CHLORINATED ETHANES
Ambient Water Quality Criteria
Criteria and. Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERION DOCUMENT
CHLORINATED ETHANES
CRITERIA
Aquatic Life
1,2-dichloroethane
The data base for freshwater aquatic life is insuffi-
cient to allow use of the Guidelines. The following recommen-
dation is inferred from toxicity data on pentachloroethane and
saltwater organisms.
For 1,2-dichloroethane the criterion to protect fresh-
water aquatic life as derived using procedures other than the
Guidelines is 3,900 ug/1 as a 24-hour average and the concentra-
tion should not exceed 8,800 ug/1 at any time.
The data base for saltwater aquatic life is insufficient
to allow use of the Guidelines. The following recommendation is
inferred from toxicity data on pentachloroethane and saltwater
organisms.
For 1,2-dichloroethane the criterion to protect salt-
water aquatic life as derived using procedures other than the
Guidelines is 880 ug/1 as a 24-hour average and the concentration
should not exceed 2,000 ug/1 at any time.
1,1,1-trichloroethane
The data base for freshwater aquatic life is insuffi-
cient to allow use of the Guidelines. The following recommen-
dation is inferred from toxicity data on pentachloroethane and
saltwater organisms.
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For 1,1,1-trichloroethane the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 5,300 u.g/1 as a 24-hour average and the concentra-
tion should not exceed 12,000 ug/1 at any time.
The data base for saltwater aquatic life is insufficient
to allow use of the Guidelines. The following recommendation is
inferred from toxicity data on pentachloroethane and saltwater
organisms.
For 1,1,1-trichloroethane the criterion to protect salt-
water aquatic life as derived using procedures other than the
Guidelines is 240 ug/1 as a 24-hour average and the concentration
should not exceed 540 ug/1 at any time.
1,1,2-trichloroethane
The data base for freshwater aquatic life is insuffi-
cient to allow use of the Guidelines. The following recommen-
dation is inferred from toxicity data on pentachloroethane and
saltwater organisms.
For 1,1,2-t ichloroethane the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 310 ug/1 as a 24-hour average and the concentration
should not exceed 710 ug/1 at any time.
For saltwater aquatic life, no criterion for 1,1,2-tri-
chloroethane can be derived using the Guidelines, and there are
insufficient data to estimate a criterion using other procedures.
1,1,1,2-tetrachloroethane
The data base for freshwater aquatic life is insuffi-
cient to allow use of the Guidelines. The following recommenda-
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tion is inferred from toxicity data on pentachloroethane and
saltwater organisms.
For 1,1,1,2-tetrachloroethane the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 420 ug/1 as a 24-hour average and the concentration
should not exceed 960 ug/1 at any time.
For saltwater aquatic life, no criterion for 1,1,1,2-
tetrachloroethane can be derived using the Guidelines, and there
are insufficient data to estimate a criterion using other pro-
cedures .
*
1,1,2,2-tetrachloroethane
The data base for freshwater aquatic life is insuffi-
cient to allow use of the Guidelines. The following recommenda-
tion is inferred from toxicity data on pentachlqroethane and salt-
• water organisms.
For 1,1,2,2-tetrachloroethane the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 170 ug/1 as a 24-hour average and the concentration
should not exceed 380 ug/1 at any time.
The data base for saltwater aquatic life is insufficient
to allow use of the Guidelines. The following recommendation is
inferred from toxicity data on pentachloroethane and saltwater
organisms.
For 1,1,2,2-tetrachloroethane the criterion to protect
saltwater aquatic life as derived using procedures other than the
Guidelines is 70 ug/1 as a 24-hour average and the concentration
should not exceed 160 ug/1 at any time.
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Pentachloroethane
The data base for freshwater aquatic life is insuffi-
cient to allow use of the Guidelines. The following recommenda-
tion is inferred from toxicity data on pentachloroethane and salt-
water organisms.
For pentachloroethane the criterion to protect fresh-
water aquatic life as derived using procedures other than the
Guidelines is 440 ug/1 as a 24-hour average and the concentration
should not exceed 1,000 ug/1 at any time.
For pentachloroethane the criterion to protect saltwater
aquatic life as derived using the Guidelines i 38 ug/1 as a
24-hour average and the concentration should not exceed 87 ug/1 at
any time.
Hexachloroethane
The data base for freshwater aquatic life is insuffi-
cient to allow use of the Guidelines. The following recommenda-
tion is inferred from toxicity data on pentachloroethane and salt-
water organisms.
For hexachloroethane the criterion to protect freshwater
aquatic life as derived using procedures other than the Guidelines
is 62 ug/1 as a 24-hour average and the concentration should not
exceed 140 ug/1 at any time.
The data base for saltwater aquatic life is insufficient
\
to allow uise of the Guidelines. The following recommendation is
inferred from toxicity data on pentachloroethane and saltwater
organisms.
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For hexachloroethane the criterion to protect saltwater
aquatic life as derived using procedures other than the Guidelines
is 7.0 ug/1 as a 24-hour average and the concentration should not
exceed 16 ug/1 at any time.
Human Health
For the maximum protection of human health from the potential
/
carcinogenic effects of exposure to 1,2-dichloroethane, 1,1,2-tri-
chloroethane, 1,1,2,2-tetrachloroethane and hexachloroethane
through ingestion of water and contaminated aquatic organisms, the
ambient water concentration is zero. Concentrations of these
chlorinated ethanes estimated to result in additional lifetime
cancer risks ranging from no additional risk to an additional risk
of 1 in 100,000 are presented in the Criterion Formulation section
of this document. The Agency is considering setting criteria at
an interim target risk level in the range of 10~5, 10~6, or 10~7
with corresponding criteria as follows:
Compound Risk Levels and Corresponding Criteria
i n-5 in-6 in-7
1,2-dichloroethane 7.0 ug/1 -70 ug/1 .07 ug/1
1,1,2-trichloroethane 2.7 ug/1 .27 ug/1 .027 ug/1
1,1,2,2-tetrachloroethane 1.8 ug/1 .18 ug/1 .018 ug/1
hexachloroethane 5.9 ug/1 .59 ug/1 .059 ug/1
For the protection of human health from the toxic properties of
1,1,1-trichloroethane ingested through the consumption of water and
fish, the criterion is 15.7 mg/1.
At the present, there are .insufficient data to derive criteria
for monochloroethane, 1,1-dichloroethane, 1,1,1,2-tetrachloroethane
and pentachloroethane.
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CHLORINATED ETHANES
Introduction
The chlorinated ethanes are produced in large quantities
and used for production of tetraethyl lead and vinyl chloride
as industrial solvents, and as intermediates in the production
of other organochlorine compounds. All of the chlorinated
ethanes studies 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 (see Table 1). Both water solubility, in most cases,
and vapor pressure decrease with increasing 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 chloro-
ethane (S.G. 0. 9214).
The chlorinated ethanes form azeotropes with water
(Kirk and Othmer, 1963), a characteristic which could influence
their persistences in the water column. All are very soluble
in organic solvents (Lange, 1956). The chlorinated ethanes
undergo the usual dehalogenation and dehydrohalogenation
reactions of chlorinated aliphatic ompounds in the laboratory
(Morrison and Boyd, 1966).
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Pearson and McConnell (1975) were unable to demonstrate
microbial degradation of the chlorinated ethanes, but did
report chemical degradation of chlorinated hydrocarbons.
Chlorinated ethanes do not bioconcentrate significantly;
however, they do exhibit a greater bioconcentrating potential
with increased chlorination. Bluegill are found to biocon-
cantrate hexachloroethane at a factor of nearly 140, whereas
they bioconcentrate dichloroethane at 2.
i
Acute toxicity to both freshwater and marine vertebrates
and invertebrates seems to be dependent on the number of
chlorine atoms associated with the ethane molecule. Penta-
chloroethane, in several instances, is the exception to
this observation (e.g., freshwater invertebrates and saltwater
fishes) . Aquatic chronic toxicity data are sparce.
•
In regard to human and mammalian health, no literature
concerning the teratogenicity of the chlorinated ethanes
was found. Mutagenicity data were non-existent except for
a finding that showed the mild mutagenesis of 1,2-di- and
1,1,2,2-tetrachloroethane in the Ames Salmonella assay.
1,2-Dichloroethane induced a higher frequency of somatic
mutations in Drosophila. 1,2-Di-; 1,1,2-tri-; 1,1,2,2-terta-;
and hexachloroethanes have all proved to be carcinogenic
in rodents.
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REFERENCES
American Industrial Hygiene Association. 1956. 1,2-Dichloro-
ethane (ethylene dichloride). Hyg. Guide Ser. Am. Ind.
Hyg. Assoc. Jour. 17: 447.
American Industrial Hygiene Association. 1963. Ethyl chloride.
Am. Ind. Hyg. Assoc. Jour. 24: 531.
Kirk, R.E., and D. Othmer, 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 hydro-
carbons in the marine environment. Proc. R. Soc. London,
Ser. B. 189: 305.
Price, K.S., et al. 1974. Brine shrimp bioassay and sea
water Bon (biochemical oxygen demand) of petrochemicals.
Jour. Water Pollut. Control Fed. 46: 63.
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Walter, P., et al. 1976. Chlorinated hydrocarbon toxicity
(1,1,1-trichloroethane, trichloroethylene, and tetrachloro-
ethylene): a monograph. Rep. PB-25-7185. Natl. Tech.
Inf. Serv., Springfield, Va.
Weast, R.C., ed. 1976. Handbook of chemistry and physics.
57th ed. CRC Press, Cleveland, Ohio.
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
Acute toxicity determinations on compounds of this class have
been conducted with bluegill, Daphnia magna, and Selenastrum
capricornutum. No chronic effects data are available.
Acute Toxicity
All data reported for bluegill are from 96-hour static toxic-
ity tests with measured concentrations (Table 1). The unadjusted
96-hour LC50 values for 1,2-dichloroethane were 550,000 ug/1
(Dawson, et al. 1977) and 431,000 ug/1 (U.S. EPA, 1978). The
other unadjusted bluegill 96-hour LC50 values (U.S. EPA, 1978)
were: 1,1,1-trichloroethane - 69,700 ug/lr 1,1,2-trichloroethane
9
- 40,200 ug/1/ 1,1,1,2-tetrachloroethane - 19,600 ug/1/ 1,1,2,2-
tetrachloroethane - 21,300 ug/1/ pentachloroethane - 7,240 ug/1/
and hexachloroethane - 980 ug/1.
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life [43 FR 21506
(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order to better
understand the following discussion and recommendation. The fol-
lowing tables contain the appropriate data that were found in the
literature, and at the bottom of each table are the calculations
for deriving various measures of toxicity as described in the
Guidelines.
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Alexander, et al. (1978) conducted acute toxicity tests with
t: e fathead minnow and 1,1,1-trichloroethane under static and
flow-through conditions with unmeasured and measured concentra-
tions, respectively (Table 1). The flow-through, measured LC50
value before adjustment (52,800 ug/D is about one-half that
(105,000 ug/D for the static, unmeasured LC50 value. After
adjustment the values are essentially the same and this result
indicates that the adjustment values for test conditions are
probably appropriate for 1,1,1-trichloroethane.
Unadjusted 48-hour LC50 values for Daphnia magna are (Table
2): 1,2-dichloroe thane - 218,000 v.g/1, 1,1,2-trichloroethane -
18,000 ug/lf 1,1,1,2-tetrachloroethane - 23,900 ug/1/ 1,1,2,2-
tetrachloroethane - 9,320 ug/1/ pentachloroethane - 62,900 ug/1,
and hexachloroethane - 8,070 ug/l« The 48-hour LC50 value for
1,1,1-trichloroethane was greater than the highest exposure con-
centration, 530,000 ug/1 (U.S. EPA, 1978).
For the bluegill, 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 greater toxicity with increased chlorination. The less
chlorinated compounds seem to be more toxic to Daphnia magna than
to bluegill, whereas the more heavily chlorinated compounds are
more toxic to bluegill.
The Final Acute Values are: 1,2-dichloroethane - 8,800 ug/1,
1,1,2-trichloroethane - 710 ug/1, 1,1,1,2-tetrachloroethane - 960
ug/1, 1,1,2,2-tetrachloroethane - 380 ug/1, all based on Daphnia
magna data. The Final Acute Values for pentachloroethane and
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hexachloroethane are 1/000 and 140 vg/l, respectively, based on
bluegill data. No invertebrate data are available for 1,1,1-tri-
chloroethane and its Final Acute Value, 12,000 ug/1/ is based on
the fathead minnow and bluegill data.
Chronic Toxicity
No chronic toxicity data are available for fish or inverte-
brate species.
Plant Effects
Ninety-six-hoar EC50 tests, using chlorophyll £ and cell num-
ber as measured responses, were conducted with the green alga,
Selenastrum capricornutum, with the following results (Table 3)s
1,1,2,2-tetrachloroethane - 136,000 and 146,000 ug/l» respec-
tively, pentachloroethane - 121,000 and 134,000 ug/lf respective-
ly; and hexachloroethane - 87,000 and 93,200 ug/1. The highest
concentration of 1,1,1-trichloroethane tested, 669,000 ug/lf
(U.S. EPA, 1978) was not high enough to produce a 96-hour EC50
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 data. The alga was approxi-
mately 7 to 15 times less sensitive than bluegill to a specific
compound. The Final Plant Values are: 136,000 ug/1 for 1,1,2,2-
/
tetrachloroethane, 121,000 ug/1 for pentacloroethane, and 87,000
ug/1 for hexachloroethane.
Residues
The chlorinated ethanes do not strongly bioconcentrate (Table
4), but do show an increased bioconcentration potential with in-
creased chlorination particularly for penta- and hexachloroethane.
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The following steady-state bioconcentration factors were measured
for bluegill: 1,2- dichloroethane - 2 (14 days); 1,1,1-trichloro-
ethane -9 (28 days); 1,1,2,2-tetrachloroethane - 8 (14 days);
pentachloroethane - 67 (14 days); and hexachloroethane - 139 (28
days). All of the chlorinated ethanes have an elimination half-
life of less than two days as measured by whole body levels in
exposed bluegill.
No measured steady-state bioconcentration factors (BCF) are
available for 1,1,2-trichloroethane and 1,1,1,2-tetrachloroethane.
BCFs can be estimated using the octanol-water partition coeffi-
cients of 117 and 457, respectively. These coefficients are used
to derive estimated BCFs of 22 and 62 for 1,1,2-trichloroethane
and 1,1,1,2-tetrachloroethane, respectively, and aquatic organisms
that contain about 8 percent lipids. If it is known that the diet
of the wildlife of concern contains a significantly different
lipid content, appropriate adjustments in the estimated BCFs
should be made.
Miscellaneous
All available and pertinent data were discused previously.
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CRITERION FORMULATION
Freshwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures. . ;
1,2-d ichloroethfcne.
Final Fish Acute Value = 68,000 ug/1
jt,
Final Invertebrate Acute Value = 8,800 ug/1
Final Acute Value = 8,800 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not available
0.44 x Final,Acute Value = 3,900 ug/1
1,1,1-trichloroethane
Final Fish Acute Value = 12,000 ug/1
Final Invertebrate Acute Value = not available
Final Acute Value = 12,000 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not available
0.44 x Final Acute Value = 5,300 ug/1
1,1,2-trichloroethane
Final Fish Acute Value = 5,700 ug/1
Final Invertebrate Acute Value = 710 ug/1
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Final Acute Value • 710 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value. = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not available
0.44 x Final Acute Value = 310 ug/1
1,1,1,2-tetrachloroethane
Final Fish Acute Value = 2,700 ug/1
Final Invertebrate Acute Value = 960 ug/1
Final Acute Value = 960 ug/1
f Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not available
0.44 x Final Acute Value = 420 ug/1
1,1,2,2-tetrachloroethane
Final Fish Acute Value = 3,000 ug/1
Final Invertebrate Acute Value = 380 ug/1
Final Acute Value = 380 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value.= 140,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 140,000 ug/1
0.44 x Final Acute Value = 170 ug/1
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Pentachloroethane
Final Fish Acute Value = 1,000 ug/1
Final Invertebrate Acute Value = 2,500 ug/1
Final Acute Value = 1,000 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 120,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = .120,000 ug/1
0.44 x Final Acute Value = 440 ug/1
Hexachloroethane
Final Fish Acute Value = 140 ug/1
Final Invertebrate Acuce Value = 330 ucj/l
Final Acute Value = 140 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 87,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 87,000 ug/1
0.44 x Final Acute Value = 62 ug/1
No freshwater criterion can be derived for any chlorinated
ethane using the Guidelines because no Final Chronic Value for
either fish or invertebrate species or a good substitute for
either value is available.
However, data for pentachloroethane and saltwater organisms
can be used as the basis for estimating criteria.
For pentachloroethane and saltwater organisms, 0.44 times the
Final Acute Value is less than the Final Chronic Value derived
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from a life cycle test with the musid shrimp. Therefore, a rea-
sonable estimate of criteria for other chlorinated ethanes and
freshwater organisms would be 0.44 times the Final Acute Value.
1,2-dichloroethane
The maximum concentration of 1,2-dichloroethane is the Final
Acute Value of 8,800 ug/1 and the estimated 24-hour average con-
centration is 0.44 times the Final Acute Value. No important
adverse effects on freshwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average con-
f
centration.
CRITERION: For 1,2-dichloroethane the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 3,900 ug/1 as a 24-hour average and the concentra-
tion should not exceed 8,800 ug/1 at any time.
1,1,1-trichloroethane
The maximum concentration of 1,1,1-trichloroethane is the
Final Acute Value of 12,000 ug/1 and the estimated 24-hour average
concentration is 0.44 times the Final Acute Value. No important
adverse effects on freshwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average con-
centration.
CRITERION: For 1,1,1-trichloroethane the criterion to pro-
tect freshwater aquatic life as derived using procedures other
than the Guidelines is 5,300 ug/1 as a 24-hour average and the
concentration should not exceed 12,000 ug/1 at any time.
