EPA-540/1-86-040
ice of Emergency and
medial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
&EPA
HEALTH EFFECTS ASSESSMENT
FOR CHLOROBENZENE
-------
EPA/540/1-86-040
September 1984
HEALTH EFFECTS ASSESSMENT
FOR CHLOROBENZENE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and H has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with chloroben-
zene. All estimates of acceptable Intakes and carcinogenic potency pre-
sented in this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data
bases. The basic literature searched supporting this document 1s current up
to September, 1984. Secondary sources of Information have also been relied
upon In the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The fol-
lowing Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Chlorinated
Benzenes. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA 440/5-80-028. NTIS PB 81-117392.
U.S. EPA. 1982a. Hazard Profile for Chlorobenzene. Prepared by
the Environmental Criteria and Assessment Office, Cincinnati, OH,
OHEA for the Office of Solid Waste and Emergency Response, Wash-
ington, DC.
U.S. EPA. 1985. Health Assessment Document for Chlorinated Ben-
zenes. Environmental Criteria and Assessment Office, Cincinnati,
OH. EPA 600/8-84-015F. NTIS PB 85-150332.
The Intent In these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
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The AIC, acceptable Intake chronic, 1s similar In concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the llfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable expo-
sure for a given route with the Implicit assumption that exposure by other
routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained In U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogenldty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-j*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
The liver and kidneys appear to be target organs for chlorobenzene tox-
Iclty. Three separate subchronlc oral exposure studies (one In dogs, two 1n
rats) define comparable NOELs. The observed adverse effects Indicated a
higher sensitivity of the dog to chlorobenzene than the rat. Based on these
findings, the highest NOEL of 27.3 mg/kg/day from the dog study (Monsanto,
1967a) was considered appropriate to derive an ADI. The estimated AIC 1s
1.9 mg/day, estimated by applying an uncertainty factor of 1000. This esti-
mate may be considered to provide adequate protection against adverse human
health effects. Long-term (lifetime) animal exposure data are needed to
better characterize the toxldty of this compound. A CS of 8 was calculated
for the low blood sugar levels, vomiting, diarrhea and conjunctivitis
observed In dogs at 55 mg/kg/day.
Subchronlc Inhalation data from several species are available, but
chronic Inhalation exposure assessments for chlorobenzene are lacking. A
AIC for Inhalation exposure has been estimated based upon the lowest sub-
chronic LOAEL reported (75 ppm) (Dllley, 1977). This AIC, 0.4 mg/day, may
be conservative. More experimental data are needed addressing lower concen-
trations and longer durations of exposure to more completely characterize
chlorobenzene toxldty.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball wasithe Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann'and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
vl
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 2
2.1. ORAL 2
2.2. INHALATION 2
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3
3.1. SUBCHRONIC 3
3.1.1. Oral 3
3.1.2. Inhalation 7
3.2. CHRONIC 10
3.2.1. Oral 10
3.2.2. Inhalation 11
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 11
3.4. TOXICANT INTERACTIONS 12
4. CARCINOGENICITY 13
4.1, HUMAN DATA 13
4.2. BIOASSAYS 13
4.3. OTHER RELEVANT DATA 15
4.4. WEIGHT OF EVIDENCE 18
5. REGULATORY STANDARDS AND CRITERIA 19
6. RISK ASSESSMENT 21
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 21
6.1.1. Oral 21
6.1.2. Inhalation 22
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 22
6.2.1. Oral 22
6.2.2. Inhalation 23
6.3. CARCINOGENIC POTENCY (q-|*) 23
6.3.1. Oral 23
6.3.2. Inhalation 23
7. REFERENCES 24
APPENDIX: Summary Table for Chlorobenzene 31
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LIST OF TABLES
No.
3-1
3-2
4-1
4-2
4-3
5-1
Title
Subchronlc Oral ToxIcHy of Chlorobenzene 1n Experimental
Animals
Subchronlc Inhalation ToxIcHy of Chlorobenzene In
Experimental Animals . .
Statistical Comparisons of Liver Tumors 1n Male Rats
Treated with Chlorobenzene
Pituitary Tumors 1n Rats Treated with Chlorobenzene
Mutagenlcity Testing of Chlorobenzene
Current Regulatory Standards and Criteria for
Chlorobenzene
Page
4
8
14
16
17
20
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LIST OF ABBREVIATIONS
ADI
AIC
AIS
BCF
CAS
CNS
CS
DNA
GGTP
LOAEL
MED
NOAEL
NOEL
ppm
RVd
RVe
SAP
SGOT
SGPT
STEL
TLV
TWA
Acceptable dally Intake
Acceptable Intake chronic
Acceptable Intake subchronlc
B1oconcentrat1on factor
Chemical Abstract Service
Central nervous system
Composite score
Deoxyr1bonucle1c add
y-Glutamyl transpeptldase
Lowest-observed-adverse-effect level
Minimum effective dose
No-observed-adverse-effect level
No-observed-effect level
Parts per million
Dose-rating value
Effect-rating value
Serum alkaline phosphatase
Serum glutamlc oxalacetlc transamlnase
Serum glutamlc pyruvlc transamlnase
Short-term exposure limit
Threshold limit value
Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
chlorobenzene (CAS No. 108-90-7) are as follows:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Octanol/water partition
coefficient:
Soil mobility
(predicted as retardation
factor for soil depth of
140 cm and organic carbon
content of 0.087%):
BCF:
monocycllc aromatic (purgeable
aromatic)
112.56
11.7 mm Hg at 20°C (Mabey et
al., 1981)
466.3 mg/8. at 20°C (Horvath,
1982)
692 (Hansch and Leo, 1981)
Half-lives 1n A1r:
Water:
1.9 (Wilson et al., 1981)
45.7 (Rainbow trout (muscle);
Salmo galrdnerl) (Branson, 1978)
446.7 (Fathead minnow; P1me-
phales promelas) (Velth et al.,
1979)
3.5 days (Kanno and Nojlma, 1979)
0.3 days In river (Zoeteman et
al., 1980)
The half-life of chlorobenzene 1n soil could not be located 1n the
available literature; however, evaporation 1s expected to be the predominant
loss mechanism from the soil surface (Wilson et al., 1981). The halfUfe
for soil evaporation should be longer than Us evaporation half-life from
water. In subsurface soil, a fraction of monochlorobenzene may undergo bio-
degradation, and a fraction may leach through the soil (Wilson et al., 1981).
