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EPA/600/8-88/080
June 1988
Summary Review of Health Effects
Associated with Monochloroethane
Health Issue Assessment
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
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.
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Contents
Page
Tables jv
Preface '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. v
Authors, Contributors, and Reviewers vi
1. Summary and Conclusions 1
2. Introduction 5
3. Air Quality and Environmental Fate 11
3.1 Sources 11
3.2 Distribution , '.'.'.'.'.'.'.'.'. 12
3.3 Ambient Concentrations 12
3.3.1 Exposure Levels 12
3.4 Fate .'..'.'.'.'.'." 12
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 15
5. Genotoxicity and Carcinogenicity 17
5.1 Genotoxicity "... 17
5.2 Carcinogenicity '.','.'.'.' 17
6. Developmental and Reproductive Toxicity 19
7. Other Toxic Effects 21
7.1 Acute Toxicity 'm\]\ 21
7.1.1 Humans '.'.'.'.'.'. 21
7.1.2 Animals '.'.'.'.'.'.'. 21
7.2 Subchronic Toxicity '.'.'.'.'.'.'.'.'. 23
7.2.1 Humans 23
7.2.2 Animals 23
7.3 Chronic Toxicity '.'.'.'.'.'.'.'.'.'.'.'. 24
7.3.1 Humans ' ' 24
7.3.2 Animals ' ' ' ' 24
7.4 Biochemical Effects '.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 24
8. References 25
iii
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No.
2-1
3-1
7-1
7-2
List of Tables
Chemical and Physical Properties of Monochloroethane
Atmospheric Levels of Monochloroethane
Acute toxicity of Monochloroethane Vapor to Humans .
Acute Toxicity of Monochloroethane Vapor to
Guinea Pigs
7
13
22
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
monocnloroethane 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,
Environmental 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.
VI
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1. Summary and Conclusions
Monochloroethane (C2H5CI, CAS No. 75-00-3, also referred to as
chloroethane 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
production 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.
Monochloroethane is unreactive towards O3. 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
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is needed to determine to what extent such reactions occur under natural
conditions.
The mean atmospheric residence times reported for rnonochloroethane,
as 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
rnonochloroethane is inhalation. The compound is readily absorbed into the
blood through the lungs and rapidly eliminated in exhaled breath. Blood/air
partition coefficients of 2.3 and 2.5 have been reported. Little information is
available concerning tissue distribution of absorbed rnonochloroethane. 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
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 intoxication 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 rnonochloroethane
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 subchrpnic and
chronic toxicity of monochloroethane to humans. One animal study indicated
that exposures 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 pressure, 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 in vitro cell transformation assay
using BALB/ c-3T3 cells in the absence of exogenous metabolic activation.
Based on the in vitro mutagenic activity of monochloroethane (with and
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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 monochloroethane may have carcinogenic potential.
However, there were no standard chronic carcinogenicity studies found in the
literature which report direct clinical, epidemiological, 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
teratogenicity 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
information concerning the potential health effects associated with exposure
to monbchloroethane (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, including 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 CgHsCI and a
molecular 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 monochloroethane produced in the United States is made by the
hydrochlorination of ethylene (Morris and Tasto, 1979). In 1976, United States
production of monochloroethane 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
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
anesthetics, 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
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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
monochloroethane (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 Administration is 1000 ppm (2600 pg/m3) for an 8-hr
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 being 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 106lbs/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; Shamel 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
neoprene, polyvinyl chloride compositions, polyurethane rigid foam, and
creosotetreated wood (Hartstein and Forshey, 1974).
Singh et al. (1981) reported that 0.01 million tons (22 x 1Q6|bs) 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 environmental media in industrial effluents. Perry et al. (1979) found
it in 2 of 63 effluents from chemical manufacturing plants. Concentrations
were below 10 pg/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).
Partitioning of monochloroethane between the atmosphere and
hydrosphere was calculated by Dilling (1982, 1977) from vapor pressure and
water solubility data using the following formula:
H
C .
air
water
16.04 X P X M
TXS
where:
H = partition coefficient
C = concentration
P = vapor pressure (mm Hg)
M = molecular weight
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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 al., 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
monochloroethane 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.