1,1,2-trichloroethane
The maximum concentration of 1,1,2-trichloroethane is the
Final Acute Value of 710 ug/1 and the estimated 24-hour average
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concentration is 0»44 times the Final Acute Value. No important
adverse effects on freshwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average con-
centration.
CRITERION: For 1,1,2-trichloroethane the criterion to -pro-
tect freshwater aquatic life as derived using procedures other
than the Guidelines is 310 ug/1 as a 24-hour average and the con-
centration should not exceed 710 ug/1 at any time.
1,1,1,2-tetrachloroethane
The maximum concentration of 1,1,1,2-tetrachloroethane is the
Final Acute Value of 960 ug/1 and the estimated 24-hour average
concentration is 0.44 times the Final Acute Value. No important
adverse effects on freshwater aquatic organisms have been reported
to be caused by concentrations lower then the 24-hour average con-
centration.
CRITERION: For 1,1,1,2-tetrachloroethane the criterion to
protect freshwater aquatic life as derived using procedures other
than the Guidelines is 420 ug/1 as a 24-hour average and the con-
centration should not exceed 960 ug/1 at any time.
1,1,2,2-tetrachloroethane
The maximum concentration of 1,1,2,2-tetrachloroethane is the
Final Acute Value of 380 ug/1 and the estimated 24-hour average
concentration is 0.44 times the Final Acute Value. No important
adverse effects on freshwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average con-
centration.
CRITERION: For 1,1,2,2-tetrachloroethane the criterion to
protect freshwater aquatic life as derived using procedures other
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than the Guidelines is 170 ug/1 as a 24-hour average and the con-
centration should not exceed 380 ug/1 at any time.
Pentachloroethane
The maximum concentration of pentachloroethane is the Final
Acute Value of 1,000 ug/1 and the estimated 24-hour average con-
centration is 0.44 times the Final Acute Value. No important
adverse effects on freshwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average con-
centration.
CRITERION: For pentachloroethane the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 440 ug/1 as a 24-hour average and the concentration
should not exceed 1/000 ug/1 at any time.
Hexachloroethane
The maximum concentration of hexachloroethane is the Final
Acute Value of 140 ug/1 and the estimated 24-hour average concen-
tration is 0.44 times the Final Acute Value. No important adverse
effects on freshwater aquatic organisms have been reported to be
caused by concentrations lower than the 24-hour average concentra-
tion.
CRITERION: For hexachloroethane the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 62 ug/1 as a 24-hour average and the concentration
should not exceed 140 ug/1 at any time.
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Table 1. Freshwater fish acute values for chlorinated ethanes
Adjusted
Bicussay Test Chemical
Oijjaniam Method* Cone.** Description
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill,
I.epomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
S U
FT M
S U
S U
S U
S U
S U
S U
S U
S U
1,1,1-tri-
chloroethane
1,1.1-tri-
chloroethane
1,2-dichloro-
ethane
1,2-dichloro-
ethane
1.1,1-tri-
chloroethane
1,1,2-tri-
chloroethane
1,1.1,2-tetra-
chloroethane
1,1,2,2-tetra-
chloroethane
Pentachloro-
ethane
Hexachloro-
ethane
Time
(his)
96
96
96
96
96
96
96
96
96
96
LCt>U
(U=J/i)
105.000
52.800
550,000
431,000
69.700
40,200
19.600
21,300
7,240
980
LOU
57,404
52,800
300,000
236,000
38,100
22,000
10,700
11.600
3,960
540
Ketertnce
Alexander, et al.
1978
Alexander, et al.
1978
Dawson, et al.
1977
U.S. EPA. 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA. 1978
* S = static, FT = flow-through
** U = unmeasured, M = measured -
Geometric mean of adjusted values: 1,2-dichloroethane = 266,000 iig/1
266,000
= 68.000 ug/1
1,1,1-trichloroethane = 45,799 pg/1 — t^|- = 12,000 ug/1
1,1.2-trichloroethane = 22.000 ug/1 22.000 = 5 7QO fl
1.1,1,2-tetrachloroethane = 10.700 ug/1- 10.700 = 2.700 ug/1
1,1,2,2-tetrachloroethane ™ 11.600 ug/1 *-- = 3,000 ug/1
Pentachloroethane = 3,960 ug/1 ^|p = 1.000 ug/1
Hexachloroethane = 540 ug/1 -— = 140 ug/1
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Table 2. Freshwater invertebrate acute values for chlorinated ethanes (U.S. EPA. 1978)
Bioussay Tt-st Chemical Time LCbO
Method* Cone.** Description (tirti)
Adjusted
(uy/1) Kelereuce
vyi. Hu** * JMI
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Cd Daphnia magna
1
j^ Cladoceran,
Daphnia magna
S U 1,2-dichloro- 48
ethane
S U 1,1.2-trichloro- 48
ethane
S U 1.1.1.2-tetra- 48
chloroethane
S U 1,1,2,2-tetra- 48
chloroethane
S U Pentachloro- 48
ethane
S U Hexachloro- 48
ethane
.»...* -. — •— •— ^ • — •••- • • •- — ••• • -
218.000 185.000
18.000 15.000
23.900 20,200
9.320 7.890
62,900 53,300
8,070 6.840
* S = static
** U = unmeasured
Geometric mean of adjusted values: 1,2-dichloroethane = 185,000 pg/1 185'0.PQ = 8,800
1,1,2-trichloroethane = 15,000 pg/1 11.00P. = 710 ,,g/l
1,1,1.2-tetrachloroethane = 20,200 ug/1 2°.200 = 960 pg/1
1,1.2.2-tetrachloroethane = 7,890 ug/1 7.^90 = 330 wg/l
Pentachloroethane = 53.300 pg/1 53.300 = 2,500 ug/1
Hexachloroethane = 6,840 |lg/l . = 330 pg/1
-------
Table 3. Freshwater plant effects for chlorinated ethanes (U.S. EPA. 1978)
Organism
Concentration
(ug/il
Alga,
Selenastrum
capricornututn
Alga,
Selenastrum
capricornutum
1,1,2,2-tetrachloroethane
136,000
EC50 96-hr
chlorophyll a
EC50 96-hr
cell numbers
146,000
Pentachloroethane
DJ
I
M
u>
Alga.
Selenastrum
capricornutum
Alga.
Selenastrum
capricornutum
EC50 96-hr
chlorophyll a
EC50 96-hr
cell numbers
121.000
134.000
Hexachloroethane
Alga.
Selenastrum
capricornutum
Alga,
Selenastrum
capricornutum
EC50 96-hr
chlorophyll a
EC50 96-hr
cell numbers
87,000
93.200
Lowest plant value: 1.1,2, 2-cetrachloroethane = 136,000 iig/1
Pentachloroethane = 121,000 Mg/1
Hexachloroethane = 87.000 Mg/l
-------
Ot n.mism
Tafcle It. Freshwater residues for chlorinated ethanes (U.S. EPA, 1978)
Time
biooonceiitrdtion Factoi (days;
Bluegill,
I.epomis macrochirus
1.2-dichloroethane
2
14
Bluegill.
Lepomis macrochirus
1,1,1-trichloroethane
9
28
Bluegill,
I.epomis macrochirus
1,1,2.2-tetrachloroethane
8 14
CD
I
Bluegill,
Lepomis macrochirus
Pentachtoroethane
67
14
Bluegill.
Lepomis macrochirus
Hexachloroethane
139
28
-------
Table 5. Other freshwater tlaUa for chlorinated ethanes (U.S. EPA, 1978)
CO
I
H1
U1
Organism
Alga.
Solenastrum
caprTcornutum
Alga.
Selenastrum
caprTcornutum
Cladoceran,
Daphnia magna
Test
Duration Ktiect
Result
iuq/ll
1.1,1-trichloroethane
96 hrs EC50 chlorophyll a >669.000
96 hrs EC50 cell numbers >669,000
48 hrs LC50 >530.000
-------
SALTWATER ORGANISMS
Introduction
The toxicity data base for the 1,2-di-, 1,1,1-tri-, 1,1,2,2-
tetra-, penta-, and hexachloroethane to saltwater organisms is
limited to an alga, Skeletonetna costatum, a mysid shrimp,
Mysidopsis bahia, and the sheepshead minnow. Effects of salinity,
temperature, or other water quality factors on the toxicity of
chlorinated ethanes are unknown.
Acute Toxicity
Toxicity tests with the sheepshead minnow have been conducted
*
with four chlorinated ethanes (Tables 6 and 9). All tests were
conducted under static conditions and concentrations in water were
not measured. The LC50 values for this saltwater fish do not cor-
relate as well with the number of chlorine atoms as did the values
for the bluegill, Lepomis macrochirus (Table 1). When sensitivi-
ties of the bluegill and sheepshead minnow are compared to each of
these chlorinated ethanes, the LC50 values differ by less than a
factor of three, except for pentachloroethane values which differ
by a factor of 16. The adjusted 96-hour LC50 values for sheeps-
head minnows ranged from 1,312 ug/1 for hexachloroethane to 63,417
ug/1 for pentachloroethane. Since only one test was completed
with each chemical, when the adjusted LC50 values are divided by
the sensitivity factor (3.7), the following Final Acute Values are
obtained: hexachloroethane, 350 ug/1; pentachloroethane, 17,000
ug/1; 1,1,2,2-tetrachloroethane, 1,800 ug/1; 1,1,1,-trichloro-
ethane, 10,000 ug/1.
Mysidopsis bahia, the only invertebrate species tested in
static acute tests, and sheepshead minnows were similar in their
B-16
-------
sensitivites to the chlorinated ethanes tested, except for penta-
chloroethane (Table 7). For pentachloroethane and hexachloro-
ethane, the LC50 values for mysid shrimp were lower than those for
the freshwater species, Daphnia magna, a cladoceran, (Tables 2 and
7). Sensitivity to chlorinated ethanes increased as the amount of
chlorine increased and, generally, this trend occurred also with
the freshwater and saltwater invertebrate and fish species. When
the adjusted LC50 values for each of the five compounds tested
with Mysidopsis bahia are divided by the species sensitivity fac-
tor of 49, the Final Invertebrate Acute Values are: hexachloro-
ethane, 16 ug/1; pentachloroethane, 87 ug/1; 1,1,2,2- tetrachloro-
ethane, 160 ug/1; 1,1,1-trichloroethane, 540 ug/1; and 1,2-di-
chloroethane, 2,000 ug/1. These are also the Final Acute Values
since they are lower than the equivalent values for fish.
Chronic Toxicity
Only one chronic value is available for any chlorinated
ethane and saltwater organisms. The chronic value for the mysid
shrimp and pentachloroethane is 580 ug/1 (Table 8). The Final
Invertebrate Chronic Value is 110 ug/1* which is obtained by
dividing the chronic value by the species sensitivity factor of '
5.1. Since no chronic data for saltwater fish are available, 110
ug/1 also becomes the Final Chronic Value for pentachloroethane.
Plant Effects
The saltwater alga, Skeletonema costaturn, was as sensitive to
1,1,2,2-tetrachloroethane as the mysid shrimp and sheepshead min-
now (Table 9). The 96-hour EC50 value for growth, based on cell
count, was 6,230 ug/1. The Final Plant Values for pentachloro-
ethane and hexachloroethane, based on the same algal species, are
B-17
-------
58,200 and 7,750 ug/1/ respectively. There are no data reported
in the literature on effects of chlorinated ethanes on saltwater
vascular plants.
Miscellaneous
Plant data for l,2-dichl6iroethane and 1,1,1-trichloroethane
indicate" that those compounds are not very toxic to the alga,
Skeletonema costatum (Table 10).
B-18
-------
CRITERION FORMULATION
Saltwater-Aquatic Life
S'-mmary of Available Data
The concentrations below have been rounded to two significant
figures.
1,2-d ichloroethane
Final Fish Acute Value = not available
Final Invertebrate Acute Value = 2,000 ug/1
Final Acute Value = 2,000 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = greater than 433,000 ug/1
Residue Limited Toxicant Concentration = not available
9
Final Chronic Value = greater than 433,000 ug/1
0.44 x Final Acute Value = 880 ug/1
1,1,1-trichloroethane
Final Fish Acute Value = 10,000 ug/1
Final Invertebrate Acute Value = 540 ug/1
Final Acute Value = 540 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = greater than 669,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = greater than 669,000 ug/1
0.44 x Final Acute Value = 240 ug/1
1,1,2,2-tetrachloroethane
Final Fish Acute Value = 1,800 ug/1
Final Invertebrate Acute Value = 160 ug/1
Final Acute Value = 160 ug/1
B-19
-------
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 6,200 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 6,200 ug/1
0.44 x Final Acute Value = 70 ug/1
Pentachloroethane
Final Fish Acute Value = 17,000 ug/1
Final Invertebrate Acute Value = 87 ug/1
Final Acute Value = 87 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = 110 ug/1
Final Plant Value = 58,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value - 110 ug/1
0.44 x Final Acute Value = 38 ug/1
Hexachloroethane
Final Fish Acute Value = 350 ug/1
Final Invertebrate Acute Value = 16 ug/1
Final Acute Value = 16 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 7,800 ug/1
)'
Residue Limited Toxicant Concentration - not available
/
Final Chronic Value = 7,800 ug/1
0.44 x Final Acute Value =7.0 ug/1
B-20
-------
Pentachloroethane
The maximum concentration of pentachloroethane is the Final
Acute Value of 87 ug/1 and the 24-hour average concentration is
the Final Chronic Value of 38 ug/1. No important adverse effects
on saltwater aquatic organisms have been reported to be caused by
concentrations lower than the 24-hour average concentration.
CRITERION: For pentachloroethane the criterion to protect
saltwater aquatic life as derived.using the Guidelines is 38 ug/1
as a 24-hour average and the concentration should not exceed 87
ug/1 at any time.
No saltwater criteria can be derived for other chlorinated
ethanes using the Guidelines because no Final Chronic Value for
either fish or invertebrate species or a good substitute for
either value is available.
However, data for pentachloroethane and saltwater organisms
can be used as the basis for estimating criteria.
For pentachloroethane and saltwater organisms, 0.44 times the
Final Acute Value is less than the Final Chronic Value derived
from a life cycle test with the mysid shrimp. Therefore, a
reasonable estimate of criteria for other chlorinated ethanes and
saltwater organisms would be 0.44 times the Final Acute Value.
1,2-dichloroethane
The maximum concentration of 1,2-dichloroethane is the Final
Acute Value of 2,000 ug/1 and the estimated 24-hour average
concentration is 0.44 times the Final Acute Value. No important
adverse effects on saltwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average
concentration.
B-21
-------
CRITERION! For 1,2-=dichloroethane the criterion to protect
saltwater aquatic life as derived using procedures other than the
Guidelines is 880 ug/1 as a 24-hour average and the concentration
should not exceed 2,000 ug/1 at any time.
1,1,1-trichloroethane
The maximum concentration of 1,1,1-trichloroethane is the
Final Acute Value of 540 ug/1 and the estimated 24-hour average
concentration is 0.44 times the Final Acute Value. No important
adverse effects on saltwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average
concentration.
CRITERION: For 1,1,1-trichloroethane the criterion to
protect saltwater aquatic life as derived using procedures other
than the Guidelines is 240 ug/1 as a 24-hour average and the
concentration should not exceed 540 ug/1 at any time.
1,1,2,2-tetrachloroethane
The maximum concentration of 1,1,2,2-tetrachloroethane is the
Final Acute Value of 160 ug/1 and the estimated 24-hour average
concentration is 0.44 times the Final Acute Value. No important
adverse effects on saltwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average
concentration.
CRITERION: For 1,1,2,2-tetrachloroethane the criterion to
protect saltwater aquatic life as derived using procedures other
than the Guidelines is 70 ug/1 as a 24-hour average and the
i
concentration1should not exceed 160 ug/1 at any time.
B-22
-------
Hexachloroethane
The maximum concentration of hexachloroethane is the Final
Acute Value of 16 ug/1 and the estimated 24-hour average
concentration is 0.44 times the Final Acute Value. No important
adverse effects on saltwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average
concentration.
CRITERION: For hexachloroethane the criterion to protect
saltwater aquatic life as derived using procedures other than the
Guidelines is 7.0 ug/1 as a 24-hour average and the concentration
should not exceed 16 ug/1 at any time.
B-23
-------
Table 6. Marine, fish acute values for chlorinated ethanes (U.S. EPA, 1978)
DO
1
to
*>.
Biuctssay Test
orumiism Method* COnC .