-1-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Quantitative studies regarding absorption of chlorobenzene 1n humans or
laboratory animals following 1ngest1on were not located 1n the available
literature. Reports of toxic effects 1n humans following 1ngest1on or
Inhalation (Reich, 1934; Rosenbaum et al., 1947; Tarkhova, 1965) suggested
absorption by these routes. Delchmann (1981) reported that chlorobenzene
absorption from the gastrointestinal tract was facilitated by 1ngest1on of
fats and oils. Studies of the metabolism of chlorobenzene in several mam-
malian species indicated that absorption from the gastrointestinal tract
occurred readily (Williams, 1959).
2.2. INHALATION
No quantitative studies regarding absorption 1n humans or experimental
animals following inhalation exposure to chlorobenzene could be located in
the available literature. Delchmann (1981) stated that chlorobenzene was
absorbed rapidly from the lungs. No supporting data accompanied this
statement.
-2-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. No reports of subchronlc oral exposure of humans to chloro-
benzene could be located In the available literature. Table 3-1 summarizes
pertinent subchronlc oral exposure data 1n laboratory animals. Most of
these data were taken from summaries provided by Delchmann (1981) and U.S.
EPA (1980b, 1985). The studies reviewed by these authors seemed to define
similar NOELs: Monsanto Company (1967a) found no effects In dogs exposed by
capsule to 27.3 mg/kg/day. Following dietary exposure for 93-99 days, no
effects were reported In rats at 50 mg/kg/day (Monsanto Company, 1967b),
although slight and Inconstant elevated liver and kidney weights were
reported at this level In the published version of this study (Knapp et a!.,
1971). Irish (1963) found no effects In rats given 14.4-18.8 mg/kg/day, 5
days/week, for 192 days.
A study by Varshavskaya (1967) described CNS, liver, hematopoletlc and
endocrine effects 1n groups of seven male rats exposed to 0.01 and 0.1 mg
chlorobenzene/kg/day by gavage. The U.S. EPA (1980b) considered the results
of Varshavskaya (1967) to be questionable primarily because these data sug-
gested effects at dosages far lower than those Indicated by other Investi-
gators (Table 3-1). Also, data generated by HolUngsworth et al. (1956) in
a similar study of the toxlcity of o-d1chlorobenzene Indicated similar
effects, but were associated with dosages >3 orders of magnitude greater
than those reported by Varshavskaya (1967).
The NTP (1983) conducted 13-week range-finding studies In groups of five
male and five female rats and mice with chlorobenzene administered by
gavage. Both species were treated with 60, 125, 250, 500 or 750 mg/kg on 5
days/week (transfomed doses 42.9, 89.3, 178.6, 357 and 538 mg/kg bw/day).
-3-
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TABLE 3-1
Subchronlc Oral Toxldty of Chlorobenzene 1n Experimental Animals
Species
Dogs (4M, 4F)
Rats
Rats
Dose
(mg/kg/day)
27.3
54.6
272.5
12.5 or 50
100
250
14.4
144 and 288
Duration
(days)
90
90
90
93-99
93-99
93-99
192
192
Effects Reference
none Monsanto Company,
1967a;
Knapp et al., 1971
diarrhea and vomiting; conjunctivitis
mortality 4/8 1n 3-5 weeks; Increased
Immature leukocytes, SGOT, blUrubln,
cholesterol; decreased blood sugar;
hlstopathologlcal changes In liver,
kidneys, spleen
none Monsanto Company,
1967b
Increased liver and kidney weights
Increased liver and kidney weights;
retarded growth In males
none Irish, 1963
Increased liver, kidney weights,
given 5 days/
week
salivation; partial alopecia
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TABLE 3-1 (cont.)
Species
Rats
House
Dose
(mg/kg/day)
12.5
50 or 100
250
42.9
89.3
Duration
(days)
93-99
93-99
93-99
13 weeks
13 weeks
Effects Reference
none Knapp et al., 1971
Increased liver and kidney weights
Increased liver and kidney weights,
retarded growth In males
one male with hepatic necrosis NTP, 1983
Increased liver weights 1n males;
I
en
I
178.6
357
538
one male with hepatic necrosis
13 weeks >505C reduction 1n weight gain, Increased
excretion of coproporphyrlns In females,
Increased liver weights, lesions of the
liver, kidney, bone marrow, spleen and
thymus
13 weeks 100% lethal to males within 1 week,
reduced body weight gains, polyurla
In females. Increased liver weights,
lesions of the liver, kidney, bone
marrow, spleen and thymus
10 weeks 100% lethal to males within 1 week
and to female mice within 10 weeks,
lesions of the liver, kidney,
bone marrow, spleen and thymus at
death
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TABLE 3-1 (cont.)
