EPA-560/11-80-015
June 1980
SUPPORT DOCUMENT
HEALTH EFFECTS TEST RULE:
CHLOROMETHANE
ASSESSMENT DIVISION
OFFICE OF TOXIC SUBSTANCES
Washington, D.C. 20460
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDES AND TOXIC SUBSTANCES
WASHINGTON, D.C. 20460
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CONTENTS
Introduction 1
I. Identity of Chloromethane 2
II. Exposure Aspects 5
A. General 5
B. Occupational Exposure 6
C. General Population Exposure 10
III. Health Effects 14
A. Systemic Effects 14
B . Neurotoxicity 26
C. Mutagenicity 35
D. Oncogenicity 44
E. Teratogenicity « 49
F. Metabolism , 54
G. Epidemiology 63
IV. Summary 64
References Cited , 67
References Reviewed but not Cited . .79
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INTRODUCTION
In its first report to the EPA in October 1977, the Toxic
Substances Control Act Interagency Testing Committee (TSCA ITC)
recommended that chloromethane be given priority consideration
for the development of testing requirements under Section 4 of
the Toxic Substances Control Act (TSCA ITC 1970). Specifically,
the ITC recommended that chloromethane be tested for its
carcinogenicity, mutagenicity, teratogenicity, and other chronic
effects. With regard to chronic effects, the ITC expressed
particular concern for chloromethane's effects on the central
nervous system, liver, kidney, bone marrow, and the
cardiovascular system.
On the basis of information presented in the following
sections, the EPA is proposing that chloromethane be tested for
oncogenicity and structural teratogenicity. This document
supports the EPA's proposed test rules requiring such testing.
Test standards for oncogenicity and structural teratogenicity
have been proposed.
In addition the EPA is recommending that chloromethane be
tested for potential chronic neurotoxic effects, mutagenicity,
and behavioral teratogenicity but is not proposing testing at
this time. Because the EPA has not yet proposed test standards
for chronic neurotoxic effects, behavioral teratogenicity, or
some of the mutagenicity tests, the Agency is deferring proposal
of test rules. The EPA is requesting comment from the public on
the pertinent issues set forth in this document and the
accompanying Preamble pertaining to such testing.
The EPA has concluded that sufficient information is already
available to evaluate chloromethane's effects on the liver,
kidney, bone marrow, and cardiovascular system. Thus, testing
will not be required.
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I• Identity of Chloromethane
Chloromethane, CH3ci, (also known as methyl chloride) is a
colorless, noncorrosive gas at room temperature and normal atmos-
pheric pressure. Other physical properties of this chemical
include: molecular weight, 50.49; boiling point, -23.7°C;
melting point, -97.6°C; specific gravity, 0.92 at 20°C; solubil-
ity in water, 0.74 g/100 ml at 25°C (DeForest 1979); vapor
pressure, 5 atm at 20°C; and an estimated logarithm of the
octanol/water partition coefficient (log Poct) of 0.91 (Hansch et
al. 1975).1
Almost all of the Chloromethane produced in this country
(greater than 98 percent) is made by the hydrochlorination of
methanol (Lowenheim and Moran 1975, CMR 1976). Ahlstrom and
Steele (1979) state that two grades of Chloromethane are
produced, the technical and the refrigerant. The refrigerant
grade must be very pure to prevent attack on the refrigeration
eguipment by impurities present in the Chloromethane, and
generally contains less than 75 ppm water. These authors give
the known contaminants of a technical grade product as no more
than 100 ppm Ho^/ vinyl chloride, ethyl chloride and residue, 50
ppm methanol and acetone, 20 ppm dimethyl ether and 10 ppm
hydrogen chloride. It has also been reported that chloroform
(trichloromethane)and carbon tetrachloride (tetrachloromethane)
are obtained as coproducts in the production of Chloromethane by
the hydrochlorination of methanol (SRI Undated, SRI 1979a), so
that possible contamination by these products may also occur.
Table 1 compiles information obtained through personal
communication with several companies on purity and contaminants
of their products.
With the exception of the solubility in water and the log of
the octanol/water partition coefficient, all physical properties
were obtained from recent editions of the CRC Handbook of
Chemistry and Physics (1978) and the Merck Index (1976).
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The direct cTilorination of methane produces a small amount
of chloromethane (less than 2 percent), in which case there is
the potential for contamination with dichloromethane, chloroform,
and carbon tetrachloride, in order of importance (Lowenheim and
Moran 1975).
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II. Exposure Aspects
A. General
The TSCA Inventory (OPTS 1980) states that the production
range (includes importation volumes) statistics for chloromethane
(CAS. No. 74-87-3) in 1977 was between 100 and 500 million
pounds. The Inventory gives ten producers at twelve sites for
chloromethane production in 1977.2
In 1979, the Chemical Marketing Reporter (CMR) reported that
U.S. production capacity was approximately 625 million pounds as
produced by nine manufacturers at eleven sites (CMR 1979). The
production volume in the United States averaged about 450 million
pounds per year between 1970 and 1976, ranging from 544 million
pounds in 1973 to 304 million pounds in 1975 (USITC 1970-1975).
CMR reported that demand for chloromethane was 485 million pounds
in 1978, 497 million pounds in 1979, and an estimated 550 million
pounds in 1983, a growth rate of 2-3 percent per year through
1983, a result mainly of the growth potential of silicones (CMR
1979). The quantities of chloromethane that are either imported
or exported are insignificant (Davis et al. 1977).
Chloromethane is used almost exclusively as an intermediate.
Approximately 50 percent of all chloromethane is consumed in the
manufacture of silicones which are used for a wide variety of
products (CMR 1979). About 30 percent of chloromethane consump-
tion is for the production of tetramethyllead, an antiknock
compound used in gasoline formulations. This use is probably
declining in the United States as a result of recent restrictions
on the use of lead in gasoline, although tetramethyllead is being
exported (CMR 1979).
'This production range information does not include any
production/importation data claimed as confidential by the
person(s) reporting for the TSCA Inventory, nor does it include
any information which would compromise Confidential Business
Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the
limitations contained in the Inventory Reporting Regulations
(40 CFR 710).
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Minor uses of chloromethane as a methylating agent in the
production of methyl cellulose, as an intermediate in the
production of quaternary amines, and as an intermediate in the
production of certain pesticides account for about 4 percent each
of total consumption. A variety of other intermediate uses such
as in the production of Triptane®, an antiknock fuel additive,
and methyl mercaptan, used to produce jet fuel additives, account
for about 4 percent of total consumption.
The major nonintermediate use of chloromethane, which
accounts for about 4 percent of consumption, is as a catalyst-
solvent in the manufacture of butyl rubber. Minor noninter-
mediate uses of chloromethane are as a foam-blowing agent for
extruded polystyrene foams, e.g., StyrofoamR (Shamel et al. 1975,
NAS 1978, SRI Undated) and as a direct contact refrigerant (SRI
1979b). At one time chloromethane was used widely as a
refrigerant in both domestic and industrial refrigerators.
Although there are some refrigeration devices using chloromethane
still in operation today, this use has been almost completely
replaced by other substances, notably the chlorofluorocarbons.
Chloromethane is also used as an aerosol propellant combined with
dichloromethane, propane, and Freon 12 for various aerosol mixes
(DeForest 1979).
B. Occupational Exposure
Because chloromethane is a gas at room temperature, the
major route of human exposure to chloromethane is almost
certainly inhalation. The 1972-74 National Occupational Hazard
Survey (NOHS) indicates that an estimated 50,575 workers have the
potential for exposure to chloromethane (NIOSH 1978). Although
the chloromethane is stored, transferred, and reacted in rela-
tively closed systems, the data discussed below indicate that
chloromethane is present in the working environment and that
significant human exposures do occur. Furthermore, elevated
short-term exposure levels of chloromethane can occur through a
leak or when operators must collect quality-control samples.
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The National Institute for Occupational Safety and Health
(NIOSH) has sponsored studies in several plants that produce or
use chloromethane to evaluate the extent of worker exposure in
various occupational settings. The exposure levels found in
these studies, described below, were generally at or below the
current threshold limit values (TLVs) for the time weighted
average (TWA) as 100 ppm (210 mg/m3) (weight/volume), the ceiling
as 200 ppm, and the peak level (5 minutes in 3 hours) as 300 ppm
(USOSHA 1974).
The American Conference of Governmental Industrial
Hygienists (ACGIH) is proposing that the present TLV be lowered
to 50 ppm, primarily on the basis of Repko's study discussed
later (see Section III.B.2.) (ACGIH 1979).
At the Dow Corning plant site in Midland, Michigan, chloro-
methane is used in the production of methyl chlorosilanes in
three buildings, and is used as a direct contact refrigerant in
three other buildings (SRI 1979b). In the first industrial
hygiene survey conducted by SRI International (SRI) at the Dow
Corning Corporation on September 27, 1977 (SRI 1979b), it was
determined that chloromethane levels in the working environment
ranged from less than 1 ppm to 51 ppm (as area samples). In
March 1979 SRI conducted a personal monitoring survey of the
operators at the Dow Corning plant site for full shift TWA
exposure concentrations. At least 38 operators work directly
within areas of the plant that produce and use chloromethane.
Additional workers with the potential for exposure include main-
tenance personnel, material handlers and laboratory personnel.
Levels of chloromethane from below detection to 12.6 ppm were
determined on operators, and short-term levels of 0.6 ppm to
5.8 ppm were determined on maintenance workers. Eight-hour TWA
concentrations in four work areas were determined to range from
below detection to 31.6 ppm. The highest levels were consis-
tently found in chloromethane compressor areas. No samples were
taken from areas in which chloromethane is used as a refrigerant.
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Dow Chemical uses chlorotnethane as a foam-blowing agent in
its polystyrene (StyrofoamR) foam process (Crandall 1978, p.
2). The StyrofoamR production occurs in a closed system until
the material comes through a die in the extruder and expands onto
a conveyer assembly. Employees are exposed to chloromethane in
the foam production area. Exposure is also known to occur when
chloromethane is liberated from the foam product while it is
cooling and in storage, or when the residual chloromethane is
released by certain operational procedures such as cutting, rou-
ting, drilling, and reaming of the finished product (Crandall
1978). Levels of 105 parts per trillion (ppt) (0.0001 ppm) and
355 ppt (0.00036 ppm) were found in two air samples collected
from the foam storage warehouse (Crandall 1978, p. .12). The
average eight-hour TWA exposure to chloromethane found in an SRI
study ranged from 15 ppm to 54 ppm at various sites in the
Styrofoam® plant, with the highest eight-hour TWA level being 101
ppm (Crandall 1978). In another SRI study, average half-hour
concentrations at sample points in Dow's fabrication plants
ranged from 2-1500 ppm (SRI Undated). In 1969 Dow Chemical
conducted a survey of nine in-plant chloromethane-containing
manufacturing operations using continuous monitoring devices for
four months for 54 job classifications. Time weighted average
concentrations ranged from 5-78 ppm with an average 30 ppm
concentration. Peak concentrations were as high as 440 ppm, but
the duration of peak concentration exposure was not reported (SRI
Undated).
DuPont Corporation produces chloromethane and uses it in the
production of tetramethyllead (SRI 1978a). Tetramethyllead is
produced in a closed system by the reaction of chloromethane with
a sodium-lead alloy and aluminum chloride. Unreacted chloro-
methane is pumped to a recovery unit. A concentration of 209 ppm
was found in the tetramethyllead compressor room. In three
operating areas where chloromethane is used, short-term levels
ranging from undetectable to 71 ppm of chloromethane were
found. Chloromethane exposure levels (as TWA) were 6 ppm to 57
ppm in the chloromethane manufacturing facility, 2 ppm to 75 ppm
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in the tetramethyllead manufacturing facility, and 1 ppm to
34 ppm in the chloromethane recovery area. The duration of
exposure to chloromethane for employees in the production area
may be up to eight hours per work shift.
Continental Oil Company (Conoco) produces chloromethane with
potential exposures in the production area and in the tank-car
loading operations (SRI 1978b). In an industrial hygiene survey
done by SRI at the Conoco Chemicals facility in Westlake,
Louisiana, on October 18-19, 1977, it was determined from sam-
pling data that chloromethane levels in the working environment
ranged from 3 to 36 ppm (as area samples) (SRI 1979a).
