820K87101
March 31. 1987
CHLOROBEN2ENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
-------
March 31, 1987
-2-
This Health Advisory (HA) is based on information presented in the Office
of Drinking Water's draft Health Effects Criteria Document (CD) for Chloroben-
zene (U.S. EPA, 1985a). The HA and CD formats are similar for easy reference.
Individuals desiring further information on the toxicological data base or
rationale for risk characterization should consult the CD. The CD is available
for review at each EPA Regional Office of Drinking Water counterpart (e.g.,
Water Supply Branch or Drinking Water Branch), or for a fee from the National
Technical Information Service, U.S. Department of Commerce, 5285 Port Royal
Rd., Springfield, VA 22161, PB #86-117769/AS. The toll-free number is (800)
336-4700; in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPOERTIES
CAS No. 108-90-7
Structural Formula
Synonyms
0 Monochlorobenzene, benzene chloride, chlorobenzol, phenyl chloride.
Uses
Production of chloronitrobenzene and diphenyl ether; rubber inter-
mediates; solvent in adhesives, paints, waxes, polishes; and inert
solvent.
Properties; (Irish, 1963)
Chemical Formula
Molecular Weight
Physical State (room temp.)
Boiling Point
Melting Point
Density
Vapor Pressure
Specific Gravity
Water Solubility
Oil/Water Coefficient
Log Octanol/Water Partition
Coefficient
Odor/Taste Threshold (water)
Odor Threshold (water)
Odor Threshold (medium unknown)
Conversion Factor (air)
C6H5C1
112.6
Colorless,
132°C
-45°C
neutral liquid
11.8 mm Hg (at 25°C)
1.106 (at 25°C)
500 mg/L (at 20°C)
918 (Sato and Nakajima, 1979)
2.84 (Leo et al., 1971)
0.41-1.5 ug/L (Tarkhova, 1965)
10-20 ug/L (Varshavskaya, 1968)
50 ug/L (Amoore and Hautala, 1983)
0.21 mg/L (A.D. Little, 1968)
1 ppm = 4.7 mg/m3
-------
Chlorobenzene March 31, 1987
-3-
Occurrence
0 There are no natural sources of Chlorobenzene.
0 Chlorobenzene production in 1984 was 256 million Ibs (USITC, 1985).
The majority of releases result from Chlorobenzene's use as a solvent.
Due to Chlorobenzene's volatility, most of its environmental releases
occur to air. Chlorobenzene is released to water and the ground
during the disposal of waste solvent. Because Chlorobenzene is used
in metal cleaning operations, releases occur in industrial areas
nationwide (U.S. EPA, 1987).
0 Chlorobenzene released to the atmosphere is expected to degrade slowly
by free radical oxidation. Chlorobenzene released to surface water
is expected to partition rapidly to air where it also is expected to
degrade. Chlorobenzene has been shown to be relatively resistant to
biodegradation. Based on limited studies, EPA estimates the half-life
of Chlorobenzene in soil to be several months. When released to the
ground, Chlorobenzene is expected to bind to soil and to migrate slowly
to ground water. Chlorobenzene has been reported to bioaccumulate in
fish, aquatic invertebrates and algae. In higher organisms, Chloro-
benzene has been shown to be metabolized to other compounds (U.S. EPA,
1979).
0 Chlorobenzene rarely occurs as an environmental contaminant. Federal
surveys of drinking waters derived from surface water have not reported
the presence of Chlorobenzene. (A few groundwater systems have been
found with Chlorobenzene levels in the low ppb range. No information
of the occurrence of Chlorobenzene in food has been identified.
Chlorobenzene has been identified as a contaminant of air at very low
levels (less than 1 ppb) in urban and suburban areas. Even with the
low levels of Chlorobenzene in air, inhalation is probably the major
route of environmental exposure (U.S. EPA, 1983).
III. PHARMACOKINETICS
Absorption
0 No data are available which demonstrate the percentage of the dose
absorbed following oral exposure. Based upon what is known about the
high lipid solubility of Chlorobenzene along with absorption charac-
teristics of benzene and the smaller chlorinated ethanes and ethylenes
which are also highly lipid soluble, it will be assumed, for the
purpose of the development of Health Advisories, that 100% of any
orally administered dose is absorbed, while 60% of a dose inhaled
over a period of one to several hours is absorbed and retained
(Astrand, 1975; Dallas et al., 1983).
Distribution
0 Sullivan et al. (1983) studied the distribution of 14C-Chlorobenzene
in male Sprague-Dawley rats following single or multiple 8-hour
inhalation exposures at 100, 400 or 700 ppm (460, 1,880 or 3,290
-------
Chlorobenzene March 31, 1987
mg/m3). The highest concentrations were found in the fat (epididymal
and perirenal). The kidneys and liver also showed significant amounts.
