EPA-540/1-86-017
environmental Protection
Agency
jf Emergency and
Remedial 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
vvEPA
HEALTH EFFECTS ASSESSMENT
FOR HEXACHLOROBENZENE
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EPA/540/1-86-017
September 1984
HEALTH EFFECTS ASSESSMENT
FOR HEXACHLOROBENZENE
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 hexa-
chlorobenzene. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases.
The basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency revlev. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Chlorinated Benzenes. Environmental Criteria and Assessment
Office, Cincinnati, OH. EPA 440/5-80-028. NTIS PB 81-117392.
U.S. EPA. 1982. Health and Environmental Effects Profile for
Hexachlorobenzene. 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. 1983a. Review of Toxlcologlc Data In Support of Evalua-
tion for Carcinogenic Potential of Hexachlorobenzene. Prepared by
the Carcinogen Assessment Group, OHEA, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1984. 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 1n 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, 1s 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 llfespan). 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
111
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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.
The AIC, acceptable Intake chronic, 1s similar 1n 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 Hfespan [see U.S. EPA (1980b) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure 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 Is explained 1n U.S. EPA (1983b).
For compounds for which there 1s sufficient evidence of carc1nogen1dty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). 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.
Hexachlorobenzene has been shown to be carcinogenic 1n rats, mice and
hamsters following oral exposure. Data for humans are not available. U.S.
EPA (1980a) derived a q-j* of 1.688 (mg/kg/day)'1 based on the Incidence
of hepatomas In male Syrian Golden hamsters. This assessment has been
extensively peer-reviewed. More recently the U.S. EPA (1984) computed a
q-j* of 1.7 (mg/kg/day)'1 based on the Incidence of hepatocellular
carcinomas 1n female rats. Data were not available which addressed the
potential carcinogenic activity of hexachlorobenzene following Inhalation
exposure.
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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 was',the Project
Officer. The final documents In 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
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . ,
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation ,
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY ,
4.1. HUMAN DATA ,
4.2. BIOASSAYS
4.3. OTHER RELEVANT DATA ,
4.4. WEIGHT OF EVIDENCE . . .
REGULATORY STANDARDS AND CRITERIA ,
RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) ,
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) ,
6.3. CARCINOGENIC POTENCY (q-|*) ,
6.3.1. Oral
6.3.2. Inhalation ,
REFERENCES
Page
1
3
. . . 3
, , 4
5
. . . 5
, . . 5
, , 8
8
. . . 8
10
11
. . . 11
14
. . . 14
, . , 16
. . . 16
. . . 16
. . . 19
20
21
. . . 23
. . . 23
. . . 23
23
. . . 23
, , , 23
. . . 24
APPENDIX: Summary Table for Hexachlorobenzene 33
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LIST OF TABLES
No. Title Page
3-1
4-1
5-1
Subchronlc Oral Tox1c1ty of Hexachlorobenzene to Laboratory
Animals
Liver and Kidney Tumors 1n Sprague-Dawley Rats Given Hexa-
chlorobenzene 1n the Diet for up to 2 years
Current Regulatory Standards and Criteria for
Hexachlorobenzene
6
18
77
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF Bloconcentratlon factor
bw Body weight
CAS Chemical Abstract Service
CS Composite score
GI Gastrointestinal
LDso Median lethal dose
LDH Lactate dehydrogenase
LOAEL Lowest-observed-adverse-effect level
NOEL No-observed-effect level
PCT PorphyMa cutanea tarda
ppb Parts per billion
ppm Parts per million
SGOT Serum glutamlc oxalacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
TLV Threshold limit value
TWA Time-weighted average
w/w Weight per weight
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
hexachlorobenzene (CAS No. 118-74-1) are given as follows:
Chemical class:
aromatic
Molecular weight:
Vapor pressure
at 20°C:
Water solubility
at 25°C:
Log octanol/water
water partition
coefficient:
Soil mobility:
BCF:
Half-lives
1n water:
Half-life
1n soil:
halogenated monocycllc
284.79
1.089xlO~s mm Hg
6
5.23
very slow and the mobility
decreases with Increase
1n soil organic content
22,000 1n whole body of
fathead minnow (Plmephales
promelas)
7800 In rainbow trout
(Salmo galrdnerl)
0.3-3.0 days In rivers
30-300 days In lakes
and groundwater
3-6 years
(Callahan et al.,
1979)
(Callahan et al.,
1979)
(Callahan et al.,
1979)
(Velth et al.,
1979)
(U.S. EPA, 1984)
(U.S. EPA, 1980a)
(U.S. EPA, 1980a)
(Zoeteman et al.,
1980)
(U.S. ,EPA, 1984)
No estimate of the half-life for hexachlorobenzene 1n the atmosphere 1s
available 1n the literature. Based on the available Information (Callahan
et al., 1979; Singh et al., 1981), significant photodlssodatlon and oxida-
tion of hexachlorobenzene 1n the atmosphere are unlikely. The likely mecha-
nisms for the removal of significant amounts of hexachlorobenzene from the
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atmosphere are ralnout and dry deposition (U.S. EPA, 1982). The detection
of hexachlorobenzene, an anthropogenic compound, 1n remote areas (U.S. EPA,
1984) suggests that H may have a long lifetime In order to participate 1n
such long-distance transport from source areas to the remote areas.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Summaries of studies of absorption of hexachlorobenzene following oral
administration were found In U.S. EPA (1980a, 1982, 1984). In many cases
details of protocol were lacking and therefore, such studies are not
reported here.
According to the U.S. EPA (1980a), Intestinal absorption of hexa-
chlorobenzene from aqueous suspension was poor In both rabbits (Parke and
Williams, 1960) and rats (Koss and Koransky, 1975). Administration of hexa-
chlorobenzene 1n cottonseed oil (Albro and Thomas, 1974) or olive oil (Koss
and Koransky, 1975) markedly Increased absorption from the Intestine. Koss
and Koransky (1975) showed that Intestinal absorption of hexachlorobenzene
In rats Increased from -6% to -80% when the vehicle was changed from water
to oil. Zablk and Schemmel (1980) fed hexachlorobenzene (32 mg/kg/day) to
female rats by h1gh-fa-t (45.3% w/w) or high-carbohydrate (67.7%. w/w, per-
centage fat presumed low but not specified) diets. The nutritional adequacy
of the diets was not mentioned and no control groups were maintained.
Administering hexachlorobenzene 1n the high-fat diet reportedly resulted 1n
greater accumulation of hexachlorobenzene In (unspecified) tissues and
decreased passage of hexachlorobenzene through the GI tract than did admin-
istration 1n the high-carbohydrate diet. The U.S. EPA (1984) suggested that
the high-fat diet enhanced GI absorption. It was further suggested (U.S.
