EPA-540/1-86-001
Environmental Protection
Agency
^.rice of 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
EPA
HEALTH EFFECTS ASSESSMENT
FOR HEXACHLOROCYCLOPENTADIENE
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EPA/540/1-86-001
September 1984
HEALTH EFFECTS ASSESSMENT
FOR HEXACHLOROCYCLOPENTADIENE
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 1n 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 1t 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-
chlorocyclopentadlene. 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 Is 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 review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Hexachloro-
cyclopentadlene. Environmental Criteria and Assessment Office,
Cincinnati, OH. EPA 440/5-80-055. NTIS PB 81-117667.
U.S. EPA. 1984. Health Assessment Document for Hexachlorocyclo-
pentadlene. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA 600/8-84-001F. NTIS PB 85-124915.
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 1n
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 1s 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 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, Is similar 1n concept to the ADI
(acceptable dally Intake). It Is 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 In U.S. EPA (1983).
For compounds for which there Is 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 (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-|*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.
Subchronlc oral exposure data are limited. Ninety day exposures of rats
and mice Indicated that rats are more sensitive to HEX toxldty than mice.
Both species showed lesions of the forestomach at their respective LOAELs.
Using the rat data, an AIS for oral exposure of 4.9 mg/day 1s estimated. In
the absence of chronic oral exposure data, an AIC of 0.49 mg/day for the
oral route 1s eslmtated by applying an additional uncertainty factor of 10
to the AIS.
Subchronlc Inhalation data are also limited. Rats and monkeys have been
tested for periods up to 14 weeks. Using the monkey data, an Inhalation AIS
of 0.2 mg/day 1s estimated.
Chronic Inhalation evaluations of HEX have been conducted 1n guinea
pigs, rabbits, rats and mice. Data are of limited use, except for the rat,
because of Incomplete reporting of results and questions concerning the
purity of the compound. However, the data are adequate to raise questions
concerning interspecles differences in sensitivity to this compound. An
Inhalation AIC of 0.0046 mg/day 1s estimated based on the rat data of Clark
et al. (1982a). This estimate is lower than an estimate which could be
derived from the TLV. Despite questions concerning available data, the
Incorporation of uncertainty factors should provide an adequate margin of
safety. These estimates should be reviewed when more complete data are
available. A CS of 62 was calculated based on mortality in mice exposed to
1.7 mg/m3, 7 hours/day, 5 days/week, for as many as 150 treatments.
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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. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was^the 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 Air 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. ENVIRONMENTAL CHEMISTRY AND FATE
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
2.3.
ORAL
INHALATION
CONCLUSIONS REGARDING HEX ABSORPTION RATES
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
4. CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
BIOASSAYS
OTHER RELEVANT DATA
4.3.1. MutagenlcHy
WEIGHT OF EVIDENCE
5. REGULATORY STANDARDS AND CRITERIA
5.1.
5.2.
5.3.
5.4.
5.5.
5.6.
5.7.
OCCUPATIONAL STANDARDS
TRANSPORTATION REGULATIONS
SOLID WASTE REGULATIONS
FOOD TOLERANCES
WATER REGULATIONS
AIR REGULATIONS
OTHER REGULATIONS
Page
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8
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8
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11
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V11
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TABLE OF CONTENTS (cont.)
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral
6.1.2. Inhalation
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral
6.2.2. Inhalation
Page
22
22
22
22
23
23
23
6.3. CARCINOGENIC POTENCY (q-|*) 25
7. REFERENCES 26
APPENDIX: Summary Table for Hexachlorocyclopentadlene 35
V111
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF file-concentration factor
bw Body weight
CS Composite score
DNA Deoxyr1bonucle1c add
PEL Frank-effect level
GC/MS Gas chromatography/mass spectrometry
105 Dose lethal to 5% of recipients
LOAEL Lowest-observed-adverse-effect level
LOEL Lowest-observed-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppb Parts per billion
ppm Parts per million
RQ Reportable quantity
RVd Dose-rating value »
RVe Effect-rating value
SMR Standardized mortality ratio
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Hexachlorocyclopentadlene (HEX) Is the most commonly used name for the
compound that 1s designated 1,2,3,4,5,5'-hexachloro-l,3-cyclopentad1ene by
the International Union of Pure and Applied Chemistry system (IUPAC). Table
1-1 cites the IUPAC name and synonyms, the Chemical Abstract number and
molecular and structural formulas for HEX.
Hexachlorocyclopentadlene 1s a nonflammable liquid with a characteristic
pungent, musty odor; the pure compound 1s light lemon-yellow. Table 1-2
presents the physical properties and constants for HEX.
Commercial HEX has various purities depending upon the route of synthe-
sis. HEX 1s a highly reactive dlene that readily undergoes addition and
substitution reactions and also participates In 01els-Alder reaction of HEX
with a compound containing a nonconjugated double bond consisting of 1:1
adducts containing a hexachloroblcyclo (2,2,1) heptene structure; the monene
derived part of the adduct 1s nearly always In the endo position. Figure
1-1 Illustrates synthetic pathways to various chlorinated pesticides for
which HEX 1s a precursor. HEX may be present 1n these pesticides as a
contaminant.
HEX 1s released Into the environment during Its manufacture and during
the manufacture of products requiring HEX. Limited monitoring data from
production sites Indicated that HEX was present at 18 mg/8, 1n the aqueous
discharge from the Memphis pesticide plant (U.S. EPA, 1984).