Species
Dose
(mg/kg/day)
Duration
(days)
Effects
Reference
Rat
42.9
89.3
178.6
357
538
13 weeks none NTP, 1983
13 weeks none
13 weeks minimal centrolobular hepatocellular
necrosis
13 weeks decreased body weight gain, Increased
GGTP and alkaline phosphatase In females,
Increased excretion of porphyrlns, cen-
trolobular hepatocellular necrosis,
nephropathy 1n males, myelold depletion
of bone marrow
13 weeks decreased body weight gain and survival
of animals, hematologlc effects, Increased
GGTP and alkaline phosphatase In females,
polyurla In males, Increased excretion of
porphyrlns, centrolobular hepatocellular
necrosis, nephropathy, lymphold depletion
of thymus and spleen, myelold depletion of
bone marrow
-------
In mice, 100% lethality to males within 1 week occurred at >500 mg/kg,
accompanied by hlstopathologlcal lesions In many organs. All females 1n the
750 mg/kg group died by week 10. A 50% reduction In body weight gain and
hlstopathologlcal lesions were noted at 250 mg/kg. Increased liver weights
In males were noted at 125 mg/kg and liver necrosis was noted In 1 male In
the 125 and 1 male In the 60 mg/kg group. Hale mice appeared to be affected
more severely than females.
In rats, decreased body weight gain 1n both sexes, altered serum bio-
chemistries 1n females and hlstopathologlcal alterations were observed at
500 and 750 mg/kg. Decreased survival was observed at 750 mg/kg. The only
effect reported at 250 mg/kg was minimal centrolobular hepatocellular necro-
sis. No effects were observed at the two lowest levels.
3.1.2. Inhalation. No studies regarding subchronlc Inhalation exposure
of humans to chlorobenzene could be located 1n the available literature.
Because of the potential for being long-term, reports of occupational expo-
sure are discussed In Section 3.2.2.
Several studies of subchronlc Inhalation exposure of laboratory animals
to chlorobenzene have been reviewed by Delchmann (1981) and U.S. EPA (1985)
and are summarized In Table 3-2. Ollley (1977) demonstrated small, focal
lesions In the adrenal cortex and kidney tubules and decreased SCOT 1n rats
exposed to 75 ppm chlorobenzene 7 hours/day, 5 days/week for 120 days. This
dosage, corresponding to an Intake of 53 mg/kg/day, defined a LOAEL In rats
from Inhalation exposure to chlorobenzene. In an earlier study, no effects
were seen In rats exposed to 142 mg/kg bw/day for 44 days (Irish, 1963).
Several reports from the foreign literature Indicate effects In rats at
exposures leading to dosages far below those associated with no effects 1n
-7-
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TABLE 3-2
Subchronlc Inhalation Toxtclty of Chlorobenzene In Experimental Animals
oo
i
Species
Rats
Rats
Rats
Rats
Rats
Rats
Exposure
200 ppm, 7 hours/day.
5 days/week
475 and 1000 ppm,
7 hours/day, 5 days/week
0.75. 1.50 or 2 rag/I
6 hours/day, 5 days/week
0.1 or 1.0 mg/m9 continuous
0.1 mg/rn3 continuous
1.0 mg/m' continuous
0.1. 1.25 or 1.5 rag/lb
0.1 mg/l, 3 hours /day
every other day
Dose3
(ing/kg/day)
142
338 and 713
99. 199 or 265
0.7 or 7.0
0.07
0.7
NO
4.6
Duration
(days)
44
44
87
72-80
60
60
49-98
259
Effects
none
Increasing severity of hepatomegaly,
hlstopathologlcal changes
none
liver necrosis and regenerations;
kidney hyperplasla. encephalopathy,
pneumonia
none
Inhibited chronaxla of antlgonlstlc
muscles at 39 days; Increased blood
chollnesterase
chronaxlmetrlc Inhibition
Inhibition of extensor tlblalls at
7-14 weeks, normal by 20 weeks
Reference
Irish. 1963
Monsanto
Company,
1976
Khanln. 1977
Tarkhova,
1965
Ptslaru,
1960
Gabor and
Raucher,
1960
Rats 75 or 250 ppm 7 hours/day. 53 or 178
5 days/week
Rabbits 75 or 250 ppm. 7 hours/day, 102 or 340
5 days/week
Rabbits 200 ppm. 7 hours/day, 271
5 days/week
Guinea pigs , 200 ppm, 7 hours/day, 102
5 days/week
120
120
44
44
focal lesions In adrenal cortex and Dllley, 1977
and kidney tubules; congestion of liver
and kidney, decreased SCOT
decreased SGOT Dllley. 1977
none Irish, 1963
none Irish, 1963
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TABLE 3-2 (cont.)
Species
Dogs
Exposure
0.75 my/I, 6 hours/day,
5 days/week
Dosed
(mg/kg/day)
15.8
Duration Effects
(days)
87 none
Reference
Honsanto
Company,
1978
l.SO mg/i, 6 hours/day,
5 days/week
200 mg/t, 6 hours/day,
5 days/week
31.6
4218
87
87
weight loss, conjunctivitis, moribund
by 31 days
weight loss, hypoactlvlty and conjunctiv-
itis; vacuolated hepatocytes, cytoplasmlc
vacuolation of renal tubules, bilateral
atrophy of seminiferous tubules; leukocyto-
poenla; elevated SAP, SGOT, SGPT; aplastlc
bone narrow, mortality In 5/8 dogs by
25-29 days
aDose In mg/kg was calculated assuming the following inhalation rates and body weights: rats - 0.26 mVday and 0.35 kg; rabbits - 1.6
mVday, 1.13 kg; guinea pigs - 0.23 mVday, 0.43 kg; dogs - 1.5 mVday, 12.7 kg
^Exposure data insufficient for calculation of dose
ND = Not derived because exposure data are insufficient
-------
reports from the domestic literature. For example, Khanln (1977) reported
hlstopathological lesions 1n several organs at 0.7 mg/kg bw/day. Neuro-
muscular dysfunction was reported 1n rats at exposures leading to dosages of
0.7-4.6 mg/kg bw/day (Tarkhova, 1965; Plslaru, 1960; Gabor and Raucher,
1960). In the absence of corroborating evidence from the domestic liter-
ature, the data are not considered reliable for use 1n risk assessment.