EPA, 1980a) that dietary hexachlorobenzene selectively partitions Into the
I1p1d portion of the diet and that absorption of hexachlorobenzene from
Uplds 1s far more rapid and complete than from an aqueous medium.
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Ingebrlgtsen et al. (1981) administered 10 mg [14C] hexachlorobenzene
1n peanut oil by gavage to male, blle-duct-cannulated Wlstar rats. By 4
days after treatment, 24.8% of the radioactivity had been recovered 1n the
feces. These authors concluded that -75% of the administered hexachloro-
benzene had been absorbed. It should be mentioned that this study did not
evaluate absorption of metabolites of hexachlorobenzene resulting from
metabolism 1n the gut, nor was the phenomenon of GI excretion evaluated.
Subsequently, Ingebrlgtsen and Nafstad (1983) administered 0.4 mg [14C]
hexachlorobenzene 1n peanut oil/kg bw to male Wlstar rats and observed peak
levels of radioactivity 1n the liver at 4 hours and 1n adipose tissue at 24
hours post-treatment. These authors Indicated that absorption of hexa-
chlorobenzene from the GI tract, when oil was used as the vehicle, was rapid
and fairly complete.
2.2. INHALATION
Pertinent data regarding the absorption of hexachlorobenzene following
Inhalation exposure could not be located 1n the available literature.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Reports of subchronlc oral exposure of humans to hexa-
chlorobenzene that would be useful 1n risk assessment were not found 1n the
available literature.
Delchmann (1981) summarized many short-term studies of oral exposure of
laboratory rodents to hexachlorobenzene. The primary purpose of these
studies was to elucidate the metabolism of hexachlorobenzene and Us role In
porphyrla. Frequently, therefore, only single dosage levels were given, or
a sufficiently wide spectrum of toxic manifestations was not reported;
therefore, these studies were not useful In risk assessment. Summaries of
data from more relevant subchronlc oral exposure studies are presented 1n
Table 3-1.
Grant et al. (1974) fed diets containing 10-160 ppm hexachlorobenzene to
rats of either sex for 9-10 months. They demonstrated that female rats
appeared to be more sensitive to hexachlorobenzene, 1n that at levels of
either 80 or 160 ppm, only females suffered reduced weight gains and
porphyrla. Males fed diets containing 40 or 60 ppm hexachlorobenzene showed
hepatic enzyme Induction and Increased cytochrome P-450. No effects were
reported 1n rats on diets containing 10 ppm hexachlorobenzene. Kulper-
Goodman et al. (1977) also reported greater sensitivity In female rats; they
reported 40% mortality 1n females (but not males) on diets containing 32 ppm
hexachlorobenzene. No effects were observed In rats on diets containing 0.5
ppm (0.025 mg/kg/day). This dietary level was considered a NOEL for rats 1n
this study.
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TABLE 3-1
Subchronlc Oral Toxlclty of Hexachlorobenzene to Laboratory Animals
Species/Strain Sex/Number Dose
Rat/Sprague- H, F/NR 10 ppm diet
Dawley
20 pom diet
40 or 60 ppm diet
80 or 160 ppm diet
i
Mlat/COBS M/70, F/70 0 or 0.5 ppm diet
2 or 8 ppm diet
32 ppm diet
Rat/Wlstar F/36/group 0.5 mg/kg 2 times
weekly
2.0, 8.0 or 32 mg/kg
2 times weekly
NIce/BALB/c M/NR 167 ppm diet
Dose* Duration
(mg/kg/day)
O.S 9-10 months
1.0
2.0 or 3.0
4.0 or 8.0
0.0 or 0.025 15 weeks
0.1 or 0.4
1.6
0.007 29 weeks
0.03. 0.1
or 0.5
21.7 3-6 weeks
Effects Reference
None Grant et al.,
1974
Pharmacologlc action of pento-
barbltal and zoxazolamlne
shortened In both sexes
Hales only: hepatic aniline
hydroxylase. N-demethylase
activity, cytochrome P-450
Increased
Dose-related Increase In relative
liver weights and hepatic content
of hexachlorobenzene females:
reduced weight gains, acquired
porphyrla
None Kul per -Goodman
et al.. 1977
Multiple sites of alopecia,
scabbing; ataxla with hind leg
paresis; hepatomegaly
Females only: 40X mortality
None Boger et al..
1979
Hepatocellular enlargement,
proliferated smooth endoplasmlc
retlculum. Increased glycogen
deposits, enlarged mltochondlra
Impaired host resistance; IgA Loose et al.,
reduced; decreased resistance to 1978a,b
S. typhosa endotoxln, £. berqhel
challenge
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TABLE 3-1 (cont.)
Species/Strain
Rat/Sprague-
Dawley
Dog/beagle,
6.3-10.3 kg
(mean 8.3 kg)
Plg/NR
Plg/NR
Sex/Number Dose
F/10/group 0 ppm diet
60, 80, 100, 120
or 140 ppm diet
N, F/NR 1 or 10 mg/dog/day
100 mg/dog/day
1000 mg/dog/day
NR/NR 0.05 mg/kg/day
0.5 or 5 mg/kg/day
50 mg/kg/day
F/NR 1 ppm diet
20 ppm diet
Dose*
(mg/kg/day)
0
3.0. 4.0,
5.0, 6.0
or 7.0
0.12 or 1.2
12 «
120
0.05
0.5 or 5
50
0.025
0.5
Duration
weaning
through two
successive
litters
(-194 days)
up to 12
months
90 days
throughout
gestation and
nursing
(-5-6 months)
Effects Reference
None Kltchln
et al.. 1982
F-|a: Increasing dose-related
mortality of offspring; depressed
growth of offspring.
F1b: 15-20X reduction In body
burden of hexachlorobenzene
Nodular hyperplasla of gastric Gralla et al.,
tissue 1977
Anorexia, body weight loss,
neutrophllla, anemia, hypocalcemla
Mortality, amyloldosls, vasculltls
None den Tonkelaar
et al.. 1978
•Hlstopathologlc liver changes*
Porphyrla, hepatomegaly, mortality
None Hansen et al..
1978
Neutrophllla, gastric Irritation.
fatty replacement of Brunner's
gland, pancreatic perlductal
flbrosls, hexachlorobenzene
accumulation In fat
*Dosages In mg/kg/day In rats were calculated assuming dietary Intake equivalent to 5X of body weight/day; mg/kg/day In .mice by assuming a dietary Intake
equivalent to 13% of body weight/day; In dogs and pigs from data given In the secondary sources.
