vvEPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-073
October 1980
e.a-
Ambient
Water Quality
Criteria for
Tetrachloroethylene
-------
AMBIENT WATER QUALITY CRITERIA FOR
TETRACHLOROETHYLENES
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
-------
DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
ii
-------
FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
-------
ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
John H. Gentile, ERL-Gulf Breeze
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Richard Bull (author) HERL
U.S. Environmental Protection Agency
Steven D. Lutkenhoff (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Herbert Cornish
University of Michigan
Charalingayya Hiremath
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Benjamin Van Duuren
New York University Medical Center
Roy E. Albert*
Carcinogen Assessment Group
U.S. Environmental Protection Agency
James Bruckner
University of Texas Medical School
Jacqueline Carr
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Kris Khanna, ODW
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, T. Highland, B. Gardiner.
*CAG Participating Members: Elizabeth L. Anderson, Larry Anderson, Dolph Arm car,
Steven eSyard, David L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard Haberman,
Charalingayya Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dharm B. Singh, and Todd W. Thorslund.
IV
-------
TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxicity B-l
Chronic Toxicity 8-3
Plant Effects B-3
Residues B-3
Miscellaneous B~4
Summary B-4
Criteria B-5
References B-12
Mammalian Toxicology and Human Health Effects: C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-l
Inhalation C-3
Dermal C-3
Pharmacokinetics C-3
Absorption C-3
Distribution C-4
Metabolism C-7
Excretion C-10
Effects C-10
Acute, Subacute, and Chronic foxicity C-10
Synergism and/or Antagonism C-16
Teratogenicity C-17
Mutagenicity C-18
Carcinogenicity C-19
Criterion Formulation C-22
Existing Guidelines and Standards C-22
Current Levels of Exposure C-22
Basis and Derivation of Criterion C-24
References C-27
Appendix C-38
v
-------
CRITERIA DOCUMENT
TETRACHLOROETHYLENE
CRITERIA
Aquatic Life
The available data for tetrachloroethylene indicate that acute and
chronic toxicity to freshwater aauatic life occur at concentrations as low
as 5,280 and 840 ug/1, respectively, and would occur at lower concentrations
among species that are more sensitive than those tested.
The available data for tetrachloroethylene indicate that acute and
chronic toxicity to saltwater aauatic life occur at concentrations as low as
10,200 and 450 ug/1, respectively, and would occur at lower concentrations
among species that are more sensitive than those tested.
Human Health
For the maximum protection of human health from the potential carcino-
genic effects due to exposure of tetrachloroethylene through ingestion of
contaminated water and contaminated aauatic organisms, the ambient water
concentrations should be zero based on the non-threshold assumption for this
chemical. However, zero level may not be attainable at the present time.
Therefore, the levels which may result in incremental increase of cancer
risk over the lifetime are estimated at 10" , 10" , and 10~ . The
corresponding recommended criteria are 8.0 ug/1, 0.80 ug/1, and 0.08 ug/1,
respectively. If the above estimates are made for consumption of aauatic
organisms only, excluding consumption of water, the levels are 88.5 wg/1,
8.85 ug/1, and 0.88 ug/1, respectively.
VI
-------
INTRODUCTION
Tetrachloroethylene (1,1,2,2-tetrachloroethylene, perchloroethlyene,
PCE) is a colorless, nonflammable liquid used primarily as a solvent in the
dry cleaning industries. It is used to a lesser extent as a degreasing sol-
vent in metal industries (Windholz, 1976).
PCE has the molecular formula C2C14 and a molecular weight of
165.85. Other physical properties of PCE include a melting point of
-23.25°C, a density of 1.623 g/ml, a vapor pressure of 19 mm Hg, a water
solubility of 483 ug/ml and an octanol/water partition coefficient of 339
(log P = 2.53) (Patty, 1963; U.S. EPA, 1978a). The log P value indicates
that PCE has an affinity for lipid material and may bioaccumul-ate.
Perchloroethylene can be widely distributed in the environment, as evi-
denced by its detection in trace amounts in U.S. and English waters, and in
aquatic organisms, air, foodstuffs, and human tissue in England (McConnell,
et al. 1975; U.S EPA, 1978b).
The highest levels of PCE are found in the work environments of the
commercial dry cleaning and metal degreasing industries [National Institute
for Occupational Safety and Health (NIOSH), 1976].
Although PCE is released into water via aqueous effluents from produc-
tion plants, consumer industries, and household sewage, its level in ambient
water is reported to be minimal due to its high volatility.
A-l
-------
REFERENCES
McConnell, 6., et al. 1975. Chlorinated hydrocarbons and the environment.
Endeavour. 34: 13.
National Institute for Occupational Safety and Health. 1976. Criteria for
a recommended standard. Occupational exposure to tetrachloroethylene (per-
chloroethylene). U.S. Dept. Health Edu. Welfare, Washington, D.C.
Patty, F. 1963. Aliphatic halogenated hydrocarbons Ind. Hyg. Toxicol.
2: 1314.
U.S. EPA. 1978a. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646. U.S. Environ. Prot.
Agency, Washington, D.C.
U.S. EPA. 1978b. Statement of basis and purpose for an amendment to the
national primary drinking water regulations on a treatment criteria for syn-
thetic orgnics. Off. Drinking Water, Crit. Stand. Div., U.S. Environ. Prot.
Agency, Washington, D.C.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Rahway,
New Jersey.
A-2
-------
Aquatic Life Toxicology*
INTRODUCTION
The data base for tetrachloroethylene and freshwater organisms in-
dicates that the rainbow trout is most sensitive and the bluegill and fat-
head minnow are about as sensitive as Daphnia magna. An embryo-larval test
has been conducted with the fathead minnow and the ratio between the acute
and chronic values for this species is 16. The data for an alga indicate
that it is much more resistant than the fishes and cladoceran. Compared to
the dichloroethylenes and trichloroethylene, tetrachloroethylene is more
acutely toxic to fish and invertebrate species.
Acute and chronic tests have been conducted with the mysid shrimp and
the acute value is 23 times the chronic value which result suggests a sub-
stantial accumulative chronic toxicity. Compared to 1,1-dichloroethylene,
tetrachloroethylene is much more toxic to the mysid shrimp. The saltwater
alga, Skeletonema costatum, is much more resistant than the mysid shrimp,
and the alga, Phaeodactylum tricornutum, has a resistance comparable to that
for the mysid shrimp.
EFFECTS
Acute Toxicity
Daphnia magna has been tested with tetrachloroethylene (U.S. EPA, 1978)
and the 48-hour EC5Q is 17,700 yg/1 (Table 1). The midge is only slightly
more resistant with a 48-hour LC5Q value of 30,840 yg/1.
*The reader is referred to the Guidelines for Deriving Water Quality
Criteria for the Protection of Aquatic Life and Its Uses in order to better
understand the following discussion and recommendation. The following
tables contain the appropriate data that were found in the literature, and
at the bottom of each table are calculations for deriving various measures
of toxicity as described in the Guidelines.
B-l
-------
The influence of the solvent carrier, dimethylformamide, has been stud-
ied using the rainbow trout (U.S. EPA, 1980), and the 96-hour LC,-Q values
were 5,800 and 4,800 wg/1 with and without the solvent, respectively (Table
1).
Alexander, et al. (1978) compared the toxicity of tetrachloroethylene
to the fathead minnow using static unmeasured and flow-through measured
procedures, the 96-hour LC5Q values were 21,400 and 18,400 ug/l,
respectively (Table 1). The flow-through result is consistent with that
determined by U.S. EPA (1980) who reported a 96-hour LC5Q of 13,460 ug/l.
The bluegill (U.S. EPA, 1978) was similarly sensitive with a 96-hour IC™
value of 12,900 yg/1.
