"
United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA-600/8-88/080F
June 1988
Research and Development
EPA Summary Review of
Health Effects
Associated With
Monochloroethane:
Health Issuo
Assessment
v ' < ' i ' - i J, ' .
:": cr., .Room 1670
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EPA-600/8-88/G!
June 1988
Summary Review of Health Effects
Associated With Monochloroethane
Health Issue Assessment
U.S. EnvIrcrrK'ntal Protection Agenoy
Region 5, Litrai-y (5PL-1&)
230 S. Dearborn Street, Eoom 1670
Chicago, IL .60604
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade names
or commercial products does not constitute endorsement or recommendation for
use.
n
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CONTENTS
TABLES iv
PREFACE v
AUTHORS, CONTRIBUTORS, AND REVIEWERS vi
1. SUMMARY AND CONCLUSIONS 1
2. INTRODUCTION 5
3. AIR QUALITY AND ENVIRONMENTAL FATE: 10
3.1 SOURCES 10
3.2 DISTRIBUTION 11
3.3 AMBIENT CONCENTRATIONS 12
3.3.1 Exposure Levels 13
3.4 FATE 13
3.4.1 Reactions with OH Radicals 13
3.4.2 Reactions with Ozone 14
3.4.3 Photodegradation 14
4. PHARMACOKINETICS 15
4.1 ABSORPTION 15
4.2 DISTRIBUTION AND TISSUE LEVELS 15
4. 3 METABOLISM 16
5.' GENOTOXICITY AND CARCINOGENICITY ' 18
5.1 GENOTOXICITY .' 18
5.2 CARCINOGENICITY 18
6. DEVELOPMENTAL AND REPRODUCTIVE TOXICITY 20
7. OTHER TOXIC EFFECTS 21
7.1 ACUTE TOXICITY 21
7.1.1 Humans 21
7.1.2 Animals 22
7.2 SUBCHRONIC TOXICITY 24
7.2.1 Humans 24
7.2.2 Animals 24
7.3 CHRONIC TOXICITY 25
7.3.1 Humans 25
7.3.2 Animals 25
7.4 BIOCHEMICAL EFFECTS 26
8. REFERENCES 27
m
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TABLES
Number Page
2-1 Chemical and physical properties of monochloroethane 6
3-1 Atmospheric levels of monochloroethane 12
7-1 Acute toxicity of monochloroethane vapor to humans 22
7-2 Acute toxicity of monochloroethane vapor to guinea pigs ... 23
IV
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PREFACE
The Office of Health and Environmental Assessment has prepared this
summary health assessment for use by the Office of Air Quality Planning and
Standards to support decision making regarding possible regulation of mono-
chloroethane as a hazardous air pollutant.
In the development of this document, the scientific literature has been
inventoried, key studies have been evaluated, and the summary and conclusions
have been prepared so that the chemical's toxicity and related characteristics
are qualitatively identified. Observed-effect levels and other measures of
dose-response relationships are discussed, where appropriate, so that the
nature of the adverse health responses is placed in perspective with observed
environmental levels. The relevant literature for this document has been
reviewed through June 1986.
Any information regarding sources, emissions, ambient air concentrations,
and public exposure has been included only to give the reader a preliminary
indication of the potential presence of this substance in the ambient air.
While the available information is presented'as accurately as possible, it is
acknowledged to be limited and dependent in many instances on assumption rather
than specific data. This information is not intended, nor should it be used,
to support any conclusions regarding risk to public health.
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
The author of this document is Dennis Opresko, Ph.D., Chemical Effects
Information Branch, Information Research and Analysis Division, Oak Ridge
National Laboratory, P.O. Box X, Oak Ridge, Tennessee 32831.
The U.S. EPA project manager for this document is William Ewald, Environ-
mental Criteria and Assessment Office, Office of Health and Environmental
Assessment, MD-52, Research Triangle Park, NC 27711.
The document was reviewed by Larry T. Cupitt, Ph.D.; Christopher DeRosa,
Ph.D.; Beth M. Hassett; Daphne Kennedy, Ph.D.; Charles Ris; and Lawrence R.
Valcovic, Ph.D. of the U.S. Environmental Protection Agency; Thomas L. Landry,
Ph.D. of Dow Chemical Company; and Gilda Loew, Ph.D. of SRI International.
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1. SUMMARY AND CONCLUSIONS
Monochloroethane (C^Cl, CAS No. 75-00-3, also referred to as chloro-
ethane or ethyl chloride) is a volatile monochloro derivative of ethane that is
present in the environment as a result of releases from anthropogenic sources.
It has been found in the atmosphere, in drinking water, in oyster tissue, and
in estuarine sediment samples.
Monochloroethane enters the atmosphere in emissions from chemical produc-
tion and use, and municipal incinerators, as a result of its use as a chemical
solvent, and as a by-product from the combustion of various commercial products
(e.g., neoprene materials, polyvinyl chloride compositions, polyurethane rigid
foam, and creosote-treated wood). Annual losses into the atmosphere in the
United States have been estimated at 0.01 million tons, a level sufficiently
high to raise questions concerning the environmental and human health impacts
of such releases.
Monochloroethane has been identified in air samples taken at a number of
locations around the United States. Atmospheric concentrations as high as
1248 parts per trillion (ppt) have been measured in some urban areas. The
average atmospheric concentration, based on the combined data collected in
several field studies, was reported to be 96 ppt in samples from urban and
suburban areas and 18 ppt in samples from source-related areas. In one field
study, the public's exposure to monochloroethane through inhalation was
estimated to average from 2.4 to 13.5 ug/day.
The major atmospheric sink for monochloroethane is the troposphere, where
the primary degradation pathway involves reactions with the hydroxyl radical.
Laboratory studies indicate that the major oxidation products are carbon
dioxide, carbon monoxide, formaldehyde, formyl chloride, and acetyl chloride.