The amounts found in these tissues were proportional to dose except
for adipose tissue which showed greatly exaggerated accumulation with
dose when compared to the other tissues. The 14c burden of adipose
tissue increased with increasing exposure concentrations. In addition,
there also was a tendency for multiply-exposed rats to exhibit higher
tissue burdens than rats exposed only once.
Metabolism
0 The metabolic transformation of Chlorobenzene has been studied in
several mammalian species, including the human (Williams et al.,
1975). While absolute quantities and ratios differ between species,
the principal metabolites for each species are p-chlorophenol/
p-chlorocatechol and p-chlorophenyl-mercapturic acid.
0 Because of its lipophilicity (log P =2.96), Chlorobenzene tends to
bioaccumulate in adipose tissue as exposure continues (Sullivan,
et al., 1983). Upon termination of exposure, the chemical would
be expected to be released from the fat stores and become available
for metabolic activation and potential continuation of induction
of toxicity.
Excretion
The chlorophenol metabolite is excreted as the ethereal sulfate or
the glucuronide (Spencer and Williams, 1950; Azouz, et al, 1953).
Other excretion products include the chlorophenyl mercapturic acid,
4-chlorocatechol, and to a lesser degree in some species, phenol and
hydroquinone (Williams et al., 1975; Sullivan et al., 1983).
When the metabolic pathways for Chlorobenzene biotransformation
become saturated, increasing amounts of the chemical are exhaled
unchanged (Sullivan et al., 1983). In rats exposed to 100 ppm
(470 mg/m3) (a dose which did not saturate metabolic pathways) in air
for 8 hours, 5% was excreted via inhalation and 95% in the urine.
Repeated dosing (8 hr/day for 4 or 5 days) at 700 ppm (a dose that
does saturate metabolic pathways) results in 32% being exhaled and
68% excreted in the urine.
IV. HEALTH EFFECTS
Humans
The only information available on the effects of Chlorobenzene in the
human comes from case reports of poisonings or occupational exposures.
No data on actual exposure concentrations are presented in any of
these reports.
Inhalation exposure to Chlorobenzene has been observed to result in
signs of central nervous depression (sedation and narcosis) as well
-------
Chlorobenzene March 31, 1987
-5-
as irritation of the eye and respiratory tract (Rozenbaum et al.,
1947; Girard et al., 1969; Smirnova and Granik, 1970).
Rozenbaum et al. (1947) also noted thrombocytopenia and leukopenia
in some of the workers described in their study. The question arises
as to whether this effect was induced by the chlorobenzene or some
contaminant.
Cardiac effects such as chest pain, bradycardia and ECG irregularities
and toxemia of pregnancy have been noted in individuals exposed to
chemicals used in the production of chlorobenzene (Ounaeveskii, 1972;
Petrova and Vishnevskii, 1972). Chlorobenzene cannot be identified
as the causative agent since these workers were exposed to mixtures
of substances over varying periods of time.
Animals
Short-term Exposure
Reported oral LD$Q'S in adult animals range from 2.8 to 3.4
(Irish, 1963; Vecerek et al., 1976). Reported inhalation
range from 0.05 (guinea pig) to 20 mg/1 (mouse-2 hour exposure)
{Rozenbaum et al., 1947; Lecca-Radu, 1959).
In rats, single subcutaneous doses greater than 5 g/kg produced hyper-
excitability and muscle spasms, followed by CNS depression and death
(Rozenbaum, et al, 1947; von Oettingen, 1955).
Chlorobenzene causes necrosis of the liver and interferes with
porphyrin metabolism (Rimington and Ziegler, 1963; Khanin, 1969;
Knapp et al., 1971). Oral doses of 1140 mg/kg/day administered to
rats for 5 days resulted in increases in urinary excretion of copro-
porphyrin III, uroporphyrin and porphobilinogen (Rimington and Ziegler,
1963). Delta-aminolevulinic acid levels also were increased as were
liver protoporphyrin and uroporphyrin.
Kidneys of rabbits receiving 2 to 20 doses of chlorobenzene at 0.9 mg/kg
by injection over a two-week period showed swelling of the tubular and
glomerular epithelia (Rozenbaum et al., 1947).
Chlorobenzene has been shown to produce alterations in bile duct-
pancreatic flow (a phenomenon of unexplained significance)(Yang et al.,
1979), and blood dyscrasias such as leukopenia and lymphocytosis
(Cameron et al. 1937; Rozenbaum et al., 1947; Zub, 1979). As noted
for the human, there is a question as to whether these hematopoietic
effects resulted from chlorobenzene or a contaminant.
