United States Office of Water EPA 440/5-80-029
Environmental Protection Regulations and Standards October 1980
Agency Criteria and Standards Division
Washington DC 20460 fj ^ |
xe/EPA Ambient
Water Quality
Criteria for
Chlorinated Ethanes
Do not weed. This document
should be retained in the EPA
Region 5 Library Collection.
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AMBIENT WATER QUALITY CRITERIA FOR
CHLORINATED ETHANES
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
« « *
Mflrt V"
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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.
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AMBIENT WATER QUALITY CRITERIA FOR
CHLORINATED ETHANES
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
• •*""- i.-.f • <-<• - -5 - . ,,, •
£t) :".•:::%'.:•• .:-.-.
-------
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.
11
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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 PR
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
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
David J. Hansen, ERL-Gulf Breeze
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Martha Radike (author)
University of Cincinnati
Caryn Woodhouse (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Bonnie Smith (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Donald Barnes
East Carolina University
James V. Bruckner
University of Texas Medical School
Geraldine L. Krueger
University of Cincinnati
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Constance Menesee
University of Cincinnati
Jean Parker, ECAO-RTP
U.S. Environmental Protection Agency
Roy E. Albert*
Carcinogen Assessment Group
Douglas L. Arnold
Health & Welfare, Canada
Joseph Arcos
Tulane University Medical Center
R.J. Bull, HERL
U.S. Environmental Protection Agency
Herbert Cornish
University of Michigan
John L. Laseter
University of New Orleans
Robert E. McGaughy,, CAG
U.S. Environmental Protection Agency
Albert E. Munson
Medical College of Virginia
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. Oenessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnel1, P. Gray, R. Rubinstein.
*CAG Particioating Members: Elizabeth L. Anderson, Larry Anderson, Dolph Arnicar,
Steven Bayard, David L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard Haberman,
Charalingayya Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dharm V. Singh, and Todd W. Thorslund.
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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 B-3
Plant Effects B-4
Residues B-5
Miscellaneous B-5
Summary B-5
Criteria B-6
References B-16
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-5
Ingestion from Water C-5
Ingestion from Food C-9
Inhalation C-12
Dermal C-14
Pharmacokinetics C-14
Absorption C-14
Distribution C-16
Metabolism C-17
Excretion C-24
Effects C-26
Acute, Subacute, and Chronic Toxicity C-26
Synergism and/or Antagonism C-42
Teratogenicity C-47
Mutagenicity C-49
Carcinogenic!ty C-52
Criterion Formulation C-73
Existing Guidelines and Standards C-73
Current Levels of Exposure C-73
Special Groups at Risk C-76
Basis and Derivation of Criteria C-76
References C-83
Appendix C-HO
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CRITERIA DOCUMENT
CHLORINATED ETHANES
CRITERIA
Aquatic Life
The available freshwater data for chlorinated ethanes indicate
that toxicity increases greatly with increasing chlorination, and
that acute toxicity occurs at concentrations as low as 118,000 >ug/l
for 1,2-dichloroethane, 18,000 og/l for 1,1,2,2-tetra-
chloroethane, 1,100 ug/l for
hexachloroethane. Acute and chronic toxicity would occur at lower
concentrations among species that are more sensitive than those
tested.
The available saltwater data for chlorinated ethanes indicate
that toxicity increases greatly with increasing chlorination and
that acute toxicity to fish and invertebrate species occurs at con-
centrations as low as 113,000 /ug/1 for 1,2-dichloroethane, 31,200
>ug/l for 1,1,1-trichloroethane, 9,020 >ug/l for 1,1,2,2-tetra-
chloroethane, 390 jug/1 for pentachloroethane, and 940 >ug/l for
hexachloroethane. Chronic toxicity occurs at concentrations as low
as 281 >ug/l for pentachloroethane. Acute and chronic toxicity
would occur at lower concentrations among species that are more
sensitive than those tested.
vi
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Human Health
For the maximum protection of human health from the potential
carcinogenic effects due to exposure of 1,2-dichloroethane through
ingestion of contaminated water and contaminated aquatic organisms,
the ambient water concentration 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 10~5, 10" , and 10" . The corresponding recom-
mended criteria are 9.4 jag/1, 0.94 ug/1, and 0.094 pg/1, respec-
tively. If the above estimates are made for consumption of aquat-
ic organisms only, excluding consumption of water, the levels are
2,430 pg/1, 243 pg/1, and 24.3 pg/1, respectively.
For the maximum protection of human health from the potential
carcinogenic effects due to exposure of 1,1,2-trichloroethane
through ingestion of contaminated water and contaminated aquatic
organisms, the ambient water concentration 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 corre-
sponding recommended criteria are 6.0 pg/1, O-6 U9/1> and 0.06
pg/1, respectively. If the above estimates are made for consump-
tion of aquatic organisms only, excluding consumption of water, the
levels are 418 pg/1, 41.8 ug/1, and 4.18 pg/1, respectively.
Vll
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For the maximum protection of human health from the potential
carcinogenic effects due to exposure of 1,1,2,2-tetrachloroethane
through ingestion of contaminated water and contaminated aquatic
organisms, the ambient water concentration 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 10~5, 10~6, and 10~7. The corre-
sponding recommended criteria are 1.7 ug/1, 0.17 jug/1, and 0.017
;ug/l, respectively. If the above estimates are made for consump-
tion of aquatic organisms only, excluding consumption of water, the
levels are 107 ug/1, 10.7 jjg/1, and 1.07 ;ig/l, respectively.
For the maximum protection of human health from the potential
carcinogenic effects due to exposure of hexachloroethane through
ingestion of contaminated water and contaminated aquatic organisms,
the ambient water concentration 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 recom-
mended criteria are 19 Ug/1, 1.9 pg/1, and 0.19 pg/1, respectively.
If the above estimates are made for consumption of aquatic organ-
isms only, excluding consumption of water, the levels are 87.4
pg/1, 8.74 pg/1, and 0.87 pg/1, respectively.
For the protection of human health from the toxic properties
of 1,1,1-trichloroethane ingested through water and contaminated
aquatic organisms, the ambient water criterion is determined to be
18.4 mg/1.
viii
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For the protection of human health from the toxic properties
of 1,1,1-trichloroethane ingested through contaminated aquatic
organisms alone, the ambient water criterion is determined to be
1.03 g/1.
Due to the insufficiency in the available data for monochloro-
ethane, 1,1-dichloroethane, 1,1,1,2-tetrachloroethane, and penta-
chloroethane satisfactory criteria cannot be derived at this time,
using the present guidelines.
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INTRODUCTION
The chlorinated ethanes are produced in large quantities and
used for production of tetraethyl lead and vinyl chloride, as indus-
trial solvents, and as intermediates in the production of other
organochlorine compounds. All of the chlorinated ethanes studied
are at least mildly toxic, toxicity increasing with degree of
chlorination. Some have been found in drinking waters, in natural
waters, and in aquatic organisms and foodstuffs.
There are nine chlorinated ethanes, the properties of which
vary with the number and position of the chlorine atoms. In most
cases, both water solubility and vapor pressure decrease with in-
creasing chlorination, while density and melting point increase.
Chloroethane is a gas at room temperature; hexachloroethane is a
solid; the rest are liquids. All are sufficiently soluble to be of
potential concern as water pollutants. The only member of the
series with a specific gravity less than 1 is chloroethane (specif-
ic gravity 0.9214).
The chlorinated ethanes form azeotropes with water (Kirk ana
Othmer, 1963), a characteristic property which could influence
their persistences in water. All are very soluble in organic sol-
vents (Lange, 1956). The chlorinated ethanes undergo the usual
dehalogenation and dehydrohalogenation reactions of chlorinated
aliphatic compounds in the laboratory (Morrison and Boyd, 1966).
Pearson and McConnell (1975) were unable to demonstrate micro-
bial degradation of the chlorinated ethanes, but did report chemi-
cal degradation of chlorinated hydrocarbons.
A-l
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REFERENCES
Kirk, R.E. and D. Othmer, (eds.) 1963. Encyclopedia of Chemical
Technology. 2nd ed. John Wiley and Sons, Inc., New York.
Lange, N.A. (ed.) 1956. Handbook of Chemistry. 9th ed. Handbook
Publishers, Inc., Sandusky, Ohio.
Morrison, R.I. and R.N. Boyd. 1966. Organic Chemistry. 6th ed.
Allyn and Bacon, Inc., Boston.
Pearson, C.R. and G. McConnell. 1975. Chlorinated hydrocarbons in
the marine environment. Proc. R. Soc. London^Ser. B. 189: 305.
A-2
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Aquatic Life Toxicology*
INTRODUCTION
Acute and chronic toxicity data for freshwater and saltwater fish and
invertebrate species and a variety of chlorinated ethanes demonstrate a di-
rect relationship of toxicity and degree of chlorination. A typical in-
crease in acute toxicity of about two orders of magnitude exists between
1,2-dichloroethane and hexachloroethane. Chronic values for the fathead
minnow decrease (toxicity increases) about 40 times between these same com-
pounds. This relationship is also true for bioconcentration factors in the
bluegill with a gradual increase from 2 to 139 from 1,2-dichloroethane to
hexachloroethane. Effects of salinity, temperature, or other water quality
factors on the toxicity of chlorinated ethanes are unknown.
EFFECTS
Acute Toxicity
The 48-hour values for Daphnia magna tested under the same conditions
(U.S. EPA, 1978) are Ug/1): 1,2-dichloroethane, 218,000; 1,1,2-trichloro-
ethane, 18,000; 1,1,1,2-tetrachloroethane, 23,900; 1,1,2,2-tetrachloro-
ethane, 9,320; petachloroethane, 62,900; and hexachloroethane, 8,070 (Table
1). The 48-hour LC50 value for 1,1,1-trichloroethane (Table 5) was great-
er than the highest exposure concentration, 530,000 yg/1 (U.S. EPA, 1978).
Adema (1978) studied the effects of feeding (algal suspension) and age (1
and 7 days old) on the toxicity of 1,1,2-trichloroethane to Daphnia magna.
After 48-hours no difference was observed, with values of 43,000 yg/1 for
each of four tests using measured concentrations (Table 1).
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand 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 tox-
icity as described in the Guidelines.
B-l
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A midge, Tanytarsus dissimilis, has also been tested and the 48-hour
LC50 value for this species and hexachloroethane is 1,700 yg/l. This re-
sult is about one-fifth that for the same chemical and Daphnia magna. How-
ever, since the midge result was based on measured concentrations and that
for Daphnia magna was not, this difference may be methodological rather than
a difference in sensitivity.
Alexander, et al. (1978) conducted acute toxicity tests with the fathead
minnow and 1,1,1-trichloroethane under static and flow-through conditions
with unmeasured and measured concentrations, respectively (Table 1). The
flow-through, measured LC5Q value (52,800 wg/l) is about one-half that
(105,000 ug/1) for the static, unmeasured LC5Q value.
Using continuous-flow procedures and measured exposure concentrations,
the fathead minnow have been exposed (U.S. EPA, 1980) to 1,2-dichloroethane,
1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane and
hexachloroethane, the 96-hour LC5Q values are 118,000, 81,700, 20,300,
7,300, and 1,530 yg/l, respectively.
All data reported for bluegill are from 96-hour static toxicity tests
with unmeasured concentrations (Table 1). The 96-hour LC5Q values for
1,2-dichloroethane were 550,000 pg/1 (Dawson, et al. 1977) and 431,000 yg/1
(U.S. EPA, 1978). The other bluegill 96-hour LC5Q values were (wg/l):
1,1,1-trichloroethane, 69,700; 1,1,2-trichloroethane, 40,200; 1,1,1,2-tetra-
chloroethane, 19,600; 1,1,2,2-tetrachloroethane, 21,300; pentachloroethane,
7,240; and hexachloroethane, 980.
For the bluegill and the fathead minnow, the toxicity of chlorinated
ethanes clearly increased as the chlorine content increased. For Daphnia
magna, no clear relationship exists, although there is a rough trend toward
B-2
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greater toxicity with increased chlorination. The less chlorinated com-
pounds seem to be more toxic to Daphnia magna than to bluegill, whereas the
more heavily chlorinated compounds are more toxic to bluegill.
Mysid shrimp and sheepshead minnow, the only saltwater animal species
studied, were similar in their sensitivities to the chlorinated ethanes
tested in static tests, except for pentachloroethane (Table 1). For penta-
chloroethane and hexachloroethane, the LC5Q values for mysid shrimp were
lower than those for the freshwater species, Daphnia magna (Table 1). Under
comparable tests conditions sensitivity to chlorinated ethanes generally in-
crease as the degree of chlorination increased, similar to the trend found
with the freshwater invertebrate and fish species.
Toxicity tests with the sheepshead minnow have been conducted with five
chlorinated ethanes (Tables 1 and 5). All tests were conducted under static
conditions and concentrations in water were not measured. The 96-hour
LCj.n values for sheepshead minnows ranged from 2,400 yg/1 for hexachloro-
O \J
ethane to 116,000 yg/1 for pentachloroethane. The LC^ values for this
saltwater fish do not correlate as well with the number of chlorine atoms as
did the values for the bluegill (Table 1). When sensitivities of the blue-
gill and sheepshead minnow are compared for each of these chlorinated eth-
anes, the LC5Q values differ by less than a factor of three, except for
pentachloroethane values which differ by a factor of 16.
Chronic Toxicity
No freshwater invertebrate species has been tested under chronic expo-
sure conditions for any chlorinated ethane. However, embryo-larval tests
have been conducted with the fathead minnow and 1,2-dichloroethane, 1,1,2-
trichloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, and hexa-
chloroethane (U.S. EPA, 1978, 1980). The chronic values for these compounds
B-3
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are 20,000, 9,400, 2,400, 1,100, and 540 yg/l, respectively (Table 2). When
these values are divided by the appropriate 96-hour LC values, the re-
sultant acute-chronic ratios range from 2.8 to 8.7.
Only one chronic value is available for any chlorinated ethane and salt-
water organisms. The chronic value for the mysid shrimp and pentachloro-
ethane is 281 ug/1 and the acute-chronic ratio is 1.4 (Table 2).
Plant Effects
Ninety-six-hour EC5Q tests (Table 3), using chlorophyll a and cell
number as measured responses, were conducted with the green alga, Selenas-
trum capricornutum, with the following results (ug/1): 1,1,2,2-tetrachloro-
ethane, 136,000 and 146,000, respectively; pentachloroethane, 121,000 and
134,000, respectively; and hexachloroethane, 87,000 and 93,000. The high-
est concentration of 1,1,1-trichloroethane tested, 669,000 ug/l, (U.S. EPA,
1978) was not high enough to obtain a 96-hour EC5Q value (Table 5).
The effects of chlorinated ethanes on plants increased slightly as
chlorination increased, but the effect was not as clear as demonstrated by
the bluegill and fathead minnow data. The alga was approximately 7 to 15
times less sensitive than bluegill to a specific compound.
The saltwater alga, Skeletonema costatum, was as sensitive to 1,1,2,2-
tetrachloroethane (Table 3) as the mysid shrimp and sheepshead minnow. The
96-hour EC5Q value for growth, based on cell count, was 6,230 yg/l. The
96-hour EC5Q values for cell number were 58,000 wg/1 for pentachloroethane
7,750 ug/1 for hexachloroethane. There are no data reported in the litera-
ture on effects of chlorinated ethanes on saltwater vascular plants.
Data for 1,2-dichloroethane and 1,1,1-trichloroethane indicate that
those compounds are not very toxic to the alga, Skeletonema costatum (Table
5).
B-4
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Residues
The chlorinated ethanes do not strongly bioconcentrate (Table 4), but do
show an increased bioconcentration potential with increased chlorination,
particularly for penta- and hexachloroethane. The following steady-state
bioconcentration factors were measured for bluegill: 1,2-dichloroethane, 2;
1,1,1-trichloroethane, 9; 1,1,2,2-tetrachloroethane, 8; pentachloroethane,
67; and hexachloroethane, 139. All of the chlorinated ethanes have an
elimiation half-life of less than two days as measured by whole body levels
in exposed bluegill.
Miscellaneous
These data (Table 5) have been discussed previously.
Summary
In general, the toxicity of the chlorinated ethanes to freshwater organ-
isms increases with increasing chlorination. The least chlorinated tested
compound was 1,2-dichloroethane, for which the 50 percent effect concentra-
tions for Daphnia magna, fathead minnow, and bluegill were in the range of
118,000 to 550,000 ug/1; the various trichloroethanes and tetrachloroethanes
are generally intermediate in toxicity, and pentachloroethane and hexa-
chloroethane are most toxic. The 50 percent effect concentrations for hexa-
chloroethane and Daphnia magna, midge larvae, rainbow trout, fathead minnow,
and bluegill are in the range of 980 to 8,070 ug/1. Embryo-larval tests
have been conducted with 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-
tetrachloroethane, pentachloroethane, and hexachloroethane and the chronic
values were 20,000, 9,400, 2,400, 1,100, and 540 ug/1, respectively. The
range of acute-chronic ratios was 2.8 to 8.7. The range of 96-hour ECgQ
values for a freshwater alga were from 136,000 pg/1 for 1,1,2,2-tetrachloro-
ethane to 87,000 vig/1 for hexachloroethane. The chlorinated ethanes do not
B-5
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bioconcentrate in the bluegill to any great extent, although the effect of a
chlorination is apparent with bioconcentration factors increasing from two
for 1,2-dichloroethane to 139 for hexachloroethane for a series of five
compounds.
As with the freshwater toxicity tests with fish and invertebrate spe-
cies, there was an increase in effects with the more highly chlorinated
compounds for saltwater toxicity tests. Under comparable test conditions
the 96-hour LC5Q values for the mysid shrimp were in the range of 113,000
yg/1 for 1,2-dichloroethane to 940 yg/1 for hexachloroethane. For the
sheepshead minnow, the range was from 70,900 yg/1 for 1,1,1-trichloroethane
to 2,400 ug/1 for hexachloroethane. Only one chronic value has been deter-
mined for the chlorinated ethanes and saltwater species and the chronic
value for pentachloroethane and the mysid shrimp is 281 yg/1. The 96-hour
EC,-0 values for a saltwater alga ranged from 6,230 to 58,200 yg/1.