In subchronlc Inhalation experiments 1n other species, no adverse
effects were observed 1n rabbits at 102-340 mg/kg bw/day (DUley, 1977;
Irish, 1963), 1n guinea pigs at 102 mg/kg bw/day (Irish, 1963) or In dogs at
15.8 mg/kg bw/day (Monsanto Company, 1978). Dogs appear to be the most
sensitive species tested, however, as weight loss and morlbundlty occurred
1n this species by 31 days of exposure to 31.6 mg/kg bw/day (Monsanto
Company, 1978).
3.2. CHRONIC
3.2.1. Oral. No reports of chronic oral exposure of humans to chloroben-
zene could be located 1n the available literature. Minimal toxldty data
are available from the 103-week cardnogenlcHy bloassay 1n rats and mice
(NTP, 1983). Groups of 50 male and 50 female B6C3F, mice were treated by
gavage with chlorobenzene In corn oil at 0, 60 and 120 mg/kg for females and
0, 30 and 60 mg/kg for males. Groups of 50 male and 50 female F344/N rats
were treated with 0, 60 and 120 mg/kg. Treatments were performed 5 days/
week for 103 weeks. Both untreated and vehicle-treated controls were
maintained.
Neither mice nor rats had clinical signs of toxldty related to treat-
ment with chlorobenzene. Statistically significant reduced survival was
observed In low-dose male mice and high-dose male rats. Increased body
weights In both treated groups of female rats were noted during the second
-10-
-------
year of the experiment. No histopathologic evidence of toxldty was was
observed In mice; however, rats had "equivocal evidence for mild chloro-
benzene-lnduced hepatocellular necrosis."
3.2.2. Inhalation. The only available reports of chronic human exposure
to monochlorobenzene were summaries by U.S. EPA (1985) and Delchmann (1981),
from which this discussion was adapted. Glrard et al. (1969) reported the
case of a 70-year-old woman exposed for 6 years to a glue containing 70%
chlorobenzene. From the time she began using the glue, she experienced
headaches and Irritation of the mucosa of the upper respiratory tract and
eyes. After 6 years, she had developed medullary aplasia. No exposure data
were available.
Rosenbaum et al. (1947) examined 28 factory workers, many of whom com-
plained of headaches and showed signs of somnolescence and dyspepsia. Other
complaints Included tingling, numbness and stiffness of the extremities (8
workers), hyperesthesia of the hands (4 workers), and spastic contractions
of the finger muscles (9 workers) or of the gastrocnemius (2 workers).
These workers had reportedly been exposed for 1-2 years, but details of
exposure were not specified. No neurotoxlc signs were displayed by 26
workers exposed to benzene and/or chlorobenzene fumes for <1 year.
No reports of chronic Inhalation exposure of laboratory animals to
chlorobenzene could be located in the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
No reports of fetotoxlcity or teratogenlcity In humans or animals asso-
ciated with either oral or Inhalation exposure to chlorobenzene could be
located in the available literature.
-11-
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3.4. TOXICANT INTERACTIONS
No pertinent data confirming the Interaction of chlorobenzene with other
xenoblotlcs could be located 1n the available literature. Generalizing that
the halogenated benzenes appeared to Increase the activity of mlcrosomal
cytochrome P-450-dependent enzyme systems, the U.S. EPA (1980b) suggested
that exposure to chlorobenzene might be expected to hasten metabolism of
other xenoblotlcs to either more or less toxic metabolites.
Shelton and Weber (1981) Investigated the hepatotoxiclty of a 1:38 molar
ratio mixture of carbon tetrachlorlde and chlorobenzene in male CF-1 mice.
The dosages used (not specified) were given by 1ntraper1toneal Injection.
Although parameters of hepatotoxiclty were not mentioned, the U.S. EPA
(1985) stated that the dose-response did not deviate from that predicted by
addition alone.
-12-
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4. CARCINOGENICITY
4.1. HUMAN DATA
No reports associating chlorobenzene with cancer 1n humans could be
located In the available literature.
4.2. BIOASSAYS
The NTP (1983) conducted a study of the cardnogenldty of chlorobenzene
in rats and mice. Based on data from a 13-week dose range-finding experi-
ment, 50 rats of each sex were treated by gavage with 60 or 120 mg/kg, 5
days/week for 103 weeks. Both untreated and vehicle-treated control groups
of 50 rats of each sex were maintained.
Throughout the study, body weight of treated and control animals
remained comparable. Survival rates were similar until about 70 weeks of
treatment, at which time survival 1n high-dose group males was significantly
reduced. Survival at the end of 2 years was 68, 78, 64 and 52% 1n untreated
control, vehicle-treated control, low-dose and high-dose males, respec-
tively. Among female rats, 2-year survival data were 74, 58, 60 and 62% In
untreated control, vehicle-treated control, low-dose and high-dose groups,
respectively.
Although there was some disagreement 1n the Interpretation of liver
lesions, pathologists evaluating the slides seemed to agree that Inflamma-
tion and cytoplasmic basophilla, manifestations of hepatic degeneration,
were less severe In chlorobenzene-treated rats than in the control groups.