Simultaneous sampling by Conoco showed chloromethane concen-
trations ranging from less than 1 to 58 ppm. Personal sampling
data accumulated by Conoco since 1975 in their quarterly sampling
program showed eight-hour TWA chloromethane concentrations
determined from personal monitoring varying from less than 0.2 to
7.5 ppm. Average eight-hour TWA concentrations in the air of 11
work aras ranged from 0.7 to 55.7 ppm. The highest
concentrations were found in the compressor areas (SRI 1979a).
Chloromethane and methyl chlorosilane manufacturing
facilities are located at a General Electric plant site (SRI
1978c). Workers were reported to be exposed to chloromethane
levels of 0.8 ppm to 75 ppm in the manufacturing facility,
recovery unit, and compressor room from three to five hours each
day.
Chloromethane is also used in the manufacturing process of
four herbicides: paraquat (1,1'-dimethyl-4,4'-bipyridinium
dichloride); DSMA (disodium methylarsonate); MSMA (monosodium
methylarsonate); and cacodylic acid (dimethylarsinic acid)
(Sittig 1977). Paraquat is made by the reaction of 4,4'-
bipyridyl and chloromethane in water. MSMA and DSMA are final
products after sodium arsenite is treated with gaseous chloro-
methane. This reaction takes place in a closed system;
additional chloromethane is consumed in a side reaction with
sodium hydroxide.Inthe production of cacodylic acid,
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chloromethane is added to the reaction chamber throughout the
reaction, then the excess is bled off. No data were found on the
occupational exposure to chloromethane in these four herbicide
manufacturing processes, although the possibility of low-level
constant air concentrations, or high-level intermittent
concentrations exists, as in other manufacturing processes using
chloromethane. No information was found on possible
chloromethane contamination of these pesticides.
C. General Population Exposure^
Chloromethane appears to be the most abundant halocarbon
present in the atmosphere (Lovelock 1975., Singh et al. 1977).
With an average background tropospheric concentration of 611 ppt
(0.0006 ppm) in the northern hemisphere, and 615 ppt (0.0006 ppm)
in the southern hemisphere (SRI 1979c), the anthropogenic (i.e.,
those resulting from human activities) sources are relatively
unimportant contributors to the atmosphere as extensive mixing
probably does not occur in upper tropospheric levels. Lower
stratospheric levels are approximately 5 percent less (Cronn et
al. 1977).
Chloromethane is decomposed when it reacts with hydroxyl
radicals in the troposphere, with a small fraction reaching the
upper stratosphere, where it is destroyed by photolysis (NAS
1976). The National Academy of Sciences (NAS 1976) estimated
that the residence time of chloromethane in the atmosphere is
about one year. More recently, SRI (1979c) estimated the
residence time in the atmosphere to be 231 days.
The National Academy of Sciences (1976) reported an esti-
mated total global emission rate (both natural and anthropogenic
of the information presented in this section is not
necessarily directly relevant to EPA's analysis of the need to
require health effects testing for chloromethane. However, this
section is included to give an indication of the exposure of the
population to chloromethane. The EPA is also evaluating the
possible environmental effects of chloromethane, and the General
Population Exposure subsection is applicable to that assessment
a s we 11. •
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emissions) of 14.7 billion pounds per year, based on an average
global concentration of 750 ppt (0.00075-ppm). Two years later
they estimated that the worldwide industrial emissions of
chloromethane were 17.4 million pounds in 1973, only about 0.1
percent of the total emissions (NAS 1978) .
The estimated intentional and unintentional U.S.
chloromethane release to the atmosphere from its production,
transport, storage, use, and presence as an impurity in other
products, amounted to 11.4 million pounds in 1973, approximately
2 percent of the annual U.S. production volume (NAS 1978).
Arthur D. Little, Inc. has similarly estimated that the United
States produced approximately 60 percent of chloromethane
worldwide in 1973 with an approximate release of 10.5 million
pounds (Shamel et al. 1975 p. 11-27 and p. 111-21.)
If is is assumed that the 2 percent release rate applies
worldwide, the total release of chloromethane would not exceed 20
million pounds. Using Singh et al.'s (1979) estimated 5-10
percent release rate from production, however, total release
could be as high as over 50 million pounds annually. However,
the chloromethane industry has calculated somewhat lower
figures. Although, for example, Dow Corning vents escaping
chloromethane from the manufacturing area through a stack to the
outside air (SRI 1979b), the industry (NSF 1975) indicates that
the fraction of total annual production escaping from the plant
site to the atmosphere during manufacture of chloromethane is
0.0011-0.005 percent. In any case, industrial emissions of
chloromethane appear to be only a small fraction of the total
amount of chloromethane estimated to be entering the atmosphere
annually.
It is believed that the oceans constitute a major natural
source of chloromethane. Singh et al. (1979) reported that the
average surface concentration of chloromethane in the Pacific
Ocean is 26.8 x 10"^ g/liter (26.8 ppt). It has been suggested
that iodomethane, found ubiquitously in ocean water, reacts with
chloride ion in the ocean surface water to form chloromethane,
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which then diffuses into the atmosphere (NAS 1976). Singh et al.
(1979) have calculated that 6.6 billion pounds of chloromethane
enters the atmosphere annually from the oceans.
It has also been suggested that burning vegetation is
another important natural source of chloromethane. Palmer (1976)
calculated that forest fires in the United States are responsible
for about 252 million pounds per year of chloromethane released
(average for 1972-1974). An additional 5.4 million pounds per
year was calculated by Palmer to have been released from agri-
cultural burning.
Another possible source of chloromethane is from photolytic
decomposition of higher alkyl halides in the environment. The
photolysis of gaseous chloroethane gives rise to chloromethane
(Cremieux and Herman 1974), which suggests that levels in the
atmosphere may be less static than is implied by the relatively
long residence time estimated by either the National Academy of
Sciences (1976) or SRI (1979c).
Although it is clear from the above information that major
sources of atmospheric chloromethane are natural, anthropogenic
sources may be responsible for significantly elevated local con-
centrations. For example, Singh et al. (1979) reported that they
found elevated urban concentrations of chloromethane in Lisbon
[2.20 parts per billion (ppb) (0.0022 ppm)] and near Los Angeles
[average 1.50 ppb (0.0015 ppm); maximum 3.80 ppb (0.0038 ppm)].
They have suggested that automobile exhaust may be an important
source of chloromethane. Palmer (1976) estimated that about 120
million pounds of chloromethane is released annually from
building fires and 40 million pounds from the burning of
polyvinyl chloride (PVC) in wastes (average for 1972-1974). The
latter source was recognized by Palmer to be decreasing as the
burning of such wastes was declining. The National Academy of
Sciences (1978) estimated that tobacco smoking worldwide results
in about 44 million pounds of chloromethane entering the
atmosphere annually. Based on average human air intake of 23
m-Vday, and rtean chloromethane concentrations over Los Angeles,
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Phoenix, and Oakland of 3.00 ppb (0.003 ppm) , 2.39 ppb (0.0024
ppm) , and 1.07 ppb (0.0011 pprn) , respectively, the average human
dose of chlororaethane was calculated to be 140 ug/day, 109
ug/day, and 60 ug/day at the three sites respectively (SRI
Elevated levels of chlorome thane can occur in indoor air.
Measurements of chloromethane in various contained atmospheres
showed between 0.65 ppb (0.00065 ppm) and 8.00 ppb (0.008 ppm) by
volume in various automobiles, 1.4 ppb (0.0014 ppm) in a
restaurant, and over 20 ppb (0.02 ppm) in an apartment after a
cigarette was smoked (Harsch 1977). Chloromethane was generally
the predominant halomethane found in indoor air and was typically
present at between two and ten times the ambient outdoor level
(Harsch 1977, NAS 1978). Tt was suggested by the National
Academy of Sciences (1978) that these elevated indoor levels may
be due to cigarette smoking.
Chloromethane is found primarily in the air and ocean
surface water, although it has also been qualitatively detected
once in United States river water, three times in effluents from
chemical plants, twice in effluents from sewage treatment plants,
and eight times in drinking water (ORD 1979), very possibly from
the chlorination of drinking water (Davis 1977, USEPA 1979c) .
The total number of times tested was not indicated. For the
protection of human health from the toxic properties of
chloromethane ingested through water and through contaminated
aquatic organisms, the ambient water criterion level for
chloromethane is 2 ug/1 (USEPA 1979c).
Although chloromethane is present in the atmosphere at a
background parts per trillion level from natural sources (e.g.,
ocean waters) and at a parts per billion level in urban
atmospheres from anthropogenic (e.g., cigarette smoke) sources,
the EPA believes that the local, high concentrations of
chloromethane in the parts per million levels found in
occupational settings present the greatest risk of health effects
resulting from exposure to chloromethane.
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III. Health Effects
A. Systemic Effects
1. Data Evaluation
a. Human Studies
The EPA is not aware of any epidemiology study which evalu-
ates the systemic effects of chloromethane in humans exposed
chronically. However, there is a substantial case history
literature of poisoning in humans, beginning with Gerbis' paper
in 1914. Smith and von Oettingen (1947a) tallied the number of
published chloromethane intoxication cases. By 1947 there were
210 reported cases, of which 1 5 were fatal. The majority of
poisonings before 1960 were due to exposure from chloromethane's
use as a refrigerant (see e.g., Kegel et al. 1929, Schwarz 1926),
while present day poisonings in this country appear to occur
mainly in the rubber and plastics industries (see e.g., MacDonald
1964, Scharnweber et al. 1974).
Most of the case histories are believed to have involved
acute exposures to levels of the chemical well in excess of the
current TLV of 100 ppm (see e.g., Gerbis 1914, Kegel et al. 1929,
Laskowski et al. 1976, Schwarz 1926) although idiosyncratic
responses to low levels could conceivably account for some known
instances of toxicity. In mild cases of acute poisoning, the
toxic manifestations are primarily neurologic in character, as
are those in chronic intoxications (see Section III.B.).
However, gastrointestinal effects such as nausea, vomiting, and
diarrhea are also common (see e.g., Mackie 1961, Sharp 1930, van
Raalte and van Velzen 1945, Wiernikowski et al. 1974). Elevated
body temperatures, pulse rate and heart rate are frequently
reported (see e.g., Hansen et al. 1953, Kegel et al. 1929,
Laskowski et al. 1976), while depressed blood pressure (see e.g.,
McNally 1946, Suntych 1956, Trubecka and Brzeski 1968, Weinstein
1937), and abnormal EKG readings (see e.g., Gaultier et al. 1965,
Gummert 1961, Noro and Pettersson 1960, Walter and Weiss 1951)
also indicate cardiovascular involvement.
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The other organs or systems primarily influenced by chloro-
methane are the liver, kidney, and blood. Hepatic injury occurs
in acute cases (see e.g., Saita 1959, Spevak et al. 1976,
Weinstein 1937), and in long-term exposures (see e.g., Del Zotti
and Gillardi 1954, Mackie 1961, Wood 1951), while kidney damage
manifests itself as renal insufficiency and anuria in the more
severe cases (see e.g., Borghetti and Gobbato 1969, Hayhurst and
Greenburg 1929, Kegel et al. 1929, Suntych 1956) and proteinuria
in less severe cases (see e.g., Birch 1935, Mackie 1961, McNally
1946).
The hematologic picture is not as clear. Although some
investigators have seen anemia (see e.g., Hayhurst and Greenburg
1929, Kegel et al. 1929, Mackie 1961) and others leukocytosis
(see e.g., McNally 1946, Noro and Pettersson 1960, Suntych 1956,
Wiernikowski 1974), in other instances the blood cell counts
remain within normal levels following severe poisonings (see
e.g., MacDonald 1964, Spevak 1976, van Raalte and van Velzen
1945, Weinstein 1937).
Although most exposures to chloromethane are assumed to be
by inhalation, the lung appears to be relatively insensitive to
the chemical.
b. Animal Studies
There have been few studies on the effect of repeated
exposure to chloromethane in animals. Details of four of the
most relevant of these studies follow.
An experiment was undertaken by White and Somers (1931) for
the purpose of determining the minimal concentration of chloro-
methane which would cause death in average-sized guinea pigs when
the exposure via inhalation covered a 72 hour period. After the
exposure period, the animals were observed for an additional
thirty days. Each of: three groups of animals (18 animals per
group) was exposed to an average concentration of 49, 77, or 140
ppm. In the group exposed to an average of 49 ppm, none of the
animals died within the 30 day observation period; in the group
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exposed to an average of 77 ppm, 50 percent of the guinea pigs
died; and in the group exposed to an average of 140 ppm, all of
the animals died within a few days after exposure. The
pathologic changes in the guinea pigs dying from the effects of
chloromethane indicated widespread systemic poisoning
characterized mainly by severe circulatory disturbances and
congestion of the lungs and meninges.