Sheepshead minnow, S U
Cyprinodon variegatus
Sheepshead minnow, S U
typrinodon variegatus
Sheepshead minnow, S U
Cyprinodon variegatus
Sheepshead minnow, S U
Cyprtnodon variegatus
* S = static
*"* U = unmeasured
Geometric mean of adjusted values:
Adjusted
Chemical Time I-CbU LCbu
.** Description jmi>) (uii/i) {ug^lj
1,1,1- 96 70,900 38,761
trichloroe thane
1,1,2,2- 96 12,300 6,724
tetrachloroe thane
Pentachloro- 96 116,000 63,417
ethane
Hexachloro- 96 2.400 1,312
ethane
1,1,1-trichloroethane = 38.761 Mg/l 3P--76l = 10.000 ug/1
3.7
1100 t- f* t- •»- .1 /->Vi 1 n-vrmt-li^,-*^ — A T) 1. ,.n 1 1 O , //H -i Qr\f\ .. „ 1 1
Pentachloroethane = 63,417 pg/1 = 17,000 ng/1
Hexachloroethane = 1,312 Mg/l ~ = 35° "S/1
-------
oryan ism
Table 7 Marine invertebrate acute values for chlorinated ethanes (U.S. EPA. 1978)
Adjusted
Bioassay Test Chemical Tiint
Hetiioq*_ Cone .** Description (in a
CD
1
NJ
Ul
Mysid shrimp,
Mysidopsis bahia
Mysid shrimp,
Mysidopsis bahia
Mysid shrimp,
Mysidopsis bahia
Mysid shrimp,
Mysidopsis bahia
Mysid shrimp,
Mysidopsis bahia
* S = static
S U 1,2- 96 113,000 95,711
dichloroethane
S U 1.1,1- 96 31,200 26,426
trichloroethane
S U 1,1.2,2- 96 9,020 7,640
tetrachloro-
ethane
S U Pentachloro- 96 5,060 4,286
ethane
S U llexachloro- 96 940 796
ethane
•** U = unmeasured
Geometric mean of adjusted values: 1 ,2-dichloroethane = 95,711 Mg/1 A 9 = 2,000 Mg/1
1,1,1-trichloroethane = 26,426 ug/1 — f$4-6= 540 ug/1
1,1,2,2-tetrachloroethane = 7,640 ng/1 -° = 16°
Pentachloroethane = 4,286 ug/1
Hexachloroethane = 796 pg/1
87
16 ug/1
-------
CO
I
M
cr>
Tattle 8. Marine invertebrate chronic values for chlorinated ethanes (U.S. EPA, 1978)
Mysid shrimp,
Mysidopsis bahia
Limits
Test*
LC
530-630**
Chronic
Value
580**
* LC = life cycle or partial life cycle
**Data are for pentachloroethane
Geometric mean of chronic values = 580 pg/1
Lowest chronic value = 580 yg/1
-------
Table 9. Marine plane effects for chlorinated ethanes (U.S. EPA. 1978)
03
N>
Organism
Alga.
Skeleconema costatum
Alga.
Skeleconema costatum
Alga,
.•Skeleconema costatum
Alga,
Skeleconema costatum
Alga.
Skeletonema costatum
Alga.
Skeletonema costatum
Effect
Concentration
(ug/it
1,1,2,2-tetrachloroethane
EC50 96-hr 6.440
chlorophyll a
EC50 96-hr
cell count
EC50 96-hr
cell count
EC50 96-hr
cell count
6.230
Pentachloroethane
EC50 96-hr 58.200
chlorophyll a
58.200
Hexachloroethane
EC50 96-hr 8.570
chlorophyll a
7.750
Lowest plant value: 1,1,2.2-tetrachloroethane = 6.230 iig/1
Pentachloroethane = 58,200 ng/1
Hexachloroe thane = 7,750 iig/1
-------
Table 10. Other marine data for chlorinated ethanes (U.S. EPA, 1978)
Organjam
Test
Duration Ett'ect
Result
fug/11
CO
NJ
oo
Alga.
Skeletonema ccstatum
Alga,
Skeletonema coscatum
Sheepshead minnow,
Cyprinodon variegatus
Alga.
Skeletonema costatum
Alga,
Skeletonema costatum
1,2-dichloroethane
96 hrs EC50 chlorophyll a >433,000
96 hrs EC50 cell count ?433,000
96 hrs LC50 >126,000
<226,000
1,1,1-trichloroethane
96 hrs EC50 chlorophyll a >669,000
96 hrs EC50 cell count
>669.000
-------
CHLORINATED ETHANES
REFERENCES
Alexander, H.C., et al. 1978. Toxicity of perchloroethylene,
trichloroethylene, 1,1,1-trichloroethaae, and methylene
chloride to fathead minnows. Bull. Environ. Contain. Toxicol.
/
20: 344.
Dawson, G.W., et al. 1977. The toxicity of 47 industrial
chemicals tc 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.
B-29
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
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 properties which make them excellent solvents,
degreasing agents, fumigants and cutting fluids. Some are
used in the manufacture of plastics, textiles and in the
synthesis of other chemicals. About 1955, Chloroethanes
began to replace more toxic industrial solvents.
A large number of humans are industrially exposed to
Chloroethanes. In addition, the general population encounters
these compounds in commercial products and as environmental
contaminants resulting from industrial emissions including
the discharge of liquid wastes.
An extensive literature has been generated by investiga-
tors who have studied the effects of Chloroethanes on biologi-
cal 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
-------
Compound Name
TABLE 1
Chloroethanes and Synonyms
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
Hexachloroethane
Chloroethane
Ethylidene Dichloride
Ethylene Dichloride
Methyl Chloroform
Ethane Trichloride
Tetrachloroethane
Acetylene Tetrachloride
Pentalin
Perchloroethane
Ethyl chloride
Ethylidene Chloride
Ethylene Chloride
Chlorothene
Vinyl Trichloride
Sym-Tetrachloroethane
Ethane Pentachloride
C-2
-------
TABLE 2
CHLOROETHANES
H H
i i
H-C-C-CI
i i
H H
H Cl
H-C-C-H .
H Cl
H H
ci-c-c-ci
i i
H H
Monochloroe thane
1,1-Dicholoro-
ethane
1,2-Dichloro-
ethane
H Cl
H-C-C-CI
H Cl
H Cl
CI-C-C-H
H Cl
H Cl
i i
CI-C-C-CI
H Cl
1,1,1-Trichloro-
ethane
1,1,2-Trichloro-
ethane
1,1,1,2-Tetra
chloroethane
Ci Cl
i i
H-C-C-H
t i
Cl Cl
Cl Cl
I I
H-C-C-CI
i i
Cl Cl
Cl CI
CI-C-C-CI
Cl CI
1,1,2,2-Tetrachloro-
ethane
Penta-
chloro-
ethane
Hexachloro-
ethane
C-3
-------
TABLE 3
Physical and Chemical Properties of Chloroethanes
n
i
Compound
Formula
Weight
Boiling
Point°C
Melting
Point C
Specific
Gravity
Solubility Vapor Vapor .
In Water Pressure Density
(mm Hg)
monoch lor oe thane
1, 1-dichloroethane
1,2-dichloroethane
1,1,1-trichloro-
ethane
1,1,2-tr ichloro-
ethane
1,1,1,2-tetrachloro-
ethane
1, 1,2,2-tetrachloro-
pentach lor oe thane
hexach lor oe thane
aAt 20°C; Water = 1.00
bAir = 1.00
64.52
98.96
98.96
133.4
133.4
167.9
167.9
202.3
236.7
at 4°C
13.1
57.3
83.4
74.1
113
129
146.3
162
186
-138.7
- 98
- 35.4
- 33
- 37.4
- 68.1
- 36
- 29
- 187
0.9214
1.1776
1.253
1.3492
1.4405
1.5532
1.596
1.6796
2.091
5.74 g/1 1,000 at 20°C
5 g/1 230 at 25°C
8.1 g/1 85 at 25°C 3.42
480 parts
per 106 w/w 96 at 20°C 4.55
Slightly
soluble
2.85 g/1
2.9 g/1 16 at 25°C 5.79
Insoluble
Insoluble
References:
Walter, et al. 1976
Price, et al. 1974
Anter. Ind. Hyg. Assoc. 1963; 1.956
Weast, 1976
-------
Ingestion from Water
The U.S. Environmental Protection Agency (1974)-identified
a number of toxic compounds in low concentrations in raw
and finished waters of which approximately 38 percent were
halogenated (U.S. EPA, 1976). Halogenated hydrocarbons
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 compounds 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-tetra-
chloroethane (Keith, et al. 1976). Other reports of halogen-
ated 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 Iraud, 1973.
Even though individual chemicals are present in relatively
small amounts in public water supplies, the toxicological
implications are a matter of great concern. Chronic ingestion
of chloroethanes may result in synergistic interactions
and alterations of basic metabolic pathways (Tardiff, et
al. ]978). Of the 289 compounds identified in U.S. drinking
water supplies (U.S. EPA, 1976) , 21 have been characterized
as having carcinogenic activity (Kraybill, 1978) . Of these
21, three are chloroethanes: 1,2-dichloroethane; 1,1,2-
C-5
-------
trichloroethane; tetrachloroethane (isomer not identified).
Studies of Harris and Epstein (1976) suggested there is
an epidemiologic link between the presence of halogenated
organic compounds in drinking water and the incidence of
cancer in populations along the lower Mississippi River,
where contamination is particularly high.
Monochloroethane is widely used as a solvent and in
chemical synthesis (Natl. Inst. Occup. Safety Health, 1978c).
No literature was found indicating the amounts discharged
as liquid industrial wastes; however, chloroethane has been
identified in finished water supplies (Kopfler, 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 above 12.3°C
the compound would volatilize into the atmosphere.
1,1-Dichloroethar.e is not reported to be produced commer-
cially in the United States (Natl. Inst. Occup. Safety Health,
1978c), but is imported for use as a solvent and cleaning
agent in specialized processes. 1,1-Dichloroethane has
been identified in the finished water of several metropolitan
areas (Coleman, et al. 1976; Kopfler, et al. 1976).
More than 80 percent of the 1,2-dichloroethane produced
in the United States is converted to vinyl chloride and
other chlorinated chemicals (U.S. EPA, 1975b); the solvent
is also used in the manufacture of tetraethyl lead and as
C-6
-------
a constituent of many products used by the general public
(U.S. EPA, 1975a). The gross annual discharge of 1,2-dichloro-
ethane was estimated at 80 tons by the U.S. EPA (1975a).
Nonpoint sources result from the use of products containing
1,2-dichloroethane such as paint, varnish, and finish removers.
The compound is difficult to degrade biologically (Price,
et al. 1974), however, activated carbon filtration 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. (U.S. EPA, 1975c, 1974).
1,1,1-Trichloroethane is used primarily as a solvent,
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 of the environmental fate in water
or estimates of annual discharge as waste.
1,1,2-Trichloroethane is used in the manufacture of
1,1-dichloroethylene, as a solvent, and in organic synthesis.
The gross annual discharge is estimated.at 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-Tri-
chloroethane persists in the environment (greater than 2
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
C-7
-------
rtudy of finished water of a metropolitan area, reported
concentrations of 0.1 to 8.5 jug/1 (U.S. EPA, 1975d) .
1,^,1,2-Tetrachloroethane is used as a solvent and
in the manufacture of a number of widely used products,
(U.S. EPA, 1975a). It is potentially formed during chlorina-
tion of water (U.S. EPA, 1975a) and has been identified
in finished water at a concentration of 0.11 pg/1 (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 discharge 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 chlorination of treated sewage.
The compound persists in the environment and is not degraded
biologically but can be removed from drinking water by acti-
vated carbon filtration which is reported to be 90 to 100
percent effective (U.S. EPA, 1975a).
Apparently pentachloroethane is not produced commercially
irf the United States (Natl. Inst. Occup. Safety Health,
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 at 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.
iJPA, 1975a) .
C-8
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Analytical Techniques: Sensitive methods for identifica-
tion of chlorinated ethanes and other organic compounds
found in water, methods of quantitation, efficiency of samp-
ling techniques and recovery were discussed by Keith, et
al. (1976). Computerized gas chromatography/mass spectroscopy
was presented as the best method available. There are many
recent publications describing water sampling and analytical
techniques for the identification of halogenated 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-Trichloroethane was found in small amounts as a contami-
nant 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 ug/kg. Of the foods
analyzed, olive oil contained the largest amount (10 ug/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; however,
residues of 1,2-dichloroethane were not detected in wheat,
flour, bran, middlings, and bread (Berck, 1974).
C-9
-------
1,2-Dichloroethane is commonly used as an extractant
in the preparation of spice oleoresins. The dichloroethane
isomer was detected in 11 of 17 spices in concentrations
ranging from 2 to 23 ug solvent per gram spice oleoresin
(Page and Kennedy, 1975).
Concentrations of seven halogenated hydrocarbons were
determined in various organs of three species of molluscs
and five species 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. The specific gravi-
ties of chloroethanes (except monochloroethane) would tend
to maximize effects in the bottom of streams or other bodies
of water. The amount present which could be incorporated
in the food chain would be limited by the solubility of
the solvents in water (Table 3).
A bioconcentration factor (BCF) relates the concentration
of a chemical in water to the concentration in aquatic organ-
isms, but BCF's are not available for the edible portions
of all four major groups of aquatic organisms consumed in
the United States. Since data indicate that the BCF for
lipid-soluble compounds is proportional to percent lipids,
•
BCF's can be adjusted to edible portions using data on percent
lipids and the amounts of various species consumed by Americans,
A recent survey on fish and shellfish consumption in the
United States (Cordle, et al. 1978) found that the per capita
C-10
-------
consumption is 18.7 g/day. From the data on the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974), the relative consumption of the four major
groups and the weighted average percent lipids for each
group can be calculated:
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4.8
Saltwater fishes 61 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lip as for each
of these groups, the weighted average percent lipids is
2.3 for consumed fish and shellfish.
Measured steady-state bioconcentration factors of 2,
9, 8, 67, and 139 were obtained for 1,2-dichloroethane,
1,1,1-trichloroethane, 1,1,2,2-tetrachloroethane, pentachloro-
ethane, and hexachloroethane, respectively using bluegills
containing about one percent lipids (U.S. EPA, 1978). An
adjustment factor of 2.3/1.0 = 2.3 can be used to adjust
the measured BCF from the 1.0 percent lipids of the bluegill
to the 2.3 percent lipids that is the weighted average for
consumed fish and shellfish. Thus, the weighted average
bioconcentration factors for 1,2-dichloroethane, 1,1,1-tri-
chloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane,
and hexachloroethane and the edible portion of all aquatic
organisms consumed by Americans are calculated to be 4.6,
21, 18, 150, and 320, respectively.
C-ll
-------
No measured steady-state bioconcentration factors (BCF)
are available for 1,1,2-trichloroethane and 1,1,1,2-tetra-
chloroethane, but the equation "Log BCF =0.76 Log P - 0.23"
can be used (Veith, et al. Manuscript) to estimate the BCF
for aquatic organisms that contain about eight percent lipids
from the octanol-water partition coefficient (P). Based
on octanol-water partition coefficients of 117 and 457,
respectively, the steady-state bioconcentration factors
for 1,1,2-trichloroethane and 1,1,1,2-tetrachloroethane
are estimated to be 22 and 62. An adjustment factor of
2.3/8.0 = 0.2875 can be used to adjust the estimated BCF
from the 8.0 percent lipids on which the equation is based
to the 2.3 percent lipids that is the weighted average for
consumed fish and shellfish. Thus, the weighted average
bioconcentration factors for 1,1,2-trichloroethane and 1,1,1,2-
tetrachloroethane and the edible portion of all aquatic
organisms consumed by Americans is calculated to be 6.3
and 18, respectively.
Inhalation
Inhalation is the major route of exposure of humans
to the volatile chloroethanes which are widely used as sol-
vents, particularly in metal degreasing and dry cleaning
operations. Many tons are reported to evaporate into the
atmosphere (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-trichloroethane reported breathing zone concentrations
ranging from 1.5 to 396 ppm (Table 4).
C-12
-------
TABLE 4
Concentrate
Range
(ppm)
Concentrations of 1,1,1-Trichloroethane
Observed in Ambient Air of Various Industries
Type of Job
or Industry
Reference
4.0 -
2.5 -
6.0 -
2.0 -
36.5 -
73.0 -
1.5 -
12.0 -
37.0
79.5
83.0
18.4
159.5
350.0
16.6
118.0
Machining, Degreasing
Electrical Industry
Electrical Industry
Manufacture Catapult
Cylinders
Manufacture Rifle Scopes
Degreasing-Cleaning
Metal Industry
Soldering-Degreasing
Kominsky, 1976
Gilles, 1976
Gilles & Philbin, 1976
Gilles & Rostand, 1975
Gunter, et al. 1977
Gilles, 1977
Levy & Meyer, 1977
Gunter & Bodner, 1974
Dermal
Normally the skin is not a major route of exposure.
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),
C-13
-------
PHARMACOKINETICS
Absc ption
Monochloroethane is absorbed rapidly into the body
following ingestion or inhalation (Sax, 1975) and has been
used as an anesthetic (Merck, 1976). Absorption through
the skin is minor.
Lethal amounts of 1,2-dichloroethane are absorbed follow-
ing ingestion of a single dose (LD50 for rats, 0.77 m/l/kg)
or a single application to the skin (LD50 for rabbits, 3.89
mgAg) (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 1,1-dichloroethane
is similar to that of the 1,2-isomer; however, the 1,1-isomer
is less toxic.
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 samples collected at 10, 20
and 30 minutes indicated slow absorption (Table 5). In
the workplace, concern for toxic effects resulting from
skin contact with 1,1,1-trichloroethane is usually one of
dermatitis (Gilles, 1977). The concentration of 1,1,1-tri-
chloroethane in the blood of victims of fatal intoxication
(ingested or inhaled) has been reported to be 60, 62, and
120 ppm (Stahl, et al. 1969) indicating rapid absorption
by both routes.
C-14
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TABLE 5
Concentrations of 1,1,1-Trichloroethane Pound in
Alveolar Air of Experimental Subjects
Duration of Thumb Alveolar Air Concentrations
Immersion (ppm)
10 minutes 0.10 - 0.10
20 minutes 0.14 - 0.37
30 minutes 0.19 - 1.02
Source: Stewart and Dodd, 1964
1,1,2-Trichloroethane is absorbed more rapidly following .
ingestion or inhalation than following a dermal exposure
as indicated by LDSOs. A dermal LD50 for 1,1,2-trichloroethane
was reported for rabbits to be 3.73 ml/kg body weight; an
ingestion LD50 for rats was reported to be 0.58 ml/kg,
for inhalation, an 8-hour exposure at 500 ppm was fatal
to four of six rats (Smyth, et al. 1969). A single application
of 1 ml of pure solvent to the skin of guinea pigs was absorbed
rapidly as indicated by the appearance of 3 to 4 jjg/ml of
the solvent in the blood in 30 minutes. After 12 hours,
the blood concentration rose to almost 5 ;ug/ml (Jakobson,
et al. 1977).