In May 1977, HEX was also detected at 0.17 mg/8. 1n the aqueous dis-
charge and at 56 ppb 1n air samples collected from a waste site 1n Montague,
MI (U.S. EPA, 1984). At a waste site In Hardeman County, TN, HEX has been
shown to be emitted Into the air, groundwater, wastewater and drinking water
(Clark et al., 1982b). Indoor air concentrations of HEX In houses with
contaminated groundwater supplies ranged from 0.06-0.10 yg/m3.
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TABLE 1-1
Identity of Hexachlorocyclopentadlene*
Identifying Characteristic
Name/Number/Structure
IUPAC Name:
Trade Names:
Synonyms:
CAS Number
CIS Accession Number:
Molecular Formula:
Molecular Structure:
l,2,3,4,5,5'-Hexachloro-l,3-cyclopentad1ene
C56; HRS 1655; Graphlox
Hexachlorocyclopentadlene
Perchlorocyclopentadlene
HEX
HCPD
HCCP
HCCPO
C-56
HRS 1655
Graphlox
77-47-4
7800117
Cl
Cl
Cl
Cl
Cl Cl
*Source: Stevens, 1979
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TABLE 1-2
Physical Properties of Hexachlorocyclopentadlene
Property
Value/Description
Reference
Molecular Weight:
Physical Form (25°C)
Odor:
Electronic Absorption
Maximum (In 50%
acetonltr He-water)
Solubility
Water (mg/l):
Organic Solvents:
Vapor Density (air = 1)
Vapor Pressure
(mmHg, °C):
Specific Gravity:
Melting Point (°C):
Boiling Point (°C):
Octanol/Water Partition
Coefficient (log P)
(measured):
(estimated):
Latent Heat of Vaporiza-
tion
Henry's Law Constant
(atm-mVmole)
272.79 Stevens, 1979
Pale yellow liquid Hawley, 1977; Irish, 1963
Pungent Hawley, 1977; Irish, 1963
322 nm
2.1 (25°C)
0.805 (25°C)
1.8 (28°C)
Mlsdble (Hexane)
9.4
0.08 (25°C)
0.975 (62°C)
1.717 (15°C)
1.710 (20°C)
1.7019 (25°C)
-9.6
-11.34
239 @ 753 mm Hg
234
5.04±0.04
5.51
176.6 J/g
2.7xlO'2
Wolfe et a!., 1982
Oal Monte and Yu, 1977
Lu et al., 1975
Wolfe et al., 1982
Bell et al., 1978
Verschueren, 1977
Irish, 1963
Stevens, 1979
Hawley, 1977
Stevens, 1979
Weast and Astle, 1980
Hawley, 1977
Stevens, 1979
Hawley, 1977; Stevens, 1979
Irish, 1963
Wolfe et al., 1982
Wolfe et al., 1982
Stevens, 1979
Atallah et al., 1980;
Wolfe et al., 1982
-3-
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OlIlMlN
•«ei|. M>» CM twiin
•MM IN co«o» c«i%
Ol 1O|C"| • IIN ton
"
Mini
FIGURE 1-1
Synthesis of Chlorinated Cyclodlene Pesticides from Hexachlorocyclopentadlene
Source: U.S. EPA. 1984
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Published reports, environmental releases and physlochemlcal properties
of HEX Imply that it will be present mainly In the aquatic compartment and
associated with bottom sediments and organic matter. Relatively much lower
concentrations will be found 1n the soil and air compartments. A1r levels
1n areas near previous dump sites have been shown to be high. High concen-
trations of HEX have been recorded 1n wastewater and, 1n two Incidences,
have Increased the ambient HEX levels Inside treatment facilities above the
ACGIH TWA.
Little relevant Information Is available to predict the fate of HEX 1n
air. Its tropospherlc residence time was estimated by CupHt (1980) to be
~5 hours based upon rates of reaction with hydroxyl radicals and ozone. The
respective reaction rates were theoretically estimated to be 59xlO~12 and
8xlO~18 cm3 molecule'1 sec"1. Atmospheric photolysis of HEX was
rated as probable, since HEX has a chromophore that absorbs light 1n the
solar spectral and 1s known to photolyze 1n aqueous media. CupHt (1980)
listed the theoretical degradation products as CUCO, dlacylchloMdes,
ketones, and free Cl radical, all of which would be likely to react with
other elements and compounds.
In the event of release Into shallow or flowing bodies of water, degra-
datlve processes such as photolysis, hydrolysis and blodegradatlon, as well
as transport processes Involving volatlzatlon and other physical loss mecha-
nisms, are expected to be prominent 1n HEX dissipation.
Under a variety of sunlight conditions, 1n both distilled and natural
waters of 1-4 cm depth, phototransformatlon half-life was <10 minutes.
Addition of sediments to distilled water containing HEX had little effect on
the phototransformatlon rate constant of HEX at this latitude on cloudless
-5-
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days (averaged over both light and dark periods for a year) that was 3.9
hour"1, corresponding to a half-life of 10.7 minutes (Zepp et al., 1979;
Wolfe et al., 1982).
