TECHNICAL REPORT DATA
fflfete read Instructions on the revertt be fort completing)
1. REPORT NO.
EPA/600/8-Sa/Q43
2.
3. RECIPIENT'S ACCESSION NO
PB88-178736/AS
*. TITLE AND SUBTITLE
Health Effects Assessment for Hexachloroethane
5. REPORT DATE
6. PERFORMING ORGANIZATION CODE
'. AUTMOR(S)
PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes.and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfOs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD 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 lifespan. For compounds for which there is sufficient evidence of
carcinogenic!"ty, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lOENTlFJERS/OPEN ENDED TERMS C. COS AT I Field/Group
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (ThisReport)
Unclassified
21. NO. Of PAGES
20. SECURITY CLASS (This page/
Unclassified
22. PRICE
EPA Form 2220-1 (R»». 4-77) PREVIOUS COITION i« O**OUCTC
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EPA/600/8-88/043
May, 1987
HEALTH EFFECTS ASSESSMENT
FOR HEXACHLOROETHANE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
U S. Environmental Protection Agenoy
•' ;-'~: on 5 , I.' ', -H.-y ; jpL-10 '
: Dear h,-::- 5;t-d?t, . • ^ I "70
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DISCLAIMER
This document has been reviewed In accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement 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-
chloroethane. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE and the CHEMFATE/OATALOG data bases. The basic literature searched
supporting this document Is current up to May, 1986. 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 Assess-
ment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Chlorinated Ethanes. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC. EPA 440/5-80-029. NTIS PB81-117400.
U.S. EPA. 1983. Reportable Quantity Document for Hexachloro-
ethane. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Emergency and Remedial Response,
Washington, DC.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
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.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose. Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the 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 assumed. Animal data used for RFD$ 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. These
values are developed for both Inhalation (RfD$j) and oral (RfD$Q)
exposures.
111
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The RfO (formerly AIC) Is similar In concept and addresses chronic
exposure. 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
RfD is route-specific and estimates acceptable exposure for either oral
(RfDo) or Inhalation (RfDi) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of cardnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, If appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In 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
Interpretation and use of the quantitative estimates presented.
In a chronic gavage study, high doses of hexachloroethane were asso-
ciated with a significant and dose-related Increase In the Incidence of
hepatocellular carcinoma In B6C3F1 mice of both sexes. U.S. EPA (1980a)
computed a q-|* of 1.42xlO~2 (mg/kg/day)"1 based on the Incidence In
male mice and has subsequently assigned an EPA Group C classification. Two
more recent analyses (U.S. EPA, 1982, 1986a) have derived RfOs for
hexachloroethane based on noncarclnogenlc endpolnts.
In this document, the q-|* of 1.42xlO~2 for oral exposure Is adopted
and RfD, RfD§ values and CSs are not calculated.
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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 OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) 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 the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
5.
6.
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
CARCINOGENICITY
4.1. HUMAN DATA' -...'.
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) . . .
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDcr) ,
Paqe
1
3
3
3
4
4
4
6
7
7
7
8
8
8
. 10
. 10
. 10
. 10
10
. 10
11
11
11
13
14
14
14
. 14
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE (RfO) 14
6.2.1. Oral (RfD0) 14
6.2.2. Inhalation (RfDj) 14
6.3. CARCINOGENIC POTENCY (q-|*) 15
6.3.1. Oral 15
6.3.2. Inhalation 15
7. REFERENCES 16
APPENDIX: Summary Table for Oral Tox1c1ty of Hexachloroethane
Using Hale Mice 21
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LIST OF ABBREVIATIONS
CS Composite score
Koc Soil sorptlon coefficient
LOAEL Lowest-observed-adverse-effect level
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PEL Permissible exposure limit
ppm Parts per million
RfO Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$Q Subchronlc oral reference dose
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant chemical and physical properties and environmental fate of
hexachloroethane (CAS No. 67-72-1) are listed In Table 1-1.