The absorption of inhaled 1,1,2,2-tetrachloroethane
in humans was determined by Morgan, et al. (1970, 1972)
38
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 tetrachloro-
C-15
-------
erhane was retained. Subjects continued to breathe room
air and exhale for one hour through charcoal traps. Only
3 8
3.3 to 6 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-tetrachlor-
oethane had the highest partition coefficient, one of the
highest rates of absorption (lungs) 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 a small amount 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, 0.6 to 1.3 percent of the dose administered. One
to 3 percent of a dose of 1,1,2-dichloroethane (0.1 to 0.2
g/kg) was retained after 3 days. The highly toxic 1,1,2,2-
tetrachloroethane (0.21 to 0.32 g/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 concentrations 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 fitted the empirical data. Hake,
et al. (1960) reported that 0.09 percent of a large dose
C-16
-------
of 1,1,1-trichloroethane was retained in the skin of rats
as the parent compound 25 hours after administration of
an i.p. dose (~700 mg per 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 solvent in the fetuses (Truhaut, et al.
1974).
TABLE 6
Concentrations of 1,1,1-Trichloroethane in Tissues
of Mice Following Inhalation Exposures
Concentration
(ppm)
Exposure
Time (h)
ug 1
Blood
,1,1-Trichloroethane/g Tissue
Liver
Kidney
Brain
10
100
1,000
5,000
10,000
24
24
6
3
6 '
0.6
6.3
36
165
404
+ 0.16a
+ 3.0
± 16
± 25
+ 158
1.5
12.2
107
754
1429
+ 0.3
+ 4.6
+ 38
+ 226
+ 418
1.1
5.9
60
153
752
+ 0.2
+ 2.2
± 16
± 27
+ 251
0.8
6.2
57
156
739
+ 0.1
± 1'3
± 17
± 24
+ 170
aValues are means and standard deviations from 4 to 10 animals.
Source: Holmberg, et al. 1977
C-17
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Metabolism (In Vivo)
In 1971, Yllner published a series of papers dealing
with the metabolism of chloroethanes. Solvents were injected
i.p. into mice and the excretion of metabolites in the urine
monitored for three days. Table 7 summarizes Yllner's obser-
vations.
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 hydro-
lytic cleavage of the chlorine-carbon bonds yielding glyoxalic
acid and carbon dioxide. Nonenzymatic oxidation of 1,1,2,2-
tetrachloroethane may produce a small amount of tetrachloro-
ethylene. The parent compound may be dehydrochlorinated
to form small amounts of trichloroethylene, precursor to
trichloroacetic acid, and trichloroethanol'.
The metabolism of pentachloroethane in the mouse is
postulated to proceed at least partly -through trichloroethylene
and its metabolite 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
metabolized decreased with an 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 (i972) 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
C-18
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TABLE 7
Major Metabolites of Chloroethanes in Mice
Compound
Dose
(g/kg)
Total %
Urinary Metabolites
Identified
% of Dose
1,2-Dichloroethane
12-15
51-73 S-carb(
Dxymethylcysteine
44-46 Free
1,1,2-Trichloroethane 10-13
O
I
(-•
vo
1,1,1,2-Tetrachloro-
ethane
1,1,2,2-Tetrachloro-
ethane (14C-)
0.21-0.32
Pentachloroethane
1.1-1.8
Thiodiacetic acid
Chloroacetic acid
2-Chloroethanol
S,S'-ethylene-bis-cysteine
6-9 S-carboxymethylcysteine
Chloroacetic acid
Thiodiacetic acid
2,2-Dichloroethanol
2,2,2-Tr ichloroethanol
Oxalic acid
Trichloroacetic acid
•17-49 Trichloroethanol
Trichloroacetic acid
23-34 Dichloroacetic ;cid
Trichloroacetic acid
Tr ichloroethanol
Oxalic acid
Glyoxylic
Urea
Half of urinary activity not accounted for
Trichloroethanol
Trichloroacetic acid
Expired air contained trichloroethylene
(2-16%) and tetrachloroethylene (3-9%)
0.5-5 Bound
33-44
6-23
0.0-0.8
0.7-1.0
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
-------
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 trichloro-
acetic acid (TCA) and trichloroethanol(TCE) (Table 8), although
relative amounts varied with the individual solvent. Meta-
bolites were determined colorimetrically by the Fujiwara
reaction; trichloroethanol was determined as the difference
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-
tetrachloroethane. 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
dechlorination 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-trichloro-
ethane was stimulated by addition of the 100,000 x g superna-
tant to the microsomal assay (Gandolfi and Van Dyke, 1973).
1,1,2,2-Tetrachloroethane and hexachloroethane (2.6
mmol/kg body weight) administered perbrally to rats, decreased
the cytochrome P-450 content and overall drug hydroxylation
activity in the liver (Vainio, et al. 1976). Working with
020
-------
TABLE 8
Urinary Metabolites from Wistar Rats Exposed "to Solvents
Solvent
- No. of
Experiments
Urinary Metabolites
(mg/kg/body weight)
TCA TCE
Inhalation
200 ppm 8 hrs.
1,1,1-Tr ichloroethane
1,1,2-Trichloroethane
1,1,1,2-Tetrachloroethane
1,1,2,2-Tetrachloroethane
8
8
8
8
0.5 + 0.2
0.3 + 0.1
39.4 T 5.0
1.7 + 0.9
3.1 + 1.0
0.3 7 0.1
159,6 + 24.4
6.5 T 2.7
Intraperitoneal
2.78 mmol per kg body weight
1, 1,1-Tr ich lor oe thane
1, 1, 2-Tr ichloroe thane
1,1,1, 2-Tetrachloroethane
1,1,2, 2-Tetrachloroethane
8
8
8
8
0.5 + 0.2
. 0.4 + 0.1
16.9 + 1.6
1.3 T 0.2
3.5 + 1.4
0.2 + 0.1
97.3 + 8.1
0.8 T 0.4
Six rats per group
Five rats per group
Source: Ikeda and Ohtsuji, 1972
C-21
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TABLE 9
Dechlorination of Chloroethanes by
Rat Liver Microsomes
Percent Cl Enzvmatically
Compound Removed
Monochloroethane < 0.5
1,1-Dichloroethane 13.5
1,2-Dichloroethane < 0.5
1,1,1-Trichloroethane ^0.5
1,1,2-Trichloroethane 9.8
1,1,1,2-Tetrachloroethane 0.8
1,1,2,2,-Tetrachloroethane 6.0
Pentachloroethane 1.7
Hexachloroethane 3.9
aUniformly labeled with chlorine-36
Results are aver ges of duplicate assays from at least six rats
Source: Van Dyke and Wineman, 1971
C-22
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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 of total uptake (Monster, 1979). The author
suggested that transformation of the parent compound takes
place by hydroxylation to trichloroethanol, followed by
4
partial oxidation of trichloroethanol 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); expired C02 was not detected. Eighty-four percent
of the 1,1,2,2-tetrachloroethane dose was excreted in 72
hours, with about half the dose excreted as C02/ and one-
fourth in the urine; approximately 16 percent remained in
the animal. About one-third of the pentachloroethane dose
was expired unchanged; the expired air also contained tri-
C-23
-------
TABLE 10
Excretion of Chloroethanes Administered to Mice3
Chloroethane
Compound
Dose
(g/kg)
Expired
Unchanged
(%)
Expired
as C09
(%)
In
Urine
(%)
In
Feces
(%)
1,2-
1,1,2-
1,1,1,2-
1,1,2,2-
Penta-
0.05-0.17
0.1 -0.2
1.2 -2.0
0.21-0.32
1.1 - 1.8
10-45
6-9
21-62
4
12-51
12-15.
10-13
-
45-61
-
51-73
73-87
18-56
23-34
25-50
0-0.6
0.1-2.0
-
-
-
Intraperitoneal injection - Excretory products collected for 3 days
Source: Yllner, (1971a, b, c, d, and e)
chloroethylene (2 to 16 percent) and tetrachloroethylene
(3 to 9 percent) indicating dechlorination of pentachloroethane.
Twenty-five to 50 percent of the dose was in the urine.
Stewart, et al. (1961, 1969, 1975) studied controlled
human exposures to 1,1,1-trichloroethane vapor. The concen-
tration of the unchanged solvent in the post-exposure expired
air was predictable enough to estimate the magnitude of
exposure. The rate of 1,1,1-trichloroethane excretion was
a function of exposure duration as well as concentration
(Table 11).
C-24
-------
TABLE 11
1,1,1-Trichloroethane Breath Concentrations of
Men and Women Exposed at 350 ppm
Men
Women
Time
No.
Mean
(PPm)
Range
No.
Mean
(ppm)
Range
Isolated 1-Hour Exposure
2 Minutes preexit exposure
1 Minute post exposure
23 Hours post exposure
3
3
3
150
76.4
1.11
144
48.
0.
6
75
157
108
1.63
o - Isolated 7.5 Hour
i
N>
en
2 Minutes preexit exposure
1 Minute post exposure
16 Hours post exposure
4
4
4
234
149
7.07
222
144
6.
62
- 252
- 153
7.73
3
2
2
183
120
0.8
173
116
0.57
- 193
- 123
1.
03
Exposure
3
4
4
254
181
6.93
247
156
4.83
- 262
- 205
8
.74
Source: Stewart, et al. 1975
-------
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,
trichloroethanol and trichloroacetic acid, excreted in the
urine, represented approximately three percent of the total
uptake. Although measurements of 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 chloroethanes were found in the literature. These data
must be obtained, however, in order to' identify populations
at risk.
EFFECTS
Acute, Sub-acute, 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 Trichloroethylene in the Environment." NIOSH
(1978b) published criteria documents for recommended standards
of occupational exposure to 1,1,1-trichloroethane (1978b),
1,2-dichloroethane (1976b), and 1,1,2,2-tetrachloroethane
(1976a). A monograph prepared by Walter, et al. (1976)
C-26
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on chlorinated hydrocarbon toxicity, included 1,1,1-trichloro-
ethane and was prepared for the Consumer Product Safety
Commission, Bureau of Biomedical Science. A comprehensive
review of 1,1,1-trichloroethane literature from 1953 through
1973 was conducted by the Franklin Institute Research Labora-
tories for the U.S. Environmental Protection Agency (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-'ronta ling hydro-
carbon it is potentially damaging to the liver and is known
to disturb cardiac rhythm (Goodman and Oilman, 1975) . Over-
doses of several volatile anesthetics including monochloro-
ethane can lead to severe contractile failure of the heart
(Doering, 1975). At the stage of maximal failure,
the myocardial stores of ATP and phosphoc'reatine 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,
Smyth, et al.(1969) reported an oral LD50 for 1,2-dichlo-
roethane in rats of 0.77 ml/kg (range 0.67 to 0.89) and
a dermal LD50 for rabbits of 3.89 ml/kg (range 3.40 to 4.46).
In both cases a single dose was administered.
C-27
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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, myocar-
dium and sometimes the adrenals (Heppel, et al. 1946; Liola,
et al. 1959; Liola and Fondacaro, 1959). Chronic inhalation
exposures, 100 to 400 ppm, from 5 weeks 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-dichloroethane (Spencer,
et al. 1951).
A correlation was found between serum ornithine carbamyl
transferase (OCT) activity and hepatocellular damage caused
by injection (i.p.) of acute doses of solvents (in corn
oil) into guinea pigs (Divincenzo and Krasavage, 1974).
Of 33 solvents tested, 5 were chlorinated ethanes: 1,1-;
1,2-; 1,1,1-; 1,1,2-; 1,1,2,2-r. At 500 mg/kg, 1,2-dichloro-
ethane caused an increase in OCT activity, however, no liver
damage was detected histologically. At 200 or 400 mg/kg,
1,1,2-trichloroethane stimulation of OCT activity was not
dose related but liver damage was observed histologically.
In this study, the remaining solvents (1,1-; 1,1,1-; 1,1,2,2-
dichloroethane) did not increase OCT activity nor cause
discernable hepatocellular damage.
Ingestion of 1,2-dichloroethane by man has often resulted
in death which was usually ascribed to circulatory and respir-
atory failure. Brief descriptions of several cases are
presented in Table 12. In addition to the signs and symptoms
listed in Table 12, a reduction in clotting factors and
C-28
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TABLE 12
Signs and Symptoms Following
1,2-Dichloroethane Ingestion
Author
Patient
Data
Amount
Consumed
Onset of
Symptoms
Progression of
Signs and Symptoms
Secchi,
•et al.
(1968)
Martin,
et al.
(1969)
Schonborn,
et al.
(1970)
Yodaiken
and
Babcock
(1973)
80-year-
old
50 ml
57-year-
old man
40 ml
18-year-
old man
50 ml
1 hour
14-year-
old boy
15 ml
2 hours
Elevated serum enzymes—
LDH, SCOT, SGPT, alkaline
phosphatase, glutamic de-
hydrogenase, RNAase; death
a few hours after inges-
tion.
Somnolence; vomiting;
sinus tachycardia ventri-
cular extrasystoles;
dyspnea; loss of blood
pressure; cardiac arrest;
death 24 hours after
ingestion.
Somnolent; cyanotic;
diarrhea; 5.5 hours later
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
6th day.
C-29
-------
platelet count were observed; 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 contrasted to the normal 12 seconds. Post
mortem examinations usually revealed thrombi in the pulmonary
arterioles and capillaries, 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 qualified clinically as toxic encepha-
lomyelopathy (Akimov, et al. 1978). One man who survived
acute poisoning suffered irreversible mental defects, acute
liver dystrophy, 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 Fostvedt,
1941). In a 1947 report, Rosenbaum reported that acute
poisonings developed rapidly with repeated exposure of workers
to concentrations of 75 to 125 ppm. 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).
C-30
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Summaries of the acute effects of human exposures to
1,2-dichloroethane 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 neurologic changes, loss of appetite and other gastroin-
testinal problems, irritation of mucous membranes, liver
and kidney impairment, and in some cases, death (Natl.
Inst. Occup. Safety Health, 1978a).
The anesthetic properties of 1,1,1-trichloroethane
have been demonstrated in rats (Torkelson, et al. 1958) ,
mice (Gehring, 1968), and dogs and monkeys (Krantz, et al.
1959) . Based on minimum 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 13).
TABLE 13
Effects of Trichloroethane
Isomers on Mice
Minimum Concentration for
Isomer
1,1,1-
1,1,2-
proneness
40
10
Response within 2 Hours
of Exposure (mg/1)
loss of reflexes
45
15
death
65
60
Source: Lazarew, 1929
C-31
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Adams, et al. (195.0) determined an LC50 for cats e'xposed
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 animals were dead in three hours (2.1 to
4.2 hours, 95 percent confidence 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
inhibitors) were administered orally to rats, mice, rabbits,
and guinea pigs for determination of an LD50 for each species
(Torkelson, et al. 1958). Single doses of undiluted solvent
were given by gavage (Table 14). 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 sensitized the heart to epinephrine-induced
ventricular extrasystoles.and ventricular tachycardia.
Cardiac sensitization, an increased susceptibility of the
heart to catecholamines, is induced by a number 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 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
C-32
-------
TABLE 14
LD50 After Oral Administration of
1,1,1-Trichloroethane in Laboratory Animals'
Characteristics of
1,1,1-Tr ichloroethane
Animal
Sex/Species
LD50 (g/kg)
Mean 95% Confidence
Limits
2.4-3.0% dioxane
0.12-0.3% butanol
Trace of 1,2-dichloro-
ethane
it
Uninhibited
Not further defined
35 male rats 12.3
35 female rats 10.3
16 female mice 11.2
16 female rabbits 5.7
16 male guinea pigs 9.5
40 male rats 14.3
50 female rats 11.0
40 female mice 9.7
40 female rabbits 10.5
30 male guinea pigs 8.6
11.0-13.7
8.3-12.8
3.5-9.4
3.5- .3
12.1-17.0
9.5-13.0
9.7-11.3
6.1-12.2
Administered undiluted by gavage
Source: Torkelson, et al. 1958
C-33
-------
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-
trichloroethane including the following: Herd, et al. (1974)
observed in dogs a dose-dependent two-phase drop in blood
pressure and decreased peripheral resistance following an
inhalation exposure; also in dogs, Reinhardt, et al. (1973)
found 27.8 mg/1 to be the minimal concentration causing
sensitization of the heart to epinephrine-induced arrhythmias;
Clark and Tinston (1973) reported the effective concentration
for sensitization to be 40.7 mg/1 in another group of dogs;
in mice, Aviado and Belej (1974) noted arrhythmias during
inhalation of 4.0 percent (v/v) 1,1,1-trichloroethane.
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
lowest concentration producing toxic effects was 73 ppm,
four hours per day from 50 to 120 days (Tsapko and Rappoport,
1972).
The effects most often reported following 1,1,1-tri-
cholorethane exposure of humans are central nervous system
disorders. These include changes in reaction time, perceptual
speed, manual dexterity, and equilibrium; however, cardio-
vascular effects have not been observed at the concentrations
C-34
-------
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, reaction times,
and manual dexterity were impaired in volunteers inhaling
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 responded with an abnorma]
modified 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 inhibited 1,1,1-trichloroethane as a general cleaning
solvent (Kramer, et al. 1976). Employees in the study popula-
tion had exposures to the solvent for six years or less
at varying concentrations measured by breathing zone sampling
and personal monitoring (eight hour time-weighted average,
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 findings which were associated
with exposure,to 1,1,1-trichloroethane.
LD50 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 (ED50) for kidney necrosis
was 0.17 ml/kg in mice and 0.4 ml/kg in dogs 24 hours after
receiving the compound. Forty-eight hours after receiving
an ED50 dose based on serum glutamic-pyruvic transaminase
C-35
-------
(SGPT) elevation (0.35 i
-------
Intravenous (i.v.) or intraperitoneal (i.p.) injection
in guinea pigs of 1,1,2,2-tetrachloroethane (total of 0.7
ml in five doses in 14 days) caused weight loss, convulsions,
death, and fatty degeneration of the liver and kidney (Muller,
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 in
corn oil on three alternate days.
Chronic exposures of rabbits by inhalation to 1,1,2,2-
tetrachloroethane (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 number of white blood cells,
pituitary adrenocorticotropic hormone, and the total fat
content of the liver (Deguchi, 1972).