In male rats, a significant Increase in neoplastlc nodules 1n the liver was
observed in the high-dose group (Table 4-1) as determined by both the Inci-
dental tumor test (p=0.021) and the Cochran-Armitage test for dose-related
trend (p=0.043). Liver carcinomas in male rats were found only in the
vehicle-treated group (2/50). Combining the incidences of neoplastic
-13-
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TABLE 4-1
Statistical Comparisons of Liver Tumors 1n Male Rats
Treated with Chlorobenzene*
Tumor Type
Neoplastlc nodule
Incidental tumor test
Cochran-Armltage test
Fisher exact test
Carcinoma
Incidental -tumor test
Cochran-Armltage test
Fisher exact test
Neoplastlc nodule or
carcinoma
Incidental tumor test
Cochran-Armltage test
Fisher exact test
Untreated Vehicle
Control Control
4/50 (8%) 2/50 (4%)
p=0.011
p=0.027
NA
0/50 (0%) 2/50 (4%)
p=0.139
p=0.098
NA
4/50 (8%) 4/50 (8%)
p=0.054
p=0.121
NA
60 mg/kg
4/49 (8%)
p=0.290
NA
p=0.329
0/49 (0%)
p=0.283
NA
p=0.253
4/49 (8%)
p=0.570
NA
p=0.631
120 mg/kg
8/49 (16%)
p=0.021
NA
p=0.043
0/49 (0%)
p=0.331
NA
p=0.253
8/49 (16%)
p=0.083
NA
p=0.168
*Source: NTP, 1983
NA = Not applicable
-14-
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nodules and carcinomas failed to create an overall tumor Incidence that was
statistically significant. There was no evidence of neoplastlc nodule or
liver tumor formation 1n female rats.
The Incidence of pituitary tumors (adenoma, adenocarclnoma and car-
cinoma) In both male and female rats was found to be significantly Inversely
related to treatment with chlorobenzene (Table 4-2).
The carclnogenlclty of chlorobenzene has also been tested 1n B6C3F..
mice (NTP, 1983). Males were treated with 30 or 60 mg/kg and females were
subjected to 60 or 120 mg/kg, 5 days/week for the 2-year (103-week) treat-
ment period. These dosages were chosen on the basis of a preliminary
13-week dose range-finding study. It appeared that the doses chosen for the
chronic bloassay were too low based on the data generated by the 13-week
preliminary study, and that the accepatable Intake had not been approached
(U.S. EPA, 1985). No tumors occurred with frequencies that differed sig-
nificantly from those 1n the control groups.
The U.S. EPA (1985) stated that the data generated by these studies were
not sufficient to draw conclusions about the carclnogenlclty of chloro-
benzene.
4.3. OTHER RELEVANT DATA
Studies of the mutagenlclty of chlorobenzene 1n microorganisms have
yielded mixed results, with positive results observed only in tests with
Saccharomyces cerevlslae (Simmon et al., 1979) and Streptomyces antlbloticus
(Kesklnova, 1968) (Table 4-3).
In a sex-Hnked recessive lethal test 1n DrosophUa melanogaster (Bio-
assay Systems Corp., 1982), male flies were exposed to 36,000 or 128,400 ppm
of chlorobenzene for 1 hour. The exposed flies were mated at 1-3 days
-15-
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TABLE 4-2
Pituitary Tumors In Male Rats Treated with Chlorobenzene*
cr>
i
Untreated
Tumor Type Control
Adenoma 20/49 (4154)
Incidental tumor test
Cochran-Armltage test
Fisher exact test
Adenoma, adenocarclnoma or
carcinoma 20/49 (4154)
Incidental tumor test
Cochran-Armltage test
Fisher exact test
•
Vehicle
Control
10/50 (20%)
p=0.109
p=0.047
NA
12/50 (2454)
p=0.044
p=0.016
NA
60 mg/kg
9/42 (2154)
p=0.532
NA
p=0.534
9/42 (2154)
p=0.462
NA
p=0.484
120 mg/kg
3/47 (654)
p=0.101
NA
p=0.046
3/47 (654)
p=0.044
NA
p=0.015
*Source: NTP, 1983
NA -- Not applicable
-------
TABLE 4-3
Mutagenicity Testing of Chlorobenzene*
Test System
Metabolic
Activation
Concentration
Result
Reference
Asperlqlllus nldulans
Salmonella strains TA1535, TA1537,
TA1538, TA92, TA98, TA100
Salmonella typhirourium strains
*Source: U.S. EPA. 1985
NR = Not reported
200
0.1-0.5 pi/plate
100 yg/plate
negative Prasad, 1970
negative Simmon et al., 1979
negative Merck and Company,
1978
Saccharomyces cerevislao
S. cerevlslae
Mouse lymphoma L5178Y
(forward mutation of TK)
Escherlchla coll
(polAVpolA-)
Bacillus subtilis
(rec~/recf)
Streptomyces antlblotlcus
f 0.05-654
t- 0.01-5 ul/plate
0.001-0.1 til/mi
H 0.0001-0.01 jii/mfc
10^20 pi/plate
10-20 yi/plate
NR
positive
negative
negative
negative
negative
negative
positive
Simmon et al., 1979
Monsanto Company,
1976
Monsanto Company,
1976
Simmon et al., 1979
Simmon et al., 1979
Keskinova. 1968
-------
(to sample effects on spermatozoa), 4-5 days (to sample effects on sper-
matlds) and 6-7 days (to measure effects on spermatocytes) after exposure.
No evidence of mutagenldty was found 1n 11,543 chromosomes from treated
flies compared to 9430 chromosomes from control flies.
A positive response was obtained 1n a test for 1j\ vitro Induction of
chromosomal aberrations 1n Chinese hamster ovary cells (U.S. EPA, 1982b).
Concentrations of 444, 266 and 178 yg/ms, were tested 1n assays not
Incorporating a metabolic activating system and concentrations of 493, 296,
197 and 99 yg/mj. were assayed with an S-9 activating system. A positive
response was observed 1n the S-9 activated system after a 4-hour exposure
but not after a 2-hour exposure.