Administration of chlorobenzene in corn oil by gavage for 14 consecutive
days to male and female F344/N rats and B6C3F1 mice was ineffective
in rats and mice at doses of 500 mgAg/day. Rats were also given
1,000 and 2,000 mg/kg/day doses, which were fatal. Survival, body
weights and necropsies data were obtained. Histopathology was not
performed.
-------
Chlorobenzene March 31, 1987
-6-
Long-term Exposure
0 Adolescent dogs (6/sex/group) were exposed to Chlorobenzene vapors
at target levels of 0, 0.78, 1.57 or 2.08 mg/1 air for 6 hr/day, 5
days/week for 6 months (Monsanto, 1980). Significant changes included
a decrease in absolute adrenal weights in males at the mid- and high-
dose levels, an increase in liver: body weight ratio in females at the
mid- and high -doses, a sex-independent, dose-related increased inci-
dence in emesis and an increase in the frequency of abnormal stools
in treated females. The NOAEL is 0.78 mg/L.
0 Oral administration of Chlorobenzene by capsule at doses of 0, 27.25,
54.5 or 272.5 mg/kg/day to male and female beagle dogs daily, 5 days/
week, until sacrifice at 93 days resulted in observable effects
(mortality, lesions, various toxic effects) only at the high dose
(Knapp et al., 1971; Hazelton, 1967a). The NOAEL is 54.5 mg/kg/day.
0 Oral dosing of rats at levels of 14.4, 144 or 288 mg/kg/day, 5 days/
week for 6 months yielded significant increases in liver and kidney
weights and histopathological changes in the livers of mid- and
high-dose animals (Irish, 1963). No changes were observed at the
low dose. The NOAEL is 14.4 mg/kg/day.
0 Male and female rats were fed Chlorobenzene in their diets at levels
equal to 12.5, 50, 100 or 150 mg/kg/day for 90 to 99 days (Knapp, et
al., 1971; Hazelton, 1967b). Males showed retarded growth at the
highest dose. At the mid- and high dose levels, significant increases
in liver and kidney weights were noted. The two lowest dose produced
no adverse effects. The NOAEL is 50 mg/kg/day.
0 In subchronic (90 or 91 day) studies in which both sexes of rats and
mice received Chlorobenzene in corn oil by gavage five times weekly
with 0, 60, 125, 250, 500 or 750 mg/kg/day (NTP, 1985; Battelle,
1978a,b). Rats and mice showed depressed body weight gain at the
highest three doses. In rats, polyuria and porphyria were noted at
the two highest doses. Histopathology was noted in the liver, kidney
and lymphoid tissue in both species at the three highest doses.
Liver and liver/body weights were increased in male mice and female
rats at doses above 60 mg/kg. The NOAEL is 60 mg/kg/day.
0 The only chronic exposure study available on Chlorobenzene is the NTP
gavage bioassay in rats and mice (NTP, 1985). On five days/week, both
sexes of rats and female mice received 60 or 120 mg chlorobenzene/kg
day in corn oil; male mice received 30 or 60 mg/kg/day. Significant
changes included equivocal mild to minimal liver necrosis in the rats
and a decrease in the survival rate for low dose male mice, but not
high dose male mice. The NOAEL is 60
Reproductive Effects
8 There are no available data on reproductive effects of Chlorobenzene.
-------
Chlorobenzene March 31, 1987
-7-
Developmental Effects
0 John et al. (1984) and Hayes et al. (1982) have reported the results
of a two-phase teratology study in which pregnant rats and rabbits
were exposed via inhalation to 0, 75, 210 or 590 ppm Chlorobenzene,
6 hr/day, during the period of major organogenesis (days 6 through
15 for rats;days 6 through 18 for rabbits). In the rats, maternal
toxicity (decreased body weight gain) was observed at the highest
dose. No teratological changes were observed in fetuses from rats
exposed at any dose. Rabbits showed maternal toxicity (statistically
significant increase in relative and absolute liver weights) at the
mid and high doses. Again, no structural malformations were noted
in the fetuses. However, since the control group exhibited malforma-
tions at levels higher than historically noted, the rabbit study was
repeated, using doses of 0, 10, 30, 75 or 590 ppm. In this study, no
significant changes in rates and types of malformations were observed.
Mutagenicity
0 Chlorobenzene has been shown to cause mitotic disturbances in Allium
cepa (Ostergen and Levan, 1943) and reverse mutations in Streptococcus
antibioticus (Koshkinova, 1968) and Aspergillus nidulans (Prasad and
Pramer, 1968;Prasad, 1970).
0 Chlorobenzene was not mutagenic in the Ames Salmonella assay or in
E. coli, either with or without metabolic activation (Monsanto, 1976a;
Dup"on€, 1977,-Merck, 1978; Simmon et al., 1979).