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). In cases 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-tetrachloroethane (Wilcox,
et al. 1915).
C-37
-------
Acute testing in laboratory animal- indicated that
hexachloroethane was moderately toxic when administered
orally (Weeks, et al. 1979). The compound was dissolved
in corn oil (50 percent, weight to volume) or methylcellolose
(five percent, weight to volume) and administered by stomach
tube to male and female rats and male guinea pigs. Following
a 14-day observation period, the oral LD50 for male rats
was 5,160 mg/kg in corn oil and 7,690 mg/kg in methylcellulose;
in female rats, the oral LD50 was 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 degenera-
tion 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, 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 remainder
12 weeks later. Evaluation of animals exposed to 48 ppm
or 15 ppm revealed no adverse effects related to hexachloro-
ethane exposure (Weeks, et al. 1979).
C-38
-------
TABLE 15
o
Chemicals
monoch lor oe thane
1,1-dichloro-
ethane
1,2-dichloro-
ethane
1,1,1,-trichloro-
ethane
1, lf 2-tr ichloro-
ethane
1,1,1, 2-tetra-
chloroethane
1,1,2.2-tetra-
chloroethane
pen tach loco-
ethane
hexachloro-
ethane
Adverse Effects of Chloroethanes Reported in Animal Studies
Species
unspecified
cat
dog
rat
bacterium
cat
dog
fruit fly
guinea pig
monkey
rabbit
rat
cat
dog
guinea pig
mouse
monkey
cat
dog
guinea pig
rabbit
rat
bacterium
dog
guinea pig
monkey
mouse
rabbit
rat
cat
dog
sheep
cattle
mouse
rat
sheep
Adverse Effect
kidney damage; fatty changes in liver, kidney and heact
kidney damage
livec injucy
liver injury; retarded fetal development
mutagen
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 livery 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
neucomuscular 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; respicatocy failuce
liver and kidney injury
liver and kidney injury
embryotoxin
embryotoxin; liver dysfunction; mutagen
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;
altered immune system; altered blood chemistry; liver and kidney degeneration;
degeneration of liver and kidney; corneal reflex changes; liver enlacgement;
paralysis; death
blood cell changes; fatty degeneration of liver; liver dysfunction; death'
liver, kidney, and lung changes
fatty degeneration of liver; kidney and lung injury
liver dysfunction
liver and kidney damage
liver and kidney damage
liver and kidney damage
liver and kidney damage
death
fatty
Source: National Institute for Occupational Safety and Health, 1978c.
-------
TABLE 16
Summary of Human Toxicity, Chloroethanes
Chemical
System
Adverse Effect
monochloroethane
neurologic
gastrointestinal
respiratory
cardiovascular
decmatological
other
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
1,1-dichloroe thane
neurologic central nervous system depression
respiratory respiratory tract irritation
dermatolog ic skin burn
1,2-dichlor ethane
o
i
neurologic
hepatic
headache, dizziness, unconsciousness, vertigo, hand tremors, generalized
weakness, sleepiness, nervousness, mental confusion
liver function abnormalities, cellular damage, toxic chemical hepatitis,
jaundice, liver enlargement
l,l,l-trichloro-
ethane
neurologic
hepatic
gastrointestinal
cardiovascular
hematologic
dermatologic
other
central nervous system depression, headache, dizziness, incoordination,
feeling inebriated, unconsciousness; impaired perceptual speed, manual
dexterity and equilibrium; increased reaction time, lightheadeness,
drowsiness, sleepiness, generalized weakness, ringing sound in ears, un-
steady 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 changes
dryness, cracking, scaliness, inflammation
eye irritation, fatigue, death
eye
NIOS
1,1,2-trichloroethane
OSH is unaware of reports of adverse occupational exposure
1,1,1,2-tetrachloroethane
NIOSH is unaware of reports of adverse occupational exposure
-------
TABLE 16 (continued)
Chemical
1,1,2,2-tetrachloro-
System
neurologic
Adverse Effect
ethane
o
i
hepatic
gastrointestional
urologic
respiratory
cardiovascular
hematologic
dermatologic
other
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, inflamma-
tion of the peripheral nerves, slight paralysis of the soft palate, loss
of the gag reflex, irritability, mental confusion, delirium, convulsions,
stupor, coma
liver function abnormalitits, 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 blood cells, (and blood platelets)
dryness,cracking, scaliness, inflamation, purpuric rash
insomnia, general malaise, fatigue, excessive sweating, weight loss
aentachloroethane
NIOSH is unaware of reports of adverse occupational exposure
lexacnloroethane
neurologic
inability to close eyelid; eye irritation,tearing of eyes, inflammation
of delicate membrane lining the eye, visual intolerance to light,
(photophobia)
Source: National Institute for Occupational Safety and Health, 1978c.
-------
Laboratory animals (Table 15) and humans (Table 16)
exposed to chloroethanes show similar symptoms of toxicity
including eye and skin irritations, liver, kidney, and heart
degeneration, and central nervous system depression.
Based on data derived from animal studies, the relative
toxicity of chloroethanes is: 1,2-dichloroethane >1,1,2,2-
tetrachloroethane > 1,1,2-trichloroethane 7 hexachloroethane
J 1,1-dichloroethane > 1,1,1-trichloroethane > monochloroethane
Available data are not sufficient to judge the relative
toxicity of 1,1,1,2-tetrachloroethane 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 to produce an increased hepato-
toxic 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 administered after acetone or
isopropyl pretreatment, SGPT activity was significantly
increased. 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
sulfobromophthalein (BSP) retention, an indicator of liver
dysfunction (Kla*assen and Plaa, 1966). The chlorinated
hydrocarbon administered on day four (2.75 ml/kg, i.p.)
C-42
-------
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-trichloroethane hepatotoxicity as judged by SCOT activity.
Pretreatment of rats with phenobarbital (i.p.) did not alter
the effect of 1,1,1-trichloroethane 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 time following
the i.p. administration 24 hours post-exposure of hexobarbital,
meprobamate, or zoxazolamine. Inhibitors of protein synthesis
blocked the effect of 1,1,1-trichloroethane on hexobarbital-*
induced sleeping time (Puller, et al. 1970). The concept
that hepatic microsomal enzymes were induced was supported
•
by jln 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
studies with a mixture (by weight) of 1,1,1-trichloroethane
(75 percent) and tetrachloroethylene (25 percent) 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-
tetrachloroethane, 1,1,2,2-tetrachloroethane or pentachloro-
ethane.
Inhalation of 1,1-dichloroethane (3,800 or 6,000 ppm)
by pregnant rats seven hours per day on days 6 through 15
C-43
-------
of gestation had no effect on the incidence of fetal resorp-
tions, on fetal body measurements, or on the incidence of
gross or soft tissue anomalies. A significantly increased
incidence of delayed ossification of sternebrae was associated
with exposure to 6,000 ppm 1,1-dichloroethane which reflects
*
retarded fetal development rather than a teratological effect
(Schwetz, et al. 1974).
After a six-month exposure of female rats by inhalation
of 1,2-dichloroethane (57 mg/m , four hours/day, six days/week),
animals were bred and exposed throughout gestation. Litter
size, the number of live births, and fetal weights were
reduced (Table 17). Tissue and skeletal anomalies were
not reported (Vozovaya, 1974).
TABLE 17
Effect of 1,2-Dichloroethane
on Fetal Rat Development
Treatment Litter PercentFetal
Size Live Weight(g)
Fetuses
Filtered Air 9.7 94.9 6.44
l,2-dichloroethanea 6.5 76.9 5.06
a57 mg/m , 4 hrs/day, 6 days/week, throughout gestation
Source: Vozovaya, 1974
Twenty-three pregnant Sprague-Dawley rats and 13 Swiss-
Webster mice inhaled 875 ppm 1,1,1-trichloroethane seven
hours a day, from days 6 through 15 of gestation. There
was no effect on the average number of implantation sites
per litter, litter size, the incidence of fetal resorptions,
sex ratios, or fetal body measurements among mice
C-44
-------
or rats (Dunnett test p< 0.05). Soft tissue 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 adminis-
tered 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 mono -; 1,1-di -; 1,1,1-tri -; 1,1,2-
tri -; 1,1,1,2-tetra -; or penta - chloroethane.
1,2-Dichloroethane and 1,1,2,2-tetrachloroethane were
moderately mutagenic in the Ames Salmonella assay for strains
TA 1530 and TA 1535, and for the £_._ coli DNA polymerase-
deficient system (Brem, et al. 1974). Rosenkranz (1977)
determined the order of mutagenic activity toward S. typhimurium
and £_._ coli to be 1,1,2,2-tetrachloroethane > 1,2-dichloro-
ethane. Mutagenicity of 1,2-dichloroethane was not dependent
on NADPH (Rannug and Ramel, 1977) or microsomes (Rannug,
et al. 1978) but metabolic activation was accomplished by
a factor in the soluble fraction (115,000 x g supernatant).
G-45
-------
A conjugation product, S-chloroethyl cysteine, proved to
be more mutagenic than the parent compound (Rannug, et al.
197o).
Metabolites of 1,2-dichloroethane varied in their muta-
genic activity for Salmonella strains: 2-chloroacetaldehyde
was mutagenic for strain TA100 (McCann, et al. 1975) and
strains TA1530 and TA1535 (Rannug, et al. 1978); 2-chloro-
ethanol was less mutagenic and 2-chloroacetic acid was inactive
(McCann, et al. 1975).
1,2-Dichloroethane induced highly significant increases
in somatic mutation frequencies in Drosophila melanogaster
(Nylander, et al. 1978). Morphological and chlorophyll
mutations in eight varieties of peas were induced by treatment
of seeds with 1,2-dichloroethane (Kirichek, 1974).
Hexachloroethane was not mutagenic for five strains
of Salmonella or yeast (Saccharomyces cerevisiae D4) in
the absence or presence of induced rat liver S-9 preparations
(Weeks, et al. 1979).
Carcinogenicity
1,2-Dichloroethane: A bioassay of 1,2-dichloroethane
for carcinogenic potential was conducted by the National
Cancer Institute (1978a). Technical grade 1,2-dichloro-
ethane (impurities less than ten percent) 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 treatments
for 35 weeks; from week 36 through week 78, periods of one
week of no treatment were alternated with periods of four
C-46
-------
weeks of treatment. 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;
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 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 (Natl. Cancer Inst., 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 animals. Untreated controls were not intubated.
Treatment of rats and mice with 1,2-dichloroethane
induced a number of benign and malignant neoplasms (Table 18).
The incidences of squamous cell carcinomas of the fore-
stomach, subcutaneous fibromas, and hemangiosarcoma in male
rats and the incidence of mammary adenocarcinomas in female
rats -were significantly correlated with increased doses
of 1,2-dichloroethane according to the Fisher exact test
and the Cochran-Armitage test (Table 19).
C-47
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TABLE 18
Summary of Incidence of Neoplasms in Rats and Mice
Ingesting 1,2-Dichloroethane for 78 Weeks
Total Number of Animals
Species Sex Dose with Tumors
Benign Malignant Metastases
Rat 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
Compound administered in corn oil by stomach tube
five days/week. Concentration is a time-weighted average
expressed in mg/kg/day.
bTwo control groups: 20 animals per group.
Experimental groups: 50 animals at each dosage level.
Source: National Cancer .Institute, 1978a.
C-48
-------
TABLE 19
Percent3 of Rats with 1,2-Dichloroethane Induced Neoplasms
Tumor Type Malec Female0
Low dose High dose6 Low dose High dose6
Squamous-cell carcinoma:
stomach
Hemang iosarcoma :
all sites
Fibroma:
6
22
10
18
16
12
subcutaneous
Adenocarcinoma: — — 2 36
mammary gland
aPercent: animals with tumors/animals examined x 100
Includes only neoplasms that were statistically correlated with
1,2-dichloroethane treatment
Experimental groups: 50 animals at each dosage level
Two control groups: 20 animals per group-receiving corn oil
or no treatment
The low time-weighted average dose: 47 mg/kg/day
6The high time-weighted average dose: 95 mg/kg/day
Source: National Cancer Institute, 1978a.
C-49
-------
In male and female mice treated with 1,2-dichloroethane,
the incidence of alveolar/bronchiolar adenomas was statis-
tically significant. The incidence of mammary adenocarcinomas
and of endometrial tumors in female mice and the incidence
of hepatocellular carcinomas in male mice were statistically
positively correlated with treatment (Table 20; Natl. Cancer
Inst., 1978a).
1,1,1-Trichloroethane: The National Cancer Institute
(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 species
(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 (Natl. Cancer Inst., 1977).
Control groups consisted of 20 animals of each sex
and species. Carbon tetrachloride was administered as the
positive control.
C-50
-------
TABLE 20
Percent3 of Mice with 1,2-Dichloroethane Induced Neoplasms
Tumor Type Male0 Female0
Low dose High dose6 Low dose High doseg
Alveolar /bronchiolar-
adenoma
Endometrial sarcoma
2
__
31 14
4
31
6
Hepatocellular carcinoma 13 25
aPercent: animals with tumors/animals examineu x 100
Includes only neoplasms that were statistically correlated
with 1,2-dichloroethane treatment
Experimental g-roups: 50 animals at each dosage level
Two control groups: 20 animals per group-receiving corn oil
or no treatment
The low time-weighted average dose: 97 mg/kg/day
eThe high time-weighted average dose: 195 mg/kg/day
The low time-weighted average dose: 149 mg/kg/day
high time-weighted average dose: 299 mg/kg/day
Source: National Cancer Institute, 1978a.
C-51
-------
There was a moderate depression of body weight in male
and female rats and mice throughout the study. Male and
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 significantly decreased; in female
mice there was a dose-related trend in the numbers surviving
(P=0.002). Fewer rats receiving 1,1,1-trichloroethane sur-
vived at both 78 and 110 weeks than did positive control
rats receiving carbon tetrachloride, a known carcinogen
(Table 21). 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 22), 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-trichloroethane carcino-
genicity impossible (Natl. Cancer Inst., 1977). The National
Cancer Institute is currently retesting the compound.
Price, et al. (1978) demonstrated the ir± vitro transform-
ing 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 (characterized by morphology and forma-
tion of macroscopic foci in semi-soft agar) were inoculated
into newborn Fischer rats. By 68 days, the transformed
C-52
-------
TABLE 21
Comparison of Survival of Control Groups,
1,1,1-Trichloroethane-Treated and
Carbon Tetrachloride-Treated (Positive Control) Rats
1, 1 ,1-Tr ich lor oe thane
Group
MALE
Control
Low Dose
High Dose
Initital
No. of
Animals
20
50
50
Number
Alive at
78 weeks
7
1
4
Number
Alive at
110 weeks
0
0
0
Carbon Tetrachlor ide
Initial
No. of
Animals
20
50
50
Number
Alive at
78 weeks
20
34
35
Number
Alive at
110 weeks
12
15
8
FEMALE
Control
Low Dose
High Dose
20
50
50
14
9
12
3
2
1
20
50
50
18
38
21
14
20
14
Source: National Cancer Institute, 1977.
C-53
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TABLE 22
Summary of Neok . -ns in Rats and Mice Ingesting
1,1,1-Trichloroethane for 78 Weeks
Number of
Species Sex Animals
Rat Male 20
50
50
Female 20
50
n
' 50
Ul JU
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
Compound administered in corn oil by stomach tube five days per/week.
Concentration is a time-weighted average expressed in mg/kg/day.
Source: National Cancer Institute, 1977.
-------
cells had grown as undifferentiated fibrosarcomas at the
inoculation sites in all tested animals. Acetone, the negative
control, did not induce tumors by 82 days after inoculation
(Price, et al. 1978).
1,1,2-Trichloroethane: A bioassay of 1,1',2-trichloroetha'ne
for possible carcinogenicity was conducted by the Natl.
Cancer Inst. (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 animals of each test species
(Osborne-Mendel rats and B6C3F1 mice) at two dosage levels,
five days/week for 78 weeks. During the experiment, 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 mg/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
nig/kg/day. The high time-weighted average dose was 390
mg/kg/day; the low 195 mg/kg/day. After 78 weeks of treatment,
rats were observed an additional 35 weeks; mice observed
for an additional 13 weeks (Natl. Cancer Inst., 1978b).
Control groups consisted of 20 animals of each sex
and species. 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 neoplasms observed in treated, but not
control rats. Because a statistically significant difference
could not be found between the test group and the controls,
C-55
-------
carcinogenic!ty of 1,1,2-trichloroethane in Osborne-Mendel
rats cannot be inferred (Table 23; Natl. Cancer Inst., 1978b).
On the other hand, treatment of mice with 1,1,2-trichloro-
ethane was correlated with an increased incidence of hepato-
cellular carcinoma (Table 24). 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 0.001).
The Cochran-Armitage test also showed a significant dose-
related association between 1,1,2-trichloroethane 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 (Natl. Cancer Inst., 1978b).
1,1,2,2-Tetrachloroethane: Technical grade 1,1,2,2-
tetrachloroethane (90 percent pure) in corn oil was adminis-
tered 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 increased to 130 mg/kg/day and 65 mg/kg/day.
The high time-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
C-56
-------
o
ui
-j
TABLE 23
Summary of Incidence of Neoplasms in Rats and Mice Ingesting
1,1,2-Trichloroethane for 78 Weeks
Species
Ratb
Mouse
Sex Dose3
Male Untreated
Corn Oil
46
92
Female Untreated
Corn Oil
46
92
Male Untreated
Corn Oil
195
390
Female Untreated
Corn Oil
195
390
Total
Benign
1
3
11
4
9
4
29
15
2
1
6
9
1
-
4
16
Number of Animals
with Tumors
Malignant Metastases
3
5
12
8
3
-
6
9
3
5
27
38
3
4
18
40
1
—
1
—
_
-
-
2
-
-
3
—
-
-
3
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 dosage level.
Source: National Cancer Institute, 1978b.