In the atmosphere, hexachloroethane should exist primarily In the vapor
phase. It 1s expected to be unreactlve In the troposphere and diffuse Into
the stratosphere where significant photodlssoclatlon can occur (Callahan et
al., 1979; U.S. EPA, 1986b). Since the lifetime of hexachloroethane 1n the
troposphere Is unknown (Callahan et al., 1979), 1t Is not possible to esti-
mate the transfer rate of tropospherlc hexachloroethane to the stratosphere.
Monitoring data Indicate that hexachloroethane will be removed from the
atmosphere by rainfall (Pankow et al., 1984). In water, volatilization Is
apparently the dominant removal mechanism. The aquatic half-life 1s based
on the measured volatilization half-life for hexachloroethane from a stirred
(200 ppm) dilute (1 ppm), aqueous solution of 6.5 cm depth. (Dllllng,
1977). Callahan et-al. (1979) reported that the evaporative half-lives of
hexachloroethane In aquatic media may range up to several hours.
Hexachloroethane should be moderately adsorbed to suspended solids and
sediments and may bloaccumulate In some aquatic species. The half-life of
hexachloroethane In soil could not be located 1n the available literature.
Based on Its estimated K value, hexachloroethane should be moderately
mobile In son (Swann et al., 1983). The volatility of this compound from
aquatic media Indicates that volatilization from soil surfaces may be a
significant removal mechanism.
0102h -1- 01/13/87
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TABLE 1-1
Relevant Chemical and Physical Properties and
Environmental Fate of Hexachloroethane
Property
Value
Reference
Chemical class:
Molecular weight:
Vapor pressure at 20°C:
Water solubility at 22°C:
Log octanol/water
partition coefficient:
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half lives In
A1r:
halogenated aliphatic
compound
236.74
0.21 mm Hg
50 mg/l
4.04
139, blueglll sunflsh
(Lepomls macrochlrus)
513-1202, rainbow
trout (Salmo qalrdnerl)
173 (estimated)
years
MacKay and Sh1u, 1981
MacKay and Shlu, 1981
Hansch and Leo, 1985
Velth et al., 1980
Oliver and N11m1, 1983
Sabljlc, 1984
Callahan et al., 1979;
U.S. EPA, 1986b;
Dllllng, 1982
Water:
Soil:
< several hours
NA
Ollling, 1977;
Callahan et al..
1979
NA = Not available
0102h
-2-
10/22/86
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2. ABSORPTION FACTORS IN HUMAN AND EXPERIMENTAL ANIMALS
2.1. ORAL
Data briefly reviewed by IARC (1979) Indicate that hexachloroethane Is
rapidly and nearly completely absorbed. Within 3 days after Ingestlon of
500 mg/kg of 1*C-hexachloroethane, 5X of the radioactivity was Identified
In the urine of rabbits and between 14 and 24% of the administered radio-
activity was Identified In the expired air (Jondorf et al., 1957). Without
providing data regarding fecal excretion of radioactivity, IARC (1979)
stated that "the rest" of the administered dose was retained In the carcass.
In sheep, hexachloroethane appeared rapidly In the systemic circulation
after oral administration (Fowler, 1969).
2.2. INHALATION
Quantitative data regarding the absorption of hexachloroethane after
Inhalation exposure could not be located In the available literature.
0102h -3- 01/13/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In a subchronlc feeding study by Dow Chemical Company,
groups of 10 male and 10 female Fischer 344 rats were fed diets targeted to
provide 3, 30 or 100 mg/kg/day for 16 weeks (Gorz1nsk1 et al., 1985).
o
Sublimation of hexachloroethane from the food was a factor In this study;
the Investigators determined that the rats actually received 0, 1. 15 or 62
mg/kg/day of hexachloroethane from their food for the 16-week exposure
period. The dosages were estimated by the Investigators from body weights,
food consumption and diet analysis data. Endpolnts evaluated Included body
and organ weights, hematology, clinical chemistry, urlnalysls and hlsto-
pathology of the major organs In the high-dose and control groups and of the
liver and kidneys In all experimental groups. At the high-dose level.
