TECHNICAL REPORT DATA
(fUttf rarf /nttnicnonj on tht rtvtnt be fort completing/
'1. REPORT NO.
EPA/600/8-89/096
2.
4. TITLE AND SUBTITLE
Updated Health Effects Assessment for
Tetrachloroethylene
3. RECIPIENT'S ACCESSION NO
PB90-142480/AS
». REPORT DATE
E. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
I. PERFORMING ORGANIZATION REPORT NO
PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
IS SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order J2991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Croup
6. DISTRIBUTION STATEMENT
Public
EPA F*m 2220-1 (IU*. 4-77) PREVIOUS EDITION n OBCOUKTK
B. SECURITY CLASS (Thu Rtport)
Unclassified
21. NO OF PAGES
20. SECURITY CLASS
Unclassified
22. PRICE
-------
EPA/600/8-89/096
February, 1988
HEALTH EFFECTS ASSESSMENT
FOR TETRACHLOROETHYLENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
-------
DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and »
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary. Interim assessment of adverse health effects associated with tetra-
chloroethylene. All estimates of acceptable Intakes and carcinogenic
potency presented In this document should be considered as preliminary and
reflect limited resources allocated to this project. Pertinent toxlcologlc
and environmental data were located through on-line literature searches of
the TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic
literature searched supporting this document 1s current up to May, 1987.
Secondary sources of Information have also been relied upon In the prepara-
tion of this report and represent large-scale health assessment efforts that
entail extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Tetrachloro-
ethylene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-073. NTIS PB81-117830.
U.S. EPA. 1982. Hazard Profile for Tetrachloroethylene. Prepared
by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste, Washington, DC.
U.S. EPA. 1983. Reportable Quantity Document for 1,1,2,2-Tetra-
chloroethylene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Emergency and Remedial Response, Wash-
ington, DC.
U.S. EPA. 1985a. Health Assessment Document for Tetrachloroethyl-
ene (Perchloroethylene). Environmental Criteria and Assessment
Office, Research Triangle Park, NC. EPA 600/8-82-005F. NTIS
PB85-249704.
U.S. EPA. 1986a. Updated Carclnogenlclty Assessment for Tetra-
chloroethylene (Perchloroethylene, PERC, PCE): Addendum to the
Health Assessment Document for Tetrachloroethylene. Office of
Health and Environmental Assessment, Washington, DC. NTIS
PB86-174489.
U.S. EPA. 1987. Integrated Risk Information System (IRIS).
Reference dose (RfD) for oral exposure for tetrachloroethylene. On
line. (Verification date 9/87; data Input pending). Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH.
111
-------
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e.. protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the llfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (RfDgo)
exposures.
The RfD (formerly AIC) Is similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
A major Issue of concern Is the potential carc1nogen1dty of tetra-
chloroethylene to humans. Human data are confounded by composite
exposures. Results of ^ri vitro mutagenldty bloassays are Inconclusive.
Only one animal bloassay employing oral exposure has been conducted.
Results 1n rats were negative. In mice, tetrachloroethylene administration
resulted In an Increased Incidence of hepatocellular carcinoma. Using these
data, a q-|* of S.lxlO"2 (mg/kg/day)"1 was estimated.
NTP (1986) conducted 2-year Inhalation studies with mice and rats.
Tetrachloroethylene exposure was associated with Increased Incidences of
mononuclear cell leukemia In rats and liver tumors 1n mice. U.S. EPA
(1986a) estimated unit risks of 2.9xlO"7 to 9.5xlO~7 for exposure to 1
yg/m3 1n air. The weight of the evidence for the carclnogenldty of
tetrachloroethylene Is proposed as Group B2, probable human carcinogen. The
classification Is currently under review prior to f1nal1zat1on.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation for EPA's Environmental Criteria and Assessment Office,
Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the
Technical Project Monitors and John Helms (Office of Toxic Substances) was
the Project Officer. The final documents In this series were prepared for
the Office of Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1. ENVIRONMENTAL CHEMISTRY AND FATE
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.3.3. Oral
3.3.4. Dermal
TOXICANT INTERACTIONS
4. CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.2.3. Selected Pharmacoklnetlcs Relevant to
Interspedes Extrapolation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
Page
, , 1
3
... 3
3
, , , 4
... 4
... 4
. . , 5
... 12
... 12
... 12
... 13
... 13
... 13
... 16
... 16
... 17
... 18
... 18
... 18
... 18
... 19
... 19
... 20
... 24
... 26
... 26
V11
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TABLE OF CONTENTS (cont.)
Page
5. REGULATORY STANDARDS AND CRITERIA 29
6. RISK ASSESSMENT 30
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 30
6.2. REFERENCE DOSE (RfD) 30
6.3. CARCINOGENIC POTENCY (q-|*) 30
6.3.1. Oral 30
6.3.2. Inhalation 32
7. REFERENCES 37
APPENDIX: Summary Table for Tetrachloroethylene 49
-------
LIST OF TABLES
No. Title Page
3-1 Effects of Subchronlc Inhalation Exposure to Tetra-
chloroethylene 1n Animals 6
4-1 Disposition of 14C-Tetrachloroethylene 72 Hours After
Single Oral Doses to Sprague-Dawley Rats and B6C3F1 Mice. . . 25
6-1 Dose Response Data and Potency (Slope) Estimates 31
6-2 Metabolized Dose and Incidence of Mononuclear Cell Leukemia
1n Fischer 344 Rats 1n the NTP (1986) Inhalation Study. ... 34
6-3 Metabolized Dose and Incidence of Liver Tumors 1n Mice
In the NTP (1986) Inhalation Study 35
6-4 Unit Risk Estimates Calculated on the Basis of Different
Data Sets from the NTP (1986) Bloassay 36
1x
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LIST OF ABBREVIATIONS
AADI Adjusted acceptable dally Intake
BCF Bloconcentratlon factor
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
EEG Electroencephalogram
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kow Octanol/water partition coefficient
LOAEL Lowest-observed-adverse-effect level
NOAEL No-observed-adverse-effect level
ppm Parts per million
RfO Reference dose
RfDj Inhalation reference dose
RfD0 Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
SNARL Suggested no-adverse-response level
STEL Short-term exposure limit
TCA Trlchloroacetlc acid
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
tetrachloroethylene (CAS No. 127-18-4) are as follows:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log Kow:
Soil mobility:
BCF:
Half-life 1n A1r:
Half-lives In Water;
halogenated aliphatic hydrocarbon
(purgeable halocarbon)
165.83
17.8 mm Hg at 25°C
(U.S. EPA, 1982)
150 mg/l at 25°C
(Kell, 1979)
3.40 (Hansch and Leo, 1985)
2.5 (Wilson et al., 1981)
(predicted as the ratio of water velocity
to compound velocity through a soil
containing 0.087% organic carbon)
46 (Sabljlc, 1984)
49 (In blueglll, Lepomls macrochlrus)
(U.S. EPA, 1980a)
39 (1n rainbow trout, Salmo galrdnerl)
(U.S. EPA, 1980a)
47 days (U.S. EPA, 1982)
12-25 days In coastal seawater
(Wakeham et al., 1983)
3-30 days 1n river and 30-300 days In lake
and groundwater (Zoeteman et al., 1980)
The primary removal mechanism for tetrachloroethylene In the atmosphere
1s expected to be reaction with photochemlcally generated hydroxyl radicals
(U.S. EPA, 1985a). The principal product of this reaction Is tMchloro-
acetylchlorlde (U.S. EPA, 1979). The half-life value given above Is esti-
mated on the basis of tropospherlc OH concentration of 10* radicals/cm3.