CRITERIA
The available freshwater data for chlorinated ethanes indicate that tox-
icity increases greatly with increasing chlorination and that acute toxicity
occurs at concentrations as low as 118,000 pg/1 for 1,2-dichloroethane,
18,000 yg/1 for two trichloroethanes, 9,320 yg/1 for two tetrachlorethanes,
7,240 yg/1 for pentachloroethane, and 980 yg/1 for hexachloroethane. Chron-
ic toxicity occurs at concentrations as low as 20,000 yg/1 for 1,2-dichloro-
ethane, 9,400 yg/1 for 1,1,2-trichloroethane, 2,400 yg/1 for 1,1,2,2-tetra-
chloroethane, 1,100 yg/1 for pentachloroethane, and 540 yg/1 for hexachloro-
ethane. Acute and chronic toxicty would occur at lower concentrations among
species that are more sensitive than those tested.
8-6
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The available saltwater data for chlorinated ethanes indicate that tox-
icity increases greatly with increasing chlorination and that acute toxicity
to fish and invertebrate species occurs at concentrations as low as 113,000
ug/l for 1,2-dichloroethane, 31,200 yg/1 for 1,1,1-trichloroethane, 9,020
ug/1 for 1,1,2,2-tetrachloroethane, 390 yg/1 for pentachloroethane, and 940
yg/1 for hexachloroethane. Chronic toxicty occurs at concentrations as low
as 281 ug/1 for pentachloroethane. Acute and chronic toxicity would occur
at lower concentrations among species that are more sensitive than those
tested.
8-7
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Table 1. Acute values for chlorinated ethanes
Species
Method* Chemical
LC50/EC50
Species Acute
Value (yg/1) Reference
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
co Cladoceran,
Daphnla rnagna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
C ladoceran,
Daphnla magna
Midge,
Tanytarsus disslmllis
Rainbow trout,
Sainio gairdneri
Fathead minnow,
Plmephales promelas
Fathead minnow,
Pimephales promelas
S, U
S, U
S, M
S, M
S, M
S. M
S, U
S, U
S, U
S, U
S, M
FT, M
FT, M
S, U
FRESHWATER
1,2-dich loro-
ethane
1,1,2-trichloro-
ethane
1,1,2-trich loro-
ethane
1,1,2-trlch loro-
ethane
1,1,2-trlch loro-
ethane
1,1,2-trlch loro-
ethane
1,1,1,2-tetra-
ch loroethane
1,1,2,2-tetra-
ch loroethane
pentach loro-
ethane
hexach loro-
ethane
hexach loro-
ethane
hexach loro-
ethane
1,2-dich loro-
ethane
1,1,1-trlchloro-
ethane
SPECIES
218,000
18,000
43,000
43,000
43,000
43,000
23,900
9,320
62,900
8,070
1,700
980
118,000
105,000
218,000
-
-
-
-
36,000
23,900
9,320
62,900
8,070
1,700
980
118,000
-
I \W • Wl VIIVcQ
U.S. EPA, 1978
U.S. EPA, 1978
Adema, 1978
Adema, 1978
Adema, 1978
Adema, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1980
Alexander, et a
1978
-------
Table t. (Continued)
Species
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Pimep hales promelas
B 1 ueg ill,
Lepomls macrochirus
B 1 ueg 1 1 1 ,
Lepomls macrochirus
Bluegi 1 1,
Lepomls macrochirus
Bluegill,
Lepomis macrochirus
B 1 ueg I 1 1 ,
Lepomis macrochirus
Bluegi 1 1,
Lepomls macrochirus
B 1 ueg 1 1 1 ,
Lepomls macrochirus
B 1 ueg III,
Lepomls macrochirus
LC50/EC50
Method* Chemical (ug/l)
FT, M 1,1,1-trichloro- 52,800
ethane
FT, M 1,1,2-trlchloro- 81,700
ethane
FT, M 1,1,2,2-tetra- 20,300
ch loroethane
FT, M pentach loro- 7,300
ethane
FT, M hexach loro- 1,530
ethane
S, U 1,2-dichloro- 550,000
ethane
S, U 1,2-dichloro- 431,000
ethane
S, U 1,1,1-trichloro- 69,700
ethane
S, U 1,1,2-trlchloro- 40,200
ethane
S, U 1,1,1,2-tetra- 19,600
ch loroethane
S, U 1,1,2,2-tetra- 21,300
ch loroethane
S, U pentach loro- 7,240
ethane
S, U hexach loro- 980
ethane
Species Acute
Value (jig/I) Reference
52,800 Alexander, et a
1978
81,700 U.S. EPA, 1980
20,300 U.S. EPA, 1980
7,300 U.S. EPA, 1980
1,530 U.S. EPA, 1980
Dawson, et al.
1977
489,000 U.S. EPA, 1978
69,700 U.S. EPA, 1978
40,200 U.S. EPA, 1978
19,600 U.S. EPA, 1978
21,300 U.S. EPA, 1978
7,240 U.S. EPA, 1978
980 U.S. EPA, 1978
-------
Table 1. (Continued)
Species
Method* Chemical
LC50/EC50
(ug/l)
Species Acute
Value (ug/l) Reference
SALTWATER SPECIES
Mysld shrimp,
Mysldopsis bah I a
Mysid shrimp,
Mysldopsis bah I a
Mysid shrimp,
Mysidopsis bah la
Mysld shrimp,
Mysidopsfs bahia
Mysid shrimp,
Mysldopsis bahia
Mysid shrimp,
Mysidopsis bahia
Ul
j_, Sheepshead minnow,
o Cyprinodon variegatus
Sheepshead minnow,
Cyprinodon variegatus
Sheepshead minnow,
Cyprinodon variegatus
Sheepshead minnow,
Cyprinodon variegatus
S, U 1,2-d I ch loro-
ethane
S, U 1,1,1-trlchloro-
ethane
S, U 1,1,2,2-tetra-
ch loroethane
S, U pentach loro-
ethane
FT, M pentach loro-
S, U he xach loro-
ethane
S, U 1,1,1-trlch loro-
ethane
S, U 1,1,2,2-tetra-
ch loroethane
S, U pentach loro-
ethane
S, U hexach loro-
ethane
113,000
31,200
9,020
5,060
390
940
70,900
12,300
116,000
2,400
1 13,000 U.S. EPA, 1978
31,200 U.S. EPA, 1978
9,020 U.S. EPA, 1978
U.S. EPA, 1978
390 U.S. EPA, 1979
940 U.S. EPA, 1978
70,900 U.S. EPA, 1978
12,300 U.S. EPA, 1978
116,000 U.S. EPA, 1978
2,400 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 chlorinated ethanes
Species Method*
Fathead minnow, E-L
Plmephales promelas
Fathead minnow, E-L
Plmephales promelas
Fathead minnow, E-L
Plmephales promelas
Fathead minnow, E-L
Plmephales promelas
Fathead minnow, E-L
Pimephales promelas
Chemical
FRESHWATER
1,2-dichloro-
ethane
Chronic
Limits Value
(ug/D
SPECIES
14,000- 20,000
29,000
1,1,2-trichloro- 6,000- 9,400
ethane
1,1,2,2-tetra-
ch loroethane
pentach loro-
ethane
hexach loro-
ethane
14,800
1,400- 2,400
4,000
900- 1 , 100
1,400
410- 540
700
Reference
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1980
U.S. EPA, 1978
SALTWATER SPECIES
Mysld shrimp, LC
Mysldopsis bahia
* E-L = embryo- larval, LC = partial 1!
Species
Fathead minnow.
Plmephales promelas
Fathead minnow.
Plmephales promelas
Fathead minnow,
Pimephales promelas
pentach loro-
ethane
1 fe cycle or ful 1 1
Acute-Chronic
Chemical
1,2-dlch loro-
ethane
1,1,2-trichloro-
ethane
1,1,2,2-tetra-
ch loroethane
220- 281
360
ife cycle
Ratio
Chronic Acute
Value Value
-------
Table 2. (Continued)
Acute-Chronic Ratio
Species
Fathead minnow.
Plmephales promelas
Fathead minnow.
Plmephales promelas
Mysld shrimp,
Mysldopsis bah la
Chemical
pentachloro-
ethane
hexach loro-
ethane
pentach loro-
ethane
Chronic Acute
Value Value
(ug/l) (ug/l) Ratio
1,100 7,300 6.6
540 1,530 2.8
281 390 1.4
03
I
M
to
-------
Table 3. Plant values for chlorinated ethanes (U.S. EPA, 1978)
W
I
Species
Alga,
Se 1 enastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Se 1 enastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Selenastrum caprlcornutum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga.
Skeletonema costatum
Chemical
FRESHWATER SPECIES
1, 1,2,2- tetra-
chloroethane
1,1,2,2-tetra-
ch loroethane
pentach loro-
ethane
pentach loro-
ethane
hexach loro-
ethane
hexach loro-
ethane
SALTWATER SPECIES
1,1,2,2-tetra-
ch loroethane
1, 1,2,2-tetra-
ch loroethane
pentach loro-
ethane
pentach loro-
ethane
hexach 1 oro-
ethane
hexach loro-
ethane
Effect
Chlorophyll a
96- hr EC50
Cel 1 numbers
96-hr EC50
Ch lorophy 1 1 a
96-hr EC50
Cel 1 numbers
96- hr EC50
Ch lorophy 1 1 a
96-hr EC50
Cel 1 numbers
96-hr EC50
Chlorophyll a
96- hr EC50
Cel 1 count
96-hr EC50
Chlorophyll a
96- hr EC50
Cel 1 count
96- hr EC50
Ch lorophy 1 1 a
96- hr EC50
Cel 1 count
96- hr EC50
Result
(ug/l)
136,000
146,000
121,000
134,000
87,000
93,200
6,440
6,230
58,200
58,200
8,570
7,750
-------
Table 4. Residues for chlorinated ethanes (U.S. EPA, 1978)
Species
Tissue
Bloconcentratlon Duration
Chemical Factor (Hays)
FRESHWATER SPECIES
Bluegi II.
Lepomls macrochirus
Bluegi 1 1,
Lepomls macrochirus
Bluegi 1 1,
Lepomls macrochirus
Bluegi 1 1,
Lepomls macrochirus
Bluegi 1 1,
Lepomls macrochirus
whole body
whole body
whole body
whole body
whole body
1,2-dlchloro- 2
ethane
1,1, 1-tr ich loro- 9
ethane
1,1,2,2-tetra- 8
ch loroethane
pentach loro- 67
ethane
hexach loro- 139
ethane
14
28
14
14
28
DO
I
-------
Table 5. Other data for chlorinated ethanes (U.S. EPA, 1978)
to
I
I-1
Ln
Species
Alga,
Selenastrum capricornutum
Alga,
Selenastrum capricornutum
Cladoceran,
Daphnla magna
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Sheepshead minnow,
Cvorinodon varieqatus
Chemical
FRESHWATER
1,1,1-trichloro-
ethane
1,1,1-trIchloro-
ethane
1,1,1-trlchloro-
ethane
SALTWATER
1,2-dlchloro-
ethane
1,2-dlchloro-
ethane
1,1,1-trlchloro-
ethane
J,J,]-tr!chloro-
ethane
1,2-dichloro-
ethane
Duration
SPECIES
96 hrs
96 hrs
48 hrs
SPECIES
96 hrs
96 hrs
96 hrs
96 hrs
96 hrs
Effect
EC50
chlorophyll a
EC50
ce 1 1 numbers
EC50
EC50
chlorophy 1 1 _£
EC50
eel 1 count
EC50
chlorophyll a
EC50
eel 1 count
LC50
Result
(ug/i)
>669,000
>669,000
> 530,000
>433,000
>433,000
>669,000
>669,000
> 126, 000
<226,000
-------
REFERENCES
Adema, D.M.M. 1978. Daphnia magna as a test animal in acute and chronic
toxicity tests. Hydroblol. 59: 125.
Alexander, H.C., et al. 1978. Toxicity of perchloroethylene, trichloro-
ethylene, 1,1,1-trichloroethane, and methylene chloride to fathead minnows.
Bull. Environ. Contain. Toxicol. 20: 344.
Dawson, G.W., et al. 1977. The toxicity of 47 industrial chemicals to
fresh and saltwater fishes. Jour. Hazard. Mater. 303.
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. 1979. Unpublished laboratory data. Environ. Res. Lab. Gulf
Breeze, Florida.
U.S. EPA. 1980. Unpublished laboratory data. Environ. Res. Lab. Duluth,
Minnesota.
B-16
-------
Mammalian Toxicology and Human Health Effects
INTRODUCTION
Chloroethanes are hydrocarbons in which one or more of the
hydrogen atoms have been replaced by a chlorine atom or atoms.
Chloroethanes are widely used because of their low cost and proper-
ties which make them excellent solvents, degreasing agents, fumi-
gants and cutting fluids. Some are used in the manufacture of
plastics, textiles and in the synthesis of other chemicals. Around
1955, chloroethanes began to replace more toxic industrial sol-
vents.
A large number of humans are industrially exposed to chloro-
ethanes. In addition, the general population encounters these com-
pounds in commercial products and as environmental contaminants
resulting from industrial emissions including the discharge of
liquid wastes.
Extensive literature has been generated by investigators who
have studied the effects of chloroethanes on biological systems and
the distribution of these compounds in the environment. The use of
similar names for related chlorinated hydrocarbons has lead to
possible confusion in the literature as to which compound elicited
various toxicological effects.
Table 1 indicates the chemical names and some synonyms; Table
2 depicts the chemical structures of the chloroethanes. Chemical
and physical properties of chloroethanes are listed in Table 3.
C-l
-------
TABLE 1
Chloroethanes and Synonyms
Compound Name
Synonyms
Monochloroethane
1,1-Dichloroethane
1,2-Dichloroethane
1,1,1-Trichloroethane
1,1,2-Trichloroethane
1,1,1,2-
Tetrachloroethane
1,1,2,2-
Tetrachloroethane
Pentachloroethane
Hexachloroe thane
Chloroethane
Ethylidene Bichloride
Ethylene Bichloride
Methyl Chloroform
Ethane Trichloride
Tetrachloroethane
Acetylene Tetra-
chloride
Pentalin
Perchloroethane
Ethyl Chloride
EthylideneChloride
Ethylene Chloride
Chlorothene
Vinyl Trichloride
Sym-Tetrachloro-
ethane
Ethane Penta-
chloride
C-2
-------
TABLE 2
Chloroethanes
H-C-C-C1
I l
H H
Monochloroethane
H Cl
I I
H-C-C-H
H Cl
1,1-Dicholoro-
ethane
H H
I I
C1-C-C-C1
I i
H H
1,2-Dichloro-
ethane
H Cl
I I
H-C-C-C1
i i
H Cl
1,1,1-Trichloro-
ethane
H Cl
i l
Cl-C-C-H
i I
H Cl
1,1,2-Trichloro-
ethane
H Cl
C1-C-C-C1
I J
H Cl
1,1,1,2-Tetra-
chloroethane
Cl Cl
l i
H-C- C-H
i I
Cl Cl
1,1,2,2-Tetrachloro-
ethane
Cl Cl
! I
H-C- C-C1
i I
Cl Cl
Pentachloroethane
Cl Cl
I I
Cl-C- C-C1
Cl Cl
Hexachloroethane
C-3
-------
TABU3 3
Physical and Chemical Properties of Chloroethanes*
O
I
Compound
mo no chlo toe thane
1 , 1-dichloroe thane
1, 2-dichloroe thane
1,1, 1-tr ichloro-
e thane
1 , 1 ,2-tr ichloro-
elhane
1 , 1,1,2-tetrachloro-
e thane
1,1,2, 2- tetrachloro-
pentachloroethane
hexachloroethane
Formula
Wei glit
64.52
98.96
98.96
133.4
133.4
167.9
167.9
202.3
236.7
Boiling
Point C
13.1
57.3
83.4
74.1
113
129
146.3
162
186
Melting
Point C
-138.7
- 98
- 35.4
- 33
- 37.4
- 68.1
- 36
- 29
- 187
Specific
Grav i tya
0.921.4
1.1776
1. 253
1.3492
1.4405
1.5532
1.596
1.6796
2.091
Solubil ity
In Water
5.74 g/1
5 g/1
8.1 g/1
0.48 g/1
Slightly
soluble
2.85 g/1
2.9 g/1
Insoluble
Insoluble
Vapor Vapor .
Pressure Density
(mm Hg)
1,000 at 20°C
230 at 25°C
85 at 25°C 3.42
96 at 20°C 4.55
16 at 25°C 5.79
aAt 20°C; Water
bAir = 1.00
1.00 at 4UC
*Source:
Walter, et al. 1976
Price, et al. 1974
American Industrial Hygiene Association (AIIIA), 1956;
Weast, 1976
1963
-------
EXPOSURE
Ingestion from Water
The U.S. EPA (1974) identified a number of compounds in low
concentrations in raw and finished waters of which approximately
38 percent were halogenated (U.S. EPA, 1976). Halogenated hydro-
carbons have also been identified in 80 domestic water supplies by
Symons, et al. (1975). Bellar, et al. (1974a) observed the highest
concentration of organohalides in chlorinated finished water
originating from surface water (37 to 150 mg/1). Among the com-
pounds identified in raw or treated water are: 1,2-dichloroethane
(Brass, et al. 1977); 1,1,1-trichloroethane (Kopfler, et al. 1976);
in finished water, 1,1- and 1,2-dichloroethane, and 1,1,1-
trichloroethane, (Coleman, et al. 1976); 1,1,2-trichloroethane,
1,1,1,2-tetrachloroethane (Keith, et al. 1976). Other reports of
halogenated compounds in water or industrial waste water include
the following: U.S. EPA., 1975a; Keith, 1972; Dowty, et al.
1975a,b; Bellar, et al. 1974b; Dietz and Traud, 1973.
Even though individual chemicals are frequently present in
relatively small amounts in public water supplies, the potential
toxicological implications are a matter of great concern. Of the
289 compounds identified in U.S. drinking water supplies (U.S. EPA,
1976), 21 were characterized as having carcinogenic activity
(Kraybill, 1978). Of these 21, three were chloroethanes: 1,2-
dichloroethane; 1,1,2-trichloroethane; tetrachloroethane (isom.er
not identified).
Monochloroethane is widely used as a solvent and in chemical
synthesis (National Institute for Occupational Safety and Health
(NIOSH), 1978c). No literature was found indicating the amounts
C-5
-------
discharged as liquid industrial wastes; however, monochloroethane
has been identified in finished drinking water supplies (Kopfler et
al., 1976). Brown, et al. (1975) reported that from six companies
producing monochloroethane, 5.8 million pounds per year were lost
into the environment from 575.5 million pounds produced; major
losses would be into the atmosphere. Due to its low solubility in
water (5.74 g/1), monochloroethane would be present only in water
near point sources. In surface waters the compound would volatil-
ize into the atmosphere.
1,1-Dichloroethane is not reported to be produced commercially
in the United States (NIOSH, 1978c), but is imported for use as a
solvent and cleaning agent in specialized processes. 1rl-Dichloro-
ethane has been identified in the finished water of several metro-
politan areas (Coleman, et al. 1976; Kopfler, et al. 1976).