The data from acute static tests with the bluegill under similar condi-
tions (U.S. EPA, 1978) in this and other documents on chloroethylenes show a
correlation between increasing chlorination and toxicity. The 96-hour
LC5Q values for this species are 73,900 and 135,000 yg/1 for 1,1- and 1,2-
dichloroethylene, respectively, 44,700 yg/1 for trichloroethylene, and
12,900 ug/1 for tetrachloroethylene. These results indicate an increase in
the lethal effect on bluegills with an increase in chlorination. This tox-
icity correlation for Daphnia magna data is not as clear. The 48-hour
LC50 values were 79,000, 85,200, and 17,700 ug/1 for 1,1-dichloroethylene,
/
trichloroethylene, and tetrachloroethylene, respectively.
The mysid shrimp has been tested (U.S. EPA, 1978) using static unmea-
sured procedures, and the 96-hour IC™ value for sheepshead minnow was
10,200 ug/1 (Table 1). The 96-hour LC5Q value for sheepshead minnow is
between 29,400 and 52,200 wg/l (Table 6).
The 96-hour LCcg for the mysid shrimp and tetrachloroethylene under
static conditions is, as stated above, 10,200 yg/1 (U.S. EPA, 1978). The
B-2
-------
96-hour LC50 for the same species under similar test conditions (U.S. EPA,
1978) is 224,000 yg/1 for 1,1-dichloroethylene. As was suggested in the
freshwater part of this document, acute toxicity of these structurally re-
lated compounds increases with increasing chlorination.
Chronic Toxicity
A chronic value of 840 yg/l for the fathead minnow was obtained using
embryo-larval test procedures (Table 2). This result together with the re-
lated 1C value of 13,460 yg/l (Table 1) results in an acute-chronic
ratio of 16.
The chronic value for the mysid shrimp was 450 yg/l (Table 2) and the
acute-chronic ratio is 23. This ratio is very similar to that for the fat-
head minnow.
The geometric mean acute-chronic ratio for these two species is 19. A
summary of species mean acute and chronic values is given in Table 3.
Plant Effects
No adverse effects on chlorophyll a_ or cell numbers of the freshwater
alga, Selenastrum capricornutum, were observed at exposure concentrations as
high as 816,000 yg/l (Table 4).
Two saltwater species have been tested, providing EC5Q values that
range from 10,500 to 509,000 yg/l (Table 4).
Residues
The bioconcentration factor for bluegill (U.S. EPA, 1978) was deter-
mined to be 49 using 14C-tetrachloroethylene with verification by thin-
layer chromatography (Table 5). Equilibrium was reached within 21 days and
the depuration rate was rapid with a half-life of less than one day. Using
similar methods (U.S. EPA, 1978), the bioconcentration factor for trichloro-
ethylene was 17, not appreciably different from that for tetrachloroethy-
lene. No comparable data are available for any dichloroethylene.
B-3
-------
An estimated steady-state bioconcentration factor for tetrachloroethy-
lene and the rainbow trout was determined by Neely, et al. (1974) to be 39
(Table 6).
Miscellaneous
Alexander, et al. (1978) also determined a 96-hour EC5Q based on loss
of equilibrium by the fathead minnow. This was 14,400 yg/1 (Table 6), a
concentration slightly lower than the 96-hour 1C values of 18,400 and
21,400 ug/1 for the same species.
As stated earlier, the 96-hour LC5Q for the sheepshead minnow is be-
tween 29,400 and 52,200 yg/1 (Table 6). No 96-hour LC5Q could be calcu-
lated using the statistical procedures employed (U.S. EPA, 1978) since no
data for partial mortality were obtained.
Summary
The acute toxicity results of tests with two freshwater invertebrate
and three fish species and tetrachloroethylene range from 4,800 to 30,840
yg/1 with no appreciable differences between or within those two groups.
The chronic value for the fathead minnow is 840 yg/1, which result provides
an acute-chronic ratio of 16. The freshwater alga, Selenastrum capricornut-
um, was much more resistant than the invertebrate and fish species with no
observed effects at concentrations as high as 816,000 yg/1. Estimated and
measured bioconcentration factors for two fish species were within the range
of 39 to 49.
For mysid shrimp the 96-hour LCrQ and chronic values for tetrachloro-
ethylene were 10,200 and 450 yg/1, respectively, and these results yield an
acute-chronic ratio of 23. The saltwater alga, Skeletonema costatum, was
much more resistant than the shrimp with observed effects in the range of
504,000 to 509,000 yg/1. Another algal species, Phaeodactylum tricornutum,
was more sensitive with an EC5Q of 10,500 yg/1.
8-4
-------
CRITERIA
The available data for tetrachloroethylene indicate that acute and
chronic toxicity to freshwater aquatic life occur at concentrations as low
as 5,280 and 840 yg/1, respectively, and would occur at lower concentrations
among species that are more sensitive than those tested.
The available data for tetrachloroethylene indicate that acute and
chronic toxicity to saltwater aquatic life occur at concentrations as low as
10,200 and 450 u9/l» respectively, and would occur at lower concentrations
among species that are more sensitive than those tested.
B-5
-------
Table U Acute values for tetrachloroethylene
DO
I
CTl
Species
Cladoceran,
Daphnia magna
Midge,
Tanytarsus dlssimllls
Rainbow trout,
Sal mo gairdnerl
Rainbow trout.
Salmo galrdneri
Fathead minnow.
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow.
Pimephales promelas
Bluegl 1 1,
Lepomis macrochlrus
Mysid shrimp,
Mysidopsis bahia
LC50/EC50 Species Acute
Method* (ug/l) Value (ug/l)
FRESHWATER SPECIES
S, U 17,700 17,700
S, M 30,840 30,840
FT, M 4,800
FT, M 5,800 5,280
FT, M 13,460
FT, M 18,400
S, U 21,400 15,700
S, U 12,900 12,900
SALTWATER SPECIES
S, U 10,200 10,200
Reference
U.S. EPA, 1978
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, I960
Alexander, et al.
1978
Alexander, et al.
1978
U.S. EPA, 1978
U.S. EPA, 1978
* S = static, FT = flow-through, U = unmeasured, M = measured
No Final Acute Values are calculable since the minimum data base requirements are not met.
-------
Table 2. Chronic values for tetrachloroethylene
Species
Fathead minnow,
Plmephales promelas
Mysld shrimp,
Mysldopsls bah Ia
Chronic
Limits Value
Method* (ug/l) (ug/1) Reference
FRESHWATER SPECIES
E-L 500-1,400 840
SALTWATER SPECIES
LC
300-670
450
U.S. EPA, 1980
U.S. EPA, 1978
GO
I
* E-L = embryo-larva I, LC = life cycle or partial life cycle
Acute-Chronic Ratio
Species
Fathead minnow.
Plmephales promelas
Mysld shrimp.
Mysidopsis bahia
Chronic
Value
(ug/l)
840
450
Acute
Value
(U9/D
13,460*
10,200
Ratio
16
23
"This acute value was selected because it was determined by the same investigator
who determined the chronic value.
Geometric mean acute-chronic ratio = 19
-------
CO
I
oo
Table 3. Species mean acute and chronic values for tetrachloroethylene
Species Mean Species Mean
Number
5
4
3
2
1
1
Acute Value* Chronic Value
Species (ug/l) (yg/1)
FRESHWATER SPECIES
Midge, 30.840
Tany tarsus d I ss 1 mi 1 1 s
Cladoceran, 17,700
Daphnla magna
Fathead minnow, 15,700 840
Pimep hales promelas
Blueglll, 12,900
Lepomis macrochlrus
Rainbow trout, 5,280
Sal mo galrdner 1
SALTWATER SPECIES
Mysld shrimp, 10,200 450
Mysldopsis bah la
Acute-Chronic
Ratio**
16
23
* Rank from high concentration to low concentration by species mean acute value.
»*See the Guidelines for derivation of this ratio.