0 Chlorobenzene did not induce specific locus forward mutations in mouse
lymphoma L5178Y cells, either with or without activation (Monsanto,
1976b).
0 Chlorobenzene did induce reciprocal recombination in the yeast
Saccharomyces cerevisiae strain D3 in the presence of the metabolic
activation system (Simmon et al. 1979).
Carcinogenicity
0 Chlorobenzene has been tested for carcinogenic potential in rats and
mice in the NTP Bioassay Program (NTP, 1985). The report of these
studies states that the chemical produced a statistically significant
increase in the incidence of neoplastic nodules of the liver in high
dose (120 mgAg/day) male rats. Incidences of neoplastic nodules in
male rats were 2/50 in untreated controls, 2/50 in vehicle controls,
4/49 in low dose and 8/49 in high dose. However, there were also
hepatocellular carcinomas in two vehicle control male rats, and
combining these with the neoplastic nodule data results in an increase
in high dose males of borderline significance (P = 0.048) by one
statistical test (life table) of the three used (also incidental tumor
test and Fischer's exact test) by the NTP. No increased incidence
was observed in numbers of hepatocellular carcinomas in male rats or
of neoplastic nodules or hepatocellular carcinomas in female rats or
mice of either sex.
-------
Chlorobenzene March 31, 1987
-8-
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
where:
HA = (NOAEL or LOAEL) x (BW) = _ m/L ( _ ug/L)
(UF) x ( _ L/day)
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
_ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day and Ten-day Health Advisories
No satisfactory data are available from which to calculate One-day and
Ten-day HAs for the 10 kg child. The 14-day studies in rats and mice by the
NTP (1985) are not selected because of inadequate assessment of toxicity in
these studies. It is recommended that, for this duration of exposure, the
Longer-term HA for a 10-kg child be applied. Therefore, the One-day and
Ten-day Health Advisories are 4.3 mgA (4,300 ugAK
Longer-term Health Advisory
Subchronic studies were conducted in which both rats and mice were dosed
by gavage five times weekly with chlorobenzene at 0, 60, 125, 250, 500 or 750
mg/kg in corn oil (10 animals/species/sex/dose level) (NTP, 1985; Battelle,
1978a,b). Deaths were found with the three highest doses in mice and the two
highest doses in rats. Food consumption did not vary among the groups in
mice, but it was lower in the two highest dose rat groups. Body weight gain
was affected in both species, with significant changes observed in mice and
rats at the three highest doses. No clinically significant chlorobenzene-
related changes were observed in any of the hematological parameters measured
in either species. None of the clinical chemistry parameters measured in mice
were changed. However, in the rats, alkaline phosphatase and GGPT levels
were slightly elevated at 500 and 750 mg/kg. Urinalyses of the controls and
two highest dose groups revealed a dose-dependent polyuria with concomitant
decreases in specific gravity and creatinine concentration. At the two highest
doses, urinary coproporphyrin excretion was increased in rats. In mice, this
increase was observed only in females at 250 and 500 mgAg- Liver and liver:
body weights were increased significantly in female mice at 250 and 500 mgAg
and in male mice at 125 and 250 mgAg. Both male and female rats at 250 and
-------
Chlorobenzene March 31, 1987
-9-
500 mgAg and females at 125 mg/kg showed these increases. Absolute and
organ/body weights for spleen were decreased in all treated groups of male
rats but with no clear dose response. Mice and rats at the three highest
doses (250, 500 and 750 mgAg) all exhibited significant histopathological
changes including hepatic necrosis, nephrosis, myeloid depletion, lymphoid
depletion and lymphoid necrosis. The 60 mgAg/day NOAEL with 5 days/week
treatment of rats and mice in the NTP (1985) study is equivalent to the 54.5
mgAg/day, 5 days/week NOAEL in dogs and the 50 mg/kg/day, 7 days/week NOAEL
in the Hazelton (1967a,b) studies.
From the NTP (1985) data, a NOAEL of 60 mgAg/day was identified.
A Longer-term Health Advisory is calculated as follows:
For the 10-kg child:
Longer-term HA = (60 mgAg/day) (10 kg) (5) = 4>3 /L {4f300 /L)
y (100) (1 L/day) (7)
where:
60 mgAg/day = NOAEL, based Upon absence of various effects at
higher doses in rats and mice.
10 kg = assumed body weight of a child.
5/7 = conversion of 5 day/week exposure to 7 day/week
exposure.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
For the 70-kg adult:
Longer-term HA = (60 mg/kg/day) (70 kg) (5) = 15.0 mg/L (15,000 ug/L)
(100) (2 L/day) (7)
where:
60 mgAg/day = NOAEL, based upon absence of various effects at
higher doses in rats and mice.