-------
TABLE 24
Incidence of Hepatocellulac Carcinoma In Mice Ingesting
1/1,2-Trichloroethane for 78 weeks
Sex
Maleb
Female
Dosea
Untreated
Corn Oil
195
390
Untreated
Corn Oil
195
390
Number of
Animals Examined
17
20
49
49
20
20
48
45
Hepatocellular
No. of Animals
2
2
18
37
2
0 _.
16
40
Carcinoma
Percent
12
10
37
76
10
— —
33
89
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 dosage level.
Source: National Cancer Institute, 1978b.
C-58
-------
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 an additional 12 weeks (Natl. Cancer Inst.,
1978c).
Control groups consisted of 20 animals of each sex
and species. Vehicle controls were treated wit^ 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 39). Although one neoplastic nodule and two
hepatocellular 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 signifi-
cant (Table 25; Natl. Cancer Inst., 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 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
C-59
-------
TABLE 25
Incidence of Hepatocellular Carcinoma in Mice
Ingesting 1,1,2,2-Tetrachloroethane for 78 Weeks
Sex
Male0
Female0
Dose
Untreated
Corn Oil
142
282
Untreated
Corn Oil
142
282
Number of
Animals Examined
16
18
50
49
18
20
48
47
Hepatocellular
Carcinoma
Number Percent
2
1
13
44
0
0
30
43
13
6
26
90
—
63
91
alncidence of hepatocellular carcinoma indicated a highly
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.
Source: National Cancer Institute, 1978c.
C-60
-------
TABLE 26
Summary of Incidence of Neoplasms in Rats and Mice Ingesting
1,1,2,2-Tetrachloroethane for 78 Weeks
Species
Ratb
Mouse
Sex Dosea
Male Untreated
Corn Oil
62
108
Female Untreated
Corn Oil
43
76
Male Untreated
Corn Oil
142
282
Female Untreated
Corn Oil
142
282
Total Number
Benign
2
9
11
13
12
11
24
21
2
3
3
3
1
-
2
2
of Animals
Malignant
6
6
7
9
6
1
7
5
9
1
17
45
1
1
33
43
with Tumors
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.
Source: National Cancer Institute, 1978c.
C-61
-------
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 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 570 mg/kg/day (Natl. Cancer Inst., 1978d). After 78
weeks of treatment, rats were observed for an additional
33 or 34 weeks, mice an additional 12 or 13 weeks.
Control groups consisted of 20 animals of 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 treated animals: in rats, 18 to 66 percent, and in mice,
C ' 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 (Natl. Cancer Inst., 1978d).
In mice of both sexes, the incidence of hepatocellular
carcinoma was positively correlated (P< 0.001) with hexachloro-
ethane treatment (Table 27). There was no evidence of hexa-
chloroethane induced neoplasms in rats of either sex (Table
28; Natl. Cancer Inst., 1978d).
A summary of the results of the NCI bioassays of chloro-
ethanes is presented in Table 29.
C-62
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TABLE 27
Incidence of Hepatocellulac Carcinoma in Mice
Ingesting Hexachlocoethane for 78 Weeks
Sex
Maleb
Female
Dosea
Untreated
Corn Oil
590
1179
Untreated
Corn Oil
590
1179
Number of
Animals Examined
18
20
50
49
18
20
50
49
Hepatocellular
No. of Animals
1
3
15
31
0
2
20
15
Carcinoma
Percent
6
15
30
63
0
10
40
31
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 dosage level.
Source: National Cancer Institute, 1978d.
C-63
-------
TABLE 28
Summary of Incidence of Neoplasms in Rats and Mice3
Ingesting Hexachlocoethane for 78 Weeks
Total Number of Animals with Tumors
Species Sex Dose BenignMalignantMetastases
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
^m
1
2
-
1
1
1
1
1
-
1
-
1
-
1
~
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.
Source: National Cancer Institute, 1978d.
C-64
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An estimated five million workers are potentially exposed
to one or more chloroethanes (Natl. Inst. Occup. Safety
Health, 1978c). To date, no epidemiological relationship
has been found between chloroethane exposure and human cancer.
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CRITERION FORMULATION
Existing Guidelines and Standards
OSHA standards and NIOSH recommended standards are
based on exposure by inhalation (Table 30). Based on informa-
tion available in 1976b, the National Institute for Occupa-
tional Safety and Health recommended that occupational expo-
sures to 1,2-dichloroethane 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 exposure standard is
50 ppm, time-weighted average for up to a 10-ho_r work day,
40-hour work week. NIOSH (1976b) issued criteria 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 concentrations below the proposed
limit.
Current Levels of Exposure
Estimates of human exposure to chloroethanes via inges-
tion 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-dichloroethane or 1,1,1-trichloroethane
(Table 31).
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TABLE 30
Chloroethane Exposure Standards
Chemical
monochloroe thane
1,1-dichloroethane
1, 2-dichloroethane
1 , 1 , 1- tr ichloroe thane
1 , 1 , 2- tr ichloroe thane
1,1,1,2-tetrachloroethane
1,1,2, 2-tetrachloroethane
pen tachloroe thane
hexachloroethane
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
*
*
*NIOSH has tentative plans for a Criteria Document for
a Recommended Standard for this substance
Source: National Institute for Occupational Safety and
Health, 1978c.
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TABLE 31
Chloroethane Exposures and Production
Chemical
Estimated number
of workers exposed
Annual
Production quantities
(pounds)
monochloroethane
1,1-dichloroethane
1,2-dichloroethane
1,1,1-tr ichloroethane
1,1,2-trichloroethane
1,1,1,2-tetrachloroethane
1,1,2,2-tetrachloroethane
pentachloroethane
hexachloroethane
113,000
4,600
1,900,000
2,900,000
112,000
a
11,000
a
1,500
670 million (1976)
b
8 billion (1976)
630 million (1976)
c
b
c
b
b,d
NIOSH estimates not available
3Does not appear to be commercially produced in the United States
'Direct production information not available
3730,000 kg were imported in 1976
Source: National Institute for Occupational Safety and Health, 1978c.
In the general population there are chronic exposures
to variable amounts in air and finished water. Chloroethanes
are present in many commercial products, and exposure of
the population depends on the tendency of individuals to
read and heed instructions.
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Special Groups at Risk
Workers who are occupationally exposed to chloroethanes
by inhalation and/or dermal absorption represent a special
group at risk (Table 31). 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 (Natl. Cancer
Inst., 1978a,b,c,d). Those individuals who are exposed
to known hepatotoxins or have liver disease may constitute
a group at risk.
Basis and Derivation of Criterion
TABLE 32
Criteria for Chloroethanes
Compound
Criterion
Reference
Monochloroethane
1,1-Dichloroethane
1,2-Dichloroethane
1,1,1-Tr ichloroethane
1,1,2-Trichloroethane
1,1,1,2-Tetrachloroethane
1,1,2,2-Tetrachloroethane
Pentachloroethane
Hexachloroethane
None
None
7.0 ;ag/l - Carcinogenicity
data
15.7 mg/1 - mammalian
toxicity data
2.7 jug/1 - Carcinogenicity
data
None
1.8 jug/1 - Carcinogenicity
data
None
5.9jug/l - Carcinogenicity
' data
NCI, 1978a
NCI, 1977
NCI, 1978b
NCI, 1978c
NCI, 1978d
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At the present time, there is insufficient mammalian
toxicological information to establish a water criterion
for human health for the following chloroethanes: monochloro-
ethane, 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-tetrachloroethane and pentachloro-
ethane. 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 conduct'
more extensive toxicologic studies with these chloroethanes.
The criterion for 1,1,1-trichloroethane is based on
the National Cancer Institute bioassay for possible carcino-
genicity (1977). Results of the study showed that the survi-
val of both Osborne-Mendel rats and B6C3F1 mice was signifi-
cantly decreased in groups receiving oral doses of 1,1,1-
trichloroethane. Chronic murine pneumonia may have been
responsible for the high incidence of natural deaths. A
variety of neoplasms was observed in both species, however,
the incidence of specific malignancies was not significantly
different from those observed in control animals. Survival
time was significantly decreased in rats receiving the high
dose, therefore, the criterion for 1,1,1-trichloroethane 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-observ-
able-adverse-effect level (NOAEL) will be lower. 'However,
C-71
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use of the lowest-minimal-effect dose as an estimate
of an "acceptable daily intake" has been practiced by the
National Academy of Sciences (1977). Thus, assuming a 70
kg body weight and using a safety factor of 1,000 (Natl.
Acad. Sci., 1977) the following calculation can be derived:
750 mg/kg x 70^ x 5/7 day = 3?>5 mg/day
Therefore, consumption of 2 liters of water daily and 18.7
grams of contaminated fish having a bioconcentration factor
of 21, would result in, assuming 100 percent gastrointestinal
absorption of 1,1,1-trichloroethane, a maximum permissible
concentration of 15.7 mg/1 for ingested water:
37.5 mg/day _ ,,. - ..
2 liters + (21 x .ulav) x i.o my/J-
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 (Natl. Cancer Inst., 1978b,c,d).
In the case of these three chloroethanes, a statistical
evaluation of the incidences of hepatocellular 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 hexachloro-
ethane are carcinogenic in B6C3F1 mice, inducing (in all
cases) hepatocellular carcinomas in either male or female
mice.
Estimated risk levels for these chloroethanes in water
can be calculated using a linear, non-threshold model with
the results from the NCI bioassays (see Appendix 1 for detail-
ed assumptions and calculations). The model assumes a risk
C-72
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of 1 in 100,000 of developing cancer as a result of drinking
2 liters of water per day containing chloroethane at the
concentrations used in the bioassays. Allowances are also
made for consuming fish from chloroethane contaminated waters.
Based upon these assumptions, the following criteria can
be calculated:
Chloroethane Dosea Criteria
(mg7T
-------
trations of a chemical. Those who assess risk should be
aware of the following: impurities in technical grade chloro-
ethanes were not identified; chloroethanes were administered
in oil which may affect absorption and metabolism; high
concentrations were used; a time-weighted average dose was
reported; however, doses causing toxic responses were often
administered cyclically (one week, no treatment, followed
by four weeks of treatment, five days/week); during some
experiments dose levels were lowered or raised; for criteria
calculations, doses administered five days/week were adjusted
to an average daily dose as if administered seven days/week.
Under the Consent Decree in NRDC vs. 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-Dichloroethane, 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 concentrations 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
C-74
-------
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
ambient water quality criteria, EPA stated that it is con-
sidering setting criteria at an interim target risk level
of 10" , 10 or 10 as shown in the table below.
Exposure Assumptions Risk Levels and Corresponding Criteria
£ ICf7 1£~6 10_~5
2 liters of drinking water
and consumption of 18.7
grams of fish and shellfish (2)
1,2-dichloroethane 0 0.07 jug/1 0.07 ug/1 7.0 /ig/1
1,1,2-trichloroethane 0 0.027 pg/1 0.27 jag/1 2.7 jug/1
1,1,2,2-tetrachloroethane 0 0.018 jug/1 0.18 ;ug/l 1-8 ;ug/l
hexachloroethane 0 0.059 jjg/1 0.59 ug/1 5.9 >ag/l
Consumption of fish
and shellfish only.
1,2-dichloroethane 0 1.708 ;ug/l 17.08 jug/1 170.8 >ag/l
1,1,2-trichloroethane 0 0.483 pg/1 4.83 ;ug/l 48.3 ;ug/l
1,1,2,2-tetrachloroethane 0 0.127 jug/1 1.27 jag/1 12.7 >ig/l
hexachloroethane 0 0.079 ;ug/l 0.79 jug/1 7.9 >ag/l
(1) Calculated by applying a modified "one hit" extrapolation
model described in the FR 15926, 1979. Appropriate bioassay
data used in the calculation of the model are presented
C-75
-------
in Appendix I. Since the extrapolation model is linear
to 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
' y multiplying or dividing one of the risk levels and corres-
ponding water concentrations shown in the table by factors
such as 10, 100, 1,000, and so forth.
(2) Four percent of 1,2-dichloroethane exposure results
from the consumption of aquatic organisms which exhibit
an average bioconcentration potential of 4.6 fold. The
remaining 96 percent of 1,2-dichloroethane exposure results
from drinking water.
Six percent of 1,1,2-trichloroethane exposure results
from the consumption of aquatic organisms which exhibit
an average bioconcentration potential of 6.3 fold. The
-?maining 94 percent of 1,1,2-trichloroethane exposure results
from drinking water.
Fourteen percent of 1,1,2,2-tetrachloroethane exposure
results from the consumption of aquatic organisms which
exhibit an average bioconcentration potential of 18 fold.
The remaining 86 percent of 1,1,2,2-tetrachloroethane exposure
results from drinking water.
Seventy-five percent of hexachloroethane exposure results
from the consumption of aquatic organisms which exhibit
an average bioconcentration potential of 320 fold. The
remaining 25 percent of hexachloroethane exposure results
from drinking water.
C-76
-------
Concentration levels were derived assuming a lifetime
exposure to various amounts of these chlorinated ethanes
(1) occurring from the consumption of both drinking water
and aquatic life grown in water containing the corresponding
chlorinated ethane concentrations and, (2) occurring solely
from the consumption of aquatic life grown in the waters
containing the corresponding chlorinated ethane concentrations.
Although total exposure information for the above chlorinated
ethanes is discussed and an estimate of the contributions
from other sources of exposure can be made, this data will
not be factored into the ambient water quality Criteria
formulation because of the tenuous estimates. The criteria
presented, therefore, assume an incremental risk from ambient
water exposure only.
C-77
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REFERENCES
Adams, E.M., et al. 1950. Vapor toxicity of 1,1,1-trichloro-
ethane (methyl chloroform) determined by experiments on
laboratory animals. Arch. Ind. Hyg. Occup. Med. 1: 225.
Akimov, G.A., et al. 1978. Neurologic disorders in acute
dichloroethane poisoning. Zh. Nevropatol. Psikhiatr. 78: 687.
American Industrial Hygiene Association. 1956. 1,2-Dichloro-
ethane (ethylene dichloride). Hyg. Guide Ser. Am. Ind.
Hyg. Assoc. Jour. 17: 447.
American Industrial Hygiene Association. 1963. Ethyl chloride.
•
Am. Ind. Hyg. Assoc. Jour. 14: 531.
Aviado, D.M., and M.A. Belej. 1974. Toxicity of aerosol
propellants on the respiratory and circulatory systems.
I. Cardiac arrhythmia in the mouse. Toxicology 2: 31.
Aviado, D.M., et al. 1976. Methyl chloroform and trichloro-
ethylene in the environment. CRC Press, Cleveland, Ohio.
Belej, M.A., et al. 1974. Toxicity of aerosol propellants
in the respiratory and circulatory systems—IV. Cardiotoxicity
in the monkey. Toxicology 2: 381.
C-78
-------
Bellar, T.A., et al. 1974a. Occurence of organohalides in
chlorinated drinking waters. Jour. Am. Water Works Assoc.
66(12), 703: 6.
Bellar, T.A., et al. 1974b. Occurrency of organohalides
in chlorinated drinking waters. EPA-670/4-74-008. Off.
Res. Dev. U.S. Environ. Prot. Agency.
Berck, B. 1974. Fumigant residues of carbon tetrachloride,
ethylene dichloride, and ethylene dibromide in wheat, flour,
bran, middlings, and bread. Jour. Agric. Food Chem. 22,
977: 84.
Bonitenko, Y.Y., et al. 1977. Acute dichloroethane poisoning
and an intensive treatment procedure. Voen.-Med. Zh. (11),
75:7
Brass, H.J., et al. 1977. The National Organic Monitoring
Survey: samplings and analyses for purgeable organic compounds.
Drinking Water Qual. Enhancement Source Prot. 393: 416.
Brem H., et al. 1974. The mutagenicity and DNA-Modifying*
effect of haloalkanes. Cancer Res. 34: 2576.
Brown, S.L., et al. 1975. Research program on hazard priority
ranking of manufactured chemicals (chemicals 21-40). Stanford
Res. Inst. Prepared for the Natl. Sci. Foundation, Washington,
D.C.
C-79
-------
Browning, E. 1965. Toxicity and metabolism of industrial
solvents. Elsevier Publishing Co., Amsterdam.
Byers, D.H. 1943. Chlorinated solvents-in common wartime
use. Ind. Med. 12: 440.
Cavallaro, A., and P. Grassi. 1976. Determination of chlorin-
ated hydrocarbons in potable waters. Boll. Chim. Unione
Ital. Lab. Prov. 12: 337.
Clark, D.G., and D.J. Tinston. 1973. Correlation of the
cardiac sensitizing potential of halogenated hydrocarbons
with their physicochemical properties. Br. Jour. Pharmacol.
49: 355.
*
Coleman, W.E., et al.. 1976. The occurrency of volatile organics
in five drinking water supplies using gas chromatography/mass
spectrometry. Identif. Anal. Organ. Pollut. Water Chem.
Congr. North Am. Cont., 1st 1975 305-27.
Conkle, J.P., et al. 1975. Trace composition of human respira-
tory gas. Arch. Environ. Health 30: 290.
Cordle, F., et al. 1978. Human exposure to polychlorinated
biphenyl.s and polybrominated biphenyls. Environ. Health
Perspect. 24: 157.
C-80
-------
Cornish, H.H., et al. 1973. Phenobarbital and organic solvent
toxicity. Am. Ind. Hyg. Assoc. Jour. 34: 487.
Deetman, A.A., et al. 1976. Standardization of methods for
the determination of traces of some volatile chlorinated
aliphatic hydrocarbons in air and water by gas chromatography.
Anal. Chim. Acta. 82: 1.
Deguchi, T. 1972. A fundamental study of the threshold limit
values for solvent mixtures in the air—Effects of single
and mixed chlorinated hydrocarbons upon the level of serum
transaminases in rats. Osaka City Med. Jour. 21: 187 (Jap).