Increased relative and absolute Hver and kidney weights were observed In
the males and Increased relative, but not absolute, liver weight In the
females. Slight swelling of hepatocytes was also observed 1n high-dose
males. Atrophy and degeneration of the renal tubules were observed In high-
dose male and female rats. At 15 mg/kg/day of hexachloroethane, atrophy and
degeneration of renal tubules were observed without any changes In relative
or absolute kidney weight In the males. The Incidence of kidney lesions In
mid- and high-dose male rats appeared to be dose-related. No effects were
reported In females Ingesting 15 mg/kg/day of hexachloroethane. No effects
were reported In either *ex Ingesting 1 mg/kg/day of hexachloroethane.
There were no effects on food consumption, body weight gains, hematologlc or
biochemical parameters or urlnalysls In any of the doses tested.
The NTP (1983) performed a subchronlc gavage study In F344 rats In
preparation for a chronic carc1nogen1c1ty experiment still In progress.
0102h 4- 01/13/87
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Only a draft report of this study consisting of the narrative without the
tables of Incidence data is available. Groups of 10 male and 10 female rats
were treated by gavage with 0, 47, 94, 188, 375 or 750 mg/kg/day of hexa-
chloroethane 5 days/week for 13 weeks (NTP, 1983). Endpoints evaluated
Included body and organ weights, hematology, clinical chemistry, urinalysls
and histology of the major organs of control and high-dose males and females
and of the males treated with 375 mg/kg/day of hexachloroethane. Only the
kidney were evaluated In males receiving the lowest dosage; the kidneys and
the liver were evaluated In the females receiving the four lowest dosages of
hexachloroethane and In the males receiving 94 or 188 mg/kg/day of hexa-
chloroethane. Convulsions were observed in male and female rats treated
with >375 mg/kg/day of hexachloroethane; five high-dose males and two
high-dose females died during the treatment period. Rate of body weight
gain was unaffected except for a significant depression in high-dose males.
Hyperactivlty was reported in both sexes receiving >94 mg/kg/day. At
necropsy, grossly granular, pale or reddened kidneys were noted in male rats
at >94 mg/kg; these lesions were not seen in female rats. A granular
appearing Hver, however, was observed in female rats at >375 mg/kg.
Biologically and statistically significant alterations in relative organ
weights Included kidney weights In 375 and 750 mg/kg males and liver and
kidney weights In 375 and 750 mg/kg females. A dose-related Increase in
renal tubular nephrosls was observed in all treated groups of male rats;
renal papillary necrosis and a severe hemorrhagic necrosis of the urinary
bladder were seen In high-dose males that had died. In females, "minimal
tubular changes in the kidney occurred only at 750 mg/kg. Hepattc lesions
prevailed in female rats and consisted of focal hepatocellular necrosis,
predominantly at 375 and 750 mg/kg. Granular and cellular casts and the
0102h -5- 01/13/87
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presence of epithelial cells and blood cells In the urine were observed In
all treated males, whereas granular, but not cellular, casts occasionally
0>
occurred In the urine of 3/10 control males.
3.1.2. Inhalation. Weeks et al. (1979) exposed groups of 25 male and 25
female Sprague-Oawley rats, 4 male beagle dogs and 10 male Hartley guinea
pigs by Inhalation to 0, 15, 48 or 260 ppm (0, 145, 465 or 2520 mg/m3) of
hexachloroethane for 6 hours/day, 5 days/week for 6 weeks. Half the animals
were killed after 6 weeks of treatment and the rest were killed 12 weeks
after the end of treatment. Endpolnts evaluated Included body and organ
weight changes, overt signs of toxldty and survival rates In all species,
behavioral evaluation In 15 male rats, sensltlzatlon In guinea pigs, pulmo-
nary function, hematology and clinical chemistry In the dogs and hlsto-
pathology of major organs In all the rats and dogs. Adverse effects were
seen In rats, dogs and guinea pigs exposed to 260 ppm, but not at lower
levels. Two rats died during, treatment. In addition. Increased relative
kidney, spleen, testes and lung weights and decreased body weight gains In
the males and Increased relative liver weight In the females were observed.