Studies of the hydrolysis of HEX Indicate that at 25-30°C and In the
environmental pH range of 5-9, a hydrolytlc half-life of -3-11 days Is
observed (Wolfe et al., 1982). Hydrolysis 1s much slower than photolysis,
but may be a significant load-reducing process 1n waters where photolysis
and physical transport processes are not Important (I.e., 1n deep, nonflow-
1ng waters).
Wolfe et al. (1982) found hydrolysis of HEX to be Independent of pH over
a range of 3-10. With a variation 1n temperature, these rates changed
somewhat.
HEX 1s not expected to be oxidized under ordinary environmental condi-
tions. Based on an estimated first order oxidation rate constant, a com-
puter simulation predicted that HEX would not be oxidized 1n the simulated
river, pond or eutrophlc lake.
Tabak et al. (1981) stated that HEX 1s blodegraded fairly rapidly 1n a
static laboratory culture. Upon release onto soil, HEX 1s likely to adsorb
strongly to any organic matter or humans present (Kenaga and Goring, 1980;
Weber, 1979). With time, HEX concentrations should decrease as populations
of soil microorganisms better adapted to metabolize HEX increase (Rieck,
1977a,b,c; Thuma et al., 1978).
The log octanol/water partition coefficient (log P) of HEX has been
experimentally determined to be 5.04 (Wolfe et al., 1982) and 5.51 (Velth et
al., 1979), which indicates a substantial potential for bloconcentration,
bioaccumulation and biomagification. Actual determinations of bioconcentra-
-6-
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tlon and bloaccumulatlon In several aquatic organisms Indicate that HEX does
accumulate to a great extent (Podowski and Khan, 1979; VeHh et al., 1979;
Spehar et al., 1979).
VeHh et al. (1979) determined the BCF for HEX to be 29 In the fathead
minnow, P^. promelas. Spehar et al. (1979) conducted a 30-day early-Hfe
stage, flowthrough toxldty test at 25°C with the fathead minnow. HEX
residues 1n the fish after 30 days of continuous exposure to HEX were <0.1
mg/kg for all concentrations tested (0.78-9.1 vg/8. 1n water). In two
other studies (Velslcol Chemical Corporation, 1978; Bennett, 1982), HEX was
not detected 1n any of the fish tissue samples analyzed by GC/MS.
The fate and transport of HEX 1n the atmosphere are not well documented,
but available Information suggests that the compound does not persist. In
water, HEX 1s likely to dissipate rapidly by means of photolysis, hydrolysis
and blodegradatlon. B1odegradat1on may also be a significant process 1n
certain waters, although the evidence 1s weak. HEX 1s known to volatilize
from water; however, It 1s possible that volatilization Is limited by diffu-
sion, particularly 1n waters that are not well mixed, and by sorptlon on
sediments.
The fate and transport of HEX 1n soils are affected by Us strong
tendency to adsorb onto organic matter. HEX 1s predicted to be relatively
Immobile 1n soil based on Us high log P value. Volatilization, which 1s
likely to occur primarily at the soil surface, Is Inversely related to the
organic matter levels and water-holding capacity of the soil. Leaching of
HEX by groundwater should be very limited, and chemical hydrolysis and
mlcroblal metabolism are expected to reduce environmental levels. HEX Is
metabolized by a number of soil microorganisms. HEX may be found In areas
where there was no HEX production or usage, because It may be present as a
contaminant In products made from It.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Absorption rates have not been calculated for HEX. Dorough (1979)
studied the oral absorption of HEX 1n male and female Sprague-Dawley rats
and mice. Although absorption was shown by the presence of the radlolabeled
compound 1n the feces (72%) and urine (14%), the rates were not calculated.
In a study by Yu and Atallah (1981), male and female Sprague-Dawley rats
(240-350 g) were given a single dose of 3 or 6 mg/kg 14C-HEX 1n 0.5 ms,
corn oil by oral gavage. Radioactivity appeared 1n the blood within 30
minutes, reached a maximum value at 4 hours, and then gradually decreased.
The excretion levels were near the values of Dorough (1979).
2.2. INHALATION
Dorough (1980) studied the absorption and fate of Inhaled HEX 1n female
Sprague-Dawley rats (175-250 g). Animals were exposed to vapors of
14C-HEX over a 1-hour period to achieve doses of -24 vg/kg bw. The
radlolabel was recovered 1n the feces and urine; however, no absorption
rates were calculated.
2.3. CONCLUSIONS REGARDING HEX ABSORPTION RATES
From the data reviewed 1n the pharmacok1net1c studies of HEX, the fol-
lowing points can be made regarding the fate of HEX 1n biological systems:
HEX reacts with biological tissues and macromolecules at the
point of administration as Indicated by the high concentration
of HEX equivalents 1n the lung and trachea following Inhalation
exposure.
HEX 1s not readily absorbed through the gastrointestinal tract
as Indicated by the following: the 2- to 3-fold higher fecal
elimination of HEX equivalents following oral administration as
compared with Intravenous or Inhalation administration, and the
reactivity of HEX with the gastrointestinal contents as Indi-
cated by the fact that no unchanged HEX 1s excreted following
oral administration.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In a range-finding study, Litton B1onet1cs Inc. (1978a)
determined the oral LD_ of HEX 1n Charles River CD-I rats to be 76 mg/kg.