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Beagle dogs appeared to be quite sensitive to hexachlorobenzene. Gralla
et al. (1977) exposed male and female beagle dogs to 1, 10, 100 or 1000
mg/dog/day for up to 12 months. Assuming a mean body weight of 8.3 kg,
these dosages correspond to 0.12, 1.2, 12 or 120 mg hexachlorobenzene/kg/
day. All exposed dogs exhibited nodular hyperplasla of gastric lymphold
tissue. Dosages >12 mg/kg/day produced anorexia, body weight loss, neutro-
phH1a, anemia, hypocalcemla and hypoglycemla. At 120 mg/kg/day, mortality
occurred. A dosage of 0.12 mg/kg/day was designated a LOAEL 1n this study.
Oelchmann (1981) cited a study by den Tonkelaar et al. (1978) 1n which
"hlstopathologlcal liver changes" were observed 1n pigs exposed to dosages
of 0.5-5 mg hexachlorobenzene/kg/day for 90 days. Apparently, no effects
were observed at a dosage of 0.05 mg/kg/day, which defined a NOEL 1n this
study. Hansen et al. (1978) observed neutrophlUa, gastric Irritation,
fatty replacement of Brunner's glands, pancreatic perlductal flbrosls and
hexachlorobenzene accumulation In the fat of pigs at a dosage of 0.5
mg/kg/day for -5-6 months.
3.1.2. Inhalation. Pertinent data concerning subchronlc Inhalation of
hexachlorobenzene In laboratory animals or man could not be located 1n the
available literature. Reports of occupational exposure to hexachlorobenzene
will be discussed 1n Section 3.2.2.
3.2. CHRONIC
3.2.1. Oral. Accidental 1ngest1on of hexachlorobenzene In humans
occurred 1n Turkey as a result of hexachlorobenzene-treated seed grain being
ground Into flour and made Into bread. More than 600 patients were observed
during a 5-year period during which time a total of -3000 people were
affected (Cam, 1959, 1960; Cam and Nlgogosyan, 1963). The resultant
syndrome, known as PCT, 1s a manifestation of disturbed porphyrin metabolism
and caused blistering and epldermolysls of exposed parts of the body,
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particularly the face and hands. Exposure to direct sunlight exacerbated
the syndrome; consequently, more cases were examined during the summer.
Symptoms subsided after 20-30 days of no exposure. Relapses were common,
either as a result of reexposure to contaminated bread or as the result of
redistribution of hexachlorobenzene following mobilization from body fat.
Other symptoms Included hyperplgmentation, hypertrlchosls or alopecia (1n
some cases, permanent), cornea! opacities, deformation of the digits, weight
loss and a characteristic port wine color of the urine, Indicative of
porphyria.
A disorder called "pembe yara" or "pink sore" was described 1n infants
of mothers who either had PCT or had eaten hexachlorobenzene-contaminated
bread (Cam, 1959, 1960). At least 95% of these children died within a year
of birth, and 1n many villages no children between the ages of 2-5 years
survived during the period 1955-1960. It was estimated that PCT and pink
sore occurred 1n individuals who had consumed 50-200 mg hexachlorobenzene/
day for a "relatively long period of time" before skin symptoms were
manifested.
Delchmann (1981) reported a 20-year follow-up study by CMpps et al.
(1978), who reported that affected individuals exhibited the following
symptoms; hyperplgmentation, hirsutism, scarring of hands and face, hepato-
megaly, asdtes, jaundice, recent episodes of red urine, weakness, pares-
thesia, enlarged thyroid and painless arthritis.
Burns and Miller (1975) conducted an ep1dem1ologic study of 86 residents
living or working or both in an area exposed to the production, transporta-
tion and disposal of hexachlorobenzene and other chlorinated hydrocarbon
wastes 1n Louisiana. Levels of hexachlorobenzene 1n plasma were measured
and attempts were made to correlate them with demographic characteristics,
occupational hazards, food sample analyses and house dust analyses.
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Significantly greater (p<0.05) hexachlorobenzene levels 1n plasma were
found 1n male subjects (4.71 ppb) compared with female subjects (2.79 ppb);
no effects were associated with race or exposure through consumption of
homegrown vegetables or animal food products. Hexachlorobenzene levels 1n
the plasma appeared to be correlated with concentrations 1n house dust: 68%
of the samples from homes of exposed workers contained an average of 380 ppb
hexachlorobenzene, compared with 20 ppb 1n dusts from houses of control
subjects.
Few reports have been located 1n the available literature concerning
chronic oral exposure of laboratory animals to hexachlorobenzene. Koss et
al. (1978) reported "changes 1n the histology of the Hver and spleen" asso-
ciated with exposure of rats to 50 mg hexachlorobenzene/kg every other day.
Exposure was for 53 weeks. Cabral et al. (1977) exposed male and female
Syrian golden hamsters to 50, 100 or 200 ppm hexachlorobenzene 1n the diet
(lifetime exposure) 1n order to Investigate the cardnogenldty of hexa-
chlorobenzene. This study will be reviewed 1n more detail 1n Section 4.2.
Dose levels employed In these studies were too large to be useful 1n risk
assessment.
3.2.2. Inhalation. Few reports were located 1n the available literature
concerning repeated occupational exposure to hexachlorobenzene. Burns et
al. (1974) found hexachlorobenzene levels 1n blood ranging from 0-310 ppb 1n
20 spraymen exposed to hexachlorobenzene. These Individuals exhibited no
signs of PCT; no correlations were observed between blood concentrations of
hexachlorobenzene and urinary porphyMn excretion, SGOT, SGPT or serum LDH
concentrations. Currier et al. (1980) performed a medical survey of 50
employees exposed to hexachlorobenzene 1n a chlorinated solvents plant In
Louisiana. During various times of this study, TWA air concentrations
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ranged from <1-13 ppb. Wipe samples 1n a control area, laboratory areas and
clerical work areas ranged from 0.03-1.24 yg/100 cm2. Physical examina-
tions and laboratory analyses (hematologlc parameters, blood chemistries and
uMnalyses) did not reveal evidence of PCT. A positive correlation was
found between blood concentrations of hexachlorobenzene and the number of
years worked 1n the plant.
Studies on the chronic toxldty of Inhalation exposure of hexachloro-
benzene to experimental animals could not be located 1n the available
literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. A condition known as "pink sore" was described (Cam, 1959,
1960) as occurring 1n children of mothers affected by the PCT epidemic In
Turkey discussed 1n Section 3.2.1. At least 95% of affected children died
within 1 year of birth. It was estimated that the mothers with affected
children had consumed 50-200 mg hexachlorobenzene/day for a "relatively long
period of time." The presence of hexachlorobenzene 1n the mothers' milk
suggested that pink sore was a manifestation of toxldty due to lactatlonal
rather than placental transfer of hexachlorobenzene.
The effects of hexachlorobenzene on fetotoxldty 1n laboratory animals
have been studied by a number of Investigators. Grant et al. (1977) exposed
groups of 20 female and 10 male weanling Sprague-Dawley rats to diets
containing 0, 10, 20, 40, 80, 160, 320 or 640 ppm hexachlorobenzene. At 100
days of age, the FQ generation was mated to produce the F, generation.