The acute and chronic toxicity of chloromethane have been
studied (Smith and von Oettingen 1947a,b, Smith 1947, Dunn and
Smith 1947): the mortality, symptomatology, effects on
hematopoietic and biochemical parameters, and the histopathologic
changes resulting from exposure. In these studies, the chemical
was administerd to 10 species of animals via inhalation
6 hours/day, 6 days/week for up to 64 weeks, at concentrations of
300-4000 ppm.
Table 2 summarizes the mortality data at 500 and 2000 ppm in
terms of the number of days from first exposure to death of 50
percent of the experimental animals (LT50) (Smith and von
Oettingen 1947a). The most sensitive species at the 500 ppm
concentration was the dog; the least sensitive was the rat. No
apparent effect was noted in guinea pigs, mice, dogs, monkeys,
rabbits, and rats exposed to 300 ppm, 6 hours/day, 6 days/week
for 64 weeks. The other four species were not exposed to this
concentration.
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TABLE 2
Mortality of Animals Exposed to Chloromethane
6 Hours/Day, 6 Days/Week
LT50 (Days)
Species 500 ppm 2000 ppm
Guinea pig
Mouse
Goat
Dog
Monkey
Rat
Rabbit
Cat
Ch i eke n
Frog
71
143
NSa
23
110
NEb
192
NS
NS
NE
3
3
3
4
in
15
23
27
38
NE
aNS—not studied
bNE—not lethal
Smith and von Oettingen (I947a) also found that several
factors influenced survival time within a species. These factors
included exposure frequency, age, and certain dietary
constituents. As shown in Table 3, the interval between
exposures (i.e., exposure-free period) greatly influenced the
mortality rate. Allowing exposure-free periods may decrease the
cumulative effects of chloromethane. The work of White and
Somers (1931) also indirectly supports this hypothesis. In their
study, the T-jDc-f) for guinea pigs exposed to chloromethane
continuously for 72 hours was only 77 ppm, indicating that
uninterrupted contact is much more lethal.
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TARLE 3
Mortality of Animals Exposed to Chloromethane
for Different Exposure Intervals
Species
Mouse
Guinea
Pig
Concentration
(ppm)
1,000
2,000
2,000
2,000
2,000
Exposure Time
(hours/day)
6
3
6
6
6
Frequency
(days/week)
6
6
6
6
3a
LT50
(days)
5
131
3
3
201
aThree alternate days a week
Variation in age also influenced mortality. Younger animals
appeared to be more resistant than older animals. For example,
when adult and weanling rats were exposed to 2000 ppm, 6
hours/day, 6 days/week, the LT50 for the adult animals was 15
days, while that for the weanlings was 27 days.
Supplementing the diet of guinea pigs exposed to 1000 ppm
with ascorbic acid, or the diet of rats exposed to 2000 ppm with
thiamine hydrochloride, nicotinic acid, or calcium pantothenate
did not increase resistance to the lethal effects of chloro-
methane. However, increasing dietary casein by 20 to 35 percent
or supplementing moderate to low casein diets with cystine or
methionine led to an increase in the time before 50 percent of
the rats died.
No differences in LT50 could be attributed to differences in
sex.
Smith and von Oettingen (1947b) also studied the symptoma-
tology of the animals poisoned by chloromethane. Commonly seen
were anorexia, discharge of fluid from the respiratory tract,
hyperactive reflexes, disturbances in ability to correct
position, and extreme spasticity. The neurologic behavior of
monkeys (tonic-clonic convulsions and periods of unconscious-
ness) , was different from that of dogs (sustained tonic spasms
18
-------
without remission). However, both types of neurotoxicity have
been reported in humans (see Section III.E.).
Development of toxicity signs varied with concentration and
frequency of exposure: delayed or gradual with low
concentrations or, with high concentrations, separated by longer
exposure-free intervals. Young animals responded with a slow
development at some concentrations where older animals developed
symptoms acutely. Although animals generally recovered from
acute symptoms if exposure was discontinued when symptoms first
appeared, effects acquired over a long period of time were
sometimes irreversible.
Smith (1947) reported hematologic and biochemical results on
certain of the animals studied by Smith and von Oettingen
(1947a,b). No hematologic or biochemical test was purported to
be useful in the diagnosis of chloromethane poisoning in the
species studied. No evidence of liver dysfunction, renal
failure, or of a primary effect upon the formed elements of the
blood were detected without severe neuromuscular disturbances
having preceded the detected hematologic or biochemical
changes. These data indicate the CNS to be the system most
sensitive to chloromethane toxicity.
Histopathologic examination of the same group of experi-
mental animals was reported by Dunn and Smith (1947). Morpho-
logic changes that appeared to be a direct result of inhalation
of chloromethane 6 hours/day, 6 days/week, for 9 months were
variable degrees of necrosis of the convoluted tubules of the
"kidney in mice and rats (2,000 ppm) and fatty metamorphosis of
the liver in the smaller species. Pulmonary edema appeared to be
a direct result of the irritation due to inhalation of chloro-
methane. No morphologic changes v/ere found in the brains of
those dogs and monkeys examined which showed severe neuromuscular
disturbances. No morphologic changes were observed in the rats
exposed to 500 or 1000 ppm, 6 hours/day, 6 days/week for nine
months. However, the tissues examined were not specified.
Guinea pigs surviving 9 months of exposure at 500 ppm also
19
-------
demonstrated no histopathologic changes, although guinea pigs
were the second most sensitive species (LT50) at 500 ppm while
rats showed no lethality at 500 or 1000 ppm (Smith and von
Oettingen 1947a).
The major limitations of the four studies done by Smith, von
Oettingen, and Dunn are:
(1) small numbers of animals were used in certain test
groups (e.g., two goats at 2000 ppm, four rabbits at
1000 ppm, two monkeys at 500 ppm)•
(2) histopathologic examinations were not reported on
animals exposed to 300 ppm for 64 weeks for species
which showed effects at 500 ppm; and
(3) no indication of the animals or tissues routinely
examined was given.
Therefore, while the studies indicate at what levels major
effects of concern might appear, they are insufficient for
determining more subtle adverse effects detectable at the present
state of the art.
Yevtushenko (1966) studied the chronic effects of chloro-
methane on rats (10 animals/group) and rabbits (4 animals/group),
exposed to 40 or 240 mg/m3 (i.e., approximately 20 and 120 ppm,
respectively), 4 hours/day, daily for 6 months. In both groups
of rats hematologic examination revealed consistent decreases in
erythrocyte number. In both rats and rabbits exposed to 240
mg/rrp, excretory function of the liver was disturbed while no
effect was observed in the animals exposed to 40 mg/m^. In rats
of both groups, kidneys functioned normally, but microscopic
examination of the blood-forming organs indicated depletion of
lymphoid elements and proliferation of the reticular base of the
organs examined (spleen, lymph nodes). Cnanges in parenchyma!
tissues were unpronounced. The rabbits were also used to examine
effects on the eyes. These were observed in both eKposure groups
20
-------
and included discoloration of the optic disc and histopathologic
disturbances of the retina and optic nerve. The most significant
changes occurred in the CNS (see Section III.B.).
CUT has sponsored a 90-day inhalation study using rats and
mice performed by Battelle Laboratories (1979). Groups of
animals (10 animals/sex/dose) were exposed to 375, 750, or 1500
ppm of chloromethane 6 hours/day, 5 days/week for 13 weeks. All
three groups of treated male rats showed a significant decrement
in body weight compared to controls, while female rats treated
with 750 and 1500 ppm also showed significant decrements in body
weight compared to controls. There was a significant difference
in final body weight between treated and control mice only at the
1500 ppm dose level in females, however. No clinical signs of
toxicity or overt behavioural changes were noted during the
study. The group of male mice treated with 1500 ppm had
significantly higher serum glutamic-pyruvic transaminase (SGPT)
activity than controls. However, this activity was increased in
only two of the mice. One was found to have a liver infarction
while the other had severe hepatic changes. Other clinical and
hemotologic parameters measured were reported to be within the
normal clinical range. The major histopathologic finding was
cytoplasmic vacuolar changes of the hepatocytes in mice. Sixty-
four percent (9/14) of the mice treated with 1500 ppm exhibited
this effect, 39 percent in the 750 pprn group, and 37 percent of
controls. The effect was highest in females in all groups. One
female not in the high dose group had a massive liver
infarction. Thirteen of the 60 treated mice had eye lesions
which were reported to be compound related.
However, deficiencies in the design and conduct of this
study, have led the EPA to decide that the findings from it
cannot be used as the sole determinant of the chronic toxicity of
chloromethane:
21
-------
(1) The rat does not appear to be the most appropriate
test species for systemic chronic effects at the dose
levels used. This species was previously shown to be
unaffected by exposure to 1000 ppm chloromethane,
6/hours/day, 6 days/week for 64 weeks (Smith and von
Oettingen 1947 a,b). Also, since the toxicity of
chlororaethane decreases as the exposure-free period
is increased, one would anticipate that decreasing
the exposure frequency to 5 days/week over 90 days
would lead to little, if any, toxicity even at 1500
ppm. Dogs or monkeys may be more appropriate since
they showed signs of toxicity even at 500 ppm, 6
hours/day, 6 days/week and exhibited neurologic and
behavioral effects seen in humans exposed to
chloromethane (Smith and von Oettingen 1947a, Smith
1947).
(2) Of the 80 mice used in the study, 19 died during the
13-week study; 14 of which died due to stated
problems with new cages. Seven of those dying of
trauma were in the high dose group of male mice.
(3) There was a wide range of response in the control
groups. A large standard deviation in a control
group means that the difference between a treated
group and the control group needs to be larger in
order to detect a significant difference. Therefore,
in a better controlled study, perhaps more
significant differences would have been detected.
Also in progress at the contract laboratory, CUT has
sponsored a 24-month chronic inhalation study in mice and rats.
This study was initiated in June 1978; to date, the EPA has
received a 6 month interim report (Mitchell et al. 1979). The
exposure levels being administered are 50, 225, and 1000 ppm.
The frequency of administration is 6 hours/day, 5 days/week for
22
-------
24 months. As originally planned, during the last 6 months of
the study, the animals would not be exposed to chloromethane but
would be held for observation. CUT has chosen to extend the
dosing period to the full 24 months. There are 120 animals of
each sex in each of the three exposure groups and in each of two
control groups. Interim sacrifices are scheduled at 6, 12, and
18 months. In the interim report submitted to the EPA. (Mitchell
et al. (1979), it was revealed that female mice in all treated
groups and male .mice treated with 1000 ppm showed significant
body weight decrements compared to controls. This is in contrast
to the results reported in the 90-day probe study. Chronic
inhalation of chloromethane in the interim-sacrificed mice
(1000 ppm) was reported to be associated with focal acute
scleritis (3/10 males, 1/10 females), hepatocellular degeneration
(7/10 males, 7/10 females), splenic lymphoid depletion (8/10
males, 4/10 females) and thymic lymphoid necrosis (4/10 males,
1/10 females). In rats chronic administration of the chemical
was reported to be associated with sperm granuloma (2/10),
interstitial pneumonia (1/10 males, 4/10 females) and subacute
tracheitis in females (5/10). No significant histopathologic
findings were discovered in the liver of rats or in the kidneys
of rats or mice.
2. Current and Planned Testing
The Chemical Industry Institute of Toxicology (CUT) has in
progress a toxicologic evaluation of chloromethane in laboratory
animals. The major components of the CUT program are a pharma-
cokinetics study, a 90-day preliminary study, teratogenesis-
reproduction studies, and a 24-month chronic inhalation toxicity
study.
The 90-day probe study performed by Battelle (1979),
involved the inhalation exposure of F-344 albino rats and BgC^F^
hybrid mice to various levels (300, 750, 1500 ppm) of
chloromethane, 6 hours per day, 5 days per week for 13 weeks.
Results from this study are discussed in Section III.A.I.. The
purpose of this study was to select appropriate exposure levels
23
-------
for the subsequent long-term toxicity study. However, in the 90-
day study (Battelle 1979), there was no significant weight
decrement in treated male mice even at 1500 ppm, while female
mice showed such a decrement only at 1500 ppm. In contrast, in
the 6-month interim report of the 24-month study, weight loss has
been recorded in all groups of treated female mice. The EPA
believes that in a chronic/oncogenicity study, the lowest dose
should represent a level demonstrating no toxicity at such an
early stage, even weight loss.
