nodules, existing data are
inadequate to characterize the potential for chlorobenzene to cause
cancer in humans and animals.
2.5 BIOMARKERS OF EXPOSURE AND EFFECT
Biomarkers are broadly defined as indicators signaling events in
biologic systems or samples. They have been classified as markers of
exposure, markers of effect, and markers of susceptibility (NAS/NRC
1989).
A biomarker of exposure is a xenoblotic substance or its
metabolite(s) or the product of an interaction between a xenobiotic
agent and some target molecule or cell that is measured within a
compartment of an organism (NAS/NRC 1989). The preferred biomarkers of
exposure are generally the substance itself or substance-specific
metabolites in readily obtainable body fluid or excreta. However,
several factors can confound the use and interpretation of biomarkers of
exposure. The body burden of a substance may be the result of exposures
from more than one source. The substance being measured may be a
metabolite of another xenobiotic (e.g., high urinary levels of phenol
can result from exposure to several different aromatic compounds).
Depending on the properties of the substance (e.g., biologic half-life)
and environmental conditions (e.g., duration and route of exposure), the
substance and all of its metabolites may have left the body by the time
biologic samples can be taken. It may be difficult to identify
individuals exposed to hazardous substances that are commonly found in
body tissues and fluids (e.g., essential mineral nutrients such as
copper, zinc, and selenium), Biomarkers of exposure to chlorobenzene
are discussed in Section 2.5.1.
Biomarkers of effect are defined as any measurable biochemical,
physiologic, or other alteration within an organism that, depending on
magnitude, can be recognized as an established or potential health
impairment or disease (NAS/NRC 1989) . This definition encompasses
biochemical or cellular signals of tissue dysfunction (e.g., increased
liver enzyme activity or pathologic changes in female genital epithelial
-------
TABLE 2*4. Genotoxicity of Chlorobenzene In Vitro
Results
End Point
Species (Test System)
With
Activation
Without
Activation
Reference
Prokaryotic organisms:
Gene mutation
Gene mutation
Eukaryotic organisms:
Fungi:
Gene mutation
Mammalian cells:
Genetic endpoint unknown
DNA Repair
Salmonella typhimuriuro
S. typhimurium
Aspergillus nidulans
Rat (cellular
transformation)
Rat (UDS)
No data
No data
No data
48 negative result: + « positive result? UDS = unscheduled DNA synthesis.
NTP 1985
Havorth et al.
1983
Prasad 1970
Shimada et al.
1983
Shimada et al,
1983
X
w
>
t-4
H
X
M
**3
C*3
O
H
to
ro
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33
2. HEALTH EFFECTS
cells), as well as physiologic signs of dysfunction such as increased
blood pressure or decreased lung capacity. Note that these markers are
often not substance specific. They also may not be directly adverse,
but can indicate potential health impairment (e.g., DNA adducts).
Biomarkers of effects caused by chlorobenzene are discussed in
Section 2.5.2.
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. It can be an intrinsic genetic or
other characteristic or a preexisting disease that results in an
increase in absorbed dose, biologically effective dose, or target tissue
response. If biomarkers of susceptibility exist, they are discussed in
Section 2.7, "POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE."
2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to
Chlorobenzene
Levels of chlorobenzene and its metabolites have been measured in
blood, urine, and exhaled air; however, no studies were located linking
any level of chlorobenzene in humans with a biological effect. Levels
ranging from 0.05 to 17 ng/L were detected in the blood and 25 to
120 *ig/L in the urine of residents living near a former toxic chemical
dump, while trace amounts were found in exhaled air (Barkley et al.
1980).
2.5.2 Biomarkers Used to Characterize Effects Caused by Chlorobenzene
Neurological damage is a characteristic biomarker of effect in
humans exposed to chlorobenzene. Additional information on health
effects associated with exposure to chlorobenzene can be found in
Section 2.2. Various clinical signs and symptoms of people exposed to
chlorobenzene which may be monitored include headaches, dizziness,
muscle spasms, and cyanosis (from respiratory depression). No data were
found on biochemical changes which may exist.
Studies in animals suggest that chlorobenzene may also cause injury
to the liver. In rats, alkaline phosphatase, SGOT, and delta-amino
levulinic acid levels were increased as were liver protoporphyrin and
uroporphyrin. Data suggest that the kidneys may be affected following
exposure to chlorobenzene as polyuria was noted in rats at high dose
levels. Since other chemicals may produce similar effects, these are
not specific indicators of chlorobenzene exposure.
2.6 INTERACTIONS WITH OTHER CHEMICALS
In an attempt to identify the proposed epoxide intermediate of
chlorobenzene, Oesch (1973) co-administered the epoxide hydrase
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34
2. HEALTH EFFECTS
InhibiCor 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.
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
No studies were located regarding human populations that are
unusually susceptible to chlorobenzene. By analogy to other lipophilic
chlorinated benzenes such as hexachlorobenzene, which is found in human
milk (Weisenberg et al. 1985), nursing infants may be susceptible to
chlorobenzene toxicity.
2.8 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, 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 the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine the health effects (and
techniques for developing methods to determine such health effects) of
chlorobenzene.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
are defined as substance - specific informational needs that, if met would
reduce or eliminate the uncertainties of human health assessment. In
the future, the identified data needs will be evaluated and prioritized,
and a substance - specific research agenda will be proposed.