70 kg = assumed body weight of an adult.
5/7 = conversion of 5 day/week exposure to 7 day/week
exposure.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
-------
Chlorobenzene March 31, 1987
-10-
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The data base used for the derivation of the Longer-term Health Advisories
also is selected for deriving the Lifetime Health Advisory in that more toxico-
logic endpoints and species were assessed in the subchronic studies compared
to the NTP (1985) carcinogenicity bioassay.
The Lifetime Health Advisory is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (60 mg/kg/day)(5) = 0<043 /kg/day
1,000) (7)
where:
60 mg/kg/day = NOAEL based upon absence of various effects at higher
doses.
5/7 - conversion of 5 day/week exposure to 7 day/week exposure.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = ..(0.043 mg/kg/day) (70 kg) = K51 mg/L (1/510 /L)
(2 L/day)
-------
Chlorobenzene March 31, 1987
-11-
where:
0.043 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = 1.5 mg/L x 20% = 0.3 mg/L (300 ug/L)
It is important to note that the taste and odor threshold in water has
been identified at levels ranging from 0.41 to 1.5 ug/L (Tarkhova, 1965) to
10 to 20 ug/L (Varshavskaya, 1967). All of the Health Advisories derived in
this document have been developed on the basis of toxicity, not on the aesthetic
characteristics of the water quality. Any guidance developed on a site-specific
basis may, however, require one to consider the aesthetic, in addition to the
toxic, consequences following exposure to chlorobenzene in the drinking water.
Evaluation of Carcinogenic Potential
0 The EPA Carcinogenic Assessment Group (CAG) did not derive a carcino-
genic potency factor or range of risk estimates for chlorobenzene
(U.S. EPA, 1985b).
0 EPA has classified chlorobenzene as to its carcinogenic potential,
using the weight of evidence classification scheme in its risk assess-
ment guidelines for carcinogens (U.S. EPA, 1986). The Agency has
placed the chemical in Group D: Inadequate evidence. EPA's Carcinogen
Assessment Group has not derived a carcinogenicity potency factor
(qi*) or a range of excess lifetime cancer risk estimates.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
"° EPA (1980) proposed ambient water quality criteria for chlorobenzene,
one based upon available toxicity data (488 ug/L) and one based upon
organoleptic effects (20 ug/L). These criteria were derived for the
70 kg adult, assumed to drink 2 liters of water per day and eat
6.5 g of contaminated fish and seafood per day. The toxicity-based
criteria were calculated using the 14.4 mg/kg/day NOAEL from the
study by Irish et al. (1963) and an uncertainty factor of 1,000.
0 ACGIH (1982) has adopted a TLV of 75 ppm (350 mg/m3) for chloro-
benzene in the workplace.
0 On the basis of a 1983 draft of the NTP report (NTP, 1985), the
National Academy of Sciences performed a quantitative risk assessment
to estimate excess lifetime cancer risk (NAS, 1983). The upper 95%
confidence limit estimate of that risk was 2.13 x 10-7 per ug/L of
drinking water. This corresponds to a drinking water concentration
of 2.35 ug/L being equivalent to a 1 in a million excess risk.
-------
Chlorobenzene March 31, 1987
-12-
Assumptions were defined for a 70-kg adult, drinking 2 liters of
water per day.
0 WHO (1984) recommended a guideline for chlorobenzene of 3 ug/L
based upon avoidance of taste and odor problems.
0 The U.S. EPA Office of Drinking Water proposed an RMCL of 0.06 mg/L
(U.S. EPA, 1985c).
VII. ANALYTICAL METHODS
0 Analysis of chlorobenzene is by the purge-and-trap gas chromatographic
procedure used for the determination of volatile organohalides in
drinking water (U.S. EPA, 1984a). This method calls for the bubblir/g
of an inert gas through the sample and trapping chlorobenzene on an
adsorbant material. The adsorbant material is heated to drive off
the chlorobenzene onto a gas chromatographic column. This method is
applicable to the measurement of chlorobenzene over a concentration
range of 0.05 to 1500 ug/L. Confirmatory analysis for chlorobenzene
is by mass spectrometry (U.S. EPA, 1985d). The detection limit for
confirmation by mass spectometry is 0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Treatment techniques which are effective in removing chlorobenzene
from drinking water include adsorption on granular activated carbon
(GAC) or powdered activated carbon (PAC). Aeration, reverse osmosis
and boiling also are capable of removing chlorobenzene.
0 Dobbs and Cohen (1980) developed adsorption isotherms for a number
of organic chemicals, including chlorobenzene. They found that
Filtrasorb * 300 carbon had a capacity of 91 mg of chlorobenzene
per gram of carbon at an equilibrium concentration of 1.0 mg/L and
9.3 mg/g at a concentration of 100 ug/L.