However, when the LD5 was administered to rats for 5 consecutive days, all
24 animals died. In a comparable range-finding study 1n Fischer 344 rats
(SRI, 1980b) no mortality was reported at doses of 25, 50 or 100 mg/kg when
given 12 doses 1n 16 days.
The subchronlc toxldty of HEX 1s summarized 1n Table 3-1. In the oral
dose studies (Abdo et al., 1984), dose levels of 19, 38, 75, 150 and 300
mg/kg HEX (94.3-97.4% pure) in corn oil were administered by gavage to
groups of 10 male and 10 female mice. Doses were administered 5 days/week
for 13 weeks. At the highest dose level (300 mg/kg), all male mice died by
day 8 and 3 females died by day 14. In female mice, the liver was enlarged.
Dose levels of >38 mg/kg HEX. caused lesions in the forestomach, including
ulceration in both males and females. At doses of >75 mg/kg, toxic nephro-
sis was seen In females. In the rat portion of this study, doses of 10, 19,
38, 75 and 150 mg/kg HEX were administered. Mortality and toxic nephrosls
were noted In both males and females at doses of >38 mg/kg. The male rats
treated at 19 mg/kg dose level did not show any highly abnormal effects,
while females exhibited lesions of the forestomach. Such lesions were
observed In male rats at the >38 mg/kg dose levels. There was a dose-
related depression of body weight gain relative to the controls. The NOAEL
for rats was selected to be the 10 mg/kg level.
3.1.2. Inhalation. Rand et al. (1982) and Alexander et al. (1980)
performed inhalation studies 1n rats and monkeys. Groups of 40 male and 40
female Sprague-Dawley rats weighing 160-226 g, or groups of 12 cynomolgus
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TABLE 3-1
Subchronlc Toxlclty of HEX
o
i
Study Species
90-Day rat
Feeding
90-Day mouse
Feeding
14 -Week rat
Inhalation
Toxlclty
14 -Week monkey
Inhalation
Toxlclty
Dose
10, 19, 38, 75,
150 or 300 mg/kg
(by gavage)
19, 38, 75, 150
or 300 mg/kg
(by gavage)
0.01, 0.05 and
0.2 ppm
(5 days/week)
0.01, 0.05 and
0.2 ppm
(5 days/week)
Results
NOAEL
LOEL
NOAEL
LOEL
NOAEL
LOEL
NOAEL
LOEL
- 10 mg/kg
- 19 mg/kg
- 19 mg/kg
- 38 mg/kg
- 0.2 ppm
- NE
- 0.2 ppm
- NE
Effects at LOEL or
Lowest Dose
Lesions of forestomach
In female rats at
19 mg/kg
Lesions of forestomach
In both sexes at
38 mg/kg
No statistically
significant effects
No effects noted
Reference
Abdo et al
1984b
Abdo et al
1984
Rand et al
1982
* t
* »
* t
Alexander
et al., 1980
NE = Not established
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monkeys weighing 1.5-2.5 kg (average 2.0 kg), were exposed to HEX, 6 hours/
day, 5 days/week, for 14 weeks. Levels of exposure were 0, 0.01, 0.05 and
0.20 ppm HEX. In monkeys, there were no mortalities, adverse clinical
signs, weight gain changes, pulmonary function changes, eye lesions, hemato-
loglc changes, clinical chemistry abnormalities or hlstopathologlc abnormal-
ities at any dose level tested.
Male rats 1n this study (Rand et al., 1982) had a transient appearance
of dark-red eyes at 0.05 and 0.2 ppm HEX. At 12 weeks, there were marginal,
but not statistically significant, Increases 1n hemoglobin concentration and
erythrocyte count In 0.01 ppm males, 0.05 ppm females and 0.20 ppm males and
females. There were no treatment-related abnormalities 1n gross pathology
or hlstopathology.
3.2. CHRONIC
3.2.1. Oral. The chronic oral toxldty of HEX has not been determined.
The longest oral study to date was the previously reviewed work of Abdo et
al. (1984).
3.2.2. Inhalation. Treon et al. (1955) exposed guinea pigs, rabbits,
rats and mice to a concentration of 0.33 ppm for 7 hours/day, 5 days/week
for 25-30 exposures. Guinea pigs survived 30 exposures; however, rats and
mice did not survive 5 exposures, and 4/6 rabbits did not survive 30
exposures. Using a lower concentration (0.15 ppm HEX), guinea pigs, rabbits
and rats survived 150 7-hour exposure periods. This level was too high for
a chronic level study 1n mice since 4/5 animals did not survive. Slight
renal and hepatic degeneration was noted In all species; mice, rats and
guinea pigs also developed lesions 1n the lungs.
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A 30-week chronic Inhalation study of technical grade HEX (96%) 1n rats
was conducted by Shell Toxicology Laboratory (Clark et al., 1982a). Four
groups of 8 male and 8 female Wlstar Albino rats were exposed to HEX at
nominal concentrations of 0, 0.05, 0.1 and 0.5 ppm for 6 hours/day, 5 days/
week, for 30 weeks and were observed for a 14-week recovery period without
HEX exposure. At the highest dose level, 4 males and 2 females died. In
males, there was depressed body weight gain 1n the 0.5 ppm group relative to
controls beginning at 7 weeks of exposure and persisting throughout the
remainder of the study. Females 1n the medium and high dose groups had
lower body weights at the end of the recovery period as compared with
controls. At 0.5 ppm, pulmonary degenerative changes were noted 1n both
sexes although the males were affected more severely. At the highest dose,
there were mild degenerative changes 1n the Hver and kidneys at 30 weeks 1n
a few rats and kidney weights were significantly Increased 1n the females.