The 24-month toxicity study was initiated by GIIT's
contractor in June 1978, and a six-month interim report has been
received by the EPA. A memorandum from CUT (GralLa 1979) has
raised various questions about the conduct of the study as
reported, which the Agency finds of concern. For instance, in
the six-month interim report, CUT reported a significant death
rate due to trauma, especially within the first 6 months in male
mice. There was an overall death rate due to trauma of 4.5
percent. For male mice this rate was almost 9 percent. CUT has
informed the EPA that the number of male mice reached a criti-
cally low level, at which time (22-months) they were sacri-
ficed. This high death rate due to trauma indicates concern that
good laboratory practices are not always followed.
Regarding chronic toxicity specifically, various factors
potentially will affect the usefulness of the results:
(1) As discussed previously in Section III.A.l., the
protocol calls for exposing rats to dose levels which
previously have been shown to cause no effects on the
liver, kidney, cardiovascular or hematopoietic
systems of rats.
(2) Because a non-rodent, the dog, appears to be the
species most sensitive to chloromethane, the use of
two rodent species may give spurious no-effect levels
when used to evaluate the risk to humans.
24
-------
(3) No tests will be conducted to determine the more dis-
criminating aspects of behavior and performance.
3. Conclusions
Several major conclusions about the chronic hoxicity of
chloromethane can be drawn from the human studies and from the
animal studies of White and Somers (1931), Smith and von
Oettingen (1947a, b) , Smith (1947), Dunn and Smith (1947),
Yevtushenko (1966), and CUT (1979a). These conclusions are:
(1) chloromethane is toxic to a variety of species
including humans;
(2) the major systems affected include the CNS, liver,
kidney, blood forming elements, and ocular tissue;
(3) the most sensitive system affected in humans and
animals appears to be the CMS; and
(4) the level of toxicity is not only affected by the
exposure concentration but also by the length of the
exposure-free period and the amount of cystine or
methionine in the diet.
4. Te sting
Although the Tnteragency Testing Committee (ITC) recommended
testing to determine chronic effects on the liver, "kidneys, bone
marrow, and cardiovascular system, the EPA is not proposing such
studies. Results available from previous studies, especially
those of Smith and von Oettingen (1947a,b), Smith (1947), Dunn
and Smith (1947), Yevtushenko (1966), Battelle (1979) and that
which will be available from the current CTTT study (CUT 1977)
are deemed by the Agency to provide sufficient information to
evaluate the chronic effects of chloromethane on the liver,
kidney, bone marrow, and cardiovascular system. In the earlier
studies the liver, kidneys, and bone marrow were affected, but at
25
-------
exposure levels higher than those that induced CNS effects. This
means that no-effect levels were in essence established for
liver, kidney, and bone marrow toxicity. The no-effect levels
varied with the frequency of exposure. For example, in rats
exposed to 500 ppm, 6 hours per day, 6 days per week for nine
months, no signs of liver, kidney, or bone marrow toxicity were
detected (Dunn and Smith 1947), while exposure to less than 120
ppm was needed if the exposure frequency was 4 hours/day daily
for 6 months (Yevtushenko 1966). Because no-effect levels have
been determined for liver, kidney, and bone marrow toxicity under
a series of test conditions, the EPA finds that no further
chronic toxicity study to examine these systems is needed.
Effects on the cardiovascular system are associated with
acute lethal concentrations of the chemical and not with non-
lethal chronic exposure. Human and animal data already available
are sufficient to evaluate the acute toxicity of chloromethane.
Because of these two factors the EPA is not proposing further
chronic studies to evaluate cardiovascular toxicity.
B. Neurotoxicity
1. Data Evaluation
a. Acute Effects
i. Human Studies
There have been numerous human case reports of acute intoxi-
cation (see e.g., Noro and Pettersson 1960, Spevak et al. 1976,
Thordarson et al. 1965, Wiernikowski et al. 1974). The first
column of Table 4 shows the frequency and nature of reported
signs and symptoms. Neurologic signs include ataxia, tremor,
motor reflex changes, and signs of cranial nerve involvement such
as blurred vision, weakened convergence, mydriasis, and
vertigo. Mood changes such as apathy, irritability, euphoria in
earlier stages of acute exposure and/or depression in later
stages also occur. Cognitive deficits relate to difficulties in
concentration and memory loss. More severe CNS alterations also
occur in acute poisoning. Convulsions of both the tonic-clonic
type (Hartman et al. 1955, McNally 1946) and that characterized
26
-------
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by sustained tonic contractures (Kegel el al. 1929, Schwarz 1926)
have been seen. Other major symptoms are headache, fatigue, and
sleep disturbances. The onset of these signs and symptoms may be
delayed by several hours following exposure, and they can persist
indefinitely following cessation of exposure (see e.g.,
Gudmundsson 1977, Walter and Weiss 1951). These studies
generally lack any quantitative estimates of levels or duration
of exposure, which makes them difficult to use as more than
suggestive evidence.
Although victims of acute exposure usually show complete and
rapid recovery, very long lasting changes have also been
reported. Gudmundsson (1977) did a follow-up study 13 years
after 15 people were exposed to chloromethane from a leaking
refrigerator on a fishing boat (Thordarson et al. 1965). One
patient died within 24 hours of the incident, two suffered severe
depression and committed suicide within 2 years of the incident,
and one man who had been seriously disabled, died ten years later
of a coronary occlusion. Ten of the eleven survivors were
examined. Nine patients reported a reduced tolerance to alcohol
and six had chronic fatigue and depression. Five patients showed
neurologic signs: 3 with tremor, 2 with paralysis of
accommodation, and 2 with peripheral neuropathies complicated,
however, by a history of alcohol abuse. Hartman et al. (1955)
reported that 1.5 years following a severe acute exposure, a
woman still displayed intention tremor, headaches, insomnia, and
"nervousness". Few of the other studies in the literature have
reported any long term follow-up.
There have been 2 recent laboratory studies of acute
exposure in humans. Putz et al. (1979) reported behavioral per-
formance deficits in a complex visual vigilance task during and
after 3 hours of exposure to 200 ppm, but no effects at 100
ppm. Stewart et al. (1977) exposed 4 humans to 100 ppm for 5
days for 7.5 hours a day. Analysis by the authors revealed no
impairment on a battery of neurologic and behavioral tests,
including 2 timing tasks, one with no cues and one with auditory
27
-------
cues. However, their analysis of variance revealed a significant
impairment in a timing task that relied on visual cues. Although
th-a investigators concluded that there was no cognitive
impairment of timing behavior, the EPA believes that the
demonstration of a visual system-related decrement in such a
controlled study seerns significant when considered in light of
Putz's visual task deficits after 3 hours at 200 ppm.
ii. Animal Studies
Yevtushenko (1966) reported that the four hour T_,C50 (lethal
concentration in 50 percent of the animals) for rats was roughly
11,000 ppm. Depression of motor activity occurred, as well as
widespread edema and vascular congestion of the brain and other
organs. A four hour exposure to 114 ppm was reported to produce
a behavioral deficit, namely, an increase in the time required to
develop a conditioned reflex.
b. Subchronic and Chronic Effects
i. Human Studies
Based on a study of refrigeration workers, Klirnkova-
Deutschova (1957) suggested that fatigue, headache, sleep dis-
turbances, and difficulty in concentration are among the earliest
symptoms of chronic intoxication, that cerebellar neurologic
signs predominate early, but that extrapyramidal signs are more
frequent with a later onset. In addition, onset of toxicity was
insidious and once signs and symptoms appeared they were
sometimes permanent.
In many reports it appears that signs and symptoms were
reported in workers exposed both chronically at low levels and
acutely at much higher levels from accidental spills or leaks
(see e.g., Baker 1927, MacDonald 1964, Scharnweber et al. 1974;
see also the second column of Table 4). This makes these studies
difficult to evaluate in relation to separating chronic from
acute effects. As in acute case reports, quantitative exposure
data or correlation with employment duration are generally absent
for both mixed and chronic exposure studies.
28
-------
Belova and Yevtushenko (1967) performed detailed exami-
nations of the visual system of chronically exposed workers. In
those exposed to chloromethane for 2 to 3 years, roughly one-
third showed a. decline in corneal sensitivity and in some there
was slight discoloration of the optic disc. Two-thirds of those
exposed for 5 to 8 years showed a decline in corneal
sensitivity. In addition, half of the workers displayed a
complex group of visual changes. Although age-related
deficiencies were apparently not factored out, the authors felt
that these ocular problems were related to exposure to the
chemical.
Repko et al. (1976) performed a behavioral, neurologic, and
psychological study of chronically exposed workers (1-311 months,
mean=34 months) in comparison with a control group. This study,
performed for NIOSH, may be indicative of neurobehavioral effects
in workers exposed long-term to low levels of chloromethane.
However, the data could also be interpreted to mean that acute
exposures to low levels of chloromethane adversely affect those
tested. Additional defects in the test, listed below, reduce the
e6feetiveness of such conclusions and leave the results open to
question.
The exposed cases consisted of 171 "physically normal" paid
volunteers from eight different plants at seven locations in six
states (11 female/160 male, 10 black or minority/161 white). The
controls (comparisons), who were matched (attempted) by sex, age,
and race to the cases, consisted of 49 workers who were not known
to be exposed to chloromethane or other neurotoxicants (3
female/46 male, 3 black or minority/46 white). Regardless of
matching, the differences in mean age and level of education
between cases and controls were statistically significant. These
differences, and the case selection procedure (paid volunteers),
as well as "physically normal" persons, may enter bias into the
study, as a random sampling is the preferred type of selection.
There were also serious problems with the time sequence of
exposure and effect measurements in the study. Behavioral
29
-------
testing, performance measurements and urine samples were taken
among the workers in groups of five, three times a day, at times
corresponding to the end of eight-hour work days. Alveolar
breath samples of chloromethane were taken immediately before the
end of this eight-hour work day. The following day, neurologic
and EEC examinations were performed, and blood samples were
collected. No mention was made of quality control for the
behavioral, neurologic and EEG testing. During the period in
which these examinations were conducted, ambient concentrations
of chloromethane were determined for the various work locations
(2-70 ppm, mean=34 ppm). This short-term sampling does not
estimate long-term chronic exposure. However, Repko et al.
state: "most of the information for subject exposures to methyl
chloride vapors obtained by short-term air sampling techniques
correlated well with the information obtained by the permanently
installed monitoring instrumentation"(p. 104). Nevertheless,
these ambient air measurements do not quantify chronic exposure,
because the duration of each individual's exposure to
chloromethane was not considered in most analyses.
The data analysis performed by Repko et al. to determine
thi.s relationship exemplifies the limitations of the study.
Overall, the statistical comparisons are not sensitive to
cumulative exposure simply because this information is not
contained within the data. However, an attempt was made to
establish a relation-ship between duration of chloromethane
exposure (months employed) and physiologic effects of exposure.
Duration of exposure was compared with measurements of breath
chloromethane, urine pH, hematocrit, and ambient air concentra-
tions of chloromethane, A statistically significant positive
correlation was found between breath and air levels, and a
negative correlation was found between air concentration and
hematocrit levels. In subsequent analyses, correlations between
neurologic effects and these physiologic variables were
investigated. For the behavioral data, means from cases and
controls were compared. Such a technique does not distinguish
levels of exposure among cases. Behavioral data were
30
-------
investigated via scatter plots of ambient air concentration
versus factors related to behavioral tasks. This comparison
investigates the responses to various doses measured in the
workplace. Repko et al. (1976) concluded that performance levels
were reduced among workers exposed to chloromethane. Due to the
aforementioned limitations of the study design, this reduction is
only suggested rather than conclusively supported. No
measurements of performance previous to exposure (pre-employment)
were obtained. Therefore, there is no certain means of knowing
whether or to what extent the workers' performance levels were
affected by exposure.
Therefore, although Repko et al. found a significant
decrement among the workers in complex math tasks, increases in
the latency of responses to visual stimuli, and increases in
resting tremor, a relationship between these effects and chloro-
methane levels could only be suggested because of these
methodological problems.
ii. Animal Studies
As noted above, the major study of chronic toxicity in
animals (rats, mice, guinea pigs, rabbits, dogs, monkeys, others)
was performed by Smith and von Oettingen (1947a,b) (sea also
Section III.A.). Neurologic effects seen in the 500, 1000 and
2000 ppm groups exposed for 6 hours/day, 6 days/week are
summarized in Table 5. In general, they found that 300 ppm for
64 weeks "had no apparent effect on any species tested", but that
500 ppm produced serious toxicity in most species, with parti-
cularly pronounced neurologic signs in dogs and mice.