0 PAC gave inconsistent removal rates when it was added to well water
containing several contaminants including chlorobenzene (U.S. EPA,
1985b).
0 Conventional coagulation filtration treatment does not appear to be
effective in chlorobenzene removal. Limited data collected at Water
Factory 21 indicated that there was an 18.2% removal of chlorobenzene
when only filtration was used (U.S. EPA, 1985b). Another study of
conventional treatment practices found them to be completely ineffectiv
in chlorobenzene removal (Love et al., 1983).
0 The Henry's Law Constant for chlorobenzene is 145 atm at 20°C (U.S.
EPA, 1985b). This indicates that the chemical might be amenable to
removal by aeration. In a bench-scale study, a diffused air aerator
reduced the chlorobenzene in a 97 ug/L solution by 90% using a 15:1
air-to-water ratio (Love et al., 1983).
-------
Chlorobenzene March 31, 1987
-13-
Air stripping is an effective, simple and relatively inexpensive
process for removing chlorobenzene and other volatile organics from
water. However, the use of this process then transfers the contaminant
directly into the air stream. When considering use of air stripping
as a treatment process, it is suggested that careful consideration be
given to the overall environmental occurrence, fate, route of exposure
and various hazards associated with the chemical.
Degradation with ozone is ineffective as a method for removing
chlorobenzene (U.S. EPA, 1985d).
Reverse osmosis appears to have the potential for use in chlorobenzene
removal. A laboratory study reviewed by EPA reported successful
decontamination with 97 to 100% of the chlorobenzene removed.
-------
Chlorobenzene March 31, 1987
-14-
IX. REFERENCES
ACGIH. 1982. American Conference of Government Industrial Hygienists.
TLVs. Threshold limit values for chemical substances and physical
agents in the work environment with intended changes for 1982.
Cincinnati, Ohio. p. 13.
Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety:
Odor threshold compounds with threshold unit values and volatilities for
714 industrial chemicals in air and water dilution. J. Appl. Toxicol.
3:272-290.
Astrand, I. 1975. Uptake of solvents in the blood and tissue of man.
Scand. J. Work Environ. Hlth. 1:199-218.
Azouz, W.M., D.V. Parke and R.T Williams. 1953. Studies in detoxication.
51: The determination of catechols in urine, and the formation of
catechols in rabbits receiving halogenobenzenes and other compounds,
dihydroxylation in vivo. Biochem. J. 55(1):146-151.
Battelle. 1978a. Battelle's Columbus Laboratories. Chlorobenzene.
Prechronic test phase review - mouse. Establishment of doses for sub-
chronic. Unpublished report. NTP Subcontract No. 76-34-106002.
Battelle. 1978b. Battelle's Columbus Laboratories. Chlorobenzene. Pre-
chronic test phase review - rat. Establishment of doses for subchronic.
Unpublished report. NTP Subcontract No.76-34-106002.
Cameron, G.R., J.C. Thomas, S.A. Ashmore, J.L. Buchan, E.H. Warren and A.W.
McKenny Hughes. 1937. The toxicity of certain chlorine derivatives of
benzene with special reference to o-dichlorobenzene. J. Path. Bact.
44:281-296.
Dallas, C.E., F.W. Weir, S. Feldman, L. Putcha and J.V. Bruckner. 1983. The
uptake and disposition of 1,1-dichloroethylene in rats during inhalation
exposure. Toxicol. Appl. Pharmacol. 68:140-151.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600/8-80-023. MERL, Cincinnati, Ohio.
Dunaeveskii, G.A. 1972. Functional condition of circulatory organs in workers
employed in the production of organic compounds. Gig. Tr. Prof. Zabol.16:48.
Dupont, 1977. Mutagenic activity of monochlorobenzene in the Salmonella-
microsome assay. Haskell Laboratory for Toxicology and Industrial
Medicine. Unpublished Report.
Girard, R., F. Tolot, P. Martin and J. Bourret. 1969. Serious blood disorders
and exposure to chlorine derivatives of benzene (A report of seven
cases). J. Med. Lyon 50(1164):771-773. (Fr.)
-------
Chlorobenzene March 31, 1987
-15-
Hayes, W.C, T.S. Gushaw, K.A. Johnson, T.R. Hanley, Jr., J.H. Ouellette and
J.A. John. 1982. Monochlorobenzene inhalation teratology study in rats
and rabbits. Unpublished Report. Toxicology Research Laboratory. Dow
Chemical Company. 115 pp.
Hazelton Laboratories. 1967a. 13-Week oral administration — dogs. Mono-
chlorobenzene. Final report. Submitted to Monsanto Company. Project
No. 241-105. February 24.