-------
Table 4. Plant values for tetrachloroethylene
Spec I es
Alga,
SeIenastrum caprIcornutum
Alga,
SeIenastrum capricornutum
ResuIt
Effect (yg/D
FRESHWATER SPECIES
Ch lorophy11 ^ >816,000
96-hr EC50
Cel I number
96-hr EC50
>816,000
Reference
U.S. EPA, 1978
U.S. EPA, 1978
Alga,
PhaeodactyIurn trIcornutum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
SALTWATER SPECIES
EC50
10,500 Pearson AMcConnell, 1975
Chlorophyll^ 509,000 U.S. EPA, 1978
96-hr EC50
Cel I number
96-hr EC50
504,000 U.S. EPA, 1978
-------
Table 5. Residues for tetrachloroethylene (U.S. EPA, 1978)
Bloconcentratlon Duration
Tissue Factor (days)
FRESHWATER SPECIES
Bluegll I, whole body 49 21
Lepomls macrochlrus
I
h-1
o
-------
Table 6. Other data for tetrachloroethylene
Result
Rainbow trout,
Salmo galrdnerl
Fathead minnow,
Plmephales promelas
Duration Effect
FRESHWATER SPECIES
Estimated
steady-state
b loconcentrat Ion
factor = 39
96 hrs Loss of
equi I i brium,
EC50
14,400
Reference
Neely, et al.
1974
Alexander, et al.
1978
03
I
Sheepshead minnow,
Cyprlnodon varlegatus
96 hrs
SALTWATER SPECIES
LC50
>29,400
<52,200
U.S. EPA, 1978
-------
REFERENCES
Alexander, H.C., et al. 1978. Toxicity of perchloroethylene, trichloro-
ethylene, 1,1,1-trichloroethane, and methylene chloride to fathead minnows.
Bull. Environ. Contam. Toxicol. 20: 344.
Neely, W.B., et al. 1974. Partition coefficient to measure bioconcentra-
tion potential of organic chemicals in fish. Environ. Sci. Tech. 8: 1113.
Pearson, C.R., and G. McConnell. 1975. Chlorinated C, and C2 hydrocar-
bons in the marine environment. Proc. R. Soc. London B. 189: 305.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No. 68-01-
4646.
U.S. EPA. 1980. Unpublished laboratory data. Environ. Res. Lab., Duluth,
Minnesota.
B-12
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingestion from Water
The National Organics Monitoring Survey (U.S. EPA, 1978a)
detected tetrachloroethylene (perchloroethylene, PCE) in nine of
105 drinking waters sampled between November 1976 and January 1977
(range,
-------
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent lip-
ids for consumed freshwater and estuarine fish and shellfish is 3.0
percent.
A measured steady-state bioconcentration factor of 49 was
obtained for tetrachloroethylene using bluegills (U.S. EPA, 1978b).
Similar bluegills contained an average of 4.8 percent lipids (John-
son, 1980). An adjustment factor of 3.0/4.8 = 0.625 can be used to
adjust the measured BCF from the 4.8 percent lipids of the bluegill
to the 3.0 percent lipids that is the weighted average for consumed
fish and shellfish. Thus, the weighted average bioconcentration
factor for tetrachloroethylene and the edible portion of all fresh-
water and estuarine aquatic organisms consumed by Americans is cal-
culated to be 49 x 0.625 = 30.6.
C-2
-------
Inhalation
General environmental PCE concentrations tend to be low.
Pearson and McConnell (1975) observed concentrations in city atmo-
spheres in Great Britain ranging from less than 0.68 to 68 ug/m .
In a suburb of Munich, Loechner (1976) found concentrations of 4 ug
PCE/m3 whereas air in the center of Munich contained 6 ug/m . Sur-
veys at eight locations in the U.S. indicated concentrations up to
6.7 ug/m as observed in urban areas and less than 0.013 ug/m in
rural areas (Lillian, et al. 1975). As with a number of related,
low molecular weight, chlorinated hydrocarbon solvents by far the
most significant exposure to PCE is in industrial environments
(Fishbein, 1976) . The major uses of PCE are in textile and dry
cleaning industries (69 percent), metal cleaning (16 percent), and
as a chemical intermediate (12 percent). Exposure to as much as
178 ppm (eight-hour, time-weighted average) of PCE have been ob-
served in the dry cleaning industry, particularly during high pro-
duction periods [National Institute for Occupational Safety and
Health (NIOSH), 1974].
Dermal
As with inhalation exposures, dermal exposures of significance
would be primarily confined to occupational exposure.
PHARMACOKINETICS
Absorption
Using inhalation exposure, Stewart, et al. (1961a) found that
PCE reached near steady-state levels in blood of human volunteers
with two hours of continuous exposure. Such results suggest a
rapid attainment of steady-state levels of PCE within the body.
C-3
-------
This may be deceptive, however, since the biological half-life of
PCE metabolites (as measured as total trichloro compounds) is 144
hours (Ikeda and Imamura, 1973). The relative stability of PCE
concentrations in blood beyond two hours probably represents a re-
distribution phenomenon common to a number of volatile anesthetics
(Goodman and Gilman, 1966). Later studies (Stewart, et al. 1970)
have shown that PCE concentrations in expired air immediately fol-
lowing exposure increase with repeated exposures over a five day
period. These data confirm that the steady-state implied by the
leveling off of blood PCE concentrations has not been reached with
short-term exposures. Retention of inhaled PCE has been estimated
to approximate 57 percent of the administered dose (Ogata, et al.
1971).
Stewart and Dodd (1964) demonstrated absorption of PCE through
the skin by immersing the thumbs of volunteers in PCE for 40 min-
utes and measuring the PCE in the exhaled air. High concentrations
of PCE in exhaled breath (160 to 260 yg/m ) were measurable five
hours after exposure.
Distribution
Once in the body, PCE tends to distribute to body fat. Al-
though the human data available are quite limited, in those indivi-
duals which have significant body burdens (subjects E and F in
Table 1) , ratios of fat to liver concentrations are greater than
six.
A more marked distribution of PCE to fat is observed using
controlled exposures to rats. The data in Table 2 (Savolainen, et
al. 1977) were obtained from animals who had been exposed to 1,340
C-4
-------
TABLE 1
Distribution of Tetrachloroethylene
in Human Tissue at Autopsy*
Concentrations
Subject Age
A 76
B 76
C 82
D 48
E 65
F 75
G 66
H 74
Sex
F
F
F
M
M
M
M
F
in ug/kg (wet
Tissue
Body fat
Kidney
Liver
Brain
Body fat
Kidney
Liver
Brain
Body fat
Liver
Body fat
Liver
Body fat
Liver
Body fat
Liver
Body fat
Body fat
tissue)
Tetrachloro-
ethylene
6
0.5
0.5
0.5
1
6
2
5
0.4
1.2
0.8
0.7
21
3.4
29.2
4.3
0.5
4
*Source: McConnell, et al. 1975
C-5
-------
TABLE 2
Changes in the Organ Content of PCE with Duration of Exposure
in Rats Having Prior History of PCE Exposure3
Duration o
Exposure
(h)
0
o 2
i
3
4
6
f
— Cerebrum
3
14
18
16
23
.1 H
.9 H
.0 H
.8 H
.7 H
h 0.6
h 2.8
h 0.8
h 2.9
h 1.2
Concentration
Cerebellum
2.2 H
10.3 H
12.0 H
11.3 H
15.3 H
h 0.7
1- 1.2
h 0.7
h 0.9
h 0.2
Lungs
1.6
7.6
8.7
9.9
12.2
+ 0
+ 1
+ 1
+ 2
+ 0
.3
.7
.6
.2
.6
Liver
5.8
17.8
22.4
22.2
26.7
+ 1.5
+ 4.5
+ 0.2
+ 0.1
+ 4.0
Per irenal
Fat
103 H
162 H
134 H
183 H
286 H
h 3
h 29
h 6
h 32
h 70
Blood
0.7
3.5
4.2
4.1
5.0
+ 0.2
-f 0.7
+ 0.2
+ 0.6
+ 1.1
Source: Savolainen, et al. 1977
yg/9 wet weight of tissue or yg/ml blood + range of two animals
-------
mg/m3 of PCE for six hours/day on four orior days. The zero time
values represent the residual PCE from these previous exposures on
the fifth day. Each succeeding time interval indicates the kinet-
ics of PCE build-up in each organ with the identical exposure condi-
tions on day 5. As can be seen in the table, a substantial residual
concentration of PCE is found in fat from the previous exposures.