0009H
-1-
12/11/87
-------
Because of Us relatively long half-life In the atmosphere, tetrachloro-
ethylene may be transported long distances from Us emission sources, but
Insignificant amounts will be transported from the troposphere to the
stratosphere.
The primary removal mechanism for tetrachloroethylene 1n water will be
volatilization. Bloaccumulatlon 1n aquatic organisms and adsorption to
suspended solids and sediments are not expected to be Important fate
processes (NLM, 1987).
The half-life of tetrachloroethylene In soil could not be located 1n the
available literature. Tetrachloroethylene 1s expected to volatilize rapidly
from soil surfaces. The half-life for evaporation from soil should be
longer than Its evaporation half-life from water (Wilson et al., 1981). In
subsurface soil, no significant degradation Is expected to occur under
aerobic conditions; however, blodegradatlon may be an Important process In
anaerobic soils (NLM, 1987). Because of Us relatively low K value,
tetrachloroethylene 1s expected to be quite mobile 1n soil and undegraded
residue 1s expected to leach Into groundwater. Detection of this compound
1n a number of groundwater supplies supports this prediction (NLM, 1987).
0009H -2- 12/11/87
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2. ABSORPTION FACTORS IN HUMAN AND EXPERIMENTAL ANIMALS
2.1. ORAL
Tetrachloroethylene 1s absorbed to some extent from the gastrointestinal
tract (quantification and species not specified) (von Oettlngen, 1964).
Intestinal absorption by dogs 1s facilitated by fats and oils (Lamson et
al., 1929).
Daniel (1963) found that 98% of a single oral dose of 3*Cl-tetra-
chloroethylene was eliminated 1n expired air and 2% In urine of rats.
Schumann et al. (1980) reported that 85% of a single oral dose of 500 mg/kg
14C-tetrachloroethylene was eliminated 1n expired air and 12% In urine of
mice. These two studies Indicate that tetrachloroethylene was almost
completely absorbed from the gastrointestinal tract.
2.2. INHALATION
The principal route by which tetrachloroethylene enters the human body
Is by pulmonary absorption from the alveolar air (U.S. EPA, 1985a).
Pulmonary absorption of tetrachloroethylene Is rapid, and the amount of
tetrachloroethylene absorbed at a given vapor concentration (for exposures
of <8 hours) 1s directly related to the respiratory minute volume (Hake and
Stewart, 1977). von Oettlngen (1964) also reported that tetrachloroethylene
1s readily absorbed through the lungs (quantification and species not
specified). Monster et al. (1979) found that tetrachloroethylene uptake by
humans was Influenced more by lean body mass than by respiratory minute
volume or adipose tissue. The amount of metabolite produced 1s Influenced
primarily by metabolic rate constants. Since many of the effects of
tetrachloroethylene are attributable to Us metabolites, both update and
metabolism are Important variables.
0009H -3- 03/08/88
-------
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Hayes et al. (1986) administered nominal doses of 0, 15,
400 or 1400 mg/kg/day tetrachloroethylene In drinking water to groups of 20
male and 20 female Sprague-Dawley rats for 90 consecutive days. Body
weights were decreased, and relative liver and kidney weights were Increased
at the higher two doses. S'-Nucleotldase activity was elevated In a
dose-related manner, which Indicated possible hepatotoxldty; however, other
serum Indicators of hepatotoxldty were unaffected. There were no effects
on hematologlcal, clinical chemistry or urlnalysls parameters, or on gross
appearance of tissues.
Groups of male Swiss-Cox mice were administered tetrachloroethylene
(>99X pure) 1n corn oil by gavage at doses of 0, 20, 100, 200, 500, 1000,
1500 or 2000 mg/kg on 5 days/week for 6 weeks (Buben and O'Flaherty, 1985).
Group sizes were 26 (0 ppm), 13-19 (100-1000 ppm), and 6 (1500 and 2000
ppm). Four parameters of hepatotoxldty were evaluated at all dose levels:
relative liver weight, trlglycerldes, glucose-6-phosphatase (G6P) activity
and SGPT activity. There were no effects on these parameters at 20 mg/kg.
Liver weight and trlglycerldes were significantly Increased at >100 mg/kg
and G6P was significantly decreased and SGPT was significantly Increased at
>500 mg/kg. The effects were nearly all dose-dependent although liver
trlglycerldes peaked and SGPT levels plateaued at 1000 mg/kg. Hlstologlcal
examination of livers from mice 1n the 200 and 1000 mg/kg dose groups showed
severe degenerative changes with evidence of karyorrhexls (nuclear disinte-
gration); centrllobular necrosis occurred In some of the livers at 1000
mg/kg. Plots of the heptotoxlclty parameters against total urinary
metabolites were linear 1n all cases, suggesting that the hepatotoxldty Is
directly related to the degree of tetrachloroethylene metabolism.
0009H -4- 12/22/87
-------
3.1.2. Inhalation. The effects of subchronlc Inhalation exposure to
tetrachloroethylene have been examined 1n rats, mice, rabbits, guinea pigs
and monkeys. These effects are summarized 1n Table 3-1.
Carpenter (1937) exposed three groups of albino rats to tetrachloro-
ethylene vapors at average concentration levels of 70, 230 or 470 ppm, 8
hours/day, 5 days/week for 7 months. The control group consisted of 18
unexposed rats. After exposure and a 46-day recovery period, rats exposed
to 470 ppm tetrachloroethylene had cloudy and congested livers with swelling
but no evidence of fatty degeneration or necrosis. Increased renal secretion
with cloudy swelling and desquamatlon of kidneys, and congested spleens with
Increased pigment. Following exposure to 230 ppm tetrachloroethylene and a
20-day recovery period, treated rats had similar but less severe pathologic
changes than the highest exposure group. These changes Included renal and
splenic congestion and reduced hepatic glycogen storage. There was no
evidence of pathologic changes 1n the liver, kidneys or spleen of rats
exposed to 70 ppm tetrachloroethylene for 7 months, and apparently sacri-
ficed without a recovery period. Upon microscopic examination of rats at
each exposure level, Carpenter (1937) did not observe pathologic changes In
the heart, brain, eyes or nerve tissue. Functional parameters (Icteric
Index, Van den Bergh test for blllrubln, blood and urlnalysls) were normal
at all exposure levels. The fertility Index (actual number of Utters/
possible number of Utters) was Increased for female rats exposed 150 times
to 230 or 470 ppm tetrachloroethylene. A NOEL of 70 ppm tetrachloroethylene
for rats can be estimated from this study.