Formyl chloride, the principal carbon-chlorine product, may undergo further
degradation in the atmosphere to form hydrogen chloride. The hydrogen chloride
is removed from the atmosphere by precipitation, and thus may contribute to
some degree to the acidification of surface waters.
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Monochloroethane is unreactive towards 03. Photodissociation is not
expected to occur in the visible and near ultraviolet region of the spectrum.
Laboratory studies, however, indicate that photodegradation occurs at shorter
wavelengths. Ethylene and hydrogen are the major photodecomposition products
at wavelengths of <147 nm. Ethane, ethylene, vinyl chloride, and n-butane are
the major products produced at higher wavelengths. In a laboratory simulation
of conditions that might occur in urban atmospheres, formaldehyde and hydrogen
chloride were the major products formed when monochloroethane in air underwent
photochemical decomposition in the presence of nitrogen oxides.
Although monochloroethane is very volatile, its chemical reactivity, as
indicated by rate data for its reaction with hydroxyl radicals, is relatively
low, and on this basis, it is not expected to participate to any great extent
in photochemical smog formation. However, because laboratory studies indicate
that photochemical decomposition reactions result in the release of such
respiratory irritants as hydrogen chloride and formaldehyde, further evaluation
is needed to determine to what extent such reactions occur under natural
conditions.
The mean atmospheric residence times reported for monochloroethane, as
4
calculated from hydroxyl radical rate data, range from 0.04 to 0.4 years:
consequently, some regional and continental transport through the atmosphere
might be expected.
Because of its high volatility, the major route of exposure to monochloro-
ethane is inhalation. The compound is readily absorbed into the blood through
the lungs and rapidly eliminated in exhaled breath. Blood/air partition coeffi-
cients of 2.3 and 2.5 have been reported. Little information is available
concerning tissue distribution of absorbed monochloroethane. One study found
that the .highest levels were in perirenal fatty tissue. The log octanol/water
partition coefficient has been calculated to be 1.49 and 1.54, indicating a
relatively low potential for bioaccumulation. The available evidence suggests
that the compound undergoes only a limited amount of metabolic breakdown to
the expected by-products: acetaldehyde, acetic acid, and ethanol.
It has been suggested that because monochloroethane is not metabolized to
a great extent, and because it is rapidly eliminated, it is not likely to have
severe toxic effects on specific organ systems unless concentrations are
extremely high. Histopathological changes in lungs, liver, and kidney have
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been observed in animals, but only at concentrations >20,000 ppm, and severe
toxic effects, such as hyperemia, edema, and hemorrhages in the internal
organs, brain, and lungs were produced only at concentrations above 40,000 ppm.
Humans exposed to monochloroethane have exhibited central nervous system
depression, headaches, dizziness, incoordination, inebriation, unconsciousness,
abdominal cramps, respiratory tract irritation, respiratory failure, cardiac
arrhythmias, cardiac arrest, skin irritation and freezing, allergic eczema, and
eye irritation. Studies have shown that exposure to 13,000 ppm (1.3 percent)
monochloroethane in air results in only a slight subjective feeling of intoxi-
cation after 17 min. Inhalation of 19,000 ppm produces weak analgesia within
12 minutes: 25,000 ppm produces slight incoordination after 15 min: and
33,600 ppm produces incoordination, cyanosis, and nausea after 8.5 min.
Respiratory arrest has been observed at a monochloroethane concentration of
60,000 ppm. Concentrations producing acute toxic effects are several orders
of magnitude above the highest measured ambient level of monochloroethane
(1.25 ppm). In comparison, the current United States occupational exposure
standard for monochloroethane is 1000 ppm for an 8-hr time-weighted average.
No conclusive information was found concerning the subchronic and chronic
toxicity of monochloroethane to humans. One animal study indicated that expo-
sures for 4 hr per day for six months to air concentrations as low as 0.57 mg/L
(220 ppm) resulted in changes in liver function, decreased arterial blood pres-
sure, lowered phagocytic activity of leukocytes, lipid degenerative changes in
the liver, and some dystrophic changes in the lungs. However, these results
were disputed by several other subchronic and chronic studies in which there
was no evidence of histopathological lesions even at concentrations as high as
10,000 ppm.
Monochloroethane vapor was found to be mutagenic to various Salmonella
strains when tested with and without the addition of metabolic activation
systems. It was inactive in an ui vitro cell transformation assay using BALB/
C-3T3 cells in the absence of exogenous metabolic activation. Based on the
i_n vitro mutagenic activity of monochloroethane (with and without metabolic
activation), and in view of the demonstrated carcinogenicity, DNA-protein
adduct-forming ability, and mutagenic activity of acetaldehyde, a predicted
metabolite of monochloroethane, there is suggestive evidence that monochloro-
ethane may have carcinogenic potential. However, there were no standard chronic
carcinogenicity studies found in the literature which report direct clinical,
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epidemiologies!, or experimental evidence for monochloroethane. According to
EPA cancer assessment guidelines, this compound should be considered to be in
Group D. NTP is currently preparing a technical report on a new inhalation
bioassay for this compound. The report is being internally peer reviewed by
NTP as of June 1988.
Monochloroethane was reported to be nonteratogenic in a recent study.
Detailed results of the study are not yet available. No other information was
found on the developmental or reproductive toxicity of the compound.
There is only limited information on the potential genotoxicity and terato-
genicity of the compound and no experimental data on carcinogenicity. A major
concern that has arisen relates to the known mutagenicity and carcinogenicity
of acetaldehyde, the predicted main metabolite of monochloroethane. Thus,
further understanding of the potential for long-term adverse health effects
may be dependent on the pharmacokinetics and degree of metabolism of
monochloroethane.
Further study is also needed to determine to what degree the photochemical
oxidation products of monochloroethane (hydrogen chloride and formaldehyde)
contribute to the overall degradation of air quality, particularly in urban
areas where the-concentrations are highest.