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 al., 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.
3.3.7 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 pg/day in Houston, TX, 2.7 ug/day in
St. Louis, MO, 2.4 ng/day in Denver, CO, and 5.1 u,g/day in Riverside, CA.
These doses were calculated based on the breathing rate for a 70 kg man.
j
3.4 Fate
The U.S. Environmental Protection Agency (1975b) reported that
monochloroethane emitted to the atmosphere is relatively rapidly lost through
photochemical reactions. The following sections deal with the various types of
these reactions.
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Tattle 3-1. Atmospheric Levels of Monochloroethane
Locality
Concentration
(PPt)
Reference
<5
Rural Washington State
Grimsrud and Rasmussen,
1975
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.)
Iberville Parish, LA
Houston, TX
St. Louis, MO
Denver, CO
Riverside, CA
Staten Island, NY
Pittsburgh, PA
Chicago, IL
Pellizzari, 1977a
Singh etal., 1981
Singh etal., 1981
Singh etal., 1981
Singh etal., 1981
Singh etal., 1983
Singh etal., 1983
Singh et al., 7983
aAs reported in Pellizzari et at. (1979).
3.4.1 Reactions with -OH Radicals
Although monochloroethane was reported to be relatively unreactive
towards.hydroxyl radicals (Brown et al., 1975), this is now 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 cmS/molecule-sec at 265°K
(Singh et al., 1979), 3.9 x 10-13 cmS/molecule-sec at 296eK (Howard and
Evenson, 1976) and 300°K (Guesten et al., 1984), and 44 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/cm3, and 2 x 105/cm3) (Snelson et
al., 1978), and 0.041 to 0.16 years (for -OH concentration of 2 x 106/cm3 to 5
x 105/cm3) (Dilling, 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 concentrations 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 photodissociation 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 carbonchlorine 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 03; 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 compound 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
formation of formaldehyde and hydrogen chloride (Kanno et at., 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). Adrian! (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,';1 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 perirenal 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 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
dependent 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,
15
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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 HCI. A similar metabolic pathway was
suggested for monochloroethane, 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. (1984)
found that the data indicated that the initial hydroxylation of chloroethanes 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,l;l-trichloroethane, a compound which is not
extensively metabolized, compared to other chloroethanes.
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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
computerized searches of major bibliographic data bases (MEDLARS II,
Chemical Abstracts) covering the period from 1976 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 in 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
Carcinogenicity of a series of chloroethanes and compared the data with the
observed and predicted extent of metabolic conversion of the parent
compounds to the suspected 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 in vitro genotoxicity assays
(see Lam et al., 1986 for review), and that it forms DNA-protein adducts in
vitro and in vivo (Lam et al., 1986). As Lam et al. (1986) noted, the
concentrations of acetaldehyde required for the formation 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
aforementioned 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.
17
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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 classification 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.
18
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6. Developmental and Reproductive Toxicity
In a recent laboratory study monochloroethane was reported to be
nonteratogenic (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
mcoordmation, feeling inebriated, unconsciousness, abdominal cramps'
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
(Adrian!, 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
monochloroethane 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 feelina of
intoxication 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 reaction 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 cramphke effect on the stomach. Three or four breaths of a 2 percent vanor
caused dizziness and slight stomach cramps.
Eczematous reactions were observed in three individuals exposed to
monochloroethane (van Ketel, 1976). All three subjects, however, had also
exhibited 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 probablv auite
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.