A Russian study (Yevtushenko 1966), which the author cited
as one basis for the 1965 Soviet TLV of 2.5 ppm, reported behav-
ioral and pathologic effects in rats and rabbits exposed for 4
hours/day to either 120 ppm or 20 ppm for 6 months. Development
time for a food conditioned reflex to a bell increased in both
groups of exposed rats compared to controls, while the uncondi-
tioned reflex to the sight and smell of food was significantly
delayed in rats exposed to 240 mg/m3- Microscopic examination
31
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symptoms appeared in second month of exposure when
nate gait was replaced with gamboling gait with frequent
ing. Tn the third month the more severely affected pup
d tremors, and after 11 weeks intermittent convulsive
res, attacks of hiccups, audible grinding of the jaws and
sardonicus, and sustained contraction of tongue and jaw
es. Kxposures were discontinued at 12 weeks, and the
al condition of the more severely affected animal improved
bout one month, but after the fourth month, it grew worse and
acrificed three months later. The other pup was observed
0 1/2 months and the general condition was excellent, though
up could not stand without sagging or swaying of the posterior
and legs and there was a tendency for the hind legs to remain
aced posteriorly.
several weeks exposure to chloromethane rabbits were first
e to bring the hind legs to the normal position for hopping, am
the hind legs gradually became permanently adducted.
three weeks the legs became weak and abducted and the chickens
e to walk. Debility and paralysis increased until the entire
except head and neck were paralyzed and cold to touch.
a week, cats became weak, ataxic, lost righting reflex.
oms progressed until cats unable to walk and had frequent
sor spasm. Hyperactive reflexes.
on stock diet occasionally showed opisthotonus. On somi-
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ure, culminating in paralysis of the hind legs several
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established that the brain was significantly affected in both
groups of rats with vacuolization of protoplasm being the
predominant change noted.
Belova and Yevtushenko (1967) performed visual pathologic
examination of the rabbits exposed in the same study. In the
initial weeks of the experiment, slight hyperemia of the con-
junctiva and the appearance of a small amount of discharge from
the eyes were observed. In animals of both groups (20 and 120
ppm) the optic disc was pale or grayish and frequently had dif-
fused edges. * Edema of the optic disc was noted in rabbits
exposed to the higher level. Blood vessels of the eye were of
uneven caliber, arterial vessels were primarily constricted, and
small hemorrhages were noted in the retina of some animals. His-
tologic examination of the retina and optic nerve indicated mor-
phologic changes, as well as increased vascularization,
plasmorrhdgia and hemorrhaging. No information on the optic
system of the rats exposed at the same dose was given.
In the 90-day inhalation study of chloromethane sponsored by
CUT (see Section IV), rats exposed to 375, 750, or 1500 ppm
exhibited no gross pathologic alterations of the eye. However,
mice exposed to the 375 and 750 ppm dose had a high incidence of
eye lesions that began as a mucopurulent conjunctivitis and
progressed until some animals' eyes were totally destroyed
(Battelle 1979).
2. Conelusions
The following conclusions on the neurotoxicity of chloro-
me thane can be made:
(1) adult dogs and mice appear to be the species most
sensitive to the chronic neurologic motor effects of
chloromethane; and
(2) neurobehavioral symptoms seen acutely in monkeys and
dogs are similar to those expressed in acute human
toxicity.
32
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Several investigators have detailed the permanent
neurobehavioral effects of long-terra exposure to chloromethane,
Klimkova-Deutschova (1957) and Langauer-Lewowicka et al.
(1974). In representative studies, groups of workers exposed to
chloromethane exhibited chronic neurologic or behavioral changes
from apparent long-term, low-level exposure ; there were no stated
high-level acute exposures. In a slightly different type of
study, Repko et al. (1977) found significant decrements in
complex math tasks, increases in resting tremor, and increases in
the latency to visual stimuli in a group of occupationally-
exposed workers. The EPA feels that while these studies suggest
that long-term exposure to chloromethane may pose an unreasonable
risk, they are inadequate to determine the extent of that risk.
Many problems have been encountered in evaluating animal
studies. In several species of animals it was concluded that 300
ppm had "no apparent effect in 64 weeks of exposure" on any
species tested, but that the acute effects of chloromethane in
dogs and monkeys had much in common with neurologic symptoms
described for humans acutely exposed (Smith and von Oettingen
1947a,b). More recent animal studies of chronic exposure have
produced suggestive evidence of functional and pathologic effects
after a shorter duration of exposure at lower concentrations
(Yevtushenko 1966), although not enough information is presented
in the papers to enable the EPA to adequately assess
chloromethane's neurotoxicity.
3• Testing Under Consideration
While the Agency is not prepared at this time to propose
standards for the conduct of neurobehavioral testing, set forth
below are current views on the proposed testing, and related
issues relevant to the development of these standards. Comments
are solicited from all sectors on the appropriateness and conduct
of the suggested testing.
The EPA is considering proposing animal studies to determine
toxicity levels for neurobehavioral effects of chronic exposure.
Among the variables to be determined are choice of species,
33
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length of test, days per week exposed, type of exposure and type
of testing. The EPA is asking for public comment on these
i s s ue s .
One neurobehavioral area of concern has been identified for
testing, namely, changes in function and morphology of the
nervous system due to chronic exposure. Changes in complex
cognitive functions and visual function as measured by behavioral
tasks may be the most sensitive human indicators of exposure to
chloromethane (Putz et al. 1979, Repko et al. 1977, Stewart et
al. 1977). The report on exposed workers by Klimkova-Deutschova
(1957) and the 13-year follow-up study of exposed fishermen by
Gudmundsson (1977) suggest that chloromethane intoxication may
produce signs of damage of the cranial nerves, other ocular
involvement., pyramidal and extrapyramidal neurologic signs, a
reduced tolerance to alcohol, fatigue, and depression.
The choice of species for animal testing will involve
several considerations. First, Smith and von Oettingen (1947a)
have suggested that effects in dogs and monkeys most resemble
human intoxication. The inappropriateness of rats as a test
species is suggested by the same authors' failure to observe any
overt effects in rats but not in other mammalian species exposed
to 500 ppm. On the other hand, Yevtushenko (1966) reported
behavioral effects from both acute and chronic exposure at low
levels in rats; the apparent discrepancy may be due to their use
of quantified behavioral testing as compared to the presumably
less objective observational techniques of Smith and von
Oettingen (1947b). However, the reports of neither study are
adequate to determine if this is, in fact, the case.
The Agency is also considering the appropriateness and best
means of defining adequate post-exposure testing to assess the
severity and persistence of any observed effects. If exposure in
the chronic study is noncontinuous, post-exposure observation
could be performed prior to the beginning of daily or weekly
exposure.
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In addition, the EPA is considering whether testing for
abuse potential, interaction with ethano.l and/or a mixed schedule
of exposures (long-terra low-level plus acute high-level) would be
appropriate additions to the requirements. Details are presented
in the Preamble.
C. Mutagenicity
1. Data Evaluation
a. Gene Mutation
A review of the data available shows that chloromethane is a
direct-acting mutagen. This means that chloromethane does not
have to be metabolized by mammalian enzymes to an active form.
In bacterial systems capable of detecting gene mutations,
chloromethane produces a strong, positive, reproducible dose-
response curve of chemically induced mutations in Salmonella
typhimurium strains TA 15.35 and TA 100. These strains normally
cannot synthesize the amino acid histidine and this must be added
to the nutrient medium to support their growth. When the proper
mutation occurs in the specific portion of deoxyribonucleic acid
(DNA) of these organisms that regulates this effect, they are
able to synthesize histidine and are then capable of growth in
histidine-frea medium. The bacterial strains which demonstrate
chloromethane mutagenicity are mutated by agents which cause
changes in a specific guanine-cytosine base pair, and possibly
others in the DWA molecule as well. Agents such as chloromethane
that cause substitutions of specific nucleotides are called base
pair mutagens. S_. typhirrmrium TA 1535 and TA 100 are the same
basic strain; TA 100 is TA 1535 with the addition of a resistance
factor, pKM 101, which confers resistance to the antibiotic
ampicillin and, at the same time, increases the sensitivity to
mutagenic agents.
After exposure to chloromethane, both with and without
metabolic activation, increased numbers of bactsria of strains TA
1535 and TA 100 were capable of growth in histidine-froe
medium. On a quantitative basis, increasing concentrations of
chlorouiethane caused the mutation of greater numbers of
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bacteria. For example, in a population of approximately 1 x 108
strain TA 100 bacteria, there will ordinarily be approximately
100 bacteria capable of growth in histidine-free medium.
Exposure to 2.5 percent chloromethane in the atmosphere increased
this number to approximately 400 in 1 x in**, exposure to 20
percent chloromethane increased the number to approximately 1,100
in a total population of 1 x 10^ bacteria (Simmon 1977). Similar
results were reported by Andrews et al. (1976), and Haskell
Laboratory (E.I. du Pont 1977). In this test system, therefore,
chloromethane is a base pair mutagen which causes an alteration
in at least one guanine-cytosine base pair of the DMA molecule.
In addition, Haskell Laboratory (E.I. du Pont 1977) tested
chloromethane in two strains of S. typhimurium that detect
frameshift mutagens (i.e., a mutagen which causes the addition or
loss of nucleotide pairs), TA 98 and TA 1537, and reported it to
be inactive. It is not uncommon, however, for a chemical which
is a positive base pair mutagen to be inactive in a frameshift
strain and vice versa. This is one reason that a good Ames test
will include strains of both types of S. typhimuriuTi. The EPA
believes that positive results in only one strain are adequate to
determine that a chemical may pose a risk of human 'riutagenicity
and should be tested further. Given the universality of the
structure of DNA, it is reasonable to assume that chloromethane
may also cause base pair alterations in the DNA of higher
organisms, including humans.
The Diamond Shamrock Corporation (1978a) has submitted a
series of test results in which chloromethane is reported to be
non-mutagenic for S. typhimurium strains TA 1535 and TA 100 and
Escherichia coli ATCC 23221 and A'TCC 23233 and inactive in a
host-mediated assay in mice with strain TA 100 as the tester
strain. However, the significance of these negative test results
is questionable because of the experimental techniques reported.
Chloromethane is a gas under conditions of normal temperature and
pressure. To adequately test such substances in bacterial
mutation systems requires special test methods and procedures
36
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that were not mentioned in the reporter} study. The test as
described in the Diamond Shamrock submission is a spot test. In
a spot test, bacteria are incorporated into top agar and poured
over a base plate of minimal medium. The test agent is then
placed on the plate (either in crystalline form or on a liquid
saturated filter paper disc) and allowed to diffuse into the
medium. The formation of a ring or concentrated zone of mutant
colonies in the vicinity of the test sample is generally
considered to be a positive result. The report submitted by
Diamond Shamrock states that 1 to 5 ug of test chemical
(chloromethane was one of a series tested) were added to the
plate with a spatula. The results of this assay are open to
question because the spot test, as described, is inappropriate
foe testing a gas. In addition, the EPA feels that the evidence
of a single negative test result conducted under less than
optimal conditions is outweighed by the positive results obtained
in three independent studies. The EPA., therefore, considers
chloromethane to be mutagenic for S. typhimurium strains TA 1535
and TA 100.
Chloromethane was also reported to be inactive in a host-
mediated assay in which S. typhiiiarjLum strain TA 100 was used as
an indicator organism (Diamond Shamrock 1978a). The host-
mediated assay employs an intact mammalian host as the activation
system for a microbial mutagen. The test chemical is adminis-
tered to animals over a period of time which may range from
several hours to several days. At the end of the treatment
period, the indicator organism (bacteria, yeast or some mammalian
cells capable of growth in culture) is administered to the host
animal and allowed to incubate, presumably in tha presence of the
test agent and/or its metabolites, over a period of several
hours. At the end of the incubation period, the indicator
organisms are removed and plated on a selective medium to
determine mutation. The study submitted by Diamond Shamrock has
severe problems. The test chemical was administered orally,
dissolved or suspended in 10 percent ethanol or peanut oil,
without specifying which was used for chloromethane and without
37
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specifying how gaseous chloromethane was added to the solvent.