Tremors and an Increased Incidence and severity of mycoplasma-related
lesions In the respiratory epithelium In the males and females were also
observed 1n rats exposed to 260 ppm. No behavioral effects were observed.
One of four dogs exposed to 260 ppm died, tremors, ataxla and hypersallva-
tlon also occurred during exposure. No other exposure-related effects were
observed. Four of the 10 guinea pigs exposed to 260 ppm died during treat-
ment, but Increased sensltlzatlon to hexachloroethane was not observed. No
effects related to hexachloroethane exposure were observed In rats, dogs or
guinea pigs exposed to 15 or 48 ppm.
0102h ' 6- 01/13/87
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3.2. CHRONIC
3.2..1. Oral. In the NCI (1978) bloassay, both Osborne-Mendel rats
(50/sex/group) and 86C3F1 mice (50/sex/group) were treated by gavage with
hexachloroethane In corn oil. Detailed treatment regimens are described In
Section 4.2.1. Depression In the rate of body weight gain occurred 1n a
dose-related manner In males and In high-dose females. Overt signs of
toxIcHy occurred In all treated groups of rats and Included a hunched
appearance, abdominal urine stains, tremors, ataxla and abnormal ocular and
vaginal discharge.
A dose-related Increased mortality rate, beginning within the first 5
weeks of treatment, and a dose-related Increased Incidence of renal tubular
nephropathy were seen 1n rats treated with a TWA dosage of 212 or 423
mg/kg/day of hexachloroethane. Toxic tubular nephropathy occurred In 0/20
untreated control, 0/20 vehicle control, 22/49 low-dose and 33/50 high-dose
males, and 1n 0/20 untreated control, 0/20 vehicle control, 9/50 low-dose
and 29/49 high-dose females. No other significant lesions were reported In
the rats. In addition to an Increased Incidence of hepatocellular carcinoma
(Section 4.2.1.), an Increased Incidence of toxic nephropathy was seen 1n
the mice treated with a TWA dosage of 590 or 1179 mg/kg/day of hexachloro-
ethane. The toxic nephropathy occurred 1n 0/18 untreated control, 0/20
vehicle control, 49/50 low-dose and 47/49 high-dose males and 1n 0/18
untreated control, 0/20 vehicle control, 50/50 low-dose and 45/50 high-dose
females. There were no clear-cut effects on survival but survival of
control males was measurably low; body weight was not affected. Treated
mice had an Increased Incidence of a hunched appearance starting at week 28.
3.2.2. Inhalation. Pertinent data regarding the toxic effects of
chronically Inhaled hexachloroethane could not be located 1n the available
literature.
0102h -7- 10/22/86
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3.3. TERATOLOGY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Groups of 22 pregnant Sprague-Dawley rats were treated by
gavage with 0, 50, 100 or 500 mg/kg/day of hexachloroethane 1n corn oil on
days 6-16 of gestation and were killed on day 20 (Weeks et al., 1979)-.
Endpolnts evaluated included maternal and fetal body weight, fetal length
and sex and the number of corpora lutea Implantation sites, resorptlon sites
and viable fetuses. All fetuses with gross malformations and 4/sex/l1tter
without gross malformations were fixed for examination for soft tissue and
skeletal malformations. There was no significant Increase In the Incidence
of soft tissue or skeletal malformations 1n the offspring of treated rats
compared with controls. A decrease 1n the number of viable fetuses/dam as
well as an Increase 1n resorptlon rates were observed 1n the rats treated
with 500 mg/kg/day of hexachloroethane. In addition, the maternal body
weight of rats treated with 500 mg/kg/day was significantly decreased and
tremors were observed In the dams on days 15 and 16 of gestation. Evidence
of upper respiratory tract Infections was apparent In 70% of the high-dose
rats, but In only 10% of controls.