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2. INTRODUCTION
The purpose of this review is to briefly summarize the available informa-
tion concerning the potential health effects associated with exposure to mono-
chloroethane (CAS No. 75-00-3). Available data on pharmacokinetics, acute and
chronic toxicity, teratogenicity, mutagenicity, and carcinogenicity are covered
in this report. Physical and chemical properties and air quality data, includ-
ing sources, distribution, fate, and ambient concentrations in the United
States, are also included to allow a preliminary evaluation of the effects of
monochloroethane on human health at ambient conditions commonly encountered by
the general public.
Monochloroethane (also referred to as chloroethane or ethyl chloride) is a
monochloro derivative of ethane with a molecular formula of CpHrCl and a mole-
cular weight of 64.5. It is a colorless liquid with a burning taste and an
ether-like odor. It is very volatile and forms a gas at room temperature
(vapor pressure 900 to 1000 mm Hg at 20°C). The major physical and chemical
properties of monochloroethane are summarized in Table 2-1.
Monochloroethane is produced commercially by the free radical chlorination
of ethane, by the hydrochlorination of ethanol or ethylene, or by the action of
chlorine on ethylene in the presence of copper or iron chlorides (Fishbein,
1979a,b; Processes Research, Inc., 1972). About 90 to 95 percent of the mono-
chloroethane produced in the United States is made by the hydrochlorination of
ethylene (Morris and Tasto, 1979). In 1976, United States production of mono-
chloroethane was 670 million pounds (U.S. International Trade Commission, 1976,
as reported in National Institute of Occupational Safety and Health, 1978).
United States production of monochloroethane in 1984 was 290,232,000 pounds
(U.S. International Trade Commission, 1985). As listed by Hughes (1983), the
major manufacturers of monochloroethane in the United States are
Dow Chemical U.S.A., Freeport, TX
E.I. du Pont de Nemours & Company, Inc., Deepwater, NJ
Ethyl Corporation, Houston, TX
Hercules Incorporated, Hopewell, VA
PPG Industries, Incorporated, Lake Charles, LA
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Monochloroethane is used primarily in the production of tetraethyl lead
and ethylcellulose (Hughes, 1983). Small amounts may also be used in the
production of ethylbenzene, alkyl catalysts and Pharmaceuticals, as local anes-
thetics, in aerosols, and as a dye vehicle (Hughes, 1983; Fishbein, 1979).
Although it has been reported to be useful as a solvent and refrigerant, it is
probably no longer used for such purposes (Hughes, 1983).
According to the National Institute of Occupational Safety and Health
(1978), monochloroethane is used in the following industries:
Medical and health services
Automotive dealers and service stations
Wholesale trade
Electric, gas and sanitary services
Machinery, except electrical
Special trade contractors
Fabricated metal products
Printing and publishing
Rubber and plastics products
Food and kindred products
Pre-1978 figures indicated that 113,000 workers were exposed to monoohloro-
4
ethane (SRI, 1978, as reported in the National Institute of Occupational Safety
and Health, 1978; Parker et al., 1979). The occupational exposure limit for
monochloroethane as adopted by the U.S. Occupational Safety and Health Admini-
3
stration is 1000 ppm (2600 M9/m ) f°r an 8~nr time-weighted average (TWA)
(Code of Federal Regulations, 1979). The OSHA IDLH level (immediately dangerous
to life or health) is 20,000 ppm. The occupational exposure limit in other
countries ranges from 100 to 1250 ppm (International Labour Office, 1980). The
TLV-TWA adopted by the American Conference of Governmental Industrial Hygienists
(1985) (ACGIH) is also 1000 ppm. Although the ACGIH has a TLV-STEL (short-term
exposure limit) of 1250 ppm for monochloroethane, this standard is bei.ng
deleted by ACGIH, and in the absence of a specific TLV-STEL, the generic ACGIH
standard for excursion limits above the TLV-TWA would apply. This standard
states that "short-term exposures should exceed three times the TLV-TWA for no
more than a total of 30 minutes during the work day and under no circumstances
should they exceed five times the TLV-TWA," (American Conference of Governmental
Industrial Hygienists, 1985).
The U.S. Environmental Protection Agency has listed chlorinated ethanes,
thus including monochloroethane, as priority pollutants (Arbuckle and Vanderver,
-------
1983). Monochloroethane has a production volume of approximately 180 x
10 Ibs/yr, is very volatile, and has been identified in air samples taken from
around the United States (see Section 3). In addition, it has been found in
drinking water (Kopfler et al., 1975), and in oyster tissue and sediment
samples taken from an estuarine locality (Ferrario et al., 1985). Because of
its occurrence in various environmental media, and particularly in urban
atmospheres, the potential exists for significant environmental and/or human
health effects.
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3. AIR QUALITY AND ENVIRONMENTAL FATE
3.1 SOURCES
There are no known natural sources of monochloroethane. The general
public is exposed to the compound as a result of losses from anthropogenic
sources (Singh et al. , 1979). It has been found in emissions from chemical
manufacturing plants (Processes Research, Inc., 1972; Shame! et al., 1975),
and from municipal waste incinerators (Busso, 1971, as reported in Graedel,
1978). It may be lost to the atmosphere during its use as a chemical solvent
(U.S. Environmental Protection Agency, 1975a, as reported in Graedel, 1978).
It has also been identified as a combustion product of such materials as neo-
prene, polyvinyl chloride compositions, polyurethane rigid foam, and creosote-
treated wood (Hartstein and Forshey, 1974).
Singh et al. (1981) reported that 0.01 million tons (22 x 106lbs) of
monochloroethane are released into the atmosphere every year in the United
States. Processes Research, Inc. (1972) estimated that emissions during
production would average 32 to 42 pounds per ton of final product. Using
pre-1975 data, Brown et al. (1975) reported that 1 percent, or 5.8 million
pounds per year, of the total United States production of monochloroethane
would be lost during production processes. In addition, it was reported that
5 percent, or 28.8 million pounds per year, went to nonintermediate dispersive
uses. The total release rate was therefore reported to be 34.6 million pounds
per year.
