United States FINAL DRAFT
Environmental Protection ECAO-CIN-G041
August, 1989
9EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR HEXACHLOROETHANE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE HMHIMNMUKWRY
ENVMWMBfEftL PROTECTION AGENCY
NOTICE
:")
U5
c" This document 1s a preliminary draft. It has not been formally released
cn by the U.S. Environmental Protection Agency and should not at this stage be
t construed to represent Agency policy. It 1s being circulated for comments
=(on Us technical accuracy and policy Implications.
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DISCLAIMER
'This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Haste and Emergency Response (OSUER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSUER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 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 focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), 1s provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and cardno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and cardno-
genUHy) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined In U.S.
EPA. 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
Hexachloroethane Is a white or colorless crystalline solid at room
temperature (Hawley, 1981; Archer, 1979). It 1s prepared by chlorlnatlon of
tetrachloroethylene 1n the presence of ferric chloride, and Is also formed
1n minor amounts In many Industrial chlorlnatlon processes designed to
produce lower chlorinated hydrocarbons (Archer, 1979). U.S. EPA (1977)
listed five manufacturers and three Importers of this compound; four of the
five manufacturers used this compound for site-limited use only. Apparently
hexachloroethane Is not produced by domestic manufacturers as an end-use
chemical, but 1s currently Imported Into the United States. During 1982,
1.12 million pounds of hexachloroethane was Imported Into the United States
(HSDB, 1988). Hexachloroethane Is used primarily 1n the rubber manufactur-
ing and explosive Industries (CMddle et al., 1986).
In the atmosphere, hexachloroethane 1s expected to exist almost entirely
In the vapor phase (Archer, 1979; Elsenrelch et al., 1981). This compound
will not degrade 1n the troposphere (U.S. EPA, 1987a; Ma bey et al., 1981).
Hexachloroethane will be removed from the northern troposphere by partition-
Ing between air and the oceans, and by transfer Into the southern tropo-
sphere by slow diffusion Into the stratosphere above the ozone layer where
1t should photolyze (Class and Ballschmlter, 1987; Callahan et al., 1979).
The half-life for diffusion Into the stratosphere Is estimated to be -30
years (Callahan et al., 1979). Because of Us persistence In the tropo-
sphere, hexachloroethane has the potential to be transported long distances
from Its sources of emission. In water, volatilization appears to be an
Important, 1f not the dominant, removal mechanism. The volatilization
half-life from a model river 1 m deep, flowing 1 m/sec with a wind speed of
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3 m/sec was estimated to be 15 hours. Hexachloroethane could also adsorb
appreciably to suspended solids and sediments (Jafvert and Wolfe, 1987). In
anaerobic sediments, hexachloroethane 1s expected to degrade to tetrachloro-
ethylene by both blotlc and abiotic processes {Jafvert and Wolfe, 1987;
Griddle et a!., 1986). Hexachloroethane 1s not expected to degrade under
aerobic condHons. Hexachloroethane may bloaccumulate significantly 1n some
aquatic organisms (Oliver and Nlmll, 1983; Velth et al.( 1980). In soil, 1t
appears that hexachloroethane would be susceptible to reduction to tetra-
chloroethylene by both blotlc and abiotic processes. Hexachloroethane
should be slightly mobile In soil (Abdul et al., 1987; Swann et al., 1983),
and Is expected to volatilize slowly from dry soil surfaces.
Hexachloroethane has been detected In finished drinking water, surface
water, wastewater, groundwater, landfill leachate, biota and ambient air.
During the mld-to-late 1970s hexachloroethane was found 1n finished drinking
water from Philadelphia, PA, Cincinnati, OH, Miami, PL, New Orleans, LA,
Jefferson City. HO and Evansvllle, IN (Lucas, 1984; Shackelford and Keith,
1976; U.S. EPA, 1975; Keith et al., 1976; Kleopfer and Falrless, 1972).
Hexachloroethane was found 1n water samples obtained from Lake Ontario and
the Ganaraska River and In fish collected from Lake Ontario (Great Lakes
Water Quality Board, 1983; Oliver and N1m11, 1983). This compound was found
In wastewater from a chemical plant, a Kraft paper mill and a coal mining
operation 1n the United States (IARC, 1979; Keith, 1976; U.S. EPA, 1981).
Groundwater 1n Hardeman County, TN, was found to contain hexachloroethane
from contamination from a hazardous waste landfill (Harris et al., 1984).
This compound was also Identified 1n leachate from a landfill adjacent to
the water treatment plant In Niagara Falls, NY (Tallan et al., 1986). These
data suggest that the origin of hexachloroethane 1n most water samples 1s
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principally anthropogenic. Results of the Nationwide Urban Runoff Program,
as of July 31, 1982, Indicated that hexachloroethane was not detected In
samples of urban runoff collected from various cities throughout the United
States (Cole et al., 1984). Based on monitoring data obtained between March
1982 and March 1986, the baseline concentration of hexachloroethane In the
atmosphere of the Northern Hemisphere has been estimated to be 0.28+0.03 ppt
(Class and Ballschmlter, 1987). Hexachloroethane was detected In air
samples, but not rain samples, collected during rain events In Portland, OR,
between February and April 1984 (Llgockl et al., 1985).
The acute toxlclty of hexachloroethane to aquatic organisms was deter-
mined for seven species of freshwater fish, one species of saltwater fish,
five species of Crustacea, and single species of amphibian, echlnoderm and
luminescent bacteria. The 96-hour LC5Q values for freshwater fish ranged
from 0.856 mg/i, for blueglll sunflsh to 2.36 mg/l for channel catfish
and >2.1 mg/8. for goldfish. The acute toxlclty of hexachloroethane to a
saltwater fish (sheepshead minnow) and frog tadpoles was comparable with
that generated with freshwater fish (96-hour LC5Q=2.4 and 3.18 mg/t,
respectively). Tests with different size frog tadpoles, fathead minnow or
channel catfish did not produce changes 1n the LC5Q value by more than a
factor of 2. Results of a study with crayfish (96-hour LC50=2.70 mg/i)
were comparable with those produced by exposure of freshwater fish to hexa-
chloroethane. The 48-hour EC and IC values for the various species
of Cladocera exposed to hexachloroethane ranged from 1.8 mg/l for D. maqna
to 13.0 mg/t for 0. pulex. Hexachloroethane Inhibited development of sea
urchin embryos at concentrations of -5-10 mg/l and luminescence 1n
bacteria at a concentration of -0.1 mg/i.
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Pertinent data regarding the effects of chronic exposure of aquatic
organisms or the effects of exposure of aquatic plants to hexachloroethane
were not located In the available literature cited In Appendix A.
The extent of absorption of hexachloroethane following oral exposure may
be estimated from excretion data. At least 20-30% of an oral hexachloro-
ethane dose was absorbed In rabbits {Jondorf et al., 1957) and -70X of an
orally administered dose was absorbed 1n B6C3F1 mice and Osborne-Mendel rats
(Mltoma et al., 1985). Following absorption, hexachloroethane appears to be
distributed primarily to the fat tissue and kidney, while much lower levels
(I.e., -100 times lower) are found In the liver and blood (Gorzlnskl et al.,
1985). In vivo studies have shown that hexachloroethane Is metabolized
slowly (Jondorf et al., 1957), and a large percentage of an orally adminis-
tered dose appears to be exhaled as the parent compound (Mltoma et al.,
1985). Urinary metabolites Identified 1n rabbits, rats and mice Include
trlchloroethanol, trlchloroacetlc acid, dlchloroethanol, dlchloroacetlc
acid, monochloroacetlc acid and oxalic add (Jondorf et al., 1957; Mltoma et
al., 1985). Metabolites found In the expired air of rabbits were carbon
dioxide, tetrachloroethylene and 1,1,2,2-tetrachloroethane. In. vitro
metabolism of hexachloroethane has been studied extensively and appears to
Involve reductive dehalogenatlon catalyzed by cytochrome P-450 (Town and
Lelbman, 1984; Thompson et al., 1984; Salmon et al., 1985; Nastalnczyk et
al., 1982a,b). Elimination of hexachloroethane from the tissues (I.e., fat,
liver, kidney and blood) of rats followed apparent first-order elimination
kinetics; half-lives of elimination were between 2.3 and 2.7 days (Gorzlnskl
et al., 1985). Most of the radioactivity excreted by orally dosed rabbits,
rats and mice appeared to be unmetabollzed parent compound In the expired
air {Jondorf et al., 1957; Mltoma et al., 1985).
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The liver and kidney appear to be target organs of toxldty following
hexachloroethane exposure. Subchronlc oral toxldty studies In Fischer 344
rats Indicated that hexachloroethane exposure at doses greater than or equal
to -15 mg/kg/day produces both liver and kidney effects (Gorzlnskl et al.,
1985; NTP, 1983); kidney effects (Including tubular atrophy and degen-
eration) appeared to be more common In male rats, whereas liver effects
(Including Increased weight and focal hepatocellular necrosis) appeared to
be more common 1n females. Chronic oral exposure to hexachloroethane
produced toxic tubular nephropathy 1n both male and female rats at TWA doses
of >212 mg/kg/day and In male and female mice at TWA doses of >590 mg/kg/day
(NCI, 1978). Subchronlc Inhalation exposure to 260 ppm (2517 mg/m3) hexa-
chloroethane for 6 weeks caused reduced body weight gain and a significant
Increase In the I1ver-to-body weight ratio In guinea pigs (Weeks et al.,
1979). In rats, 260 ppm hexachloroethane produced significant Increases 1n
the relative weights of the kidney, spleen and testes In male rats and the
liver In female rats. The acute oral toxldty of hexachloroethane, as
measured by oral LD5Q values (see Table 6-1), appears to be fairly low,
with values ranging from -3000 to >7000 mg/kg. In a long-term (I.e.,
78-week) carclnogenlcHy study, hexachloroethane was carcinogenic 1n mice
but not In rats (NCI, 1978). Hexachloroethane exposure at TWA doses of >590
mg/kg/day produced hepatocellular carcinomas 1n mice. Another chronic oral
cardnogenlcUy study Indicated that hexachloroethane produced renal
neoplasms 1n male rats (NTP, 1988). Hexachloroethane 1s placed In Group 82,
probable human carcinogen. Hexachloroethane was not mutagenlc to bacteria
and yeast (Haworth et al., 1983; Weeks et al., 1979} and did not produce
cell transformation In BALB/C-3T3 cells (Tu et al., 1985) or chromosome
aberration 1n CHO cells (Galloway et al., 1987). Hexachloroethane at an
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oral dose of 500 mg/kg/day caused decreased body weight of dams and fetal
mortality but was not teratogenlc In rats (Weeks et al.( 1979). Inhalation
exposure to 48 and 260 ppm, 6 hours/day, caused decreased body weight of
dams but had no effect on fetuses (Weeks et al., 1979). Data regarding
other reproductive effects following hexachloroethane exposure were not
located 1n the available literature.
An Inhalation q * of 1.4xlO~2 (mg/kg/day)'1 or 4.0xlO~* pg/m3
based on an oral hexachloroethane carclnogenlclty study using 86C3F1 mice
(NCI, 1978) has been adopted by CRAVE and this document, as a measure of the
carclnogenlclty of hexachloroethane following Inhalation exposure. An oral
q * of 1.4xlO~2 (mg/kg/day)"1 derived from this same study (NCI, 1978}
has also been adopted by CRAVE and this document as a measure of the
carclnogenlcUy of hexachloroethane following oral exposure. Because of
linkage of renal tumoMgenlclty to accumulation of alpha-2-mlcroglobullns In
male F344 rats (not seen In humans), an oral q * of 9.6x10~z
(mg/kg/day)'1 derived for NTP (1988) data Is not recommended for the
carclnogenlclty of hexachloroethane. Because hexachloroethane was
carcinogenic 1n B6C3F1 mice (NCI, 1978), 1t was Inappropriate, for the
purposes of this document, to develop subchronlc or chronic Inhalation or
oral RfDs. A chronic oral RfD of 0.001 mg/kg/day based on a rat study by
Gorzlnskl et al. (1985) has, however, been verified by the U.S. EPA
(1988b). An RQ of 1000, based on systemic toxlclty, has been determined
from a subchronlc oral study by NTP (1983) 1n which male rats developed
renal tubular nephrosls associated with evidence of kidney dysfunction. A
cancer RQ of 100 was calculated from the NCI (1978) study In which male mice
exposed orally to hexachloroethane developed hepatocellular carcinomas.
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Chemical Degradation 5
2.1.2. Physical Removal Processes 5
2.2. WATER : 6
2.2.1. Chemical Degradation 6
2.2.2. Mlcroblal Degradation 6
2.2.3. Volatilization 6
2.2.4. Adsorption 7
2.2.5. B1oaccumulat1on 7
2.2.6. Persistence 8
2.3. SOIL 8
2.3.1. Degradation 8
2.3.2. Adsorption 8
2.3.3. Volatilization 8
2.4. SUMMARY 9
3. EXPOSURE 10
3.1. WATER 10
3.2. FOOD 11
3.3. INHALATION 12
3.4. DERMAL 12
3.5. SUMMARY 12
4. AQUATIC TOXICITY 14
4.1. ACUTE TOXICITY 14
4.2. CHRONIC EFFECTS 19
4.3. PLANT EFFECTS 19
4.4. SUMMARY 20
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TABLE OF CONTENTS (cent.)
Page
5. PHARMACOKINETCS 21
5.1. ABSORPTION 21
5.2. DISTRIBUTION 21
5.3. METABOLISM 23
5.4. EXCRETION 25
5.5. SUMMARY 25
6. EFFECTS 27
6.1. SYSTEMIC TOXICITY 27
6.1.1. Inhalation Exposure 27
6.1.2. Oral Exposure 28
6.1.3. Other Relevant Information 33
6.2. CARCINOGENICITY 35
6.2.1. Inhalation 35
6.2.2. Oral 35
6.2.3. Other Relevant Information 40
6.3. MUTAGENICITY 40
6.4. TERATOGENICITY 42
6.5. OTHER REPRODUCTIVE EFFECTS 42
6.6. SUMMARY 43
7. EXISTING GUIDELINES AND STANDARDS 45
7.1. HUMAN 45
7.2. AQUATIC 45
8. RISK ASSESSMENT 46
8.1. CARCINOGENICITY 46
8.1.1. Inhalation 46
8.1.2. Oral 46
8.1.3. Other Routes 47
8.1.4. Weight of Evidence 47
8.1.5. Quantitative Risk Estimates 47
8.2. SYSTEMIC TOXICITY 48
8.2.1. Inhalation Exposure 48
8.2.2. Oral Exposure 50
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TABLE OF CONTENTS (cont.)