More than 80 percent of the 1,2-dichloroethane produced in the
United States is used to manufacture vinyl chloride and other
chlorinated chemicals (U.S. EPA, 1975b) ; the solvent is also used
in the manufacture of tetraethyl lead and as a constituent of many
products used by the general public (U.S. EPA, 1975a). The gross
annual discharge of 1,2-dichloroethane was estimated at 80 tons by
the U.S. EPA (1975a). Nonpoint sources of 1,2-dichloroethane
result from the use of products containing the compound, such as
paint and varnish removers. The compound is difficult to degrade
biologically (Price, et al. 1974), however, activated carbon fil-
tration is 90 to 100 percent effective in removing the solvent from
finished water (U.S. EPA, 1975a). Of 80 water supplies surveyed,
27 contained 1,2-dichloroethane at concentrations of 0.2 to 8 ug/1
C-6
-------
(U.S. EPA, 1975c, 1974). In a separate survey, Symons, et al.
(1975) reported that of 80 water supplies surveyed during the
National Organics Reconaissance Survey for Halogenated Organics,
only 32.5 percent contained detectable amounts of 1,2-dichloro-
ethane, and the highest concentration found was 6.0 jug/1. The U.S.
EPA (1979) concluded that 1,2-dichloroethane is not common in muni-
cipal water supplies, and when present, it is usually in neglible
amounts; this compound is not usually present in ground water.
1,1,1-Trichloroethane is used primarily as a solvent, and as a
cleaning and degreasing agent (Dow Chemical Co. 1969, 1973). The
compound was found in the drinking water of three of five cities
studied by Kopfler, et al. (1976). No information was found on the
environmental fate in water or estimates of annual discharge as
waste.
1,1,2-Trichloroethane is used in the manufacture of 1,1-di-
chloroethylene, as a solvent, and in organic synthesis. The gross
annual discharge is estimated to be 2,000 tons. The compound is
not produced by the biological decomposition of sewage or solid
wastes or by incineration, but small amounts are formed by the
chlorination process. 1,1,2-Trichloroethane persists in the envi-
ronment (greater than two years) and is not degraded biologically;
however, activated carbon filtration is reported to be 90 to 100
percent effective in removing the chloroethane from drinking water
(U.S. EPA, 1975a). Of 10 water supplies surveyed by the U.S. EPA
(1975a), only one contained 1,1,2-trichloroethane, while a second
study of finished water from a metropolitan area, reported concen-
trations of 0.1 to 8.5 ug/1 (U.S. EPA, 1975d) .
C-7
-------
1,1,1,2-Tetrachloroethane is used as a solvent and in the man-
ufacture of a number of widely used products, (U.S. EPA, 1975a).
It is potentially formed during chlorination of water (U.S. EPA,
1975a) and has been identified in finished water at a concentration
of 0.11 pg/l (U.S. EPA, 1974).
1,1,2,2-Tetrachloroethane is used in the manufacture of 1,1-
dichloroethylene, as a solvent, in the manufacture of, and as a
constituent of many widely used products. The gross annual dis-
charge from industrial sources was estimated to be 2,000 tons. The
compound is not formed during biological decomposition of sewage or
solid waste or by incineration, but may be formed during chlorina-
tion of treated sewage. The compound persists in the environment
and is not degraded biologically but can be removed from drinking
water by activated carbon filtration which is reported to be 90 to
100 percent effective (U.S. EPA, 1975a).
Apparently pentachloroethane is not produced commercially in
the United States (NIOSH, 1978c) and is rarely found in drinking
water.
Hexachloroethane is used in the manufacture of a number of
products and the gross annual industrial discharge is estimated to
be 2,000 tons. It is not formed in biological decomposition of
wastes but can be produced in small quantities by chlorination of
drinking water. The compound persists in the environment and is
not degraded biologically (U.S. EPA, 1975a).
Analytical Techniques: Sensitive methods for identification
of chlorinated ethanes and other organic compounds found in water,
methods of quantitation, efficiency of sampling techniques and
-------
recovery were discussed by Keith, et al. (1976). Computerized gas
chromatograph/mass spectrometry was presented as the best method
available. There are many recent publications describing water
sampling and analytical techniques for the identification of halo-
genated aliphatic hydrocarbons including the following: Dowty, et
al. 1975b; Van Rossum and Webb, 1978; Lillian and Singh, 1974;
Gough, et al. 1978; Glaze, et al. 1976; Deetman, et al. 1976;
Coleman, et al. 1976; Fujii, 1977; Kopfler, et al. 1976; Cavallaro
and Grassi, 1976; Nicholson and Meresz, 1975.
Ingestion from Food
The two most widely used solvents, 1,2-dichloroethane and
1,1,1-trichloroethane, are most often found in food. 1,1,1-Tri-
chloroethane was found in small amounts as a contaminant in various
food stuffs from the United Kingdom (Walter, et al. 1976) . In
meat, oils and fats, tea, and fruits and vegetables, amounts ranged
from 1 to 10 pg/kg. Of the foods analyzed, olive oil contained the
largest amount (10 pg/kg).
1,2-Dichloroethane is used in washing or lye peeling of fruits
and vegetables (42 FR 29856) and represents a possible source in
the diet of man. The volatile compound is also used as a fumigant
in the storage of grain. Some fumigant can react with the grain to
form nonvolatile residues; the health effects of these residues
are not known (U.S. EPA, 1979). The amount of 1,2-dichloroethane
remaining on grain after fumigation seems to depend on a number of
factors, including grain type, grain size, storage conditions, and
subsequent ventilation. Residues of 1,2-dichloroethane were not
detected in wheat, flour, bran, middlings and bread (Berck, 1974).
C-9
-------
However, using a different technique, in an earlier study, the same
author found that 51 cereal grains sorbed from 0 to 84 percent of
the applied dose, depending on the type and size of the grain
(Berck, 1965, as cited in U.S. EPA, 1979). Because of the com-
pounds volatility, only negligible amounts remain on foods prepared
from treated grain (U.S. 2?A, 1979).
1,2-Dichloroethane is commonly used as an extractant in the
preparation of spice oleoresins. The dichloroetharie isomer was
detected in 11 of 17 spices in concentrations ranging from 2 to 23
ug of the compound per gram spice oleoresin (Page and Kennedy,
1975).
Concentrations of seven halogenated hydrocarbons were deter-
mined in various organs of three species of molluscs and five spe-
cies of fish (Dickson and Riley, 1976). 1,1,1-Trichloroethane was
found in the digestive tissue of one mollusc species (4 ng/g on a
dry weight basis) and in three fish species where the compound was
most strongly concentrated in the brain (4 to 16 ng) and gills (2 to
14 ng). No other data were found concerning the biological fate of
chloroethanes in the food chain.
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
C-10
-------
percent 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
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
Measured steady-state BCFs of 2, 9, 8, 67, and 139 were ob-
tained for 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2,2-
tetrachloroethane, pentachloroethane, and hexachloroethane,
respectively using bluegills (U.S. EPA, 1978). Similar bluegills
contained an average of 4.8 percent lipids (Johnson, 1980). An
adjustment factor of 3.0/4.8 = 0.625 can be used to adjust the
measured BCF from the 1.0 percent lipids of the bluegill to 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 BCFs for 1,2-dichloroethane, 1,1,1-trichloro-
ethane, 1,1,2,2-tetrachloroethane, pentachloroethane, and hexa-
chloroethane for the edible portion of all freshwater and estuarine
aquatic organisms consumed by Americans are calculated to be 1.2,
5.6, 5.0, 41.9, and 86.9, respectively.
No measured steady-state BCFs are available for 1,1,2-
trichloroethane and 1,1,1,2-tetrachloroethane, but the equation
C-ll
-------
"Log BCF = (0.85 Log P) - 0.70" can be used (Veith, et al. 1979) to
estimate the BCF for aquatic organisms that contain about 7.6 per-
cent lipids (Veith, 1980) from the octanol-water partition coeffi-
cients (P) . Since no measured log P values could be found, log P
values of 2.07 and 2.66 were calculated for 1,1,2-trichloroethane
and 1,1,1,2-tetrachloroethane using the method described in Hansch
and Leo (1979). Thus, the steady-state bioconcentration factors
were estimated to be 11.5 and 36.4. An adjustment factor of
3.0/7.6 = 0.395 can be used to adjust the estimated BCF from the
7.6 percent lipids on which the equation is based to the 3.0 per-
cent lipids that is the weighted average for consumed fish and
shellfish. Thus, the weighted average BCFs for 1,1,2-trichloro-
ethane and 1,1,1,2-tetrachloroethane and the edible portion of all
freshwater and estuarine aquatic organisms consumed by Americans
are calculated to be 4.54 and 14.4, respectively.
Inhalation
Inhalation is the major route of exposure of humans to the
volatile chloroethanes which are widely used as solvents, partic-
ularly in metal degreasing and dry cleaning operations. Many tons
of chlorinated ethanes are reported to evaporate into the atmos-
phere (Kover, 1975; Murray and Riley, 1973). Inhalation exposure
data for the general population are not available; however, some
estimates can be made for occupational exposures. For example,
health hazard evaluations of industries using 1,1,1-trichloro-
ethane reported breathing zone concentrations ranging from 1.5 to
350 ppm (Table 4).
C-12
-------
TABLE 4
Concentrations of 1,1,1-Trichloroethane
Observed in Ambient Air of Various Industries
n
i
Concentration
Range
ppm mg/m
4.
2,
6.
2.
36.
7
3.
1.
12.
0 -
5 -
0 -
0 -
5 -
0 -
5 -
0 -
37
79
83
18
159
350
16
118
.0
.5
.0
.4
.5
.0
.6
.0
21
13
32
10
199
398
8.
65
.8 -
.6 -
.1 ~
.9 -
.0 -
.0 -
18 -
.4 -
201.7
433. 4
452.5
100.3
869.6
1897
90.5
643.3
Type of Job
or Industry
Machining, Degreasing
Electrical Industry
Electrical Industry
Manufacture Catapult
Cylinders
Manufacture Rifle Scopes
Degreasing-Cleaning
Metal Industry
Solder ing-Deg re as ing
Reference
Kominsky, 1976
Gilles
Gilles
Gilles
Gunter
Gilles
Levy &
Gunter
, 1976
& Philbin, 1976
& Rostand, 1975
, et al. 1977
, 1977
Meyer, 1977
& Bodner, 1974
-------
Dermal
Normally the skin is not a major route of exposure to chlor-
inated ethanes. As with most solvents, chloroethanes are absorbed
through the skin, but in general, skin contact is avoided in the
workplace and commercial products carry warnings. Most laboratory
gloves are permeable to these solvents and should not be relied
upon for protection (Sansone and Tewari, 1978).
PHARMACOKINETICS
Absorption
Monochloroethane is absorbed rapidly into the body following
ingestion or inhalation (Sax, 1975) and has been used as an anes-
thetic (Merck, 1976). Absorption through the skin is minor.
Lethal amounts of 1,2-dichloroethane are absorbed following
ingestion of a single dose (LD^Q for rats, 0.97 mg/kg) or a single
application to the skin (LD5Q for rabbits, 3.89 mg/kg) (Smyth, et
al. 1969). According to NIOSH (1978a) the effects of large doses
of 1,2-dichloroethane are similar for all routes of entry.
Absorption of liquid 1,1,1-trichloroethane through the skin
was studied by Stewart and Dodd (1964). Six subjects each immersed
a thumb in a beaker of 1,1,1-trichloroethane for 30 minutes.
Analysis of alveolar air collected during exposure at 1C), 20 and 30
minutes indicated slow absorption (Table 5) . In the workplace,
dermatitis often results from skin contact with 1,1,1-trichloro-
ethane (Gilles, 1977). The concentration of 1,1,1-trichloroethane
in the blood of three victims of fatal intoxication (ingested or
inhaled) has been reported to be 60, 62, and 120 ppm, respectively
(Stahl, et al. 1969) indicating rapid absorption by both routes.
C-14
-------
TABLE 5
Concentrations of 1,1,1-Trichloroethane Found in
Alveolar Air of Experimental Subjects*
Duration of Thumb Alveolar Air Concentrations
Immersion (ppro)
10 minutes 0.10 - 0.10
20 minutes 0.14 - 0.37
30 minutes 0.19 - 1.02
*Source: Stewart and Dodd, 1964
C-15
-------
A single application of 1 ml of 1,1,2-trichloroethane to the
skin of guinea pigs was absorbed rapidly as indicated by the
appearance of 3 to 4 jug/ml of the solvent in the blood in 30 min-
utes. After 12 hours, the blood concentration rose to almost 5
jug/ml (Jakobson, et al. 1977) .
The absorption of inhaled 1,1,2,2-tetrachloroethane in humans
•5 O
was determined by Morgan, et al. (1970, 1972) using Cl-labeled
1,1,2,2-tetrachloroethane. Volunteers deeply inhaled 2.5 mg of
labeled vapor, held their breath for 20 seconds, exhaled through an
activated-charcoal trap, inhaled room air, then exhaled through the
trap a second time. Ninety-four to 97 percent of the inhaled
tetrachloroethane was retained. Subjects continued to breathe room
air and exhale for one hour through charcoal traps. Only 3.3 to 6
3 8
percent of the initially retained vapor (as Cl) was exhaled one
hour after the single inhalation exposure. Carbon dioxide was not
monitored. Of a number of halogenated hydrocarbons tested (Morgan,
et al. 1972), 1,1,2,2-tetrachloroethane had the highest partition
coefficient (olive oil/gas, serum/gas), one of the highest rates of
3 8
absorption (human inhalation of Cl vapors) and one of the lowest
rates of elimination by exhalation.
Distribution
In studying the metabolism of chloroethanes, Yllner
(1971a,b,c,d,e) reported that 0.6 to 1.3 percent of an intra-
peritoneal (i.p.) dose of 1,2-dichloroethane (0.05 to 0.17
g/kg body weight) administered to mice was retained after 3 days.
One to 3 percent of a dose of 1,1,2-dichloroethane (0.1 to
0.2 g/kg) was retained after three days. The highly toxic
C-16
-------
1,1,2,2-tetrachloroethane (0.21 to 0.32 a/kg) was metabolized more
slowly or stored, since 16 percent of the dose was retained 3 days
after the dose was injected i.p. (Yllner, 1971d).
Holmberg, et al. (1977) studied the distribution of 1,1,1-
trichloroethane in mice during and after inhalation. Solvent con-
centrations in the kidney and brain were about the same at a given
exposure concentration, but concentrations in the liver were twice
those observed in the kidney and brain following exposures to 100
ppm or more (Table 6). A pharmacokinetic model with both uptake
and elimination of the first order best fit the empirical data.
Hake, et al. (1960) reported that 0.09 percent of a large dose of
1,1,1-trichloroethane was retained in the skin of rats as the par-
ent compound 25 hours after administration of an i.p. dose ( 700
mg/kg). The blood contained 0.02 percent, the- fat 0.02 percent,
and other sites 0.1 percent of the dose administered.
A study of solvents in post mortem human tissue was reported
by Walter, et al. (1976). 1,1,1-Trichloroethane was found in body
fat (highest concentration), kidney, liver, and brain. Data from
autopsies of humans dying from acute exposures indicate that the
highest tissue concentration was in the liver, followed by brain,
kidney, muscle, lung, and blood (Stahl, et al. 1969).
In pregnant rats and rabbits, inhalation or ingestion of
1,1,1,2-tetrachloroethane resulted in the presence of high levels
of the compound in the fetuses (Truhaut, et al. 1974).
Metabolism
In 1971, Yllner published a series of papers dealing with the
metabolism of chloroethanes. Solvents were injected i.p. into mice
C-17
-------
TABLE 6
Concentrations of 1,1,1-Trichloroethane in Tissues
of Mice Following Inhalation Exposures*
Concentration .,
ppm mg/m
o
CD
10
100
1,000
5,000
10,000
54.2
545.2
5452.0
27,260
54,520
Exposure
Time (h)
24
24
6
3
6
pg 1,1,1-Trichloroethane/g Tissue
Blood
0.6
6.3
36
165
404
+ 0.16a
+ 3.0
± 16
± 25
+ 158
Liver
1.5
12.2
107
754
1429
+ 0.3
+ 4.6
+ 38
+ 226
+ 418
Kidney
1.1
5.9
60
153
752
+ 0.2
+ 2.2
± 16
+ 27
+ 251
Brain
0.8
6.2
57
156
739
+ 0.1
+ 1.3
± 17
± 24
+ 170
*Source: Holmberg, et al. 1977
aValues are means and standard deviations from 4 to 10 animals.
-------
and the excretion of metabolites, in the urine was monitored for
three days. Table 7 summarizes Yllner's observations.
Metabolism of the highly toxic 1,1,2,2-tetrachloroethane,
14
based on the identification of C-labeled metabolites in the urine
of mice (Yllner, 1971d), involved a stepwise hydrolytic cleavage of
the chlorine-carbon bonds yielding glyoxalic acid and carbon di-
oxide. Nonenzymatic oxidation of 1,1,2,2-tetrachloroethane may
produce a small amount of tetrachloroethylene. The parent compound
may be dehydrochlorinated to form small amounts of trichloro-
ethylene, a precursor to trichloroacetic acid and trichloroethanol.
The metabolism of pentachloroethane in the mouse is postulated
to proceed at least partly through trichloroethylene and its meta-
bolite chloral hydrate. The latter compound could also be formed
from pentachloroethane by hydrolytic fission—of carbon-chlorine
bonds (Yllner, 1971e).
In Yllner's experiments, the percentage of the dose metabol-
ized decreased with sn increasing dose (1971a,b,c,d,e), suggesting
that degradative pathways become saturated and an increasing amount
is expired unchanged or retained in the body.