7.7.2 Animals
Sayers et al. (1929) evaluated the acute toxicity of monochloroethane to
guinea pigs (see Table 7-2). Vapor concentrations of 23 percent (230000
ppm) for 8 min, 15.3 percent (153,000 ppm) for 30 min, 8 percent (80000
21
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Table 7*1. Acute Toxlclty of Monochloroethane Vapor to Humans
Concentration
(mg/L)
(ppm)
Exposure
Period
Effects
34.3
50.4
52.8
66.0
88.7
105.6
13,000 17 min Slight subjective symptoms of
intoxication
19,000 1 min Initial signs of intoxication
12 min Slight analgesia
20,000 -- After 4 inhalations, dizziness and slight
abdominal cramps
25,000 50 sec Initial signs of intoxication
15 min Slight incoordination
33,600 30 sec Initial signs of intoxication
5 min Incoordination
8.5 min Cyanosis, nausea
40,000 -- After 2 inhalations., stupor, irritation
of eyes, and stomach cramps
Source: Adapted from Davidson (1926) and Lehmann and Flury (1943).
ppm) for 90 min, and 4 percent (40,000 ppm) for 540 min caused some
deaths. Histopathological changes in lungs, liver, and kidney occurred in
some test animals. A 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
LCso 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.
In tests on dogs, Van Liere et al. (1966) found that high concentrations of
monochloroethane (levels not reported) caused a severe drop in blood
pressure 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,
22
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Table 7-2. Acute Toxicify of Monochloroethane Vapor to Guinea Pigs
Concentra-
tion (%) Time (min) Effects
24.1
23.2
15.3
12.7
9.1
8.0
5.1
4
2
1
5
10
40
90
30
90
40
122
270
540
270
540
810
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, histopathological degeneration
of lungs, liver, kidney, spleen
1 death in 2 days, lungs congested
All survived: abnormal breathing, loss of equilibrium
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 animals
All survived, no symptoms
Source: Adapted from Sayers et al. (1929).
there was a transient elevation in intraocular pressure followed by transient
hypotony (Puscariu and Cerkez, 1926).
7.2 Subchronic Toxicity
7.2.7 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 dysarthna, 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
towered hippuric acid formation in liver, and histopathological changes in the
liver, brain, and lungs.
he N?'Tau Toxicol°9y Program (1981, as reported in Landry et al.,
reported that 90-day inhalation exposures of rats and mice to 0, 2500,
23
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5000 10000 or 19,000 ppm monochloroethane resulted in no identifiable
Wstopathologi'cal changes^e final report for the NTP study has not yet
andyetal. (1982) conducted a two-week long inhalation study
evaluating the toxic effects of monochloroethane on male and fern Je Fischer
344 rats and male beagle dogs. Exposures were for 6 hr per day, 5 days per
wtek S 0 1600 4f!oO, or 10,000 ppm monochloroethane. There were no
Sment-related effects on body weights, clinical chemistry' ematology
urinalysis, neurology (dogs only), gross pathology or to^*^ft TJJT?
was. however, a slight but significant increase in l.ver-to-body weight ratios
of male rats exposed to 4000 and 10,000 ppm. In separate 6-hr tests on
maS rats and male B6C3F1 mice, liver non-protein sul hydryl concentrations
Sn 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 n rats exposed to 10,000 ppm. This effect was not considered to be a
3?n of toxictty, but rather an indication of "adaptive tissue react,on and
detoxification processes."
7.3 Chronic Toxicity
7.3.7 Humans
Troshina (1966, as reported in Biol. Abstr. 64: 20506b) reported that
some workers occupational^ exposed to monochloroethane exhibited some
pathological changes in the sympathetic nervous system and decreased
Phagocyte activity of leukocytes. Shirokov (1976, as reported in MEDLARS \\
1986) reported that women occupational^ exposed to ethyle ned.am.ne .and
various chlorinated hydrocarbons, including monochloroethane exh oited
gynecological abnormalities such as inflammatory diseases of the cervix and
uterine appendages, colpitis (vaginitis), conditional anomalies of mternal
gentalia, 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
oer week for 6.5 months exhibited normal weight gams and showed no
Knee o 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 pprn) monochloroethane for six months and found changes ,,n live
unction, 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
fourteen chlorinated ethanes and ethylenes that inhibited 9'utamff.a"d
malate oxidation in rat mitochondria. Of the compounds tested,
monochloroethane produced the lowest level of inhibition.
m°nfn a Sudy Conducted by Loprinzi and Verma (1984), topically applied
monochloroethane had a variable and unpredictable effect on i 2 :-0-
tetradecanoylphorbol-13-acetate (TPA)-induced ornithme decarboxylase
activity in human skin.
24
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