After 30 weeks of study, there was no biologically significant toxlclty
noted 1n animals exposed to concentrations of 0.05 or 0.1 ppm HEX (Clark et
al., 1982a).
A chronic Inhalation study has been scheduled by the National Toxicology
Program (Abdo, 1983).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. The teratogenlc potential of HEX was evaluated In pregnant
Charles River CD rats that were administered HEX (98.25%) by gastric Intuba-
tion 1n corn oil at dose levels of 3, 10 and 30 mg/kg/day from days 6-15 of
gestation. A control group received the vehicle (corn oil) at a dose volume
of 10 ma/kg/day. Survival was 100%, and there was no difference In mean
maternal body weight gain between dosed groups and controls. There were no
differences 1n the mean number of Implantations, corpora lutea, live
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fetuses, mean fetal body weights or male/female sex ratios among any of the
groups; and there were no statistical differences In malformation or devel-
opmental variations compared with the controls when external, soft tissue
and skeletal examinations were performed (IRDC, 1978).
Murray et al. (1980) evaluated the teratogenlc potential of HEX (98%) 1n
CF-1 mice and New Zealand White rabbits. Mice were dosed at 0, 5, 25 or 75
mg/kg/day HEX by gavage from days 6-15 of gestation, while rabbits received
the same dose from days 6-18 of gestation. The fertility of both the treat-
ed mice and the rabbits was not significantly different from the control
groups. In the mice, no evidence of maternal toxldty, embryotoxldty or
teratogenlc effects was observed. A total of 249-374 fetuses (22-33
Utters) were examined 1n each dose group.
In rabbits, maternal toxldty was noted at 75 mg/kg/day (diarrhea,
weight loss and mortality), but there was no evidence of maternal toxldty
at the lower levels. There were no embryotoxlc effects at any dose level.
Although there was an Increase 1n the proportion of fetuses with 13 ribs at
75 mg/kg/day over controls, this was considered a minor skeletal variation,
and the authors concluded that HEX was not teratogenlc at the levels tested.
3.3.2. Inhalation. Studies on the teratogenlc potential of Inhaled HEX
were not located 1n the review of the scientific literature.
There were no studies located 1n the literature that addressed other
reproductive effects from exposure to HEX.
3.4. TOXICANT INTERACTIONS
In the review of available literature, HEX has not been shown to Inter-
act with other compounds. However, 1n many experiments on absorption of
HEX, some common observations have been ascertained regarding HEX and living
tissue. Repeated exposure of several animal species to levels of HEX vapor
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1n the 0.1-0.2 ppm range has been found to cause pulmonary degenerative
changes (Treon et a!., 1955; Clark et al., 1982a). The Interaction of HEX
within human tissue has caused mild degenerative changes In the kidneys,
"liver, brain, heart and adrenal glands.
There are Insufficient data to Identify clearly the site most sensitive
to prolonged, repeated exposure of HEX. However, researchers found 1n
comparing routes of administration over a wide variety of doses and lengths
of exposures that, regardless of which route was used, damage to the lungs
occurred (Lawrence and Dorough, 1982). When HEX 1s administered orally to
animals, the kidneys may be the most sensitive site, since subchronlc dosing
of rats and mice was found to cause nephrosls. Although the oral route may
not be significant In human exposure, the fact that the kidneys are a
possible target organ 1n subchronlc exposure Indicates that low-level,
prolonged systemic exposure from any ambient route may affect the kidneys.
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4. CARCINOGENICITY
4.1. HUMAN DATA
Mortality studies have been conducted on workers Involved In the produc-
tion of HEX or formulation of HEX products. The Shlndell and Associates
(1980) report was a cohort study of workers employed at the Velslcol Chemi-
cal Corporation plant at Marshall, IL between 1946 and 1979. The analysis
showed no significant differences 1n mortality rates between these employees
and the United States population.
Wang and MacMahon (1979) conducted a study on a group of 1403 males
employed In plants producing or using HEX. The SMR was used to compare the
workers with the general population. The two highest SMRs were 134 for lung
cancer and 183 for cerebrovascular disease, but only the latter was statis-
tically significant. The authors noted that these effects were unrelated to
exposure because the deaths showed no consistent pattern with duration of
employment or with duration of follow-up.
Other studies (Shlndell and Associates, 1981; Buncher et al., 1980)
showed similar results. In all of these studies, no carcinogenic effects of
HEX exposure were noted.
4.2. BIOASSAYS
There are no animal bloassay data Indicating that HEX 1s carcinogenic to
animals by any route of exposure. An Inhalation cardnogenesls bloassay 1n
rats and mice 1s being conducted by NTP (Abdo, 1983).