Rowe et al. (1952) exposed rats, rabbits, guinea pigs and monkeys to
tetrachloroethylene vapors at levels of 100-400 ppm, 7 hours/day, 5 days/
week for ~6 months. No abnormal growth, organ function or hlstopathologlc
0009H -5- 12/11/87
-------
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findings were seen at any exposure level among treated rats, rabbits or
monkeys. Guinea pigs, however, were more susceptible to tetrachloroethy]-
ene, with adverse effects occurring at all exposure levels. Female guinea
pigs exposed to tetrachloroethylene vapors at a level of 100 ppm had
Increased liver weights, while both sexes of guinea pigs exposed to 200 ppm
had Increased liver weights with some fatty degeneration, a slight Increase
In hepatic I1p1d content, and the presence of several small hepatic fat
vacuoles. Guinea pigs exposed to the highest exposure level used In this
study (400 ppm tetrachloroethylene) had more pronounced liver changes than
at the 200 ppm exposure level, Including cirrhosis. Increased liver weight,
Increased hepatic neutral fat and esterlfled cholesterol, and moderate
hepatic central fatty degeneration. A LOAEL of 100 ppm tetrachloroethylene
for hepatic effects In guinea pigs can be derived from this study. Rowe et
al. (1952) reported no hlstopathologlc lesions of the brains of any species
at any concentration. It 1s unclear from what animals brains were taken for
examination.
NTP (1986) conducted preliminary 13-week studies where rats and mice
were exposed to 100-1600 ppm tetrachloroethylene, 6 hours/day, 5 days/week.
Tetrachloroethylene caused 20-70% mortality In both species at the highest
dose. At 200-800 ppm, minimal to mild hepatic congestion occurred 1n rats.
In mice, 1600 ppm caused mortality, and 400-1600 ppm produced minimal to
mild hepatic leukocytlc Infiltration, centrllobular necrosis and bile
stasis. H1tot1c alteration 1n the liver occurred at >200 ppm and minimal
renal cell karyomegaly occurred at >400 ppm. No adverse effects were noted
In rats or mice at 100 ppm.
Four studies from the foreign literature (Dmltrleva, 1966, 1968; Mazza,
** 1972; Navrotskll et al., 1971) of subchronlc Inhalation exposure to tetra-
0009H -9- 12/11/87
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chloroethylene were summarized by U.S. EPA (1985a). EEG changes and proto-
plasmal swelling of cerebral cortical cells, and the presence of some
vacuolated cells and signs of karyolysls were reported 1n the brains of rats
exposed to 15 ppm tetrachloroethylene vapors, 4 hours/day for 5 months
(Dmltrleva, 1966). Mice exposed to 15-74 ppm tetrachloroethylene for 5
hours/day for 3 months reportedly had decreased electroconductance of muscle
and "amplitude" of muscular contraction (Dmltrleva, 1968). Rabbits exposed
to tetrachloroethylene vapors at a level of 15 ppm for 3-4 hours/day for
7-11 months had depressed agglutlnln formation (Mazza, 1972), and moderately
Increased urinary urobHlnogen and pathomorphologlcal changes In hepatic and
renal parenchyma (Navrotskll et al., 1971). The lack of further details and
dose-response data In these four studies and the lack of similar observa-
tions In several well conducted domestic experiments precludes their use for
quantitative human risk assessment for Inhalation exposure to tetrachloro-
ethylene.
Rosengren et al. (1986) exposed groups of four male and four female
Mongolian gerblls to 60 or 320 ppm (407 or 2170 mg/m3) continuously for 3
months to determine effects on subtle biochemical parameters of the brain.
A control group of eight males and eight females was maintained. The only
effect observed at 60 ppm was decreased concentration of DNA In the frontal
cerebral cortex. At 320 ppm, there was a significant reduction 1n the wet
weight of the cerebral cortex and alterations In the concentrations of
S-100, DNA and protein In several regions of the brain. According to the
Investigators, these observations suggested that tetrachloroethylene caused
frontal cortical atrophy and affected the astrogllal cells of several
regions of the brain.
0009H -10- 12/11/87
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t
f
Brain amlno add and glutathlone concentrations were determined In
groups of six Mongolian gerblls (3/sex) that were exposed to 0 or 120 ppm
tetrachloroethylene continuously for 12 months (BMvIng et al., 1986).
Treatment-related effects Included decreased taurlne content 1n the
hippocampus and posterior part of the cerebellar vermls and Increased
glutamlne content In the hippocampus. Uptake of glutamate and
gamma-aminobutyrlc acid (GABA) Into the cerebellum and hippocampus was
unaffected.
Continuous exposure of six male Mongolian gerblls to 120 ppm
tetrachloroethylene for 12 months also caused an alteration In the fatty
acid composition of a phosphollpld (phosphatldylethanolamlne) 1n the
cerevral cortex and hippocampus (Kyrklund et al., 1984).
Liver weight, liver pathology, and plasma butyrylchollnesterase (BuChe)
activity were evaluated In groups of 30 NMRI mice of each sex that were
exposed to 0, 9, 37, 75 or 150 ppm tetrachloroethylene continuously for 30
days (KJellstrand et al., 1984). Treatment-related effects Included
abnormal gross pathological appearance at >9 ppm, significantly Increased
liver weight at >9 ppm and significantly Increased BuChe activity at >37
ppm. Gross pathological alterations Included enlargement and yellowish
coloration. Hlstologlcal examination revealed enlargement and vacuollzatlon
of hepatocytes from all areas of the liver but normal trabecular arrange-
ment. Although the pathologic alterations were observed at the 9 ppm
exposure concentration, they were most pronounced above 75 ppm. Increased
liver weight and serum BuChe activity also occurred 1n mice that were
exposed continuously to 150 ppm tetrachloroethylene for 4, 8 or 14 days, and
Intermittently to tetrachloroethylene at a time-weighted average concen-
tration of 150 ppm for 30 days. Liver weights were still Increased (10%)
0009H -11- 12/22/87
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120 days following 30 days of continuous exposure to 150 ppm. It should be
noted that the significance of Increased serum BuChe activity In this study
Is unclear because there was wide variability In BuChe activity In the
controls and because serum BuChe can be modulated by nonhepatlc factors
(Kjellstrand et al., 1984).