Monochloroethane can also enter the atmosphere as a result of evaporative
losses from the hydrosphere. The compound is released into aqueous environ-
mental media in industrial effluents. Perry et al. (1979) found it in 2 of
63 effluents from chemical manufacturing plants. Concentrations were below
10 ug/L. The evaporative half-life of monochloroethane from water was reported
by Dilling (1977) to be 23.1 min, indicating a relatively rapid transport to
the atmosphere. Half-lives of 16.8 and 21 min have also been reported (Neely,
1976).
10
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Partitioning of monochloroethane between the atmosphere and hydrosphere
was calculated by Dill ing (1982, 1977) from vapor pressure and water solubility
data using the following formula:
u - Cair _ 16.04 x P x M
n 7; =:= ;=
Cwater T x S
where:
H = partition coefficient
C = concentration
P = vapor pressure (mm Hg)
M = molecular weight
T = temperature (°Kelvin)
S = solubility (mg/L)
According to Dilling, a coefficient of 1.0 indicates that, in the absence
of degradation reactions, and with sufficient time and complete mixing, a
compound would be distributed almost entirely (>99 percent) to the atmosphere
(Dilling, 1982). A compound with a partition coefficient of 0.01 would be
distributed to the atmosphere in amounts >50 percent. Dilling (1977) reported
a partition coefficient of 0.46 for monochloroethane, indicating substantial
distribution to the atmosphere.
3.2 DISTRIBUTION
The major atmospheric sink for monochloroethane is the troposphere, where
the primary degradation pathway involves reactions with the hydroxyl radical
(Singh et a!., 1979). The amount entering the stratosphere has been estimated
to be approximately 0.6 percent of the amount released at ground level (Singh
et al., 1979).
Considering that the mean atmospheric residence times reported for mono-
chloroethane range from 0.04 to 0.4 years and the fact that air masses move
across the North American continent in about one week (Altshuller, 1980a), it
is possible that under certain conditions there would be some regional and
continental transport of monochloroethane through the atmosphere. Further
study is needed to determine the distribution patterns at various distances
from major source localities.
11
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3.3 AMBIENT CONCENTRATIONS
The average global concentration of monochloroethane from dispersive
losses was computed to be about 0.5 ppt, and the average concentration in the
northern hemisphere was estimated to be about 1 ppt (Altshuller, 1980b). The
compound has been identified in air samples taken from various localities
around the United States, particularly in urban and industrial areas such as
Houston, TX, Baltimore, MD, Belle, WV, Edison, NJ, and the Los Angeles basin
(Pellizzari, 1977b; Pellizzari et a!., 1976). In rural areas concentrations
are generally only a few ppt. The maximum reported atmospheric level was
1248 ppt in Houston, TX. Average and maximum levels reported for several
United States localities are given in Table 3-1.
TABLE 3-1. ATMOSPHERIC LEVELS OF MONOCHLOROETHANE
Concentration
(ppt) Locality Reference
<5
510.
*
227 (avg.)
1248 (max.)
46 (avg.)
182 (max.)
41 (avg.)
125 (max.)
87 (avg.)
312 (max.)
110 (avg.)
312 (max.)
86 (avg.)
229 (max.)
66 (avg.)
296 (max.)
Rural Washington State
Iberville Parish, LA
Houston, TX
St. Louis, MO
Denver, CO
Riverside, CA
Staten Island, NY
Pittsburgh, PA
Chicago, IL
Grimsrud and Rasmussen, 1975
Pellizzari,- 1977a
Singh et al., 1981
Singh et al., 1981
Singh et al., 1981
Singh et al., 1981
Singh et al., 1983
Singh et al., 1983
Singh et al., 1983
As reported in Pellizzari et al. (1979).
12
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3.3.1 Exposure levels
On the basis of measured ambient concentrations of monochloroethane,
averaged over 9 to 11 days (Table 3-1) during the summer of 1980, Singh et al.
(1981) calculated that the general public's exposure to the chemical through
inhalation would average 13.5 ug/day -jn Houston, TX, 2.7 ug/day in St. Louis,
MO, 2.4 pg/day in Denver, Co, and 5.1 ug/day in Riverside, CA. These doses
were calculated based on the breathing rate for a 70 kg man.
3.4 FATE
The U.S. Environmental Protection Agency (1975b) reported that monochloro-
ethane emitted to the atmosphere is relatively rapidly lost through photoche-
mical reactions. The following sections deal with the various types of these
reactions.
3.4.1 Reactions With -OH Radicals
Although monochloroethane was reported to be relatively unreactive towards
hydroxyl radicals (Brown et al., 1975), this is n'ow generally considered to be
the major mechanism accounting for the removal of the compound from the
atmosphere (Singh et al., 1979). The rate constants for the reaction have been
given as 2.57 x 10"13 cm3/molecule-sec at 265°K (Singh et al., 1979), 3.9 x
10"13 cm3/molecule-sec at 296°K (Howard and Evenson, 1976) and 300°K (Guesten
et al., 1984), and 4.4 x 10"13 cm3/molecule-sec at 302.5°K (Butler et al.,
1978).
The half-life for the reaction with -OH was reported by Brown et al.
(1975) to be about one year. However, Howard and Evenson (1976) estimated that
the atmospheric lifetime of monochloroethane would be about 1 month, and other
studies have indicated that the mean atmospheric residence time would be
0.3 years (Singh et al., 1979), 0.4 years (Altshuller, 1980a,b), 0.2 or 0.6 yr
(for -OH concentrations of 6 x 105/cm , and 2 x 105/cm ) (Snelson et al.,
1978), and 0.041 to 0.16 years (for -OH concentration of 2 x 106/cm to 5 x
105/cm3) (Oilling, 1982).