The F, offspring were weaned at 21 days, and the F» rats were again
mated after an additional 14-day rest period to produce the F,. genera-
tion. The F,. rats were allowed to mature to 100 days and then were
mated. This sequence was followed until production of the F.. generation.
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The two highest doses (320 and 640 ppm hexachlorobenzene) resulted 1n 20
and 50% mortality, respectively, of F_ dams before first whelping. Addi-
tionally, the fertility Index In rats 1n these two highest dose groups was
reduced, and average litter size was decreased 1n the F,. , F~ and F^.
generations. In these Utters from dams exposed to the two highest dietary
concentrations of hexachlorobenzene, there was an Increase 1n the number of
stillbirths, and all pups born alive were dead within 5 days. From dams fed
diets containing 160 ppm hexachlorobenzene, 55% of the pups survived to day
5, but survival to weaning at 21 days was "greatly reduced." The number of
live births and survival to weaning were normal 1n Utters from dams exposed
to diets containing 80 ppm hexachlorobenzene for the first 2 generations.
Subsequent generations suffered an Increased Incidence of stillbirths,
reduced survival and reduced birth weights and weaning weights of offspring.
Utters from dams exposed to diets containing 40 ppm hexachlorobenzene
experienced only a significantly Increased liver weight at weaning (21
days); no other abnormalities were reported. No terata were found in off-
spring from dams exposed to any dietary level of hexachlorobenzene. Litters
from rats fed diets containing <20 ppm hexachlorobenzene seemed normal in
all respects. Therefore, 20 ppm in the diet, corresponding to 1 mg
hexachlorobenzene mg/kg bw/day (assuming rats consume food equivalent to 5%
of their bw/day), was a NOEL for reproductive effects 1n this study.
KHchin et al. (1982) exposed groups of 10 female Sprague-Dawley rats to
diets containing 0, 60, 80, 100, 120 or 140 ppm hexachlorobenzene. After 96
days of treatment, females were mated to untreated males to produce an F,
generation and were remated 12 days after weaning of the F, generation.
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.Fertility and fecundity -were not affected by treatment. No terata were
reported, but 21-day survival 1n both generations was reduced, with LD5Q
estimates of 100 and 140 ppm hexachlorobenzene 1n the maternal diets for the
f, and F,. generations, respectively.
Reduced survival at weaning was attributed by Mendoza et al. (1978) to
hexachlorobenzene transmission to nursing pups by milk. These authors fed
five Wlstar rats diets containing 80 ppm hexachlorobenzene from 2 weeks
before mating until whelping. A reciprocal exchange of Utters was made
with Utters from dams not previously treated with hexachlorobenzene. Pups
from control dams nursed on hexachlorobenzene-treated dams showed signifi-
cantly Increased liver weights, compared to pups from treated dams nursed on
control dams. Mendoza et al. (1978) concluded that hexachlorobenzene expo-
sure by milk had greater effects on the pups than transplacental exposure.
Subsequently, Mendoza et al. (1979) fed Wlstar rats diets containing 80
ppm hexachlorobenzene from 2 weeks before mating until 35-36 days after
Utters were weaned. They reported no marked differences 1n the external
appearance, body weight, Hver weight, gestatlonal survival or neonatal
survival of Utters from treated rats, compared to the Utters of controls.
Additionally, there were no differences In the number of Utters, average
number of pups/litter, average number of pups at birth or gestation Index,
compared to Utters from control rats.
Lactatlonal transfer of hexachlorobenzene 1n rhesus monkeys was Investi-
gated by Bailey et al. (1980), who treated three nursing dams for 60 days
(presumably starting at parturition) with 64 mg hexachlorobenzene/kg bw/day
by gavage. Analyses of the milk from these dams revealed concentrations
ranging from 7.51-186 ppm. Hypoact1v1ty and lethargy, progressing to ataxla
and death, occurred 1n one Infant by day 29. A second nursing Infant died
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by day 38. Necropsies revealed congested lungs 1n one Infant, and a
subdural'hematoma and bilateral hemorrhaglc pneumonia In the other. Blood
levels (0.42-49.44 ppm hexachlorobenzene) and tissue levels -(unreported) 1n
Infants were higher than those (0.41-16.16 ppm hexachlorobenzene In blood)
1n dams. Infants developed clinical signs (unspecified) of toxldty, while
dams remained asymptomatic.
Khera (1974) studied the teratogenldty of hexachlorobenzene by treating
groups of 7-16 Wlstar rats by gavage with 0, 10, 20, 40, 60, 80 or 120 mg
hexachlorobenzene 1n corn oil or 2% aqueous gum tragacanth/kg bw/day during
days 6-21 of gestation. Maternal toxldty (manifestations unspecified) and
reduced fetal weights resulted from the two highest dosages. A significant
Increase 1n the Incidence of unilateral or bilateral 14th Mb was observed
1n Utters from dams exposed to the two highest dosages of hexachloroben-
zene. In this study, 60 mg/kg/day seemed to be a NOEL for teratogenldty.
3.3.2. Inhalation. Reports of effects on reproduction or teratogenldty
In humans or animals associated wHh Inhalation exposure to hexachloroben-
zene could not be located 1n the available literature.
3.4. TOXICANT INTERACTIONS
Hayes (1975) stated that porphyMa 1s probably the most frequent and
serious cause of photosens1t1zat1on 1n man. Some people previously exposed
to hexachlorobenzene experience a latent, acute form of porphyMa, which 1s
often manifested as cutaneous photosensHlzatlon. Acute attacks may be
Initiated by consumption of alcohol or exposure to barbiturates, which Hayes
(1975) Interpreted as evidence for synerglsm of action between hexachloro-
benzene and these compounds.
More recently, Teschke et al. (1983) exposed female Wlstar rats to 50
ppm hexachlorobenzene 1n the diet to evaluate the effects of porphyMa on
hepatic alcohol-metabolizing enzymes. Exposure for 60 days resulted 1n
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porphyria, as evidenced by Increased hepatic 6-am1nolevul1n1c acid
synthase activity and Increased urinary excretion of s-am1nolevul1n1c
add, porphoblllnogen and total porphyMns. Hepatic mlcrosomal ethanol-
oxldlzlng system activities were Increased 213%, compared to the activities
1n nonhexachlorobenzene-exposed controls. Hepatic alcohol dehydrogenase
activities remained virtually unchanged. Considering earlier reports that
link alcohol consumption with porphyria, Teschke et al. (1983) suggested
that high levels of Hver acetaldehyde, the result of oxidation of ethanol,
may trigger episodes of porphyria and potentiate the action of hexachloro-
benzene.