3.2. CHRONIC
3.2.1. Oral. The only source of Information regarding chronic oral
toxldty resulting from exposure to tetrachloroethylene Is the NCI (1977)
cardnogenlcHy bloassay with Osborne-Mendel rats and B6C3F1 mice. Groups
of 50 male and 50 female rats and equal numbers of mice received various
levels of tetrachloroethylene 1n corn oil by gavage, 5 days/week for 78
weeks. TWA doses for this study were 450 and 550 mg/kg/day for male mice,
300 and 400 mg/kg/day for female mice, 471 and 941 mg/kg/day for male rats,
and 474 and 949 mg/kg/day for female rats. Control groups consisted of 20
male and 20 female animals of each species that were untreated and equal
numbers of vehicle-treated animals. Toxic nephropathy was observed at all
dose levels In both sexes of mice and rats.
3.2.2. Inhalation. Pegg et al. (1978) reported the results of a disposi-
tion study 1n Sprague-Dawley rats following Inhalation exposure to tetra-
chloroethylene at a level of 4 g/m3 (600 ppm), 6 hours/day, 5 days/week
for 12 months. Unspecified reversible liver damage was observed In the
treated rats.
In a 2-year NTP (1986) Inhalation study, groups of 50 male and 50 female
F344/N rats were exposed to 0, 200 or 400 ppm and 50 male and 50 female
B6C3F1 mice were exposed to 0, 100 or 200 ppm; both species were exposed 6
hours/day, 5 days/week for 103 weeks. Exposure had no effect on body
weights, but survival of high-dose male rats, high-dose mice of both sexes,
0009H -12- 12/11/87
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and low-dose male mice (at 74 weeks) was significantly less than controls
after >74 weeks of exposure. Reduced survival was attributed by NTP (1986)
possibly to the development of mononuclear cell leukemia 1n rats and hepato-
cellular carcinomas In mice. Nonneoplastlc lesions were restricted to the
kidney and 1n rats consisted of karyomegaly In all exposed groups and
tubular cell hyperplasla In males at 0/49, 3/49 and 5/50 and In females at
0/50, 0/49 and 1/50 In the control, low and high groups, respectively. In
mice, tubular cell karyomegaly was observed 1n all exposed groups.
Nephsosls was evident In both exposed groups of female mice.
Human health effects as a result of chronic Inhalation exposure to
various concentrations of tetrachloroethylene Include respiratory tract
Irritation, nausea, headache, sleeplessness, abdominal pains and constipa-
tion (Chmlelewskl et al., 1976; Coler and Rossmlller, 1953; Stewart et al.,
1970; von Oettlngen, 1964). Liver cirrhosis, hepatitis and nephritis have
also been reported (Stewart, 1969). Side effects from the therapeutic use
of tetrachloroethylene as an ant1helm1nt1c agent also have been reported
(von Oettlngen, 1964). Lack of dose quantification and a dose-response
relationship precludes the use of these human data for quantitative risk
assessment for Inhalation exposure to tetrachloroethylene.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding teratogenldty of tetrachloro-
ethylene following oral administration were not located In the available
literature.
3.3.2. Inhalation. Schwetz et al. (1975) exposed 17 pregnant Sprague-
Dawley rats and 17 pregnant Swiss-Webster mice to tetrachloroethylene by
Inhalation at a level of 300 ppm for 7 hours/day on days 6-15 of gestation.
Caesarean sections were done on day 18 (mice) or 21 (rats). Rats had a
0009H -13- 12/11/87
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statistically significant reduction 1n mean maternal body weight, while mice
had Increased mean relative maternal liver weight. The fetal body weights
of mice were depressed significantly. A significantly Increased number of
rat fetuses were resorbed. For mice, the Incidences of subcutaneous edema,
delayed ossification of skull bones and split sternebrae were Increased
significantly, compared with Incidences In control mice.
Carpenter (1937) did not detect any adverse effects on reproductive
performance among rats exposed to 70, 230 or 470 ppm tetrachloroethylene, 8
hours/day, 5 days/week for 28 weeks. In an unpublished teratogenldty study
reported by U.S. EPA (1985a), Sprague-Dawley rats were exposed to 0 or 300
ppm (2034 mg/m3) tetrachloroethylene for 7 hours dally (Bellies et al.,
1980). Additional Information regarding experimental design lis ambiguous:
exposures were 5 days/week (schedule during gestation exposure not
specified), 19-24 rats were examined (numbers exposed not specified),
one-half of the rats were exposed for 3 weeks prior to mating, and all rats
were exposed during gestation on days 0-18 or 6-18 (numbers exposed or
examined 1n each group not specified). Concentrations 1n the exposure
chamber either fluctuated or were higher than Intended as measurements taken
15 minutes before the end of exposure showed 568 ppm. Treatment-related
effects reportedly Included maternal ataxla, loss of balance and death
during pregestatlonal exposure, decreased maternal weight gain, and
Increased maternal absolute (not relative) liver and kidney weights, and
unspecified fetal skeletal ossification anomalies. Teratogenlc or
additional embryotoxlc effects were not observed.
In an associated study, Hardln et al. (1981) exposed Sprague-Dawley rats
to 500 ppm tetrachloroethylene for 6-7 hours/day on gestatlonal days 1-19.
It 1s stated that the target number of litters per group was 30; however,
0009H -14- 12/11/87
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the actual numbers were not given. Tetrachloroethylene was scored negative
for maternal toxldty, fetal toxldty, and teratogenlcHy (actual data not
reported). The brevity of result and protocol reporting makes this study
difficult to Interpret.
In the same paper, results of exposure of rabbits to 500 ppm tetra-
chloroethylene for 6-7 hours/day on days 1-24 of gestation are also
discussed. The target number of Utters/group was given as 20 (actual
numbers not reported). Again, tetrachloroethylene was scored negative for
maternal toxldty, fetal toxldty, and teratogenlcHy.
In a behavioral teratology study, groups of 13-21 Sprague-Dawley rats
were exposed for 7 hours/day to 0 or 100 ppm terachloroethylene on days
14-20 of gestation, 0 or 900 ppm terachloroethylene on days 14-20 of gesta-
tion, and 0 or 900 ppm terachloroethylene on days 7-13 of gestation (Nelson
et al., 1980). Seven behavioral tests were used to evaluate effects at
several stages of development (postnatal days 4-46); one male and one female
from each Utter were used for each test. Neurochemlcal analyses of whole
brains except cerebellum and hlstologlcal examination of brains were
conducted on pups at 0 or 21 days of age. Effects were not associated with
100 ppm treatment. Effects occurred 1n rats exposed to 900 ppm Including
reduced maternal feed consumption and weight gain without liver or kidney
hlstologlcal alterations, and decreased performance of pups exposed on
gestation days 7-13 on the tests of neuromuscular ability (ascent and
rotorod) on certain days of testing. Offspring from dams exposed on days
14-20 also performed poorly on the ascent test on one test day, but later In
development performance was superior to controls and activity was Increased
In the open field test. The neurochemlcal analyses showed, for the
0009H -15- 12/11/87
-------
21-day-old offspring, decreases In dopamlne 1n those exposed on gestation
days 14-20 and decreases In acetylchollne In those exposed on days 7-13 or
14-20.