4.3. OTHER RELEVANT DATA
4.3.1. Mutagen1c1ty. Goggelman et al. (1978) found that HEX was not
mutagenlc before or after liver mlcrosomal activation at 2.7xlO~3 M 1n an
Escherlchla coll K,2 back mutation system. In this test there was 70%
survival of bacteria at 72 hours. HEX was not tested at higher concentra-
tions because H was cytotoxlc to E.. coll. An earlier report by Grelm et
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al. (1977) from the same laboratory Indicated that HEX was also not muta-
genlc 1n Salmonella typhlmurlum strains TA1535 (base-pair mutant) or TA1538
(frame shift mutant) after liver mlcrosomal activation; however, no details
of the concentrations tested were given. Although tetrachlorocyclopenta-
dlene Is mutagenlc 1n these systems, probably through metabolic conversion
to the dlenone, 1t appears that the chlorine atoms at the C-l position of
HEX hindered metabolic oxidation to the corresponding acylatlng dlenone
(Grelm et al., 1977).
A study conducted by Industrial B1o-Test Laboratories (IBT, 1977) also
suggests that HEX 1s not mutagenlc In S. typhlmurlum. Both HEX and Us
vapors were tested with and without metabolic activation. The vapor test
was done In desiccators with only the TA100 strain of J>. typhlmurlum. It 1s
not clear from the presented data of the vapors test that sufficient amounts
of HEX or adequate times of exposure were used. Exposure times of 30, 60 or
120 minutes were 'studied. Longer exposures 1n the presence of the HEX
vapors may be necessary for observation of a potential mutagenlc effect.
The statement 1n the text that testing was conducted 1n the toxic range 1s
not supported convincingly by the Investigators' results.
At concentrations of up to 1.25xlO~3 yg/ms. In the presence of an S-9
Hver activating system, HEX was not mutagenlc 1n the mouse lymphoma muta-
tion assay. Mutagenldty could not be evaluated at higher concentrations
because of the cytotoxldty of HEX (Litton B1onet1cs, Inc., 1978b). This
assay uses L5178Y cells that are heterozygous for thymldlne klnase (TK+/-)
and are bromodeoxyuMdine (BUdR) sensitive. The mutation 1s scored by
cloning with BUdR 1n the absence of thymldlne. HEX 1s highly toxic to these
cells, particularly 1n the absence of an activating system (at 4xlO~5
yfc/ms.); a positive control, dimethylnitrosamine, was mutagenlc at
0.5 yl/ms..
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Williams (1978) found that HEX (10 6 M) was Inactive 1n the Hver
epithelial culture hypoxanthlne-guanlne-phosphorlbosyl transferase locus/
mutation assay. At 10~s M HEX also failed to stimulate DNA repair synthe-
sis in hepatocyte primary cultures. Negative results were also obtained in
an additional unscheduled DNA synthesis assay (Brat, 1983).
Two recent studies provided by NTP (Juodeika, 1983) also failed to
demonstrate the mutagenidty of HEX. In S. typhimurium strains TA98, TA100,
TA1535 and TA1537, levels of up to 3.3 yg/plate were not mutagenic without
activation and levels of up to 100.0 vg/plate were not mutagenic after
mlcrosomal activation. Higher levels could not be tested because of exces-
sive bacterial mortality. In the Drosophila sex-linked recessive lethal
test, HEX was not mutagenic. The doses used 1n this study were 40 ppm by
feeding for 3 days or by a single injection of 2000 ppm.
HEX has also been assayed 1n the mouse dominant lethal test (Litton Bio-
netlcs, Inc., 1978a). In this assay, 0.1, 0.3 or 1.0 mg/kg HEX was adminis-
tered by gavage to 10 male CD-I mice for 5 days and these mice were then
mated throughout spermatogenesls (7 weeks). This test determines whether
the compound induces lethal genetic damage to the germ cells of males.
There was no evidence of dominant lethal activity at any dose level by any
parameter; e.g., fertility Index, implantations/pregnancy, average resorp-
tions/pregnancy. In this study, the highest dose used was the LD,., deter-
mined by a 5-day mortality study in male CD-I mice.
4.4. WEIGHT OF EVIDENCE
No reports of carclnogenicity of HEX have been found 1n the available
literature. The data base is neither extensive nor adequate for assessing
the carcinogenicity of HEX. The National Toxicology Program has recently
completed a subchronlc animal study and Is conducting a chronic animal
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Inhalation bloassay using both rats and mice (Abdo, 1984). Applying the
criteria proposed by the Carcinogen Assessment Group of the U.S. EPA
(Federal Register, 1984) for evaluating the overall weight of evidence, HEX
1s most appropriately considered a Group D - Not Classified chemical.
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5. REGULATORY STANDARDS AND CRITERIA
5.1. OCCUPATIONAL STANDARDS
There 1s no current Occupational Safety and Health Administration (OSHA)
standard for HEX levels 1n the workplace. However, the AC6IH (1982) has
adopted a TLV, expressed as an 8-hour TWA of 0.1 mg/m3 (0.01 ppm). A
STEL, the maximum allowable concentration 1n a !5-m1nute period, of 0.3
mg/m3 (0.03 ppm) for HEX has also been adopted (ACGIH, 1982). The levels
are based on Treon et al. (1955).
NIOSH (1978) classlfed HEX as a Group II pesticide and recommended
criteria for standards for occupations 1n pesticide manufacturing and formu-
lating. These standards rely on engineering controls, work practices and
medical surveillance programs, rather than workplace air limits, to protect
workers from the adverse effects of pesticide exposure 1n manufacturing and
formulating (NIOSH, 1978).