Ikeda and Ohtsuji (1972) exposed rats by inhalation to 200 ppm
chloroethanes (1,1,1-tri; 1,1,2-tri; 1,1,1,2-tetra; or 1,1,2,2-
tetrachloroethane) for eight hours and collected the urine for 48
hours from the beginning of exposure. Equimolar amounts of the
same four solvents were injected i.p. into rats. Metabolites in
the urine following inhalation or i.p, administration of all four
solvents were trichloroacetic acid (TCA) and trichloroethanol(TCE)
(Table 8), although relative amounts varied with the individual
:-i9
-------
TABLE 7
Major Metabolites of Chloroethanes in Mice*
o
N>
o
Compound
1,2-Dichloroethane
( C- )
Dose
(g/kg)
12-15
Urinary Metabolites
Total % Identified
51-73 S-carboxymethylcysteine
Thiodiacetic acid
Chloroacetic acid
2-Chloroethanol
S,S' -ethylene-bis-cysteine
% of
44-46
0.5-5
33-44
6-23
0.0-0
0.7-1
Dose
Free
Bound
.8
.0
1,1,2-Trichloroethane 10-13
1,1,1,2-Tetrachloro
ethane
1,1,2,2-Tetrachloro
ethane (14C-)
0.21-0.32
Pentachloroethane
1.1-1.8
6-9 S-carboxymethylcysteine
Chloroacetic acid
Thiodiacetic acid
2,2-Dichloroethanol
2,2,2-Trichloroethanol
Oxalic acid
Trichloroacetic acid
17-49 Trichloroethanol
Trichloroacetic acid
23-34 Dichloroacetic acid
Trichloroacetic acid
Trichloroethanol
Oxalic acid
Glyoxylic
Urea
Half of urinary activity
not accounted for
87.3 Trichloroethanol
Trichloroacetic acid
Expired air contained
trichloroethylene (2-16%) and
tetrachloroethylene (3-9%)
29-46 Free
3-10 Bound
6-31
38-42
17-49
1-7
16-32
9-18
*Source: Yllner, 1971a, b, c, d, and e
-------
TABLE 8
Urinary Metabolites from Wistar Rats Exposed to Solvents*
Solvent
No. of
Experiments
Urinary Metabolites3
(mg/kg body weight)
TCA
TCE
Inhalation
200 ppm 8 hrs.
1,1,1-Trichloroethane 8
1,1,2-Trichloroethane 8
1,1,1,2-Tetrachloroethane 8
1,1,2,2-Tetrachloroethane 8
0.5 + 0.2
0.3 + 0.1
39.4 + 5.0
1.7 + 0.9
3.1 + 1.0
0.3 + 0.1
159.6 + 24.4
6.5 + 2.7
Intraperitoneal0
2.78 mmol per kg body weight
1,1,1-Trichloroethane 8
1,1,2-Trichloroethane 8
1,1,1,2-Tetrachloroethane 8
1,1,2,2-Tetrachloroethane 8
0.5 + 0.2
0.4 + 0.1
16.9 + 1.6
1.3 + 0.2
3.5 + 1.4
0.2 + 0.1
97.3 + 8.1
0.8 + 0.4
*Source: Ikeda and Ohtsuji, 1972
numbers represent mean + std. dev.
Six rats per group
Five rats per group
021
-------
solvent. Metabolites were determined colorimetrically by the
Fujiwara reaction; trichloroethanol was determined as the differ-
ence between the total trichlorocompounds and trichloroacetic acid.
Truhaut (1972) identified metabolites in the urine of rats,
rabbits and guinea pigs given oral doses of 1,1,1,2-tetrachloro-
ethane. His results indicate that the solvent is metabolized to
trichloroethanol and excreted in the urine as trichloroethyl-^ -D-
glucuronic acid. In rats, small amounts of trichloroacetic acid
were also formed.
Van Dyke and Wineman (1971) investigated the enzymatic de-
chlorination of a series of chloroethanes by rat liver microsomes
(Table 9). The system required NADPH and oxygen and was induced by
phenobarbitol and benzo(a)pyrene, but not by methylcholanthrene.
Dechlorination of 1,1,2-trichloroethane was stimulated by addition
of rat 100,000 x g supernatant to the microsomal assay (Gandolfi
and Van Dyke, 1973).
1,1,2,2-Tetrachloroethane (437 mg/kg body weight) and hexa-
chloroethane (615 mg/kg body weight) administered perorally to
rats, decreased the cytochrome P-450 content and overall drug
hydroxylation activity in the liver (Vainio, et al. 1976). Working
with hepatic microsomes isolated from phenobarbital-induced rats,
Ivanetich, et al. (1978), found that 1,1,1-trichloroethane and 1,2-
dichloroethane degraded the heme moiety of cytochrome P-450;
degradation appeared to require metabolic activation since NADPH
was a requirement for binding.
In controlled human exposure studies, metabolism of inhaled
1,1,1-trichloroethane (70 ppm for 4 hours) represented 3.5 percent
C-22
-------
TABLE 9
Dechlorination of Chloroethanes by
Rat Liver Microsomes*
Compound'
36(
Removed'
Percent Cl Enzymatically
,b
Monochloroethane
1,1-Dichloroethane
1,2-Dichloroe thane
1,1,1-Trichloroethane
1,1,2-Trichloroethane
1,1,1,2-Tetrachloroethane
1,1,2,2,-Tetrachloroethane
Pentachloroethane
Hexachloroethane
<0.5
13.5
<0.5
<0.5
9.8
0.8
6.0
1.7
3.9
*Source: Van Dyke and Wineman, 1971
aUniformly labeled with chlorine-36
Results are averages of duplicate assays from at least six rats
C-23
-------
of total uptake (Monster, 1979). The author suggested that trans-
formation of the parent compound takes place by hydroxylation to
trichloroethanol, followed by partial oxidation of trichloro-
ethanol to trichloroacetic acid.
Excretion
Yllner quantitated the excretory products of 1,2-di; 1,1,2-
tri; 1,1,1,2-tetra; 1,1,2,2-tetra; and penta-chloroethane in mice
(1971a,b,c,d,and e) (Table 10). Compounds were administered i.p.
and excretion was monitored for 3 days; urinary metabolites are
listed in Table 7.
More than 90 percent of the doses of 1,2-dichloroethane or
1,1,2-trichloroethane was excreted in the first 24 hours with more
than half found in the urine. Seventy-eight percent of the
1,1,1,2-tetrachloroethane administered was excreted in 72 hours
with 48 percent expired unchanged (21 to 62 percent). Eighty-four
percent of the 1,1,2,2-tetrachloroethane dose was eliminated in 72
hours, with about half the dose lost as C00, and one-fourth ex-
.£*
creted in the urine; approximately 16 percent remained in the ani-
mal. About one-third of the pentachloroethane dose was expired un-
changed; the expired air also contained trichloroethylene (2 to 16
percent) and tetrachloroethylene (3 to 9 percent) indicating de-
chlorination of pentachloroethane. Twenty-five to 50 percent of
the dose was excreted in the urine.
Stewart, et al. (1961, 1969, 1975) studied controlled human
exposures to 1,1,1-trichloroethane vapor. The concentration of the
unchanged solvent in the post-exposure expired air was predict-
able enough to estimate the magnitude of exposure. The rate of
c-:
-------
TABLE 10
Excretion of Chloroethanes Administered to Mice
Chloro-
ethane
Compound
1,2-
1,1,2-
1,1,1,2-
1,1,2,2-
Penta-
Dose
(g/kg)
0.05-0.17
0.1 -0.2
1.2 -2.0
0.21-0.32
1.1 - 1.8
Expired
Unchanged
10-45
6-9
21-62
4
12-51
Expired
as C02
12-15
10-13
-
45-61
-
In In
Urine Feces
51-73 0-0.6
73-87 0.1-2.0
18-56
23-34
25-50
*Source: Yllner, 1971a,b,c,d,e
Intraperitoneal injection - Excretory products collected for
3 days
C-25
-------
1,1,1-trichloroethane excretion was a function of exposure duration as
well as concentration (Table 11).
Monster, et al. (1979) reported that 60 to 80 percent of
1,1,1-trichloroethane (70 or 140 ppm for 4 hours) inhaled by human
volunteers was expired unchanged; two metabolites, trichloro-
ethanol and trichloroacetic acid, excreted in the urine, represent-
ed approximately three percent of the total uptake. Although mea-
surements of the parent compound and its metabolites are commonly
used to estimate uptake of 1,1,1-trichloroethane, studies by
Monster and Houtkooper (1979) have shown that the best estimates of
uptake are provided by concentrations present in blood,
A multistage cryogenic trapping system was used to concentrate
trace organic compounds in human respiratory gas: three chlorinated
ethanes, 1,1,1-trichloroethane, 1,1- and 1,2-dichloroethane, were
identified in the expired air of subjects with no known history of
exposure (Conkle, et al. 1975). No estimates of half-lives and
body burdens of chlorosthanes were found in the literature. These
data must be obtained, however, in order to identify populations at
risk.
EFFECTS
Acute, Subacute, and Chronic Toxicity
A number of excellent publications are available which review
the acute and chronic effects of some chloroethanes. Aviado, et
al. (1976) published a monograph on "Methyl Chloroform and Tri-
chloroethylene in the Environment." NIOSH (1978b) published cri-
teria documents for recommended standards of occupational exposure
to 1,1,1-trichloroethane (NIOSH, 1978b), 1,2-dichloroethane
C-26
-------
TABLE 11
1,1/1-Trichloroethane Breath Concentrations of
Men and Women Exposed at 350 ppm*
Tirrm
No.
Men
Mean
(ppm)
Women
Range
(ppm)
Isolated
o
1
ro
"~J
2 Minutes
1 Minute
23 Hours
pre-exit exposure
post
post
exposure
exposure
3
3
3
150
76.4
1.11
144 -
48.6 -
0.75 -
157
108
1.63
Isolated 7.5
2 Minutes
1 Minute
16 Hours
pre-exit exposure
post
post
exposure
exposure
4
4
4
234
149
7.07
222 -
144 -
6.62 -
252
153
7.73
No.
Mean
(ppm)
Range
(ppm)
1-Hour Exposure
3
2
2
Hour Exposure
3
4
4
183
120
0.8
254
181
6.93
173
116
0.57
247
156
4.83
- 193
- 123
- 1.03
- 262
- 205
- 8.74
*Source: Stewart, et al. 1975
-------
(NIOSH, 1976b), and 1,1,2,2-tetrachloroethane (NIOSH, 1976a). The
U.S. EPA (1979) has recently published a comprehensive review of
the health and environmental effects of 1,2-dichloroethane. A
monograph prepared by Walter, et al. (1976) on chlorinated hydro-
carbon toxicity, included 1,1,1-trichloroethane and was prepared
for the Consumer Product Safety Commission, Bureau of Biomedical
Science. A comprehensive review of 1,1,1-trichloroethane litera-
ture from 1953 through 1973 was conducted by the Franklin Institute
Research Laboratories for the U.S. EPA (Kover, 1975).
Only a representative portion of the literature available on
the toxic effects of chloroethanes will be discussed since the
focus of this document is on the effects of chronic ingestion and
possible carcinogenic effects.
Monochloroethane is considered one of the least toxic of the
chloroethanes; however, as a halogen-containing hydrocarbon it is
potentially damaging to the liver and is known to disturb cardiac
rhythm (Goodman and Oilman, 1975). Overdoses of several volatile
anesthetics including monochloroethane can lead to severe contract-
ile failure of the heart (Doering, 1975). At the stage of maximal
failure, the myocardial stores of ATP and phosphocreatine were
increased indicating a reduction in the utilization of energy
stores.
1,1-Dichloroethane is less toxic than the 1,2-isomer but the
1,1-isomer's use as an anesthetic was discontinued because of
marked excitation of the heart (Browning, 1965). Liver injury has
been reported in experimental animals (Sax, 1975) following acute
exposures ranging from 4,000 to 17,500 ppm.
C-28
-------
The U.S. EPA reports that 1,2-dichloroethane is toxic to
humans by ingestion, inhalation, and absorption through skin and
mucus membranes. Symptoms of 1,2-dichloroethane toxicosis include
central nervous system depression, gastrointestinal upset, and
systemic injury to the liver, kidneys, lungs, and adrenals (U.S.
EPA, 1979). Smyth, et al.{1969) reported an oral LD5Q for 1,2-
dichloroethane in rats of 0,77 ml/kg (range 0.67 to 0.89) and a
dermal LD5Q for rabbits of 3.89 ml/kg (range 3.40 to 4.46). In both
cases a single dose was administered.
Acute and subacute inhalation studies with dogs, rabbits,
guinea pigs, rats and mice indicated that 1,2-dichloroethane was
toxic to the liver, bone marrow, blood, kidneys, myocardium and
sometimes the adrenals (Heppel, et al. 1946; Liola, et al. 1959;
Liola and Fondacaro, 1959). Chronic inhalation exposures, 100 to
400 ppm, for 5 to 32 weeks in several species were reported to be
toxic in the liver at 200 ppm and above (Spencer, et al. 1951;
Hofmann, et al. 1971). Increased liver weights were observed in
guinea pigs following a 32 week exposure to 100 ppm 1,2-dichloro-
ethane (Spencer, et al. 1951).
DiVincenzo and Krasavage (1974) used ornithine carbamyl trans-
ferase (OCT) activity as a specific indication of the hepatotoxic
properties of various organic solvents. Of the 33 solvents tested,
5 were chlorinated ethanes (1,1-; 1,2-; 1,1,1-; 1,1,2-; 1,1,2,2-).
The solvents were injected intraperitoneally into mature naive male
guinea pigs, and the serum OCT level was measured 24 hours later.
Of the five chlorinated ethanes tested, only two (1,1,2- and 1,2-)
showed an increase in serum OCT activity. 1,1,2-Trichloethane
C-29
-------
showed elevations in serum OCT activity at dosages of 200 and 400
rog/kg, indicating a moderate level of hepatotoxicity. Liver damage
was confirmed by histological examination. 1,2-Dichloroethane
showed an elevated OCT activity at 600 mg/kg, but not at 300 or 150
mg/kg, indicating a low level of hepatotoxicity. Liver damage was
not confirmed by histological examination. The remaining chlori-
nated ethanes tested in this study (1,1,2,2-; 1,1,1-; and 1,1-) did
not show elevated serum OCT activity or discernable hepatocellular
damage. These data are summarized in Table 12.
Ingestion of 1,2-dichloroethane by man has often resulted in
death which was usually ascribed to circulatory and respiratory
failure. Brief descriptions of several cases are presented in
Table 13. Clinical symptoms of toxicosis were usually present
within 2 hours after ingestion. In addition to the signs and
symptoms listed in Table 13, a reduction in clotting factors and
platelet count were observed, and fibrinolysis was increased up to
four times its normal value. Martin, et al. (1969) reported a
"thrombin time" after fibrinogen substitution of 59 seconds as com-
pared to the normal value of 12 seconds. Post mortem examinations
usually revealed thrombi in the pulmonary arterioles and capillar-
ies, hemorrhages into the mucosa of the esophagus, stump of the
stomach, rectum, and myocardial tissues.
Patients suffering from acute 1,2-dichloroethane poisoning
developed diffuse dystrophic changes in brain and spinal cord cells
which were described clinically as toxic encephalomyelopathy
(Akimov, et al. 1978). One man who survived acute poisoning
suffered irreversible mental defects, acute liver dystrophy,
C-30
-------
TABLE 12
Evaluation of Acute Hepatotoxic Properties of Organic Solvents*
O
I
u>
Solvent
Te t r ac h lor oe thane
(C12CHCHC12)
1,
1,
1,
1,
1 , 1-Tr ichloroethane
(C13CCH3)
1 , 2-Tr ichloroethane
(C12CHCH2C1)
1-Dich lor oe thane
(C12CHCH3)
2-Dichloroethanee
(C1CH2C»2C1)
*Source: Divincenzo
na
4
8
4
4
4
4
4
4
4
4
4
4
4
4
4
4
and
Dose (mg/kg)
75
150
300
75
150
300
600
200
400
150
300
500
750
150
300
600
Krasavaqe, 1974
Mean Serum OCT . Results
activity (I.U.)
2
3
4
0
0
0
1
47
55
1
1
1
3
3
3
34
.9
.2
.5
.9
.9
.9
.6
.3
.9
.3
.8
.2
.2
.0
.1
.6
Lacks hepatotoxic properties,
even at near lethal doses
Shows no acute hepatotoxic
properties
elevation in serum OCT level does
not appear to be dose-related;
tissue necrosis seen at both doses;
lipid deposition at higher dose
Histology normal; dosages failed
to elici t a change in serum
OCT activity
Liver damage indicated by serum
OCT activity; elevation was not
confirmed by histological examination
Relative
llepatotoxicity°
None
None
Moderate
None
Low
at 500 mq/kq, all 4 animals tested died
at 600 mg/kg, 1 of 4 animals tested died
Serum OCT activity in hoalthy guinea pigs (117 animals
tested) is 2.02 + 1.61 with a range of 0-8.9
°Low indicates an elevated OCT at a dose 500 mg/kq
Moderate indicates an elevated OCT at dosages between
500 and 50 kg
None indicates that no OCT activity changes were noted
at levels tested
-------
TABLE 13
Signs and Symptoms
1,2-Dichloroethane
Following
Ingestion
o
Author
Secchi ,
et al.
(1968)
Patient
Data
80-year-
old
Amount
Consumed
50 ml
Onset of Progression of
Symptoms Signs and Symptoms
Elevated serum enzymes -
LDH, SCOT, SGPT, alkaline
phosphatase, glutamic de-
hydrogenase, RNAase; death
a few hours after ingestion.
Marti n,
et al.
(1969)
57-year-
old man
Schonborn,
et al.
(1970)
Yodaiken
and
Babcock
(1973)
18-year-
old man
14-year-
old boy
40 ml
50 ml
1 hour
15 ml
2 hours
Somnolence; vomiting;
sinus tachycardia; ventri-
cular extrasystoles;
dyspenea; loss of blood
pressure; cardiac arrest;
death 24 hours after ingestion.
Somnolent; cyanotic;
shock of circulatory
system; death after 17
hours in irreversible shock.
Headache; staggering;
lethargy; periodic
vomiting; blood pressure
drop; cardiac arrest;
pulmonary edema; refractory
hypotension; death on
sixth day.
-------
nephropathy, and anemia (Dorndorf, et al. 1976). Acute poisoning
also caused an elevation of leukocytes in the blood and protein in
the urine (Bonitenko, et al. 1977).
The effects of acute inhalation exposures to 1,2-dichloro-
ethane are similar to those observed after ingestion, with death
being attributed to respiratory and circulatory failure. (Wendel,
1948; Wirtschafter and Schwartz, 1939; Troisi and Cavallazzi,
1961). Nonfatal acute exposures have also been reported
(Wirtschafter and Schwartz, 1939; McNally and Fostedt, 1941). In
a 1947 report, Rosenbaum reported that acute poisonings developed
rapidly following repeated exposure of workers to concentrations of
75 to 125 ppm (Rosenbaum, 1947). Many persons exposed to lower
concentrations of 1,2-dichloroethane reported delayed effects with
the most severe reactions occurring after the evening meal (Byers,
1943).