Page
9. REPORTABLE QUANTITIES 53
9.1. BASED ON SYSTEMIC TOXICITY 53
9.2. BASED ON CARCINOGENICITY 59
10. REFERENCES 63
APPENDIX A: LITERATURE SEARCHED 78
APPENDIX B: SUMMARY TABLE FOR HEXACHLOROETHANE 81
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LIST OF TABLES
No. Title Page
1-1 1977 Production/Import Data for Hexachloroethane In the
United States 3
6-1 Acute Toxldty of Hexachloroethane 36
6-2 Incidence of Tumors In B6C3F1 Mice Given Oral Doses of
Hexachloroethane (>98%) 1n Corn Oil for 78 Weeks 38
6-3 HutagenlcHy Testing of Hexachloroethane 41
8-1 Cancer Potency Derivation 49
9-1 Toxldty Summary for Hexachloroethane 54
9-2 Oral Composite Scores for Hexachloroethane 57
9-3 Hexachloroethane: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 60
9-4 Derivation of Potency Factor (F) for Hexachloroethane .... 62
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LIST OF ABBREVIATIONS
AP Alkaline phosphatase
BCF Bloconcentratlon factor
BOD Biochemical oxygen demand
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CHO Chinese hamster ovary
CS Composite score
DNA Deoxyr1bonucle1c acid
ECjg Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
GC Gas chromatography
GLC Gas liquid chromatography
HPLC High performance liquid chromatography
«d Desorptlon coefficient
Km Mlchales constant
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kow Octanol/water partition coefficient
LCso Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
LD5Q Dose lethal to 50% of recipients
MED Minimum effective dose
NADPH N1cot1nam1de adenlne dlnucleotlde phosphate
(reduced form)
NOEC No-observed-effect concentration
NOEL No-observed-effect level
PEL Permissible exposure limit
ppm Parts per million
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LIST OF ABBREVIATIONS (cont.)
ppt Parts per trillion
RFD Reference dose
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
SCE Slster-chromatld exchange
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc-pyruvlc transamlnase
TLV Threshold limit 'value
TWA Time-weighted average
UV Ultraviolet
°/»<> Salinity concentration In parts per thousand
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1 . INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Hexachloroethane 1s also known as perchloroethane, hexachloroethylene
and carbon hexachlorlde (IARC, 1979). The structure, molecular weight,
empirical formula and CAS Registry number for hexachloroethane are as
follows:
Cl Cl
I I
Cl-C-C Cl
I I
Cl Cl
Molecular weight: 236.74
Empirical formula: C-CI,
CAS Registry number: 67-72-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Hexachloroethane Is a colorless or white crystalline solid with a
camphor-like odor at room temperature (Hawley, 1981; Archer, 1979). It
occurs In three different crystalline forms: rhombic at <46°C, trlcllnlc at
46-71°C and cubic at >71°C (Archer, 1979). It Is soluble 1n alcohol, ether,
benzene, chloroform and oils (Hawley, 1981; IARC, 1979). Selected physical
properties of hexachloroethane are presented below:
Melting point:
Vapor pressure, 20°C:
Water solubility, 22.3'C:
Log Kow:
Density, 20°C:
Air odor threshold:
185°C (sublimes)
0.21 mm Hg
50 mg/l
3.82-4.04
2.094
0.15 ppm
Archer, 1979
Archer, 1979
Archer, 1979
Hansch and Leo, 1985
Archer, 1979
Amoore and Hautula,
1983
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Water odor threshold: 0.010 ppm Amoore and Hautula,
1983
I Air conversion factors
at 25°C: 1 mg/m3 = 0.10 ppm Verschueren, 1983
1 ppm =9.68 mg/m3
1.3. PRODUCTION DATA
Hexachloroethane 1s prepared by chlorlnatlon of tetrachloroethylene In
the presence of ferric chloride at 100-140°C (Archer, 1979). It Is also
formed In minor amounts In many Industrial chlorlnatlon processes designed
to produce lower chlorinated hydrocarbons (Archer, 1979). Table 1-1 lists
production/Import data for hexachloroethane In the United States In 1977.
Apparently, hexachloroethane Is not produced 1n the United States as an
end-use chemical since production Information regarding this compound was
not located In the available literature cited In Appendix A. The 1987 OPO
Chemical Buyers' Directory (Van, 1986) lists Atochem. Hummel, ICI Americas
and Rhoune-Poulenc as suppliers of hexachloroethane, which suggests that
hexachloroethane 1s currently Imported Into the United States. During 1982,
1.12 million pounds of hexachloroethane was Imported Into the United States
(HSDB. 1988).
1.4. USE DATA
Hexachloroethane 1s used as a constituent of candles and grenades for
the generation of smoke or fog; a rubber accelerator to reduce the time
needed to vulcanize rubber while Improving the aging and other physical
properties; a degassing agent for magnesium; a component of extreme pressure
lubricants such as those used for exhaust heat valve seats In Internal
combustion engines; an Ignition suppressant 1n combustible liquids; an
anthelmlnthU 1n veterinary medicine; a retardant In fermentation processes;
0119d -2- 07/13/88
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TABLE 1-1
1977 Production/Import Data for Hexachloroethane
In the United States*
Company/Location
Production/Import Volume
(million pounds)
Dow Chemical
PHtsburg, CA
Dow Chemical
Plaquemlne, LA
PPG Industries
Lake Charles, LA
PPG IndutMes
New Martlnsvllle, UV
Dupont
Ingleslde, CA
Hummel Chemical
South Plalnfleld, NJ
Rhone-Poulenc
Freeport, TX
ICI Americas
Wilmington, DE
0.10-1
(limited use)
1-10
(limited use)
1-10
(limited use)
0.01-0.10
confidential
(site-limited use)
0.01-0.10
(Imported)
1-10
(Imported)
1-10
(Imported)
*Source: U.S. EPA, 1977
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05/27/88
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a component of submarine paints; an additive to fire-extinguishing fluids; a
plastldzer for cellulose esters; a moth repellent; a camphor substitute In
nitrocellulose solvent; and a constituent of various funglcldal and 1nsect1-
cldal formulations (IARC, 1979; Verschueren, 1983). Hexachloroethane 1s
used primarily 1n the rubber manufacturing and explosive Industries (Griddle
et a!., 1986).
1.5. SUMMARY
Hexachloroethane Is a white or colorless crystalline solid at room
temperature (Hawley, 1981; Archer, 1979). It 1s prepared by chloMnatlon of
tetrachloroethylene 1n the presence of ferric chloride, and 1s also formed
In minor amounts In many Industrial chlorlnatlon processes designed to
produce lower chlorinated hydrocarbons (Archer, 1979). U.S. EPA (1977)
listed five manufacturers and three Importers of this compound; four of the
five manufacturers used this compound for site-limited use only. Apparently
hexachloroethane 1s not produced by domestic manufacturers as an end-use
chemical, but Is currently Imported Into the United States. During 1982,
1.12 million pounds of hexachloroethane was Imported Into the United States
(HSDB, 1988). Hexachloroethane Is used primarily 1n the rubber manufactur-
ing and explosive Industries (Crlddle et al., 1986).
0119d -4- 07/13/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
' Based on a vapor pressure of 0.21 mm Hg at 25°C {Archer, 1979), hexa-
chloroethane 1s expected to exist predominantly 1n the vapor phase 1n the
atmosphere (Elsenrelch et al., 1981).
2.1.1. Chemical Degradation. As a fully chlorinated aliphatic hydro-
carbon, hexachloroethane 1s expected to be Inert to reaction with photo-
chemlcally generated hydroxyl radicals and ozone molecules In the tropo-
sphere (U.S. EPA, 1987a). Hexachloroethane contains no chromophores that
absorb UV light In the environmentally significant range (>290 nm);
therefore, this compound would not be susceptible to direct photolysis 1n
the troposphere (Callahan et al., 1979; Habey et al., 1981).
2.1.2. Physical Removal Processes. Hexachloroethane Is not known to
undergo significant reaction In the atmosphere. As a result, It has a very
long tropospherlc lifetime (>2.3 years) (Class and Ballschmlter, 1987).
Diffusion from the troposphere Into the stratosphere, partitioning between
air and the oceans and transfer from the northern hemisphere to the southern
hemisphere are Important fate processes In the atmosphere (Class and
Ballschmlter, 1987). Class and BallshmUer (1987) estimated that the net
flow of hexachloroethane from the northern to southern hemisphere 1s -0.45
kton/year, the net transfer rate from the troposphere to the stratosphere Is
-0.14 kton/year and the maximum flux Into the northern oceans 1s -0.4 ktons/
year. In other words, -14% of tropospherlc hexachloroethane will diffuse
Into the stratosphere. Upon diffusion Into the stratosphere, significant
photodlssoclatlon of the compound may occur (Callahan et al., 1979). The
resultant chlorine radicals may contribute to the destruction of the strato-
spheric ozone layer.
0119d -5- 05/27/88
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2.2. MATER
2.2.1. Chemical Degradation. Hexachloroethane should not be susceptible
to chemical hydrolysis under environmental conditions (Mabey et al., 1981).
Hexachloroethane 1s expected to be Inert to reaction with singlet oxygen.
hydroxyl radicals and alkylperoxy radicals found 1n natural waters (Habey et
al., 1981; U.S. EPA, 1981), and would not be susceptible to direct photoly-
sis {Habey et al., 1981).
2.2.2. Mlcroblal Degradation. Hexachloroethane 1s reported to be resis-
tant to aerobic biological treatment and Inhibitory to anaerobic biological
reactions (Abrams et al., 1975; Johnson and Young, 1983). Results of the
Japanese MITI Test Indicate that hexachloroethane 1s generally resistant to
blodegradatlon; <30% degradation was observed when 100 ppm hexachloroethane
was Incubated In an aqueous solution containing 30 ppm activated sludge
under aerobic conditions for 2 weeks (Kawasaki, 1980; Sasaki, 1978). In
standard BOD dilution water, loss of hexachloroethane was found to corre-
spond with formation of tetrachloroethylene. Hexachloroethane at an Initial
concentration of 25.6 nmol/t, underwent 18% loss 1n 60 days. No loss of
hexachloroethane was observed In chemically sterilized controls, suggesting
that loss 1n the unsteMUzed BOD dilution water was a result of mlcroblal
activity (Crlddle et al., 1986). Hexachloroethane was added to groundwater
samples Inoculated with aquifer material. Incubation for 66 days resulted
1n 22-47% loss 1n unsteMUzed samples, 11-59% loss In chemically sterilized
samples and 13-76% loss 1n autoclaved samples, suggesting that transforma-
tion of hexachloroethane to tetrachloroethylene was the result of both
blotlc and abiotic activity (CMddle et al., 1986).
2.2.3. Volatilization. Henry's Law constant for hexachloroethane was
measured to be 2.8xlO~3 atm-mVmol at 20°C (Munz and Roberts, 1987).
0119d -6- 05/27/88
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Based on this Henry's Law constant value the volatilization half-life from a
model river 1 m deep, flowing 1 m/sec with a wind speed of 3 m/sec was esti-
mated to be ~5 hours using the method of Thomas (1982). The volatilization
half-life of a dilute solution of hexachloroethane (Initial concentration 1
ppm) 1n a 250 mi beaker 6.5 cm deep, stirred at 200 rpm In still air was
determined to be 40.7 minutes (Dllllng, 1977). These data Indicate that
hexachloroethane 1s a sufficiently volatile compound and that volatilization
would be an Important, If not the dominant, removal process 1n surface
waters.
2.2.4. Adsorption. A measured K value of 2188 (Abdul et al., 1987)
suggests that adsorption of hexachloroethane to suspended solids and
sediments 1n water would be a significant fate process. Jafvert and Wolfe
(1987) reported that hexachloroethane adsorbs appreciably to sediments.
2.2.5. Bloaccumulatlon. Blueglll sunflsh, Lepomls macrochlrus. exposed
to hexachloroethane at a concentration of 6.17 yg/8. for 28 days had a
whole body BCF of 139 (Velth et al., 1980). The half-life (time required
for 50% reduction 1n concentration) for depuration of this compound from
tissue of blueglll sunflsh upon transfer of the fish to uncontamlnated water
was measured to be <1 day (Velth et al., 1980). Rainbow trout, Sal mo
qardnerl. exposed to hexachloroethane at concentrations of 0.32 and 7.1
ng/l for 7-119 days had average whole body BCF values of 510 and 1200,
respectively (Oliver and Nlmll, 1983). The difference In BCF values at the
different exposure levels probably Indicates that the rate of detoxification
and elimination of this chemical 1s concentration-dependent (Oliver and
N1m11, 1983). These BCF values suggest that this compound may bloaccumulate
significantly In some aquatic organisms.
0119d -7- 05/27/88
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2.2.6. Persistence. A 12 ma solution containing hexachloroethane at an
Initial concentration of 20 yg/i. was Injected Into an unconflned sand
aquifer 1n Bordon, Ontario. Based on monitoring data hexachloroethane
attained breakthrough 1n -60 days (Josephson, 1983).
Hexachloroethane added to anoxlc sediment-water suspensions at an
Initial concentration of 0.10 and 0.093 iimol/i underwent 30-65% loss In
20 minutes. The amount of 1,1,2,2-tetrachloroethane recovered from these
sediment-water slurries ranged from 26-43% of theoretical yield. Indicating
that reduction Is an Important fate process for hexachloroethane. Both
blotlc and abiotic processes appeared to be responsible for degradation of
hexachloroethane (Jafvert and Wolfe, 1987).
2.3. SOIL
2.3.1. Degradation. Based on studies performed with hexachloroethane In
water. It appears that this compound would be reduced to tetrachloroethylene
In soil by both blotlc and abiotic processes.