PCE levels rise more or less continuously with duration of exposure
in brain, lungs, and fat, but tend to level out in blood and liver
after a three hour exposure. It is notable that brain concentra-
tions of PCE exceed blood levels by about fourfold and are indepen-
dent of duration of the exposure. On the other hand, the ratio of
concentration in fat relative to blood decreases aporoximately
150:1 to 50:1 over the course of the exposure. These data suggest
that turnover of PCE in fat is slower than that observed in other
tissues.
Metabolism
Metabolism of PCE has been studied extensively in humans and
experimental animals. In a qualitative sense metabolic products
appear to be similar in humans (Ikeda, et al. 1972; Ikeda, 1977)
and experimental animals (Yllner, 1961; Daniel, 1963; Ikeda and
Ohtsuji, 1972). The metabolic-pathway is summarized:
o I1
Cl
C
Cl
Cl
Cl
Cl
-^V"
Cl
r1 \ p l - c
Cl C
•c » ci—c—c
XC1 / XOH
Cl
Tetrachloro- Tetrachloro- Trichloro- Trichloroacetic
ethylene ethylene oxide acetvl chloride acid
C-7
-------
A similar reaction has been observed when PCE is exposed to oxyqen,
excess chlorine, and sunlight at 36 to 40°C (Frankel, et al. 1957) .
It has been postulated that the symmetrical epoxide formed from
tetrachloroethylene is not mutagenic (in E. coli K-,-) because it is
more stable and less reactive towards cellular nucleophiles than
the unsymmetrical epoxides formed from vinyl chloride, 1,1-di-
chloroethylene, and tr ichloroethylene, (Henschler, et al. 1976;
Henschler, 1977b) .
Ogata, et al (1971) reported that 1.8 percent of PCE retained
by humans was converted to trichloroacetic acid and 1.0 percent to
an unknown metabolite in 67 hours. Metabolism of PCE is apparently
saturable, in that exposures exceeding 70 mg/m do not increase
excretion of trichloroacetic acid in the urine (Ikeda, 1977) . How-
ever, metabolism of PCE is inducible by phenobarbital (Ikeda and
Imamura, 1973) and Aroclor 1254* (Moslen, et al. 1977), suggesting
that a higher percentage of metabolic conversion is possible under
certain conditions.
Schumann, et al. (1979) recently showed that the B6C3F, mouse
metabolizes a significantly greater proportion of doses of PCE than
does the Sprague-Dawley rat, and that the reactive metabolites of
PCE are bound to hepatic macromolecules in the mouse to a greater
degree than in the rat. Species differences reaarding the metabo-
lism and hepatic macromolecular binding of tetrachloroethylene were
evaluated in BecSF^ mice and Sprague-Dawley rats exposed to 10 or
600 ppm of C-PCE vapor for six hours or orally to 500 mg/kg. At
10 ppm, 63 percent of the total recovered radioactivity from the
mouse appeared in the urine as nonvolatile metabolite (s) and 12
*Registered Tradename for a mixture of polychlor inated biphenyls
C-8
-------
.percent was excreted unchanged in expired air (19 and 68 percent,
respectively, for the rat) . The mouse metabolized 7 to 8 times
more PCE per kg of body weight than did the rat following 10 ppm and
1.6 times at 500 mg/kg. Approximately 7 to 9 times more radio-
activity was irreversibly bound to hepatic macromolecules in the
mouse than in the rat at all exposure levels. No radioactivity was
detected bound to purified hepatic DMA at times of peak macromolec-
ular binding in the mouse. These results support the view that
mice are more sensitive than rats to the hepatic effects of PCE due
to greater metabolism of PCE to a reactive intermediate(s).
Excretion
PCE itself is primarily eliminated in humans from the body via
the lungs. The respiratory half-time for PCE elimination has been
estimated at 65 hours (Stewart, et al. 1961a, 1970; Ikeda and Ima-
mura, 1973).
Trichloroacetic acid, as a metabolite of PCE, is eliminated,
with a half-time of 144 hours, via the urine (Ikeda and Imamura,
1973). Since the half-time for elimination of trichloroacetic acid
as a metabolite of trichloroethylene is only 36 to 58 hours in nor-
mal humans (Ikeda and Imamura, 1973), this rate is more a reflec-
tion of delayed respiratory turnover of the parent compound than
for trichloroacetic acid itself. In all likelihood this is a re-
sult of the greater lipophilicity of PCE relative to trichloro-
ethylene.
C-9
-------
EFFECTS
Acute, Subacute, and Chronic Toxicity
As with all other members of the chloroethylene family, acute
effects of PCE are very much dominated by central nervous system
depression. Because of its widespread use in industry the acute
effects on the central nervous system of PCE have been studied
under controlled conditions using human volunteers. The first of
these studies, by Carpenter (1937), exposed individuals to concen-
trations of PCE averaging 3,183 and 6,258 mg/m for 95 and 130 min-
utes, respectively. At the low concentration sensory changes and a
slight feeling of elation were observed. However, at the higher
concentration more definite signs of central nervous system depres-
sion were observed, i.e., lassitude, mental fogginess and exhilara-
tion. When this concentration was raised to 10,000 mg/m signs of
inebriation were observed and at 13,400 mg/m all were forced to
leave the chamber within 7.5 minutes. Rowe, et al. (1952) report-
ed the exposure of humans to vapor concentrations of PCE averaging
710 mg/m failed to produce significant central nervous system
effects whereas minimal effects could be observed at 1,340 mg/m .
Stewart, et al. (1961a) noted impaired ability to perform a
Romberg test, a measure of reflex coordination, in volunteers sub-
jected to 1,300 mg/m for more than 30 minutes. In a later paper
this same group (Stewart, et al. 1970), found that three of their
subjects were not capable of performing a normal Romberg test after
three hours of exposure to 670 mg/m PCE. In addition, 25 percent
of the individuals reported subjective complaints ranging from mild
irritation, lightheadedness and mild frontal headache, to feeling
slightly sleepy and experiencing some difficulty in speaking.
C-10
-------
More recently, Stewart, et al. (1977) examined a group of 12
volunteers exposed to 168 and 670 mg PCE/m for 5.5 hours a day
repeated up to 53 days. In this study they were unable to document
any consistent neurological changes due to PCE exposure, although
they did observe a statistically significant decrement in the per-
formance of a Flanagan coordination test (which the authors stated
as being inconsistent). In a group of workers occupationally ex-
posed to concentrations of approximately 400 mg/m (one for 15
years) subjective complaints, such as headache, fatigue, somno-
lence, dizziness, and a sensation of intoxication were noted (Medek
and Kovarik, 1973). In confirmation of shorter-term volunteer
studies no objective neurological effects could be associated with
PCE exposure.
Rowe, et al. (1952) indicated that rats, guinea pigs, rabbits
and monkeys exposed repeatedly for seven hours per day displayed no
changes in behavior at vapor concentrations of PCE up to 2,720
mg/m . At 10,999 mg/m , rats were drowsy during the first week of
exposure. However, in the second week marked salivation, restless-
ness, irritability, and loss of equilibrium and coordination were
observed. Rowe, et al. (1952) suggested that this resulted from an
hypercholinergic state since the excited state could be prevented
by atropine.
Goldberg, et al. (1964) reported that PCE caused an 80 percent
loss of both avoidance and escape responses in rats after a single
four-hour exposure to 15,400 mg/m . These effects were primarily
attributable to an overt ataxia. In contrast, Savolainen, et al.
(1977) observed increased ambulation in the open field by rats
-------
exposed to 1,340 mg/m for five days, six hours daily. These
changes were paralleled by a small but significant decrease in
brain RNA content and an increase in nonspecific cholinesterase
activity. The only indications of long-term effects on the central
nervous system are findings of changed EEG patterns in rats associ-
ated with increased electrical impedence of the cerebral cortex at
exposures as low as 100 mg PCE/m , 4 hour/day for 15 to 30 days
(Dmitrieva, 1966; Dmitrieva and Kuleshov, 1971). These effects
were reported to be associated with sporadic swollen and vacuolized
protoplasm in some cells (Dmitrieva and Kuleshov, 1971). Although
information available from experimental animals is limited, it
generally supports findings of acute central nervous system depres-
sion. As in the case of human clinical studies essentially no
information is available concerning long term effects (i.e., great-
er than one week exposures) of PCE on the central nervous system.