4.4. WEIGHT OF EVIDENCE
No evidence of cardnogenldty associated with exposure to chlorobenzene
In humans could be located 1n the available literature. The NTP (1983) bio-
assay failed to confirm or deny the cardnogenldty of chlorobenzene 1n rats
or mice. IARC has not evaluated the risk to humans associated with oral or
Inhalation exposure to chlorobenzene. By applying the criteria proposed by
the Carcinogen Assessment Group of the U.S. EPA for evaluating the overall
weight of evidence for cardnogenldty to humans (Federal Register, 1984), a
designation of chlorobenzene as a Group D - Not Classified chemical seems
most appropriate.
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5. REGULATORY STANDARDS AND CRITERIA
A summary of regulatory standards and criteria for chlorobenzene 1s
presented in Table 5-1. Both the ACGIH (1980) and NIOSH (1982) have set the
TWA for chlorobenzene at 75 ppm. No STEL has been set.
The U.S. EPA (1980b) has suggested an ambient water quality criterion of
488 yg/a. to protect human health. This criterion Is based on an ADI of
1.008 mg/day, assumes consumption of 2 i water/day and takes Into con-
sideration consumption by fish and shellfish.
-19-
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TABLE 5-1
Current Regulatory Standards and Criteria for Chlorobenzene
Standard or Criterion
Value
Reference
TLV
TWA
Ambient water quality criteria:
Freshwater aquatic life
Acute toxlclty
Saltwater aquatic life
Acute toxldty
Chronic toxlclty
Ambient water quality criterion:
Human life
Organoleptlc
75 ppm (-350 mg/m3)
75 ppm
250 pg/8,
160
129
488 vg/l
20
AC6IH, 1980
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
-20-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. NOAELs from subchronlc oral studies Include 14.4 mg/kg/day
In rats (Irish, 1963), 50 mg/kg/day in rats (Monsanto Company, 1967b), 89.3
mg/kg/day 1n rats (125 mg/kg, 5 days/week) (NTP, 1983), 12.5 mg/kg/day In
rats (Knapp et a!., 1971) and 27.3 mg/kg/day In dogs (Monsanto Company,
1967a; Knapp et al.. 1971). The Irish (1963) study reported a NOEL of 14.4
mg/kg/day and LOAEL of 144.4 mg/kg/day, however, Intermediate doses were not
evaluated. The Monsanto (1967a,b) study defined a NOAEL of 50 mg/kg/day and
LOAEL of 100 mg/kg/day In the rat. In contrast, a NOEL of 27.3 mg/kg/day
and a LOAEL of 55 mg/kg/day were defined for the dog. The observed adverse
effects Indicated a higher sensitivity of the dog to chlorobenzene than the
rat. Based on these findings the highest dog NOEL of 27.3 mg/kg/day (Mon-
santo, 1967b) was considered appropriate to derive an ADI for subchronlc
exposure. An uncertainty factor of 100 1s applied, a factor of 10 to
account for Interspecles extrapolation and a factor of 10 to provide greater
protection for especially sensitive populations. Assuming a body weight 1n
man of 70 kg, an AIS for man can be calculated as follows:
AIS = (27.3 mg/kg/day days x 70 kg) f 100
(the uncertainty factor derived above)
AIS =19.1 mg/day
In dogs Immature leukocytes, low blood sugar, conjunctivitis, vomiting
and diarrhea were reported at 55 mg/kg/day, whereas higher doses caused
mortality and histopathologlcal lesions In liver and kidneys (Monsanto,
1967a). A human MED was calculated by multiplying the dog MED by the cube
root of the ratio of the body weight of dogs (assumed: 12.7 kg) to that of
humans (assumed: 70 kg) and dividing the result by 10, an uncertainty
-21-
-------
factor chosen to reflect the unknowns 1n extrapolating from a subchronlc
study to chronic application. The result, 3.1 mg/kg/day, 1s multiplied by
70, resulting in an MED of 218 mg/day for a 70 kg man. This MED corresponds
to an RVd of 2.0; the effects of vomiting, diarrhea, conjunctivitis and
Immature luekocytes rate an RV of 4. A CS of 8, the product of RV. and
RVe, 1s calculated.
6.1.2. Inhalation. No pertinent data regarding the effects of subchronlc
Inhalation exposure of humans to chlorobenzene could be located 1n the
available literature. Studies by Irish (1963) defined NOELs in rats, rab-
bits and guinea pigs of 142, 271 and 102 mg/kg/day, respectively. Dilley
(1977) found small focal lesions 1n the adrenal cortex and kidney tubules,
congestion of the liver and kidney, and decreased SGOT in rats exposed to 75
ppm chlorobenzene for 7 hours/day, 5 days/week for 120 days. This concen-
tration resulted in an intake of 53 mg/kg/day (applying the assumptions
stated in Table 3-2), which was designated as a LOAEL in this study. An
interim AIS can be calculated from these data by assuming a body weight of
man of 70 kg and using an uncertainty factor of 1000; a factor of 10 to
account for interspecies conversion, another factor of 10 to convert from a
LOAEL to a NOEL and a final factor of 10 to afford greater protection to
unusually sensitive populations. The resultant interim AIS is 3.7 mg/day.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. No reports of chronic oral exposure of humans or animals to
chlorobenzene could be located 1n the available literature. An Interim AIC
for chronic oral exposure can be derived from the subchronic AIC by applying
an additional uncertainty factor of 10 to convert from a subchronic study to
chronic exposure; this results 1n an overall uncertainty factor of 1000.
The resultant AIC is 1.9 mg/day.