2.3.2. Adsorption. Hexachloroethane has a measured K of 2188 (Abdul
et al., 1987), which Is Indicative of very slight mobility In soil (Swann et
al., 1983). A K, of 8.1 was measured In a study performed 1n a sand
aquifer (Mackay et al., 1986). Based on this value for K, and given that
the organic content of the aquifer material was 0.018%, a KQC of 45,222
can be estimated, which also Indicates that hexachloroethane would be
relatively Immobile In soil. An organic carbon content of 0.018%, however,
1s well below the threshold value of 0.1%, which 1s believed to be the
minimum to ensure predominance of the organic partitioning mechanism
(Roberts et al., 1986).
2.3.3. Volatilization. A vapor pressure of 0.21 mm Hg at 20°C (Archer,
1979) suggests that hexachloroethane would volatilize slowly from dry soil
surfaces.
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2.4. SUMMARY
In the atmosphere, hexachloroethane Is expected to exist almost entirely
1n the vapor phase (Archer, 1979; Elsenrelch et al., 1981). This compound
will not degrade 1n the troposphere (U.S. EPA, 1987a; Mabey et al., 1981).
Hexachloroethane will be removed from the northern troposphere by partition-
Ing between air and the oceans, and by transfer Into the southern tropo-
sphere by slow diffusion Into the stratosphere above the ozone layer where
1t should photolyze (Class and Ballschmlter, 1987; Callahan et al., 1979).
The half-life for diffusion Into the stratosphere Is estimated to be -30
years (Callahan et al., 1979). Because of Us persistence 1n the tropo-
sphere, hexachloroethane has the potential to be transported long distances
from Its sources of emission. In water, volatilization appears to be an
Important, 1f not the dominant, removal mechanism. The volatilization
half-life from a model river 1 m deep, flowing 1 m/sec with a wind speed of
3 m/sec was estimated to be 15 hours. Hexachloroethane could also adsorb
appreciably to suspended solids and sediments (Jafvert and Wolfe, 1987). In
anaerobic sediments, hexachloroethane Is expected to degrade to tetrachloro-
ethylene by both blotlc and abiotic processes (Jafvert and Wolfe, 1987;
Crlddle et al., 1986). Hexachloroethane 1s not expected to degrade under
aerobic condltons. Hexachloroethane may bloaccumulate significantly 1n some
aquatic organisms (Oliver and N1m11, 1983; Velth et al., 1980). In soil, It
appears that hexachloroethane would be susceptible to reduction to tetra-
chloroethylene by both blotlc and abiotic processes. Hexachloroethane
should be slightly mobile In soil (Abdul et al.. 1987; Swann et al.. 1983),
and 1s expected to volatilize slowly from dry soil surfaces.
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3. EXPOSURE
3.1. WATER
Staples et al. (1985) summarized monitoring data on hexachloroethane
from U.S. EPA STORET sampling stations between January 1980 and January
1984, and reported the following: whole water, 882 samples, 0.1X positive,
median concentration <10 yg/l; effluent, 1253 samples, 2% positive,
median concentration <10 jig/l; sediment, 356 samples, OX positive; and
biota tissue, 116 samples, 0% positive. Gross analysis data from the U.S.
EPA STORET Data Base (U.S. EPA, 1988a) are as follows: whole water, 7990
samples, mean concentration 34.3 ug/l; sediments, 68 samples, mean
concentration 0.02 mg/kg wet weight basis; and biota tissue, 763 samples,
mean concentration 27.8 mg/kg wet weight basis.
During the mid-to-late 1970s hexachloroethane was found In finished
drinking water from Philadelphia, PA, Cincinnati, OH, Miami, FL, New
Orleans, LA, Jefferson City, MO, and EvansvUle, IN (Lucas, 1984;
Shackelford and Keith, 1976; U.S. EPA, 1975; Keith et al., 1976; Kleopfer
and Falrless, 1972). Results of the 1975 U.S. EPA National Organlcs Recon-
nalsance Survey Indicate that the average level of hexachloroethane 1n
Miami, FL, drinking water was 0.5 yg/l (U.S. EPA, 1975). Hexachloro-
ethane was not detected (detection limit <0.1 yg/i.) 1n finished drinking
water from 10 Canadian water treatment plants {Otson et al., 1986). In
1978, hexachloroethane was found In 19 of 31 private wells In the Toone-
Teague Area of Hardeman County, TN. Concentrations ranged between trace to
4.6 yg/l with a median concentration of 0.26 v.q/1. The origin of
this contamination was a hazardous waste landfill operated by Velslcol
Chemical Corporation (Harris et al., 1984). Hexachloroethane was Identified
In leachtate from the Occidental Chemical Company S-Area landfill adjacent to
0119d -10- 07/13/88
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the Niagara Falls, NY, water treatment plant (Tallan et al., 1986). Hexa-
chlorethane was also found 1n groundwater In Switzerland, at concentrations
of 15-21 vg/i, as a result of leaching from a chemical waste disposal
site (G1ger and Schaffner, 1981).
Hexachloroethane was detected In the open waters of Lake Ontario and the
Ganaraska River (Great Lakes Water Quality Board, 1983). Hexachloroethane
was sought, but not found In the Cuyahoga River (Great Lakes Water Quality
Board, 1983). Hexachloroethane was detected 1n 1 of 204 water samples
collected from 14 heavily Industrialized river basins across the United
States. The detection limit for this study was 1 yg/t (Ewlng et al.,
1977). During 1980, hexachloroethane was detected In so11/sed1ment/waters
samples from Love Canal 1n Niagara Falls, NY (Mauser and Bromberg, 1982).
Results of the Nationwide Urban Runoff Program, as of July 31, 1982,
Indicated that hexachloroethane was not detected 1n 86 samples of urban
runoff collected from 15 cities 1n the United States (Cole et al., 1984).
Hexachloroethane was found 1n the effluent from a United States chemical
plant at a concentration of 8.4 yg/i. (IARC, 1979). During 1972,
hexachloroethane was detected at a concentration of <1 yg/i 1n treated
wastewater from a Kraft paper mill located 1n RUeboro, GA (Keith, 1976).
Hexachloroethane was Identified In treated wastewater from a coal mining
operation at a maximum concentration of 3 pg/s. (U.S. EPA, 1981).
3.2. FOOD
Adult rainbow trout collected from Lake Ontario during the spring of
1981 contained hexachloroethane at levels of 0.01-0.06 ng/g wet weight
(Oliver and N11m1, 1983).
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3.3. INHALATION
Hexachloroethane was monitored 1n the atmosphere above the Atlantic
Ocean between March 1982 and March 1986. Based on results of this study,
the mean baseline concentration of this compound 1n the Northern Hemisphere
was determined to be 0.28+0.03 ppt (Class and Ballschmlter, 1987).
Hexachloroethane was monitored In ambient air of the United States between
1976 and 1978 with the following results: rural/remote locations, 6 samples,
mean concentration 4,0+3.2 ppt; urban/suburban locations, 76 samples, mean
concentration 0.34+2.4 ppt; and source dominated areas, 42 samples, none
detected (Brodzlnsky and Singh, 1982). Hexachloroethane was detected at
concentrations of 0.28-0.41 ppt In air samples collected during rain events
In Portland, OR, between February and April 1984; however, the compound was
not detected 1n rain samples collected during these same rain events,
Indicating a lack of dissolution or sorptlon In the raindrops (Llgockl et
al., 1985).
The global emission rate of hexachloroethane Is estimated to be <1
kton/year (Class and Ballschmlter, 1987). Hexachloroethane was Identified
1n atmospheric emissions from a hazardous waste Incinerator test burn (James
et al., 1984). Hexachloroethane was also found In fly ash from waste
Incineration (Junk and Ford, 1980).
3.4. DERMAL
Pertinent data regarding exposure to hexachloroethane by dermal contact
were not located 1n the available literature cited 1n Appendix A.
3.5. SUMMARY
Hexachloroethane has been detected 1n finished drinking water, surface
water, wastewater, groundwater, landfill leachate, biota and ambient air.
0119d -12- 05/27/88
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During the mid-to-late 1970s hexachloroethane was found In finished drinking
water from Philadelphia, PA, Cincinnati, OH, Miami, FL, New Orleans, LA,
Jefferson City, HO and. Evansvllle, IN (Lucas, 1984; Shackelford and Keith,
1976; U.S. EPA, 1975; Keith et al., 1976; Kleopfer and Falrless, 1972).
Hexachloroethane was found In water samples obtained from Lake Ontario and
the Ganaraska River and In fish collected from Lake Ontario (Great Lakes
Water Quality Board, 1983; Oliver and N1m11, 1983). This compound was found
1n wastewater from a chemical plant, a Kraft paper mill and a coal mining
operation In the United States (IARC, 1979; Keith, 1976; U.S. EPA, 1981).
Groundwater 1n Hardeman County, TN, was found to contain hexachloroethane
from contamination from a hazardous waste landfill (Harris et al., 1984).
This compound was also Identified In leachate from a landfill adjacent to
the water treatment plant In Niagara Falls, NY (Tallan et al.. 1986). These
data suggest that the origin of hexachloroethane in most water samples is
principally anthropogenic. Results of the Nationwide Urban Runoff Program,
as of July 31, 1982, Indicated that hexachloroethane was not detected 1n
samples of urban runoff collected from various cities throughout the United
States (Cole et al., 1984). Based on monitoring data obtained between March
1982 and March 1986, the baseline concentration of hexachloroethane In the
atmosphere of the Northern Hemisphere has been estimated to be 0.28±0.03 ppt
(Class and Ballschmlter, 1987). Hexachloroethane was detected 1n air
samples, but not rain samples, collected during rain events 1n Portland, OR,
between February and April 1984 (Llgockl et al., 1985).
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Heltmuller et al. (1981) exposed sheepshead minnow, Cypr1n1don
varlegatus. to hexachloroethane 1n filtered natural seawater In static tests
for 96 hours at 25-31°C. Test solutions were not aerated during the study.
Nominal 24-, 48- and 72- to 96-hour LC5_ values with 9554 confidence limits
of 3.1 (2.4-4.1), 2.8 (2.2-3.6) and 2.4 mg/l (1.9-3.1), respectively, were
reported. The Investigators also reported a NOEC of 1.0 mg/i.
Buccafusco et al. (1981) exposed blueglll sunflsh, Lepomls macroch1 rus,
to hexachloroethane 1n a static acute study at 21-23°C. The test was
conducted with well water 1n capped jars to minimize volatilization of
hexachloroethane; there was a precipitate present In the test jars during
the exposure period. Nominal 24- and 96-hour LC5(}s of 1.8 (confidence
Interval, not reported) and 0.98 mg/i (95% confidence Interval, 0.85-1.1
mg/a), respectively, were reported.
HalbMdge et al. (1983) exposed fathead minnows, Plmephales promelas. to
hexachloroethane In a flowthrough study with Lake Superior water at 25H°C.
The concentration of hexachloroethane 1n each test container was measured
dally. The authors reported 24-, 48- to 72- and 96-hour LC5Q values with
9554 confidence Intervals of 1.8 (1.70-1.91), 1.55 (1.47-1.63) and 1.51
mg/a. (1.43-1.58), respectively. Apparently, the 96-hour LC5Q of 1.5
mg/a reported for exposure of fathead minnows to hexachloroethane by Velth
et al. (1983) was generated by Hal bridge et al. (1983).
Phlpps and Holcombe (1985) reported the results of a study In which five
species of fish were simultaneously exposed to hexachloroethane 1n a flow-
through test. Test fish Included fathead minnows, £. promelas. goldfish,
Carasslus auratus. channel catfish, Ictalurus punctatus. blueglll sunflsh,
0119d -14- 05/27/88
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I. macrochlrus and rainbow trout, Sal mo ga_1_rdner 1. The measured test
temperature was 17.3±Q.6°C; dilution water was drawn from Lake Superior.
Hexachloroethane concentrations were measured dally. The 96-hour LC
reported for goldfish was >2.1 mg/l. Fathead minnow LC..S for 24, 48,
72 and 96 hours were 1.74, 1.44, 1.29 and 1.23 mg/i. (95% confidence
Interval, 1.08-1.40 mg/i), respectively. Rainbow trout LC5Qs for 24 and
48-96 hours were 1.51 and 0.970 mg/i (95% confidence Interval, 0.73-1.28
mg/a.), respectively. LCcgs for channel catfish for 48, 72 and 96 hours
were 1.93, 1.60 and 1.52 mg/a. (95% confidence Interval, 1.39-1.65 mg/i),
respectively. LC5Qs for blueglll sunflsh for 24, 48, 72 and 96 hours were
1.82, 1.60, 1.13 and 0.970 mg/i (95% confidence Interval, 0.73-1.28
mg/a,), respectively.
Thurston et al. (1985) exposed fathead minnows, £. promelas. goldfish,
£. auratus. channel catfish, I_. punctatus. blueglll sunflsh, L,. macrochlrus.
mosqu1tof1sh, GambusVa affinis, rainbow trout, S. galrdnerl. and the frog,
Rana catesblana. to hexachloroethane. Susceptibility of fishes and tadpole
frogs to hexachloroethane was determined 1n a flowthrough system for 96
hours. Dilution water for all studies was obtained from a groundwater
spring source, Hexachloroethane concentrations were measured dally 1n all
tests. Tests with rainbow trout were conducted at a mean temperature of
13.5°C; average test temperatures for the other test species ranged from
16.7-19.5°C. LC5Q values (96 hours) and 95% confidence Intervals for two
experiments with frog tadpoles of different average sizes (4.12 and 4.21 g)
were 3.18 (confidence Interval, 2.88-3.51) and 2.44 mg/t, (confidence
Interval, 1.47-4.06), respectively. LC5Q values (96 hours) and 95% confi-
dence Intervals for two studies with fathead minnows with average sizes of
0.56 and 0.44 g were 1.39 (confidence Interval, 1.08-1.78) and 1.10 mg/i
0119d -15- 05/27/88
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(confidence Interval, 0.967-1.25), respectively. For catfish with average
sizes of 3.48 and 0.31 g, LC values (96 hours) and 95% Confidence
Intervals were 2.36 (confidence Interval, 1.90-2.94) and 1.77 mg/i (confi-
dence Interval, not reported), respectively. LC5Q values (96 hours) and
95% confidence Intervals for studies with trout, sunflsh, mosqu1to-f1sh and
goldfish were 1.18 (95% confidence Interval, not reported), 0.856 (confi-
dence Interval, 0.712-1.03), 1.38 (confidence Interval, 1.05-1.81) and 1.42
mg/i (confidence Interval, 1.03-1.95), respectively.