Altshuller (1980a) reported that a 1 percent depletion of monochloroethane
by -OH radicals would take 6.6 days in January and 0.4 days in July at 40° N
latitude. Altshuller also noted that the atmospheric depletion of organics by
reaction with -OH radicals would vary with latitude due to higher concentra-
tions of -OH radicals in the lower latitudes.
13
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The likely oxidation products resulting from hydroxyl radical attack on
monochloroethane and other chlorinated ethanes were identified by Spence and
Hanst (1978) in a laboratory study in which hydroxyl radical abstraction of
hydrogen from the chloroethane molecule was simulated by using chlorine atoms
to abstract the hydrogen. The chlorine atoms were generated by the UV photo-
dissociation of molecular chlorine. Monochloroethane and 1,1,1-trichloroethane
were the least reactive of the species studied. The oxidation products of
monochloroethane were carbon dioxide, carbon monoxide, formaldehyde, formyl
chloride, and acetyl chloride. Formyl chloride was the principal carbon-
chlorine product formed. Spence and Hanst (1978) noted that in the atmosphere
many of the chlorinated oxidation products would be further attacked to produce
hydrogen chloride, carbon dioxide, and carbon monoxide.
3.4.2 Reactions With Ozone
Brown et al. (1975) reported that monochloroethane was unreactive towards
0.,; the half-life for the reaction was given as 10 years.
3.4.3 Photodegradation
According to Callahan et al. (1979), photodissociation of monochloroethane
in the "terrestrial environment" would not be expected to occur since the com-
pound has no chromophores which absorb in the visible or near-ultraviolet
region of the spectrum. However, several laboratory studies have shown that
the compound undergoes photodegradation when subjected to shorter-wavelength
ultraviolet light. Ethylene was found to be the major decomposition product at
wavelengths of <147 nm (Ichimura et al., 1976; Tiernan and Hughes, 1968;
Cremieux and Herman, 1974). Shold and Ausloos (1979) reported that hydrogen,
in addition to ethylene, was a dominant decomposition product at such short
wavelengths. At slightly longer wavelengths the major products observed were
ethane, ethylene, vinyl chloride, and n-butane.
Under laboratory conditions, and in the presence of nitrogen oxides,
photochemical decomposition of monochloroethane in air resulted in the forma-
tion of formaldehyde and hydrogen chloride (Kanno et al. , 1977).
14
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4. PHARMACOKINETICS
4.1 ABSORPTION
Because monochloroethane is highly volatile, the major route of exposure
is by inhalation. The compound is readily absorbed into the body through the
lungs (Konietzko, 1984). Adriani (1960) reported that at 38°C five volumes of
vapor dissolve in one volume of blood. According to Killian and Weese (1954,
as reported in Konietzko, 1984), approximately 75 percent is bound to cell
constituents in the blood and 25 percent to the plasma. Buch and Buch (1980,
as reported in Konietzko, 1984) calculated that the Ostwald solubility
coefficient of monochloroethane in a blood/air system was 2.5: the oil/blood
partition coefficient was 960. Similarly, Morgan et al. (1972) reported that
the partition coefficient in a blood serum/air system was 2.3, while that for
an olive oil/gas system was 26. The blood/air coefficient is relatively low
compared to that for other chlorinated ethanes, indicating that the compound
would be .rapidly excreted (Morgan et al., 1972: Konietzko, 1984). The major
portion of an inhaled dose is eliminated unchanged in exhaled breath, but
minute traces may remain in the blood for some time (Adriani, 1960). Some of
the compound is also excreted in the urine, feces, and sweat (Adriani, 1960).
4.2 DISTRIBUTION AND TISSUE LEVELS
Adriani (1960) reported that monochloroethane had a high lipid solubility
(data not given): however, the octanol/water partition coefficient has been
calculated to be only 1.54 (Leo et al., 1971). The highest concentrations of
the compound have been found in peri renal fatty tissue and the lowest in
cerebrospinal fluid: the concentration in the brain was twice that in the blood
(Killian and Weese, 1954, as reported in Konietzko, 1984; no other data
reported). Adriani (1960) reported that the concentration of monochloroethane
in the blood was 20 mg/100 mL in cases of light anesthesia and 30 mg/100 mL in
cases of deep anesthesia. A blood level of 40 mg/100 mL was reported to be
15
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lethal. Monochloroethane was one of a number of halogenated organic compounds
found in samples of human milk collected from women residing in several United
States urban areas (Pellizzari et al., 1982).
4.3 METABOLISM
Van Dyke and Wineman (1971) evaluated the dechlorination of a number of
chloroethanes and chloropropanes, using hepatic microsome preparations from
rats. For most of the compounds studied, dechlorination appeared to be
achieved through an enzyme system similar in function to a mixed-function
oxidase system requiring oxygen and NADPH, but which was only slightly depen-
dent on, or not rate-limited by, cytochrome P-450. For monochloroethane,
enzymatic losses of chlorine amounted to less than 0.5 percent of the initial
amount of radiolabel used. It was reported, however, that some dechlorination
(not quantified) occurred in the absence of NADP, suggesting an alternate
pathway of metabolism or a nonenzymatic breakdown of the compound.
Loew et al. (1973) attempted to relate the extent of metabolism of a
series of chloroethanes with the molecular energy conformational or electronic
properties of the compounds. Electronic properties, particularly the electron
deficiency of the most electron-deficient carbon orbital were found to be
predictive of the extent of dechlorination. This indicated that the initial
rate determining step in the dechlorination process was a nucleophilic attack
at the carbon atom orbital. It was suggested that the carbon-chlorine bond is
cleaved and the chlorine displaced by an anion such as OH . The relatively low
level of enzymatic dechlorination of monochloroethane was supported by these
calculations.