As suggested by Stewart, et al. (1970) , the current threshold limit
value (50 ppm) [American Conference of Governmental Industrial
Hygienists (ACGIH), 1977] for PCE has a negligible factor of safety
even for short-term exposures. That more serious central nervous
system problems may be associated with chronic PCE exposure is sug-
gested by a few sporadic case reports (Gold, 1969; McMullen, 1976)
and small scale epidemiological and clinical studies (Coler and
Rossmiller, 1953). However, the latter studies have often been
complicated by exposures to other solvents (Tuttle, et al. 1977).
Short-term PCE exposures at higher concentrations can produce
damage to kidney and liver (Klaasen and Plaa, 1967). Increased
weight and mild to marked central fatty degeneration of the liver
C-12
-------
were observed with up to 158 repeated 7-hour exposures of guinea
pigs to PCE at 670 to 16,750 mg/m3 (Rowe, et al. 1952). Lower con-
centrations appeared to be less effective. Rabbits, rats, and mon-
keys appeared less sensitive in that no significant effects were
observed following repeated 7-hour exposures at concentrations up
to 2,680 mg/m3. Rowe, et al. (1952) indicated that at 2,680 mg
PCE/m3 increased kidney weights were also observed in guinea pigs
but not in other species. However, the prior work of Carpenter
(1937) had shown congestion and granular swelling in the kidney of
rats exposed for eight hours, five days per week over a period of
seven months to 1,540 mg/m3. More recently, the National Cancer
Institute's (NCI) carcinogenesis bioassay of PCE revealed a high
incidence of toxic nephropathy in both male and female 8603^ mice
exposed orally to 536 and 386 mg PCE/kg, respectively, for five
days a week for 78 weeks (NCI, 1977). Similar results were ob-
tained in both male and female Osborne-Mendel rats exposed to 471
and 474 mg PCE/kg, respectively, over the same treatment course.
Kylin, et al. (1963) noted moderate fatty degeneration of the
liver with a single 240 minute exposure to 1,340 mg PCE/m . Expo-
sure to this same concentration four hours daily, six days a week
for up to eight weeks was found to increase the severity of the
lesions caused by PCE (Kylin, et al. 1965).
Fujii (1975) dosed male rabbits once orally with 2,158 mg/kg
of PCE and observed increases in serum lipoprotein concentrations
which were still evident two weeks after treatment. Changes in
serum enzyme activities (i.e., alkaline phosohatase, glutamate-
oxalacetate transaminase, glutamate-pyruvate transaminase), indic-
C-13
-------
a'tive of liver damage, were mild and transient. Single doses of
PCE (0.3 to 2.0 ml/kg) injected by Cornish, et al. (1973), appeared
to increase serum glutamate oxalacetate transaminase activity.
Liver and/or kidney damage in humans have been reported. Out
of six case histories of acute, high-level inhalation exposure to
PCE where there was evidence of liver damage (Hughes, 1954; Stew-
art, et al. 1961b; Meckler and Phelos, 1966; Saland, 1967; Stewart,
1969; Hake and Stewart, 1977), kidney damage was detected in just
one individual (Hake and Stewart, 1977). Hepatic injury itself is
uncommon in persons exposed to PCE vapors, as there are numerous
accounts of intoxication where there was no detectable organ
damage.
The data of Coler and Rossmiller (1953) involving a group of
men occupationally exposed to concentrations of 1,890 to 2,600
mg/m of PCE supports animal data indicating that liver iniury may
result from PCE. Three of seven men had evidence of impaired liver
function. An individual accidentally acutely exposed to an anes-
thetic dose of PCE exhibited a transient increase in serum gluta-
mate oxalacetate transaminase activity and a delayed elevation of
urinary urobilinogen, both indicative of hepatic injury (Stewart,
1969) .
The possible cardiovascular effects of PCE have not been sys-
tematically investigated. Unlike its analog, trichloroethvlene,
PCE does not appear to sensitize the myocardium to epinephrine
(Reinhardt, et al. 1973). However, in controlled human studies
involving exposure to PCE at 1,140 mg/m3 for three hours Ogata, et
C-14
-------
al. (1971) indicated an increase of diastolic blood pressure aver-
aging 15 mm Hg compared to a decrease of 5 mm Hg in a non-exposed
group over the same time interval. Systolic blood pressure changed
only slightly in both groups (+2 mm Hg with PCE and -4 mm Hg in
controls). Although not specifically addressed in the discussion
of the results, a group of six volunteers exposed to 1,300 mg
PCE/m3 for 187 minutes uniformly showed an increase in systolic
blood pressure which averaged 13 mm Hg (Stewart, et al. 1961a).
Other groups exposed to the same concentration for only 83 minutes
or to a lower concentration of PCE (670 mg/m ), showed no consis-
tent change in blood pressure.
PCE, as with a number of other low molecular weight chlori-
nated compounds, greatly increases bile duct-pancreatic fluid flow
in rats (Hamada and Peterson, 1977). The resulting fluid has a
markedly depressed protein content and a significantly altered
ionic composition. The physiological significance of these obser-
vations has not yet been determined.
Occasional reports have associated PCE with the symptomatology
of more serious chronic diseases such as Raynaud's disease (Lob,
1957; Sparrow, 1977). Sparrow (1977) has reported a case which in-
volved depressed immune function, mildly depressed liver function,
polymyopathy, and severe acrocyanosis. Such isolated reports are
difficult to evaluate, but deserve mention here because of a simi-
lar disease which has been observed in vinyl chloride workers.
It should be noted here that very little work has been done to
delineate the absorption and distribution of orally ingested PCE.
C-15
-------
JBynergism and/or Antagonism
As PCE is metabolized by mixed function oxidases, compounds
which alter the functional activity of this system might be expect-
ed to affect its toxicity. Cornish, et al. (1973, 1977), however,
were unable to demonstrate that phenobarbital pretreatment was cap-
able of modifying the hepatotoxicity of PCE. Moslen, et al.
(1977) and Reynolds and Moslen (1977) report that PCE oroduces
vacuolization of rough endoplasmic reticulum and increases in serum
glutamate oxalacetate transaminase activity following Aroclor
125^y induction of mixed function oxidases. It must be kept in
mind that only a small percent of retained PCS is metabolized when
compared to other members of the chloroethylene series (Ogata, et
al. 1971). Consequently, both the experiments conducted by Moslen,
et al. (1977) and Reynolds and Moslen (1977) were of too short
duration to fully assess the influence of metabolism on the long-
term toxicity of PCE.
Intolerance of alcohol has been reported with PCE exposure
(Gold, 1969) . As both compounds are central nervous system depres-
sants such effects are to be expected. There do not appear to be
any documented metabolic interactions of PCE with alcohol as there
are with trichloroethylene (Cornish and Adefuin, 1966; Gessner,
1973) . Stewart, et al. (1977) were unable to document any signifi-
cant interactions between alcohol or diazepam with PCE exposures up
to 670 mg/m . However, the question of synergism between ethanol
and PCE has not been addressed experimentally over a sufficiently
large dose range to rule out such an interaction.
C-1S
-------
PCE interactions with benzene and toluene have been studied
systematically with lethality as an endpoint (Withey and Hall,
1975). Intubation of rats with mixtures of benzene and PCE yielded
a combined toxicity which was only slightly less than additive.
Mixtures of toluene and PCE resulted in LD5Q values of less than
that predicted for simple additivity, indicating synergistic
effects.
Since PCE is metabolized to trichloroacetic acid there may be
a possibility of its synergizing with compounds, such as warfarin,
that bind significantly with serum albumin (Wardell, 1974). Al-
though this has been suggested for trichloroethylene (Ertle, et al.
1972), this question has not been systematically investigated with
PCE.