3.3.2. Inhalation. Groups of 22 pregnant Sprague-Dawley rats were
exposed to 0, 15, 48 or 260 ppm (0, 145, 465 or 2520 mg/m3) of hexachloro-
ethane for 6 hours/day on days 6-16 of gestation and were killed on day 20
(Weeks et al., 1979). Endpolnts evaluated Included maternal and fetal body:
weight, fetal length and sex and the number of corpora lutea, Implantation
sites, resorptlon sites and viable fetuses. All fetuses with gross malfor-
mations and 4/sex/11tter without gross malformations were fixed for examina-
tion for soft tissue and skeletal malformations. There was no Increase 1n
the Incidence of soft tissue or skeletal malformations In treated rats
compared with controls, and no evidence of fetotoxldty. Decreased maternal
body weight was observed 1n dams Inhaling 48 or 260 ppm of hexachloroethane.
0102h -8- 10/22/86
-------
Tremors were reported 1n the dams exposed to 260 ppm of hexachloroethane.
Increased mucopurulent nasal exudate was observed in 85% of the dams exposed
•
to 48 ppm (465 mg/m3) and 1n 100% of the dams exposed to 260 ppm (2520
mg/m3) of hexachloroethane, compared with -10% 1n controls.
0102h -9- 10/22/86
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the cardnogenlcHy of Ingested
hexachloroethane 1n humans could not be located In the available literature.
4.1.2. Inhalation. Pertinent data regarding the cardnogenlclty of
Inhaled hexachloroethane In humans could not be located 1n the available
literature.
4.2. BIOASSAYS
4.2.1. Oral. In a study conducted by the National Cancer Institute (NCI,
1978; Helsburger, 1977) groups of 50 male and 50 female Osborne-Mendel rats
and 50 male and 50 female 86C3F1 mice were treated by gavage with hexa-
chloroethane (>98% purity) In corn oil 5 days/week for 78 weeks. Groups of
20 rodents/sex/specles served as vehicle controls and the same numbers of
rodents served as untreated controls. After 22 weeks of treatment, the rats
received no treatment for 1 week alternated with 4 weeks of treatment during
weeks 23 through 78 and were observed for an additional 33 or 34 weeks. The
TWA 5 days/week dosages for the 78-week treatment period were 212 and 432
mg/kg for the rats. The mice received treatment for 78 weeks and were
observed for an additional 12 weeks. The TWA 5 days/week dosages for the
78-week treatment period were 590 and 1179 mg/kg for the mice. Although the
treated rats had a higher total number of tumors, which Included Inter-
stitial-cell tumors of testes and renal tubular-cell adenomas In male rats
and pituitary chromophobe adenomas In female rats, there was no statistic-
ally significant association between hexachloroethane treatment and tumor
formation In the rats. The Increased nortalHy rate, however, may have
precluded observation of late developing tumors. In treated mice, there was
a statistically significant, dose-related Increase In the Incidence of
hepatocellular carcinomas 1n both sexes. The Incidences In males were 6/60
0102h -10- 03/31/87
-------
(10%) pooled vehicle controls, 3/20 (15%) matched vehicle controls, 15/50
(30%) low dose and 31/49 (63%) high dose. The Incidences In females were
2/60 (3%) pooled vehicle controls, 2/20 (10%) matched vehicle controls,
20/50 (40%) low dose and 15/49 (31%) high dose. On the basis of these data,
the NCI (1978) concluded that hexachloroethane was carcinogenic to male and
female B6C3F1 mice.
Another chronic carclnogenlcHy and tox1c1ty experiment with hexachloro-
ethane has been performed by gavage 1n rats (NTP, 1986) and the chronic
quality assessment 1s In progress.