2.8.1 Existing Information on Health Effects of Chlorobenzene
The existing data on health effects of inhalation, oral, and dermal
exposure of humans and animals to chlorobenzene are summarized in
Figure 2-4. The purpose of this figure is to illustrate the existing
information concerning the health effects of chlorobenzene. Each dot in
the figure indicates that one or more studies provide information
associated with that particular effect. The dot does not imply anything
about the quality of the study or studies. Gaps in this figure should
not be interpreted as "data needs" information.
As summarized in Figure 2-4, there is a paucity of data on health
effects of chlorobenzene in humans. Existing data relate to inhalation
and oral exposures. No data were found on dermal exposures.
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35
2. HEALTH EFFECTS
SYSTEMIC
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
FIGURE 2-4. Existing Information on Health Effects
of Chlorobenzene
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lb
2. HEALTH EFFECTS
The toxicity of chlorobenzene has been studied in animals by oral
and inhalation exposures, but there are no data on dermal exposures.
Oral studies have focused on systemic toxicity (liver and kidney) and
genotoxic and carcinogenic effects. There are inhalation studies
evaluating neurologic, developmental, and reproductive effects.
2.8.2 Identification of Data Needs
Acute-Duration Exposure. No information is available on the
effects of acute-duration exposure of humans to chlorobenzene by any
route of exposure. Animal studies indicate that acute inhalation and
oral exposures can result in death. No other treatment-related effects
were reported. There are no data on effects of chlorobenzene following
dermal exposure in animals. Since data on effects in humans are not
available and animal data are limited to lethality, data afe not
sufficient to derive an acute MRL. Further studies would be useful to
identify target tissues and threshold levels for effects that may exist.
Intermediate-Duration Exposure, No studies are available in humans
on the effects of intermediate-duration exposure to chlorobenzene by any
route. Inhalation and oral studies in animals indicate that the nervous
system, liver, and kidneys are principal target tissues following
exposure to chlorobenzene. An intermediate oral MRL was derived based
on liver effects in rats. There are no data on effects following dermal
exposure in animals. Because there is potential for exposure to
chlorobenzene through skin contact, additional studies by dermal
exposure would add to the database on chlorobenzene toxicity.
Chronic-Duration Exposure and Cancer. Limited studies are
available on the effects in humans chronically exposed to chlorobenzene
via inhalation and suggest that nervous system is a target tissue.
Specific exposure data were not provided. No information is available
on effects of ch.Lorobeuz.ene in. humans fallowing, ch.tor.ic oral or tiexroal
exposure. Inhalation and oral studies in animals identified the same
target tissues as for intermediate-duration exposure. One study in rats
demonstrated that the immune system can also be adversely affected via
oral exposure. Inhalation studies in humans and inhalation and oral
studies in animals are sufficient to identify main target tissues. A
chronic MRL was not derived since human exposure data were lacking and
the one animal study did not evaluate a sufficient number of end points
and test animals. Further studies via the dermal route would provide
additional toxicity data for an assessment of potential risk to humans.
No studies were found in humans regarding the carcinogenic effect
of chlorobenzene via inhalation. Since this is the primary route of
environmental exposure, additional studies would be useful to assess
potential risk to people who may be exposed to low levels of
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37
2. HEALTH EFFECTS
chlorobenzene in air near hazardous waste sites. There was no evidence
for carcinogenicity in both sexes of mice or female rats following oral
exposure to chlorobenzene. Since the animals were tested at the maximum
tolerated dose and a no-effect level for tumors in rats and mice has
been determined, additional oral studies are not warranted at this time.
Genotoxicity, No studies were found on the genotoxic effects of
chlorobenzene in humans by any route of exposure. Results of animal
assays were mixed. Chlorobenzene induced statistically significant
increases in polychromatic erythrocytes containing micronuclei in mice
following intraperitoneal injections. Results of cellular
transformation assays of rat liver epithelial cells were positive, but
chlorobenzene did not induce unscheduled DNA synthesis in primary rat
hepatocytes. Studies evaluating the mutagenic potential of
chlorobenzene have been negative. Since existing data do not suggest a
significant genotoxic risk associated with exposure to chlorobenzene,
additional studies are not warranted at this time.
Reproductive Toxicity. No studies were found on the reproductive
toxicity of chlorobenzene by any route in humans. Chlorobenzene did not
affect various reproductive parameters in a two-generation inhalation
study in rats. Additional animal studies employing another species
would provide further information for assessing potential effects on the
reproductive functions of chlorobenzene. These studies should provide
histological evaluations of organs related to reproduction function
(i.e., epididymis, vas deferens, accessory sex glands, and pituitary)
since these organs have not been evaluated. Slight increases in the
incidence of degeneration of testicular epithelium are also noteworthy
for further consideration.
Developmental Toxicity. No studies have been conducted to evaluate
the developmental toxicity of chlorobenzene in humans. Chlorobenzene
did not affect the developing fetus following inhalation and oral
exposures by rats and rabbits. While there is a potential for exposure
via the dermal route, the absence of significant effects by the primary
exposure route (inhalation) suggests that additional studies may not be
needed at this time.
Immunotoxicity. There are no data available on the inummotoxicity
of chlorobenzene in humans by any route of exposure. Histological
examination of organs and tissues of the immunological system in mice
and rats provide some evidence that chlorobenzene is potentially
immunotoxic. Immune function tests would provide a better assessment of
potential immunotoxic effects in humans.