Dickson, A.G., and J.P. Riley. 1976. The distribution of
short-chain halogenated aliphatic hydrocarbons in some marine
organisms. Mar. Pollut. Bull. 79: 167.
Dietz, P., and J. Iraud. 1973. Gas chromatographic determina-
tion of low-molecular-weight chlorohydrocarbons in water
samples and sediments. Vom Wasser. 41: 137.
Divincenzo, G.D., and W. Krasavage. 1974. Serum ornithine
carbamyl transferase as a liver response test for exposure
to organic solvents. Am. Ind. Hyg. Assoc. Jour. 35: 21.
Doering, H.J. 1975. Reversible and irreversible forms of
contractile failure caused by disturbances by general anesthe-
tics in myocardial ATP utilization. Recent Adv. Stud. Car.
Struct. Metab. 5.: 395.
C-81
-------
Dorndorf, W., et al. 1976. Dichloroethane poisoning with
myocloi.ic syndrome, seizures and irreversible cerebral defects.
Arch. Psychiatr. Nervenkr. 220:373.
Dow Chemical Co. 1969. Dowclene WR—the space age solvent.
Midland, Mich.
Dow Chemical Co. 1973. Chorothene NU solvent—the one with
a thousand and one uses. Midland, Mich.
Dowty, B., et al. 1975a. Halogenated hydrocarbons in New
Orleans drinking water and blood plasma. Science 187: 75.
Dowty, B.J., et al. 1975b. New Orleans drinking water sources
tested by gas chromatography-mass spectrometry. Occurrence
and origin of aromatics and halogenated aliphatic hydrocarbons.
Environ. Sci. Technol. 9: 762.
Elliott, J.M. 1933. Report of a fatal case of poisoning
by tetrachloroethane. Jour. Array Med. Corps. 60: 373.
Forbes, G. 1943. Tetrachloroethane poisoning. Br. Med.
Jour. 1: 348.
Fujii, T. 1977. Direct aqueous injection gas chromatography-
mass spectrometry for analysis of organohalides in water
at concentrations below the parts per billion level. Jour.
Chromatogr. 139: 297.
C-82
-------
Fuller, G.C., et al. 1970. Induction of hepatic drug metabolism
in rats by methylchloroform inhalation. Jour. Pharmacol.
Ther. 175: 311.
Gamberale, F., and M. Hultengren. 1973. Methylchloroform
exposure. II. Psychophysiological functions. Work Environ.
Health 10: 82.
Gandolfi, A.J., and R.A. Van Dyke. 1973. Dechlorination
of chloroethane with a reconstituted liver microsomal system.
Biochem. Biophys. Res. Commun. 53: 687.
Gehring, P.J. 1968. Hepatotoxic potency of various chlorinated
hydrocarbon vapours relative to their narcotic and lethal
potencies in mice. Toxicol. Appl. Pharmacol. 13: 287.
Gilles, D. 1976. Health hazard evaluation/toxicity determina-
tion. Rep. 75-147-318. Westinghouse Electric Corp. East
Pittsburgh, Pa. PB Rep. PB-264802. Natl. Tech. Inf. Serv.,
Springfield, Va.
Gilles, D. 1977. Health hazard evaluation/toxicity determina-
tion. Rep. 77-5-362. Matryx Co., a division of Xomox Corp.
Cincinnati, Ohio. PB Rep. PB-273912. Natl. Tech. Inf. Serv.
Springfield, Va.
C-83
-------
GlUes, D., and E. Philbin. 1976. Health hazard evaluation
determination. Rep. 76-61-337. TRW Inc. Philadelphia, Pa.
PB Rep. PB-273739. Natl. Tech. Inf. Serv., Springfield,
Va.
Gilles, D., and R.A. Rostand. 1975. Health hazard evaluation/
toxicity determination. Rep. H.H.E. 75-26-245. Babcock and
Wilcox Co. Canton, Ohio. PB Rep. PB-249425. Natl. Tech.
Info. Serv., Springfield, Va.
Glaze, W.H., et al. 1976. Analysis of new chlorinated organic
compounds in municipal wastewaters after terminal chlorination,
Page 247 _i£ H.L. Keith, ed. Identification and analysis
of organic-pollutants in water, Ann Arbor Science, Ann Arbor,
Mich.
Goodman, L.S., and A. Gilman, eds. 1975. The pharmacological
basis of therapeutics. 3rd ed. Macmillan, New York.
Gough, T.A., et al. 1978. Response of a hydrogen-rich flame
ionisation detector to some chlorinated hydrocarbons. Jour.
Chromatogr. 150: 533.
Griffiths, W.C., et al. 1972. Rapid identification of and
assessment of damage by inhaled volatile substances in the
clinical laboratory. Clin. Biochem. 5: 222.
C-84
-------
Gunter, B.J., and A. Bodner. 1974. Health hazard evaluation
toxicity determination. Rep. 73-180/183-159. Docutel Corp.
Irving, Tex. PB Rep. PB-246470. Natl. Tech. Inf. Serv.,
Springfield, Va.
Gunter, B.J., et al. 1977. Health hazard evaluation determina-
tion. Rep. 76-99-397. Redfield Co. Denver, Colo. PB Rep.
PB-273746. Natl. Tech. Inf. Serv., Springfield, Va.
Hake, C.L., et al. 1960. The metabolism of 1,1,1-trichloro-
ethane by the rat. Arch. Environ. Health 1: 101.
Harris, R.H., and S.S. Epstein. 1976. Drinking water and
cancer mortality in Louisiana. Science 193: 55.
Heppel, L.A., et al. 1946. The toxicology of 1,2-dichloroethane
(ethylene dichloroethane) V. The effects of daily inhalations.
Jour. Ind. Hyg. Toxicol. 28: 113.
Hepple, R.A. 1927. An unusual case of poisoning. Jour.
Army Med. Corps. 49: 442.
Herd, P.A., et al. 1974. Cardiovascular effect of 1,1,1-
trichoroethane. Arch. Environ. Health 28: 227.
Hofmann, H.T., et al. 1971. On the inhalation toxicity of
1,1-and 1,2-dichloroethane. Arch. Toxicol. 27: 248 (Ger).
C-85
-------
Holmberg, B., et al. 1977. A study of the distribution of
methylchloroform and n-octane in the mouse during and after
inhalation. Scand. Jour. Work Environ. Health 3: 43.
Horiguchi, K., et al. 1962. Studies on the industrial tetra-
chloroethane poisoning (2). Osaka City Med. Jour. 8: 29.
Horiguchi, S., and K. Horiguchi. 1971. An experiement of
1,1,1-trichloroethane vapor exposure to mice—Supplementary
report on the toxicity of 1,1,1-trichloroethane I. Jap.
Jour. Ind. Health 13: 226.
Ikeda, M., and H. Ohtsuji. 1972. Comparative study of the
excretion of Fujiwara reaction-positive substances in urine
of humans and rodents given trichloro- or tetrachloro-deriva-
tives of ethane and ethylene. Br. Jour. Ind. Med. 29: 99.
Ivanetich, K.M., et al. 1978. Organic compounds: Their inter-
action with and degradation of hepatic microsomal drug-metabo-
lizing enzymes in vitro. Drug Metabol. Deposition 6: 218.
Jakobson, I., et al. 1977. Variations in the blood concentra-
tion of 1,1,2-trichloroethane by percutaneous absorption
and other routes of administration in the guinea pig. Acta.
Pharmacol. Toxicol. 41: 497.
Keith, L.H. 1972. Chemical characterization of industrial
effluents. Am. Chem. Soc. Div. Water Air Waste Chem. Gen.
Pap. 12: 113.
C-86
-------
Keith, L.H., et al. 1976. Identification of organic compounds
in drinking water from thirteen U.S. Cities. Identif. Anal.
Organ. Pollut. Water, Chem. Congr. North Am. Cont., 1st
1975 329-73.
Kiricheck, Y.F. 1974. Effect 1,2-dichloroethane on mutations
in peas. Usp. Khim. Mutageneza Se. 232.
Klaassen, C.D., and G.L. Plaa. 1966. Relative effects of
various chlorinated hydrocarbons on liver and kidney function
in mice. Toxicol. Appl. Pharmacol. 9: 139.
Klaassen, C.D., and G.L, Plaa. 1967. Relative effects of
various chlorinated hydrocarbons on liver and kidney function
in dogs. Toxicol. Appl. Pharmocol. 10: 119.
Kominsky, J. 1976. Health hazard evaluation. Rep. 76-24-
350. Dana Corp. Tipton, Ind. Pub. Health Serv. Natl. Inst.
Occup. Safety Health, U.S. Dep. Health Edu. Welfare.
Kopfler, F.C., et al. 1976. GC/MS determination of volatiles
for the National Organics Reconnaissance Survey (NORS) of
drinking water. Identif. Anal. Organ. Pollut. Water. 1st
1975 (Publ. 1976), 87-104. Keith Lawrence, ed. Ann Arbor
Science, Ann Arbor, Mich.
C-87
-------
Kover, F.D. 1975. Preliminary study of selected potential
environmental contaminants. Optical brighteners, methyl
chloroform, trichloroethylene, and ion exchange resins.
PB Rep. PB-243910. Natl. Tech. Inf. Serv., Springfield,
Va.
Kramer, C.G., et al. 1976. Health of workers exposed to
1,1,1-trichloroethane—a matched pair study. Dow Chemical
Co., Midland, Mich.
Krantz, J.C. Jr., et al. 1959. Anesthesia LX—The anesthetic
properties of 1,1,1-trichloroethane. Anesthesiology 20: 635.
Kraybill, H.F. 1978. Origin, classification and distribution
of chemicals in drinking water with an assessment of their
carcinogenic potential. Ir± R.L. Jolley, ed. Water chlorina-
tion-environemtnal impact and health effects. Vol. 1. Ann
Arbor Science, Ann Arbor, Mich.
Lazarew, N.W. 1929. Concerning the strength of the narcotic
effect of the vapors of the chlorine derivitives of methanes,
ethanes, and ethylenes. Arch. Exp. Pathol. Pharmakol. 141: 19.
Lehmann, K.B., and L. Schmidt-Kehl. 1936. Study of the 13
most important chlorohydrocarbons from the standpoint of
industrial hygienics. Arch. Hyg. 116: 132.
C-88
-------
Levy, B.S.B., and C.R. Meyer. 1977. Health hazard evaluation
determination. Rep. 76-1-388. Bohr Aluminum and Brass Corp.
Danville, 111. PB Rep. PB-273733. Natl. Tech. Inf. Serv.,
Springfield, Va.
Lilliman, B. 1949. Suggested mechanism of poisoning by liquid
tetrachloroethane. Analyst 74: 510.
Lillian, D., and H.B. Singh. 1974. Absolute determination
of atmospheric halocarbons by gas phase coulometry. Anal.
Chem. 46: 1060-3.
Liola, N., and S. Fondacaro. 1959. Toxicity of 1,2-dichloro-
V
ethane-III. Liver function in experimental poisoning. Folia
Med. (Napoli) 42: 1524 (Ita).
Liola, N., et al. 1959. Toxicity of 1,2 dichloroethane-II.
Research of cytochemistry of the blood. Folis Med. (Napoli)
42: 1400 (Ita).
Lobo-Mendonca, R. 1963. Tetrachloroethane—a survey. Br.
Jour. Ind. Med. 20: 50.
Lynch, J.B. 1967. Acute tetrachloroethane poisoning. A
report on a fatal case. Journ. Forensic Med. 14: 118.
C-89
-------
MacEwen, J.D., and E.H. Vernot. 1974. The biological effect
of continuous inhalation exposure of 1,1,1-trichloroethane
(methyl chloroform) on animals. Tox. Hazards Res. Unit Ann. >s
A
Tech. Rep.—1974, AMRL-TR-74-78. Wright Patterson Air Force
Base, Ohio. Aerospace Med. Res. Lab. Natl. Inst. Occup.
Safety Health, Natl. Aeronautic Space Admin, (joint study).
Martin, G., et al. 1969. Clinical features, pathogenesis
and management of dichloroethane poisoning. Ger. Med. Mon.
14: 62.
McCann, J., et al. 1975. Mutagenicity of chloroacetaldehyde,
a possible metabolic product of 1,2-dichloroethane (ethylene
dichloride), chloroethanol (ethylene chlorohydrin), vinyl
chloride, and cyclophosphamide. Proc. Natl. Acad. Sci.
72: 3190.
McNally, W.D., and G. Fostedt. 1941. Ethylene dichloride-
Poisoning Ind. Med. 10: 373.
Merck Index. 1976. The Merck Index. Merck and Co. Inc. Rahway, N.J,
Monster, A.C. 1979. Difference in uptake, elimination,
and metabolism in exposure to trichloroethylene, 1,1,1-tri-
chloroethane and tetrachloroethylene. Int. Arch. Occup.
Environ. Health 42: 311.
C-90
-------
Monster, A.C., and J.M. Houtkooper. 1979. Estimation of
endividual uptake of trichloroethylene, 1,1,1-trichloroethane
and tetrachloroethylene from biological parameters. Int.
Arch. Occup. Environ. Health 42: 319.
Monster, A.C., et al. 1979. Kinetics of 1,1,-trichloroethane
in volunteers; influence of exposure concentration and work
load. Int. Arch. Occup. Environ. Health 42: 293.
Morgan, A., et al. 1970. The excretion in breath of some
aliphatic halogenated hydrocarbons following administration
by inhalation. Ann. Occup. Hyg. 13: 219.
Morgan, A., et al. 1972. Absorption of halogenated hydrocarbons
and their excretion in breath using chlorine-38 tracer techni-
ques. Ann. Occup. Hyg. 15: 273.
Muller, L. 1932. Experimental contribution to tetrachloroethane
poisoning. Arch. Gewerbepathol. Gewebehg. 2: 326 (Ger).
Murray, A., and J. Riley. 1973. Occurence of some chlorinated
aliphatic hydrocarbons in the environment. Nature 242: 37.
National Academy of Sciences. 1977. Drinking water and health.
Washington, D.C.
National Cancer Institute. 1977. Bioassay of 1,1,-trichloro-
ethane for possible carcinogenicity. Carcinog. Tech. Rep.
Ser. NCI-CG-TR-3.
C-91
-------
National Cancer Institute. 1978a. Bioassay of 1,2-dichloro-
ethane for possible carcinogenicity. Natl. Inst. Health,
Natl. Cancer Inst. Carcinogenesis Testing Program. DHEW
Publ. No. (NIH) 78-1305. Pub. Health Serv. U.S. Dep. Health
Ecu. Welfare.
National Cancer Institute. 1978b. Bioassay of 1,1,2-trichloro-
ethane for possible carcinogenicity. Natl. Inst. Health,
Natl. Cancer Inst. DHEW Publ. No. (NIH) 78-1324. Pub. Health
Serv. U.S. Dep. Health Edu. Welfare.
National Cancer Institute. 1978c. Bioassay of 1,1,2,2-tetra-
chloroethane for possible carcinogenicity. Natl. Inst.
Health, Natl. Cancer Inst. DHEW Publ. No. (NIH) 78-827.
Pub. Health Serv. U.S. Dep. Health Edu. Welfare.
National Cancer Instil ,te. 1978d. Bioassay of hexachloroethane
for possible carcinogenicity. Natl. Inst. Health, Natl.
Cancer Inst. DHEW Publ. No. (NIH) 78-1318. Pub. Health Serv.
U.S. Dep. Health Edu. Welfare.
National Institute for Occupational Safety and Health. 1976a.
Criteria for a recommended standard occupational exposure
to 1,1,2,2,-tetrachloroethane. DHEW (NIOSH) Publ. No. 77-
121. Washington, D.C.
C-92
-------
National Institute for Occupational Safety and Health. 1976b.
Criteria document: recommendations for an occupational exposure
standard for ethylene dichloride (1,2-dichloroethane). DREW
Publ. (NIOSH) 76-139.
National Institute for Occupational Safety and Health. 1978a.
Ethylene dichloride (1,2-dichloroethane). Current Intelligence
Bull. 25. DHEW (NIOSH) Publ. No. 78-149.
National Institute for Occupational Safety and Health. 1978b.
Criteria for a recommended standard for occupational exposure
to 1,1,1-trichloroethane (methyl chloroform). DHEW Publ.
No. (NIOSH) 76-184.
f
National Institute for Occupational Safety and Health. 1978c.
Chloroethanes, review of toxicity. Current Intelligence
Bull. 27. DHEW (NIOSH) Publ. No. 78- 181.
National Research Council. 1952. Table V—toxicity tests,
in summary table of biological tests. Vol. 4. Chem. Biolog.
Coord. Center, Washington, D.C.
Navrotskiy, VK., et al. 1971. Comparative assessment of
the toxicity of a number of industrial poisons when inhaled
in low concentrations for prolonged periods. Trudy S'ezda
Gigenistov, Ukranixoi 8: 224 (Russ).
C-93
-------
Nicholson, A.A., and 0. Meresz. 1975. Analysis of volatile,
halogenated organics in water by -direct aqueous injection-
gas chromatography. Bull. Environ. Contam. Toxicol. 14: 453.
Nylander, P.O., et al. 1978. Mutagenic effects of petrol
in Drosophila melanogaster. I. Effects of benzene of and
1,2-dichloroethane. Mutat. Res. 57: 163.
Page, B.D., and B.P.C. Kennedy. 1975. Determination of mthylene
chloride, ethylene dichloride, and trichloroethylene as
solvent residues in spice oleoresins, using vacuum distillation
and electron-capture gas chromatography. Jour. Assoc. Off.
Anal. Chem. 58: 1062.
Plaa, G.L., and R.E. Larson. 1965. Relative nephrotoxic
properties of chlorinated methane, ethane, and ethylene
derivatives in mice. Toxicol. Appl. Pharmacol. 7: 37.
Price, K.S., et al. 1974. Brine shrimp bioassay and sea
water BOD (biochemical oxygen demand) of petrochemicals.
Jour. Water Pollut. Control Fed. 46: 63.