Additional developmental testing of rats exposed to high concentrations
of tetrachloroethylene has been conducted. In an unpublished study reported
by U.S. EPA (1985a), Long-Evans hooded rats were exposed to 0 or 1000 ppm
(6780 mg/m3) tetrachloroethylene for 6 hours/day, 5 days/week for 2 weeks
before mating through gestation day 20 or on days 0-20 of gestation (Tepe et
al., 1982; Hanson et al., 1982). Treatment-related effects Included
Increased maternal liver weight, reduced fetal body weight, Increased unspe-
cified skeletal and soft-tissue anomalies Indicative of embryotoxldty.
Neurobehavloral testing of offspring at 10-170 days of age was unremark-
able. In a pilot study to the Nelson et al. (1980) behavioral teratology
study, exposure of Sprague-Dawley rats to 900 ppm tetrachloroethylene
(schedule not specified) on days 7-13 or 14-20 of gestation did not produce
fetal external or skeletal malformations.
3.3.3. Oral.
3.3.3.1. HUMAN STUDIES — Information regarding the developmental
effects of Ingested terachloroethylene 1n humans was not located In the
available literature.
3.3.3.2. ANIMAL STUDIES -- Information regarding the developmental
effects of orally administered terachloroethylene In animals was not located
In the available literature.
3.3.4. Dermal.
3.3.4.1. HUMAN STUDIES — Information regarding the developmental
effects of dermally applied terachloroethylene 1n humans was not located In
the available literature.
0009H -16- 12/11/87
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3.4. TOXICANT INTERACTIONS
Compounds that alter the functional activity of mlcrosomal enzyme
systems may affect the toxldty of tetrachloroethylene because H Is metabo-
lized by mixed function oxldases (U.S. EPA, 1980a). Phenobarbltal pretreat-
ment, however, did not modify the acute hepatotoxlclty of tetrachloroethyl-
ene (Cornish et al., 1973, 1977). Induction of mixed function oxldases by
pretreatment with Aroclor 1254 resulted In altered tetrachloroethylene acute
toxlclty, manifested by vacuollzatlon of rough endoplasmlc retlculum and
Increased serum glutamate oxaloacetate transamlnase activity (Moslen et al.,
1977; Reynolds and Moslen, 1977).
Tetrachloroethylene has been associated with Intolerance to alcohol,
probably because both tetrachloroethylene and alcohol are CNS depressants
(Gold, 1969). Synerglstlc effects, which are Identified by lethality as the
endpolnt, of mixtures of tetrachloroethylene and benzene following Intuba-
tion to rats have been reported (WUhey and Hall, 1975).
Smyth et al. (1969) administered tetrachloroethylene and 26 other
solvents 1n all possible combinations to rats. The results followed a
predictive additive toxldty model except for polyethylene glycol 400, butyl
ether, dloxane and acetophenone, which had greater than additive toxldty
when administered with tetrachloroethylene.
0009H -17- 12/11/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the cardnogenlclty of orally
administered tetrachloroethylene to humans were not located In the available
literature.
4.1.2. Inhalation. Ep1dem1olog1c studies of dry cleaning and laundry
workers have determined significant excesses In mortality due to cancers of
the lung, cervix, kidney, skin and/or colon (Blair et al., 1979; Kaplan,
1980; Katz and Jowett, 1981; Duh and Asal, 1984; Brown and Kaplan, 1985).
Although these studies suggest a possible association between chronic
occupational exposure to tetrachloroethylene and Increased cancer risk, the
evidence must be regarded as Inconclusive because the workers were exposed
to petroleum solvents and other dry cleaning agents as well as
tetrachloroethylene, because other confoudlng factors such as smoking and
low sodoeconomlc status were not considered In the analyses, because the
numbers of site-specific deaths were low and/or because attempts were not
made to distinguish between laundry and dry cleaning workers.
The only Investigation of dry cleaning workers with no known exposure to
petroleum solvents was a subcohort of 615 workers from the Brown and Kaplan
(1985) retrospective mortality study. Excess risk for cancer at any site
was not Identified 1n the subhcohort. In the entire cohort, which was
comprised of 1690 workers with >23 years of employment and Included workers
who had potential occupational exposure to petroleum solvents, there were
significant excesses of mortality from kidney and bladder cancer (8 cases
vs. 2.7 expected; SMR=296) and cancer of the cervix (10 observed vs. 5.1
expected; SMR=296).
0009H -18- 12/11/87
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Lin and Kessler (1981) did a case-control study of 109 pancreatic cancer
cases diagnosed during the period 1971-1975 from 115 hospitals 1n five
metropolitan areas. The control group was composed of subjects who were
free from cancer but who were similar to the study group In age (+3 years),
sex, race and marital status, and who had been selected at random from among
contemporaneous admissions to the same hospital. Cases and controls were
asked about demographic characteristics, residential history, toxic
exposures* animal contacts, smoking habits, diet, medical history,
medications and family history. Males were asked about sexual practices and
urogenHal conditions. Females were questioned on these topics and also on
their marital, obstetric and gynecologic histories. Among other
statistically significant associations, an association was found between
pancreatic cancer and employment either as a dry cleaner or In a job
Involving exposure to gasoline. It Is not known, however, how many
Individuals with pancreatic cancer were employed as dry cleaners and how
many were employed In occupations Involving exposure to gasoline.
Furthermore, the dry cleaners may have used a variety of dry cleaning agents
other than PCE. Thus this study, although suggestive of an association
between employment as a dry cleaner and an excess risk of pancreatic cancer,
cannot be said to demonstrate an association between pancreatic cancer and
PCE exposure.
4.2. BIOASSAYS
4.2.1. Oral. In an NCI (1977) carclnogenlcHy bloassay with Osborne-
Hendel rats and B6C3F1 mice, groups of 50 male and 50 female rats and equal
numbers of mice received various levels of tetrachloroethylene 1n corn oil
by gavage, 5 days/week for 78 weeks. TWA doses for this study were 536 and
1072 mg/kg/day for male mice, 386 and 772 mg/kg/day for female mice, 471 and
941 mg/kg/day for male rats, and 474 and 949 mg/kg/day for female rats.
0009H -19- 02/09/88
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Control groups consisted of 20 male and 20 female animals of each species
that were untreated and equal numbers of vehicle-treated animals. All
surviving mice were killed at 90 weeks and all surviving rats at 110 weeks.
Decreased survival rates were observed for both species. No Increases 1n
tumor Incidences were observed for treated rats. Mice, however, had highly
significant Increases 1n hepatocellular carcinomas. The Incidences of this
tumor type In mice were 2/17 untreated control males, 2/20 vehicle control
males, 32/49 low-dose males, 27/48 high-dose males, 2/20 untreated control
females, 0/20 vehicle control females, 19/48 low-dose females and 19/48
high-dose females. Metastases were reported for one untreated control male,
three low-dose males, one low-dose female and one high-dose female.