Neurotoxicity. Limited data in humans indicate that exposure to
chlorobenzene via inhalation and oral exposures can result in effects on
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38
2. HEALTH EFFECTS
the nervous system. Clinical signs and symptoms were observed, but
histological lesions were not reported. Results of inhalation studies
in animals confirm clinical aberrations, but no data were found in
animals following oral exposure. Further studies employing other animal
species and various dose levels would be useful to determine if similar
effects exist following oral and dermal exposures. Although the
inhalation of contaminated air is the most probable route of exposure to
chlorobenzene, there is also potential for exposure through skin contact
or by consumption of contaminated water. Animal studies in which
chlorobenzene is administered orally or dermally would allow
determination of neurotoxicity by these routes.
Epidemiological 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
occupational exposures and identified the nervous system as a target
tissue following chronic inhalation of chlorobenzene. Reliable exposure
data were not reported. Additional studies which provide quantitative
exposure data would be useful in evaluating potential risk to humans and
providing a better understanding of levels which lead to effects that
may exist.
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 vapors of chlorobenzene 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 found
on 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.
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39
2. HEALTH EFFECTS
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. There are limited
animal data which 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. Although ultimate products of metabolic oxidation
are known, the oxidative pathway and possible intermediates have not
been established. 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.
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 in 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. Existing studies regarding
toxicokinetics of chlorobenzene in humans are limited, but data do
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 physiological based pharmacokinetic
modeling would be useful in determining the most suitable animal model
for assessing human risk.
2.8.3 On-going Studies
Chlorobenzene is one of 47 chemicals to be tested by NTP for
heritable genetic effects in Drosophila and for mutagenesis in the mouse
lymphoma cell mutagenesis assay.
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41
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Table 3-1 lists common synonyms, trade names and other pertinent
identification information for chlorobenzene.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Table 3-2 lists important physical and chemical properties of
chlorobenzene.
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42
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Chlorobenzene
Characteristic
Value
Reference
Chemical name
Synonyms
Trade name
Chemical formula
Chemical structure
Chlorobenzene
Monochlorobenzene;
benzene chloride;
phenylchloride;
MCB; chlorobenzol
Caswell no. 183A
C6H5C1
ci
NLM 1988
NLM 1988
NLM 1988
NLM 1988
NLM 1988
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO Shipping
HSDB
NCI
108-90-7
CZ0175000
U037,F002
No data
UN 1134
IMCO 3.3
55
C54886
NLM 1988
HSDB 1988
HSDB 1988
NLM 1988
HSDB 1988
NLM 1988
NLM 1988
CAS — Chemical Abstracts Service; NIOSH - National Institute for
Occupational Safety and Health; RTECS - Registry of Toxic Effects of
Chemical Substances; EPA - Environmental Protection Agency; OHM/TADS -
Oil and Hazardous Materials/Technical Assistance Data System;
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North
America/International Maritime Dangerous Goods Code; HSDB - Hazardous
Substances Data Bank; NCI - National Cancer Institute.
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43
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Chlorobenzene
Property Value 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,
Sax and Lewis 1987
almond-like
Odor threshold:
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
Weast 1985
alcohol, ether,
benzene
Partition coefficients:
Log octanol/water
2.84
Verschueren 1983
Log Koc
2 .52
Mabey et al. 1982
Vapor pressure at 20°C
8.8 mmHg
Verschueren 1983
Henry's law constant
3.58xl0~3 atm-m3/mol
Mabey et al. 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
Verschueren 1983
1 mg/m3 - 0.22 ppm
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45
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
Production of chlorobenzene in the United States has declined by
nearly 60%, from the peak production volume of 274,000 kkg in 1960 to
112,000 kkg 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 1980c, 1985; Hughes et al. 1983; USITC 1988).
Chlorobenzene is 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 has remained constant since 1985 although it appears that actual
production has declined slightly during that period (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 1985a; Hughes et al.
1983) .
4.2 IMPORT
Import and export data for chlorobenzene are not readily available.
Estimates indicate that for the last ten years, both imports and exports
have been negligible (Hughes et al. 1983).
4.3 USE
The current primary uses of chlorobenzene are as a solvent for
pesticide formulations, diisocyanate manufacture, degreasing automobile
parts, and for the production of nitrochlorobenzene. 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
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46
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
is also used in silicone resin production and as an intermediate in the
synthesis of other halogenated organics. The past major use of
chlorobenzene was as an intermediate in phenol and DDT production
(Hughes et al. 1983) .
4.4 DISPOSAL
Because chlorobenzene is listed as a hazardous substance, disposal
of waste chlorobenzene is controlled by a number of federal regulations
(see Chapter 7). 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 1988a, 1989b; HSDB 1988). 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 to 50% of the
annual production of chlorobenzene is released to the atmosphere, while
less than 0.1% is found in wastewater and less than 1% is disposed of on
land (EPA 1985a).
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47
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Chlorobenzene is used as a solvent and as an intermediate in
industry. A portion of that is lost to the environment in water and air
discharges. Chlorobenzene adsorbs moderately to soil and is biodegraded
comparatively rapidly. With a moderate index of bioaccumulation,
chlorobenzene was found in almost every individual tested for it in the
United States. The EPA has identified 1,177 NPL sites. Chlorobenzene
has been found at 97 of the sites evaluated for the presence of this
chemical. As more sites are evaluated by the EPA, the number may
change. The frequency of these sites within the United States can be
seen in Figure 5-1.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
The production of chlorobenzene by seven major producers was
reported to be 112,000 kkg in 1987. Estimates of environmental releases
vary widely. The EPA (1982d) estimated the release of chlorobenzene to
be about 200 tons, or 0.2% of production, while Dow Chemical Company
estimated that about 50,000 tons, or 30% to 50% of their annual
production was released to the air (EPA 1980a).