5.2. TRANSPORTATION REGULATIONS
The Hazardous Materials Transportation Act specifies the requirements to
be observed 1n the preparation for shipment and transport of hazardous
materials. The transport of HEX by air, land and water 1s regulated by
these statutes, and the Department of Transportation has designated HEX as a
"hazardous material," a "corrosive material" and a "hazardous substance."
The maximum net quantity for transport by passenger-carrying aircraft or
rallcar has been set at 10 gallons per package. Transport on deck or below
deck by cargo vessel 1s also permitted.
5.3. SOLID WASTE REGULATIONS
Under the Resource Conservation and Recovery Act (RCRA), the U.S. EPA
has designated HEX as a hazardous toxic waste, Hazardous Waste No. U 130,
subject to disposal and permit regulations (40 CFR 262-265 and 122-124).
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5.4. FOOD TOLERANCES
Under the Federal Insecticide Fumlgant and Rodentldde Act (FIFRA), a
tolerance of 0.3 ppm has been established for chlordane residues, which are
not to contain >1% of HEX (40 CFR 180.122).
5.5. WATER REGULATIONS
Under Section 311 of the Federal Water Pollution Control Act, the U.S.
EPA designated HEX as a hazardous substance and established an RQ of 1 pound
(0.454 kg) for HEX. Discharges equal to or greater than the RQ Into or upon
United States waters are prohibited unless the discharge 1s In compliance
with applicable permit programs.
Under the Clean Water Act, the U.S. EPA has designated HEX as a toxic
pollutant (I.e., priority pollutant). Effluent limitations guidelines, new
source performance standards, and pretreatment standards have been developed
or will be developed for the priority pollutants for 21 major Industries.
Under the Clean Water Act, Ambient Water Quality Criteria (AWQC) for HEX
were also developed (U.S. EPA, 1980a). Based on available toxldty data for
the protection of public health, the level derived was 206 yg/l.
Using organoleptlc data for controlling undesirable taste and odor of
ambient water, the estimated level was 1 yg/8, (U.S. EPA, 1980a).
5.6. AIR REGULATIONS
HEX 1s not regulated under the Clean A1r Act.
5.7. OTHER REGULATIONS
Pursuant to rules under sections 8{a) and 8(d) of the Toxic Substances
Control Act, all manufacturers of HEX are required to report health and
safety Information on HEX to EPA's Office of Toxic Substances. The deadline
for submission of Preliminary Assessment Information Manufacturer's Report
on HEX was November 19, 1982.
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In 1979, the Interagency Testing Committee recommended that HEX be
considered for health and environmental effects testing under Section 4{a)
of the TSCA (44 FR 31866). This recommendation was based on evidence of
potential human exposure and a potential for environmental persistence and
bloaccumulatlon. The U.S. EPA (1982) responded 1n the Federal Register.
The following 1s the statement from that notice:
EPA has decided not to Initiate rulemaklng to require testing of
HEX under section 4 of TSCA because EPA does not believe that there
Is a sufficient basis to find that current manufacture, distribu-
tion 1n commerce, processing, use or disposal of HEX may present an
unreasonable risk of Injury to the environment or of mutagenlc and
teratogenlc health effects. Neither has the EPA found evidence
that there 1s substantial or significant environmental release of
HEX. In addition, certain new studies have become available since
the ITC's report or are underway, making additional testing for
chronic and oncogenlc effects unnecessary.
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6. RISK ASSESSMENT
Pertinent risk assessment data are summarized In the Appendix of this
report.
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. Short-term studies by IROC (1978) and Abdo et al. (1984)
provide Information on oral toxldty to rats and mice; however, the study
sizes were small (5 and 10 animals/dose group, respectively). The studies
by Abdo et al. (1984) are the only short-term studies yielding no-adverse-
effect levels. Based upon the rat and mouse data, these short-term oral
studies Indicate a lowest-effect level for dally exposure to be 19 and 38
mg/kg, respectively. Multiplying by 5/7 to estimate a continuous exposure
expanded from treatment on 5 days/week results In estimates of 13.6 and
27.14 mg/kg/day, respectively. The NOAELs estimated for continuous exposure
for the rat and mouse were 7 and 14 mg/kg/day, respectively. Using the rat
NOAEL of 7 mg/kg/day an AIS can be calculated. For a 70 kg man, an AIS for
HEX by oral exposure would be 7 mg/kg/day x 70 kg * 100 = 4.9 mg/day.
Division by 100 represents an uncertainty factor of 10, Introduced for
Interspedes extrapolation, combined with another uncertainty factor of 10
1n an attempt to protect unusually sensitive populations.
6.1.2. Inhalation. In 14-week Inhalation studies a NOAEL for cynomolgus
monkeys of 0.2 ppm HEX was established when exposures were 6 hours/day, 5
days/week. This same concentration was determined to be a NOAEL for rats
using the same exposure regimen.
Using a monkey respiratory volume of 1.4 mVday, a dally exposure
estimate can be calculated as follows: 2.27 mg/m3 (0.2 ppm) x 1.4
mVday x 6/24 x 5/7 = 0.568 mg/day. Dividing this exposure estimate by
2.0 kg, the average body weight of the monkeys used 1n this experiment,
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applying an uncertainty factor of TOO and multiplying by 70 kg, the assumed
body weight of an average human, results in an AIS for Inhalation exposure
of 0.2 mg/day for a human. This AIS assumes that exposure will be uniformly
distributed over the day.