Loeb and Kelly (1963) attempted to determine the acute oral toxlclty of
hexachloroethane to carp, Cyprlnus carplo. that were force-fed hexachloro-
ethane at 264, 383 and 462 mg/kg. Fish were collected In the field, and
ranged 1n size from 1-10 pounds (average -3 pounds). Approximately three
fish were force-fed hexachloroethane 1n gelatinous capsules that disinte-
grated after ~1 hour. The test was conducted at 65°F and fish were observed
for 24 to >40 hours after feeding. There was no effect on test fish after
43 hours. The authors concluded that the results of this study and of those
for 1495 other chemicals could not be explained adequately because of the
lack of trends 1n the results.
LeBlanc (1980) exposed the water flea, Daphnla magna. to hexachloro-
ethane In delonlzed reconstituted well water at 22+l°C with a mean hardness
of 72+6 nig/a, as CaCO_. Test concentrations were not measured during the
48-hour static test. The test was conducted 1n 250-ml beakers that were
covered with plastic wrap secured with an elastic band. The reported
24- and 48-hour LCr_s with 95% confidence Intervals were 26 (confidence
t)U
Interval, 13-48) and 8.1 mg/l (confidence Interval, 4.3-16), respectively.
The NOEC was 0.28 mg/l.
0119d -16- 05/27/88
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Rlchter et al, (1983) exposed D. maqna to hexachloroethane 1n the
absence and presence of food (20 mg/l dry weight, trout chow and yeast) to
generate both an ECgQ and a LC5Q. Diluent water was drawn from Lake
Superior. Concentrations of hexachloroethane were determined at the start
and end of each test. Static tests were conducted at a constant temperature
of 20±1°C with 200 or 160 ml of solution for unfed and fed tests, respec-
tively. Death and Immobilization were determined after 48 hours. The
EC5Q values with 95X confidence Intervals 1n studies with unfed and fed
daphnlds were 2.1 (confidence Interval, 1.8-2.5) and 1.8 mg/t (confidence
Interval, 1.6-2.1), respectively. The LC5Q values with 95% confidence
Intervals for unfed and fed daphnlds were 2.9 (confidence Interval, 2.5-3.3)
and 2.4 mg/a, (confidence Interval, 2.0-2.9), respectively. Binomial,
moving average and problt statistical analyses were used to generate these
data.
Mount and Norberg (1984) reported the results of static tests 1n four
species of Cladocera exposed to hexachloroethane. Dilution water was drawn
from Lake Superior. Hexachloroethane concentrations were not measured.
Test vessels contained 50,000-100,000 bacterial cells/ml. The 48-hour
LCcr. values with 95X confidence Intervals were 2.7 (confidence Interval,
t>u
2.0-3.6) for D. maqna. >10 for D. pulex. 3.3 (confidence Interval, 2.3-4.7)
for CeModaphnla retlculata and 5.8 mg/i (confidence Interval, 3.7-9.1)
for Slmocephalus vetulus. respectively.
Phlpps and Holcombe (1985) reported 96-hour LC5()s >2.1 mg/l for
crayfish, Oronectes Immunls. and snails, Aplexa hypnorum. exposed to hexa-
chloroethane 1n flowthrough tests. Test conditions were the same as those
reported previously for their tests with fish.
0119d -17- 05/27/88
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Thurston et al. (1985) determined the acute toxldty of hexachloroethane
to daphnlds, 0. tnagna. and chlronlmlds, Tanytarsus d1ss1m1l1s. 1n static
tests conducted for 48 hours at 20-24°C. Dilution water was obtained from a
groundwater spring source. The 48-hour LC5Q values with 95X confidence
Intervals for D_. maqna and T. dlsslmllls were 1.36 (confidence Interval,
1.04-1.79) and 1.23 mg/8, (confidence Interval, 1.07-1.42), respectively.
Thurston et al. (1985) also determined the acute toxlclty of hexachloro-
ethane to the crayfish, 0. Imrmmls. 1n flowthrough tests at 13.9'C. Cray-
fish were Isolated from each other during the test to minimize cannibalism.
Dilution water was obtained from a gro.undwater spring source. The 96-hour
LC5Q with a 95X confidence Interval was reported to be 2.70 mg/i (confi-
dence Interval, 2.13-3.49).
Elnabarawy et al. (1986) exposed D. maqna. D. pulex and C_. retlculata to
hexachloroethane 1n static tests at 23il°C. Dilution water was unchlorl-
nated, carbon-filtered well water. The nominal 48-hour LC50s with 95%
confidence Intervals based on mortality and Immobility were 10 (confidence
Interval, 8.8-12), 13 (confidence Interval, 12-15) and 6.8 mg/8, (confi-
dence Interval, 4.7-8.6), respectively.
The toxlclty of hexachlorethane to sea urchin embryos, Arbada punctu-
lata. was assessed by Jacklm and Nacd (1984). Experiments were conducted
at 20il°C In seawater (30+1 °/00) that was filtered (0.22 ym) and auto-
claved. One hour after fertilization, 1 ml of embryo suspension was added
to 99 mil of seawater 1n 70x50 mm culture dishes to yield an embryo density
of 100 embryos/ml. Inhibition of cell division (growth of embryo) was
used to generate ECrn values after 2 hours of exposure to hexachloro-
ethane. Cell division was determined by measuring the Incorporation of
exogenously administered radlolabeled thymldlne, a method by which DNA
0119d -18- 05/27/88
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synthesis could be measured. The extent of thymldlne Incorporation was
determined by transferring embryos exposed to experimental treatments for 2
hours to 20 mi glass vials containing 1.52 WC1 [3H]thym1d1ne. After 2
hours, the embryos were processed 1n order to determine total radioactivity
on a liquid scintillation counter. EC5Q values with 95X confidence
Intervals of 9.32 (confidence Interval, 8.29-10.6) and 8.51 mg/l (confi-
dence Interval, 7.43-9.19) were reported In separate trials. Nacd and
Jacklm (1985) expanded the original study of Oacklm and Nacc! (1984) by
Initiating exposure of A. punctulata embryos to hexachloroethane 1 hour
before fertilization, at fertilization and 1 hour after fertilization. They
reported EC^ns with 95X confidence Intervals for pre-, at and postexposure
periods of 6.05 (confidence Interval, 4.67-7.60), 4.97 (confidence Interval,
4.04-5.91} and 8.31 (confidence Interval, 5.80-12.93), respectively.
Curtis et al. (1982) assessed the effect of hexachloroethane on
luminescent bacteria In the Hlcrotox toxlclty analyzer (Beckman Instruments,
Inc., Carlsbad, CA). The concentration of hexachloroethane that produced a
50% Inhibition of luminescence In Photobacterlum phosphoreum after 5 minutes
of exposure was determined. The authors reported a 5-m1nute EC~Q of
0.14 mg/l.
4.2. CHRONIC EFFECTS
Pertinent data regarding the effects of chronic exposure of aquatic
organisms to hexachloroethane were not located 1n the available literature
cited In Appendix A.
4.3. PLANT EFFECTS
Pertinent data regarding the effects of exposure of aquatic plants to
hexachloroethane were not located 1n the available literature cited 1n
Appendix A.
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4.4. SUMMARY
The acute toxldty of hexachloroethane to aquatic organisms was deter-
mined for seven species of freshwater fish, one species of saltwater fish,
five species of Crustacea, and single species of amphibian, echlnoderm and
luminescent bacteria. The 96-hour LC5Q values for freshwater fish ranged
from 0.856 mg/i for blueglll sunflsh to 2.36 mg/i for channel catfish
and >2.1 mg/a. for goldfish. The acute toxldty of hexachloroethane to a
saltwater fish (sheepshead minnow) and frog tadpoles was comparable with
that generated with freshwater fish (96-hour LC5Q=2.4 and 3.18 mg/i,
respectively). Tests with different size frog tadpoles, fathead minnow or
channel catfish did not produce changes In the IC50 value by more than a
factor of 2. Results of a study with crayfish (96-hour LC5Q=2.70 mg/4)
were comparable with those produced by exposure of freshwater fish to
hexachloroethane. The 48-hour EC and LC5Q values for the various
species of Cladocera exposed to hexachloroethane ranged from 1.8 mg/l for
J). magna to 13.0 mg/8. for D. pulex. Hexachloroethane Inhibited develop-
ment of sea urchin embryos at concentrations of -5-10 mg/i and lumines-
cence In bacteria at a concentration of -0.1 mg/i.
Pertinent data regarding the effects of chronic exposure of aquatic
organisms or the effects of exposure of aquatic plants to hexachloroethane
were not located In the available literature dted In Appendix A.
0119d -20- 07/13/88
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5. PHARHACOKINETICS
5.1. ABSORPTION
Toxlclty, carclnogenlcHy and teratogenlclty studies Indicate that hexa-
chloroethane 1s absorbed following oral and Inhalation exposure (Chapter 6);
however, specific studies on the rate and extent of absorption were not
located 1n the available literature cited In Appendix A.
Information regarding hexachloroethane absorption can be obtained from
studies on the excretion of the compound following oral administration to
mice, rats and rabbits. Rabbits given an oral dose of radlolabeled
hexachloroethane (500 mg/kg) excreted between -20 and SOX of the compound In
the exhaled air and urine (Jondorf et al., 1957); these values, therefore,
represent a minimum estimate of the percentage of the dose absorbed.
Absorption of ~70X of an oral dose of radlolabeled hexachloroethane
{125-1000 mg/kg) 1n Osborne-Mendel rats and B6C3F1 mice was Indicated by the
appearance of this percentage of unmetabollzed parent compound 1n the
exhaled air (MHoma et al.. 1985).
5.2. DISTRIBUTION
The distribution of hexachloroethane was studied In Fischer rats (four
rats/sex/dose level) given the compound 1n the diet at dose levels of 1, 15
or 62 mg/kg/day for 16 weeks, or In 20 male rats fed 62 mg hexachloroethane/
kg/day for 8 weeks (Gorzlnskl et al., 1985). Fat, liver, kidneys and whole
blood were analyzed for hexachloroethane content. The tissues were
extracted with hexane and analyzed for hexachloroethane by GLC. In male
rats fed hexachloroethane for 8 weeks, the concentration of the compound In
various tissues was determined 1n a group of three animals sacrificed 3 days
after exposure to hexachloroethane had been terminated. The concentration
0119d -21- 05/27/88
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1n fat was ~300 jjg/g tissue; this was 2.5-5 times greater than the concen-
tration 1n kidney (-80 vg hexachloroethane/g) and more than 100 times
greater than the concentrations found 1n the liver or blood (-1.0 »g/g
tissue). Distribution studies In male and female rats given different doses
of the compound for 16 weeks Indicated that the concentration of hexachloro-
ethane 1n the kidneys of male rats was higher than that In females at all
dose levels. The kidney concentration of hexachloroethane In male rats was
proportional to dose, whereas kidney hexachloroethane levels In females
showed smaller, disproportionate Increases with Increasing dose. For both
sexes, the concentrations of hexachlorpethane 1n the fat, liver and blood
were similar. Increases In the concentration of hexachloroethane 1n the
liver and blood were disproportionately small with Increasing dose;
Gorzlnskl et al. (1985) attributed this to saturation of protein binding
sites. The Investigators concluded that blood concentration of hexachloro-
ethane did not provide a reliable estimate of hexachloroethane exposure 1n
the rat.
The tissue clearance of hexachloroethane was studied In a group of 20
male Fischer 344 rats (Gorzlnskl et al., 1985). The rats were fed the
compound at a dose of 62 mg/kg/day for 8 weeks, and then were fed untreated
control diets. Three to four rats were sacrificed at time points of 3, 6,
13, 22 and 31 days on the control diet and samples of fat, liver, kidney and
whole blood were analyzed for hexachloroethane content. Tissue hexachloro-
ethane content was determined by GC following extraction of the tissue with
hexane. The concentration of hexachloroethane decreased 1n all of the
tissues examined, I.e., fat, liver, kidney and blood, 1n an apparent first-
order manner, and the half-lives of elimination were 2.7, 2.3, 2.7 and 2.5
days, respectively. Gorzlnskl et al. (1985) concluded that the apparent
0119d -22- 05/27/88
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first-order elimination from the tissues Indicated that hexachloroethane
metabolism and excretion were not saturated 1n rats at dose levels of <62
mg/kg/day.
5.3. METABOLISM
The metabolism of hexachloroethane has been studied extensively In vitro
but only two _^n vivo metabolism studies were found 1n the available litera-
ture. Radlolabeled hexachloroethane (containing 14C at both carbon atoms)
was fed to rabbits at a dose of 500 mg/kg bw (Jondorf et al., 1957). The
compound was found to be metabolized very slowly and only 5% of the radio-
activity appeared 1n the urine 1n 3 da^s. During this time, 14-24% of the
radioactivity appeared 1n the expired air. Urinary metabolites Identified
were trlchloroethanol (1.3X), dlchloroethanol (0.4%), trlchloroacetlc add
(1.3%), dlchloroacetlc add (0.8%), monochloroacetlc add (0.7X) and oxalic
add (0.1%). Carbon dioxide, hexachloroethane, tetrachloroethylene and
1,1,2,2-tetrachloroethane were found In the expired air.
A comparative study of the metabolism of hexachloroethane 1n Osborne-
Mendel rats and B6C3F1 mice was conducted by MHoma et al. (1985). Hexa-
chloroethane (98% pure and unlabeled) was dissolved 1n corn oil and given
orally to groups of rats at doses of either 125 or 500 mg/kg, or to mice at
doses of either 250 or 1000 mg/kg. The unlabeled compound was administered
5 days/week for 4 weeks, followed by a single dose of the corresponding
radlolabled compound. The animals were then placed 1n Individual rodent
metabolism cages for 48 hours. The expired air (volatile metabolites and
C0?) was collected 1n a series of traps and after 48 hours, the animals
were killed and the feces and urine were removed from the cages. Liver and
kidneys were removed from each animal and homogenized 1n water; carcasses
were dissolved 1n KOH. Allquots of these solutions (I.e., traps, urine,
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organ and feces homogenates, carcass digest) were than analyzed for radio-
activity. Hepatic protein-bound radioactivity was also assayed and urinary
metabolites were analyzed by HPLC. The results Indicated that most of the
dose (I.e., 64.55X 1n rats and 71.SIX In mice) was eliminated 1n the expired
air as the unmetabollzed parent compound, whereas ~25X of the dose {I.e.,
28.12% 1n rats and 23.95X 1n mice) was excreted or retained as metabolites.