5.2.2 Water
The principal source of chlorobenzene in water is release from
chemical manufacturing facilities. Dow Chemical Company estimated that
0.1% of its annual production enters waters (EPA 1980a). Perry et al.
(1979) found chlorobenzene in 6/63 industrial effluent in concentrations
up to 100 ^g/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. Data from the Contract Laboratory Program (CLP)
Statistical Database indicate that chlorobenzene occurred in surface
water at 13 sites at a geometric mean concentration of 17 ppb In
positive samples and in groundwater at 28 sites at a geometric mean
concentration of 62 ppb in positive samples (CLPSD 1988). It should be
noted that the CLP Statistical Database includes data from both NPL and
non-NPL sites.
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FREQUENCY E
3 TO 4 SITES
OVER 15 SITES
FIGURE 5-1. Frequency of Sites with Chlorobenzene Contamination
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49
5. POTENTIAL FOR HUMAN EXPOSURE
5.2.3 Soil
Chlorobenzene was detected at 34 sites at a geometric mean
concentration of 37 ppm in positive soil samples (CLPSD 1988) . It
should be noted that the CLP Statistical Database includes data from
both NPL and non-NPL sites.
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
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 hrs (Garrison and Hill 1972). The air,
undoubtedly, plays a large role in the environmental transport and
degradation of chlorobenzene, although studies addressing this aspect
were not found.
5.3.2 Transformation and Degradation
5.3.2.1 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 UV-absorption,
chlorobenzene has a half-life of 20 to 40 hrs 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) and in rural air (not detected) in 1982
(Brodzinsky and Singh 1983).
5.3.2.2 Water
Biodegradation in a waste water inoculum was studied by Tabak
et al. (1981). Among 57 environmental pollutants tested, chlorobenzene
at 5 mg/L 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.
5.3.2.3 Soil
Biodegradation of chlorobenzene is rapid, leaving no detectable
residues after 1 or 2 weeks. Adaptation is also rapid (Tabak et al.
1981).
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50
5. POTENTIAL FOR HUMAN EXPOSURE
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
Air samples at 56 localities in the United States in 1982 had mean
chlorobenzene concentrations of about 3,000 ng/m ; e ighest
concentrations in urban and suburban areas, at much lower levels at the
sites of production, but was not detectable m rural and remote areas
(Brodzinsky and Singh 1983). This suggests a substantial contribution
to urban air levels by small industry and consumer products but also a
short residence time in the air. A study of New Jersey yaste sites
found similar air levels of chlorobenzene (2,^00 ng/m ) (Harkov et al.
1985) However, air levels found by another study done for the United
States EPA (Pellizzari 1978a) 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 (4
sites) to traces (4 sites) and 120 ng/m3 (1 site) (Barkley et al. 1980).
5.4.2 Water
Chlorobenzene, along with other chlorinated chemicals, was found in
United States' rivers at levels up to and exceeding 10,000 ng/L
(Shackelford and Keith 1976; Sheldon and Hites 1978). Private wells
near a hazardous waste site contained as much as 41 Ug/L (Clark 1982)
and tap water at Love Canal contained 10 to 60 ng/L of chlorobenzene
(Barkley et al. 1980).
Chlorobenzene contamination of industrial waste waters up to and
exceeding 100 /ig/L was found in 6/63 samples (Perry et al. 1979) and in
147/31,194 samples with a mean concentration of 667 Mg/L (EPA 1985a).
5.4.3 Soil
Staples et al. (1985) reported that the median concentration of
chlorobenzene in the United States was estimated to be less than 5 ppb
dry sediments. In 347 measurements recorded in the STORET data base, 2%
of the samples contained detectable concentrations of chlorobenzene.
5.4.4 Other Media
No studies of chlorobenzene in food or other media are available.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Chlorobenzene was found in 98/100 human adipose tissue samples from
all regions of the United States at levels ranging from 1 to 9 ng/g
(Stanley 1986). At Love Canal, Niagara Falls, chlorobenzene could be
-------
51
5. POTENTIAL FOR HUMAN EXPOSURE
detected in the breath of one of nine people evaluated for exposure and
in the urine of six of nine persons at 20 to 120 ng/L (Barkley et al.
1980).
Personal sampling at chemical companies (Cohen et al. 1981)
indicated that chlorobenzene levels (up to 18 mg/m3) in work place air
did not exceed the current federal level (350 mg/m3) .
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
Occupational settings provide the greatest potential for high
exposures to chlorobenzene. Since chlorobenzene is a volatile compound
and is used extensively as a solvent, large quantities may be released
to the workplace air. Other populations who might be exposed include
persons living near industrial facilities where chlorobenzene emissions
are not properly controlled.
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, 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 the NTP, is
required to assure the initiation of a program of research designed to
determine the health effects (and techniques for developing methods to
determine such health effects) of chlorobenzene.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
are defined as substance-specific informational needs that, if met would
reduce or eliminate the uncertainties of human health assessment. In
the future, the identified data needs will be evaluated and prioritized,
and a substance-specific research agenda will be proposed.
