TOXICOLOGICAL PROFILE FOR
 

CHLOROBENZENE
 

Agency for Toxic Substances and Disease Registry
 

U.S. Public Health Service
 

December 1990
 
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.
 










1
 

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
 
2
 

1. PUBLIC HEALTH STATEMENT
 

contaminated with chlorobenzene, or by getting chlorobenzenecontaminated 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
 
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 l-l and l-3). Tables l-2 and
 

l-4 show the relationship between exposure to chlorobenzene and known
 

health effects in animals. A Minimal Risk Level (MRL) is included in
 

Table l-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
 

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
 

cholorobenzene 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 minimum 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 Substance 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.
 
9
 

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
 
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) are 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 (4,300 ppm) for 2 hours resulted
 

in 100% mortality in mice (Rozenbaum et al. 1947). 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 inhalation
 

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.
 



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 mg/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 [LDH] and serum
 

glutamic-oxaloacetic transaminase [SGOT]) 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 may
 

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-l
 

and plotted in Figure 2-l.
 

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 275 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.
 
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-l
 

and plotted in Figure 2-l.
 

2.2.1.3 Immunological Effects
 

No studies were located regarding the immunological effects in
 

humans or animals following inhalation exposure to chlorobenzene.
 

2.2.1.4 Neurological Effects
 

Chlorobenzene affects the central nervous system. Humans
 

occupationally 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-l and plotted in Figure 2-l. 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-l 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 F1 generations) and the
 

F1 mid-dose (150 ppm) males. The significance of this finding is
 
16
 

2. HEALTH EFFECTS
 

unclear since the mean mating, pregnancy, and male fertility indices for
 

both F0 and F1 generations were comparable for all groups and the
 

incidences of testicular lesion were identical in F0 and F1 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 >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 l-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.
 
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 

≥ 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 >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 l-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 >250 mg/kg in mice and >500 mg/kg in
 

rats (NTP 1985). Repeated doses of >100 mg/kg/day for 90 to 99 days
 

(Hazleton 1967) caused an increase in kidney weights.
 



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
 

>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 1985). 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
 
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 
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 14C-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 14C-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,
 
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.
 

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 mmol/kg. Urinary p-chlorophenylmercapturic acid,
 

and 4-chlorocatechol, after hydrolysis of its conjugate, were reported.
 

Lindsay-Smith et al. (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 14C-chlorobenzene vapor at concentrations of
 

100, 400, and 700 ppm for 8 hours (Sullivan et al. 1983). The plasma
 

concentration-time profile for chlorobenzene on cessation of exposure,
 

as estimated by respiratory elimination of radioactivity, indicated a
 

two compartment elimination. Increase in exposure by a factor of 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
 
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-chlorophenylmercapturic acid was reported to be markedly lower than that of 4­

chlorocatechol. However, the ratio of mercapturic-acid to 4­

chlorocatechol in the urine of human subjects receiving oral
 

chlorobenzene was similar to that of workers inhaling chlorobenzene.
 

Lindsay-Smith et al. (1972) reported that rabbits administered
 14C-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.
 
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
 
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
 

2.5 

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.
 

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 xenobiotic 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
 

 

 

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 a
 

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 mg/L were detected in the blood and 25 to 

120 μg/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 we
 

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
 
 

34
 

2. HEALTH EFFECTS
 

inhibitor cyclohexane oxide together with chlorobenzene to rats.
 

Instead of increasing the toxicity of chlorobenzene as expected, through
 

the inhibition of epoxide hydrase, cyclohexane oxide actually decreased
 

the metabolism of chlorobenzene and its necrotic toxicity on the liver,
 

suggesting that the metabolism of chlorobenzene is partially responsible
 

for its liver toxicity.
 

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.
 

36
 

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 are not
 

sufficient to derive an acute MEL. 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 chlorobenzene in humans following chronic oral or dermal
 

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
 
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 immunotoxicity
 

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
 
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.
 
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.
 

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.
 



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 distiller
 

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
 
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).
 