The actual percentages of the dose excreted as CCL were 2.37 and 1.84 for
rats and mice, respectively. Metabolites found 1n the excreta (urine and
feces) accounted for 6.33X of the dose In rats and 16.21X of the dose 1n
mice; carcass-retained metabolites accounted for 20.02X of the dose 1n rats
and 5.90X of the dose In mice. The urinary metabolite patterns were quali-
tatively similar between rats and mice; trlchloroethanol and trlchloroacetlc
acid were the major metabolites.
The metabolism of hexachloroethane has been studied extensively In vitro
and appears to Involve a cytochrome P-450 catalyzed dechlorlnatlon reaction.
An early report on the dechlorlnatlon of hexachloroethane by rat liver
mlcrosomes Indicated that the dechlorlnatlng system was Induclble by pheno-
barbltal or benzpyrene pretreatment and required oxygen and NADPH (Van Dyke
and Hlneman, 1971). In this early study, the role of cytochrome P-450 In
the dechlorlnatlon reaction was not known.
Subsequent studies have shown that the dehalogenatlon reaction Is
catalyzed by cytochrome P-450, but the exact mechanism of this reaction 1s
not clear. Host Investigators have suggested that the \t± vitro dechlorlna-
tlon of hexachloroethane by cytochrome P-450 takes place by a reductive
mechanism that 1s optimized by anaerobic conditions and Inhibited by oxygen
(Town and Lelbman, 1984; Thompson et al., 1984; Salmon et al., 1985;
Nastalnczyk et al., 1982a,b). An exception Is Van Dyke (1977), who
0119d -24- 07/13/88
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suggested that dehalogenatlon catalyzed by cytochrome P-4SO can take place
by both oxldatlve and reductive mechanisms. Regardless of the mechanism U
Is generally agreed that NAOPH Is required for dechlorlnatlon of hexachloro-
ethane and the main product of this reaction Is tetrachloroethylene (Town
and Lelbman, 1984; Nastalnczyk et al., 1982a,b). Minor products resulting
from the dechlorlnatlon of hexachloroethane Include pentachloroethane and
tMchloroethylene (Town and Lelbman, 1984; Nastalnczyk et al., 1982a,b).
The kinetics of dechlorlnatlon of hexachloroethane by rat liver mlcrosomes
has been studied by Salmon et al. (1981); a K of 2.37 mM and a Vmav of
in (llaX
0.91 nmol/mln/mg of protein were reported.
5.4. EXCRETION
In a study summarized In Section 5.3., rabbits given an oral dose of
r.adlolabeled hexachloroethane (500 mg/kg) excreted ~5% of the administered
radioactivity In the urine and 14-24% of the radioactivity In the exhaled
air over a period of 3 days {Jondorf et al., 1957). Osborne-Mendel rats and
86C3F1 mice given oral doses of unlabeled hexachloroethane {125-1000 mg/kg)
1n corn oil, 5 days/week for 4 weeks followed by a single oral dose of
radlolabeled compound excreted most of the radioactivity (I.e., -70%) over a
48-hour period as unmetabollzed parent compound 1n the exhaled air (Mltoma
et al., 1985). Approximately 2% of the dose was exhaled as CO,, and
between -6 and 16% of the dose was excreted as metabolites In the feces and
urine.
5.5. SUMMARY
The extent of absorption of hexachloroethane following oral exposure may
be estimated from excretion data. At least 20-30% of an oral hexachloro-
ethane dose was absorbed In rabbits (Jondorf et al., 1957) and ~70% of an
orally administered dose was absorbed 1n B6C3F1 mice and Osborne-Mendel rats
0119d -25- 07/13/88
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(MHoma et al., 1985). Following absorption, hexachloroethane appears to be
distributed primarily to the fat tissue and kidney, while much lower levels
(I.e., -100 times lower) are found In the liver and blood (Gorzlnskl et al.,
1985). irt vivo studies have shown that hexachloroethane Is metabolized
slowly {Jondorf et al., 1957), and a large percentage of an orally adminis-
tered dose appears to be exhaled as the parent compound (MUoma et al.,
1985). Urinary metabolites Identified 1n rabbits, rats and mice Include
trlchloroethanol, trlchloroacetlc add, dlchloroethanol, dlchloroacetlc
add, monochloroacetlc add and oxalic add (Jondorf et al., 1957; Hltoma et
al., 1985). Metabolites found In the. expired air of rabbits were carbon
dioxide, tetrachloroethylene and 1,1,2,2-tetrachloroethane. In. vitro
metabolism of hexachloroethane has been studied extensively and appears to
Involve reductive dehalogenatlon catalyzed by cytochrome P-450 (Town and
Lelbman, 1984; Thompson et al., 1984; Salmon et al., 1985; Nastalnczyk et
al., 1982a.b). Elimination of hexachloroethane from the tissues (I.e., fat,
liver, kidney and blood) of rats followed apparent first-order elimination
kinetics; half-lives of elimination were between 2.3 and 2.7 days (Gorzlnskl
et al., 1985). Most of the radioactivity excreted by orally dosed rabbits,
rats and mice appeared to be unmetabollzed parent compound In the expired
air (Jondorf et al., 1957; MHoma et al., 1985).
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6. EFFECTS
6.1. SYSTEHIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SU8CHRONIC A 6-week Inhalation toxUHy study of hexa-
chloroethane was conducted with male and female Sprague-Dawley rats, male
beagle dogs and male Hartley guinea pigs (Weeks et al., 1979). The animals
were exposed to hexachloroethane concentrations of 0, 15, 48 and 260 ppm {0,
145, 464.8 and 2517 mg/ma) 6 hours/day, 5 days/week. At each level, 25
rats/sex, 4 male dogs and 10 male guinea pigs were exposed. Toxldty
parameters examined Included body weight, general appearance and behavior,
sensltlzatlon 1n guinea pigs and hematologUal and pulmonary function 1n
dogs. Half of all the animals were sacrificed and necropsled (Including
hlstopathologlcal examination) at the end of the 6-week exposure period, and
the other half were necropsled 12 weeks after termination of exposure. The
highest exposure concentration (260 ppm) produced no effect on the body
weight of dogs and no effect on any of the blood parameters measured. This
exposure level produced a reduction 1n body weight gain In guinea pigs and a
significant Increase 1n the llver-to-body weight ratio. Challenge of these
exposed guinea pigs with an Intradermal Injection of a 0.1% suspension of
hexachloroethane In saline Indicated that hexachloroethane exposure had not
produced sensltlzatlon. In rats, this level of hexachloroethane (260 ppm)
produced no exposure-related gross hlstopathologlcal changes. There was,
however, a higher Incidence and severity of mycoplasma-related lesions In
the nasal turblnates, trachea and lung when compared with nonexposed
controls. The relative weights of the kidney, spleen and testes In male
rats and the liver In female rats were significantly larger than In controls.
0119d -27- 07/13/88
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In addition, this exposure level of hexachloroethane produced a significant
decrease 1n oxygen consumption 1n rats, Indicating an alteration 1n general
metabolism. Weeks et al. (1979) concluded, however, that In the absence of
other supportive pathology this lowered basal metabolic rate did not appear
to portend a serious health problem, but may have been a normal response to
Inhalation of an upper respiratory Irritant. The lower exposure levels of
hexachloroethane (15 and 48 ppm) had no effect on body weight or organ
weights of any of the animal species examined and no gross hlstopathologlcal
changes were observed. No sensltlzatlon response was observed 1n guinea
pigs exposed at these hexachloroethane levels (15 and 48 ppm) following
challenge with a 0.1% saline suspension of hexachloroethane. No reduction
1n oxygen consumption was noted 1n rats following exposure to these
hexachloroethane levels (15 and 48 ppm). Pulmonary function testing 1n dogs
revealed that hexachloroethane did not affect compliance or resistance at
any exposure level.
6.1.1.2. CHRONIC -- Pertinent data regarding the systemic toxlclty of
hexachloroethane following chronic Inhalation exposure were not located 1n
the available literature cited 1n Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC Male and female CDF Fischer 344 rats were fed
hexachloroethane (99.4% pure) 1n the diet for 16 weeks at approximate dose
levels of 0, 1, 15 or 62 mg/kg/day (Gorzlnsky et al., 1985). The dose
levels were reported as approximate because of the correction required for
sublimation of hexachloroethane from the prepared diet. There were 10
animals/sex 1n each dose group. During the 13th week of the study,
urlnalyses and hematologlc determinations were conducted. Urlnalyses
Included measurement of specific gravity, urinary pH, glucose, protein,
0119d -28- 07/13/88
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ketones, occult blood and uroblllnogen. Hematoloqlc parameters measured
Included packed cell volume, erythrocyte count, hemoglobin concentration and
total and differential leukocyte counts. In addition, clinical biochemical
determinations were made of BUN, creatlnlne and SGPT and AP activities. At
necropsy, several organs (I.e., brain, heart, liver, kidneys and testes)
were excised and weighed and hlstopathologlc examination was conducted on
>35 different organs.
At the end of the 16-week test period, no differences were noted between
treated and control groups with respect to body weight gain, food consump-
tion, hematologlc parameters, uHnalysIs and clinical biochemical determina-
tions. At the highest dose level (62 mg/kg/day), kidney effects observed 1n
male rats consisted of significantly Increased kidney weights, gross
pathologic alterations and microscopic alterations (I.e., tubular atrophy,
degeneration, hypertrophy and dilation). Renal toxldty 1n females at this
dose level consisted of very slight renal tubular atrophy and degeneration.
At the highest dose, the absolute and relative IWer-to-body weight ratio
was Increased significantly In males; this was accompanied by a slight
swelling of the hepatocytes. Only the relative liver weight was Increased
significantly 1n females at the high dose and this was unaccompanied by
microscopic alterations. At the next highest dose of 15 mg/kg/day, Msto-
pathologlcal alterations of the kidney (I.e., tubular atrophy, degeneration,
hypertrophy and dilation) and slight swelling of hepatocytes were observed
1n males but not 1n females. No effects In male and female rats occurred at
1 mg/kg/day.
In preparation for a chronic carclnogenldty study, the NTP (1983)
performed a subchronlc gavage study In F344 rats. The rats (10/sex/group)
were given hexachloroethane 1n corn oil at doses of 0, 47, 94, 188, 375 or
750 mg/kg/day. The dosage schedule was 5 days/week for 13 weeks.
0119d -29- 07/13/88
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Individual body weights were recorded weekly throughout the study and dally
observations were made for any gross abnormalities. Necropsies were
performed on all animals killed at the end of the study and all animals
found dead during the study (except In cases of autolysls or severe
cannlballzatlon). Organ weights were determined for the brain, liver, right
kidney, thymus, heart, lungs and right testls. Extensive hlstologlcal
examination was performed on the major organs of the control rats, the
high-dose males and females and the males 1n the 375 mg/kg/day treatment
group. Hlstopathologlc evaluation was performed on the kidneys and liver of
females receiving the four lowest dosages of hexachloroethane and of males
receiving 94 and 188 mg hexachloroethane/kg/day. Only the kidneys were
examined 1n males receiving the lowest dosage of hexachloroethane. Other
parameters examined Included urlnalyses, hematology and clinical chemistry.
Body weight gain was decreased significantly at the highest dose level
In male rats. At hexachloroethane dose levels of >94 mg/kg/day, both sexes
exhibited hyperactlvHy and at the two highest dose levels (375 and 750
mg/kg/day), both sexes had convulsions. Hexachloroethane at the doses used
1n this study appeared to produce kidney effects 1n male rats, whereas liver
effects were more prevalent In female rats. A dose-related Increase 1n
renal tubular nephrosls was observed 1n all treated groups of males and
grossly granular, pale or reddened kidneys were noted In male rats at
hexachloroethane doses >94 mg/kg/day. Granular and cellular casts and
epithelial and blood cells were observed 1n the urine of all treated males.
Statistically significant Increases In relative kidney weights were seen In
males In the 375 and 750 mg/kg/day treatment groups. In addition, males In
the highest treatment group (750 mg/kg/day} showed signs of renal papillary
0119d -30- 05/27/88
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necrosis and severe hemorrhaglc necrosis of the urinary bladder. Hemato-
loglc evaluation of males revealed significantly decreased hematocrlts In
the 375 and 750 mg/kg/day treatment groups. Five of 10 males 1n this
high-dose group died during the treatment period. At the two highest doses
of hexachloroethane (375 and 750 mg/kg/day), hepatic lesions consisting of
focal hepatocellular necrosis were observed 1n female rats. There were only
minimal tubular changes In the kidney at the highest dose level 1n females.
Consistent with the minimal tubular changes observed In females, urlnalyses
revealed no significant differences between control and treated animals. At
these dose levels of hexachloroethane 1n females, there was a statistically
significant Increase In the relative weights of the kidneys and liver, and
the liver had a granular appearance. Hematologlc evaluation revealed no
significant differences between control and hexachloroethane-treated
females. Two of 10 females In the highest dose group died during treatment.
Serum enzyme determinations appeared to reveal changes consistent with renal
and hepatic damage 1n both sexes; wide variations 1n the Individual serum
enzyme levels may, however, have accounted for the lack of statistical
significance associated with these changes.
6.1.2.2. CHRONIC A chronic oral carclnogenldty study of hexa-
chloroethane was conducted with Osborne-Mendel rats and B6C3F1 mice by NCI
(1978). In this study, a number of toxlclty parameters were also Investi-
gated and are summarized In this section. Over the course of the 78-week
study, rats (50/sex/group) were given TWA doses of hexachloroethane (>98%
pure) 1n corn oil of 212 and 423 mg/kg/day. There was also a control group
(20/sex) that received no treatment and a vehicle-treated control group
(20/sex). In this study (NCI, 1978), mice were administered two dose levels
of hexachloroethane by gavage; the TWA doses over the 78-week period were
0119d -31- 07/13/88
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590 and 1179 mg/kg/day. The doses were administered 5 days/week for both
mice and rats. Further Information on the hexachloroethane dosing schedule
1n rats and mice Is provided 1n Section 6.2.2. Information on body weights,
appearance, behavior and signs of toxic effects were recorded at weekly time
Intervals. All animals were necropsled regardless of whether they died,
were killed during the study or were sacrificed at the end of the study. An
extensive gross and microscopic hlstopathologlc examination was made of a
number of tissues and organs.