Teratogenicity
Only one report has appeared concerning the possibility of
PCE-induced teratogenesis (Schwetz, et al. 1975). Female rats and
mice were exposed to 2,000 mg PCE/m for seven hours daily on days 6
to 15 of gestation. Primary effects of PCE included a decrease in
fetal body weight of mice, a small but significant increase in
fetal resorptions in the rat, subcutaneous edema in mice pups, and
delayed ossification of skull bones and sternabrae in the mice.
These effects were mild, leading the authors to conclude that PCE
was not teratogenic. However, it must be oointed out that these
experiments were conducted with only one dose, which was only three
times greater than the current TLV and involved intermittent (i.e.,
seven hours/day) exposure to the chemical during a limited segment
(10 days) of a short gestational period (21 days). If PCE behaves
-------
in mice as it does in humans, at least five days exposure would be
necessary to achieve steady-state concentrations in the animal.
Although the effects were minor, they were statistically signifi-
cant. Additional work is necessary to clarify whether PCE possess-
es teratogenic activity.
Mutagenicity
Henschler (1977a,b) and coworkers have postulated that the
mutagenicity and carcinogenicity of chloroethylenes are dependent
upon the reactivity of their metabolically formed epoxide interme-
diates. Unsymmetrically substituted chlorines result in unbalanced
electron withdrawal by chlorine atoms and a more reactive epoxide
intermediate. Support for this hypothesis is gained from the
demonstration of an increased rate of spontaneous mutation in E.
coli K-^2 in the presence of liver microsomes when treated with
chloroethylene (vinyl chloride), 1,1-dichloroethylene, and tri-
chloroethylene, and an absence of increased rate of mutation with
the symmetrically substituted 1,2-dichloroethylenes and tetra-
chloroethylene (Greim, et al. 1975). Comparison of the compounds
using Salmonella typhimurium was said not to be possible because of
a high primary toxicity of some of the compounds (Henschler,
1977a,b). Nevertheless, Cerna and Kypenova (1977) indicate finding
elevated mutagenic activity in Salmonella strains sensitive to both
base substitution and frameshift mutation treated with PCE and cis-
1,2-dichloroethylene, both symmetrically substituted compounds.
However, these data are insufficient evidence as to the mutagenici-
ty of PCE.
C-18
-------
Bonse, et al. (1975) has shown that tetrachloroethylene oxide
was reasonably stable but that the trichloroacetvl chloride formed
from the epoxide was hiqhly reactive. The acyl halide was found to
covalently bind with cellular constituents. This may account for
the discrepancy of the prediction of Henschler (1977b) regarding
the carcinogenicity of PCE (NCI, 1977).
Carcinogenicity
PCE has been demonstrated to be a liver carcinogen in BSCSF-j^
mice (NCI, 1977). Results in Osborne-Mendel rats were negative,
but a high rate of early mortality precluded use of rat data in
evaluating the carcinogenicity of PCE. Furthermore, recent data in
which carbon tetrachloride was used as a positive control revealed
that Osborne-Mendel rats have a low sensitivity to induction of
hepatocellular carcinoma by chlorinated organic compounds in gen-
eral (NCI, 1976).
The only tumor which occurred in either male or female B6C3F^
mice that could be related to PCE administration was hepatocellular
carcinoma. The data are depicted in Table 3.
Low dose males received a time weighted average dose of 536
mg/kg, 5 days/week for 78 weeks. High dose males received 1,072
mg/kg on the same schedule. Low dose and high dose female groups
received 386 and 772 mg/kg, respectively, also on the same
schedule.
Male and female rats exposed for 12 months to 300 and 600 ppm
of a PCE formulation by inhalation did not show evidence of carci-
nogenic effects during the 12-month observation period following
termination of exposure (Leong, et al. 1975). However, the mortal-
C-19
-------
TABLE 3
Incidence of Hepatocellular Carcinoma
in PCE-treated B6C3F, Mice*
Males Females
Control 2/17 2/20
Vehicle Control 2/20 0/20
Low dose 32/49 (536 mg/kg) 19/48 (386 mg/kg)
High dose 27/48 (1,072 mg/kg) 19/49 (772 mg/kg)
*Source: NCI, 1977
C-20
-------
jLty of male rats exposed to 600 ppm was significantly higher than
that of the controls. Gross pathological examination failed to
detect any differences between either treatment group and the con-
trols.
No systematic studies of PCE exposure and the incidence of
human cancer seem to be available.
C-21
-------
CRITERION FORMULATION
Existing Guidelines and Standards
Existing tetrachloroethylene (PCE) standards are primarily
applicable to occupational exposures. The American Conference of
Governmental Industrial Hygienists threshold limit value (TLV),
listed in Table 4, has been established primarily on the basis of
measurable deficits in central nervous system function resulting
from short-term exposures of healthy male volunteers. As Stewart,
et al. (1970) point out, this figure incorporates a negligible fac-
tor of safety even for this group. Thus, sensitive populations or
the possibility of other environmental conditions which might syn-
ergize with PCE toxicity have not been considered (ACGIH, 1977).
Additionally, it does not yet incorporate consideration of PCE car-
cinogenicity (NCI, 1977).
Current Levels of Exposure
The National Organics Monitoring Survey (U.S. EPA, 1978a)
detected tetrachloroethylene (perchloroethylene, PCE) in nine of
105 drinking waters sampled between November 1976 and January 1977
(range, < 0.2 to 3.1 ug/1; median ^ 0.2 ug/1). The mean concentra-
tion of the nine positive samples was 0.81 ug/1. PCE was one of two
halogenated compounds indentified both in the drinking water and in
the plasma of individuals living in New Orleans (Dowty, et al.
1975) .
No data were found on levels of PCE in United States food. In
England, PCE concentrations in foods ranged from nondetectable
amounts (<0.01 ug/kg) in orange juice to 13 ug/kg in English but-
ter (McConnell', et al. 1975) .
C-22
-------
TABLE 4
Industrial Hygiene Standards for
Tetrachloroethylene in Various Countries*
3 Calculated
mg/m Allowable Daily Exposure
mg/day
USA 670 4,793
German Democratic Republic 250 1,786
USSR 1 7
*Source: Fishbein, 1976
C-23
-------
General environmental PCE concentrations tend to be low. Sur-
veys at eight locations in the U.S. found concentrations of up to
6.7 yg/m3 in urban areas and less than 0.013 ug/m in rural areas
(Lillian, et al. 1975). By far the most significant exposure to
PCE occurs in industrial environments (Fishbein, 1976). The maior
uses of PCE are in textile and dry cleaning industries (69 per-
cent) , metal cleaning (16 percent), and as a chemical intermediate
(12 percent). As with inhalation exposures, dermal exposures of
significance would be primarily confined to occupational exposure.
Basis and Derivation of Criterion
No additional human or animal data exist that may be used to
refine the AGCIH estimate of noncarcinogenic risks from exposure to
PCE, with the exception of the data of Dmitrieva (1966) and
Dmitrieva and Kuleshov (1971). These Russian papers suggest that
central nervous system effects can be observed in rats at exoosures
to PCE as low as 100 mg/m in an experiment lasting five months.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where aporopriate, zero) consistent with the protection of aauatic
organisms, human health, and recreational activities." Tetra-
chloroethylene is suspected of being a human carcinogen. Because
there is no recognized safe concentration for a human carcinogen,
the recommended concentration of tetrachloroethylene in water for
maximum protection of human health is zero.
Because attaining a zero concentration level may be infeasible
in some cases and in order to assist the Agency and states in the
possible future development of water quality regulations, the con-
C-24
-------
centrations of tetrachloroethylene corresponding to several incre-
mental lifetime cancer risk levels have been estimated. A cancer
risk level provides an estimate of the additional incidence of can-
cer that may be expected in an exposed population. A risk of 10
for example, indicates a probability of one additional case of can-
cer for every 100,000 people exposed, a risk of 10 indicates one
additional case of cancer for every million people exposed, and so
forth.
In the Federal Register notice of availability of draft ambi-
ent water quality criteria, EPA stated that it is considering set-
ting criteria at an interim target risk level of 10 ,10 , or
10 as shown in the following table.