S.7.1 Identification of Data Needs
Physical and Chemical Properties. Physical and chemical properties
of chlorobenzene have been thoroughly measured.
Production, 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.
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52
5. POTENTIAL FOR HUMAN EXPOSURE
According to the Emergency Planning and Community Right to Know Act
of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries
are required to submit release information to the EPA. The Toxic
Release Inventory (TRI), which contains release information for 1987
became available in May of 1989. This database will be updated yearly
and should provide a more reliable estimate of industrial production and
emission.
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.
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, ground, and drinking water but
no information was found on levels in 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.
Food Chain Bioaccumulation. No information is available regardine
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.
Exposure Levels in Humans. Studies have been conducted measuring
chlorobenzene levels in drinking water and air (including indoor air)
Conflicting data on chlorobenzene air levels point to a need for
confirmation and, possibly, validation of analytical methods. Less
conflicting estimates of environmental emissions are the prerequisite
for any attempt to prioritize control measures.
Exposure Registries. No exposure registries for chlorobenzene were
located. This compound is not currently one of the compounds for which
a subregistry has been established in the National Exposure Registry.
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53
5. POTENTIAL FOR HUMAN EXPOSURE
The compound will be considered in the future when chemical selection is
made for subregistries to be established. The information that is
amassed in the National Exposure Registry facilitates the
epidemiological research needed to assess adverse health outcomes that
may be related to the exposure to this compound.
5.7.2 On-going studies
Studies on the migration and in situ biodegradation of
chlorobenzene in hazardous waste sites are being conducted in the
laboratory of Perry McCarty and others.
As part of the Third National Health and Nutrition Evaluation
Survey (NHANES III), the Environmental Health Laboratory Sciences
Division of the Center for Environmental Health and Injury Control,
Centers for Disease Control, will be analyzing human blood samples for
chlorobenzene and other volatile organic compounds. These data will
give an indication of the frequency of occurrence and background levels
of these compounds in the general population.
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55
6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods
that are available for detecting and/or measuring and monitoring
chlorobenzene in environmental media and in biological samples. The
intent is not to provide an exhaustive list of analytical methods that
could be used to detect and quantify chlorobenzene. Rather, the
intention is to identify well-established methods that are used as the
standard methods of analysis. Many of the analytical methods used to
detect chlorobenzene in environmental samples are methods approved by
federal agencies such as EPA and the National Institute for Occupational
Safety and Health (NIOSH). Other methods presented in this chapter are
those that are approved by a trade association such as the Association
of Official Analytical Chemists (AOAC) and the American Public Health
Association (APHA). Additionally, analytical methods are included that
refine previously used methods to obtain lower detection limits, and/or
to improve accuracy and precision.
6.1 BIOLOGICAL MATERIALS
Many of the considerations regarding the analysis of halogenated
alkanes and alkenes in biological samples (Fishbein 1985) similarly
apply to the determination of chlorobenzene in these samples. Although
most environmentally significant halogenated alkanes and alkenes have
boiling points below 100°C, chlorobenzene is relatively less volatile
with a boiling point of 132°C. The water solubility (25°C) of
chlorobenzene is 472 mg/L, which is lower than the water solubilities of
most environmentally and toxicologically significant halogenated alkanes
and alkenes. Along with many halogenated alkanes and alkenes,
chlorobenzene is classified as a purgeable species for purge-and-trap
analysis (EPA 1982a, 1982b). Therefore, many of the approaches and
methods used for the determination of halogenated alkanes and alkenes in
biological samples are applicable to chlorobenzene, although they have
not been validated as a sampling method.
Because chlorobenzene is volatile, has limited water solubility,
and has a moderate affinity for lipid tissue, chlorobenzene is easily
lost from biological samples. Appropriate care must be exercised in
handling and storing such samples for analysis of chlorobenzene.
The methods that generally are used to remove volatile organic
chemicals (VOCs) from biological samples for analysis are applicable to
chlorobenzene. These include headspace analysis, purge-and-trap (gas
stripping) collection from aqueous solutions or slurry samples, solvent
extraction, and direct collection on resins. Headspace analysis offers
speed, simplicity, and good reproducibility for a particular type of
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56
6. ANALYTICAL METHODS
sample. However, partitioning of the analyte between the headspace and
the sample matrix is dependent upon the nature of the matrix and must he
determined separately for different kinds of matrices (Walters 1986).
Purge-and-trap collection is well suited to biological samples that
are soluble in water and is readily adapted to biological samples from
techniques that have been developed for the analysis of halocarbons such
as chlorobenzene in water and wastewater. For water-insoluble
materials, the purge-and-trap approach is complicated by the uncertainty
of partitioning the analyte between sample slurry particles and water.
Homogenization of tissue with the extractant and lysing of cells
improves extraction efficiency. When multiple analytes are determined
using solvent extraction, selective extraction and loss of low-boiling
compounds can cause errors. The commercial availability of highly
purified solvents has largely eliminated problems with solvent
impurities, although high costs, solvent toxicities, and restrictions on
spent solvent disposal must be considered. Directly coupled
supercritical fluid extraction-gas chromatography has been used for the
determination of polychlorinated biphenyls (Hawthorne 1988) and should
work well for the determination of chlorobenzene in biological samples.
Analytical methods for the determination of chlorobenzene in
biological samples are given in Table 6-1.