4.2.2. Inhalation. Pertinent data regarding the carclnogenlcHy of
Inhaled hexachloroethane In animals could not be located 1n the available
literature.
4.3. OTHER RELEVANT DATA
Hexachloroethane was not mutagenlc to Salmonella typhlmurlum strains
TA1535, TA1537, TA1538, TA100 or TA98 or to Saccharomyces cerevlslae strain
04 with or without metabolic activation (Weeks et al., 1979). Although some
cytotoxlclty was exhibited, hexachloroethane was negative 1n the BALB/C-3T3
cell transformation assay In the absence of an exogenous metabolic activa-
tion system (Tu et al., 1985). The effect of hexachloroethane on cultivated
BALB/C-3T3 cells was not evaluated In the presence of an exogenous metabolic
activation system.
4.4. HEIGHT OF EVIDENCE
Applying the criteria described In the U.S. EPA guidelines for assess-
ment of carcinogenic risk (U.S. EPA, 1986a), hexachloroethane may be classi-
fied 1n Group C, Possible Human Carcinogen, which Is reserved for agents
0102h -11- 07/09/87
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with limited evidence of carclnogenlclty In animals and an absence of human
data. This classification was determined for EPA's CERCIA reportable
quantity proposed rule making (U.S. EPA, 1986c). IARC has not classified
hexachloroethane regarding Us carclnogenlclty to humans (IARC, 1982).
0102h -12- 07/09/87
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1986a,b) has recommended a TWA TLV of 10 ppm (-100 mg/m3)
based on the Weeks et al. (1979) study, which reported that no adverse
effects were observed In rats, dogs or guinea pigs exposed to 15 or 48 ppm
(145 or 465 mg/m3) of hexachloroethane. The former TLV was 1 ppm. The
skin notation was dropped based on low dermal toxldty reported by Weeks et
al. (1979). The current OSHA PEL for hexachloroethane 1s 1 ppm (-10
mg/m3) (OSHA, 1985). NIOSH (1985), however, recommends that hexachloro-
ethane be treated as 1f H were a carcinogen.
A q * of 1.42xlO~2 (mg/kg/day)'1 of hexachloroethane for humans
has been estimated by the U.S. EPA (1980a), based on the dose-response data
for the Induction of hepatocellular carcinomas 1n male B6C3F1 mice (NCI,
1978). The corresponding dose associated with an Increased lifetime cancer
risk of 10~5 Is 7.04xlO~4 mg/kg/day (0.70 ^g/kg/day or 49 jig/day for
a 70 kg man). The value was used to calculate the ambient water quality
criterion of 19 jig/l (assuming consumption of contaminated drinking
water, fish and shellfish), corresponding to an Increased lifetime cancer
risk of 10"s.
0102h -13- 07/15/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfOso). The results of the NCI (1978) bloassay In which
Ingestlon of hexachloroethane was associated with a significantly Increased
Incidence of hepatocellular carcinoma 1n male and female mice preclude the
derivation of an RfDSQ for hexachloroethane.
6.1.2. Inhalation (RfD..). The results of the NCI (1978) bloassay In
which hexachloroethane was associated with a significantly Increased
Incidence of hepatocellular carcinoma 1n male and female mice preclude the
derivation of an RfD-, for hexachloroethane.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). The results from the NCI (1978) bloassay Indicate
that a significant Increase In the Incidence of hepatocellular carcinomas In
male and female mice Is associated with the Ingestlon of hexachloroethane.
Therefore, 1t 1s not appropriate for the purposes of this document to derive
an RfDQ or a chronic toxldty CS based on the systemic toxldty of
hexachloroethane.