Chadwlck et al. (1977) demonstrated that rats exposed to 7.5 mg hexa-
chlorobenzene/kg/day orally for 7 days had Increased ability to metabolize
and eliminate Undane. Body elimination of Undane Increased about 3-fold.
Concentrations of Undane 1n body fat of treated animals were nearly half
those In non-hexachlorobenzene-exposed controls following a single oral dose
of Undane.
Kluwe et al. (1982) exposed male Sprague-Dawley rats to 30 mg hexa-
chlorobenzene/kg by gavage every 72 hours for seven administrations (20
days). Following treatment, rats were given 0, 0.03, 0.25 or 2.00 ma
carbon tetrachlorlde by 1ntraper1toneal Injection. Carbon tetrachloMde-
Induced growth retardation, renal tubular function Impairment and hepato-
cellular necrosis were quantitatively greater 1n hexachlorobenzene-
pretreated rats than In non-pretreated rats. Body weight gain was evaluated
over a 48-hour period; renal function was evaluated by relative kidney
weight, blood urea nitrogen and various urlnalysls parameters; and hepato-
cellular function was evaluated by relative Hver weight, serum enzymes and
hlstochemlcal evaluation.
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the cardnogenldty of hexachlorobenzene 1n
humans could not be located In the available literature.
4.2. BIOASSAYS
Several studies of the cardnogenldty of hexachlorobenzene administered
orally to laboratory animals have been located 1n the available literature.
Smith and Cabral (1980) exposed female MRC Wlstar and Agus rats to 100 ppm
hexachlorobenzene 1n their diets for 75 and 95 weeks, respectively. There
was an Increased Incidence of Hver cell tumors in both strains of rats, but
the statistical significance was not evaluated. Among hexachlorobenzene-
exposed MRC Wlstar rats, 4/6 developed liver cell tumors, compared to 0/4 of
the control group; 14/14 treated Agus rats developed liver cell tumors,
compared to 0/12 of the control rats (U.S; EPA, 1983a).
More recently, Lambrecht et al. (1983a,b) fed groups of 94 male and 94
female Sprague-Dawley rats diets containing 0, 75 or 150 ppm hexachToroben-
zene. Interim sacrifices for hlstopathologlcal examination were performed
on four rats of each sex/group at 10 Intervals up to 64 weeks of treatment.
The remaining 58 rats/group were allowed to continue to natural death or
until 2 years of treatment. The number at risk was considered to be those
surviving at least 12 months, as this was the earliest time to tumor
observed.
Based on an average (weighted) food consumption of 22.6 and 16.5 g/rat/
day In males and females, respectively, with average adult body weight of
400 and 265 g the low-dose was converted to 4-5 mg/kg/day and the high-dose
to 8-9.5 mg/kg/day. The Incidence of tumors observed 1n this study are
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presented 1n Table 4-1. The most striking observations were the high Inci-
dences and dose-related Incidences of hepatocellular carcinoma 1n female
rats and renal cell adenoma 1n male rats.
In an earlier study, Lambrecht et al. (1982) exposed rats to dietary
concentrations of 0, 200 or 400 ppm hexachlorobenzene for 90 days. Further
details of the protocol and statistical analysis are lacking (U.S. EPA,
1983a), but the authors associated treatment with an Increased Incidence of
liver neoplasma, generalized lymphatic leukemlas and a variety of renal
lesions.
U.S. EPA (1979) exposed Swiss mice of either sex to dietary concentra-
tions of 300, 200, 100, 50 or 0 ppm hexachlorobenzene for 15, 101, 106, 120
or 120 weeks, respectively. An Increased Incidence of liver cell tumors was
observed at dietary concentrations >100 ppm hexachlorobenzene. Liver cell
tumor Incidences were 1/16 for males, 1/26 for females; 7/44 for males,
14/41 females; 3/29 for males, 3/30 for females 1n groups exposed to 300.,
200 or 100 ppm hexachlorobenzene, respectively. Liver cell tumors were not
observed In mice exposed to 0 or 50 ppm hexachlorobenzene. No other tumors
were reported as having an Increased Incidence 1n either sex.
Cabral et al. (1977) fed diets containing 0, 50, 100 or 200 ppm hexa-
chlorobenzene to Syrian golden hamsters for life. These diets reportedly
(U.S. EPA, 1982) contained 4, 8 or 16 mg/kg/day hexachlorobenzene and
resulted 1n Increased rates of alveolar adenomas of the thyroid, hepatomas
of the liver and hemangloendothellomas of both the liver and spleen In male
and female hamsters. The Incidence of total tumor-bearing animals appeared
to be dose-related: 10% of the control group, 56% of the low-dose group, 75%
of the middle-dose group and 92% of the high-dose group developed tumors.
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TABLE 4-1
Liver and Kidney Tumors In Sprague-Dawley Rats Given Hexachlorobenzene 1n the Diet for up to 2 years*
oo
Exposure
Level
0
Percentage
75 ppm
Percentage
150 ppm
Percentage
Hepatocellular
Hepatoma Carcinoma
M F H F
0/54 0/52 0/54 0/52
00 00
10/52 26/56 3/52 36/56
19 46 6 64
11/56 35/55 4/56 48/55
20 64 7 87
Renal Cell Renal Cell
Adenoma Carcinoma
M F M
7/54 1/52 0/54
13 2 0
41/52 7/56 0/52
79 13 0
42/56 15/54 0/56
75 28 0
F
1/52
2
2/46
4
2/54
4
*Source: Lambrecht et al., 1983a,b
-------
Tumor Incidence data were highly significant. Probability values for the
Incidence of hepatomas 1n male hamsters were 7.5xlO~7, 2.45xlO~ls and
1.3xlO"19 for low-, middle- and high-dose groups, respectively. In males
fed the middle and high concentrations of hexachlorobenzene, probability
values were 4.5xlO~3 and 4.0xlO~«, respectively, for the Incidence of
hepatic hemang1oendothel1omas. Probability values for the Incidence of
hepatomas 1n females fed low, middle and high dosages were 7.5xlO~7,
2.0xlO~8 and 3.05xlO~19, respectively. The probability value for the
Incidence of hepatic hemang1oendothel1omas 1n middle group females was 0.026.
4.3. OTHER RELEVANT DATA
Very few data concerning the mutagenldty of hexachlorobenzene have been
located 1n the available literature. According to the U.S. EPA (1984),
mutagenldty has been observed 1n Saccharomyces cerevlslae at a minimum
concentration of 100 ppm. Lawlor et al. (1979) tested the mutagenlc
activity of hexachlorobenzene 1n Salmonella typhlmuMum strains TA98, TA100,
TA1535, TA1537 and TA1538, with and without activation by Aroclor
1254-lnduced rat hepatic mlcrosomes. Hexachlorobenzene was associated with
no detectable mutagenldty 1n any of the strains tested, with or without
metabolic activation. Dosage levels were unspecified.