Loew et al. (1984) reviewed the available information on the metabolism of
a number of chloroethanes and noted that in most cases the initial oxidative
metabolites were found to be chlorophenols which then formed chloroaldehydes as
a result of loss of HC1. A similar metabolic pathway was suggested for mono-
chloroethane, with the predicted metabolic by-products of acetic acid and
ethanol (formed from acetaldehyde and monochloroethanol). Slight metabolic
conversion of monochloroethane to ethanol was reported by Elfskind (1929, as
reported in Konietzko, 1984), but only following high anesthetic doses.
By calculating the relative heat of reaction for the various metabolic
steps leading from the chloroethanes to the chloroacetaldehydes, Loew et al.
16
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(1984) found that the data indicated that the initial hydroxylation of chloro-
ethanes by the cytochrome P-450 system occurs by a radical oxene mechanism
through the intermediacy of aliphatic hydrocarbon radical formation. These
data were used to predict that the metabolism of monochloroethane would be
comparable to that for 1,1,1-trichloroethane, a compound which is not exten-
sively metabolized, compared to other chloroethanes.
17
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5. GENOTOXICITY AND CARCINOGENICITY
5.1 GENOTOXICITY
Riccio et al. (1983; see also Milman et al., 1984, as reported in MEDLARS
II [Cancerline] 1986) reported that monochloroethane vapor was found to be
mutagenic to various Salmonella strains when tested in desiccators both with
and without the addition of metabolic activation systems.
5.2 CARCINOGENICITY
According to Fishbein (1979a,b), no information was available as of 1979
concerning the potential carcinogenicity of monochloroethane. In recent com-
puterized searches of major bibliographic data bases (MEDLARS II, Chemical
Abstracts) covering the period from 19'76 to 1986, no epidemiological, clinical,
or experimental studies on the potential carcinogenicity of monochloroethane
were found. Tu et al. (1985) reported that chloroethane was inactive in an
i_n vitro cell transformation assay using BALB/C-3T3 cells in the absence of an
exogenous metabolic activation system.
Loew et al. (1984) reviewed the available information on the carcinogeni-
city of a series of chloroethanes and compared the data with the observed and
predicted extent of metabolic conversion of the parent compounds to the sus-
pected active carcinogenic metabolites (i.e., aldehydes). Carcinogenicity was
found to be correlated to several electrophilic properties of the active
metabolites. Because of the low electrophilicity of acetaldehyde, the predicted
main intermediate metabolite of monochloroethane, it was predicted by Loew
et al. that monochloroethane would not be carcinogenic. However, several
laboratory studies have shown that acetaldehyde does induce carcinomas in the
nasal cavity and larynx of rodents (Feron et al. , 1982; Woutersen et al.,
1984). There is also evidence that acetaldehyde is a weak mutagen in certain
i_n vitro genotoxicity assays (see Lam et al., 1986 for review), and that it
forms DNA-protein adducts j_n vitro and j_n vivo (Lam et al., 1986). As Lam
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et al. (1986) noted, the concentrations of acetaldehyde required for the forma-
tion of DNA-protein adducts and those producing carcinogenic effects in rodents
are also cytotoxic concentrations that cause considerable cellular degeneration,
stratified squamous metaplasia, and hyperplasia. These investigators were of
the opinion that both cytotoxicity and DNA - protein crosslink formation may
have been responsible for the observed carcinogenicity. In addition, they also
point out that the known tumor promoter peroxyacetic acid, a compound which
forms when acetaldehyde is exposed to air, may have also contributed to the
development of the nasal tumors.
Because acetaldehyde has been identified as a carcinogen in the aforemen-
tioned animal studies, and structure-activity relationships can be hypothesized
with other chlorinated ethanes that show carcinogenic activity, monochloroethane
might be viewed as having a potential to be carcinogen. There is however, no
presently available data to resolve the uncertainties regarding the presence or
lack of a carcinogenic potential. More specific information is needed on the
extent of metabolism of monochloroethane and on the nature of the carcinogenic
potential of acetaldehyde, a metabolite. Under the circumstances, the weight-
of-evidence for monochloroethane's carcinogenic potential is inadequate for
assessment. Using the EPA cancer assessment guidelines, a group D classifica-
tion is appropriate.
NTP has recently tested ethyl chloride (monochloroethane) and is
presently peer reviewing the technical report prior to submitting the report
to the clearinghouse for final review. In this new bioassay, rats and mice
were exposed to ethyl chloride by inhalation. The technical report number
will be number 346 when it is made available. The carcinogenicity evaluation
should be updated when these new data are available.
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6. DEVELOPMENTAL AND REPRODUCTIVE TOXICITY
In a recent laboratory study monochloroethane was reported to be nonterato-
genic (detailed results are not available) (Submitting Company, 1986). No
other information was found on the developmental or reproductive toxicity of
the compound.
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7. OTHER TOXIC EFFECTS
7.1 ACUTE TOXICITY
7.1.1 Humans
As summarized by Parker et al. (1979; see also NIOSH, 1978), specific
adverse effects reported in humans exposed to monochloroethane have included
central nervous system depression, headaches, dizziness, incoordination,
feeling inebriated, unconsciousness, abdominal crampi, respiratory tract
irritation, respiratory failure, cardiac arrhythmias, cardiac arrest, skin
irritation and freezing, allergic eczema, and eye irritation.
In the past, monochloroethane had been used as a general anesthetic
(Adriani, 1970). Von Oettingen (1958) reported that deaths due to cardiac or
respiratory failure were not uncommon following such use. Anesthetic doses of
the compound result in cerebral cortex blocks, depression of respiration and
vasomotor control, an increase followed by a decrease in the heart rate, and a
reduction in blood pressure. Respiratory arrest has been observed at a mono-
chloroethane concentration of 60,000 ppm (Adrian, 1967, as reported in
Konietzko, 1984). Lawson (1965) suggested that monochloroethane affects the
heart by vagal stimulation and by direct myocardial depression.