6.2.2. Inhalation (RfD.). The results from the NCI (1978) bloassay
Indicate that the Ingestlon of hexachloroethane Is associated wHn a
significant Increase In the Incidence of hepatocellular carcinomas 1n male
and female mice; therefore, 1t 1s not appropriate to derive an RfD, or a
chronic toxldty CS based on the systemic toxldty of hexachloroethane. If
It becomes evident that the cardnogenldty of hexachloroethane Is route-
specific, however, values for an RfD, and chronic toxldty CSs could be
derived from the study of Weeks et al. (1979). The U.S. EPA (1983) derived
CS values from the LOAEL Identified at exposure to 260 ppm (2520 mg/m3)
associated with tremors and decreased survival rate In rats and guinea pigs,
respectively.
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6.3. CARCINOGENIC POTENCY
6.3.1. Oral. Hexachloroethane was associated with a significantly
Increased Incidence of hepatocellular carcinoma 1n male and female B6C3F1
mice (NCI, 1978). Based on the data from male mice, the U.S. EPA (1980a)
calculated a human q,* of 1.42xlO"a (mg/kg/day)"1. This q * 1s
adopted as the estimate of carclnogenlcHy of hexachloroethane by. oral
exposure for the purposes of this document.
6.3.2. Inhalation. Pertinent data regarding the carclnogenlclty of hexa-
chloroethane after Inhalation exposure could not be located In the available
literature.
0102h -15- 07/15/87
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986a.
TLVs: Documentation of the Threshold Limit Values, 5th ed. (Includes
Supplemental Documentation through 1984). Cincinnati, OH. p. 301.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
TLVs: Threshold Limit Values. Chemical Substances 1n the Work Environment.
Adopted by ACGIH with Intended Changes for 1986-1987. Cincinnati, OH.
p. 20.
Callahan, M.A., M.W. Sllmak, N.W. Gabel, et al. 1979. Water-Related
Environmental Fate of 129 Priority Pollutants-Volume II. EPA 440/4-79-0298.
U.S. EPA, Washington, DC.
«
DUlIng, W.L. 1977. Interphase transfer process. II. Evaporation rates of
chloromethanes, ethanes, ethylenes, propanes and propylenes from dilute
aqueous solutions. Comparisons with theoretical predictions. Environ. Scl.
Techno!. 11: 405-409.
Dllllng, W.L. 1982. Atmospheric environment. In: Environmental Risk
Analysis for Chemicals, R.A. Conway, Ed. Van Nostrand Relnhold Co., New
York. p. 154-197.
Fowler, J.S.K. 1969. Some hepatotoxlc actions of hexachloroethane and Its
metabolites In sheep. Br. J. Pharmacol. 35: 530-542. (Cited 1n IARC, 1979)
0102h -16- 07/09/87
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Gorzlnskl, S.J., R.J. Nolan, S.B. McColUster, R.J. Koclba and J.L. Mattsson.
1985. Subchronlc oral toxlclty, tissue distribution and clearance of hexa-
chloroethane In the rat. Drug Chem. Toxlcol. 8(3): 155-170.
Hansch, C. and A.J. Leo. 1985. Hedchem Project Issue No. 26. Pomona
College, Claremont, CA.
IARC {International Agency for Research on Cancer). 1979. Hexachloroethane.
hK Some Halogenated Hydrocarbons. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans. WHO, IARC, Lyons, France. Vol.
20, p. 467-475.
IARC (International Agency for Research on Cancer). 1982. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Chemi-
cals, Industrial Processes and Industries Associated with Cancer In Humans.
IARC Monographs, Volumes 1-29. Supplement 4.
Jondorf, W.R., O.V. Parks and R.T. Williams. 1957. The metabolism of
[14C] hexachloroethane. Blochem. J. 65: 14-15. (Cited 1n IARC, 1979)
MacKay, 0. and W.Y. Shiu. 1981. A critical review of Henry's Law constants
for chemicals of environmental Interest. 3. Phys. Chem. Ref. Data. 19:
1175-1199.
NCI (National Cancer Institute). 1978, Bloassay for Hexachloroethane for
Possible CarclnogenlcHy. CAS No. 67-72-1. Cardnog. Test. Program,
Bethesda, MD. ISS DHEW/PUB/NIH-78-1318, NCI-CG-TR-68; NTIS PB 282668. 90 p.