Farther, concentrations are given in mg/kg but with no indication
of how this was determined. No positive control data were
presented. In general, the test data are inadequate and not
subject to critical review and evaluation. In addition, the
variables inherent in this system, e.g., concentration of test
agent in the animal, animal strain insensitivity, less than
optimal amounts of test substance administered, failure of the
test chemical or its active metabolites to reach the bacteria in
effective amounts, or administration of either test agent or
bacteria by the least effective route, may have resulted in
false-negative or seemingly incongruous results with
chloromethane in this assay. For these reasons, the EPA
considers the aforementioned host-mediated assay test results to
be of questionable value in assessing the mutagenic potential of
chloromethane.
The EPA believes that in any instance where contradictory
data is received on lower tier mutagenicity tests, even if all
tests are well-conducted, further testing in a more sophisticated
system is necessary to resolve the questions raised by the tests
producing positive results.
b. Heritable Translocation
Chloromethane has also been reported to cause chromosome
breaks in pollen grains of Tradescantia paludosa (Smith and Lotfy
1954). At the doses which gave the greatest response, chlorome-
thane (9231 ppm) caused a higher percentage of chromatid breaks
(240 breaks/5,932 chromosomes, or 4.04 percent) than did ethylene
oxide at 7692 ppm (24 breaks/2,150 chromosomes, or 1.12
percent). At equivalent ppm (10,769) chloromethane was also more
potent than ethylene oxide in causing chromatid breaks (3.09
percent vs. 0.65 percent). Chloromethane produced only chromatid
breaks, however, while ethylene oxide also induced erosions and
contractions, leading to a higher level of total chromosomal
abnormalities than chloromethane at optimal levels (5.21 percent
vs. 4.04 percent). There were six breaks per 6,590 chromosomes,
38
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or 0.09 percent, in untreated control pollen grains. Ethylene
oxide is one of the best-studied mutagens known and has
demonstrated rautagenicity in almost every system in which it has
been tested (USEPA 1978a).
Diamond Shamrock (1978b) also submitted the results of a rat
dominant lethal study in which chloromethane proved to be
inactive. A dominant lethal mutation is a change in the germ
cell, either egg or sperm, which is lethal to aygotes produced by
the mutated germ cell. In mammals, dominant lethal mutations
will reduce litter size. This redaction in litter size can be
due to the failure of the fertilized egg to implant or to develop
after implantation has taken place. Brewen et al. (1975) have
shown that dominant lethality results from chromosome breakage,
and that the incidence of broken chromosomes at metaphase of the
first cleavage of the fertilized egg corresponds to the incidence
of dominant lethal eggs. From the tenth day of pregnancy onward
in rats and mice, uterine contents can be recognized and
classified into living embryos and early and late fetal deaths.
Dominant lethal tests can be performed by exposing either male or
female animals to the test substance and mating them with
untreated members of the opposite sex. The test is most commonly
performed by treating male animals and mating them to untreated
females.
Diamond Shamrock's results are suspect for several reasons.
First, as described by Diamond ShamrocK (I978b), chloromethane
was administered by oral intubation as a saturated solution in
dichloromethane. Given the gaseous nature of chloromethane,
exposure by inhalation is considered to be more appropriate and
would have eliminated the need to use a solvent such as
dichloromethane which is itself a biologically active material
(see Sections IIT.E., and III.F.). In any case, a dichloro-
methane control should have been included in the study and this
was not reported.
The assay is also difficult to evaluate because of apparent
inconsistencies in the data and because of the manner in which
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the data are presented (Diamond Shamrock 1978b). For instance,
survival rates of the animals used for the positive control are
shown in a table that presents survival data only and are
presented later in a table which shows fertility data. The data
in the two tables do not agree. The narrative text of the report
and the survival data table imply that separate groups of animals
were used as negative controls in the acute and subacute parts oF
the study, whereas the tables which present fertility data imply
that the same animals served as negative controls for both parts
of the study.
Another problem is that data necessary to properly evaluate
such aspects of the study as corpora lutea counts and preimplan-
tation loss, are not presented. Further, a table listing average
implants fails to specify whether it is referring to total
implants (live plus dead embryos), or living embryos only. In
all, the data as presented are difficult to interpret, and do not
lend themselves to statistical evaluation and critical review.
As a result, the validity of the dominant lethal study as
presented is open to question.
2. Current and Planned Testing
The EPA is planning on performing a Drosophila sex-linked
recessive lethal test, a mammalian cell culture gene mutation
test if the Drosophila test is negative and a dominant lethal
test in rats.
3. Conclusions
There is evidence from bacteria and higher plants that
chloromethane is capable of causing both gene mutations and
chromosomal aberrations. In bacteria, chloromethane is a direct-
acting mutagen capable of inducing base pair substitutions in the
DN^ of S. typhimurium strains TA 1535 and TA 100 (Andrews et al.
1976, E.I. du Pont 1978, Simmon 1977). In Tradescantia pollen
grains, chloromethane is more effective than ethylene oxide in
inducing chromatid breakage (Smith and Lotfy 1954). Although
this information indicates that exposure to chloromethane may
present an unreasonable risk of mutation to humans, it is insuf-
40
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ficient by itself to assess chloromethane's risk as a potential
human mutagen.
4. Testing Under Consideration
In recent years, mutagenicity experts have discussed, and
provided guidance on, hazard estimation procedures for
determining if a chemical is a potential human mutagen. The
EPA's decisions concerning mutagenicity testing for chloromethane
is based upon the guidance discussed below.
Between 1975 and 1979 four major reports on the hazards of
environmental mutagens were issued (Drake 1975, Flamm 1977
McElheny and Abrahamson 1979, NAS 1977); in 1973 the Office of
Pesticide Programs proposed Guidelines for Registering Pesticides
in the U.S. (USEPA 1978b).
The reports agree that to perform a mutagenicity hazard
estimation for humans, scientists must first demonstrate that a
substance and/or its metabolite(s) does or does not cause herit-
able gene or chromosomal mutations (the two classes of mutagenic
damage which have been shown to be responsible for a portion of
human genetic disease) and whether the active form can reach the
significant target molecules in mammalian germinal tissue.
A discussion of the principles and practices of mutagenicity
testing in terms easily understood by persons unfamiliar with
mutagenicity is presented in the EPA's booklet "Short-Term Tests
for Carcinogens, Mutagens and other Genetoxic Agents" (Trontell
and Connery 1979).
The rationale for utilizing mutagenicity data which are not
derived from humans (all present data) has been previously
detailed (OPP 1978) and is based on an extensiva body of know-
ledge in the field of genetics. The following points are essen-
tial to such a rationale and are generally accepted by experts in
the field of mutagenesis (see e.g., Drake 1975, Flamm 1977,
McElheny and Abrahamsom 1979, NAS 1977). They are:
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(1) All organisms (except for a few viruses) have DNA as
the genetic material which is basic for survival and
reproduction;
(2) The DNA code is the same in all organisms;
(3) The cellular machinery for decoding the information
stored in the DNA code is similar among all-
organisms ;
(4) Eukaryotic organisms contain nuclei in their cells,
and their DNA is associated with protein to form
complex bodies called chromosomes. Prokaryotic
organisms lack nuclei, and their chromosome
structure differs from that of eukaryotic organisms;
(5) Unless there is a mutational event, the information
in DNA is faithfully replicated in each cell
generation in unicellular organisms and in somatic
and germ cells of multicellular organisms;
(6) DNA can be altered by chemicals. If this damage is
repaired properly there is no mutation. If it is
repaired with error or not repaired prior to
replication of DNA, mutation can result. A single
lesion in DNA may lead to a mutation;
(7) Point mutations usually involve changes in the bases
of the DNA chain: the replacement of one purine or
pyrimidine DNA unit by another is called base pair
substitution: insertion or deletion of a base pair
into the DNA chain is called a frameshift mutation;
(8) Breaks in DNA may lead to structural chromosomal
aberrations 7
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(9) Disturbances in the distribution of individual
chromosomes or chromosome sets can occur during cell
division and result in numerical chromosomal aber-
rations ; and
(10) Mutations are generally considered to be deleterious
in reference to the normal environment for an
organism and to result in decreased survival and
reproduction.
Although not all mutations are deleterious (e.g., the Ames
test measures a mutation which is advantageous to the organism),
it is impossible to tell if any alteration in the genome would be
good, bad, or of no importance.
Given the ubiquitous nature of DMA as the genetic material,
the universality of the genetic code, and the similarity in
response of genes and chromosomes of various lifeforras, a ration-
ale for using the results from different test systems develops.
Humans, as well as bacteria, fungi, and higher eukaryotes suffer
DNA damage and gene mutations; humans, as well as other
eukaryotes, show structural and numerical chromosomal aberra-
tions. For these reasons, cells of any species inay be used to
detect genetic changes and to predict genetic change or damage in
other species.
There are two single tests each of which measures one of the
genetic endpoints (gene mutation or chromosomal aberration) and
the ability of the mutagenically active form of a chemical to
reach germinal tissue. These tests are the mouse specific locus
test which detects gene mutations, and the heritable
translocation test which detects chromosomal aberrations in mice
as its genetic endpoint.
The EPA. is requiring neither a mouse specific locus test nor
a heritable translocation test at present. Although evidence in
the lower orders suggests that there is a possible risk to man,
the EPA believes that the most appropriate approach for this
effect is to use a sequenced testing scheme. However, while the
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tests for such a scheme are available, at this time the Agency is
unable to propose triggers for the process, i.e., criteria for
determining whether a given result is positive of negative.
While such triggers are being defined, the EPA. is planning to
perform and evaluate a Drosophila sex-linked recessive lethal
test, a mammalian cell culture test if the Drosophila test is
negative, and a dominant lethal test. The EPA will require the
higher sequenced testing if the results of these tests indicate
the need. For more details see the Preamble.
D. Oncogenicity
1. Data Evaluation
a. Mutagenic Activity
As described earlier, chloromethane has been reported to
possess mutagenic activity in bacterial systems that detect gene
mutations and to cause chromosomal aberrations in higher plants
(see Section III.C.I. for detailed discussion and evaluation of
each of these studies). In assays employing S. typhimurium test
strains TA 1535 and TA 100, the chemical induced a strong,
positive dose-dependent mutagenic response, both with and without
metabolic activation (Andrews et al. 1976, E.I. du Pont 1978,
Simmon 1977). These tester strains detect base pair mutagens.
In Tradescantia paludosa pollen tubes, chloromethane increased
the chromatid breakage rate about forty-fold (Smith and Lotfy
1954). Considering chloromethane's activity in S. typhimurium
strains TA 100 and TA 1535 and in Tradescantia paludosa pollen
tubes, the EPA considers chloromethane to be a direct acting
mutagen (i.e., it does not have to be metabolized to be active).
The concept that neoplasms arise from mutations in somatic
cells was originally postulated by Boveri in 1914 to account for
both the unlimited variety of tumor types, and the fact that
daughter cells maintain their neoplastic properties upon cell
division (Chu et al. 1977, Trosko and Chang 1978). Oncogens and
mutagens have two properties in common: 1) the ability to induce
new properties in cells that can be transmitted to their daughter
cells; and 2) the ability to convert normal cells into
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irreversibly changed cells (Suss et al. 1973). Although the
mutation theory of oncog^rtesis has not been confirmed, the
validity of the theory has recently gained more attention because
of three important findings. First, in the 1960's, the Millers
at the University of Wisconsin discovered that the majority of
oncogens need to be metabolized in order to be active (Miller
1978, Miller 1979, Miller and Miller 1974); second, _in vitro
metabolic activation systems which could be incorporated into
mutagenicity assay systems were developed (Mailing and Chu 1974);
and third, comparison of the ultimate reactive metabolites of
structurally diverse oncogens and mutagens revealed that the
common denominator of these substances is their electrophilicity,
(i.e., they are compounds whose atoms have an electron deficiency
that enables them to react with electron-rich sites in cellular
nucleic acids and proteins) (Bartsch 1976, Miller 1979). These
three findings have now been verified by a host of experimental
data which show that many oncogens can induce different types of
mutations including gene mutations (both base pair substitution
and frameshift alterations), chromosomal aberrations, and non-
disjunctions. The oncogenic potential of a chemical has also
been correlated with its ability to interact with and modify DNA
(Rosenkranz and Poirier 1979).