6.2 ENVIRONMENTAL SAMPLES
Purgeable organic compounds such as chlorobenzene can be determined
in water by the purge-and-trap technique. This method consists of
bubbling inert gas through a small volume of the sample and collecting
the vapor in a trap packed with sorbent. The analytes are then removed
from the trap by heating it and backflushing the analytes onto a gas
chromatographic column. The two materials most widely used for
adsorption and thermal desorption of volatile organic compounds
collected by the purge-and-trap technique are Carbotrap® consisting of
graphitized carbon black, and Tenax® a porous polymer of 2,6-diphenyl-p-
phenylene oxide (Fabbri et al. 1987).
-------
TABLE 6-1. Analytical Methods for Determining Ghlorobenxene La Biological Materials
Sample
Detection
Sample Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Breath, blood,
urine
Fish tissue
Breath collected on Tenax,
blood and urine subjected to
purge-and-trap, concentrated
on cryogenic capillary trap,
thermally removed to GC.
Grind with sodium sulfate,
extract with hexane/acetone
GC/MS
GC/ECD
No data
No data
No data
Barkley et al.
1980
Oliver and
Nicol 1982a,
1982b
Adipose tissue Extraction, bulk lipid removal,
Florisil fractionation
Adipose tissue Heated dynamic headspace
purge-and-trap
Biofluids* Dilute vith water, sealed vial,
collection o£ headspace vapors
Blood, tissue Macerate tissue in water, warm
blood or tissue, pass inert gas
through, trap on Tenax,
thermal desorption
HRGC/MS
HRGC/MS
GC/ECD
GC/MS
0.1 fj%! g
2 ng/g
No data
3 ng/roL
blood
6 ng/g
tissue
No data
No data
No data
No data
Mack and
Stanley 1984
Stanley 1986
Suithe inter
et al. 1982
Pellizz&ri
et al. 1985
>
5
o
>
r
H
jr
o
©
to
ui
Among the compounds for which this method was used are benzene, m-xylene, carbon tetrachloride and chloroform,
be adapted to chlorobenzene although the procedures do not list this compound specifically as an analyte.
The method can
GC m gas chromatography; MS ¦ mass spectrometry; ECD » electron capture detector; HRGC » High Resolution Gas Chromatography;
jjg/g * microgram per gram; ng/g * nanogram per gram.
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58
6. ANALYTICAL METHODS
The introduction of capillary column chromatography has markedly
improved both the sensitivity and resolution of gas chromatographic
analysis of environmental samples such as chlorobenzene. Because of the
very small quantities of sample required, capillary column chromato-
graphy has made sample delivery more difficult. One of the more
promising approaches to sample introduction using capillary columns with
purge-and-trap collection is the use of cryofocussing. Basically, this
procedure consists of collecting purged analyte on a short section of
the capillary column cooled to a low temperature (e.g., -100°C)
temperature, followed by heating and backflushing of the sample onto the
analytical column. Chlorobenzene has been determined in water by this
method (Washall and Wampler 1988).
Chlorobenzene can be removed from water by adsorption on synthetic
polymers contained in cartridges, followed by thermal desorption of
analyte (Pankow et al. 1988). Among the products used for this purpose
are Tenax-GC® and Tenax-TA®.
Analytical methods for the determination of chlorobenzene in
environmental samples are given in Table 6-2.
6.3 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, 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 the NTP, is
required to assure the initiation of a program of research designed to
determine the health effects (and techniques for developing methods to
determine such health effects) of chlorobenzene.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
are defined as substance-specific informational needs that, if met would
reduce or eliminate the uncertainties of human health assessment. In
the future, the identified data needs will be evaluated and prioritized,
and a substance-specific research agenda will be proposed.
-------
TABLE 6-2. Analytical Methods for Determining Ghlorobenzene in Environmental Samples
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
References
Air
Water
Water
Water
Water
Contaminated
soil
Wastes (non-
vater miscible)
and soil
Wastes (water
miscible
and non-water
miscible) and
soil
Collect on Tenax GC, thermal
desorption, cryogenic collection
on a capillary trap, thermal
transfer to GC
Coconut shell charcoal sorption,
carbon disulfide desorption
Purge-and-trap
Purge-and-trap
Pu rge -and-1 rap
Sorption on small dead volume
Tenax cartridges, thermal
desorption
Purge-and-1 rap
Purge-and-1 rap
Purge-and-trap
GC/MS
GC/FID
GC/HSD
GC/MS
GC/MS
HRGC/MS
GC/HSD
GC/MS
GC/MS
0.47 parts
per trillion
10 jig per
sample
0.25 pg/1-
0.2 Aig/L
6.0 fj&/L
No data
300 Mg/kg
250 ^g/kg
250-2500
4Jg/kg
No data
No data
No data
No data
No data
No data
No data
No data
Krost et al. 1982
NIOSH 1984
EPA 1982a
EPA 1982b
EPA 1982c
Pankow et al. 1988
EPA 1986a
EPA 1986b
EPA 1986c
>
H
t
O
>
f
PS
w
H
EC
O
a
00
GC * gas chromatography; MS = mass spectrometry; FID * flame ionization detector; jig = microgram; HSD * halide specific detector;
L * liter; ERGC * high resolution gas chromatography; leg ~ kilogram.
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60
6. ANALYTICAL METHODS
6.3.1 Identification of Data Needs
Methods for Determining Biomarkers of Exposure and Effect.