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NIOSH (National Institute for Occupational Safety and Health). 1985.
Current Intelligence Bulletin 27. Chloroethanes: Review of Toxlclty. Govt.
Reports, Announcements & Index. 4: 26.
NTP (National Toxicology Program). 1983. Subchronlc study with hexachloro-
ethane 1n rats. Unpublished report submitted by contract laboratory.
Internal working document.
NTP (National Toxicology Program). 1986. Toxicology Research and Testing
Program. Management Status Report. June 10, 1986. NTP, Research Triangle
Park, NC.
Oliver, B.G. and A.J. N11mi: 1983. Bloconcentratlon of chloroebenzenes
from water by rainbow trout: Correlations with partition coefficients and
environmental residues. Environ. Sc1. Technol. 17: 287-291.
OSHA (Occupational. Safety and Health Administration). 1985. Occupational
Standards. Permissible Exposure Limits. 29 CFR 1910.1000.
Pankow, J.F., L.M. Isabelle and W.E. Asher. 1984. Trace organic compounds
1n rain. I. Sampler design and analysis by adsorption. Thermal desorptlon
(ATD). Environ. Scl. Technol. 18: 310-318.
Sabljlc, A. 1984. Predictions of the nature and strength of soil sorptlon
of organic pollutants by moTecular topology. J. AgMc. Food Chem. 32:
243-246.
0102h -18- 07/09/87
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Swann, R.L., O.A. Laskowskl, P.J. McCall, K. VanderKuy and H.J. Olshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 23.
Tu, A.S., T.A. Murray, K.M. Hatch, A. Swak and H.A. MUman. 1985. In vitro
transformation of BALB/C-3T3 cells by chlorinated ethanes and ethylenes.
Cancer Lett. 28: 85-92.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Chlorinated Ethanes.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water
Regulations and Standards, Washington, DC. EPA 440/5-80-029. NTIS PB
81-117400.
U.S. EPA. 1980b. " Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(2310): 49347-49357.
U.S. EPA. 1983. Reportable Quantity Document for Hexachloroethane.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC.
0102h -19- 07/15/87
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U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic ToxIcHy Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH, for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986b. Graphical Exposure Modeling System (GEMS). Fate of Atmo-
spheric Pollutants (FAP). Office of Toxic Substances, Washington, DC.
U.S. EPA. 1986c. Evaluation of the Potential Carclnogenlclty of Hexa-
chloroethane. Prepared by the Office of Health and Environmental Assess-
ment, Carcinogen Assessment Group, Washington, DC for the Office of Solid
Waste and Emergency Response, Washington, DC.
Velth, G.D., K.J. Macek, S.R. Petrocelll and J. Carrol. 1980. An evalua-
tion of using partition coefficients and water solubility to estimate bio-
concentration factors for organic chemicals In fish. ASTM STP 707. Aquatic
Toxicology, J.G. Easton et al., Ed. Am. Soc. Test. Mater, p. 116-129.
Weeks, M.H., R.A. Angerhofer, R. Bishop, J. Thomaslno and C.R. Pope. 1979.
The toxldty of hexachloroethane 1n laboratory animals. Am Ind. Hyg. Assoc.
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Welsburger, E.K. 1977. Cardnogenldty studies on halogenated hydrocarbons.
Environ. Health Perspect. 21: 7-16.
0102h -20- 07/15/87
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APPENDIX
Summary Table for Oral Tox1c1ty of Hexachloroethane Using Male Mice
Experimental Exposure/Dose
(mg/kg/day)
Effect
q-|* or
Unit Risk
0, 590 or 1179 mg/kg/day.
5 days/week for 78 weeks
(gavage)
Statistically significant
Increased Incidence
of hepatocellular
carcinoma
K42xlO~2
{mg/kg/day)"1
*Source: NCI, 1978; U.S. EPA, 1980a
Chicago.
60604
"""*
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