-22-
-------
6.2.2. Inhalation. No reports of chronic exposure of humans to chloro-
benzene that were satisfactory for risk assessment, or studies of chronic
animal exposure could be located In the available literature. The study by
Dllley (1977), used to derive an AIS, can be used to derive an AIC for
Inhalation exposure. An additional uncertainty factor of 10 to account for
derivation of an AIC from subchronlc data results 1n an AIC of 0.4 mg/day,
starting with the AIS of 3.7 mg/day (see Section 6.1.2).
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The NTP (1983) bloassay failed to demonstrate conclusively
the cardnogenldty, or lack of cardnogenldty, of chlorobenzene admin-
istered to rats and mice by gavage. No other reports of cardnogenldty 1n
humans or animals resulting from oral exposure to chlorobenzene could be
located 1n the available literature. Therefore, Insufficient data are
available from which to estimate carcinogenic potency.
6.3.2. Inhalation. No reports of cardnogenldty 1n humans or animals
associated with Inhalation exposure to chlorobenzene could be located 1n the
available literature; hence, no estimation of carcinogenic postency has been
made.
-23-
-------
8. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1980.
Documentation of the Threshold Limit Values for Substances In Workroom A1r,
4th ed. Cincinnati, OH. p. 84-85. (Cited In U.S. EPA, 1982a)
Bloassay Systems Corp. 1982. DrosophHla sex-linked recessive lethal test
on monochlorobenzene. U.S. EPA, Office of Pesticides and Toxic Substances,
Washington, DC. TSCA Section 8(d) submission. (Cited 1n U.S. EPA, 1985)
Branson, D.R. 1978. Predicting the fate of chemicals In the aquatic
environment from laboratory data. ASTM STP 657. American Society for
Testing and Materials, Philadelphia, PA. p. 55-76.
Delchmann, W.B. 1981. Halogenated Cyclic Hydrocarbons. In_: Toxicology.
Patty's Industrial Hygiene and Toxicology, 3rd ed.. Vol. 2B, G.O. Clayton
and E.E. Clayton, Ed. John Wiley and Sons, Inc., NY. p. 3605-3611. (Cited
In U.S. EPA, 1982a)
DUley, J.V. 1977. Toxic Evaluation of Inhaled Chlorobenzene. NIOSH,
DHEW, Cincinnati, OH. Contract 210-76-0126. (Cited In U.S. EPA, 1985)
Federal Register. 1984. Environmental Protection Agency. Proposed guide-
lines for carcinogenic risk assessment. 49 FR 46294-46299.
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-------
Gabor, S. and K. Raucher. 1960. Studlen zur Bestlmmung der zulasslgne
benzol und monochorbenzol grenzkonzentratlonen. J. Hyg. Epidemic!.
Mlcrobiol. Immunol. 4: 223-231. (Ger.) (CHed In U.S. EPA, 1985)
Glrard, R., F. Tolot, P. Martin and J. Bourret. 1969. Serious blood dis-
orders and exposure to chlorine derivatives of benzene (A report of 7
cases). J. Med. Lyon. 50: 771-773. (CHed 1n U.S. EPA, 1985)
Hansch, C. and A.J. Leo. 1981. Medchem Project. Issue No. 19. Pomona
College, Claremont, CA.
Holllngsworth, R.L., V.K. Rowe, F. Oyen, H.R. Hoyle and H.C. Spencer. 1956.
Toxldty of paradlchlorobenzene: Determination on experimental animals and
human subjects. AMA Arch. Ind. Health. 14: 138-147. (Cited In U.S. EPA,
1980b)
Horvath, A.L. 1982. Halogenated Hydrocarbons: Solub1lity-H1sc1b1l1ty with
Water. Marcel Dekker, Inc., New York, NY. p. 889.
Irish, D.D. 1963. Halogenated Hydrocarbons: II. Cyclic. ITK Industrial
Hygiene and Toxicology, Vol. II, 2nd ed., F.A. Patty, Ed. Intersclence, NY.
p. 1333-1361. (Cited 1n U.S. EPA, 1980b)
Kanno, S. and K. Nojima. 1979. Studies on photochemistry of aromatic
hydrocarbons. V. Photochemical reaction of chlorobenzene with nitrogen
oxides In air. Chemosphere. 8: 225-232.
-25-
-------
Keskinova, D.V. 1968. The effect of d1methylcyclod1azomethane In chloro-
benzene solution on mutagenesls In Actlnomyces antlbiotlcus 400. Genetlka.
4(8): 121-125. (Cited In U.S. EPA, 1985)
Khanln, A.6. 1977. Pathological changes In the general nervous system and
Internal organs of experimental animals after chronic continuous Inhalation
of toxic substances. Chem. Abstr. 74: 97-106. (Cited In U.S. EPA, 1985)
Knapp, W.K., Jr., W.M. Busey and W. Kundzlns. 1971. Subacute oral toxldty
of monochlorobenzene 1n dogs and rats. Toxlcol. Appl. Pharmacol. 19: 393.
(Abstr.) (Cited In U.S. EPA, 1980b)
Mabey, W.R., J.H. Smith and R.T. Podoll. 1981. Aquatic Fate Process Data
for Organic Priority Pollutants. Monitoring and Data Support Division,
Office of Water Regulations and Standards, Washington, DC. EPA 440/4-81-014.
Merck and Company. 1978. Summary of Monochlorobenzene Bacterial Mutagen
Test (Ames Test). Office of Pesticides and Toxic Substances, U.S. EPA,
Washington, DC. TSCA Sec 8(d) submission 8DHQ-1078-0302. (Cited 1n U.S.