Exposure Assumptions Risk Levels and Corresponding Criteria(l)
(per day) 7 _6 _5
10 7 10 6 10 5
2 1 of drinking water
and consumption of 0.08 yg/1 0.80 ug/1 8.00 ug/1
6.5 g fish and shell-
fish. (2)
Consumption of fish Q>88 n Q^5 n 88>5 n
and shellfish only. p^)/
(1) Calculated by applying a linearized multistage model as dis-
cussed in the Human Health Methodology Appendices to the Octo-
ber 1980 Federal Register notice which announced the avail-
ability of this document, to the animal bioassay data present-
ed in the Appendix and in Table 3. Since the extrapolation
model is linear at low doses, the additional lifetime risk is
directly proportional to the water concentration. Therefore,
water concentrations corresponding to other risk levels can be
derived by multiplying or dividing one of the risk levels and
C-25
-------
corresponding water concentrations shown in the table by fac-
tors such as 10, 100, 1,000, and so forth.
(2) Approximately 9 percent of the tetrachloroethylene exposure
results from the consumption of aquatic organisms which exhib-
it an average bioconcentration potential of 30.6-fold. ^he
remaining 91 percent of tetrachloroethylene exposure results
from drinking water.
Concentration levels were derived assuming a lifetime exposure
to various amounts of tetrachloroethylene, (1) occurring from the
consumption of both drinking water and aquatic life grown in waters
containing the corresponding tetrachloroethylene concentrations
and, (2) occurring solely from consumption of aquatic life grown in
the waters containing the corresponding tetrachloroethylene con-
centrations. Because data indicating other sources of tetrachloro-
ethylene exposure and their contributions to total body burden are
inadequate for quantitative use, the figures reflect the increment-
al risks associated with the indicated routes only.
Thus, the criterion associated with human lifetime carcino-
genic risk of 10" is 8.0 ug/1- Because additional data are ex-
pected to be published in the near future, this criterion will be
reevaluated at that time.
C-26
-------
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977.
Documentation of the threshold limit values. 3rd ed.
Bonse, G., et al. 1975. Chemical reactivity, metabolic oxirane
formation and biological reactivity of chlorinated ethylenes in the
isolated perfused rat liver preparation. Biochem. Pharmacol.
24: 1829.
Carpenter, C.P. 1937. The chronic toxicity of tetrachloroethyl-
ene. Jour. Ind. Hyg. Toxicol. 19: 323.
Cerna, M. and H. Kypenova. 1977. Mutagenic activity of chloro-
ethylenes analyzed by screening system tests. Mutat. Res.
46: 214.
Coler, F.R. and H.R. Rossmiller. 1953. Tetrachoroethvlene expo-
sure in a small industry. Arch. Ind. Hyg. Occup. ^ed. 8: 227.
Cornish, H]Hl and J. Adefuin. 1966. Ethanol potentiation of halo-
genated aliphatic solvent toxicity. Am. Ind. Hyg. Assoc. Jour.
27: 57.
Cornish, H.H., et al. 1973. Phenobarbital and organic solvent
toxicity. Am. Ind. Hyg. Assoc. Jour. 34: 487.
C-27
-------
Cornish, H.H., et al. 1977. Influence of aliphatic alcohols on
the hepatic response to halogenated olefins. Environ. Health Per-
spect. 21: 149.
Daniel, J.W. 1963. The metabolism of Cl-labelled trichloro-
ethylene and tetrachloroethylene in the rat. Biochem. Pharmacol.
12: 795.
Dickson, A.G. and J.P. Riley. 1976. The distribution of short
chained halogenated aliphatic hydrocarbons in some marine orga-
nisms. Mar. Pollut. Bull. 7: 167.
Dmitrieva, N.V. 1966. Maximum permissible concentration of tetra-
chloroethylene in factory air. Hyg. Sanit. 31: 387.
Dmitrieva, N.V. and E.V. Kuleshov. 1971. Changes in the bioelec-
tric activity and electric conductivity of the brain in rats chron-
ically poisoned with certain chlorinated hydrocarbons. Hyg. Sanit.
36: 23.
Dowty, B., et al. 1975. Halogenated hydrocarbons in New Orleans
drinking water and blood plasma. Science. 187: 75.
Ertle, T., et al. 1972. Metabolism of trichloroethylene in man.
Arch. Toxicol. 29: 171.
C-28
-------
Fishbein, L. 1976. Industrial mutagens and potential mutagens. I.
Halogenated aliphatic hydrocarbons. Mutat. Res. 32: 267.
Frankel, D.M., et al. 1957. Preparation and properties of tetra-
chlorethylene oxide. Jour. Org. Chem. 22: 1119.
Fujii, T. 1975. The variation in the liver function of rabbits
after administration of chlorinated hydrocarbons. Jap. Jour. Ind.
Health. 17: 81.
Gessner, P.K. 1973. Effect of trichloroethanol and of chloral
hydrate on the ir± vivo rate of disappearance of ethanol in mice.
Arch. Int. Pharmacodyn. 202: 392.
Giger, W. and E. Molnar-Kubiea. 1978. Tetrachloroethylene in con-
taminated ground and drinking waters. Bull. Environ. Contam. Toxi-
col. 19: 475.
Gold, J.H. 1969. Chronic perchloroethylene poisoning. Can. Psy-
chiat. Assoc. Jour. 14: 627.
Goldberg, M.E., et al. 1964. Effect of repeated inhalation of
vapors of industrial solvents on animal behavior. I. Evaluation of
nine solvent vapors on pole-climb performance in rats. Am. Ind.
Hyg. Assoc. Jour. 25: 369.
C-29
-------
Goodman, L.S. and A. Gilman. 1966. The Pharmacological Basis of
Therapeutics. MacMillan Co., New York.
Greim, H. , et al. 1975. Mutagenicity _in vitro and potential car-
cinogenicity of chlorinated ethylenes as a function of metabolic
oxirane formation. Biochem. Pharmacol. 24: 2013.
Hake, C.L. and R.D. Stewart. 1977. Human exposure to tetrachloro-
ethylene: Inhalation and skin contact. Environ. Health Perspect.
21: 231.
Hamada, N. and R.E. Peterson. 1977. Effects of chlorinated ali-
phatic hydrocarbons on excretion of protein and electrolytes by rat
pancreas. Toxicol. Appl. Pharmacol. 39: 185.
Henschler, D. 1977a. Metabolism of chlorinated alkenes and al-
kanes as related to toxicity. Jour. Environ. Pathol. Toxicol.
1: 125.
Henschler, D. 1977b. Metabolism and mutagenicitv of halogenated
olefins - A comparison of structure and activity. Environ. Health
Perspect. 21: 61.
Henschler, D., et al. 1976. Carcinogenic potential of chlorinated
ethylenes tentative molecular rules. INSERM Symp. Ser. 52: 171.
C-30
-------
Hughes, J.P. 1954. Hazardous exposure to some so-called safe sol-
vents. Jour. Am. Med. Assoc. 156: 234.
Ikeda, M. 1977. Metabolism of trichloroethylene and tetrachloro-
ethylene in human subjects. Environ. Health Perspect. 21: 239.
Ikeda, M. and T. Imamura. 1973. Biological half-life of tri-
chloroethylene and tetrachloroethylene in human subjects. Int.
Arch. Arbeitsmed. 31: 209.
Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excre-
tion of Fujiwara - reaction-positive substances in urine of humans
and rodents given trichloro- or tetrachloro- derivatives of ethane
and ethylene. Br. Jour. Ind. Med. 29: 99.
Ikeda, M., et al. 1972. Urinary excretion of total trichloro-com-
pounds, trichloroethanol and trichloracetic acid as a measure of
exposure to trichloroethylene and tetrachloroethylene. Br. Jour.
Ind. Med. 29: 328.
Johnson, K. 1980. Memorandum to D.W. Kuehl. U.S. EPA. March 10.
Klaassen, C.D. and G.L. Plaa. 1967. Relative effects of chlori-
nated hydrocarbons on liver and kidney function in dogs. Toxicol.
Appl. Pharmacol. 10: 119.
C-31
-------
Kylin, B., et al. 1963. Hepatotoxicity of inhaled trichloroethyl-
ene, tetrachloroethylene and chloroform. Single exposure. Acta
Pharmacol. Toxicol. 20: 16.