The toxic effects of exposure to monochloroethane in humans were evaluated
by Davidson (1926) (see Table 7-1). Exposure to 13,000 ppm (1.3 percent)
monochloroethane in air resulted in only a slight subjective feeling of intoxi-
cation after 17 min. Inhalation of 19,000 ppm produced weak analgesia within
12 minutes: 25,000 ppm produced slight incoordination: and 33,600 ppm produced
incoordination, cyanosis, and nausea. There was an initial increase in reac-
tion times following all exposure levels.
Sayers et al. (1929) reported that two breaths of a 4 percent vapor caused
marked dizziness, an oily taste in the mouth, slight eye irritation, and a
cramplike effect on the stomach. Three or four breaths of a 2 percent vapor
caused dizziness and slight stomach cramps.
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TABLE 7-1. ACUTE TOXICITY OF MONOCHLOROETHANE VAPOR TO HUMANS
Concentration
(mg/L) (ppm)
34.3
50.4
52.8
66.0
88.7
105.6
13,000
19,000
20,000
25,000
33,600
40,000
Exposure
period
17 min
1 min
12 min
50 sec
15 min
30 sec
5 min
8.5 min
Effects
Slight subjective symptoms of intoxication
Initial signs of intoxication
Slight analgesia
After 4 inhalations, dizziness and slight
abdominal cramps
Initial signs of intoxication
Slight incoordi nation
Initial signs of intoxication
Incoordi nation
Cyanosis, nausea
After 2 inhalations, stupor, irritation
of eyes, and stomach cramps
Source: Adapted from Davidson (1926) a'nd Lehmann and Flury (1943).
Eczematous reactions were observed in three individuals exposed to mono-
chloroethane (van Ketel, 1976). All three subjects, however, had also exhib-
ited severe allergic reactions when exposed to deodorant sprays and other
chemicals, such as trichloromonofluoromethane. Torkelson and Rowe (1981)
suggest that allergic reactions to monochloroethane are probably quite rare
except in highly sensitized individuals.
Konietzko (1984) states that because monochloroethane is not metabolized
to a great extent, and because it is rapidly eliminated, it is not likely to
have severe toxic effects on specific organ systems at low concentrations.
7.1.2 Animals'
Sayers et al. (1929) evaluated the acute toxicity of monochloroethane to
guinea pigs (see Table 7-2). Vapor concentrations of 23 percent (230,000 ppm)
for 8 min, 15.3 percent (153,000 ppm) for 30 min, 8 percent (80,000 ppm) for
90 min, and 4 percent (40,000 ppm) for 540 min caused some deaths. Histopatho-
logical changes in lungs, liver, and kidney occurred in some test animals. A
22
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TABLE 7-2. ACUTE TOXICITY OF MONOCHLOROETHANE VAPOR TO GUINEA PIGS
Concentration
(%)
24.1
23.2
15.3
12.7
9.1
8.0
5-1
4
2
1
Time
(min)
5
10
40
90
30
90
40
122
270
540
270
540
810
Effects
Loss of equilibrium: unconscious
Unconscious, 1 death
Some deaths in 30 to 39 min: some survived 40 min
Some deaths in 65 to 90 min
1 death in 1 day, lungs hemorrhagic and edematous,
liver and pancreas congested
All died in 1 to 3 days, hi stopatho logical
degeneration of lungs, liver, kidney, spleen
1 death in 2 days, lungs congested
All survived: abnormal breathing, loss of
equil ibrium
All survived, slight congestion in lungs and
spleen
Some deaths in 45 min to 2 days
All survived
All survived, slight histopathological changes in
lungs, liver, pancreas, and kidneys in some
animal s
All survived, no symptoms
Source: Adapted from Sayers et al. (1929).
concentration of 3.6 percent (36,000 ppm) was reported to be narcotic in rodents
(Frey, 1912; Konig, 1933, as reported in Konietzko, 1984). At concentrations
above 10 percent (100,000 ppm), all test animals were anesthetized (Elfskind,
1928, as reported in Konietzko, 1984). Nuckolls (1933) reported that guinea
pigs exposed to 2.0 to 2.5 percent (20,000 and 25,000 ppm) monochloroethane for
2 hr were unable to stand, had forced and irregular breathing, showed frequent
violent retching, and gradually became unconscious.
Troshina (1964, as reported in Biol. Abstr. 63:17017f) reported a 2-hr LC5Q
of 152 mg/L (57,600 ppm) for rats. Hyperemia of the internal organs, cerebral
edema, and hemmorrhages in the brain and lung were found in histological studies.
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In tests on dogs, Van Liere et al. (1966) found that high concentrations
of monochloroethane (levels not reported) caused a severe drop in blood pres-
sure and decreases in uterine motility and in muscle tonus.
Monochloroethane is an agent for sensitizing the heart to epinephrine
(Reinhardt et al., 1971). Dogs anesthetized with monochloroethane exhibited
cardiac irregularities when injected with epinephrine (Hermann and Vial, 1934;
Morris et al., 1953). Monochloroethane and other volatile anesthetics may
cause cardiac failure by permanently damaging myocardial ultrastructures
involved in excitation-contraction coupling (Doering, 1975).
When placed in the eye of a rabbit, monochloroethane produced corneal
opacity which was attributed to chemically induced epithelial damage (Vannas,
1954). When sprayed for 5 sec on the bared sclera in rabbit eyes, there was a
transient elevation in intraocular pressure followed by transient hypotony
(Puscariu and Cerkez, 1926).
7.2 SUBCHRONIC TOXICITY
7.2.1 Humans
Reversible cerebellar dysfunction was reported in one case of a 28-yr-old
woman who had used monochloroethane as a narcotic for several months (Hes
et al., 1979). The neurological signs included ataxia, nystagmus and scanning
dysarthria, dysdiadochokinesis of each arm, and sluggish lower limb reflexes.
A slight disturbance in liver function and hepatomegaly were also noted.