Summaries of the acute effects of human exposures to 1,2-di-
chloroethane are similar for all routes of entry: ingestion,
inhalation, and skin absorption. Such exposures result in nausea,
vomiting, dizziness, internal bleeding, cyanosis, rapid but weak
pulse, and unconsciousness. Acute exposures often lead to death
from respiratory and circulatory failure. Chronic exposures to
1,2-dichloroethane have resulted in neurological changes, loss of
appetite and other gastrointestinal problems, irritation of mucous
membranes, liver and kidney impairment, and in some cases, death
(NIOSH, 1978a; U.S. EPA, 1979).
The anesthetic properties of 1,1,1-trichloroethane have been
demonstrated in rats (Torkelson, et al. 1958), mice (Gerhring,
C-33
-------
1968), and dogs and monkeys (Krantz, et al. 1959). Based on mini-
mum concentrations causing prostration in two hours, Lazarew (1929)
determined that the 1,1,2-isomer was four times more toxic than the
1,1,1-isomer (Table 14).
Adams, et al. (1950) determined an LC5Q for rats exposed up to
seven hours by inhalation to 1,1,1-trichloroethane (contained up to
one percent 1,1-dichloroethane). At 18,000 ppm, half of the ani-
mals were dead in three hours (2.1 to 4.2 hours, 95 percent confi-
dence limits); at 14,250 ppm half the animals were dead in seven
hours (12,950 to 15,675 ppm, 95 percent confidence limits).
Both commercial grade and 1,1,1-trichloroethane (no inhibi-
tors) were administered orally to rats, mice, rabbits, and guinea
pigs for determination of an LD5Q for each species (Torkelson, et
al. 1958). Single doses of undiluted solvent were given by gavage
(Table 15). No differences were observed in toxic responses of
animals to solvents of varying purity.
During 1,1,1-trichloroethane anesthesia of dogs, two of the
animals died suddenly (Rennick, et al. 1949). Further inhalation
experiments indicated that at 0.33 to 0.53 g/kg, the solvent sensi-
tized the heart to epinephrine-induced ventricular extrasystoles
and ventricular tachycardia. Cardiac sensitization, an increased
susceptibility of the heart to catecholamines, is induced by a num-
ber of halogenated hydrocarbons (Reinhardt, et al. 1973).
Electrocardiogram changes in three dogs were observed after an
abrupt drop in blood pressure induced by 1,1,1-tricholoroethane
anesthesia (Griffiths, et al. 1972). Dogs were sedated with sodium
pentobarbital (20 mg/kg) before administration of about 125,000 ppm
C-34
-------
TABLE 14
Effects of Trichloroethane
Isomers on Mice*
Isomer
1,1,1-
1,1,2-
Minimum Concentration for
Response within 2 Hours
of Exposure (mg/1)
proneness loss of reflexes
40 45
10 15
death
65
60
*Source: Lazarew, 1929
C-35
-------
LD
50
TABLE 15
After Oral Administration of
1/lfl-Trichloroethane in Laboratory Animals
Characteristics of
1,1,1-Tr ichloroethane
Animal
Sex/Species
2.4-3.0% dioxane
0.12-0.3% butanol
Trace of 1,2-dichloro-
ethane
Uninhibited
Not further defined
35 male rats
35 female rats
16 female mice
16 female rabbits
16 male guinea pigs
40 male rats
50 female rats
40 female mice
40 female rabbits
30 male guinea piqs
Mean
12.3
10.3
11.2
5.7
9.5
14.3
11.0
9.7
10.5
8.6
(g/kg)
95% Confidence
Limits
11.0-13.7
8.3-12.8
3.5-9.4
3.5-13.3
12.1-17.0
9.5-13.0
9.7-11.3
6.1-12.2
*Source: Torkelson, et al. 1958
Administered undiluted by gavage
-------
1,1,1-trichloroethane. Krantz, et al. (1959) noted a drop in blood
pressure to about one-half of its normal value prior to respiratory
failure in 11 dogs and 10 monkeys administered 0.60 ml/kg and 0.59
ml/kg, respectively. EKG abnormalities were also noted.
Recent studies have demonstrated a relationship between
changes in cardiovascular parameters and exposure to 1,1,1-tri-
chloroethane including the following: Herd, et al. (1974) observed
a dose-dependent two-phase drop in blood pressure and decreased
peripheral resistance following an inhalation exposure in dogs;
also in dogs, Reinhardt, et al. (1973) found 27.S mg/1 to be the
minimum concentration causing sensitization of the heart to epin-
ephrine-induced arrhythmias; Clark and Tinston (1973) reported the
effective concentration for sensitization to be 40.7 mg/1 in an-
other group of dogs; in mice, Aviado and Bele_j (1974) noted ar-
rhythmias during inhalation of 2.2 x 10 mg/mJ 1,1,1-trichloro-
ethane.
In summary, inhalation of 1,1,1-trichloroethane by various
species of animals induces toxic effects in the central nervous,
cardiovascular, and pulmonary systems, and in the liver and kidney
(Truhaut, et al. 1973; Horiguchi and Horiguchi, 1971; Tsapko and
Rappoport, 1972; Belej, et al. 1974; Herd, et al. 1974; Torkelson,
et al. 1958; MacEwen and Vernot, 1974). In most animal studies,
high concentrations were used. In the experiments cited, the low-
est concentration producing toxic effects was 73 ppm, administered
four hours per day from 50 to 120 days (Tsapko and Rappoport,
1972).
>37
-------
The effects most often reported following 1,1,1-tricholor-
ethane exposure of humans are central nervous system disorders.
These include changes in reaction time, perceptual speed, manual
dexterity, and equilibrium; however, cardiovascular effects have
not been observed at the concentrations used in human exposures.
Inhalation exposures of 450 ppm for eight hours caused eye, nose,
and throat irritation, and decreased perceptive capabilities under
stress conditions (Salvini, et al. 1971). Perceptual speed, reac-
tion times, and manual dexterity were impaired in volunteers inhal-
ing 350 ppm for three hours; impairment was not evident following
inhalation of 250 ppm for two hours (Gamberale and Hultengren
1973). Two of 11 men inhaling 500 ppm 1,1,1-trichloroethane for
6.5 to 7 hours/day for five days showed abnormal results in a modi-
fied Romberg's test (Stewart, et al. 1961).
An epidemiologic study of 151^matched pairs of employees was
conducted in two adjacent textile plants, one of which used inhib-
ited 1,1,1-trichloroethane as a general cleaning solvent (Kramer,
et al. 1976). Employees in the study population had exposures to
the solvent for six years or less at varying concentrations mea-
sured by breathing zone sampling and personal monitoring tech-
niques. The eight hour time-weighted average of personal sampling
concentrations ranged from 4 ppm to 217 ppm. Cardiovascular and
hepatic observations were of primary interest. Statistical
analysis of the data did not reveal any clinically pertinent find-
ings which were associated with exposure to 1,1,1-trichloroethane.
A dermal LD5Q for 1,1,2-trichloroethane in rabbits was report-
ed to be 3.73 ml/kg body weight; an ingestion LD5_ for rats was
C-38
-------
reported to be 0.53 ml/kg; for inhalation, an 8-hour exposure at 500
ppm was fatal to four of six rats (Smyth, et al. 1969).
LD 0 concentrations of 1,1,2-trichloroethane (0.35 ml/kg in
mice and 0.45 ml/kg in dogs, i.p.) caused kidney necrosis (Klaassen
and Plaa, 1967). The effective dose for 50 percent of the animals
(ED,- ) which produced kidney necrosis was 0.17 ml/kg in mice and
0.4 ml/kg in dogs, examined 24 hours after receiving the compound.
Forty-eight hours after receiving an ED5Q dose, (0.35 ml/kg, i.p.),
the livers of treated dogs exhibited centrolobular necrosis as
indicated by elevated serum glutamate pyruvate transaminase (SGPT)
levels.
Acute exposures of mice by inhalation to vapors of 1,1,2-tri-
chloroethane (3750 ppm for 30 minutes) produced a significant ele-
vation in SGPT measured 24 hours post exposure (Gehring, 1968). In
comparison to the hepatotoxins, carbon tetrachloride and chloroform,
1,1,2-trichloroethane was judged a moderate hepatotoxin based on
SGPT elevation.
Twenty-four hours after the administration of a subacute oral
dose of 1,1,1,2-tetrachloroethane to rabbits (0.5 g/kg body
weight), the activity of enzymes indicating hepatoxicity (SGPT,
SCOT, LDH and -X-hydroxy-butyrate dehydrogenase) was enhanced
(Truhaut, et al. 1973), and remained enhanced 72 hours after
poisoning. Blood cholesterol and total lipid levels were also
increased.
Acute exposures by inhalation to vapor of 1,1,2,2-tetrachloro-
ethane produced anesthesia, death, fatty degeneration of the liver,
C-39
-------
and tissue congestion in mice (Mullet, 1932; Horiguchi, et al.
1962) and rats (Horiguchi, et al. 1962). Exposure concentrations
ranged from 5,900 ppm (three hours) to 11,400 ppm (six hours, two
days). In monkeys exposed to 1,000 ppm or 4,000 ppm, two hours/day
for 190 days, marked vacuolation of the liver was observed
(Horiguchi, et al. 1962). A single four-hour exposure of rats to
1,000 ppm of the compound caused the death of three of six animals
in 14 days (Smyth, et al. 1969). A three-hour exposure of mice to
600 ppm increased hepatic triglycerides and total lipids and de-
creased hepatic energy stores (Tomokuni, 1969).
Intravenous (i.v.) or intraperitoneal (i.p. ) injection of
1,1,2,2-tetrachloroethane (total of 0.7 ml in five doses in 14
days) in guinea pigs caused weight loss, convulsions, death, and
fatty degeneration of the liver and kidney (Mullet, 1932). Two-
tenths of a gram administered i.v. to rabbits was lethal in 30
hours (Muller, 1932). In mice, i.p. injection of 200 mg/kg was
lethal in seven days (Natl. Res. Counc., 1952). Plaa and Larson
(1965) reported death of nine of ten mice and increased urinary
protein and glucose in the survivor resulting from the i.p.
injection of 1.6 g/kg of the compound in corn oil on three alter-
nate days.
Chronic exposures of rabbits by inhalation to 1,1,2,2-tetra-
chloroethane (14.6 ppm, four hours/day for 11 months) induced liver
and kidney degeneration (Navrotskiy, et al. 1971). Inhalation by
rats of 1.94 ppm, four hours/day up to 265 days, increased the num-
ber of white blood cells, pituitary adrenocorticotropic hormone,
and the total fat content of the liver (Deguchi, 1972).
C-40
-------
A number of human deaths have resulted from accidental or
intentional 1,1,2,2-tetrachloroethane ingestion (Hepple, 1927;
Elliot, 1933; Forbes, 1943; Lilliman, 1949; Lynch, 1967). Incases
of occupational poisoning, effects of 1,1,2,2-tetrachloroethane
have included dizziness, vomiting, malaise, headache, hand tremors,
and abdominal pain (Lehmann and Schmidt-Kehl, 1936; Horiguchi, et
al. 1962; Lobo-Mendonca, 1963; Wilcox, et al. 1915). Four deaths
have been attributed to industrial exposure to 1,1,2,2-tetrachloro-
ethane (Wilcox, et al. 1915).
Acute testing in laboratory animals indicated that hexachloro-
ethane was moderately toxic when administered orally (Weeks, et al.
1979). The compound was dissolved in corn oil (50 percent,
weight/volume) or methylcellulose (five percent, weight/volume)
and administered by stomach tube to male and female rats and male
guinea pigs. Following a 14-day observation period, the oral LD5Q
for male rats was 5,160 mg/kg in corn oil and 7,690 mg/kg in methyl-
cellulose; in female rats, the oral LD5Q values were 4,460 and
7,080 mg/kg. In guinea pigs, the oral LD50 in corn oil was 4,970
mg/kg.
Daily oral doses (12 days) of hexachloroethane of 1,000 or 320
mg/kg administered to rabbits produced liver degeneration and toxic
tubular nephrosis of the kidney. Animals were necropsied four days
after the last exposure. Liver or kidney degeneration was not
observed in rabbits receiving 100 mg/kg (Weeks, et al. 1979).
Exposure of dogs, guinea pigs, and rats by inhalation to 260
ppm hexachloroethane for six hours per day, five days/week for six
weeks produced central nervous system toxicity in dogs and rats,
C-41
-------
and significantly higher liver-to-body weight ratios in guinea pigs
and female rats. In male rats, the kidney-, spleen-, and testes-
to-body ratios were significantly higher than controls. Half of
the animals were sacrificed at the end of exposure and the remain-
der 12 weeks later. Evaluation of animals exposed to 48 ppm or 15
ppm revealed no adverse effects related to hexachloroethane expo-
sure (Weeks, et al. 1979).
Laboratory animals (Table 16) and humans (Table 17) exposed to
chloroethanes show similar symptoms of toxicity including eye and
skin irritations, liver, kidney, and heart degeneration, and cen-
tral nervous system depression.
Based on data derived from animal studies, the relative toxic-
ity of chloroethanes is: l,2-dichloroethane>1,1,2,2-tetrachloro-
ethane > 1,1,2-trichloroethane > hexachloroethane > 1,1-dichloro-
ethane >1,1,1-trichloroethane > monochloroethane. Available data
are not sufficient to judge the relative toxicity of 1,1,1,2-tetra-
chloroethane or pentachloroethane.
Synergism and/or Antagonism
Pretreatment of mice with acetone or isopropyl alcohol (2.5
ml/kg, by gavage) enhanced the effects of threshold doses of 1,1,2-
trichloroethane and produced an increased hepatotoxic response as
measured by an increase in SGPT activity (Traiger and Plaa, 1974).
Eighteen hours after pretreatment, the chlorinated hydrocarbon in
corn oil was administered i.p.; 24 hours later, blood samples were
taken by cardiac puncture. SGPT activity was not enhanced by 0.1
mg/kg 1,1,2-trichloroethane alone, but administration of acetone or
isopropyl pretreatment, produced a significant increase in SGPT
C-42
-------
O
*»
OJ
TABLE 16
Adverse Effects of Chloroethanes Reported in Animal Studies*
Chemicals
monochlo roe thane
1, 1-dichloro-
ethane
1, 2-dichloro-
ethane
1,1,1,-tc ichloro-
ethane
1,1. 2- tr ichloro-
1, 1,1,2-tetra-
1,1,2,2-tetra-
chloroethane
Species
unspecified
cat
dog
rat
bac te r i urn
cat
dog
fruit fly
guinea pig
monkey
rabbit
rat
cat
dog
guinea pig
mouse
monkey
rat
dog
quinea piq
rabbit
rat
bacter ium
dog
gu i nea pig
monkey
mouse
rabbit
Adverse Effect
kidney damage; fatty changes in liver, kidney and heart
kidney damage
liver injury
liver iniury; retarded fetal development - -
retarded growth rate, fatty changes in liver; heart dilation; lung hyperemia
corneal clouding; fatty changes in liver; liver enlargement; weight loss
mutagen
fatty changes in liver; liver enlargement; weight loss
fatty changes in liver
fatty changes in liver; hypotension; respiratory paralysis; EKG changes; anemia;
bone marrow changes; liver dysfunction, hemorrhage and degeneration; kidney degener-
ation and dysfunction
embryotoxin; pulmonary congestion; fatty changes in liver ... ...
neuromuscular reflex changes
sudden death; respiratory failure
fatty changes in liver; lung irritation
cardiac arrythmias; liver dysfunction; pulmonary congestion
cardiac arrythmias; myocardial depression; respiratory failure; staggering gait;
tachycardia; tremors
cardiac failure; pulmonary congestion; pneumonitis; staggering gait; weakness;
semiconciousness; respiratory failure
liver and kidney injury
liver and kidney injury
embryotoxin
embryotoxin; liver dysfunction; mutagen .
ascites; diarrhea; jaundice; liver enlargement; intestinal hemorrhage
convulsions, weight loss; death
anorexia; diarrhea; blood cell fluctuation; weight loss
staggering gait; breathing difficulty; fatty degeneration of liver and kidney; death
altered immune system; altered blood chemistry; liver and kidney degeneration; fatty
paralysis; death •,._.,
blood_ce 1 Lchanes LjL^^--d.e-9e-nJLratio" of liver; l_Ly_e£_dy_s fjinc tionj__de_ath_ -----
pentachloro-
ethane
hexachloro-
ethane
* Source": NIOSI1, 1978c.
^
cat
dog
sheep
"cattle
mouse
rat
sheep
_ . --.--
liver , kidney, and lung changes
fatty degeneration of liver; kidney and lung injury
liver dysfunction __________________
ITfver and kTdney damage
liver and kidney damage
liver and kidney damage
liver a^nd_Jo^ney^ damaige
-------
TABLE 17
Summary of Human Toxicity, Chloroethanes*
O
l
Chemical
monochloroethane
1,1-dichloroethane
1,2-dichloroethane
1,1,1-trichloro-
ethane
System
neurologic
gastrointestinal
respiratory
cardiovascular
dermatological
other
neurologic
respiratory
dermatologic
neurologic
hepatic
neurologic
hepatic
gastrointestinal
cardiovascular
hematologic
other
Adverse Effect
1,1, 2-tr ichloroethane
1,1,1,2-tetrachloroethane
central nervous system depression, headache, dizziness, incoordination
feeling inebriated, unconsciousness
abdominal cramps
respiratory tract irritation, respiratory failure
cardiac arrhythmias, cardiac arrest
skin irritation, frostbite, allergic eczema
eye irritation, death
central nervous system depression
respiratory tract irritation
skin burn
headache, dizziness, unconsciousness, vertigo, hand tremors, generalized
weakness, sleepiness, nervousness, mental confusion
liver function abnormalaties, cellular damage, toxic chemical hepatitis
jaundice, liver enlargement
central nervous systme depression, headache, dizziness, incoordination,
feeling inebriated, unconsciousness; impaired perceptual speed, manual
dexterity and equilibrium; increased reaction time, lightheadedness
drowsiness, sleepiness, generalized weakness, ringing sound in ears
unsteady gait, burning and/or prickling sensation in hands and/or feet
cellular damage, liver function abnormalities
nausea, vomiting, diarrhea
drop in blood pressure (hypotension), decrease in heart rate (bradycardia)
cardiac arrhythmias
blood clotting, scaliness, inflammation
eye irritation, fatigue, death
NIOSH is unaware of reports of adverse occupational exposure
NIOSH is unaware of reports of adverse occupational exposure
-------
TABLE 17 (continued)
Chemical
1,1, 2,2-tetrachloro-
ethane
O
l
.u
en
pentachloroethane
hexachloroethane
System
neurologic
hepatic
gastrointestinal
urologic
respiratory
cardiovascular
hematologic
derraatologic
other
neurologic
Adverse Effect
central nervous system depression, headache, feeling inebriated, uncon-
sciousness, drowsiness, unsteady gait, vertigo, hand tremors, numbness
in limbs, prickling sensation of fingers and toes, pain in soles of feet,
loss of knee jerk, paralysis of some muscles of the hands and feet,
inflammation of the peripheral nerves, slight paralysis of the soft palate,
loss of the gag reflex, irritability, mental confusion, delirium, con-
vulsions, stupor, coma
liver function abnormalities, massive cell damage, toxic chemical hepatitis,
jaundice, liver enlargement, sensation of pressure in the liver area
abdominal pain, nausea, vomiting, unpleasant taste in the mouth, loss of
appetite (anorexia), vomiting of blood (hematemesis), increased flatulence,
diarrhea, constipation, pale stools
kidney damage, presence of bile pigments, albumen, and casts in the urine
excessive fluid in the lungs (pulmonary edema), respiratory paralysis
fatty degeneration of the heart muscle
anemia, increase in white cells, (and blood platelets)
dryness, cracking, scaliness, inflammation, purpuric rash
insomnia, general malaise, fatigue, excessive sweating, weight loss
NIOSH
is unaware of reports of adverse occupational exposure
inability to close eyelid; eye irritation, tearing of eyes, inflammation
delicate membrane lining the eye, visual intolerane to light, (photophobia)
*Source: NIOS1I, 1978c
-------
activity. The hepatotoxicity of 1,1,1-trichloroethane was not
altered by pretreatment with acetone or isopropyl alcohol in these
experiments.