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-l.
 

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 μg/L. Based on 1,338 samples collected from about 1980 to 

1983, the medium concentration of chlorobenzene in waste effluent was 

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

the environment was not reported (Staples et al. 1985). Chlorobenzene 

has been detected in both surface and groundwater samples at hazardous 

waste sites. 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. 

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).
 
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/m3

; the highest
 

concentrations in urban and suburban areas, at much lower levels at the
 

sites of production, but was not detectable in 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 waste sites
 

found similar air levels of chlorobenzene (2,500 ng/m3

) (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 μg/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 μg/L was found in 6/63 samples (Perry et al. 1979) and in 

147/31,194 samples with a mean concentration of 667 μg/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.
 

5.7.1 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.
 
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 regarding
 

biomagnification within aquatic or terrestrial food chains. Additional
 

studies would be useful in assessing potential for human exposure to
 

chlorobenzene.
 

Exposure Levels in Environmental Media. There are studies on
 

concentrations of chlorobenzene in air and water, but many of the
 

samples measured had low levels or did not have detectable levels.
 

Additional studies using more sensitive analytical methods would be
 

useful.
 

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.
 
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.
 

6.1 

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.
 

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
 
6.2 

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 be
 

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.
 

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-diphenylpphenylene oxide (Fabbri et al. 1987). 

6.3 

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 chromatography 

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.
 

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.
 

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.
 
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 μg/L in drinking water, 

1 μg/L in surface waters, and 10 μg/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.
 

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.
 



_____________ 

67
 

8. REFERENCES
 

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Cohen JM. 1979. Monochlorobenzene Survey Report, Montrose Chemical
 

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* Dilling WL, Bredeweg CJ, Tefertiller NB. 1976. Organic photochemistry:
 

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U.S. Department of Health and Human Services, Pubic Health Service,
 

Centers for Disease Control, National Institute for Occupational Safety
 

and Health. NTIS No. PB87-174140.
 

* EPA. 1980a. TSCA chemical assessment series, assessment of testing
 

needs: chlorinated benzenes, support document for proposed health
 

effects test rule. Washington, DC: U.S. Environmental Protection
 

Agency. EPA 560/11-80-014. NTIS No. PB80-220296.
 

* EPA. 1980b. U.S. Environmental Protection Agency. Federal Register.
 

45:33084-33133.
 

* EPA. 198Oc. Ambient water quality criteria for: Chlorinated benzenes.
 

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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 (Koc) -- The ratio of the amount of a chemical
 

adsorbed per unit weight of organic carbon in the soil or sediment to
 

the concentration of the chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by 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
 

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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.
 
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 Concentration(LO) (LCLO) -- The lowest concentration of a chemical
 

in air which has been reported to have caused death in humans or
 

animals.
 

Lethal Concentration(50) (LC50) -- A calculated concentration of a
 

chemical in air to which exposure for a specific length of time is
 

expected to cause death in 50% of a defined experimental animal
 

population.
 

Lethal Dose(LO) (LDLO) -- The lowest dose of a chemical introduced by a
 

route other than inhalation that is expected to have caused death in
 

humans or animals.
 

Lethal Dose(50) (LD50) -- The dose of a chemical which has been
 

calculated to cause death in 50% of a defined experimental animal
 

population.
 

Lethal Time(50)(LT50) -- A calculated period of time within which a
 

specific concentration of a chemical is expected to cause death in 50%
 

of a defined experimental animal population.
 

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of
 

chemical in a study or group of studies which produces statistically or
 

biologically significant increases in frequency or severity of adverse
 

effects between the exposed population and its appropriate control.
 
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 (Kow) -- 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.
 

q1* -- The upper-bound estimate of the low-dose slope of the doseresponse 

curve as determined by the multistage procedure. The q1* can 

be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for 

water, mg/kg/day for food, and μg/m3

 for air). 

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
 
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 (4) the uncertainty in using LOAEL
 

data rather than NOAEL data. Usually each of these factors is set equal
 

to 10.
 
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.