In a dominant lethal assay, male rats were treated with 0, 70 or 221 mg
hexachlorobenzene/kg by gavage for 5 consecutive days. A dose-related
depression of male reproductive function occurred, but dominant lethal muta-
tions were not observed (Simon et al., 1979). Khera (1974) also reported a
lack of dominant lethal mutations 1n Wlstar rats following gavage adminis-
tration of 0, 20, 40 or 60 mg hexachlorobenzene/kg for 10 consecutive days.
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4.4. WEIGHT OF EVIDENCE
Reports of cardnogenicity of hexachlorobenzene 1n humans could not be
located 1n the available literature. Smith and Cabral (1980) demonstrated
an Increased incidence of liver cell tumors 1n female MRC Wlstar and Agus
rats exposed to dietary levels of 100 ppm hexachlorobenzene for 75 or 95
weeks. Liver neoplasms were observed 1n rats exposed to 200 or 400 ppm
hexachlorobenzene for 90 days (Lambrecht et al., 1982) and liver and kidney
tumors were noted in rats exposed to 75 or 150 ppm 1n the diet for up to 2
years (Lambrecht et al., 1983a,b). At dietary levels of >100 ppm for 106
weeks, Swiss mice showed an increased incidence of liver cell tumors (U.S.
EPA, 1979). Finally, Cabral et al. (1977) demonstrated significant
Increases in the incidences of alveolar adenoma of the thyroid, hepatomas of
the liver and hemangioendothellomas of both the liver and spleen in Syrian
golden hamsters exposed to hexachlorobenzene. These animal studies provide
sufficient evidence that hexachlorobenzene 1s an animal carcinogen. Thus,
according to the criteria for evaluating the overall weight of evidence of
cardnogeniclty to humans proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register, 1984), hexachlorobenzene is most appropriately
classified as a Group 82 (Probable Human Carcinogen) chemical.
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5. REGULATORY STANDARDS AND CRITERIA
As of March, 1984, neither OSHA nor the AC6IH has set TLVs for hexa-
chlorobenzene 1n the workroom. The government of Turkey discontinued the
use of hexachlorobenzene-treated wheat seed 1n 1959 {Cam, 1959) after Us
link with the outbreak of PCT discussed 1n Section 3.2. CommeMcal United
States production of hexachlorobenzene was discontinued In 1976 (U.S. EPA,
1980a). The Louisiana State Department of Agriculture has set the tolerated
level of hexachlorobenzene 1n meat fat at 0.3 mg/kg (U.S. EPA, 1976). In
Australia, the NHMRC has set the limit for hexachlorobenzene 1n cow's milk
at 0.3 mg/kg (Miller and Fox, 1973). WHO has set the tolerated level of
hexachlorobenzene 1n cow's milk at 20 vg/kg (Bakken and Se1p, 1976). The
New South Wales Department of Health (Australia) has decided that the level
of hexachlorobenzene 1n eggs shall not exceed 0.1 mg/kg (Slyall, 1973). The
value of 0.6 v9/kg/day 1n food was suggested as the upper limit for hexa-
chlorobenzene 1n food for human consumption (FAO, 1974). The FAO recommen-
dations for residues 1n foodstuffs were 0.5 mg/kg 1n fat for milk and eggs
and 1 mg/kg 1n fat for meat and poultry. These data are summarized 1n
Table 5-1.
Based on a q * of 1.688 (mg/kg/day)"1 for humans, the resulting
water concentration associated with an Increased carcinogenic potency 1s 7.2
ng/8. (U.S. EPA, 1980a).
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TABLE 5-1
Current Regulatory Standards and Criteria for Hexachlorobenzene
Criterion
Value
Reference
Louisiana State Dept. of
Agriculture: Permissible
level 1n meat fat
NHMRC (Australia): Limit
1n cow's milk
WHO: Limit In cow's milk
New South Wales Dept. Health
(Australia): Limit 1n eggs
FAO/WHO: Limit In food,
fat of milk, eggs
fat of meat, poultry
Concentrations 1n ambient
water associated with
Increased carcinogenic potency
0.3 mg/kg
0.3 mg/kg
20 yg/kg
0.1 mg/kg
0.6 jig/kg/day
0.5 mg/kg
1.0 mg/kg
7.2 ng/8.
U.S. EPA, 1976
Miller and Fox, 1973
Bakken and Selp, 1976
S1yal1, 1973
FAO, 1974
U.S. EPA, 1980a
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Hexachlorobenzene is a chemical associated with several types of malig-
nancies in at least three animal species and for which data are sufficient
for derivation of a q,*. It is inappropriate, therefore, to derive an AIS
for this chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Hexachlorobenzene is a chemical associated with several types of malig-
nancies in at least three animal species and for which data are sufficient
for derivation of a q,*. It 1s Inappropriate, therefore, to derive an AIC
for this chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The U.S. EPA (1980a) based calculation of a q^ on the
Incidence of hepatomas in male Syrian golden hamsters exposed by diet to
hexachlorobenzene (Cabral et a!., 1977). The q * derived from these data
is 1.688 (mg/kg/day)"1. More recently, the U.S. EPA (1984) derived a
q * of 1.7 (mg/kg/day)"1 from data regarding the Incidence of hepato-
cellular carcinoma in female rats (Lambrecht et al., 1983a,b) fed diets
containing hexachlorobenzene for up to 2 years. A complete discussion of
the computation of the q * is reported in U.S. EPA (1984).
6.3.2. Inhalation. Since no studies of the carcinogenicity of hexa-
chlorobenzene to humans or animals exposed by Inhalation have been found 1n
the available literature, no q,* can be calculated for inhalation exposure.
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7. REFERENCES
Albro, P.W. and R. Thomas. 1974. Intestinal absorption of hexachloro-
benzene and hexachlorocyclohexane Isomers In rats. Bull. Environ. Contam.
Toxlcol. 12: 289-294. (Cited 1n U.S. EPA, 1980a)
Bailey, J., V. Knauf, W. Mueller and W. Hobson. 1980. Transfer of hexa-
chlorobenzene and polychlorlnated blphenyls to nursing Infant rhesus
monkeys: Enhanced toxldty. Environ. Res. 21(1): 190-196. (CHed 1n U.S.
EPA, 1984}
Bakken, A.F. and M. Se1p. 1976. Insecticides 1n human breast milk. Act.