Pretreatment of mice for three days with ethanol (5 g/kg, by
gavage) enhanced 1,1,1-trichloroethane-induced sulfobxomophthalein
(BSP) retention, an indicator of liver dysfunction (Klaassen and
Plaa, 1966). The chlorinated hydrocarbon administered on day four
(2.75 ml/kg, i.p.) increased BSP retention from 0.91 to 3.76 mg/100
ml. The effect of 1,1,2-trichloroethane on BSP retention was not
potentiated by prior ingestion of ethanol. Cornish and Adefuin
(1966) pretreated rats with ethanol which altered 1,1,1-trichloro-
ethane hepatotoxicity as judged by SCOT activity. Pretreatment of
rats with phenobarbital (i.p.) did not alter the effect of 1,1,1-
tr ichloroethane on SCOT activity (Cornish, et al. 1973).
Exposure of rats to 3,000 ppm 1,1,1-trichloroethane for 24
hours decreased drug-induced sleeping times when followed by i.p.
administration of hexobarbital, meprobamate, or zoxazolamine 24
hours post-exposure. Inhibitors of protein synthesis blocked the
effect of 1,1,1-trichloroethane on hexobarbital-induced sleeping
time (Fuller, et al. 1970). The hypothesis that hepatic microsomal
enzymes were induced by the chlorinated hydrocarbon was supported
by data showing _in vitro stimulation of microsomal aniline
hydroxylase activity by 1,1,1-trichloroethane (Van Dyke and Rikans,
1970).
Potentiation of toxicity was not observed in extensive stud-
ies with a mixture of 1,1,1-trichloroethane (75 percent) and
C-46
-------
tetrachloroethylene (25 percent) (by weight) in mice, rats, guinea
pigs, rabbits, dogs, and human subjects (Rowe, et al. 1963).
Teratogenicity
No literature was found concerning the teratogenic effects of
monochloroethane, 1,1,2-trichloroethane, 1,1,1,2-tetrachloro-
ethane, 1,1,2,2-tetrachloroethane or pentachloroethane.
Inhalation of 1,1-dichloroethane (3,800 or 6,000 opm) by preg-
nant rats seven hours per day on days 6 through 15 of gestation had
no effect on the incidence of fetal resorptions, on fetal body mea-
surements, or on the incidence of gross or soft tissue anomalies.
A significantly increased incidence of delayed ossification of
sternebrae was associated with exposure to 24,250 mg/m 1,1-di-
chloroethane which reflects retarded fetal development rather than
a teratological effect (Schwetz, et al. 1974).
Female rats were exposed to 1,2-dichloroethane vapor (57
mg/m3, 4 hrs/day, 6 days/week) for six months prior to breeding
and throughout gestation. Litter size, number of live births, and
fetal weights were reduced, as compared to nonexposed controls
(Table 18). The first generation rats (exposed in utero) showed
decreased viability; the females of the first generation exhibited
prolonged estrus periods, and high perinatal mortality. Tissue and
skeletal anomalies were not reported. Deviations or abnormalities
in the development of the 2nd generation were not noted (Vozovaya,
1974) .
Twenty-three pregnant Sprague-Dawley rats and 13 Swiss-
Webster mice inhaled 4,740 mg/m3 1,1,1-trichloroethane seven hours a
day, from days 6 through 15 of gestation. There was no effect on
C-47
-------
TABLE 18
Effect of 1,2-Dichloroethane
on Fetal Rat Development*
Litter Percent Fetal
Treatment Size Live Weight (g)
Fetuses
Filtered Air 9.7 94.9 6.44
l,2-dichloroethanea 6.5 76.9 5.06
*Source: Vozovaya, 1974
57 mg/m , 4 hrs/day, 6 days/week, throughout gestation
C-48
-------
the average number of implantation sites per litter, litter size,
the incidence of fetal resorptions, fetal sex ratios, or fetal body
measurements among mice or rats (Dunnett test p <0.05). Soft tis-
sue and skeletal anomalies occurred in 1,1,1-trichloroethane-
exposed animals which did not occur in control animals; however,
the incidences were not statistically significant (Fisher Exact
probability test, p<^0.05) (Schwetz, et al. 1975).
Pregnant Sprague-Dawley rats were treated from day 6 through
day 16 of gestation with hexachloroethane administered either by
inhalation (15, 48 or 260 ppm, 6 hours/day) or by stomach tube (50,
100 or 500 mg/kg/day). Dams receiving 500 mg/kg/day orally had a
significantly lower number of live fetuses per litter and higher
fetal resorption rates. Fetal parameters in all other groups were
within normal limits. No significant skeletal or soft tissue
anomalies resulted from hexachloroethane exposures (Weeks, et al.
1979).
Mutagenicity
No data were found in the literature regarding the mutagenic
potential of monochloroethane or pentachloroehtane. Negative data
has been found with several others. 1,1-Dichloroethane, 1,1,2-
trichloroethane, and 1,1,1,2-tetrachloroethane were not mutagenic
in the Ames Salmonella/microsome assay (Simmon, et al. 1977;
Rannug, et al. 1978; Fishbein, 1979). Hexachloroethane was not
mutagenic for five strains of Salmonella typhimurium (TA 1535, TA
1537, TA 1538, and TA 100) or one strain of yeast (Saccharomyces
cervisiae D4) in the absence or presence of induced rat liver S-9
preparation (Weeks, et al. 1979).
C-49
-------
Several of the chlorinated ethanes have given positive re-
sults. 1,1,1-Trichloroethane was tested for mutagenic activity
using the Ames Salmonella/microsome assay; the test was conducted
in a desiccator because of the compounds' volatility. 1,1,1-
Trichloroethane was weakly mutagenic to Salmonella typhimurium
strain TA 100 (Simmon, et al. 1977; Fishbein, 1979)
1,1,2,2-Tetrachloroethane and 1,2-dichloroethane were found
to be moderately and weakly mutagenic, respectively, to DNA
polymerase-def icient E. coli (E. coli pol A+/pol A ~), and to S.
J. ~~
typhimurium strains TA 1530 and TA 1535, but not to TA 1538 (Brem,
et al. 1974; Rosenkranz, 1977). Rosenkranz (1977) states that in
E. coli pol A /pol A and £3. typhimurium systems 1,1,2,2-tetra-
chloroethane is more mutagenic than 1,2-dichloroethane.
Without metabolic activation, 1,2-dichloroethane is a weak
mutagen in tester strains of S. typhimurium and DNA polymerase-
deficient E. coli (Brem, et al. 1974; McCann, et al. 1975;
Fishbein, 1976; Rosenkranz, 1977). The mutagenic activity of
1,2-dichloroethane was not enhanced using NADPH (Rannug and Ramel,
1977), liver microsomes (Rannug, et al. 1978), or standard rat
liver S-9 mix (McCann, et al. 1975).
Rannug, et al. (1978) showed that the mutagenic activity of
1,2-dichloroethane could be greatly enhanced through metabolic
activation with a factor in the soluble liver fraction (115,000 g
supernatant). This activation is not microsomal and not dependant
on NADPH. This was thought to indicate activation through conjuga-
tion with glutathione (Rannug and Beije, 1979). Rannug and Beije
(1979) combined S. typhimurium strains TA 1530 and TA 1535 with
C-50
-------
isolated perfused rat liver and tested for mutagenicity after
treatment with 1,2-dichloroethane. The resultant bile, containing
the glutathione/l,2-dichloroethane conjugates, was shown to be
highly mutagenic. In the same study, mice treated _in vivo with
1,2-dichloroethane also produced mutagenic bile (Rannug and Beije,
1979).
1,2-Dichloroethane also induced very significant increases in
somatic mutation frequencies in Drosophilia melanoqaster
(Nylander, et al. 1978). Morphological and chlorophyll mutations
in eight varieties of peas were found after treatment of seeds with
1,2-dichloroethane (Kirichek, 1974).
Three possible metabolites of 1,2-dichloroethane, chloro-
ethanol, chloroacetaldehyde, and chloroacetic acid, were compared
with 1,2-dichloroethanol for mutagenic activity in Salmonella
tester strains. On a molar basis, chloroacetaldehdye was much more
mutagenic to strain TA 100 than were 1,2-dichloroethane, or chloro-
ethanol; chloroacetic acid was inactive in this test (McCann, et
al. 1975). Chloroacetaldehyde was also found to be mutagenic in §.
typhimurium strains TA 1530 and TA 1535 (Rannug, et al. 1978). A
conjugation product of 1,2-dichloroethane, S-chloroethyl cystein,
proved to be more mutagenic than the parent compound (Rannug, et
al. 1978).
In summary, no mutagenicity data are available in the litera-
ture concerning monochloroethane or pentachloroethane. 1,1-Di-
chloroethane, 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, and
hexachloroethane are not mutagenic in Salmonella tester strains.
1,1,1-Trichloroethane, and unactivated 1,2-dichloroethane are
C-51
-------
weakly mutagenic in various studies. 1,1,2,2-Tetrachloroethane was
shown to be moderately mutagenic to Salmonella typhimurium and E.
co_U. Metabolically active 1,2-dichloroethane is highly mutagenic
in S. typhimurium, E. coli, and D. melanogaster.
Carcinogenicity
1,2-Dichloroethane: 1,2-Dichloroethane was one of 16 contam-
inants tested for Carcinogenicity by Theiss, et al. (1977). The
compound was injected intraperitoneally into 6 to 8 week old male
strain A/st mice; tricaprylin was used as a vehicle. The experi-
mental group consisted of 20 mice at each dosage level (20, 40 and
100 mg/kg in each injection). The mice were injected 3 times a week
for 24 injections. The mice were sacrificed 24 weeks after the
first injection and examined for lung tumors. The standard student
t test was used to determine significance of frequency of tumors in
the experimental group as compared to the control group. The
author concluded that 1,2-dichloroethane produced an elevated
frequency of tumors that was not statisically significant but that
further Carcinogenicity studies of this compound are warranted
(Theiss, et al. 1977).
A bioassay of 1,2-dichloroethane for carcinogenic potential
was conducted by the National Cancer Institute (NCI, 1978a). Tech-
nical grade 1,2-dichloroethane (impurities less than ten percent)
in corn oil was administered by stomach tube to 50 male and 50 fe-
male animals of each test species (Osborne-Mendel rats and B6C3F1
mice) at two dosage levels, five days/week. Mice received contin-
uous treatments for 78 weeks. Rats received continuous treatments
C-52
-------
for 35 weeks; from week 36 through week 78, periods of one week of
no treatment were alternated with periods of four weeks of treat-
ment. Dosage levels were manipulated during the experiment: the
two initial dose levels for male and female rats were 100 and 50
mg/kg/day; doses were increased to 150 and 75 mg/kg/day, then
decreased to initial levels. The high time-weighted average dose
for rats was 95 mg/kg/day; while the low time-weighted average dose
was 47 mg/kg/day. Male mice received initial high doses of 150
mg/kg/day and low doses of 75 mg/kg/day. These doses were raised
to 200 and 100 mg/kg/day. The high time-weighted average dose was
195 mg/kg/day; the low was 97 mg/kg/day. Female mice received
initial high doses of 250 mg/kg/day and low doses of 125 mg/kg/day.
These doses were raised to 400 and 200 mg/kg/day, then decreased to
300 and 150 mg/kg/day. The high time-weighted average dose was 299
mg/kg/day; the low was 149 mg/kg/day. After 78 weeks of treatment,
rats were observed either until death or for an additional 32
weeks; mice were observed an additional 12 or 13 weeks (NCI,
1978a).
Control groups consisted of 20 male and 20 female animals of
each test species. Vehicle controls were treated with corn oil by
stomach tube according to the treatment regimen of the test ani-
mals. Untreated controls were not intubated.
Treatment of rats and mice with 1,2-dichloroethane induced a
number of benign and malignant neoplasms (Table 19).
The incidences of squamous cell carcinomas of the forestomach,
subcutaneous fibromas, and hemangiosarcoma in male rats and
the incidence of mammary adenocarcinomas in female rats were
C-53
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TABLE 19
Summary of Neoplasms in Rats and Mice Ingesting
1/2-Dichloroethane for 78 Weeks*
Total No. of animals with tumors/
Species Sex Dose no> aniroals examined
Benign Malignant Metastases
Rata male untreated
corn oil
47
95
female untreated
corn oil
47
95
Mouse male untreated
corn oil
97
195
female untreated
corn oil
149
299
2
3
7
17
12
7
20
18
-
-
1
15
1
1
12
16
6
1
15
16
6
-
8
25
2
4
15
22
3
5
26
21
—
-
1
4
1
-
-
2
-
1
1
1
-
-
6
6
*Source: NCI, 1978a
Compound administered in corn oil by stomach tube
five days/week. Concentration is a time-weighted average
expressed in mg/kg/day.
Two control groups: 20 animals per group.
Experimental groups: 50 animals at each dosage level.
C-54
-------
significantly correlated with increased doses of 1,2-dichloro-
ethane according to the Fisher exact test and the Cochran-Armitage
test (Table 20).
In male and female mice treated with 1,2-dichloroethane, the
incidence of alveolar/bronchiolar adenomas was statistically sig-
nificant. The incidence of mammary adenocarcinomas and of endo-
metrial tumors in female mice and the incidence of hepatocellular
carcinomas in male mice were statistically positively correlated
with treatment (Table 21; NCI, 1978a) .
In an inhalation study in 1951, Spencer, et al. exposed Wistar
rats to 200 ppm 1,2-dichloroethane for 7-hours per day for a total
of 151 times. The study lasted 212 days, and no evidence of carcin-
ogenicity was found (as cited in U.S. EPA, 1979) .
1,1,1-Trichloroethane: NCI (1977) conducted a bioassay of
1,1,1-trichloroethane to determine potential carcinogenicity.
Technical grade 1,1,1-trichloroethane (impurities: three percent
p-dioxane, two percent unidentified) in corn oil was administered
by stomach tube to 50 male and 50 female animals of each test spe-
cies (Osborne-Mendel rats and B6C3F1 mice) at two dosage levels,
five days/week for 78 weeks. During the experiment, doses for mice
were increased from 4,000 and 2,000 mg/kg/day to 6,000 and 3,000
mg/kg/day. The high time-weighted average dose was 5,615
mg/kg/day; the low was 2,807 mg/kg/day. Doses for rats remained
constant at 1,500 and 750 mg/kg/day. All surviving rats were
killed at 117 weeks of age; surviving mice were killed at 95 weeks
(NCI, 1977).
C-55
-------
TABLE 20
Percent* of Rats with 1,2-Dichloroethane Induced Neoplasms '
O
I
en
cn
Male
Female
Tumor Type
Vehicle Controls
Pooled Matched
Experimental ,
Low Dose High Dose
Vehicle Controls
Pooled Matched
Experimental ,
Low Dose High Dose
Squamous-cell carcinoma:
Stomach
llemangiosarcoma:
0
2
0
-
6
18
18
14
Circulatory system
Fibroma:
Subcutaneous
Adenocarcinoma:
Mammary gland
10
12
36
*Soucce: NCI, 1978a
apercent: animals with tumors/animals examined x 100
includes only neoplasms that were statistically correlated with 1,2-dichloroethane treatment.
ctwo types of control groups were used for statistical analy'sis: a vehicle control group (matched vehicle control) and
a pooled vehicle control group which combined the vehicle controls from the studies of 1,2-dichcloroethane, 1,1,2-
trichloroethane, and tr ichloroethylene. The pooled control rats were of the same strain, were housed in the same
room, were tested concurrently for at least one year, and were diagnosed by the same patliologists. The untreated
control group was not used for analysis of tumor incidence.
experimental groups 50 animals at each dosage level
eThe low time-weighted average dose: 47 mg/kg/day
The high time-weighted average dose: 95 mg/kg/day
-------
TABLE 21
Percent8 of Mice with 1,2-Dichloroethane Induced Neoplasms*'*3
O
I
Tumor Type
AlveoJar/Bronchiolar
Adenoma
Endometrial Sarcoma
Hepatocellular Carinoma
*Source: NCI, 1978a
aPercent: animals with
Male Female
Vehicle Controls0 Experimental , Vehicle Controls0 Experimental*3
Pooled Matched Low Dose High Dose Pooled Matched Low Dose9 High Dose
0
-
7
tumors/animals
02 31 3 5 14 31
004 6
5 13 25 -
examined x 100
Two types of control groups were used for statistical analysis: the vehicle control group (matched vehicle control)
and the pooled vehical control gtoup which combined the vehicle controls from the studies of 1,2-dichloroethane,
1,1,2-trichloroehtane, and trichloroethylene. The pooled control mice were of the same strain, were housed in the
same room, were tested concurrently for at least one year, and were diagnosed by the same pathologists. The untreated
control group was not used for analysis of tumor incidence.
experimental group: 50 animals at each dosage level
The low time-weighted average dose: 97 mg/kg/day
The high time-weighted average dose: 195 mg/kg/day
9The low time-weighted average dose: 149 mg/kg/day
The high time-weighted average dose: 299 mg/kg/day
-------
Control groups consisted of 20 animals of each sex and spe-
cies. Carbon tetrachloride was administered as the positive
control.