Excellent sensitive and selective methods are available for the
qualitative and quantitative measurement of the parent compound,
chlorobenzene after it is separated from its sample matrix. Methods
need to be validated for chlorobenzene.
Further studies on the transfer analytes that have been purged or
extracted from a biological or environmental sample quantitatively and
in a narrow band to the capillary GC would better characterize exposure.
Improvements in cryofocussing of VOC analytes for capillary GC
determination of VOCs (Washall and Wampler 1988) should improve
sensitivity for the determination of chlorobenzene.
Metabolites of chlorobenzene in biological materials cannot be
determined in routine practice because of the lack of standard methods
for measuring these metabolites. Further research on supercritical
fluid (SCF) extraction holds great promise for meeting the goals of
quantitative, rapid, easily performed, low cost, and safe procedures for
the determination of nonpolar organic analytes such as chlorobenzene in
biological samples.
Central nervous system, liver, and kidney injuries are characteristic
biomarkers for effects of chlorobenzene intoxication. Since the effects
are indicative of exposure to many other toxicants, methods are needed
for more specific biomarkers.
Methods for Determining Parent Compounds and Degradation Products
in Environmental Media. Methods for determining the parent compound,
chlorobenzene, in water, air, and waste samples with excellent
selectivity and sensitivity are highly developed, thus the database in
this area is good and undergoing constant improvement.
Means to measure organohalides such as chlorobenzene in situ in
water and other environmental media could contribute to environmental
studies of this compound.
Degradation products of chlorobenzene in environmental media are
difficult to determine. This difficulty is not so much an analytical
problem as it is a problem of knowing the fundamental environmental
chemistry of these compounds in water, soil, air, and biological
systems.
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61
6. ANALYTICAL METHODS
6.3.2 On-going Studies
Research is ongoing to develop a "Master Analytical Scheme" for
organic compounds in water (Michael et al. 1988), which includes
chlorobenzene as an analyte. The overall goal is to detect and
quantitatively measure organic compounds at 0.1 /ig/L in drinking water,
1 /ig/L in surface waters, and 10 Mg/L in effluent waters. Analytes are
to include numerous semivolatile compounds and some compounds that are
only "semi-soluble" in water, as well as volatile compounds
(bp < 150°C).
The Environmental Health Laboratory Sciences Division of the Center
for Environmental Health and Injury Control, Centers for Disease
Control, is developing methods for the analysis of chlorobenzene and
other volatile organic compounds in blood. These methods use purge and
trap and magnetic mass sector spectrometry which gives detection limits
in the low parts per trillion range.
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63
7. REGULATIONS AND ADVISORIES
Because of its potential to cause adverse health effects in exposed
people, a number of regulations and advisories have been established for
chlorobenzene by various national and state agencies. These values are
summarized in Table 7-1.
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64
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Chlorobenzene
Agency
Regulations:
a. Air:
OSHA
b. Water:
EPA ODW
EPA OMRS
Description
National
PEL TWA
Monitoring required for
unregulated contaminants
MCL (Proposed)
General permits under NPDES
Value
75 ppm
(350 mg/nv')
NA
0 .1 mg/L
NA
Reference
OSHA 1989
(29 CFR 1910.1000,
Table Z-l-A)
EPA 1987a, (liO CFR
141.40)
EPA 1989c
40 CFR 122,
(Appendix D,
Table II)
c. Nonspecific media:
EPA OERR
EPA OSW
EPA OTS
Guidelines:
a. Air:
ACGIH
NIOSH
Criteria and Standards for the NPDES
General pretreatment regulations for
existing and new sources of pollution
Hazardous substance
Reportable quantity
Reportable quantity
Hazardous waste constituent
(Appendix VIII)
Groundwater monitoring list
(Appendix IX)
Restriction on land disposal
Preliminary assessment information rule
Health and safety data reporting rule
Final test rule
Toxic chemical release reporting
TLV TWA
IDLH
NA
NA
NA
100 lb
100 lb
NA
NA
NA
NA
NA
NA
NA
75 ppm
(3 50 mg/ra3)
2400 ppm
40 CFR 125
40 CFR 403
EPA 1985b, (40 CFR
116)
40 CFR 117.3
EPA 1985b, (40 CFR
302.4)
EPA 1980b, (40 CFR
261)
EPA 1987b, (40 CFR
264)
EPA 1988b, 1989c,
(40 CFR 268)
EPA 1982d, (40 CFR
712)
EPA 1988c, (40 CFR
716.120)
EPA 1986e, (40 CFR
799.105)
EPA 198Bc, (40 CFR
372)
ACGIH 1986
NIOSH 1985
b. Water:
EPA ODW
MCLG (proposed)
Health advisories
1 day
10 days
0.1 mg / L
2 mg/L
2 mg/L
EPA 1989c
EPA 1987c
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65
7. REGULATIONS AND ADVISORIES
TABLE 7-1 - (Continued)
Agency
Description
Value
Reference
EPA OMRS
Longer term
child
adult
Lifet ime
Ambient water quality criteria
Ingesting water and organisms
2 mg/L
7 mg/L
100 mg/L
4.88X10"1 mg/L
EPA 1980b
Other:
EPA
Regulations:
a. Air:
Connecticut
Florida-Tampa
Massachusetts
Nevada
New York
North Carolina
North Dakota
Virginia
b. Water:
Arizona
California
Kansas
Maine
Minnesota
New Jersey
Vermont
Wisconsin
Carcinogenic classification
Oral RfD
State
Acceptable ambient air concentration
Drinking water
Group Da
2x10~2 mg/kg/day
7000 ug/m^ (8 hr)
3500 yg/m^ (8 hr)
6.3 jig/m-* (24 hr)
8.333 (ig/m^ (8 hr)
1167.0 iig/m^ (1 yr)
2200 Mg/*n^ (24 hr)
3500 t*g/m^ (8 hr)
6000 Mg/xn^ (24 hr)
60 |ig/L
30 pg/L
60 pg/L
47 |ig/L
60 |ig/L
2 jig/L
600 pg/L
600 pg/L
EPA 1987c
IRIS 1989
NATICH 1988
FSTRAC 1988
a Group D: Not classifiable as to human carcinogenicity: Inadequate human and animal evidence of
carcinogenicity.