A wide variety of assay systems have been developed to
detect effects on genetic material, including gene mutations and
chromosomal aberrations. The particular value of one test, the
Ames test, to the EPA's work is that it can be used as a
indicator of oncogenic potential. A good correlation between
mutagenic activity and oncogenic activity has been demonstrated
(Bartsch 1976, Brusick 1979). Eighty to ninety percent of the
known oncogens tested in this system have been positive. The
number of false positives is also low in this system, ranging
from 10 to 15 percent.
b. Alkylating Capabilities
Chloromethane is an alkylating agent. Alkylating agents
belong to a larger class of reactive compounds called
45
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electrophiles (electron-seekers). Representative animal tests
'"H
show that some members of virtually all classes of alkylating
agents are oncogenic (Lawley 1976). The basis for their biologic
effect is the chemical modification of cellular DNA by these
agents (Singer 1975). Oncogenesis by alkylating agents has been
reviewed (Lawley 1976) as well as their effects on nucleic acids
and the relationship of those effects to oncogenesis and
mutagenesis (Pegg 1977, Singer 1975).
With chloromethane the methyl group is transferred to a
nucleophilic (electron-donating) atom of another molecule with
simultaneous elimination of chloride ion, to form a new, stable
covalent carbon-heteroatom bond; that is, the nucleophilic
reactant is alkylated, or in this case methylated. Chloromethane
is a commercial alkylating agent, e.g., used to produce
tetramethyllead (von Oettingen 1964). The chemical also has
alkylating activity in both human (in vitro) and rat (in vivo)
tissues (Redford-Ellis and Gowenlock 1971a, Reynolds and Yee
1967), forming primarily S-methylglutathione and S-
methylcysteine.
A closely related compound, iodomethane, with an iodine (a
larger halogen) instead of a chlorine, is also an alkylating
agent. There has been some research on the oncogenic potential
of iodomethane. Iodomethane has been shown to induce lung
adenomas in strain A mice following intraperitoneal injection
(Poirier et al. 1975) and to cause local sarcomas with lung
metastases in rats following subcutaneous injections (Druckrey et
al. 1970). The development of lung adenomas in strain A mice is
considered to be a sensitive indicator of the oncogenic activity
of alkylating agents such as iodomethane (Poirier et al. 1975,
Weisburger 1978). In the case of iodomethane, 0.31 mmole/kg (44
mg/kg) given over a 24-week period (3 times per week) induced a
significant increase in the average number of lung adenomas per
mouse. In fact, iodomethane on a mmole basis was more active
than urethane, which is the usual positive control used in this
assay system. In the Druckrey et al. studies (1970), all 6 rats
receiving 20 mg/kg of iodomethane once a week for a year
46
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developed sarcomas at the site of injection. Of 12 rats
receiving 10 mg/kg once a week for a year, 11 developed sarcomas
at the site of injection. Another important finding was that in
most cases the tumours had inetastasized to the lungs. The latter
information indicates the malignant nature of the induced
tumors. Although neither of these studies provides sufficient
information on iodomethane oncogenicity to do an adequate hazard
assessment, at the least they do indicate that it has oncogenic
potential. While both chloromethane and iodomethane are
alkylators, knowledge of their relative alkylating abilities
indicates that iodomethane would be the more potent.
c• Structural Relationships
Known chemical oncogens comprise a structurally diverse
group of synthetic and naturally occurring organic and inorganic
chemicals (Miller and Miller 1974, Miller 1979). Although
knowledge of the chemical structures of known oncogens currently
provides no way of definitively assessing molecular structures of
unknown oncogenicity (Fishbein 1977), certain structural criteria
for suspecting chemicals of oncogenic activity have been
determined (Arcos 1978). Meeting these criteria are halogenated
hydrocarbons and alkylating agents. Chloromethane falls into
both categories. Its alkylating properties have been discussed
in the preceding subsection.
d. Other
In addition, CUT has reported the development of 37 nasal
squamous cell carcinomas in rats exposed to formaldehyde (a
metabolite of chlorome thane) at IS ppm (CUT 1979). The study is
not complete, but the discovery of such numbers of rare tumours
in this species is important. Exposure to formaldehyde was by
inhalation, and the carcinomas were found in the nose, so that
the irritant effect and localized high levels may play a part in
the oncogenicity. Also, the production of formaldehyde as a
metabolite of chloromethane might lead to different results,
because concentrations would be expected to be low. While
47
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demonstration that a metabolite of a chemical is an oncogen is
not sufficient by itself to establish that the initial compound
will cause tumors, under some circumstances such a finding may
support a request for further testing.
2. Conclusions
After reviewing the evidence available on the oncogenic
potential of chloromethanes, the EPA finds that chloromethane may
present an unreasonable risk from oncogenicity. While there is
no direct evidence in humans or in animals that chloromethane is
an oncogen, various indirect evidence indicates that it has
oncogenic potential. The indirect evidence is summarized as
follows:
a. chloromethane is a rnutagen: (1) inducing gene
mutations in bacteria and (2) causing chromosomal
aberrations in plants;
b. chlorornethane is a direct alkylating agent known to
alkylata human and animal tissues;
c. halogenated hydrocarbons such as chloromethane are
among the classes of chemical compounds known to
have oncogenic activity; and
d. chlorornethane is metabolized to formaldehyde, a
known animal oncogen.
3. Current and Planned Testing
CUT is at presejnt running a two-year study of the effects
of chloromethane on rats and mice, which involves exposure of the
animals for twenty-four months, 6 days a week, 6 hours a day.
Because of the deficiencies discussed earlier under III.A.2,
such as the premature decease of most of the male mouse
population, the EPA believes that the ongoing test is
insufficient and that there is a need to conduct a new, long-term
bioassay.
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4. Proposed Testing
The EPA proposes to require that a 2-year oncogenicity study
be undertaken to determine the oncogenicity potential of chloro-
methane in animals. Test standards have been proposed by the EPA
(USEPA 1979b). The EPA is, however, proposing that because of
the relative insensitivity of the rat to the toxic effects of
chloromethane as discussed in Sections III.A. and III.B, that the
species used in the oncogenicity study be mice and hamsters.
Although systemic toxicity and oncogenicity are different end-
points, and the factors that affect one such endpoint in any
species may not affect the other, the converse may also be
true. Differences in parameters such as absorption or distribu-
tion may account for species variability in systemic toxic
effects and these same parameters may also affect the ability of
the compound to reach a potential target organ. It is the EPA's
belief that testing of the most responsive species to any toxic
effect will allow the Agency to better evaluate possible risk.
Because there is no information to indicate why the rat is less
affected with regards to systemic toxicity, the Syrian hamster is
being proposed as a replacement. The EPA welcomes comment from
the public both as to theoretical basis for this proposal, and
the choice of a substitute test species.
E. '.Teratogenicity
1. Data Evaluation
a. Structural Teratogenicity
Only one report associating the birth of a severely
deformed child with maternal exposure to chloromethane and
ammonia vapors is available (Kucera 1968), and it does not give
details as to dose, time, or length of exposure. To date no
animal studies to evaluate the effects of chloromethane on the
fetus have been published. However, Smith and von Oettingen
(1947a) reported that "a rabbit conceived and born during
exposure to 500 ppm grew at a normal rate during 33 weeks of
exposure", but developed slight neuromuscular symptoms like those
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seen in adults. Because exposures continued after birth, and
only one rabbit was so exposed, no conclusion can be drawn from
this study.
A lipid-soluble, small molecular weight gas such as
chloromethane would be expected to cross the placenta readily
(Villee 1971, Nishimura and Tanimura 1976). Although no direct
evidence of chloromethane induced fetal toxicity has been found,
Hartman et al. (1955) tell of a seven-month pregnant woman
severely poisoned by chloromethane. When the unconscious woman
was found, the fetus had been aborted and was still attached to
the undelivered placenta.
b. Behavioral Teratogenicity
Additional concern for the teratogenic potential of
chloromethane is based on its documented neurotoxicity. The
central nervous system appears to be especially susceptible to
toxic insult during its development (Buelke-Sam and Kimmel
1979). The period during which the CMS develops is an extended
one and vulnerability to toxic insult continues into the post-
natal period. The possibility of fetal exposure to a
neurotoxicant such as chloromethane warrants its evaluation as a
teratogen. Evidence has been presented that suggests that both
struct.iral and behavioral deficits in adult and developing
systems are associated with exposure to other nonspecific CMS
depressant chemicals (van Stee 1976). Few purely behavioral
teratogens are T
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2. Current and Planned Testing
Although CUT has not yet initiated its teratology testing,
they have proposed a protocol for teratologic evaluation of
chloromethane (Tyl 1979). Using this protocol, CUT intends to
collect data on anatomical abnormalities, neurofunctional
deficits, and acquisition of developmental landmarks in rats
exposed to chloromethane in utero.
The CUT protocol differs significantly from that proposed
by the EPA (USEPA 1979a) in several ways:
(1) It specifies the use of a single species, the rat,
to evaluate teratogenic effects. The EPA has
proposed teratology testing in a minimum of t\vo
mammalian species. A study in one with negative
results would be considered inadequate, although
findings of malformations in a single species would
be highly suggestive of teratogenesis.
(2) The dosage selection procedure proposed by CUT
bases the two lower doses on multiples of the TLV,
which may not conform to suggested criteria for
dosage levels as published in the proposed Test
Standards (USEPA 1979a). The proposed EPA standard
for the teratogenicity study includes a high dose
which should produce some maternal toxicity, an
intermediate dose which ideally should produce some
fetal toxicity, and a no-effect dose.
(3) Although the battery of tests for the evaluation of
neurofunctional deficits and the acquisition of
developmental landmarks propos'e-d by Tyl (1979) may
not be completely appropriate, standards for the
testing of behavioral alterations have not yet been
proposed by the EPA. The Agency will consider
CIIT's proposed battery as the basis for such
testing.
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(4) Because the rat has demonstrated low sensitivity to
the toxic effects of chloromethane (Smith and von
Oettingen 1947a), other species perhaps should be
considered for the teratogenicity testing.
3. Conclusions
On the basis of chloromethane's neurotoxicity in adults,
accessibility to the fetus and in agreement with the concept that
structural and functional evaluations are complementary
approaches to CNS toxicity (Barlow and Sullivan 1975, Langman et
al. 1975), the EPA concludes that chloromethane has a potential
for teratogenicity in the human for both behavioral and
structural malformations.
4. Testing Proposed and Under Consideration
a. Structural Teratogenicity
Standards for the development of data on morphologic
teratogenic effects have been proposed (USEPA 1979a). These
standards relate to the development of data on anatomic
abnormalities.
Although CUT is planning on performing a teratology study,
the differences in protocol may yield results which would not
completely satisfy the Agency's concern about teratogenic
effects. For that reason the EPA is proposing a test rule for
structural teratogenicity testing. However, if data are sub-
mitted to the EPA to demonstrate that the test, as performed,
will be sufficient to evaluate chloromethane's teratogenic
potential, this test rule will be reconsidered before final
promulgation.
The EPA believes that its proposed teratogenicity test
standards are appropriate for the testing of chloromethane for
the induction of these effects, with one exception. The Agency
is proposing that the rat not be used for teratogenicity testing,
because of a demonstrated lack of sensitivity of this species to
52
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the toxic effects of chloromethane. As stated previously, insen-
sitivity to one toxic endpoint may not be reflected by a similar
insensitivity when observing a different effect. This is
particularly true when related to classical teratology. The
production of severe malformations in the offspring of exposed
mothers has had, at times, little correlation with the systemic
toxicity of the compounds, as exemplified by the case of
thalidomide. There are however, certain factors which may affect
both endpoints (parameters such as absorption or metabolism), and
until these are ruled out as the cause of the rat's
insensitivity, there is the significant possibility that the
insensitivity may carry over to structural malformations as
well. In addition, the structural teratogenicity test measures
such aspects as embryo- and fetotoxicity, stunting and delayed
development, which may be a reflection of the compound's systemic
toxicity, or its effects on the dam. In either of these
instances, the more responsive a species is to the chemical to be
tested, the better equipped the Agency will be to estimate
potential hazards from exposure to the compound. The EPA
requests comment on these issues.
b. Behavioral Teratogenicity
The EPA feels that an evaluation of neurologic/
behavioral abnormalities and of the acquisition of developmental
landmarks is necessary to assess the possible teratogenicity of
chloromethane (see, e.g., Vorhees et al. 1979b). Since no
standards for the development of this type of
data have been proposed, this topic will be subject to public
comment before a rule is proposed.