Hazelton Laboratories. 1967b. Three-month subacute oral study — rats.
Monochlorobenzene. Final report. Submitted to Monsanto Company.
Project No. 241-104. March 9.
Irish, D.D. 1963. Halogenated hydrocarbons. II. Cyclic In: Patty's Industrial
Hygiene and Toxicology. Volume II. D.W. Fassett and D.D. Irish, eds.
Interscience Publishers. New York, N.Y. pp. 1333-1362.
John, J.A., W.C. Hayes, T.R. Hanley, Jr., K.A. Johnson, T.S. Gushow and K.S.
Rao. 1984. Inhalation teratology study on monochlorobenzene in rats
and rabbits. Toxicol. Appl. Pharmacol. 76:365-373.
Khanin, A.G. 1969. Pathohistological changes in the central nervous system
and internal organs of experimental animals after chronic, 24-hour
inhalation of toxic substances. T. Tsent. Inst. Vsoversh, Vrachei.
135:97-106. (Russ.)
Knapp, W.K., W.M. Busey and W. Kundzins. 1971. Subacute oral toxicity of
monochlorobenzene in dogs and rats. Toxicol. Appl. Pharmacol. 19:393
(Abstract).
Koshkinova, D.V. 1968. The effect of dimethylcyclodiazomethane in chlorobenzene
solution on mutagenesis in Actinomyces antibiotius 400. Genetika.
4(8):121-125. (Russ.)
Lecca-Radu. 1959. Modifications of blood carbonic anhydrase and leucocytic
indophenol oxidase in chronic benzene and monochlorobenzene intoxication.
Igiena 8:231-240.
Leo, A., C. Hansek and B. Elkins. 1971. Partition coefficients and their
uses. Chem. Rev. 71(6):525-616.
Little, A.D. 1968. Research of chemical odors: Part I. Odor thresholds
for 53 commercial chemicals. Manufacturing Chemists Association, Wash-
ington, D.C., pp. 22-23, October.
Love, G.T., R.J. Miltner, R.G. Eilers and C.D. Fronk-Leist. 1983. Treatment
of volatile organic compounds in drinking water. U.S. EPA. MERL. EPA
600/8-83-019.
Merck. 1978. Monochlorobenzene: Bacterial mutagen test (Ames test). West
Point, PA. Merck and Co., Inc. Unpublished.
-------
Chlorobenzene March 31, 1987
-16-
Monsanto Company. 1976a. Mutagenicity evaluation of B10-76-86-CP-5535 (WGK).
Final report. LBI Project No. 2547. Kensington, MD. Litton Bionetics.
Unpublished.
Monsanto Company. 1976b. Mutagenicity evaluation of B10-76-86-CP-5535 (LOX).
Final report. LBI Project No. 2547. Kensington, MD. Litton Bionetics.
Unpublished.
Monsanto Company. 1980. Subchronic inhalation toxicity study of monochloro-
benzene to male and female dogs. Environmental Health Laboratory Report.
Number R80-53. Project #790015/DMEH ML-79-025. October, 30. Unpublished.
NAS. 1983. National Academy of Sciences. Drinking Water and Health.
Volume 5. National Academy Press, Washington, DC. pp. 28-33.
NTP. 1985. National Toxicology Program. Toxicology and carcinogenesis
studies of dichlorobenzene (CAS No. 108-90-7) in F344/N rats and B6C3F1
mice (gavage studies). U.S. Department of Health and Human Services.
Public Health Service. National Institutes of Health. NTP No. 261.
NIH Publication No. 83-2517.
Ostergren, G., and A. Levan. 1943. The connection between C-mitotic activity
and water solubility in some monocyclic compounds. Hereditas. 29:496-498.
Petrova, N.L., and A.A. Vishnevskii. 1972. Course of pregnancy and deliveries
in women working in the organosilicon varnish and enamel industries.
Nauch Jr. Inrutsk. Med. Inst. 115:102.
Prasad, I. 1970. Mutagenic effects of the herbicide 3,4-dichloroproprion-
anilide and its degradation products. Can. J. Microbiol. 16:369-372.
Prasad, I., and D. Pramer. 1968. Mutagenic activity of some chloroanilines
and chlorobenzenes. Genetics. 20:212-
Rimington, G.E., and G. Ziegler. 1963. Experimental porphyria in rats induced
by chlorinated benzenes. Biochem. Pharmacol. 12:1387-1397.
Rozenbaum, N.D., R.S. Block, S.N. Kremneva, S.L. Ginzburg and I.V. Pozhatiskii.
1947. Use of chlorobenzene as a solvent from the standpoint of industrial
hygiene. Gig. Sanit. 12(1):21-24. (Russ.)