OSHA * Occupational Safety and Health Administrations PEL - Permissible Exposure Limit; TWA « Time-Weighted
Average; EPA * Environmental Protection Agency: ODW * Office of Drinking Water; NA * Not Applicable; MCL *
Maximum Contaminant Level; OWRS » Office of Water Regulations and Standards; NPDES ™ National Pollutant
Discharge Elimination System; OERR «* Office of Emergency and Remedial Response; OSW ¦» Office of Solid Wastes;
OTS = Office of Toxic Substances; ACGIH « American Conference of Governmental Industrial Hygienist*; TLV *
Threshold Limit Value; NIOSH « National Institute for Occupational Safety and Health; IDLH ¦ Immediately
Dangerous to Life or Health Level; MCLG ¦ Maximum Contaminant Level Goal; RfD » Reference dose.
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67
8. REFERENCES
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9. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (K^) -- 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 a 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.
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 time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant increases in incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling value (CL) -- A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure - - Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
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.
Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as
a result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
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84
9. GLOSSARY
EPA Health Advisory -- An estimate of acceptable drinking water levels
for a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH) -- The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape - impairing symptoms or irreversible
health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity -- The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In Vitro -- Isolated from the living organism and artificially
maintained, as in a test tube.
In Vivo -- Occurring within the living organism.
Lethal ConcentrationC^,) (LClo) ^he l°west concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration^) (LC50) " ^ calculated concentration of a
chemical in air to which exposure tor a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal DoseU) CLDW) -- The lowest dose of a chemical introduced by a
route other than inhalation that l P to have caused death in
humans or animals.
Lethal Dose(50) (LD50) -- The dose of a ^emicai which has been
calculated to cause death in 50% ° experimental animal
a
in 50%
population.
Lethal Time(50) (LT50) -- A calculated period of time within which
specific concentration of a chemic^ s expected to cause death i
of a defined experimental animal popu ation.
Lowest-Observed-Adverse-Effect ' The lowest dose of
chemical in a study or group of stU nich produces statistically or
biologically significant increases aJUency °r severity of adverse
effects between the exposed pop^la its appropriate control.
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85
9. GLOSSARY
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level (MRL) --An estimate of daily human exposure to a
chemical that is likely to be without an appreciable risk of deleterious
effects (noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
which there are no statistically or biologically significant increases
in frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (K,^,) -- The equilibrium ratio of
the concentrations of a chemical in n-octanol and water, in dilute
solution.
Permissible Exposure Limit (PEL) -- An allowable exposure level in
workplace air averaged over an 8-hour shift.
qx* -- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The qx* can
be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually //g/L for
water, mg/kg/day for food, and ng/m3 for air).
Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps
an order of magnitude) of the daily exposure of the human population to
a potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ) -- The quantity of a hazardous substance that
is considered reportable under CERCLA. Reportable quantities are: (1) 1
lb or greater or (2) for selected substances, an amount established by
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86
9. GLOSSARY
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-hour period.
Reproductive Toxicity -- The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
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) -- A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA) -- An allowable exposure concentration
averaged over a normal 8-hour workday or 40-hour workweek.
Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a
route other than inhalation, which is expected to cause a specific toxic
effect in 50% of a defined experimental animal population.
Uncertainty Factor (UF) - - A factor used in operationally deriving the
RfD 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 humans, (3)
the uncertainty in extrapolating from data obtained in a study that is
of less than lifetime exposure, and (A) the uncertainty in using LOAEL
data rather than NOAEL data. Usually each of these factors is set equal
to 10.
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87
APPENDIX
APPENDIX
PEER REVIEW
A peer review panel was assembled for chlorobenzene. The panel
consisted of the following members: Dr. David Jollow, Professor in the
Department of Pharmacology, Medical University of South Carolina,
Charleston, South Carolina; Dr. Henry Peters, Professor in the
Department of Neurology, University of Wisconsin Clinical Science
Center, Madison, Wisconsin; Dr. Jay B. Silkworth, Research Scientist,
Wadsworth Center Labs, New York Department of Health, Albany, New York;
Dr. Frank Lu, Private Toxicology Consultant, Miami, Florida; Dr. James
Pollard, Private Consultant, Las Vegas, Nevada. These experts
collectively have knowledge of chlorobenzene's physical and chemical
properties, toxicokinetics, key health end points, mechanisms of action,
human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer
review specified in Section 104(i)(13) of the Comprehensive
Environmental Response, Compensation, and Liability Act, as amended.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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