There was a moderate depression of body weight in male and
female rats and mice throughout the study. Male and1 female rats
given 1,1,1-trichloroethane exhibited earlier mortality than the
untreated controls. The statistical test for the dose-related
trend was significant (P<0.04). Survival of mice was significant-
ly decreased; in female mice there was a dose-related trend in the
numbers surviving (P=0.002). Fewer rats receiving 1,1,1-trichloro-
ethane survived at both 78 and 110 weeks than did positive control
rats receiving carbon tetrachloride, a known carcinogen (Table 22).
Chronic murine pneumonia was the most probable cause for the high
incidence of deaths in several groups.
Although a variety of neoplasms was observed in both 1,1,1,-
trichloroethane-treated and matched-control rats and mice (Table
23), no relationship was established between dosage groups,
species, sex, type of neoplasm, or site of occurrence. The
shortened life-spans of the rats and mice made an assessment of
ingested 1,1,1-tr ichloroethane carci'nogenicity impossible (NCI,
1977). The National Cancer Institute is currently retesting the
compound.
Price, et al. (1978) demonstrated the ir\ vitro transforming
potential of 1,1,1-trichloroethane (99.9 percent pure) using the
Fischer rat embryo cell system (F1706). Rat embryo cell cultures
were treated with 1,1,1-trichloroethane, diluted in growth medium,
for 48 hours. After nine subcultures, the transformed cells
C-58
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TABLE 22
Comparison of Survival of Control Groups,
1,1,1-Trichloroethane-Treated and
Carbon Tetrachloride-Treated (Positive Control) Rats*
o
i
en
Group
Male
Control
Low Dose
High Dose
Female
Control
Low Dose
High Dose
1,
Initial
No. of
Animals
20
50
50
20
50
50
1,1-Trichloroe
Number
Alive at
78 weeks
7
1
4
14
9
12
thane
Number
Alive at
110 weeks
0
0
0
3
2
1
Initial
No. of
Animals
20
50
50
20
50
50
Carbon Tetrachlor
Number
Alive at
78 weeks
20
34
35
18
38
21
ide
Number
Alive at
110 weeks
12
15
8
14
20
14
*Source: NCI, 1977
-------
TABLE 23
Summary of Neoplasms in Rats and Mice Ingesting
1,1,1-Trichloroethane for 78 Weeks*
Species Sex Number of
Animals
O
1
g Rat Male 20
50
50
Female 20
50
50
Mouse Male 20
50
50
Female 20
50
50
Dose3
-
750
1500
-
750
1500
_
2807
5615
-
2807
5615
Total Number
of Tumors
3
6
4
14
6
12
5
2
9
5
2
3
Liver ,
Spleen Lung
1
1
-
-
-
1
2 1
1 1
8 1
2
1
1
Number of Tumors Observed
Kidney, Heart Brain,
Bladder Skin Vasculature Pituitary
1 -
1 1
1-1
3
2
11 1
_
-
-
2 1
1 -
1 -
Other
1
3
3
11
4
8
2
-
-
5
-
1
'Source: NCI, 1977
aCompound administered in corn oil by stomach tube five days per week.
Concentration is a time-ueighted average expressed in mg/kg/day.
-------
(characterized by morphology and formation of macroscopic foci in
semi-soft agar) were inoculated into newborn Fischer rats. By 68
days, the transformed cells had grown as undifferentiated fibro-
sarcomas at the innoculation sites in all tested animals. Acetone,
the negative control, did not induce tumors by 82 days after innocu-
lation (Price, et al. 1978).
1,1,2-Trichioroethane: A bioassay of 1,1,2-trichloroethane
for possible carcinogenicity was conducted by the NCI (1978b).
Technical grade 1,1,2-trichloroethane (92.7 percent pure) in corn
oil was administered by stomach tube to 50 male and 50 female ani-
mals of each test species (Osborne-Mendel rats and B6C3F1 mice) at
two dosage levels, five days/week for 78 weeks. During the experi-
ment, doses for rats were increased from 70 and 30 mg/kg/day to 100
and 50 mg/kg/day. The high time-weighted average dose was 92
nig/kg/day; the low was 46 mg/kg/day. Doses for mice were increased
from 300 and 150 mg/kg/day to 400 and 200 mg/kg/day. The high time-
weighted average dose was 390 mg/kg/day; the low was 195 mg/kg/day.
After 78 weeks of treatment, rats were observed an additional 35
weeks; mice were observed for an additional 13 weeks (NCI, 1978b).
Control groups consisted of 20 animals of each sex and spe-
cies. Vehicle controls were treated with corn oil by stomach tube
at the same rate as the high dose group of the same sex; untreated
control animals were not intubated.
Adrenal cortical carcinomas, transitional-cell carcinoma of
the kidney, renal tubule adenoma, and hemangiosarcomas of the
spleen, pancreas, abdomen, and subcutaneous tissue were some of the
C-61
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neoplasms observed in treated, but not control rats. Because a
statistically significant difference could not be found between the
test group and the controls, carcinogenicity of 1,1,2-trichloro-
ethane in Osborne-Mendel rats cannot be inferred (Table 24; NCI,
1978b).
On the other hand, treatment of mice with 1,1,2-trichloro-
ethane was correlated with an increased incidence of hepatocellular
carcinoma (Table 25). Both the Fisher exact test comparing tumor
incidences of dosed to control groups and the Cochran-Armitage test
for positive dose-related trend established that this correlation
was significant (P<10.001). The Cochran-Armitage test also showed
a significant dose-related association between 1,1,2-trichloro-
ethane treatment and incidence of pheochromocytoma of the adrenal
gland in male and female mice. Fisher exact tests, however, con-
firmed this association only for high dose female mice, not other
mouse groups (NCI, 1978b).
1,1,2,2-Tetrachloroethane: Technical grade 1,1,2,2-tetra-
chloroethane (90 percent pure) in corn oil was administered by
stomach tube to 50 male and 50 female animals of each test species
(Osborne-Mendel rats and B6C3F1 mice) at two dosage levels, five
days/week. Mice received continuous treatments for 78 weeks. Rats
received continuous treatment for 32 weeks; from week 33 through
week 78, periods of one week of no treatment were alternated with
periods of four weeks of treatment. Dosage levels were manipulated
during the experiment: the initial dosages for male and female rats
were 100 mg/kg/day and 50 mg/kg/day; dosage levels for males were
then increased to 130 mg/kg/day and 65 mg/kg/day. The high time-
C-62
-------
TABLE 24
Summary of Incidence of Neoplasms in Rats and Mice Ingesting
1,1,2-Trichloroethane for 78 Weeks*
o
i
-------
TABLE 25
Incidence of Hepatocellular Carcinoma In Mice Ingesting
1,1,2-Trichloroethane for 78 Weeks*
Number of Hepatocellular Carcinoma
Sex Dosea Animals Examined No. of Animals Percent
Male5
Female
*Source:
Untreated
Corn Oil
195
390
Untreated
Corn Oil
195
390
NCI, 1978b
... _ .
17
20
49
49
20
20
48
45
. . ,
2
2
18
37
2
0
16
40
V-\ ^11 W\ rt <£4rTs*t ;-] — i r T
12
10
37
76
10
—
33
89
Concentration is a time-weighted average expressed in mg/kg/day.
Two control groups: 20 animals per group.
Experimental groups. 50 animals per dosage level.
C-64
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weighted average dose for male rats was 108 mg/kg/day; the low was
62 mg/kg/day. For female rats, the high time-weighted average dose
was 76 mg/kg/day and the low was 43 mg/kg/day. The initial dose for
male and female mice was 200 mg/kg/day. This high dose was first
increased to 300 mg/kg/day, then to 400 mg/kg/day, and finally
lowered to 300 mg/kg/day. The initial low dose for both sexes was
100 mg/kg/day. The low dose was increased to 150 mg/kg/day. The
high time-weighted average dose for male and female mice was 282
mg/kg/day; the low was 142 mg/kg/day. After 78 weeks of treatment,
rats were observed for an additional 32 weeks and mice for an addi-
tional 12 weeks (NCI, 1978c).
Control groups consisted of 20 animals of each sex and
species. Vehicle controls were treated with corn oil by stomach
tube; untreated controls were not intubated.
The incidence of hepatocellular carcinoma in male and female
mice was positively correlated (P<0.001) with dosage level (Table
26). The incidence of total neoplasms in male and female mice is
seen in Table 27. Although one neoplastic nodule and two hepato-
cellular carcinomas, rare tumors in the Osborne-Mendel rat, were
seen in high dose male rats, the incidence of neoplasms in rats of
either sex was not statistically significant (Table 27; NCI,
1978c).
Hexachloroethane: Technical grade hexachloroethane (98
percent pure) in corn oil was administered by stomach tube to 50
male and 50 female animals of each test species (Osborne-Mendel
rats and B6C3F1 mice) at two dosage levels, five days/week.
Mice received continuous treatments for 78 weeks. Rats received
C-65
-------
TABLE 26
Incidence of Hepatocellular Carcinoma in Mice
Ingesting 1,1,2,2-Tetrachloroethane for 78 Weeks*
Sex
Male0
Female0
*Source:
a . ,
K
Dose
Untreated
Corn Oil
142
282
Untreated
Corn Oil
142
282
NCI, 1978c
, . . TIT
Number of
Animals Examined
16
18
50
49
18
20
48
47
—» *• «•* «t w* f* 4 »•» x1^ wt — » « n J 4 y* «^ ^
Hepatocellular
Carcinoma
Number Percent
2
1
13
44
0
0
30
43
_ j _ u ; «ui ..
13
6
26
90
__
--
63
91
significant (P^. 0.001) positive dose-related trend in
mice of both sexes.
Compound administered in corn oil by stomach tube five days/week.
Concentration is a time-weighted average expressed in mg/kg/day.
°Two control groups: 20 animals per group.
Experimental groups: 50 animals per dosage level.
C-66
-------
TABLE 27
Summary of Incidence of Neoplasms in Rats and Mice Ingesting
1,1,2,2-Tetrachloroethane for 78 Weeks*
Species
Ratb
Mouse
*Source:
a_ ,
a
Sex Dose
Male Untreated
Corn Oil
62
108
Female Untreated
Corn Oil
43
76
Male Untreated
Corn Oil
142
282
Female Untreated
Corn Oil
142
282
NCI, 1978c
j • • •
Total Number of Animals with Tumors
Benign
2
9
11
13
12
11
24
21
2
3
3
3
1
-
2
2
.
Malignant
6
6
7
9
6
1
7
5
9
1
17
45
1
1
33
43
Metastases
_
1
-
1
_
1
-
_
-
1
-
_
1
—
—
Compound administered in corn oil by stomach tube five days/week.
Concentration is a time-weighted average expressed in mg/kg/day.
Two control groups: 20 animals per group.
Experimental groups: 50 animals per dosage level.
C-67
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continuous treatments for 22 weeks; from week 23 through week 78,
periods of one week of no treatment were alternated with periods of
four weeks of treatment. Male and female rats received high doses
of 500 mg/kg/day and low doses of 250 mg/kg/day. Although dosage
levels remained constant throughout the study, treatment was not
continuous: the high and low time-weighted average doses for rats
were 432 and 212 mg/kg/day. Male and female mice received initial
high doses of 1,000 mg/kg/day and low doses of 500 mg/kg/day. The
doses were increased to 1,200 mg/kg/day and 600 mg/kg/day. The
high time-weighted average dose was 1,179 mg/kg/day; the low time-
weighted average dose was 590 mg/kg/day (NCI, 1978d). After 78
weeks of treatment, rats were observed for an additional 33 or 34
weeks, mice for an additional 12 or 13 weeks.
Control groups consisted of 20 animals oiF each sex and test
species. Vehicle controls were treated with corn oil by stomach
tube; untreated animals were not intubated.
Toxic tubular nephropathy was observed in all groups of treat-
ed animals: in rats, the incidence was 18 to 66 percent, and in
mice, 92 to 100 percent. Male and female rats exhibited increased
mortality rates which were statistically correlated with increased
dosage. This trend was not evident with mice of either sex (NCI,
1978d).
In mice of both sexes, the incidence of hepatocellular carcin-
oma was positively correlated (P<0.001) with hexachloroethane
treatment (Table 28). There was no evidence of hexachloroethane
induced neoplasms in rats of either sex (Table 29; NCI, 1978d).
C-68
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TABLE 28
Incidence of Hepatocellular Carcinoma in Mice
Ingesting Hexachloroethane for 78 Weeks*
Sex Dose3 Number of Hepatocellular Carcinoma
Animals Examined No. of Animals Percent
Maleb
Female
Untreated
Corn Oil
590
1179
Untreated
Corn Oil
590
1179
18
20
50
49
18
20
50
49
1
3
15
31
0
2
20
15
6
15
30
63
0
10
40
31
*Source: NCI, 1978d
Compound administered in corn oil by stomach tube five days/week.
Concentration is a time-weighted average expressed in mg/kg/day.
Two control groups: 20 animals per group.
Experimental groups: 50 animals per dosage level.
C-69
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TABLE 29
a
Summary of Incidence of Neoplasms in Rats and Mice
Ingesting Hexachloroethane for 78 Weeks*
Total Number of Animals with Tumors
Species Sex Dosea Benign Malignant Metastases
Rat Male Untreated
Corn Oil
212
423
Female Untreated
Corn Oil
212
423
Mouse Male Untreated
Corn Oil
590
1179
Female Untreated
Corn Oil
590
1179
6
7
12
8
11
11
29
18
0
1
1
5
3
2
3
4
5
4
6
1
6
4
6
3
3
3
16
33
2
6
31
24
—
1
2
-
1
1
1
1
1
-
1
—
1
-
1
"
*Source: NCI, 1978d
aCompound administered in corn oil by stomach tube five days/week.
Concentration is a time-weighted average expressed in mg/kg/day.
Two control groups: 20 animals per group.
Experimental groups: 50 animals per group.
C-70
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A summary of the results of the NCI bioassays of chloroethanes
is presented in Table 30.
An estimated five million workers are potentially exposed to
one or more chloroethanes (NIOSH, 1978c). To date, no epidemiolog-
ical relationship has been found between chloroethane exposure and
human cancer.
C-71
-------
TABLE 30
Summary of National Cancer Institute Bioassay
Results as of July, 1978*
Compound
Species/Sex
Tumor Site
Statistically
Significant Tumors
monochloroethane
no testing planned
o
i
-j
to
1,1-dichloroethane
1,2-dichloroethane
retesting recommended because initial results inconclusive
rats/female
rats/male
mice/female
mice/male
mammary gland
forestomach
circulatory system
subcutaneous tissue
mammary gland
endometrium
lungs
lungs
adenocarcinemas
squamous cell carcinomas
hemangiosarcomas
fibromas
adenocarc i nomas
stromal sarcomas
adenomas
adenomas
1,1,1-tr ichloroethane
retesting in progress
1,1,2-trichloroethane
mice/female
mice/male
mice
liver
liver
adrenal glands
hepatocellular carcinomas
hepatocellular carcinomas
pheochromocytomas
1,1,1,2-tetrachloroethane
testing in progress, no report available
1,1,2,2-tetrachloroethane
mice/female
mice/male
liver
liver
hepatocellular carcinomas
hepatocellular carcinomas
Pentachloroethane
testing in progress, no report available
hexachloroethane
mice/female
mice/male
liver
liver
hepatocellular carcinomas
hepatocellular carcinomas
*Source: NIOSH, 1978c
-------
CRITERION FORMULATION
Existing Guidelines and Standards
OSHA standards and NIOSH recommended standards are based on
exposure by inhalation (Table 31). Based on information available
in 1976b, NIOSH recommended that occupational exposures to 1,2-
dichloroethane should not exceed 5 ppm (20 mg/m ) determined as a
time-weighted average for up to a 10-hour work day, 40-hour work
week. Peak concentrations should not exceed 15 ppm (60 mg/m ) as
determined by a 15-minute sample. The current enforced OSHA expo-
sure standard is 50 ppm, time-weighted average for up to a 10-hour
work day, 40-hour work week. NIOSH (1976b) issued a criterion for
a recommended standard of 200 ppm for occupational exposures to
1,1,1-trichloroethane. This recommendation to change the standard
from 350 ppm is based on central nervous system responses to acute
exposures in man, cardiovascular and respiratory effects in man and
animals, and the absence of reported effects in man at concentra-
tions below the proposed limit.
Current Levels of Exposure
Estimates of human exposure to chloroethanes via ingestion are
not available for the general population. NIOSH (1978c) estimated
that of over five million workers exposed by inhalation and dermal
routes to chloroethanes, 4.5 million are exposed to 1,2-dichloro-
ethane or 1,1,1-trichloroethane (Table 32).
In the general population there are chronic exposures to
variable amounts in air and finished water. Chloroethanes are
C-73
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TABLE 31
Chloroethane Exposure Standards*
Chemical
mo nochlo roe thane
1,1-dichloroe thane
1,2-dichloroethane
1,1,1-tr ichloroe thane
1 , 1 , 2 - tr ichloroe thane
1,1,1, 2-tetrachloroethane
1,1,2,2- te tr achloroe thane
pen tachlo roe thane
hex achloroe thane
OSHA
Exposure
Standard
(ppm)
1,000
100
50
350
10
none
5
none
1
NIOSH
Recommended
Exposure
Standard
(ppm)
none
none
5
200
none
none
1
**
**
*Source: NIOSH, 1978c
**NIOSH has tentative plans for a Criteria Document for
a Recommended Standard for this substance
C-74
-------
TABLE 32
Chloroethane Exposures and Production*
Chemical
Estimated number
of workers exposed
Annual
Production quantities
(pounds)
monochloroethane 113,000
1,1-dichloroethane 4,600
1,2-dichloroethane 1,900,000
1,1,1-trichloroethane 2,900,000
1,1,2-trichloroethane 112,000
1,1,1,2-tetrachloroethane a
1,1,2,2-tetrachloroethane 11,000
pentachloroethane a
hexachloroethane 1,500
670 million (1976)
b
8 billion (1976)
630 million (1976)
c
b
c
b
b,d
*Source: NIOSH, 1978c
estimates not available
Does not appear to be commercially produced in the United States
Direct production information not available
730,000 kg were imported in 1976
C-75
-------
present in many commercial products, and exposure of the population
depends on the tendency of individuals to read and heed instruc-
tions.
Special Groups at Risk
Workers who are occupationally exposed to chloroethanes by
inhalation and/or dermal absorption represent a special group at
risk (Table 32). Epidemiological studies have not disclosed a
relationship between exposure to chloroethanes and cancer; however,
four chloroethanes have proved to be carcinogenic in at least one
species of rodent (NCI, 1978a,b,c,d). Those individuals who are
exposed to known hepatotoxins or have liver disease may constitute
a group at risk. Sufficient data are not available to specifically
identify other special groups at risk.