Sato, A., and T. Nakajima. 1979. A structure-activity relationship of some
chlorinated hydrocarbons. Arch. Environ. Health. (March-April) 69-75.
Simmon, V.F., B.C. Ricco and M.V. Pierce. 1979. In vitro microbiological
genotoxicity assays of chlorobenzene, m-dichlorobenzene, o-dichlorobenzene
and p-dichlorobenzene. Final report. Menlo Park, CA. SRI International.
Unpublished.
Smirnova, N.A., and N.P. Granik. 1970. Remote consequences of acute occupa-
tional poisoning by some hydrocarbons and their derivatives. Gig. Truda.
i Prof. Zabol. 5:50-51. (Russ.)
-------
Chlorobenzene March 31, 1987
-17-
Spencer, B., and R.T. Williams. 1950. Studies in detoxication. 33. The
metabolism of halogenobenzenes. A comparison of the glucuronic acid,
etheral sulfate and mercapturic acid. Conjugation of chloro-, bromo-, and
iodobenzene and of the o-, m-, and p-chlorophenyl glucuronides. Biochem. J«
47:279-284.
Sullivan, T.M., G.S. Born, G.P. Carlson and W.V. Kessler. 1983. The pharmaco-
kinetics of inhaled chlorobenzene in the rat. Toxicol. Appl. Pharmacol.
71:194-203.
Tarkhova. 1965. Cited in: Compilation of odour threshold values in air and
water. L.J. van Gemert and A.H. Nettenbreijer, eds. National Institute
for Water Supply. Voorburg, Netherlands. 1977.
U.S. EPA. 1979. U.S. Environmental Protection Agency. Water related
environmental fate of 129 priority pollutants. Office of Water Planning
and Standards. EPA-440/4-79-029. December.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water
quality criteria for chlorinated benzenes. Office of Water Regulations
and Standards. Criteria and Standards Division. Washington, D.C.
EPA 440/5-80-028.
U.S. EPA. 1983. U.S. Environmental Protection Agency. Chlorobenzene
occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1984. U.S. Environmental Protection Agency. Method 502.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268. June.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Draft health effects
criteria document for chlorobenzene. Criteria and Standards Division,
Office of Drinking Water, Washington, DC.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Health assessment
document for chlorinated benzenes. Office of Health and Environmental
Assessment. EPA 600/8-84-015F.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. National primary
drinking water regulations; Synthetic organic chemicals, inorganic
chemicals and microorganisms; Proposed rule. Federal Register.
50(219):469341-47022. November 13.
U.S. EPA. 1985d. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Enviromental Monitoring and Support Laboratory,
Cincinnati, Ohio. June.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register. 51(185):33992-34003.
September 24.
-------
Chlorobenzene March 31, 1987
-18-
U.S. EPA. 1987. U.S. Environmental Protection Agency. Occurrence of
synthetic organic chemicals in drinking water, food, and air. Office of
Drinking Water.
USITC. 1985. U.S. International Trade Commission. Synthetic organic
chemicals, United States production and sales, 1984 (Investigation No.
332-135), USITC Publication 1745. U.S. Government Printing Office.
Washington, D.C.
Varshavskaya, S.P. 1968. Comparative toxicological characteristics of chloro-
benzene and dichlorobenzene (ortho- and para- isomers) in relation to
the sanitary protection of water bodies. Gig. Sanit. 33(10):17-23.
Vecerek, B., G.I. Kondraskin, K. Hatie, L. Kyslikova and K. Jojkova. 1976.
Xenobiological characteristics of chlorobenzene. Bratisl. lek. Listy.
65(1 ):9-14.
von Oettingen, W.F. 1955. The halogenated aromatic hydrocarbons. In: The
halogenated aliphatic, olefinic/ cyclic, aromatic and aliphatic aromatic
hydrocarbons, including the halogenated insecticides, their toxicity
and potential dangers. U.S. Dept. Health, Education and Welfare,
Rockville, MD. No. 414:283-299.
WHO. 1984. World Health Organization. Guidelines for drinking-water
quality. Vol.1 Recommendations. Geneva, p. 73.
Williams, R.T., P.C. Hirom and A.G. Renwick. 1975. Species variation in
the metabolism of some organic halogen compounds. In: Ecological
Toxicological Research. A.D. Mclntrye and C.F. Mills, eds. Plenum
Press, New York, N.Y. pp. 99-105.
Yang, K.H., R.E. Peterson and J.M. Fujimoto. 1979. Increased bile duct-
pancreatic flow in benzene and halogenated benzene-treated rats.
Toxicol. Appl. Pharmacol. 47:505-514.
Zub, M. 1979. Reactivity of the white blood cell system to toxic action of
benzene and its derivatives. Acta Biol. Cracov Serv. Zool. 21(2):163-174.
------- |