A number of toxic signs were noted In hexachloroethane-treated rats.
Including reduction In body weight gal.n and several clinical signs (I.e.,
hunched appearance, reddened, squinted or lacMmatlng eyes, abdominal urine
stains). The Investigators suggested that the reduction In body weight gain
may have been due to Increased mortality In the treatment groups, which In
turn may have resulted In wide variations 1n the body weights as the size of
the group diminished. The Incidence of the clinical signs also diminished
during the second year of treatment and behavior and appearance became
comparable between treated and control animals. Survival 1n rats (both male
and female) did, however, appear to be affected adversely by hexachloro-
ethane treatment, and there was a significant association between Increased
dosage and accelerated mortality. In addition to reduced survival,
hexachloroethane treatment produced a significant Increase In toxic tubular
nephropathy In both male and female rats. The Incidence of this lesion
Increased with dose In both males and females; specific Incidences were 45
and 18% In low-dose males and females, respectively, and 66 and 59% In
high-dose males and females, respectively (control groups had a OX Incidence
of tubular nephropathy). This tubular nephropathy was characterized by
degeneration, necrosis and the presence of large hyperchromatlc regenerative
epithelial cells.
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In mice there was no difference between hexachloroethane-treated and
control groups with respect to body weight gain, and there appeared to be no
significant difference between treated and control groups with respect to
physical appearance or behavior. Survival 1n mice also appeared to be
unaffected by hexachloroethane treatment; there was no significant positive
association between hexachloroethane dose and mortality. There was a high
Incidence {I.e., >92% Incidence) of toxic nephropathy 1n all hexachloro-
ethane treatment groups (both male and female); control groups had a 0%
Incidence. The nephropathy was characterized by degeneration of the convo-
luted tubule epithelium, Infiltration _of Inflammatory cells, flbrosls and
calcium disposition.
6.1.3. Other Relevant Information. Hale New Zealand White rabbits
(5/group) were given dally oral doses of hexachloroethane (0, 100, 320 or
1000 mg/kg) suspended 1n 5% aqueous methylcellulose for 12 days {Weeks et
al., 1979). Blood samples were taken on days 1, 4, 8 and 12 of treatment
and on day 4 following termination of dosing. The parameters measured
consisted of SGOT, SGPT, BUN, AP, bH1rub1n, total protein, potassium and
sodium. On day 4 following the last dose, the rabbits were necropsled and
-15 tissues and organs were examined microscopically for lesions. In
addition, body weights were recorded dally and at necropsy the lungs, liver,
kidneys, spleen and testes were weighed. At the highest dose level (1000
mg/kg), there was a significant reduction 1n body weight and Increases In
the relative weights of the kidneys and liver. The 320 mg/kg dose level
also produced a significant reduction 1n body weight but no changes In
relative organ weights.
At the two highest dose levels (320 and 1000 mg/kg), liver degeneration
(I.e., fatty and ballooning degeneration) and necrosis were observed. Liver
-------
lesions were more severe 1n the higher dose group than In the 320 mg/kg
group. Also, kidney effects were observed In the two highest dose groups.
These Included a toxic tubular nephrosls of the convoluted tubules In the
cortlcomedullary region of the kidney (nondose-related) and a tubular
nephrocaldnosls of a minimal degree. Blood glucose and potassium levels
were decreased significantly In the 1000 and 320 mg/kg dosage levels. There
were no changes In body and organ weights, liver effects, kidney effects or
changes In blood chemistry In the control group or 1n the 100 mg hexachloro-
ethane/kg dosage group.
The effects of a single oral dose of hexachloroethane (2600 ^mol/lOO g
bw) on liver parenchymal cells of male Charles River rats were Investigated
by Reynolds and Yee (1968). The rats were killed 1, 8 and 24 hours after
dosing and the left lateral lobe of the liver was removed and sliced for
hlstochemlcal and morphologic studies. Hexachloroethane did not affect
either glucose-6-phosphatase or mldzonal calcium staining 1 hour after
dosing and did not produce centrHobular necrosis by 24 hours. Slight
centrllobular suppression of glucose-6-phosphatase was detected at 24 hours
after dosing.
Valnlo et al. (1976) measured the effects of a single dose of hexa-
chloroethane on drug metabolizing enzymes 1n the rat liver. Hale Hlstar
rats were given a single oral dose of hexachloroethane (~95% pure) In olive
oil 24 hours before sacrifice. At sacrifice, mlcrosomes were prepared from
the livers and the activities of several drug metabolizing enzymes (I.e.,
NADPH-cytochrome C reductase, epoxlde hydratase, 3,4-benzpyrene hydroxylase
and p-n1troan1sole 0-demethylase) were measured. In addition, the
cytochrome P-450 content of the liver was also measured. Hexachloroethane
0119d
-34-
05/27/88
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treatment significantly decreased the activities of 3,4-benzpyrene hydroxyl-
ase and p-nltroanlsole 0-demethylase. The cytochrome P-450 content of the
liver was also decreased significantly following hexachloroethane treatment.
Hexachloroethane at concentrations of -0.1-1.0 umol/mg protein
Inhibited the oxidation of glutamate, malate and succlnate by Isolated rat
liver mitochondria (Takano and H1yazak1f 1982). The oxidation of NADH by
sonicated submltochondrlal particles was also Inhibited by hexachloroethane.
Other acute hexachloroethane toxlclty Information (I.e., LD5Q values)
1s summarized In Table 6-1.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carc1nogen1c1ty of
hexachloroethane following Inhalation exposure were not located 1n the
available literature cited 1n Appendix A.
6.2.2. Oral. An oral cardnogenlclty study of hexachloroethane 1n
Osborne-Mendel rats and B6C3F1 mice was conducted by the National Cancer
Institute (NCI, 1978; Helsburger, 1977). Rats (50/sex/group) were given a
low dose (2SO mg/kg bw/day) and a high dose (500 mg/kg bw/day) of hexa-
chloroethane (>98X purity) 1n corn oil. These doses were administered 5
days/week for the first 22 weeks of treatment. Beginning with the 23rd week
of treatment, the rats received no treatment for 1 week followed by 4 weeks
of treatment; this cyclical regimen of treatment continued for 78 weeks,
resulting 1n TWA doses of hexachloroethane for the low-dose and the
high-dose groups of 212 and 423 mg/kg/day, 5 days/week, respectively. The
reason for the changes In the dosing regimen was not reported. Following
treatment, the animals were observed for an additional 33 or 34 weeks. In
addition to the two hexachloroethane treatment groups, there were two
control groups of rats. One group (20/sex) received no treatment, whereas
the other group (20/sex) received the corn oil vehicle.
0119d -35- 05/27/88
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The mice In this study (NCI, 1978} also received a low and a high dose
of hexachloroethane. The low-dose group (50/sex) received 500 mg hexa-
chloroethane/kg/day for the first 8 weeks of the study and 600 mg/kg/day for
the last 70 weeks of the study. The high-dose group (50/sex) received 1000
mg hexachloroethane/kg/day for the first 8 weeks and 1200 mg/kg/day for the
last 70 weeks. The reasons for the Increase In dose were not reported. In
contrast to rats, the doses were given to mice 5 days/week continuously for
78 weeks. Given this dosing schedule, the TWA dosages for hexachloroethane
1n mice were 590 and 1179 mg/kg/day, 5 days/week, for the low-dose and
high-dose groups, respectively. Following dosing, the mice were observed
for an additional 12 or 13 weeks. In addition to the two treatment groups,
there were also two control groups of mice. One group (20/sex) was
untreated whereas the other group (20/sex) received the corn oil vehicle.
Each animal was necropsled regardless of whether It died during the
experiment, was killed when moribund or was sacrificed at the end of the
bloassay. H1stopatholog1c examination consisted of gross and microscopic
examination of major tissues organs and gross lesions.
Hexachloroethane-treated rats had a higher total number of tumors than
control animals and these Included Interstitial-cell tumors of the testes
and renal tubular-cell adenomas In male rats and pituitary chromophobe
adenomas In female rats. The Investigators concluded, however, that each of
these tumor types have occurred as a spontaneous lesion In Osborne-Mendel
rats and that hexachloroethane Is not carcinogenic 1n the rat.
In hexachloroethane-treated mice, there was a statistically significant
Increase In the Incidence of hepatocellular carcinomas 1n both sexes (Table
6-2). Because of poor survival In both control groups, a pooled vehicle
control group was also used for comparison of tumor Incidences; this control
0119d
-37-
05/27/88
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TABLE 6-2
Incidence of Tumors In B6C3F1 Mice Given Oral Doses of Hexachloroethane
(>98%) In Corn 011 for 78 Weeks3
Sex
Dose
(mg/kg/day)
Duration
of Study Tumor Type
(weeks)
Tumor Incidences
(p value}
500 for 8 weeks,
600 for 70 weeks,
5 days/week
1000 for 8 weeks,
1200 for 70 weeks,
5 days/week
0
91
hepatocellular
carcinoma
91
91
91
hepatocellular
carcinoma
hepatocellular
carcinoma
hepatocellular
carcinoma
2/60 pooled vehicle
controls (p<0.001)b
2/20 matched vehicle
controls (NS)b
20/50
(p<0.001)c
15/49
(p<0.001)c
6/60 pooled vehicle
control (p<0.001)b
3/20 matched vehicle
control (p<0.001)b
H
500 for 8 weeks, 91
600 for 70 weeks,
5 days/week
1000 for 8 weeks 91
1200 for 70 weeks
5 days/week
hepatocellular
carcinoma
hepatocellular
carcinoma
15/50
(p=0.008)c
31/49
(p<0.001)c
(p<0.001)d
0119d
-38-
05/27/88
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TABLE 6-2 (cont.)
Strength of study:
Weakness of study:
QUALITY OF EVIDENCE
The compound was administered to both sexes at two dose
levels. Adequate number of animals per group; natural
route of exposure; adequate duration of exposure;
comprehensive histology and appropriate statistical
analysis.
Low survival of males In vehicle-treated and untreated
control groups and 1n low dose group. In addition, the
dose of the compound was changed after 8 weeks.
Overall adequacy: Adequate
aSource: NCI, 1978
kCochran-Armltage test; NS = not significant
cF1sher exact test for comparison of treated group with pooled vehicle
control group
dF1sher exact test for comparison of treated group with matched vehicle
control group
0119d
-39-
05/27/88
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group comprised mice used for controls 1n studies Involving other chlori-
nated hydrocarbons. NCI (1978) concluded that, under the conditions of this
bloassay, hexachloroethane was carcinogenic In male and female B6C3F1 mice
and caused hepatocellular carcinomas.
Another chronic carclnogenldty and toxlclty study using oral adminis-
tration of hexachloroethane In F344 rats has been performed and was
currently reviewed on October 3, 1988 (NTP, 1988). Some of the results of
this study were also reported In an abstract (Russfleld et a!., 1987).
Hexachloroethane In corn oil was administered by gavage to groups of male
rats (50/group) at doses of 0, 10 and 20 mg/kg and to groups of female rats
(50/group) at doses of 0, 80 and 160 mg/kg. Renal tubular neoplasms (three
carcinomas, three adenomas and one oncocytoma) were seen In high-dose males,
but no renal tumors were observed In treated females. The Investigators
concluded that hexachloroethane Induced a significant (p=0.026) number of
renal neoplasms 1n treated males as compared with control males.
6.2.3. Other Relevant Information. In an jji vivo mechanism of carcino-
genic activity study, Lattanzl et al. (1988) reported that covalent binding
Index of hexachloroethane to rat and mouse liver DNA 1s comparable to that
of compounds classified as weak-moderate Initiators and In approximately the
same order of magnitude as those of other halo compounds such as l,2-d1-
chloroethane. ln_ vitro study conducted by Lattanzl et al. (1988) demon-
strated that hexachloroethane was bloactlvated by mUrosomal enzymes
obtained for murlne liver and kidney and, to a greater extent by cytosollc
fractions for all assayed organs. The authors further commented that
hexachloroethane was less reactive than 1,1,2,2-tetrachloroethane, which 1s
more toxic and oncogenlc. Thus 1t was suggested that because of covalent
binding In vivo and In vitro hexachloroethane may be a potent chemical to
cause carclnogenesls In the mouse liver.
0119d -40- 01/24/89
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6.3. HUTAGENICITY
Hexachloroethane has been found not to be mutagenlc In bacteria and
yeast both with and without metabolic activation {Table 6-3) (Haworth et
al.. 1983; Weeks et al., 1979). Also, hexachloroethane did not produce cell
transformation 1n BALB/C-3T3 cells {Tu et al., 1985) and did not produce
chromosome aberrations 1n CHO cells (Galloway et al., 1987). Hexachloro-
ethane did, however, produce SCE In CHO cells 1n the presence of metabolic
activation, but only at doses that Induced cell cycle delay (Galloway et
al., 1987).
6.4. TERATOGENICITY
Pregnant Sprague-Dawley rats were exposed to hexachloroethane either by
Inhalation or by gavage from days 6-16 of gestation (Weeks et al., 1979).
In the gavage study, groups of 22 pregnant rats were given dally oral
dosages of either hexachloroethane {50, 100 or 500 mg/kg}, the corn oil
vehicle (5 ml/kg) or. In a positive control group, aspirin (250 mg/kg).
In the Inhalation study, three groups of 22 pregnant rats were exposed to
vapors of hexachloroethane 6 hours/day at concentrations of 15, 48 and 260
ppm (145.2, 464.8 or 2517.5 mg/m3). All rats were weighed dally and
observed for clinical signs of toxldty. On day 20 of gestatton, all
pregnant rats were sacrificed and the reproductive tracts were exposed by
laparotomy. The number of corpora lutea, Implantation sites and resorptlon
sites were recorded and the fetuses were examined for visceral abnormalities
and skeletal malformations. In addition, complete necropsy and hlstopatho-
loglcal examinations were performed on all of the sacrificed rats. Body
weight gain was reduced significantly In rats given oral doses of 500 mg
hexachloroethane/kg and In rats exposed by Inhalation to 48 and 260 ppm of
the compound. There were no teratogenlc effects attributable to hexachloro-
ethane exposure 1n any of the exposure groups. There was a significantly
0119d -41- 10/21/88
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reduced number of live fetuses/dam 1n the 500 mg hexachloroethane/kg oral
treatment group; this group also showed higher fetal resorptlon rates.