Paedlat. Scand. 65: 535. (CHed 1n U.S. EPA, 1980a)
Boger, A., 6. Koss, W. Koransky, R. Naumann and H. Frenzel. 1979. Rat
liver alterations after chronic treatment with hexachlorobenzene. Vlrchows
Arch. [Path Anat.] 382(2): 127-137. (Cited In U.S. EPA, 1984)
Burns, J.E. and F.M. Miller. 1975. Hexachlorobenzene contamination: Its
effects 1n a Louisiana population. Arch. Environ. Health. 30: 44-48.
(CHed 1n U.S. EPA, 1980a)
Burns, J.E., F.M. Miller, E.D. Jones and R.A. Albert. 1974. Hexachloro-
benzene exposure from contaminated DCPA In vegetable spraymen. Arch.
Environ. Health. 29: 192-194. (Cited 1n U.S. EPA, 1984)
-24-
-------
Cabral, J.R.P., P. Shubik, T. Mollner and F. RaHano. 1977. Carcinogenic
activity of hexachlorobenzene 1n hamsters. Nature (London). 269: 510-511.
(Cited 1n U.S. EPA, 1980a, 1982}
Callahan, M.A., M.W. SUmak, N.W. Gabel, et al. 1979. Water Related En-
vironmental Fate of 129 Priority Pollutants. Vol. I U.S. EPA, Office of
Water Planning and Standards, Office of Water and Waste Water Management,
Washington, DC. EPA-440/4-79-029a.
Cam, C. 1959. Cutaneous porphyMa related to Intoxication. D1r1m. 34:
11. (Tur.) (Cited 1n U.S. EPA, 1984)
Cam, C. 1960. Une nouvelle dermatose epldemlque des enfants. Ann.
Dermatol. SyphlUger. 87: 393. (Fre.) (Cited 1n U.S. EPA, 1984)
Cam, C. and G. Nlgogosyan. 1963. Acquired toxic porphyrla cutanea tarda
due to hexachlorobenzene. J. Am. Med. Assoc. 183: 88. (Cited 1n U.S. EPA,
1984)
Chadwlck, R.W., C.J. Chadwlck, J.J. Freal and C.C. Bryden. 1977. Compara-
tive enzyme Induction and Undane metabolism 1n rats pretreated with various
organo-chloMne pesticides. Xenob1ot1ca. 7: 235. (Cited 1n U.S. EPA, 1984)
Crlpps, D.J., H.A. Peters and A. Golman. 1978. J. Invest. Dermatol.
71(4): 277. CUn. Res. 26(3): 489A. (CHed 1n Delchmann, 1981)
-25-
-------
Currier, fLF., C.D. McCHmans and &. Barna-Lloyd. 1980. Hexachlorobenzene
blood levels and the health status of men employed 1n the manufacture of
chlorinated solvents. J. Toxlcol. Environ. Health. 6(2): 367-377. (Cited
1n U.S. EPA, 1984)
Delchmann, W.B. 1981. Halogenated cyclic hydrocarbons. In.: Patty's
Industrial Hygiene and Toxicology, Vol. 28 3rd ed., G.D. Clayton and E.E.
Clayton, Ed. John WHey and Sons, Inc., NY. p. 3626-3645.
den Tonkelaar, E.M., H.G. Verschuuren, J. Bankovska, et al. 1978. Hexa-
chlorobenzene toxldty 1n pigs. Toxlcol. Appl. Pharmacol. 43: 1370.
(Cited 1n U.S. EPA, 1980a; Delchmann, 1981)
FAO (Food and Agriculture Organization). 1974. 1973 evaluations of some
pesticide residues 1n food. FAO/A6P/1973/M/9/1; WHO Pestle. Residue Ser. 3.
WHO, Rome, Italy, p. 291, (Cited In U.S. EPA, 1980a)
Federal Register. 1984. Environmental Protection Agency. Proposed guide-
lines for carcinogenic risk assessment. 49 FR 46294-46299.
Gralla, E.J., R.W. Flelschman, Y.K. Luthra, et al. 1977. Toxic effects of
hexachlorobenzene after dally administration to beagle dogs for one year.
Toxlcol. Appl. Pharmacol. 40(2): 227-239. (Cited In U.S. EPA, 1984;
Delchmann, 1981)
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-------
Grant, D.L., F. Iverson, 6.U. Hatlna and D.C. VUleneuve. 1974. Effects of
hexachlorobenzene on Hver porphyrln levels and mlcrosomal enzymes 1n rats.
Environ. Rhyslol. Blochem. 4: 159. (Cited 1n U.S. EPA, 1983a; Oelchmann,
1981}
Grant, D.L., W.E.J. Phillips and G.U. Hatlna. 1977. Effect of hexachloro-
benzene on reproduction 1n the rat. Arch. Environ. Contam. Toxlcol. 5:
207-216. (Cited 1n U.S. EPA, 1980a, 1982, 1984)
Hansen, L.G., S.B. Dorn, S.M. Sundlof and R.S. Vogel. 1978. No title pro-
vided. J. Agrlc. Food Chem. 26(6): 1369. (Cited 1n Delchmann, 1981)
Hayes, W.J. Jr. 1975. Toxicology of Pesticides. Williams and W1lk1ns,
Baltimore. (Cited 1n Delchmann, 1981)
Ingebrlgtsen, K. and I. Nafstad. 1983. Distribution and elimination of
14C-hexachlorobenzene after single oral exposure 1n the male rat. Acta
Pharmacol. Toxlcol. 52(4): 254-260.
Ingebrlgtsen, K., J.U. Skaare, I. Nafstad and M. Foerde. 1981. Studies on
the excretion and metabolites of hexachlorobenzene In the rat. Xenob1ot1ca.
11(11): 795-800. (Cited 1n U.S. EPA, 1984)
Khera, K.S. 1974. TeratogenlcHy and dominant lethal studies on hexa-
chlorobenzene 1n rats. Food Cosmet. Toxlcol. 12: 471-477. (Cited 1n U.S.
EPA, 1984)
-27-
-------
KHchln, K.T., R.E. Under, T.M. Scottl, 0. Walsh, A.D. Curley and 0.
Svensgaard. 1982. Offspring mortality and maternal lung pathology 1n
female rats fed hexachlorobenzene. Toxicology. 23(1): 33-90. (Cited 1n
U.S. EPA, 1984)
Kluwe, W.M., J.B. Hook and J. Bernstein. 1982. Synerg1st1c toxlclty of
carbon tetrachloMde and several aromatic organohallde compounds. Toxico-
logy. 23(4): 321-336.
Koss, G. and W. Koransky. 1975. Studies on the toxicology of hexachloro-
benzene. I. Pharmacok1net1cs. Arch. Toxlcol. 34: 203-212. (Cited 1n U.S.
EPA, 1980a)
Koss, G., S. Seubert, A. Seubert, W. Koransky and H. Ippen. 1978. Studies
on the toxicology of hexachlorobenzene. III. Observations 1n a long-term
experiment. Arch. Toxlcol. (Berl.) 40(4): 285-294. (Cited 1n U.S. EPA,
1984)
Kulper-Goodman, T., D.L. Grant, C.A. Moodle, G.O. Korsrud and I.C. Munro.