Basis and Derivation of Criteria
At the present time, there is insufficient mammalian toxic-
ological information to establish a water criterion for human
health for the following chloroethanes: monochloroethane, 1,1-
dichloroethane, 1,1,1,2-tetrachloroethane and pentachloroethane.
Available evidence indicates that the general population is exposed
to only trace levels of 1,1-dichloroethane, 1,1,1,2-tetrachloro-
ethane and pentachloroethane. Although inhalation exposure to
monochloroethane is more widespread, it is considered one of the
least toxic of the chloroethanes. Should significant levels of
exposure be documented in the future, it will be necessary to con-
duct more extensive toxicological studies with these chloroethanes.
The criterion for 1,1,1-trichloroethane is based on toxic
effects observed in the National Cancer Institute bioassay for
C-76
-------
possible carcinogenicity (1977) . Results of the study showed that
the survival of both Osborne-Mendel rats and B6C3F1 mice was sig-
nificantly decreased in groups receiving oral doses of 1,1,1-tri-
chloroethane. Chronic murine pneumonia may have been responsible
for the high incidence of deaths. A variety of neoplasms was ob-
served in both species; however, the incidence of specific malig-
nancies was not significantly different from those observed in con-
trol animals. Survival time was significantly decreased in rats
receiving the high dose, therefore, the criterion for 1,1,1-tri-
chloroethane is based on the low dose in rats (750 mg/kg body
weight, 5 days/week for 78 weeks) which produced toxic effects in a
number of systems. It should be recognized that the actual no-
observable-adverse-ef feet level (NOAEL) will be lower. However,
use of the lowest-minimal-effect dose as an estimate of an "accept-
able daily intake" has been practiced by the National Academy of
Sciences (NAS, 1977) . Thus, assuming a 70 kg body weight and using
a safety factor of 1,000 (NAS, 1977) the following calculation can
be derived:
750 mg/kg xOkg x 5/7 day = 37<5 mg/day
Therefore, consumption of 2 liters of water daily and 6.5 grams of
contaminated fish having a bioconcentration factor of 5.6, would
result in, assuming 100 percent gastrointestinal absorption of
1,1,1-trichloroethane, a maximum permissible concentration of 18.4
mg/1 for ingested water:
_ _ 37.5 mg/day _
2 liters + (5.6 x 0.0065) x 1.0
=18.4 mg/1
C-77
-------
In summary, based on the use of chronic rat toxological data
and an uncertainty factor of 1,000, the criterion level of
1,1,1-trichloroethane corresponding to an acceptable daily intake
of 37.5 mg/day, is 18.4 mg/1. Drinking water contributes 98 per-
cent of the assumed exposure while eating contaminated fish prod-
ucts accounts for 2 percent. The criterion level can similarly be
expressed as 1.03 g/1 if exposure is assumed to be from the con-
sumption of fish and shellfish products alone.
Based on available literature, 1,1,2-tri-, 1,1,2,2-tetra-,
and hexachloroethane are considered to be carcinogenic in at least
one rodent species (NCI, 1978b,c,d). In the case of these three
chloroethanes, a statistical evaluation of the incidences of hepa-
tocellular carcinomas revealed a significant positive association
between the administration of the respective chloroethanes and
tumor incidence. It can be concluded that under the conditions of
the NCI bioassay, 1,1,2-tri-; 1,1,2,2-tetra-; and hexachloroethane
are carcinogenic in B6C3F1 mice, inducing (in all cases) heoatocel-
lular carcinomas in either male or female mice. Ambient water
criteria for these chloroethanes were calculated by applying a lin-
earized multistage model, as discussed in the Human Health Method-
ology Appendices to the October 1980 Federal Register notice which
announced the availability of this document to the results from the
NCI bioassays found in Appendix I.
Under the conditions of an NCI (1978a) bioassay, 1,2-dichloro-
ethane is also carcinogenic, inducing a statistically significant
number of squamous cell carcinomas of the forestomach and hemanqiosar-
comas of the circulatory system in male rats, mammary adenocarcinomas
C-78
-------
in female rats and mice, and endometrial tumors in female mice.
The criterion for 1,2-dichloroethane is also calculated by applying
the linearized multistage model to data from the appropriate NCI
bioassay found in Appendix I.
The criteria for chloroethanes is summarized in Table 33.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." 1,2-Di-
chloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane and
hexachloroethane are suspected of being human carcinogens. Because
there is no recognized safe concentration for a human carcinogen,
the recommended concentration of these chlorinated ethanes in water
for maxiumum 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-
centrations of these chlorinated ethanes corresponding to several
incremental lifetime cancer risk levels have been estimated. A
cancer risk level provides an estimate of the additional incidence
of cancer that may be expected in an exposed population. A risk of
10~ for example, indicates a probability of one additional case of
cancer 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 am-
bient water quality criteria, the U.S. EPA stated that it is
C-79
-------
TABLE 33
Criteria for Chloroethanes
Compound
Criterion
Reference
Monochloroethane
1,1-Dichloroethane
1,2-Dichloroethane
1,1,1-Dichloroethane
1,1,2-Trichloroethane
None
None
9.4 ug/1 - Carcinogen-
icity data
18.4 mg/1 - mammalian
toxicity data
6.0 ug/1 - Carcinogen-
icity data
1,1,1,2-Tetrachloroethane None
1,1,2,2-Tetrachloroethane
Pentachloroethane
Hexachloroethane
1.7 ug/1 - Carcinogen-
icity data
None
19 ug/1 - Carcinogen-
icity data
NCI, 1978a
NCI, 1977
NCI, 1978b
NCI, 1978c
NCI, 1978d
C-80
-------
considering setting criteria at an interim target risk level of
10~5, 10~6 or 10 as shown in the following table.
Exposure Assumptions
2 liters of drinking
water and consumption
of 6.5 grams of fish
and shellfish (2)
1,2-dichloroethane
1,1,2-trichloroethane
1,1,2,2-tetrachloro-
ethane
hexachloroethane
Consumption of fish
and shellfish only
1,2-dichloroethane
1,1,2-trichloroethane
1,1,2,2-tetrachloro-
ethane
hexachloroethane
Risk Levels and Corresponding Criteria
<~6 10~5
pg/i
;.(D
0
io
0
0
0
0
0.094
0.06
0.017
0.19
0.94
0.6
0.17
1.9
9.4
6.0
1.7
19
0
0
0
0
24.3
4.18
1.07
0.87
243
41.8
10.7
8.74
2,430
418
107
87.4
(1) Calculated by applying a linearized multistage model, as
previously discussed, to the appropriate bioassay data pre-
sented in Appendix I. Since the extrapolation model is linear
at low doses, the additional lifetime risk is directly propor-
tional to the water concentration. Therefore, water concen-
trations corresponding to other risk levels can be derived by
multiplying or dividing one of the risk levels and corresoond-
ing water concentrations shown in the table by factors such as
10, 100, 1,000, and so forth.
C-81
-------
(2) Zero point four percent of 1,2-dichloroethane exposure
results from the consumption of aquatic organisms which
exhibit an average bioconcentration potential of 1.2-fold.
The remaining 99.6 percent of 1,2-dichloroethane exposure
results from drinking water.
One point four percent of 1,1,2-trichloroethane exposure
results from the consumption of aquatic organisms which
exhibit an average bioconcentration potential of 4.5-fold.
The remaining 98.6 percent of 1,1,2-trichloroethane exposure
results from drinking water.
One point six percent of 1,1,2,2-tetrachloroetharie exposure
results from the consumption of aquatic organisms which ex-
hibit an average bioconcentration potential of 5-fold. The
remaining 98.4 percent of 1,1,2,2-tetrachloroethane exposure
results from drinking water.
Seventy-eight percent of hexachloroethane exposure results
from the consumption of aquatic organisms which exhibit an
average bioconcentration potential of 86.9-fold. The remain-
ing 22 percent of hexachloroethane exposure results from
drinking water.
C-82
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14
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APPENDIX I
Summary and Conclusions Regarding the Carcinogenicity of
Chlorinated Ethanes*
Chlorinated ethanes are used extensively as solvents and as
intermediates in chemical syntheses. They have been detected in
U.S. drinking water supplies and in finished drinking water.
Chlorinated ethanes, which have been detected in water, include
1,1- and 1,2-dichloroethanes, 1,1,1- and 1,1,2-trichloroethanes,
and 1,1,1,2-tetrachloroethane.
Four of the nine chlorinated ethanes are known animal car-
cinogens. They are 1,2-dichloroethane, 1,1,2-trichloroethane,
1,1,2,2,-tetrachloroethane and hexachloroethane (NCI, 1978a,b,c,d).
Carcinogenesis testing of 1,1,1-trichloroethane (retesting),
1,1,1,2-tetrachloroethane and pentachloroethane is in progress at
the National Cancer Institute (NCI). In November, 1979 carcinogen-
esis testing was planned to begin for chloroethane (NCI, 1979).
Chlorinated ethanes produce a variety of cancers in rats and
mice, receiving oral doses of these chemicals. 1,2-Dichloroethane,
administered by gavage over a period of 78 weeks, produced squamous
cell carcinomas of the stomach and hemangiosarcomas in male
Osborne-Mendel rats. None of the twenty control animals developed
either cancer type. Female Osborne-Mendel rats and B6C3F1 mice
developed adenocarcinomas of the mammary gland (NCI, 1978a).
*This summary has been prepared and approved by the Carcinogens
Assessment Group, EPA, on July 17, 1979.
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Adenocarcinomas of the mammary gland were not observed in 20
vehicle-treated controls of both species.
1,1,2-Trichloroethane, administered by gavage over a period of
78 weeks induced hepatocellular carcinomas in male and female
B6C3F1 mice (NCI, 1978b). Tumor incidences in treated males were
37/49 (76 percent) and 18/49 (37 percent) at the high and low doses
respectively, as compared to 2/20 (10 percent) in the vehicle-
treated controls. Tumor incidences in treated females were 40/45
(89 percent) and 16/48 (33 percent) at the high and low doses,
respectively, as compared to no observed cancers in twenty vehicle
controls.
1,1,1-Trichloroethane is being retested at the NCI because
high mortality rates among animals, in an earlier carcinogenesis
bioassay, made it impossible to assess the carcinogenicicty of
ingested 1,1,1-trichloroethane, even though a variety of neoplasms
were observed (NCI, 1977). In another study, 1,1,1-trichloroethane
induced the transformation of rat embryo cells and the transformed
cells, when injected into newborn Fischer rats, produced fibro-
sarcomas at the site of injection in all treated animals (Price, et
al. 1978).
1,1,2,2-Tetrachloroethane is carcinogenic to B6C3F1 mice.
This chemical, given by gavage, over a period of 78 weeks, induced
hepatocellular carcinomas in male and female mice (NCI, 1978c).
Tumor incidences in males were 44/49 (90 percent), 13/50 (26 per-
cent), and 1/18 (5 percent) in the high dose, low dose, and vehicle
control groups, r.espectively. Tumor incidences in females were
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43/47 (91 percent), 30/48 (63 percent), and 0/20 in high dose, low
dose, and vehicle control groups, respectively.
In addition to its use as a solvent, hexachloroethane is used
as a veterinary anthelmitic. This chemical has demonstrated car-
cinogenic activity in both male and female B6C3F1 mice. Thirty-one
of 49 (63 percent) and 15 of 50 (30 percent) treated male mice
developed hepatocellular carcinomas after receiving high and low
oral doses of hexachloroethane, respectively, over a 78-week period
as compared to 3 of 20 vehicle-treated controls (15 percent).
Twenty of 50 female mice (40 percent) developed hepatocellular car-
cinomas after receiving the high oral dose of hexachloroethane as
compared to 2 of 20 (10 percent) vehicle-treated controls.
Three chlorinated ethanes are known mutagens. 1,1,1-Trichoro-
ethane is weakly mutagenic to £3. typhimurium strain TA 100 (Simmon,
et al. 1977). 1,2-Dichloroethane and 1,1,2,2-tetrachloroethane
were mutagenic in the Ames Salmonella assay for strains TA 1530 and
1535, and for the E. coli DNA polymerase-deficient system (Brem, et
al. 1974). Rosenkranz (1977) determined the order of mutagenic
activity toward S_. typhimurium and E. coli to be 1,1,2,2-tetra-
chloroethane s 1,2-dichloroethane. 1,2-Dichloroethane induced
highly significant increases in somatic mutation frequencies in
Drosophila melangaster (Nylander, et al. 1978). Morphological and
chlorophyll mutations in eight varietites of peas were induced by
treatment of seeds with 1,2-dichloroethane (Kirichek, 1974).
A conjugation product of 1,2-dichloroethane, S-chloroethyl
cystein, proved to be more mutagenic than the parent compound
(Rannug, et al. 1978). Other metabolites of 1,2-dichloroethane
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varied in their mutagenic activity for Salmonella strains. 2-
Chloroacetaldehyde was mutagenic for strain TA 100 (McCann, et al.
1975), strains TA 1530 and TA 1535 (Rannug, et al. 1978). 2-
Chloroethanol was less mutagenic than the aldehyde derivative and
2-chloroacetic acid was inactive (McCann, et al. 1975).
1,1-Dichloroethane, 1,1,2-trichloroethane, and 1,1,1,2-tetra-
chloroethane were not mutagenic in the Ames Salmonella/microsome
assay (Simmon, et al. 1977; Fishbein, 1979).
Hexachloroethane was not mutagenic for five strains of Salmon-
4
el la or yeast (Sacchyaromyces cerevisiae D ) in the absence or
presence of induced rat liver S-9 preparations (Weeks, et al.
1979).
No data were found regarding the mutagenic potential of
chloroethane, or pentachloroethane.
The demonstrated carcinogenicity of 1,2-dichloroethane,
1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane and hexachloro-
ethane coupled with the mutagenicity data constitutes strong evi-
dence that these chemicals are likely to be human carcinogens.
The water quality criterion for 1,2-dichloroethane is based on
the induction of circulatory system hemangiosarcomas in male
Osborne-Mendel rats given oral doses of 1,2-dichloroethane over a
period of 78 weeks (NCI, 1978a). The concentration of 1,2-di-
chloroethane in water, calculated to keep the lifetime cancer risk
below 10~ is 9.4 pg/1.
The water quality criterion for 1,1,2-trichloroethane is based
on the induction of hepatocellular carcinomas in male B6C3F1 mice
given oral doses over a 78-week period (NCI, 1978b). The
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concentration of 1,1,2-trichloroethane in water, calculated to keep
the lifetime cancer risk below 10~ is 6.0 jug/1.
The water quality crterion for 1,1,2,2-tetrachloroethane is
based on the induction of hepatocellular carcinomas in female
B6C3F1 mice, receiving oral doses over a 78-week period (NCI,
1978c). The concentration of 1,1,2,2-tetrachloroethane in water,
calculated to keep the lifetime cancer risk below 10 is 1.7 ug/1.
The water quality criterion for hexachloroethane is based on
the induction of hepatocellular carcinomas in male B6C3F1 mice,
given oral doses over a 78-week period (NCI, 1978d). The concen-
tration of hexachloroethane in water, calculated to keep the life-
time cancer risk below 10~ is 19 ug/1.
Because carcinogenicity data are lacking for chloroethane,
1,1-dichloroethane, 1,1,1-trichloroethane, 1,1,1,2-tetrachloro-
ethane, and pentachloroethane, water quality criteria based on a
10 risk level cannot be derived.
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Summary of Pertinent Data for 1,2-Dichloroethane
The water quality criterion for 1,2-dichloroethane is based on
the induction of circulatory system hemangiosarcomas in male
Osborne-Mendel rats (NCI, 1978a). The incidences of these sarcomas
along with other parameters of the extrapolation are listed below:
Dose Incidence
(mg/kg/day) (no. responding/no.tested)
0 0/20
33.6 9/50
67.9 7/50
le = 546 days w = 0.500 kg
Le = 770 days R = 1.2 I/kg
L = 770 days
With these parameters the carcinogenic potency factor for
-2 -1
humans, q-^*, is 3.697 x 10 (mg/kg/day) . The concentration of
1,2-dichloroethane in water, calculated to keep the lifetime cancer
risk below 10 is 9.4 jug/1.
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Summary of Pertinent Data for 1,1,2-trichloroethane
The water quality criterion for 1,1,2-trichloroethane is based
on the induction of hepatocellular carcinomas in male B6C3F1 mice
(NCI, 1978b). The incidences of hepatocellular carcinomas are
listed below along with other parameters of the extrapolation:
Dose Incidence
(mg/kg/day) (no. responding/no, tested)
0 2/20
139 18/49
279 37/49
le = 546 days w = 0.033 kg
Le = 637 days R = 4.5 I/kg
L » 637 days
With these parameters the carcinogenic potency factor for
-2 -1
humans, Si*/ is 5.73 x 10 (mg/kg/day) . The concentration of
1,1,2-trichloroethane in water, calculated to keep the lifetime
cancer risk below 10~ is 6.0 jug/1.
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Summary of Pertinent Data for 1,1,2,2-Tetrachloroethane
The water quality criterion for 1,1,2,2-tetrachloroethane is
based on the induction of hepatocellular carcinomas in female
B6C3F1 mice (NCI, 1978c). The incidences of hepatocellular car-
cinomas are listed below as are additional parameters of the extra-
polation:
Dose Incidence
(mg/kg/day) (no. responding/no, tested)
0 0/20
101 30/48
203 43/47
le = 546 days w = 0.030 kg
Le = 637 days R = 5 I/kg
L = 637 days
With these parameters the carcinogenic potency factor for
humans, q]L*, is 0.2013 (mg/kg/day)~ . The concentration of
1,1,2,2-tetrachloroethane in water, calculated to keep the lifetime
cancer risk below 10~5, is 1.7 /ug/1.
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Summary of Pertinent Data for Hexachloroethane
The water quality criterion for hexachloroethane is based on
the induction of hepatocellular carcinomas in male B6C3F1 mice
(NCI, 1978d). The incidences of hepatocellular carcinomas are
listed below as are additional parameters used in the extrapola-
tion:
Dose Incidence
(mg/kg/day) (no. responding/no, tested)
0 3/20
421 15/50
842 31/49
le = 546 days w = 0.032 kg
Le = 637 days R = 86.9 I/kg
L = 637 days
With these parameters the carcinogenic potency factor for
2 -1
humans, q1*f is 1.42 x 10 (mg/kg/day) . The concentration of
hexachloroethane in water, calculated to keep the lifetime cancer
risk below 10~5, is 19 jug/1.
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4 U S GOVERNMENT PRINTING OFFICE 1980 720-016/4372
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