4.2.2. Inhalation. NTP (1986) conducted 2-year Inhalation carclnogenlc-
1ty studies with F344/N rats and B6C3F1 mice. Groups of 50 males and 50
females were exposed to 0, 200 or 400 ppm (rats) or 0, 100 or 200 ppm
(mice), 6 hours/day, 5 days/week for 103 weeks. Survival of high-dose male
rats, high-dose female mice and both treated groups of male mice were
reduced compared with controls; this was possibly due to mononuclear cell
leukemia In rats and hepatocellular carcinomas In mice.
Treated male rats had an Increased Incidence of mononuclear cell
leukemia (control 28/50, low dose 37/50, high dose 37/50). Treated female
rats had an Increased Incidence of leukemia (18/50, 30/50, 29/50) and
decreased time to occurrence of the disease. Tetrachloroethylene was also
associated with renal tubular cell adenomas or adenocarclnomas In male rats
(1/49, control; 3/49, low group; 4/50, high group). Although the Incidence
of renal tubular cell tumors was not statistically significant, these tumors
are considered uncommon 1n untreated male rats.
Tetrachloroethylene was associated with dose-related Increases In Inci-
dences of hepatocellular adenomas (11/49, 8/49, 18/50) and hepatocellular
0009H -20- 02/09/88
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carcinomas (7/49, 25/49, 26/50) 1n male mice and hepatocellular carcinomas
1n female mice (1/48, 13/50, 36/50) (control, low and high groups, respec-
tively).
NTP (1986) concluded that there was clear evidence of cardnogenldty of
tetrachloroethylene for male F344/N rats as Indicated by Increased Incidence
of mononuclear cell leukemia and uncommon renal tubular cell neoplasms.
There was some evidence of carc1nogen1dty for female F344/N rats because of
Increased Incidences of mononuclear cell leukemia. There was clear evidence
of cardnogenlcHy for B6C3F1 mice of either sex as shown by Increased
Incidences of hepatocellular adenomas and carcinomas.
Rampy et al. (1977) exposed groups of 96 male and 96 female Sprague-
Dawley rats to tetrachloroethylene vapors at levels of 2 or 4 g/m3 (300 or
600 ppm, respectively), 6 hours/day, 5 days/week for 12 months. There was
no statistically significant difference In any tumor Incidence between
treated and control animals.
Thelss et al. (1977) tested PCE for cardnogenldty In the strain A
mouse pulmonary tumor Induction system. The test sample, a product of the
Aldrlch Chemical Company, was reagent grade with a purity exceeding 95-99%.
Strain A/St male mice, 6-8 weeks old, were used In this assay. The maximum
tolerated dosage, defined as the dosage that five mice tolerated after six
Intraperltoneal Injections over a 2-week period followed by a 4-week
observation period, was determined and used In the bloassay. In the main
test, 20 mice per treatment group received three Intraperltoneal Injections
of 80, 200 or 400 mg/kg of PCE weekly until total dosages of 1120, 4800, and
9600 mg/kg, respectively, were achieved. Survivors were sacrificed at 24
weeks after the first Injection, and the number of surface adenomas was
counted. Results were compared with findings 1n vehicle (trlcaprylln) and
untreated controls by the Student t test. PCE did not statistically
0009H -21- 02/09/88
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Increase (p>0.05) the Incidence of pulmonary tumors In this study. This
strain was sensitive to the positive control chemical urethane.
U.S. EPA (1985a) concluded that a negative result In this assay 1s not
considered conclusive, since several chemicals known to be carcinogenic In
chronic rodent bloassays Induce no response In this assay.
The strain A mouse pulmonary tumor assay 1s relatively Insensitive to
mouse carcinogens for which the effect 1s confined to the liver (Thelss et
al., 1977). For example, chloroform, 2-chloroethyl ether and hexachloro-
cyclohexane Induce tumors of the liver (not other sites) 1n mice (NCI, 1976,
1977b; Innes et al., 1969) but were not carcinogenic In the assay by Thelss
et al. (1977). The reasons for the negative lung response are not
understood, but It may be due to a smaller concentration of activating
enzymes 1n the lung than In the liver.
A cardnogenldty study of purified PCE 1n ICR/Ha Swiss mice was
described by Van Duuren et al. (1979). Maximum tolerated dosages were
determined In range-finding studies 6-8 weeks 1n duration, and were selected
as dosages that did not affect body weight gain or produce clinical signs of
toxlclty. This study Included the following experiments: 1) 30 females
were treated topically on the dorsal skin with a single application of 163
mg PCE followed 14 days later by the applications of 5.0 yg phorbol
myrlstate acetate (PMA) to the skin 3 times weekly until termination of the
study at 428-576 days; median survival time was 428-576 days. 2) 30 females
were given thrice weekly topical applications of 54 mg PCE for the duration
of the test (440-594 days), with a median survival time of 317-589 days. A
vehicle (acetone) control group of 30 mice and an untreated control group of
100 mice were Included 1n these experiments.
0009H -22- 02/09/88
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In the Initiation-promotion experiment, 210 mice treated with PMA alone
were also on test. The mice were 6-8 weeks old at the beginning of the
study, and were housed six to a cage. Test sites on the skin were shaved as
necessary and were not covered; however, It was the authors' Impression that
PCE was Immediately absorbed and that evaporation from test sites was
minimal (Van Duuren, 19 ). The animals were weighed monthly and each
animal was examined by necropsy. Tumors and lesions as well as skin, liver,
stomach and kidneys were examined h1stolog1cally.
PCE did not show Initiating activity 1n the Initiation-promotion
experiment; the number of mice with skin paplllomas (squamous cell
carcinomas) was: 4 (0) Initiated with PCE, 15 (3) treated with PMA alone,
and 0 (0) 1n the control groups. The study Involving repeated application
to the skin produced lung and stomach tumors 1n 16 and 0 PCE-treated mice,
11 and 2 vehicle-treated controls, and 30 and 5 untreated controls,
respectively.
U.S. EPA (1985a) concludes that the negative results for PCE In mouse
skin as an Initiator and as a complete carcinogen can be reconciled with the
positive mouse liver response In the NCI study 1f It 1s hypothesized that
the skin does not have the necessary enzymes to convert PCE to an active
metabolite, whereas the liver does have this capability.
The lack of sensitivity of skin application test, as compared with tests
using other routes of exposure, 1s apparent from the results of Van Duuren
et al. (1979) with 1-chloroprene, c_U-l ,3-dlchloropropene and 2-chloro-
proponal. They found that none of the three compounds Induced a response as
Initiators In Initiation-promotion experiments or with repeated topical
application on the skin. However, they did observe a statistically
significant Increase In the Incidence of forestomach tumors 1n female Ha:ICR
0009H -23- 02/09/88
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Swiss mice dosed by gavage with 1-chloroprene (p<0.0005) and 2-chloro-
proponal (p<0.05) and 1n the Incidence of local sarcomas In female Ha:IGR
Swiss mice treated with c_ls-l,3-d1chloropropene (p<0.0005) by subcutaneous
Injection.