1977. Subacute toxlclty of hexachlorobenzene In the rat. Toxlcol. Appl.
Pharmacol. 40(3): 529-549. (Cited 1n U.S. EPA, 1984)
Lambrecht, R.W., E. Erturk, E.E. Grunden, et al. 1982. Renal toxlclty and
tumor1gen1c1ty of hexachlorobenzene (HCB) 1n rats (R). Proc. Am. Assoc.
Cancer. Res. 23: 210. (Cited 1n U.S. EPA, 1984)
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Lambrecht, R.W., E. Ertruk, E.E. Grunden, H.A. Peters, C.R. Morris and G.T.
Bryan. 1983a. Renal tumors 1n rats (R) chronically exposed to hexachloro-
benzene (HCB). Proc. Am. Assoc. Cancer. Res. 24: 59. (Abstr.) (Cited 1n
U.S. EPA, 1984)
Lambrecht, R.W., E. Ertruk, E.E. Grunden, H.A. Peters, C.R. Morris and G.T.
Bryan. 1983b. Hepatocasc1nogen1c1ty of chronically administered hexa-
chlorobenzene In rats. Fed. Proc. 42(4): 786 (Abstr.) (Cited 1n U.S. EPA,
1984).
Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic
activity of nine chlorinated phenols, seven chlorinated benzenes and three
chlorinated hexanes. Environ. Mutagen. 1: 143.
Loose, L.D., K.A. PHtman, K.F. BenHz, J.B. Sllkworth, W. Mueller and F.
Coulston. 1978a. Environmental chemical-Induced Immune dysfunction.
Ecotoxlcol. Environ. Safety. 2(2): 173-198. (Cited 1n U.S. EPA, 1984)
Loose, L.D., J.B. Sllkworth, K.A. PHtman, K.F. BenHz and W. Mueller.
1978b. Impaired host resistance to endotoxln and malaria 1n polychlorlnated
blphenyl- and hexachlorobenzene-treated mice. Infect. Immun. 20(1): 30-35.
(CHed 1n U.S. EPA, 1984)
Mendoza, C.E., B.T. Collins, J.B. Shields and G.W. Laver. 1978. Effects of
hexachlorobenzene or hexabromobenzene on body and organ weights of prewean-
Ung rats after a reciprocal transfer between the treated and control dams.
J. Agrlc. Food Chem. 26(4): 941-945. (CHed 1n U.S. EPA, 1984)
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Mendoza, C.E., J.B. Shields and G.W. Laver. 1979. Comparison of the por-
phyrlnogenlc activity of hexabromobenzene and hexachlorobenzene 1n pMmlpar-
ous Wlstar rats. Bull. Environ. Contam. Toxlcol. 21(3): 358-364. (CHed
In U.S. EPA, 1984)
Miller, G.J. and J.A. Fox. 1973. Chlorinated hydrocarbon pesticide resi-
dues In Queensland human milks. Med. J. Australia. 2: 261-264. (Cited 1n
U.S. EPA, 1980a)
Parke, D.V. and R.T. Williams. 1960. Studies In detoxlcatlon. Blochem. J.
74: 5-9. (CHed 1n U.S. EPA, 1980a)
Simon, G.S., R.G. Tardlff and J.F. Borzelleca. 1979. Failure of hexa-
chlorobenzene to Induce dominant lethal mutations 1n the rat. Toxlcol.
Appl. Pharmacol. 47(2): 415-519. (CHed 1n U.S. EPA, 1984)
Singh, H.B., L.J. Salas, A.J. Smith and H. Sh1ge1sh1. 1981. Measurements
of some potentially hazardous organic chemicals In urban atmospheres.
Atmos. Environ. 15: 601-612.
S1yal1, D.S. 1973. PolychloMnated blphenyls, hexachlorobenzene and other
organochlorlne pesticides 1n human milk. Med. J. Australia. 2: 815.
(CHed 1n U.S. EPA, 1980a)
Smith, A.G. and J.R. Cabral. 1980. Liver-cell tumours 1n rats fed hexa-
chlorobenzene. Cancer Let. 11(2): 169-172. (CHed 1n U.S. EPA, 1983a)
-30-
-------
Teschke, R. K. Bolsen, H. Landmann and G. Goerz. 1983. Effect of hexa-
chlorobenzene on the activity of hepatic alcohol-metabolizing enzymes.
Blochem. Pharmacol. 32(11): 1745-1751.
U.S. EPA. 1976. Environmental contamination from hexachlorobenzene. EPA
560/6-76-014. Office of Toxic Substances, Washington, DC. 1-27. (Cited In
U.S. EPA, 1980a)
U.S. EPA. 1979. Water Related Environmental Fate of 129 Priority Pollu-
tants. Vol. II. Office of Water Planning and Standards, Office of Water and
Waste Water Management, Washington, DC. EPA-440/4-79-029b
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Chlorinated
Benzenes. Environmental Criteria and Assessment Office, Cincinnati, OH.
EPA 440/5-80-028. NTIS PB 81-117392.
U.S. EPA. 1980b. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Quality
Criteria. Federal Register. 45: 79347-79357.
U.S. EPA. 1982. Health and Environmental Effects Profile for Hexachloro-
benzene. Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response,
Washington, DC.
-31-
-------
U.S. EPA. 1983a. Review of Toxlcologlc Data In Support of Evaluation for
Carcinogenic Potential of Hexachlorobenzene. Prepared by the Carcinogen
Assessment Group, OHEA, Washington, DC for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1983b. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. 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. 1984. Health Assessment Document for Chlorinated Benzenes.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
600/8-84-015F. NTIS PB 85-150332.
VeHh, 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.
36: 1040-1048.
Zablk, M.E. and R. Schemmel. 1980. Influence of diet on hexachlorobenzene
accumulation 1n Osborne-Mendel rats. J. Environ. Pathol. Toxlcol. 4(5-6):
97-103.
Zoeteman, B.C.J., K. Harmsen, J.B.H.J. Llnders, C.F.H. Morra and W. Slooff.
1980. Persistent organic pollutants In river water and ground water of The
Netherlands. Chemosphere. 9: 231-249.
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APPENDIX
Summary Table for Hexachlorobenzene
Carcinogenic
Potency
Species
Experimental
Dose/Exposure
Effect
Reference
CO
CO
I
Inhalation
Oral
rat
4-16 mg/kg/day
75 and 150 ppm
In diet
hepatocellular
carcinoma
NO
1.7
(mg/kg/day)"1
Lambrecht
et al., 1983a,b;
U.S. EPA, 1984
ND = Not derived
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