Fetuses from aspirin-treated positive controls responded appropriately.
This study reported statistical significance of fetotoxlc effects of
hexachloroethane exposure but actual percentage or number of Incidence were
not reported.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects following exposure
to hexachloroethane were not located 1n the available literature cited 1n
Appendix A.
6.6. SUMMARY
The Hver and kidney appear to be target organs of toxlclty following
hexachloroethane exposure. Subchronlc oral toxldty studies 1n Fischer 344
rats Indicated that hexachloroethane exposure at doses greater than or equal
to -15 mg/kg/day produces both liver and kidney effects (Gorzlnskl et a!.,
1985; NTP, 1983); kidney effects (Including tubular atrophy and degenera-
tion) appeared to be more common 1n male rats, whereas liver effects
(Including Increased weight and focal hepatocellular necrosis) appeared to
be more common In females. Chronic oral exposure to hexachloroethane
produced toxic tubular nephropathy In both male and female rats at TWA doses
of >212 mg/kg/day and In male and female mice at TWA doses of >590 mg/kg/day
(NCI, 1978). Subchronlc Inhalation exposure to 260 ppm (2517 mg/m3) hexa-
chloroethane for 6 weeks caused reduced body weight gain and a significant
Increase In the liver-to-body weight ratio In guinea pigs (Weeks et al.,
1979). In rats, 260 ppm hexachloroethane produced significant Increases In
the relative weights of the kidney, spleen and testes In male rats and the
liver In female rats. The acute oral toxldty of hexachloroethane, as
0119d -43- 10/21/88
-------
measured, by oral ID values (see Table 6-1), appears to be fairly low,
with values ranging from ~300Q to >7000 mg/kg. In a long-term {I.e.,
78-week) carclnogenlclty study, hexachloroethane was carcinogenic In mice
but not In rats (NCI, 1978). Hexachloroethane exposure at TWA doses of >590
mg/kg/day produced hepatocellular carcinomas 1n mice. Another chronic oral
carclnogenlclty study Indicated that hexachloroethane may produce renal
neoplasms In rats, but this study has not been subjected to peer review
(NTP, 1988; Russfleld et al., 1987). Hexachloroethane was not mutagenlc to
bacteria and yeast (Haworth et al., 1983; Weeks et al., 1979) and did not
produce cell transformation In BALB/C-3T3 cells (Tu et al., 1985) or chromo-
some aberration 1n CHO cells (Galloway et al., 1987). Hexachloroethane at
an oral dose of 500 mg/kg/day caused decreased body weight of dams and fetal
mortality but was not teratogenlc \n rats {Weeks et al., 1979). Inhalation
exposure to 48 and 260 ppm, 6 hours/day, caused decreased body weight of
dams but had no effect on fetuses (Weeks et al.t 1979). Data regarding
reproductive effects following hexachloroethane exposure were not located In
the available literature.
0119d -44- 10/21/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
The ACGIH {1986, 1987} has recommended a TLV for hexachloroethane of 10
ppm (96.8 mg/m3), yhlch Is higher than the previously recommended TLV of 1
ppm. The Increase was recommended based largely on the study by Weeks et
al. (1979), In which hexachloroethane had no effect on rats, guinea pigs and
dogs at Inhalation exposure levels of 15 and 48 ppm (145 and 465 mg/m3}.
Deletion of the skin notation has also been recommended (ACGIH, 1986}
because of the low dermal toxldty reported by Weeks et al. (1979). The
OSHA PEL for hexachloroethane 1s 1 ppm (9.7 mg/m3) (OSHA, 1985). An oral
RfD of 1xl(T3 mg/kg/day has been verified (U.S. EPA, 1988b) and oral and
Inhalation q *s of 1.4xlO~2 (mg/kg/day)'1 have also been verified for
hexachloroethane (U.S. EPA, 1988c).
7.2. AQUATIC
Pertinent guidelines and standards regarding the protection of aquatic
life from the effects of hexachloroethane were not located 1n the available
literature cited 1n Appendix A.
0119d -45- 05/27/88
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8. RISK ASSESSNENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlcHy of
hexachloroethane following Inhalation exposure were not located In the
available literature cited In Appendix A.
8.1.2. Oral. The NCI (1978) conducted a long-term (78-week) cardnogen-
1c1ty study of hexachloroethane with Osborne-Mendel rats and B6C3F1 mice.
Rats (50/sex/group) administered hexachloroethane orally at TWA doses of 212
and 423 mg/kg/day, 5 days/week had only a higher Incidence of total tumors
(I.e., Interstitial cell tumors of the-testes, renal tubular-cell adenomas
and pituitary chromophobe adenomas}; however, these were considered
spontaneous lesions In this strain of rat and unrelated to hexachloroethane
exposure. B6C3F1 mice (50/sex/group) also received hexachloroethane orally
for 78 weeks; the TWA doses were 590 and 1179 mg/kg/day, 5 days/week. There
was a dose-related Increased Incidence of hepatocellular carcinomas In male
mice (I.e., 10 and 15% In two control groups, 30% 1n the low-dose group and
63% In the high-dose group) and an Increased Incidence of hepatocellular
carcinomas In females which was not dose-related (I.e., 3 and 10% In two
control groups, 40% In the low-dose group and 31% 1n the high-dose group).
NCI (1978) concluded that hexachloroethane was carcinogenic In mice but not
In rats.
Another chronic (2-year) oral carclnogenlclty study using F344 rats
(NTP, 1988) Indicated that hexachloroethane at a dose of 20 mg/kg Induced
renal tubular neoplasms In males but not females. A lower dose male group,
10 mg/kg/day, showed no response. This study has been recently peer
reviewed and 1s also reported earlier as an abstract only (Russfleld et al.,
1987).
0119d -46- 01/24/89
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8.1.3. Other Routes. Pertinent data regarding the cardnogenldty of
hexachloroethane following administration of the compound by routes other
than the oral routes were not located In the available literature cited 1n
Appendix A.
8.1.4. Weight of Evidence. Hexachloroethane Induced statistically
significant Incidences of hepatocellular carcinomas In both sexes of mice
and renal neoplasm 1n male rats. The carcinogenic evidence In experimental
animals Is considered to be sufficient evidence of carc1nogen1c1ty (U.S.
EPA, 1986b). Supporting evidence Includes \n vivo covalent binding data for
rats and mouse liver DNA showing some Initiating potential. In. vitro data
correlates with jjn v1vo data In which hexachloroethane was bloactlvated by
mlcrosomal enzymes for liver and kidney and to a greater extent by cytosollc
fractions for all organs. From a metabolism perspective, trlchloroacetlc
add, dlchloroacetlc add, tetrachloroethylene and 1,1,2,2-tetrachloroethane
were Identified as metabolites In experimental animals. All four of these
compounds are hepatocardnogens In the mouse. No human cancer data are
available 1n the published literature. The overall carcinogenic evidence
for hexachloroethane could be placed In EPA Group 82, probable human
carcinogen.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION Pertinent data regarding the cardnogenldty
of hexachloroethane following Inhalation exposure were not located 1n the
available literature cited In Appendix A. CRAVE (U.S. EPA, 1988c) has
adopted an Inhalation q^ of 1.4xlO~2 (mg/kg/day)"1 or 4.0xlO~*
(wg/m3) based on an oral hexachloroethane cardnogenldty study using
B6C3F1 mice (NCI, 1978). This q^ 1s adopted In this document as a
measure of the cardnogenldty of hexachloroethane following Inhalation
exposure. Concentrations of hexachloroethane In air associated with risk
0119d -47- 01/24/89
-------
levels of 10 s, 10~* and 1(T7 are 3, 0.3 and 0.03 wg/m", respec-
tively (U.S. EPA, 1988c).
8.1.5.2. ORAL The long-term studies available that assess the
carclnogenlclty of hexachloroethane Indicate that exposure to the compound
Is associated with an Increased Incidence of hepatocellular carcinomas In
male and female 86C3F1 mice (NCI, 1978} and renal neoplasms 1n male rats
(NTP, 1988). Based on data from male mice, CRAVE has verified an oral q *
of 1.4xlO"2 (mg/kg/day)"1 (U.S. EPA, 1988c). In another chronic
carclnogenldty study (NTP, 1988), F344 male rats gavaged with 20 mg/kg/day
hexachloroethane showed significantly higher Incidence of renal neoplasms.
Female rats In this study did not show any renal tumors. Based on this
data, a q^ of 9.6xlO~2 (mg/kg/day)'1 has been calculated (Table 8-1);
this cancer potency Is higher than that derived for the NCI (1978) mice
data. However, the mechanism of kidney tumorlgenesls In aging F344 male
rats Is linked to alpha-2-mlcroglobulln accumulation. Since this mechanism
of tumorlgenesls 1s not universally accepted as an appropriate model for
human carclnogenesls, the q^ of 1.4xlO~2 (mg/kg/day)'1 for the NCI
(1978) study Is recommended as a measure of carclnogenldty of hexachloro-
ethane following oral exposure. Concentrations of hexachloroethane In
drinking water associated with risk levels of 10~s, 10~e and 10~7 are
30, 3 and 0.3 vq/l, respectively (U.S. EPA, 1988c).
8.2. SYSTEHIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Weeks et al.
(1979) exposed male and female Sprague-Dawley rats, male beagle dogs and
male Hartley guinea pigs to hexachloroethane by Inhalation at concentrations
of 0, 15, 48 and 260 ppm (0, 145, 465 and 2517 mg/m3}, 6 hours/day. 5
days/week for 6 weeks. The 260 ppm exposure level produced a reduction In
0119d -48- 08/03/89
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TABLE 8-1
Cancer Potency Derivation
Compound: Hexachloroethane
Reference: NTP, 1988
Species, Strain, Sex: F344 male rat
Body weight: 0.46 kg (estimated for graph)
Length of exposure (1e): 721 days
Length of experiment (Le): 721 days
Llfespan of animal (L): 730 days
Tumor site and type: kidney adenomas and carcinomas
Route, Vehicle: gavage, corn oil
Experimental Dose
(mg/kg/day. 5 days/week)
Transformed Dose
(mg/kg/day)
Incidence
No. responding/No, tested
0 0
10 7.14
20 14,3
1/38
2/36
7/37
Unajusted q-|* for study: 0.0172783 (mg/kg/day)~l
Human q^* = 9.57437xlO~2 (mg/kg/day)'1
10"5 risk level: [1.04x10"* mg/kg/day] or 7.29xlO~3 mg/day for 70 kg
man
0119d
.49-
08/03/89
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body weight gain and a significant Increase 1n the liver-to-body weight
ratio In guinea pigs. At 260 ppm, a significant Increase 1n the relative
weights of the kidney, spleen and testes was observed 1n male rats and a
significant Increase In liver weight was observed In female rats. No effect
related to hexachloroethane exposure was observed In dogs at 260 ppm, and
the two lower exposure levels (15 and 48 ppm) had no effect on any of the
animal species tested.
A long-term oral cardnogenldty study by NCI (1978) Indicated that
hexachloroethane 1s carcinogenic In male and female mice and Is associated
with an Increased Incidence of hepatocellular carcinomas. It Is, therefore.
Inappropriate for the purposes of this document to derive a subchronlc
Inhalation RfD for hexachloroethane.
8.2.1.2. CHRONIC EXPOSURES Pertinent data regarding the systemic
toxlclty of hexachloroethane following chronic Inhalation exposure were not
located 1n the available literature cited In Appendix A.
As stated In Section 8.2.1.1., hexachloroethane was carcinogenic In male
and female mice {NCI, 1978); therefore, H Is Inappropriate for the purposes
of this document to derive a chronic Inhalation RfO for hexachloroethane.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Two subchronlc
oral toxlclty studies of hexachloroethane, both 1n Fischer 344 rats, were
available. Gorzlnskl et al. (1985) fed rats (10/sex/group) hexachloroethane
1n the diet at approximate dose levels of 0, 1, 15 or 62 mg/kg/day for 16
weeks. The highest dose level caused Increased liver and kidney weights,
pathological alterations of the kidney and swelling of hepatocytes In males.
In females, 62 mg/kg/day was associated with slight renal tubular atrophy
and degeneration and an Increase In relative liver weight. The next highest
0119d -50- 08/03/89
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dose (15 mg/kg/day) was associated with pathological alterations of the
kidney and slight swelling of hepatocytes In males. The dose of 1 mg
hexachloroethane/kg/day proved to be a NOEL In both male and female rats.
In another subchronlc oral toxlclty study conducted by NTP (1983), Fischer
344 rats (10/sex/group) were given hexachloroethane at dose levels of 0, 47,
94, 188, 375 and 750 mg/kg/day, 5 days/week for 13 weeks. All hexachloro-
ethane-treated males showed signs of renal tubular nephrosls. Granular and
cellular casts and epithelial cells and blood cells were also observed In
the urine of all treated males. In males, Increased relative kidney weights
were observed at 375 and 750 mg/kg/day and renal papillary necrosis and
hemorrhagk necrosis of the urinary bladder were observed at 750 mg/kg/day.
Exposure of male rats to 750 mg/kg/day was also associated with death and a
depression In body weight gain. In contrast, females exposed to hexachloro-
ethane tended to manifest predominantly liver effects; hepatocellular necro-
sis, granular appearance of the liver and Increased relative liver weight
occurred at the highest two dose levels. Hales and females exposed to
hexachloroethane at dose levels of >94 mg/kg/day were hyperactive, and
convulsions were observed In both sexes at 375 and 750 mg/kg/day.
As stated in Section 8.2.1., hexachloroethane was demonstrated to be
carcinogenic following oral exposure 1n mice (NCI, 1978); therefore, It Is
Inappropriate for the purposes of this document to derive a subchronlc oral
RfD.