4.2.3. Selected Pharmacok1net1cs Relevant to Interspedes Extrapolation.
U.S. EPA (1985a) evaluated the pharmacoklnetlcs of tetrachloroethylene
relevant to Interspecles dose-response extrapolation; the material 1n this
section 1s taken from U.S. EPA (1985a). It 1s generally recognized that the
cardnogenldty of the chlorinated ethylenes relates to their metabolic
conversion to biologically reactive Intermediates. The metabolism of
tetrachloroethylene has been Investigated 1n mice, rats and humans. In
general, the end metabolites have been poorly characterized In these
species, but there Is no experimental evidence that Indicates qualitative
differences 1n metabolic pathways.
Pharmacok1net1c/metabol1c evaluations following oral exposure considered
most relevant to species extrapolation Include Pegg et al. (1979), Schumann
et al. (1980), and Buben and O'Flaherty (1985).
Pegg et al. (1979) and Schumann et al. (1980) administered 14C-tetra-
chloroethylene In corn oil to Sprague-Dawley rats and B6C3F1 mice as single
1ntragastr1c doses of 1 or 500 mg/kg. 14C radioactivity was measured In
exhaled breath, urine, feces and carcass for 72 hours following dosing. In
addition, pulmonary excretion of parent compound was monitored. The results
of these Investigations are shown 1n Table 4-1.
For rats, 29 and 10% of the 1 and 500 mg/kg doses, respectively, were
metabolized, which Indicated that metabolism was both limited and
saturable. In mice given 500 mg/kg, 17% of the dose was metabolized.
0009H -24- 03/08/88
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0009H
-25-
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Buben and O'Flaherty (1985) examined tetrachloroethylene metabolism 1n
male mice dosed 5 days/week for 6 weeks by gavage using a corn oil vehicle.
They found that metabolism was both saturable and dose-dependent. Metabo-
lism was evaluated based on the level of urinary TCA. U.S. EPA (1985a)
judged that urinary TCA 1s expected to represent 70-80% of total tetra-
chloroethylene metabolized. The data from this study are shown 1n Figure
4-1. Comparison of the amount metabolized from the Schumann et al. (1980)
and Pegg et al. (1979) studies, where mice were given 500 mg/kg to the
amounf metabolized for a 500 mg/kg dose based on Figure 4-1, Indicates good
agreement between the two studies. The molar equivalent metabolized dose
from Figure 4-1 (367 ymol) represents 8054 of the molar equivalent metabo-
lized dose (455 ymol) from Schumann et al. (1980) and Pegg et al. (1979).
4.3. OTHER RELEVANT DATA
Tetrachloroethylene elicited a positive response 1n the Salmonella
typhlmurlum reverse mutation assay and the host-mediated assay with mice and
using S. typhlmurlum (Cerna and Kypenova, 1977). Tetrachloroethylene was
negative 1n forward mutation assays with Escherlchla coll (Grelm et al.,
1975) and failed to Induce chromosomal aberrations 1n bone marrow cells of
mice that received 1 or 5 dally IntraperHoneal Injections of the compound
(Cerna and Kypenova, 1977).
4.4. WEIGHT OF EVIDENCE
IARC (1979) concluded that there was limited evidence that tetrachloro-
ethylene Is carcinogenic 1n mice, based on the Increased Incidence of
hepatocellular carcinomas 1n both sexes of mice following oral administra-
tion (NCI, 1977). Recent Inhalation studies with rats and mice (NTP, 1986)
Indicate that tetrachloroethylene 1s also carcinogenic by this route.
0009H -26- 03/08/88
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400 600 SOO WOO 000 1400 1600 WOO 2000
DOSE(mg/Vg)
FIGURE 4-1
Relationship Between the Tetrachloroethyle Dose and the Amount of
Total Urinary Metabolite Excreted per Day by Mice In Each Group
Source: U.S. EPA. 1985a
0009H
-27-
02/09/88
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Human cardnogenlclty data, consisting of a proportionate mortality study of
330 former laundry workers, was considered to be Inadequate for assessing
human cancer risk associated with exposure to tetrachloroethylene (IARC,
1982). Likewise, the evidence for tetrachloroethylene activity In short-
term tests was considered Inadequate (IARC, 1982). Applying the criteria of
the U.S. EPA (1986b) Carcinogen Assessment Guidelines for evaluating the
overall weight of evidence of cardnogenlclty to humans, tetrachloroethylene
has been tentatively designated 1n weight of evidence Group B2 - Probable
Human Carcinogen (U.S. EPA, 1986c). This conclusion has not yet been
formalized or "verified" by EPA pending a dialog between the agency and Us
science advisory board.
0009H -28- 03/08/88
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1986a,b) recommended a TWA-TLV of 50 ppm (335 mg/m3) and an
STEL of 200 ppm (1340 mg/m3) to prevent discomfort and subjective com-
plaints associated with prolonged exposure to 100-200 ppm. U.S. EPA (1980a)
recommended an ambient water quality criterion of 8.0 vg/l associated
with a cancer risk of 10~5 assuming dally consumption of 2 l water and
6.5 g contaminated aquatic organisms. An RfD of lxlO~2 mg/kg/day, based
on the rat oral gavage study by Buben and O'Flaherty (1985) Is presented In
IRIS (U.S. EPA, 1987) as a verified RfD.
0009H -29- 02/09/88
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD }
d
Tetrachloroethylene 1s a chemical that has been demonstrated to be
carcinogenic In animals, and for which data are sufficient for estimation of
carcinogenic potency. For the purposes of this document series, RfDs are
not estimated for compounds for which quantitative risk assessment based
upon cancer 1s conducted.
6.2. REFERENCE DOSE (RfD)
Tetrachloroethylene 1s a chemical that has been demonstrated to be
carcinogenic In animals, and for which data are sufficient for estimation of
carcinogenic potency. For the purposes of this document series RfDs are not
calculated when positive cancer data are available.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. From the data of Buben and O'Flaherty (1985), U.S. EPA
(1985a) estimated the quantity of metabolites that contributed to the
carcinogenic response for the NCI (1977) study with B6C3F1 mice.
Potency estimates expressed 1n terms of both metabolized and adminis-
tered dose are shown 1n Table 6-1. Potency 1n terms of administered dose
(A) was calculated from potency In terms of metabolized dose (M) by using
the relationship M=0.2A. This relationship was estimated by U.S. EPA
(1985a) and based on the data of Buben and O'Flaherty (1985). For
comparative purposes, potency was also calculated using metabolized dose
estimated from the data of Schumann et al. (1980); the estimates generated
by the two methods were similar. U.S. EPA (1985a) recommended that the
slope estimate calculated from tumor Incidence In female mice, S.lxlO"2
(mg/kg/day)"1, be used to represent the potency of tetrachloroethylene
0009H -30- 02/09/88
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because the data showed a clearer dose-response than for male mice. The
slope calculated on the basis of male mice was 6.8xlO~2 (mg/kg/day)"1,
which 1s consistent and supports that calculated from the female mouse data.