An RQ has been calculated for the effect of mortality In mice exposed by
Inhalation to 0.15 ppm (1.7 mg/m3) HEX, 7 hours/day, 5 days/week for up to
150 exposures (Treon et al., 1955). A human MED was calculated by expanding
to continuous exposure, assuming a human Inhalation rate of 20 mVday and
an Inhalation absorption coefficient of 0.5, and applying an uncertainty
factor of 10 to extrapolate from subchronlc to chronic data. A human MED of
0.35 mg/day was calculated, which corresponds to an RV. of 6.2. Mortality
1s assigned an RV of 10. The CS of 62 was obtained as the product of
RV . and RV .
d e
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. No chronic oral toxlcity evaluations of HEX were located
which could be used for risk assessment purposes. Based on subchronlc oral
data (Abdo et al., 1984) an AIC of 0.49 mg/man/day for oral exposure is
estimated by application of an additional uncertainty factor of 10.
6.2.2. Inhalation. Treon et al. (1955) exposed rats, guinea pigs,
rabbits and mice to 0.15 ppm HEX 7 hours/day, 5 days/week for up to 7
months. No effects were seen in any species except mice: 4/5 mice died
before the end of the exposure period. The dose-response relationship
appears to be very steep in an earlier segment of the Treon et al. (1955)
report. Exposure to 0.33 ppm HEX resulted 1n the death of 4/6 rabbits
before 25 exposure sessions were completed; no rats or mice survived 20
exposure periods and guinea pigs survived the planned series of 30 exposures.
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Clark et al. (1982a) exposed groups of Wlstar rats (8/sex/dose) to HEX
concentrations of 0, 0.05, 0.1 or 0.5 ppm 6 hours/day, 5 days/week for 30
weeks followed by a 14-week recovery period. At the 0.5 ppm exposure level,
4 males and 2 females did not survive and body weights were depressed 1n
both sexes; pulmonary degenerative changes were noted, with males more
severely affected. M1ld degenerative changes were seen 1n the Hvers and
kidneys, and kidney weights were elevated 1n females. At 0.1 ppm female
body weights were depressed. No effects were noted at 0.05 ppm.
The reason for the discrepancy between these studies Is unclear. Treon
et al. (1955) reported 100% mortality In rats exposed to 0.33 ppm for 20
6-hour exposure sessions. In contrast, Clark et al. (1982a) exposed rats
for 0.5 ppm for 30 weeks and noted 50% mortality 1n males and 25% mortality
1n females. Some differences may be attributable to the purity of the
compound. Clark et al. (1982a) reported that the compound was 96% pure,
with hexachloro-1,3-d1ene and octachlorocyclopentene as Impurities, while
Treon et al. (1955) reported 89.5% purity with contaminants not Identified.
It would be helpful to have another study 1n mice with a compound of similar
purity to that used by Clark et al. (1982a) 1n order to evaluate whether
mice are, 1n fact, more sensitive to HEX.
Using the Clark et al. (1982a) data which defined a NOEL for the rat of
0.05 ppm (0.5 mg/m3), an exposure dose of 0.066 mg/kg/day can be esti-
mated by assuming a rat ventllatory volume of 0.26 mVday, a body weight
of 0.35 mg and 100% absorption, and multiplying by 6 hours/24 hours and 5
days/7 days to estimate continuous exposure. Applying an uncertainty factor
of 1000 (10 for Interspedes conversion, 10 to reflect concern about
discrepancies 1n the available data and 10 to protect especially sensitive
members of the population) and multiplying by 70 kg, an assumed average
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human body weight, results In an Inhalation AIC of 0.00462 mg/day. This
corresponds closely to that estimated from the TLV of 0.1 mg/m3. Using a
human 8-hour ventHatory volume of 10 m3/8 hour workday and multiplying by
5 days/7 days and dividing by an uncertainty factor of 100 (10 to protect
potentially more sensitive segments of the general population, 10 to reflect
deficiencies 1n the available data base) would result 1n an estimated dally
Intake of 0.0071 mg/day based on the TLV. The AIC, 1n units of mg/day,
makes an Implicit assumption that exposure will be uniformly distributed
over the day.
6.3. CARCINOGENIC POTENCY (q.,*)
There are no available data on the long-term effects of exposure to HEX.
Because the NTP 1s testing HEX In a chronic bloassay, the U.S. EPA Carcino-
gen Assessment Group will defer any decision on the carclnogenlcity of HEX
until the completion of the bloassay.
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APPENDIX
Summary Table for Hexachlorocyclopentadlene
GO
tn
i
Species
Inhalation
AIS monkey
AIC rat
Maximum mice
composite
score
Oral
AIS mouse
AIC
Experimental
Dose/Exposure
2 mg/m3 for 14 weeks
0.5 mg/m3 for 30 weeks
0.15 ppm (1.7 mg/m3)
7 hours/day,
5 days/week for up
to 150 exposures
RVd=6.2)
27.1 mg/kg/day for
13 weeks
Effect Acceptable Intake Reference
(AIS or AIC)
NOEL 0.2 mg/day Rand et al.,
1982
NOEL 0.0046 mg/day Clark et al.,
1982a
mortality 62 Treon et al.,
(RVe=10) 1955
forestomach 4.9 mg/man/day SRI, 1981a
hyperplasla
ND
ND = Not determined
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