7.2.2 Animals
Troshina (1964, as reported in Biol. Abstr. 63:17017f) reported that in rats
repeated 2-hr exposures for 60 days to 14 mg/L (5300 ppm) monochloroethane
caused a decrease in phagocytic activity of leukocytes, lowered hippuric acid
formation in liver, and histopathological changes in the liver, brain, and
lungs.
The National Toxicology Program (1981, as reported in Landry et al., 1982)
reported that 90-day inhalation exposures of rats and mice to 0, 2500, 5000,
10,000, or 19,000 ppm monochloroethane resulted in no identifiable histopatho-
logical changes. (The final report for the NTP study has not yet been pub-
lished).
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Landry et al. (1982) conducted a two-week long inhalation study evaluating
the toxic effects of monochloroethane on male and female Fischer 344 rats and
male beagle dogs. Exposures were for 6 hr per day, 5 days per week to 0, 1600,
4000, or 10,000 ppm monochloroethane. There were no treatment-related effects
on body weights, clinical chemistry, hematology, urinalysis, neurology (dogs
only), gross pathology, or histopathology. There was, however, a slight but
significant increase in liver-to-body weight ratios of male rats exposed to
4000 and 10,000 ppm. In separate 6-hr tests on male rats and male B6C3F1
mice, liver non-protein sulfhydryl concentrations (an indicator of potential
toxicity and/or biological reactivity) were slightly but significantly less
than control levels in rats and mice exposed to 4000 ppm and in rats exposed
to 10,000 ppm. This effect was not considered to be a sign of toxicity, but
rather an indication of "adaptive tissue reaction and detoxification
processes."
7.3 CHRONIC TOXICITY
7. 3.1 Humans .
Troshina (1966, as reported in Biol. Abstr. 64: 20506b) reported that some
workers occupationally exposed to monochloroethane exhibited some pathological
changes in the sympathetic nervous system and decreased phagocyte activity of
leukocytes. Shirokov (1976, as reported in MEDLARS II, 1986) reported that
women occupationally exposed to ethylenediamine and various chlorinated
hydrocarbons, including monochloroethane, exhibited gynecological abnormalities
such as inflammatory diseases of the cervix and uterine appendages, colpitis
(vaginitis), conditional anomalies of internal genitalia, and signs of genital
infantilism. No indication was given (in the MEDLARS abstract) as to whether
the study determined if the observed effects were due to exposure to all or only
some of the chemicals.
7.3.2 Animals
In a study conducted by Adams et al. (1939, as reported in Landry et al.,
1982), rats and rabbits exposed to 10,000 ppm monochloroethane for 5 days per
week for 6.5 months exhibited normal weight gains and showed no evidence of
histopathological lesions. In contrast, Troshina (1966, as reported in Biol.
Abstr. 64: 20506b) exposed rats for 4 hr per day to only 0.57 mg/L (220 ppm)
25
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monochloroethane for six months and found changes in liver function, decreased
arterial blood pressure, lowered phagocytic activity of leukocytes, lipid
degenerative changes in the liver, and some dystrophic changes in the lungs.
7.4 BIOCHEMICAL EFFECTS
Takano and Miyazaki (1982) reported that monochloroethane was one of four-
teen chlorinated ethanes and ethylenes that inhibited glutamate and malate
oxidation in rat mitochondria. Of the compounds tested, monochloroethane
produced the lowest level of inhibition.
In a study conducted by Loprinzi and Verma (1984), topically applied mono-
chloroethane had a variable and unpredictable effect on 12-0-tetradecanoylphor-
bol-13-acetate (TPA)-induced ornithine decarboxylase activity in human skin.
26
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U.S.
Region 5,
230 S. j
Chic-:-.
Protecot:
i:?L-Iii
TECHNICAL REPORT DATA
(Please read Instructions on the reverte before completing)
1. REPORT NO. 2.
6CO/8-88/080F
4. TITLE AND SUBTITLE
Summary Review of Health Effects Associated with
Monochloroethane: Health Issue Assessment
7. AUTMOR(S)
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Environmental Criteria and Assessment Office (MD-52)
Office of Health and Environmental Assessment, ORD
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
12. SPONSORING AGENCY NAME AND ADDRESS
Office .of Health and Environmental Assessment (RD-689)
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC 20460
3. RECIPIENT'S ACCESSION NO.
6. REPORT DATE
June 1988
6. PERFORMING ORGANIZATION CODE
600/23
S. PERFORMING ORGANIZATION REPORT NO.
ECAO-R-0091
10 PROGRAM ELEMENT NO.
A! 01
W CONTRACT /GRANT NO.
DW 899229-01-0
13. TYPE OF REPORT AND PERIOD COVERED
Tier 1
14. SPONSORING AGENCY CODE
600/21
15. SUPPLEMENTARY NOTES
16. ABSTRACT
Monochloroethane (ethyl chloride) is released into the environment
from anthropogenic sources and has been identified in air samples from
locations around the U.S. The major route of exposure is inhalation.
Histopathological changes in the lungs, liver and kidneys have been
observed in animals at concentrations >20,000 ppm. Severe toxic effects
were seen at concentrations >40,000 ppm. Humans exposed to high
concentrations exhibited CNS, cardiac, and respiratory effects. There
is no conclusive information about chronic toxicity of monochloroethane
to humans, and it is in EPA's Group D as to carcinogenicity.
Monochloroethane was found to be non-teratogenic in one animal study.
17 KEY WORDS AND DOCUMENT ANALYSIS
a DESCRIPTORS
18. DISTRIBUTION STATEMENT
Release Unlimited
b. IDENTIFIERS/OPEN ENDED TERMS
19. SECURITY CLASS (This Report)
Unclassified
20. SECURITY CLASS (This page)
Unclassified
c. COSATI Field/Group
21. NO. OF PAGES
22. PRICE
EPA F«rm 2220-1 (R«v. 4-77) PREVIOUS EDITION i( OBSOLETE
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