Price, P.J., et al. 1978. Transforming activities of trichlo-
roethylene and proposed industrial alternatives. In vitro.
14: 290.
Rannug, U., and C. Ramel. 1977. The mutagenicity of waste
products from vinyl chloride industries. Jour. Toxicol.
Environ. Health 2: 1019.
C-94
-------
Rannug, U., et al. 1978. The mutagenic effect of 1,2-dichloro-
ethane on Salmonella typhimurium I. Activation through conju-
gation with glutathione in vitro. Chem.-Biol. Interact.
20: 1.
Reinhardt, C.F., et al. 1973. Epinephrine-induced cardiac
arrhythmia potential of some common industrial solvents.
Jour. Occup. Med. 15: 953.
Rennick, B.R., et al. 1949. Induction of idioventricular
rhythms by 1,1,1-trichoroethane and epinephrine. Fed. Proc.
8: 327.
Rosenbaum, N.D. 1947. Ethylene dichloride as an industrial
poison. Gig. Sanit. 12: 1721.
Rosenkranz, H.S. 1977. Mutagenicity of halogenated alkanes
and their derivatives. Environ. Health Perspect. 21: 79.
Rowe, V.K., et al. 1963. Toxicity of a solvent mixture
of 1,1,1,-trichloroethane and tetrachloroethylene as determined
by experiments on laboratory animals and human subjects.
Am. Ind. Hyg. Assoc. Jour. 24: 541.
Salvini, M., et al. 1971. Evaluation of the psychophysiological
functions in humans exposed to the threshold limit value
of 1,1,1-trichloroethane. Br. Jour. Ind. Med. 28: 286.
095
-------
Sansone, E.B., and Y.B. Tewari. 1978. The permeability of
laboratory gloves to selected solvents. Jour. Am. Ind.
Hyg. Assoc. 39: 169.
Sax, N.I., ed. 1975. Dangergous properties of industrial
materials. 4th ed. Reinhold Publishing Corp. New York.
Schonborn, H., et al. 1970. Consumption coagulation pathology
of 1,2-dichloroethane poisoning. Klin. Wochenschr. 48: 822.
Schwetz, B.A., et al. 1974. Embryo- and fetotoxicity of
inhaled carbon tetrachloride, 1,1,-dichloroethane, and methyl
ethyl ketone in rats. Toxicol. Appl. Pharmacol. 28: 452.
•
Schwetz, B.A., et al. 1975. Effect of maternally inhaled
trichloroethylene, perchloroethylene, methyl chloroform,
and methylene chloride on embryonal and fetal development
in mice and rats. Toxicol, Appl. Pharmacol. 32: 84.
Secchi, G.C., et al. 1968. Actual chemical composition
of the "commercial trieline" and their hepatotoxic effect-
-Clinical and enzymological studies. Med. Lav. 59: 486 (Ita).
Sidwell, V.D., et al. 1974. Composition of the edible portion
of raw (fresh or frozen) crustaceans, finfish, and mollusks.
I. Protein, fat, moisture, ash, carbohydrate, energy value,
and cholesterol. Mar. Fish. Rev. 36: 21.
C-96
-------
Smyth, H.F..Jr., et al. 1969. Range-finding toxicity data:
list VII. Am. Ind. Hyg. Assoc. Jour. 30: 470.
Spencer, B.C., et al. 1951. Vapor toxicity of ethylene dichlo-
ride determined by experiments on laboratory animals. Arch.
Ind. Hyg. Occup. Med. 4: 482.
/
Stahl, C.J., et al. 1969. Trichloroethane poisoning: obser-
vations on the pathology and toxicology in six fatal cases.
Jour. Forensic Sci. 14: 393.
Stewart, R.O., and H.C. Dodd. 1964. Absorption of carbon
tetrachloride, trichloroethylene, tetrachloroethylene, methy-
lene chloride, and 1,1,1-trichloroethane through the human
skin. Am. Ind. Hyg. Assoc. Jour. 25: 439.
Stewart, R.D., et al. 1961. Human exposure to 1,1,1-trichloro-
ethane vapor: relationship of expired air and blood concen-
trations to exposure and toxicity. Am. Ind. Hyg. Assoc.
Jour. 22: 252.
Stewart, R.D., et al. 1969. Experimental human exposure
to methyl chloroform vapor. Arch. Environ. Health 19: 467.
Stewart, R.D., et al. 1975. 1,1,1-Trichloroethane—development
of a biologic standard for the industrial worker by breath
analysis. Rep. No. NIOSH-MCOW-ENVM-l,l,l,-T-75-4. Dep. Environ.
Med. The Medical College of Wisconsin, Milwaukee.
C-97
-------
Symons, J.M., et al. 1975. National ocganics reconnaissance
survey for halogenated organics. Jour. Am. Water Works Assoc.
67: 634.
Tardiff, R.G., et al. 1978. Halogenated organics in tap
water: A toxicological evaluation. In R.L. Jolley, ed. Water
chlorination environmental impact and health effects. Vol.1.
Ann Arbor Science, Ann Arbor, Mich.
Tomokuni, K. 1969. Studies on hepatotoxicity induced by
chlorinated hydrocarbons—lipid and ATP metabolism in the
liver of mice exposed to 1,1,2,2-tetrachloroethane. Acta.
Med. Okayama 23: 273.
Torkelson, T. , et al. 1958. Toxicity of 1,1,1-trichloroethane
as determined in laboratory animals and human subjects.
Am. Ind. Hyg. Assoc. Jour. 19: 353.
Traiger, G.J., and G.L. Plaa. 1974. Chlorinated hydrocarbon
toxicity. Arch. Environ. Health 28: 276.
Troisi, P.M., and D. Cavallazzi. 1961. Fatal poisoning from
the inhalation of dichloroethane fumes. Med. Lav. 52: 612.
Truhaut, R. 1972. Metabolic transformations of 1,1,1,2-tetra-
chloroethane in animals (rat, rabbit). Chem. Anal. (Warsaw)
17: 1075.
C-98
-------
Truhaut, R., et al. 1973. Serum enzymic activities and bio-
chemical blood components in subacute 1,1,1,2-tetrachloro-
ethane poisoning in the rabbit. Jour. Eur. Toxicol. 6: 81.
Truhaut, R., et al. 1974. Toxicological study of 1,1,1,2-
tetrachloroethane. Arch. Mai. Prof. Med. Trav. Secur. Soc.
35: 593.
Tsapko, V.G., and H.B. Rappoport. 1972. Effect of methylchlor-
oform vapors on animals. Farmakol. Toksikol. (KIEV) 7: 149.
U.S. EPA. 1974. "Draft analytical report-New Orleans area
water supply study," EPA 906/10-74-002. Lower Mississippi
River Facility, Slidell, La., Surveill. Anal. Div. Region
VI, Dallas, Tex.
U.S. EPA. 1975a. Identification of organic compounds in
effluents from industrial sources. EPA 560/3-75-002.
U.S. EPA. 1975b. Preliminary economic impact assessment
of possible regulatory action to control atmospheric emissions
of selected ha'locarbons. EPA 450/3-75-073, PB247115, Res.
Triangle Park, N. Ca.
U.S. EPA. 1975c. Preliminary assessment of suspected carcino-
gens in drinking water. Report to Congress. EPA 56014-75-
005 PB 160961. Washington, D.C. EPA 56014-75-005 PB. 260961.
C-99
-------
U.S. EPA. 1975d. Analysis of carbon and resin extracts.
New Orleans area water supply study. Analysis of carbon
and Ljsin extracts.
U.S. EPA. 1976. List of Organics Reconnaissance Survey:
Analysis of tap water from five U.S. cities for volatile
organic compounds, a staff report. Health Effects Res. Lab.
Cincinnati, Ohio.
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.
Vainio, H. , et al. 1976. Effects of aliphatic chlorohydrocar-
bons on drug-metabolizing enzymes in raf liver ir\ vivo.
Xenobiotica 6: 599.
Van Dyke, R.A. , and L. I. Rikans. 1970. Effect of the volatile
anesthetics on aniline hydroxylase and aminopyrine demethylase
Biochem. Pharmacol. 19: 1501.
Van Dyke, R.A. , and C.G. Wineman. 1971. Enzymatic dechlorina-
tion: Dechlorination of chloroethanes and propanes Ln vitro.
Biochem. Pharmacol. 20: 463.
Van Rossum, P., and R.G. Webb. 1978. Isolation of organic
water pollutants by XAD resins and carbon. Jour. Chroma togr.
150: 381.
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-------
Veith, G.D., et al. An evaluation of using partition coeffi-
cients and water solubility to estimate bioconcentration
factors for organic chemicals in fish. (Manuscript.)
Vozovaya, M.A. 1974. Development of progeny of two generations
obtained from female rats subjected to the action of dichloro-
ethane. Gig. Sanit. 7: 25.
Walter, P., et al. 1976. Chlorinated hydrocarbon toxicity
(1,1,1-trichloroethane, trichloroethylene, and tertachloro-
ethylene): a monograph. PB Rep. PB-257185. Natl. Tech.
Inf. Serv., Springfield, Va.
Weast, R.C., ed. 1976. Handbook of chemistry and physics
- a ready reference book of chemical and physical data.
57th ed. CRC Press, Cleveland, Ohio.
Weeks, M.H., et al. 1979. The toxicity of hexachloroethane
in laboratory animals. Am. Ind. Hyg. Assoc. Jour. 40: 187.
Wendel, H. 1948. Lethal poisoning from dichloroethane (ethylene
dichloride). Pharmazie 3: 398.
Willcox, W.H., et al. 1915. An outbreak of toxic jaundice
of a new type amongst aeroplane workers. Its clinical and
toxicological aspect. Trans. Med. Soc. London 38: 129.
Wirtschafter, Z.T., and E.D. Schwartz. 1939. Acute ethylene
dichloride poisoning. Jour. Ind. Hyg. Toxicol. 21: 126.
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Yllner, S. 1971a. Metabolism of 1,2-dichloroethane- C in
the mouse. Acta. Pharmacol. Toxicol. 30: 257.
Yllner, S. 1971b. Metabolism of l,l,2-trichloroethane-l,2-
14
C in the mouse. Acta. Pharmacol. Toxicol. 30; 248.
Yllner, S. 1971c. Metabolism of 1,1,1,2-tetrachloroethane
in the mouse. Acta. Pharmacol. Toxicol. 29: 471.
Yllner, S. 1971d. Metabolism of 1,1,2,2-tetrachloroethane-
14
C in the mouse. Acta. Pharmacol. Toxicol. 29; 499.
Yllner, S. 1971e. Metabolism of pentachloroethane in the
mouse. Acta'. Pharmacol. Toxicol. 29: 481.
Yodaiken, R0E., and J.R. Babcock. 1973. 1,2-dichloroethane
poisoning. Arch. Environ. Health 26: 281.
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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- 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
carcinogens. 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). Carcinogenesis
testing is planned for chloroethane (NCI, 11/79).
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
(107 mg/kg/day) and hemangiosarcomas (54 mg/kg/day) in male
Osborne-Mendel rats. Nine of 50 animals (18 percent)
developed stomach cancers and 7 of 50 animals (14 percent)
developed hemangiomas. None of the twenty control animals
developed either cancer type. Female Osborne-Mendel
*This summary has been prepared and approved by the Carcino-
gens Assessment Group, EPA, on July 17, 1979.
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rats (95 mg/kg/day) and B6C3P1 mice (149 mg/kg/day) developed
adenocarcinomas of-the mammary gland (NCI, 1978a). Eighteen
of 50 treated rats (36 percent) and 9 of 50 treated mice
(18 percent) developed mammary cancers. 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 (195 and 390 mg/kg/day) and female (195 mg/kg/day and
390 mg/kg/day) 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 re-tested at the NCI
because high mortality rates among animals/ in an earlier
carcinogenesis bioassay, made it impossible to assess the
carcinogenicicty ingested 1,1,1-trichloroethane, even though
a variety of neoplasms was 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 fibrosarcomas 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, in average doses
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of 14-2 mg/kg/day and 284 mg/kg/day 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 percent), and 1/18 (5 percent) in the
high dose, low dose, and vehicle control groups, respectively.
Tumor incidences in females were 43/49 (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 carcinogenic activity in both male and female
B6C3F1 mice. Thirty-one of 49 treated male mice (63 percent)
developed hepatocellular carcinomas after receiving average
oral doses of 1,179 mg/kg/day 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
carcinomas after receiving average oral doses of 590 mg/kg/day
hexachloroethane as compared to 2 of 20 (10 percent) vehicle-
treated controls.
Two chlorinated ethanes are known mutagens. 1,2-Dichloro-
ethane 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-
tetrachloroethane ^ 1,2-dichloroethane. 1,2-Dichloroethane
induced highly significant increases in somatic mutation
frequencies in Drosophila melangaster (Nylander, et al.
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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
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).
Hexachloroethane was not mutagenic for five strains
A
of Salmonella 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, 1,1-dichloroethane, 1,1,1- and 1,1,2-trichloro-
ethanes, 1,1,1,2-tetrachloroethane 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
evidence that these chemicals are likely to be human carcinogens.
The water quality criterion for 1,2-dichloroethane
is based on the induction of mammary adenocarcinomas in
female Osborne-Mendel rats, given average oral doses of
197 mg/kg/day 1,2-dichloroethane over a period of 78 weeks
(NCI, 1978a). The concentration of 1,2-dichloroethane in
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water, calculated to keep the lifetime cancer risk below
10"5 is 7.0 >ug/l.
The water quality criterion for 1,1,2-trichloroethane
is based on the induction of hepatocellular carcinomas in
female B6C3F1 mice, given an average oral dose of 390 mg/kg/day
over a 78-week period (NCI, 1978b). The concentration of
1,1,2-trichloroethane in water, calculated to keep the lifetime
cancer risk below 10" is 2.7 /ig/1.
The water quality crterion for 1,1,2,2-tetrachloroethane
is based on the induction of hepatocellular carcinomas in
male B6C3F1 mice, receiving average oral doses of 284 mg/kg/day
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 1.8 jug/1.
The water quality criterion for hexachloroethane is
based on the induction of hepatocellular carcinomas in male
B6C3F1 mice, given an average oral dose of 1,179 mg/kg/day
over a 78-week period (NCI, 1978d). The concentration of
hexachloroethane in water, calculated to keep the lifetime
cancer risk below 10 is 5.9;ug/l.
Because carcinogenicity data are lacking for chloroethane,
1,1-dichloroethane, 1,1,1-tr ichloroethane, 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 mammary adenocarcinomas in female
Osborne-Mendel rats, given an average oral dose of 107 mg/kg/day
1,2-dichloroethane over a period of 78 weeks (NCI, 1978a).
The incidences of mammary adenocarcinomas were 18/50 and
0/20 in the treated and control groups, respectively. The
criterion was calculated from the following parameters:
nfc = 18 d = 76.4 mg/kg/day (107 mg/kg/day x 5/7)
Nfc = 50 f = 0.0187 kg/day
nc = 0 R = 4.6
NC = 20 w = 0.319 kg
Le = 110 wks.
le = 69 wks.
L = 110 wks.
Based on these parameters, the one-hit slope (BH) is
0.04765 (mg/kg/day)~ . The concentration of 1,2-dichloroethane
in water, calculated to keep the lifetime cancer risk below
10"5 is 7.0 jug/1.
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Summary of Pertinent Data for 1,1,2-trichloroethane
The water quality criterion for 1,1,2-trlchloroethane
is based on the induction of hepatocellular carcinomas in
female B6C3F1 mice, given an average oral dose of 390 mg/kg/day
over a 78 week period (NCI, 1978b). The incidences of hepato-
cellular were 40/45 and 0/20 in the treated and control
groups, respectively. The criterion was calculated from
the following parameters:
nfc = 40 d = 279 mg/kg/day (390 mg/kg/day x 5/7)
Nt » 45 F = 0.0187 kg/day
n^ = 0 R = 6.3
c
NC = 20 w = 0.029 kg
Le = 91 wks
le = 78 wks
L = 91 wks
Based on these parameters, the one-hit slope (BH) is
0.123 (mg/kg/day) . The concentration of 1,1,2-trichloro-
ethane in water, calculated to keep the lifetime cancer
risk bel-^w 10~5 is 2.7 jug/1.
C-109
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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
male B6C3F1 mice, receiving average oral doses of 284 mg/kg/day
over a 78-week period (NCI, 1978c). The incidences of hepato-
cellular carcinomas were 44/49 and 1/18 in the treated and
control groups, respectively. The criterion was calculated
from the following parameters:
nt = 44 d = 203 mg/kg/day (284 mg/kg/day x 5/7)
Nfc = 49 F = 0.0187 kg/day
nc = 1 R = 18
Nc = 18 w = 0.035 kg
Le = 91 wks
le = 78 wks
L - 91 wks
Based on these parameters, the one-hit slope (BH) is
0.1638 (mg/kg/day) . The concentration of 1,1,2,2-tetrachloro-
ethane in water, calculated to keep the lifetime cancer
risk below 10~5, is 1.8 jug/1.
C-110
-------
Summary of Pertinent Data for Hexachloroethane
The water quality criterion for hexachloroethane is
based on the induction of hepatocellular carcinomas in male
B6C3F1 mice, given an average oral dose of 1,179 mg/kg/day
over a 78-week period (NCI, 1978d). The incidences of hepato-
cellular carcinomas were 31/49 and 3/20 in the treated and
control groups, respectively. The criterion was calculated
from the following parameters:
nfc = 31 d = 842 mg/kg/day (1179 mg/kg/day x 5/7)
Nfc = 49 'F = 0.0187 kg/day
nc * 3 R = 320
N = 20 w - 0.032 kg
c
Le = 91 wks
le = 78 wks
L = 91 wks
Based on these parameters, the one-hit slope (BH) is
0.0149 (mg/kg/day)~ . The concentration of hexachloroethane
in water, calculated to keep the lifetime cancer risk below
10~5, is 5.9 jug/1.
C-lll
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