Kylin, B., et al. 1965. Hepatotoxicity of inhaled trichloroethyl-
ene and tetrachloroethylene. Long-term exposure. Acta Pharmacol.
Toxicol. 22: 379.
Leong, K.J., et al. 1975. Toxicologic and carcinogenic evaluation
of a perchloroethylene formulation by chronic inhalation in rats:
Interim report after 24 months. Toxicol. Res. Lab., Health Envi-
ron. Res., Dow Chemical Co., Midland, Michigan.
Lillian, D., et al. 1975. Atmospheric fates of halogenated com-
pounds. Environ. Sci. Technol. 9: 1042.
Lob, M. 1957. The dangers of perchloroethylene. Int. Arch.
Gewerbe-patholog. und Gewerbhyg. 16: 45.
Loechner, F. 1976. Perchloroathyleneine Bestandsaufnahme. Um-
welt. 6: 434.
McConnell, G. , et al. 1975. Chlorinated hydrocarbons and the
environment. Endeavour. 34: 13.
McMullen, J.K. 1976. Perchloroethylene intoxication. Br. Med.
Jour. 1563.
C-32
-------
Meckler, L.C. and O.K. Phelps. 1966. Liver disease secondary to
tetrachloroethylene exposure. Jour. Am. Med. Assoc. 197: 144.
Medek, V. and J. Kovarik. 1973. The effect of perchloroethylene
on the health of workers. Pracovni Lekarstvi. 25: 339.
Moslen, M.T., et al. 1977. Enhancement of the metabolism and
hepatoxicity of trichloroethylene and perchloroethylene. Biochem.
Pharmacol. 26: 369.
National Cancer Institute. 1976. Carcinogenesis bioassay of tri-
chloroethylene. CAS No. 79-01-6, NCI C6-TR-2 DREW Publ. No. (NIH)
76-802.
National Cancer Institute. 1977. Bioassay of tetrachloroethylene
for possible carcinogenicity. CAS No. 127-18-4 NCI-CG-TR-13 DHEW
Publ. No. (NIH) 77-813.
National Institute for Occupational Safety and Health. 1974.
Swiss Cleansing Co., Providence, R.I. Health Hazard Evaluation
Determination Rep. No. 73-86-114. Cincinnati, Ohio.
Ogata, M., et al. 1971. Excretion of organic chlorine compounds
in the urine of persons exposed to vapors of trichloroethylene and
tetrachloroethylene. Br. Jour. Ind. Med. 28: 386.
C-33
-------
Pearson, C.R. and G. McConnell. 1975. Chlorinated C^ and C2
hydrocarbons in the marine environment. Proc. R. Soc. Lond. B.
189: 305.
Reinhardt, C.F., et al. 1973. Epinephrine-induced cardiac arrhy-
thmia potential of some common industrial solvents. Jour. Occup.
Med. 15: 953.
Reynolds, E.S. and M.T. Moslen. 1977. Damage to hepatic cellular
membranes by chlorinated olefins with emphasis on synergism and
antagonism. Environ. Health Perspect. 21: 137.
Rowe, V.K., et al. 1952. Vapor toxicity of tetrachloroethylene
for laboratory animals and human subjects. AMA Arch. Ind. Hyg.
Occup. Med. 5: 566.
Saland, G. 1967. Accidental exposure to perchloroethylene. N.Y.
State Jour. Med. 67: 2359.
Savolainen, H. , et al. 1977. Biochemical and behavioral effects
of inhalation exposure to tetrachloroethylene and dichloromethane.
Jour. Neuropathol. Exp. Neurol. 36: 941.
Schumann, A.M., et al. 1979. The pharmacokinetics and macromolec-
ular interactions of perchlorethylene in mice and rats as related
to its oncogenicity. Toxicol. Appl. Pharmacol. (In press)
C-34
-------
Schwetz, B.A., et al. 1975. The effect of maternally inhaled tri-
chloroethylene, perchloroethylene, methyl chloroform, and methyl-
ene chloride on embryonal and fetal development in mice and rats.
Toxicol. Appl. Pharmacol. 32: 84.
Sparrow, G.P. 1977. A connective tissue disorder similar to vinyl
choride disease in a patient exposed to perchloroethylene. Clin.
Exp. Dermatol. 2: 17.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
Stewart, R.D. 1969. Acute tetrachloroethylene intoxication.
Jour. Am. Med. Assoc. 208: 1490.
Stewart, R.D. and H.C. Dodd. 1964. Absorption of carbon tetra-
chloride, trichloroethylene, tetrachloroethylene, methylene chlo-
ride and 1,1,1-trichloroethane through the human skin. Am. Ind.
Hyg. Assoc. Jour. 25: 439.
Stewart, R.D., et al. 1961a. Human exposure to tetrachloroethyl-
ene vapor. Arch. Environ. Health. 2: 516.
Stewart, R.D., et al. 1961b. Accidental vapor exposure to anes-
thetic concentrations of a solvent containing tetrachloroethylene.
Ind. Med. Surg. 30: 327.
C-35
-------
Stewart, R.D., et al. 1970. Experimental human exposure to tetra-
chloroethylene. Arch. Environ. Health. 20: 225.
Stewart, R.D., et al. 1977. Effects of perchloroethylene/drug
interaction on behavior and neurological function. DHEW (NIOSH)
Publ. No. 77-191.
Tuttle, T.C., et al. 1977. A behavioral and neurological evalua-
tion of dry cleaners exposed to perchloroethylene. DHEW (NIOSH)
Publ. No. 77-214.
U.S. EPA. 1978a. Statement of basis and purpose for an amendment
to the national primary drinking water regulations on a treatment
criteria for synthetic organics. Off. Drinking Water, Crit. Stand.
Div., U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1978b. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-4646.
U.S. Environ. Prot Agency.
U.S. EPA. 1980. Seafood consumption data analysis. Stanford Re-
search Institute, Menlo Park, California. Final Report, Task 11.
Contract No. 68-01-3887.
Wardell, W.M. 1974. Redistributional Drug Interactions: A Criti-
cal Examination of Positive Clinical Examples. In; P.L. Morselli,
et al. (eds.), Drug Interactions. Raven Press, New York. p. 123.
C-36
-------
Withey, R.J. and J.W. Hall. 1975. The joint toxic action of per-
chloroethylene with benzene or toluene in rats. Toxicol. 4: 5.
14
Yllner, S. 1961. Urinary metabolites of C-tetrachloroethylene
in mice. Nature. 191: 820. (Lond.)
C-37
-------
APPENDIX
Derivation of Criteria for Tetrachloroethvlene
Tetrachloroethylene administered by gavage to mice caused
hepatocellular carcinomas in both males and females in the NCI bio-
assay at both the high and low dose levels. The males were treated
at 1,072 and 586 mg/kg five times per week for 78 weeks and held
until 90 weeks for observation, ^he observed incidences of heoato-
cellular carcinomas in these dose groups and the matched vehicle
controls are shown in the table below.
The multistage model did not fit these data for tetrachloro-
ethylene sufficiently well. Therefore, the high dose group was
deleted and the criterion was recalculated. See the Human Health
Methodology Appendices to the October 1980 Federal Deaister notice
which announced the availability of this document for a complete
discussion. With a fish bioaccumulation factor of 30.6 the parame-
ters of the extrapolation model are:
Dose Incidence
(mg/kg/day) (No. resoondina/No. tested)
0 2/20
536 x 5/7 = 383 32/49
1,072 x 5/7 = 766 27/48*
le = 78 weeks w = 0.026 kg
Le = 90 weeks R = 30.6 I/kg
L =90 weeks
With these parameters the carcinogenic potency factor for
— 2 -1
humans, q-i*/ is 3.9776 x 10 (mg/kg/day) . The result is that
the water concentration should be less than 8.0 mg/L in order to
keep the individual lifetime risk below 10
*Data was not used in the calculation of the criterion.
C—3 8
U S GOVERNMENT PRINTING OFFICE 1980 720-016/4397
------- |