8.2.2.2. CHRONIC EXPOSURES A long-term carclnogenlclty study
conducted by NCI (1978) reported systemic toxic effects of chronic oral
exposure to hexachloroethane. Osborne-Hendel rats (50/sex/group) were given
250 and 500 mg/kg/day hexachloroethane In corn oil by gavage, 5 days/week on
a cyclical treatment regimen for 78 weeks. Reduced survival and tubular
0119d -51- 08/03/89
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nephropdthy wore associated with both dose levels. B6C3F1 mice (50/sex/
group) were also treated with two dose levels of hexachloroethane. The
low-dose group was given 500 mg/kg/day for 8 weeks and 600 mg/kg/day for 70
weeks. The high-dose group was given 1000 mg/kg/day for 8 weeks and 1200
mg/kg/day for 70 weeks. Renal tubular nephropathy was observed In both
treatment groups.
Although hexachloroethane was carcinogenic In mice In this study (NCI,
1978), an RfD for chronic oral exposure to hexachloroethane of 0.001
mg/kg/day has been verified (U.S. EPA, 1988b). The RfO was based on the
study by Gorz1nsk1 et al. (1985) In which male Fischer 344 rats exposed to
hexachloroethane In the diet at an experimental dose of 15 mg/kg/day for 16
weeks developed atrophy and degeneration of the renal tubules, and a dietary
exposure level of 1 mg/kg/day proved to be the NOEL. Dividing this NOEL by
an uncertainty factor of 1000 (10 to account for Interspecles extrapolation,
10 to protect sensitive human populations and 10 for the use of a subchronlc
study) resulted In a chronic oral RfO of 0.001 mg/kg/day.
0119d -52- 08/03/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The systemic toxIcUy of hexachloroethane was discussed In Chapter 6 and
dose-response data are summarized In Table 9-1.
The most severe response listed In Table 9-1 that Is associated with
exposure to hexachloroethane Is a reduction In survival. Reduced survival
was noted In rats 1n subchronlc (NTP, 1983) and chronic oral studies {NCI,
1978), and 1n guinea pigs In a subchronlc Inhalation study (Weeks et al.,
1979). The lowest equivalent human dose associated with reduced survival
was 26.4 mg/kg/day In female rats In the NCI (1978) study. Multiplying this
dose of 26.4 mg/kg/day by a reference human body weight of 70 kg (U.S. EPA,
1986c) gives an HEO of 1848 mg/day, which Is associated with an RV of
1.0. Reduced survival Is associated with an RV of 10, and multiplication
of the RVe by the RVd results 1n a CS of 10. A CS of 10 Is associated
with an RQ of 1000 (Table 9-2).
The second most severe effect associated with exposure to hexachloro-
ethane was fetotoxlclty, which occurred at a equivalent human dose of 85.5
mg/kg/day 1n an oral teratogenldty study by Weeks et al. (1979). Because
fetotoxlclty occurred at a higher equivalent human dose than the equivalent
human dose associated with reduced survival In the NCI (1978) study (I.e.,
24.6 mg/kg/day), a CS for fetotoxlclty was not derived because 1t would be
lower than the CS associated with death.
The third most severe effect associated with hexachloroethane exposure
was renal tubular nephrosls, which occurred at an equivalent human dose of
5.0 mg/kg/day In male rats In the NTP (1983) study. Although this was a
subchronlc study (NTP, 1983), this dose was not divided by an uncertainty
factor of 10 to approximate chronic exposure because renal tubular nephro-
pathy was also observed at a higher dose In the NCI (1978) chronic study.
0119d -53- 08/03/89
-------
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The equivalent human dose of 5 mg/kg/day 1s multiplied by the reference
human body weight of 70 kg to give an MED of 350 mg/day, which 1s associated
with an RV^ of 1.7. The effect of renal tubular nephrosls Is associated
with an RV of 7 because the presence of cellular and granular casts and
blood and epithelial cells 1n the urine Indicate a detectable decrement 1n
kidney function. Multiplication of the RVe by the RV. yields a CS of
12, which Is associated with an RQ of 1000 (see Table 9-2).
The remainder of the effects associated with hexachloroethane exposure
are listed In Table 9-1 and are of lesser severity than the effect of renal
tubular nephrosls associated with kidney dysfunction observed In the NTP
(1983) study. All of these effects, except one, occurred at equivalent
human doses that are higher than the dose associated with renal tubular
nephrosls; CS values were therefore not calculated for these less severe
effects. The exception 1s pathological alteration of the kidney (I.e.,
tubular atrophy, degeneration, hypertrophy and dilation) which occurred In a
subchronlc oral study (Gorzlnskl et al., 1985) at an equivalent human dose
of 2.4 mg/kg/day. This dose Is not divided by an uncertainty factor of 10
to approximate chronic exposure because data on renal effects of chronic
oral exposure are available. Multiplication of the human equivalent dose by
the reference human body weight (70 kg) yields an MEO of 168 mg/day, which
1s associated with an RV of 2.2. The pathological alterations 1n the
kidney observed In this study are associated with an RVg of 3, and
multiplication of this RV by the RV gives a CS of 7.0. This CS Is
v Q
associated with an RQ of 1000 (see Table 9-2).
The study chosen for determining an RQ for hexachloroethane Is the NTP
(1983) subchronlc oral study In rats In which renal tubular nephrosls,
associated with evidence of kidney dysfunction, occurred In males.
0119d -58- 08/03/89
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The results from this study yielded the highest CS (12) associated with
exposure to hexachloroethane. This CS warrants an RQ of 1000 (Table 9-3).
In a previous determination of the RQ by U.S. EPA (1983), the reduced
survival In guinea pigs exposed by Inhalation In the study by Weeks et al.
(1979) was used as the basis for the RQ of 1000. The reduced survival In
the NCI (1978) study was not considered and the subchronlc oral studies by
NTP (1983) and Gorzlnskl et al. (1985) were not available.
9.2. BASED ON CARCINOGENICITY
The only cardnogenlcHy study suitable for derivation of an RQ for
hexachloroethane based on cardnogenldty was NCI (1978) (see Section 6.2.2.
and Table 6-2). 86C3F1 mice and Osborrve-Mendel rats were given hexachloro-
ethane 1n corn oil at a high and low dose level (50/sex/group) for 78 weeks.
The TWA doses In mice were 590 and 1179 mg/kg/day and In rats the corre-
sponding doses were 212 and 423 mg/kg/day. A carcinogenic response attrib-
utable to hexachloroethane exposure was not observed In the NCI (1978) rat
study. In mice, hexachloroethane exposure produced a carcinogenic response
that consisted of a significantly Increased Incidence of hepatocellular
carcinomas In both males and females at both the high and low dose levels
(see Table 6-2).
Another long-term hexachloroethane cardnogenldty study was completed
and Indicates that hexachloroethane exposure Is related to an Increased
Incidence In renal neoplasms In male rats (NTP, 1988). However, the
evidence of renal neoplasms In rats Is weak, and because the renal
tumorlgenesls In F344 male rats Is linked to accumulation of
alpha-2-mlcroglobulln (not seen In humans), this tumor Incidence data was
not considered further In the derivation of an RQ based on cardnogenldty
for hexachloroethane.
0119d -59- 08/03/89
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TABLE 9-3
Hexachloroethane
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 350 mg/day
Effect: renal tubular nephrosls associated with evidence
of kidney dysfunction
Reference: NTP, 1983
RVd: 1.7
RVe: 7
Composite Score: 12
RQ: 1000
^Equivalent human dose
0119d -60- 08/03/89
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The significantly Increased Incidence of hepatocellular carcinomas In
mice given oral doses of hexachloroethane (NCI, 1978), and some evidence of
renal neoplasm Incidence In male rats (NTP, 1988) constitute sufficient
evidence for the carclnogenlclty of hexachloroethane 1n animals (U.S. EPA,
1986b). The evidence regarding metabolism Indicates that dlchloroacetlc
add, tetrachloroethylene and 1,1,2,2-tetrachloroethane are produced; these
compounds have been shown to be carcinogenic In mouse liver. Because there
1s adequate evidence for hexachloroethane carclnogenlclty In animals and no
data available on the effects of hexa- chlorethane exposure In humans
hexachloroethane Is assigned to EPA Group B2, probable human carcinogen
(U.S. EPA, 1986bt 1987b, 1988c).
The Increased Incidence of hepatocellular carcinomas In male mice
observed in the NCI (1978) bloassay was used previously to determine a q *
for hexachloroethane (see Section 8.1.5.2.). The derivation of this q *
1s associated with a 1/ED10 of 3.9xlO~3 (mg/kg/day)'1 (Table 9-4).
Multiplication of the ^/ED-m by the cube root of the ratio of the
reference human body weight (70 kg) to the body weight of the male mouse
determined 1n the study (0.032 kg) yields an adjusted 1/E01Q (F Factor) of
5.066xlO~2 (mg/kg/day)-1. Because this F Factor Is <1, hexachloroethane
Is placed In Potency Group 3. An EPA Group B2 and Potency Group 3 chemical
has a LOW Hazard Ranking under CERCLA; this Hazard Ranking Is associated
with a cancer RQ of 100.
0119d -61- 08/03/89
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TABLE 9-4
Derivation of Potency Factor (F) for Hexachloroethane
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
(TWA mg/kg/day)
Transformed doses:
(mg/kg/day)
Tumor Incidence:
Unadjusted l/EDio:
Adjusted 1/ED10:
(F Factor)
NCI, 1978
oral
mouse
86C3F1
male
corn oil
0.032 kg (measured)
78 weeks
91 weeks
91 weeks
liver
hepatocellular carcinoma
0 421
0
361
3/20 15/50
3.9028807 (mg/kg/day)'1
5.0664213xlO~2 (mg/kg/day)'1
842
722
31/49
0119d
-62-
08/03/89
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Q119d -66- 08/03/89
-------
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0119d -67- 08/03/89
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Q119d -68- 08/03/89
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0119d -69- 08/03/89
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0119d -70- 08/03/89
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NIOSH (National Institute for Occupational Safety and Health). 1988. RTECS
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0119d -71- 08/03/89
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0119d -72- 08/03/89
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0119d -73- 08/03/89
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Thompson, J.A,, a. Ho and S.L. Mastovlch. 1984. Reductive metabolism of
1,1,1,2-tetrachloroethane and related chloroethanes by rat liver mlcrosomes.
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aquatic species. Water Res. 19(9): 1145-1156.
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polychlorlnated ethanes. Drug Metab. Dlspos. 12(1): 4-8.
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vitro transformation of BALB/C-3T3 cells by chlorinated ethanes and
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drinking water. Interim report to congress. June, 1975. Washington, DC.
p. 1-33.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CID, U.S. EPA, Washington. DC.
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Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1981. Treatablllty manual - Vol. 1. Treatablllty data.
EPA-600/2-82-001a. p. 1.12.11-1 to 11-3.
0119d -74- 08/03/89
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U.S. EPA. 1983. Reportable Quantity Document for Ethane, Hexachloro.
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. p. 1-5.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty 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, Wash-
ington, DC.
U.S. EPA. 1986a. Methodology for Evaluating Cardnogenlclty In Support of
Reportable Quantity Adjustment Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment, Carcinogen Assessment
Group, Washington, DC for the Office of Solid and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
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DC.
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0119d -75- 08/03/89
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U.S. EPA. 1987b. Health Effects Assessment for Hexachloroethane. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
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04/16/87.) Office of Health and Environmental Assessment, Environmental
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U.S. EPA. 1988c. Integrated Risk Information System (IRIS): Risk estimated
for carcinogens for hexachloroethane. Online. (Verification date 07/23/86)
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0119d -76- 08/03/89
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Van Dyke, R.A. and C.G. Wlneman. 1971. Enzymatic dechloMnatlon.
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Velth, G.O., D.J. Call and L.T. Brooke. 1983. Structure-toxldty relation-
ships for the fathead minnow, Plmephales proroelas: Narcotic Industrial
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(Plmephales promelas). Arch. Environ. Contam. Toxlcol. 12(6): 661-666.
Weeks, M.H., R.A. Angerhofer, R. Bishop, J. Thomaslno and C.R. Pope. 1979.
The toxlclty of hexachloroethane 1n laboratory animals. Am. Ind. Hyg.
Assoc. 0. (40): 187-199.
Uelsburger, E.K. 1977. Carclnogenldty studies on halogenated hydro-
carbons. Environ. Health Perspect. 21: 7-16.
0119d -77- 08/03/89
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted In October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John WHey and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 26. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0119d -78- 08/03/89
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Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Quellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials. 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call in Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B, Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co..
Inc., Rahway, NJ.
0119d -79- 08/03/89
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior. Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0119d -80- 08/03/89
-------
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
CINCINNATI. OHIO 45268
SUBJECT: Health and Environmental Effects Documents
FRON1 Chris DeRosa ''jj,!*'
Chief U
Chemical Mixtures Assessment Branch
TO: Matthew Straus
Chief, Waste Characterization Branch
Office of Solid Haste (OS-330)
THRU: Steven D. Lutkenhoff ,,'
Acting Director
Environmental Criteria and Assessment Off1ce-C1n
William Farland, Ph.D.
Director
Office of Health and Environmental
Assessment (RD-689}
Attached please find two unbound copies each of the Health and
Environmental Effects Documents (HEEDs) for:
Hexachloroethane (ECAO-C1n-G04l)
Glyddylaldehyde (ECAO-C1n-G055)
These documents represent scientific summaries of the pertinent
available data on the environmental fate and mammalian and aquatic toxldty
of each chemical at an extramural effort of about 10K. These documents
received Internal OHEA, QPP and OTS reviews as well as review by two
external scientists. Any part of these document's files (e.g., drafts,
references, reviews) are available to you upon request.
Attachments
cc: K. Bruneske (OS-305) (w/enclosures)
M. Callahan (RD-689)
P. Durkln, Syracuse Research Corporation (w/enclosures)
R. Hardesty (RD-689)
B. Hostage (OS-210) (w/enclosures)
S. Irene (OS-330) (w/enclosures)
E. MeNamara (PM-211A) (w/enclosures)
J. Moore (RD-689)
M. Pfaff (RD-689) (w/enclosures)
C. R1s (RD-689)
R. Rubensteln (OS-330)
R. Scarberry (OS-330)
C. Zamuda (OS-240)
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