EPA, 1985)
Monsanto Company. 1967a. 13-Week oral administration - dogs, monochloro-
benzene. U.S. EPA, OPTS, Washington. DC. TSCA Sec 8(d) submission
8DHQ-1078-0202(2). (Cited 1n U.S. EPA, 1985)
-26-
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Monsanto Company. 1967b. 3-Month subacute oral study of monochlorobenzene
in rats. U.S. EPA, Washington. DC. TSCA Sec 8(d) submission
8DHQ-1078-Q212(3). (Cited 1n U.S. EPA, 1985)
Monsanto Company. 1976. Litton Blonetlcs mutagenldty evaluation of
B10-76-86-CP 5535 (WGK): Monochlorobenzene. Office of Pesticides and Toxic
Substances, U.S. EPA, Washington, DC. TSCA Sec 8(d) submission 8DHQ-1078-
0214(1). (Cited 1n U.S. EPA, 1985)
Monsanto Company. 1978. Industrial Bio-Test draft report of 90-day
subacute vapor Inhalation toxldty study with monochlorobenzene In beagle
dogs and albino rats. U.S. EPA, OPTS, Washington, DC. TSCA Sec 8{d)
submission 8DHQ-1078-0202(1). (Cited In U.S. EPA, 1985)
NIOSH (National Institute for Occupational Safety and Health). 1972. The
1982 Registry of Toxic Effects of Chemical Substances, R.L. Lewis and R.L.
Tatken, Ed. Cincinnati, OH. (Cited 1n U.S. EPA, 1985)
NTP (National Toxicology Program). 1983. Cardnogenesls studies of chloro-
benzene (CAS No. 108-99-7) In F344/N rats and B6C3F1 mice (gavage studies).
NTP-82-90. NIH Publ. 83-2517. (Draft)
Plslaru, V. 1960. Modlflcarl cronaxlmetrlce In 1ntox1cat1a cronlca cu
benzen s1 monochlorobenzen. Iglena. 9: 127-135. (Cited In U.S. EPA, 1985)
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Prasad, I. 1970. Mutagenlc effects of the herbicide 3',4'-d1chloroprop1o-
anHlde and Its degradation products. Can. J. M1crob1ol. 16: 369-372.
(CHed 1n U.S. EPA, 1985)
Reich, H. 1934. Puran (Monochlorobenzol)-Verg1ftung bel elnem zweljahrlgen
K1nde. Verglftungsfalle. 5: 193-194. (Ger.) (CHed In U.S. EPA, 1985)
Rosenbaum, N.D., R.S. Block, S.N. Kremneva, S.L. Glnzburg and I.V.
PozhaMskll. 1947. The use of chlorobenzene as a solvent from the point of
view of industrial hygiene. G1g. Sanlt. 12(1): 21-24. (Cited In U.S. EPA,
1985)
Shelton, D.W. and L.J. Weber. 1981. Quantification of the joint effects of
mixtures of hepatotoxlc agents: Evaluation of a threshold model In mice.
Environ. Res. 26: 33-41. (CHed 1n U.S. EPA, 1985)
Simmon, V.F., E.S Rlccio and M.V. Pelrce. 1979. In. vitro microbiological
genotoxiclty assays of chlorobenzene, m-d1chlorobenzene, o-dlchlorobenzene
and p-d1chlorobenzene. Contract No. 68-02-2947. U.S. EPA, ORD, Washington,
DC. (CHed In U.S. EPA, 1985)
Tarkhova, L.P. 1965. Maximum permissible concentration of chlorobenzene In
the atmosphere. G1g. Sanlt. 30: 8. (CHed 1n U.S. EPA, 1985)
U.S. EPA. 1980a. Guidelines and Methodology Used In the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45:79347-79357.
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U.S. EPA. 19805. Ambient Water Quality Criteria for Chlorinated Benzenes.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-028. NTIS PB 81-117392.
U.S. EPA. 1982a. Hazard Profile for Chlorobenzene. Prepared by the
Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1982b. Effects of Monochlorobenzene on the In vitro Induction of
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EPA by Bloassay Systems Corp. (Cited In U.S. EPA, 1985)
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
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Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
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Varshavskaya, S.P. 1967. Comparative toxlcologlcal characteristics of
Chlorobenzene and dlchlorobenzene (ortho- and para-1somers) 1n relation to
the sanitary protection of water bodies. (Rus. trans.) Hyg. San. 33(10):
17-23. (Cited In U.S. EPA, 1980b)
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- -I
Velth, G.D., D.L. DeFoe and B.V. Bergstedt. 1979. Measuring and estimating
the bloconcentratlon factor of chemicals 1n fish. J. Fish Res. Board Can.
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Detox1cat1on of Mechanisms, 2nd ed. John WHey and Sons, Inc., NY. p. 237.
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Baskln. 1981. Transport and fate of selected organic pollutants In a sandy
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1980.- Persistent organic pollutants 1n river water and groundwater of The
Netherlands. Chemosphere. 9: 231-249.
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APPENDIX
Summary Table for Chlorobenzene
Species
Inhalation
AIS rat
AIC rat
Oral
AIS dog
AIC dog
Maximum dog
composite
score
Experimental
Dose/Exposure
53 mg/kg/day
53 mg/kg/day
27.3 mg/kg/day
for 90 days
27.3 mg/kg/day
for 90 days
55 mg/kg/day
for 90 days
(RVd = 2.0)
Acceptable Intake
Effect (AIS or AIC)
focal lesions In liver, 3.7 mg/day
kidney tubules; hepatic
and renal congestion;
decreased SGOT
focal lesions In liver. 0.4 mg/day
kidney tubules; hepatic
and renal congestion;
decreased SGOT
none 19.1 mg/day
none 1.9 mg/day
Immature leukocytes, con- 8
junctlvltls, vomiting and
diarrhea (RVe=4)
Reference
Dllley, 1977
Dllley, 1977
Monsanto, 1967a
Monsanto. 1967a
Monsanto, 1967a
ND = Not derived
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