6.3.2. Inhalation. In the only Inhalation cancer bloassay available to
U.S. EPA (1985a), Rampy et al. (1977) did not find any statistically signi-
ficant difference 1n any tumor Incidence between control rats and those
exposed to tetrachloroethylene vapors at levels of 2 or 4 g/m3 (300 or 600
ppm, respectively), 6 hours/day, 5 days/week for 12 months. U.S. EPA
(1985a) calculated unit risks for Inhalation exposure using a variety of
pharmacoklnetlc approaches for route extrapolation. The unit risk of
4.8xlO~7 (vg/m3)"1 was recommended for use as the representative
estimate. The estimate was based upon the relationship between exposure
concentration and tetrachloroethylene metabolites In urine from the human
data of Bolanowska and Golacka (1972). In this study, five subjects were
exposed to 390,000 yg/m3 tetrachloroethylene for 6 hours. Metabolites
1n the urine were monitored for 20 hours. The quantity of metabolites for
the time period from the end of exposure up to 20 hours was taken directly
from the experimental data. The remainder of the area under the curve, 20
hours to Infinity, was estimated as follows:
Cxt1/2/0.693
where:
C = concentration of metabolites at the last sampling time
t1/2 = assumed to be 100 hours
Assuming that at low exposure concentrations, below those saturating metabo-
lism that the amount metabolized Is linearly related to the air concentra-
tion and the duration of exposure, the amount metabolized associated with 1
vg/m3 of tetrachloroethylene In air 1s:
(13 mg/39,000 mg/m3) x (24 hours/6 hours) = 1.33xlO~4 mg/day
or
1.9xlO~* mg metabolHes/kg/day/1 yg/m3 exposure
0009H -32- 03/08/88
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The cancer risk associated with exposure to 1 »jg/m3 tetrachloro-
ethylene 1s as follows (see Table 6-2):
2.5xlO~1 risk (mg metabolHes/kg/day)'1 x 1.9xlO~6 mg metabolites
produced/kg/day/1 jjg/m3 = 4.8xlO~7 (yg/m3)'1
More recently, U.S. EPA (1986a) has updated Us dose-response analysis
by using the results of the NTP (1986) bloassay with rats and mice as the
basis for cardnogenlclty risk analysis for Inhalation exposure to
tetrachloroethylene. Six sets of tumor Incidence data were used:
mononuclear cell leukemia 1n male and female rats, liver carcinomas 1n male
and female mice, and combined Incidences of liver adenomas and carcinomas 1n
male and female mice. The doses used 1n the NTP (1986) study were converted
to metabolized doses using a dose-metabolism relationship described In U.S.
EPA (1986a). These data are presented In Tables 6-2 and 6-3. The
2/3
metabolized dose Is expressed as mg/W /day, which represents the
metabolized dose per body surface area that 1s assumed to be equally potent
(equivalent) among species. The carcinogenic potency (slope) estimates were
calculated using the multistage model with these equivalent doses and
corresponding tumor Incidence data. The slope estimates calculated for the
six data sets are presented 1n Table 6-4 and range from 3.64xlO~2
9/1
(mg/w /day)"1 to 1.21xlO"i (mg/W^Vday)'1. U.S. EPA (1986a)
calculated unit risks ranging from 2.85xlO~7 to 9.47xlO~7 for humans
exposed to 1 yg/m3 In air based on these potency estimates. This range
of values Is adopted as the estimate of the carcinogenic potency of
tetrachloroethylene to humans exposed by Inhalation. The methods used to
calculate metabolized dose, potency and unit risks are described 1n detail
In U.S. EPA (1986a). The geometric mean of the six unit risk estimates was
5.78xlO~7
0009H -33- 02/09/88
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TABLE 6-2
Metabolized Dose and Incidence of Mononuclear Cell Leukemia
In Fischer 344 Rats In the NTP (1986) Inhalation Study3
Group
Male
Female
Exposure
Concentration
(ppm)
0
200
400
0
200
400
Human Equivalent
Metabolized Dose
(mg/W2/3/day)b
0
6.26
8.45
0
5.81
7.84
Incidence
Rate
28/50
37/50
37/50
18/50
30/50
29/50
aSource: U.S. EPA, 1986a
bMetabo!1zed dose = M (mg/kg/day) x (5/7) x W1/3, where M (mg/kg/day) 1s
the direct estimate of the dose metabolized; the factor 5/7 reflects that
animals were exposed only 5 days/week; and W (body weight) = 0.40 kg for
male rats and 0.32 kg for female rats. For convenience, the notation
mg/W2/3 1s used to Indicate the amount metabolized In terms of mg per
two-thirds of body weight, which Is assumed to be proportional to the body
surface area.
0009H -34- 02/09/88
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TABLE 6-3
Metabolized Dose and Incidence of Liver Tumors In Mice
In the NTP (1986) Inhalation Study3
Incidence Rate
Group
Male
Female
Exposure
Concentration
(ppm)
0
100
200
0
100
200
Human Equivalent
Metabolized Dose
(mg/W2/3/day)b
0
9.37
14.21
0
8.92
13.52
Carcinomas
7/49c
25/47
26/50
1/46
13/42
36/47
Adenomas/
Carcinomas
16/49
31/47
40/50
4/46
17/42
38/47
aSource: U.S. EPA, 1986a
Metabolized dose = M (mg/kg/day) x (5/7) x W1/3, where M (mg/kg/day) Is
the direct estimate of metabolized dose; 5/7 1s a factor to adjust for 5
days exposure In a week; and W (body weight) = 0.0374 kg for male mice and
0.0322 kg for female mice.
C0nly animals surviving beyond 60 weeks are Included In the denominator.
The first death from liver tumor occurred at 60 weeks.
0009H
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02/09/88
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TABLE 6-4
Unit Risk Estimates Calculated on the Basis of Different
Data Sets from the NTP (1986) B1oassaya
Data Set
Risk Due to
One Unit (mg/W2/3)b
Metabolized Dose
Risk Due to 1 yg/ma
of Tetrachloroethylene
In Air
Rat (leukemia):
Males
Females
Mouse (liver carcinomas):
Males
Females
Mouse (liver adenomas/
carcinomas):
Males
Females
Geometric mean:
1.21XKT1
l.OlxKT1
6.67xlO~2
3.64xlO~2
l.OSxKT1
5.05xlO"2
7.38x10'2
9.47x10'7
7.91xlO~7
5.22xlO~7
2.85xlO"7
8.46xlO~7
3.95xlO~7
5.78xlO~7
aSource: U.S. EPA, 1986a
bThe metabolized dose expressed 1n mg/W2/3 (where W 1s body weight) 1s
assumed to be equivalent (I.e., equally potent, among species).
0009H
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02/09/88
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0009H -46- 02/09/88
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0009H -47- 02/09/88
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0009H -48- 02/09/88
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