In addition to routine signs of physical development that
may reflect toxicity (e.g., body weight), the proposed testing
should include specific tests to assess in the offspring known
effects of chloromethane in adults. Acquisition of a conditioned
reflex was reported as a sensitive endpoint by Yevtushenko
(1966). Neurologic impairment of motor function in humans and
other mammals has been reported (see, e.g., Klirnkova-Deutschova
53
-------
1957, Smith and vori Oettingen 1947b) and impairment of visual
functions in humans (see, e.g., Langauer-Lewowicka et al.
1974). These three types of endpoints should be considered as
well as thorough neuropathology.
F. Metabolism
1. Data Evaluation
a. Absorption
Although it is generally believed that the principal route
of human exposure to chloromethane is by inhalation, most
inhalation experiments in both man and animals are really whole-
body exposure experiments and possible skin and GI absorption
cannot be wholly ruled out (Bus 1979, Smith and von Oettingen
1947a, Stewart et aL. 1977, Yevtushenko 1967). It has been
demonstrated, moreover, that ohloromethane can be absorbed
through the skin (NIOSH 1977). In another experiment (Morgan et
al. 1970) the human volunteers inhaled the radiolabeled
chloromethane directly through a tube placed in the mouth (which
allows the possibility of GI or mucous membrane absorption, but
does eliminate that through the skin) and showed that absorption
through the airways probably does occur.
b. Distribution
Several different experimenters have followed blood and
tissue levels of chloromethane over time. The experiments are of
two types: 1) disappearance of chloromethane from the tissue is
followed after a single brief exposure, either by injection or
inhalation; and 2) those in which the subject has been exposed
for a considerable period of time (i.e., the condition is more or
less stabilized) and the levels of the chemical are followed
after cessation of exposure.
Sperling et al. (1950) injected chloromethane into dogs
intravenously (i.v.) and measured blood and tissue chloromethane
at various times. At the first measurement just after the
injection was completed, the percentage of chloromethane present
in the blood varied between 4.5 and 13.1 percent (of .1680 mg
54
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injected); at 30 minutes, the values were 1.5 to 2.7 percent; and
at 60 minutes they ranged from 0.6 to 1.3 percent. However,
between eight and thirty minutes were required to inject the
total amount of chloromethane (as a gas), thus allowing time for
some redistribution to tissues and for biotransformation. This
group did another series of experiments in which they measured
blood and tissue levels in one group of animals immediately
following injection of various amounts of chloromethane (173-206
mg/kg), and another group (154-228 mg/kg) after one hour. The
blood chloromethane concentration initially ranged between 0.119
to 0.135 mg/cc, while at one hour, the range was 0.035 to 0.041
mg/cc. Neither of the groups showed a dose-blood level
relationship, however. Various other tissues were measured for
chloromethane content during the same experiment, with similar
results occurring. Levels at 60 minutes were on the average
lower than those at the beginning, although there was
considerable variation among dogs.
Soucek (1961) used subcutaneous (s.c.) injection in rats to
measure the disappearance of chloromethane from the blood. At
two minutes following a single 1200 ug injection of chloromethane
ln f^2^' ^-'^ percent of the dose appeared in the blood, at 10
minates 0.7 percent, while at 25 minutes, chloromethane
concentrations were below the level of detection. However, it is
difficult to compare the two experiments, as Soucek could not or
did not measure the rate of chloromethane's entrance into the
blood, and .measurements made after s.c. injection are the result
of a two-way flow, both into and out of the blood. Although
Soucek was unable to measure chloromethane in the blood beyond 10
minutes, he was still able to detect unaltered chemical in the
expired air at 120 minutes, as were Sperling et al. (1950).
CIIT's study (Bus 1979) is of the second type, but with an
additional change. Instead of measuring chloromethane, CUT
administered 14CH^C1 and measured radioactivity, which enabled
the investigators to pick up metabolites and bound compound as
well as free compound dissolved in the plasma. Blood l^C
55
-------
were measured at intervals following a 6-hour exposure to 1500
ppm in rats. At time zero (immediately after the 6-hour
exposure), the l^c-content of the blood was 0.93±0.02 umole of
CHoCl equivalents/ml, after which the level steadily dropped
until at 24 hours (30 hours from start of experiment) the value
was 0.17±0.02, umole CHgCl equivalents/ml. Levels in all other
tissues measured (liver, fat, kidney, spleen, lung, heart and
brain) acted in a similar manner. However, some tissues lost
radiolabel much more quickly than others. At 24 hours the amount
of l^C in fat was 12.1 percent of the initial value, while the
heart still carried 38.9 percent of its initial load. At time
zero, liver was highest with 2.63 umole CH3C1 equivalents/g wet
weight, while brain had the lowest concentration, 0.55 umole, but
at 24 hours levels in all the tissues were closer to each other,
from liver with 0.45 to brain with 0.12 umole GH^ci equivalents/a
wet weight. There is apparently little or no redistribution to
other tissues, nor are the organs which appear to be most
affected (i.e., brain, liver, kidney) those which retain the
greatest amounts of radioactivity.
c. Excretion
Some portion of the gas is excreted unchanged, not only
through the lungs in man (Morgan et al. 1970, Stewart et al.
1977), dogs (Sperling et al. 1950), and rats (Soucek 1961), but
in the urine and bile following i.v. injection in the dog
(Sperling et al. 1950). CUT (Bus 1979) also claimed that a
portion of the administered chemical was Pound in the expired air
(radiolabel trapped in a charcoal filter but not chemically
identified). Under the conditions of the study (6-hour
inhalation of different dose levels by rats and mice, 48 hour
observation period) the amount excreted unchanged was fairly
small and did not appear to be strictly dose-dependent. In rats,
at 100 ppm, 2.4 percent of the retained material was found in the
expired air, at 375 ppm, 1.8 percent, and at 1500 ppm, 6.3
percent? in mice, at 1500 ppm, 4.4 percent was exhaled (Bus
1979).
56
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Sperling et al. (1950), following injections of various
amounts of chloromethane into dogs, observed that about 5 percent
of the total injected was found unchanged in the expirerl air
within the first hour. However, Morgan et al. (1970) found that
one hour after inhalation of CH338ci in man, 29 percent of the
administered radioactivity was excreted through the lungs. The
EPA believes that all the radioactivity measured in the expired
air was chloromethane, rather than a metabolite, even though this
was not verified chemically, as all the known or postulated
biotransformation mechanisms produce chloride ion, a non-volatile
product. The rather large difference between these two results
may be due to the mode of administration, to the species, or to
what was measured in the expired air: chloromethane in the first
case (Sperling et al. 1950) and 38rji in the second (Morgan et al.
1970).
Morgan et al. (1970) compared the pulmonary excretion of
CHo^ci with that of the higher chlorinated methanes, and
concluded that chloromethane acted in a different manner. When
excretion rate versus time x-/as plotted (retention curve), the
di-, tri- and tetrachlorinated methanes had parallel slopes,
while monochloromethane's rate of excretion dropped more rapidly
with time. i^his may be due to a number of reasons: 1) the com-
pound is more reactive; 2) a greater percentage is excreted by
alternate routes; 3) it is more fat-soluble. The authors felt
that chloromethane behaved like iodomethane, which reacts rapidly
with sulfhydryl groups in the erythrocyte in an enzyme-catalyzed
methylation process.
Stewart et al. (1977) discovered two populations among their
human subjects. Four of their subjects, as well as two from a
previous study, had considerably elevated post-exposure breath
and blood chloromethane levels. The rest of the volunteers
carried a two to six times lower body burden than these. Stewart
and his coworkers postulated that the worker who carries a lower
body burden than the majority may be at greater risk from chloro-
methane exposure. This would appear to indicate that a larger
57
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portion of the exposed population would be at greater risk. The
data can also be interpreted to mean that those people with
greater amounts of unaltered compound in their bloodstream and
airspace might be metabolizing less of the material rather than
absorbing or carrying more. And as the metabolized material is
probably responsible for toxicity, the subjects excreting more
compound unchanged would be at a lower risk rather than a higher
one. If, on the other hand, chloromethane per se is the toxic
compound, those persons with higher blood and breath levels may
be more susceptible to overexposure. Of course, the possibility
exists that neither of these theories is important, and the
different populations are at equal risk.
^• Biotrans formations
The efirliest theories about chloromethane' s biot.ransforma-
tion (Plury 1928) dealt with its probable conversion to formalde-
hyde through methanol. Formaldehyde has been found in the blood
of rats (Yevtushenko 1967) and mice (Sujbert 1967) following
inhalation of chloromethane, and in mice (Sujbert 1967) following
intraperitoneal (i.p.) injection. Sujbert (1967) also was able
to detect methanol in the bloodstream of mice following
inhalation or i.p. injection as did Hayhurst and Greenburg (1929)
who detected methanol, formaldehyde and formates in the organs of
victims of chloromethane poisoning. Smith (1947), on the
contrary, was unable to find any methanol in the blood of dogs
that had been exposed to chloromethane by inhalation for 23 or 25
days. Other researchers have tested for formate in the urine or
tissues of subjects exposed to chloromethane, with variable
results. Baker (1927), Kegel et al. (1929) and Hayhurst and
Greenburg (1929) found formates in human tissues and urine fol-
lowing accidental exposure to the compound, whereas Hansen et al.
(1953) were unable to demonstrate increased formate in their
human subjects correlating with levels of chloromethane in the
ambient air.
The creation of formaldehyde from chloromethane is probably
analogous to that proposed for the biotransformation of
58
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chloroform (CHCl^) to phosgene, a reaction that has recently been
confirmed experimentally (Pohl et al. 1977, 1979, Pohl and
Krishna 1978).
H
Cl
• C —
c'l
• Cl
P-450
Cl
i
H - 0 - C Cl
i
Cl
NE
0 = C'
Cl
+ HC1
Cl
NE = nonenzymatic
It has been suggested that a cytochrome P-450 monooxygenase
oxidizes CHClo to unstable trichloromethanol, which spontaneously
dehydrochlorinates to yield the reactive phosgene. Dichloro-
methane seems to follow a similar initial pathway (Kubic and
Anders 1978) to eventually yield CO through a formyl chloride
intermediate:
Cl
I
H
P-450
Cl
H - 0 - C - Cl
H
NE
o = c;
Cl
H
CO + HC1
HC1
Formaldehyde production from chloromethane probably occurs as
follows:
H
H
I
C
I
H
Cl
P-450
H
i
H — 0 — P — Pi
H
NE
0 = C
H
H
HC1
Additional reactions can occur after formaldehyde production:
(1) aldehyde reduction, with formaldehyde going to methanol;
(2) aldehyde dehydrogenation, with formic acid and/or formates as
the ultimate product.
Ahmed and Anders (1978) have proposed an additional route
for metabolism of dihalomethanes, which involves alkylation and
dealkylation of glutathione (GSH). This pathway yields
formaldehyde, formic acid and inorganic halide. As it is known
that chloromethane binds very specifically to GSH in erythrocytes
59
-------
(Redford-Ellis and Gowenlock 1971a), this alternative route may
also be important for chloromethane.
P=450 NE
GS - CH2OH »CH20 + GSH
Formaldehyde dehydrogenase/NAD+
0
-II
GS - C-H
H_ C — H + GSH
I
S-Formyl glutathione hydrolase
GSH + HCOOH
E = enzymatic
CUT (Bus 1979) measured radioactivity in the expired air
for 48 hours following a 6-hour exposure to chloromethane in rats
and mice. That percentage of radioactivity trapped by a charcoal
filter they designated as chloromethane, while that trapped by
ethanolamine in methoxyethanol was considered to be CO~ . Nfo
mention was made as to whether such possible alternative volatile
metabolites as carbon monoxide, methanol, or formaldehyde would
be trapped and measured by their methods.
CUT (Bus 1979) found that in rats in the 48 hours following
a 6-hour exposure to 1500 ppm 14CH3C1, more than 41 percent of
the total recovered radioactivity was 14CO2 from the expired air,
while in mice given the same dose, less than 18 percent was
excreted as ^-^CO^. In mice, the largest percentage of recovered
radioactivity (60 percent) was excreted in the urine, while the
rat excreted only 40 percent of the retained radioactivity as
urinary components. It is possible that a portion of the urinary
radioactivity occurs as bicarbonate, for following acid
hydrolysis of the mouse urine, a small portion (9 percent) of the
urinary radioactivity was found in the headspace of the vial,
presumably as -^COo-
60
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e. Tissue Retention
In addition to measuring radioactivity in the various
excreta, CUT (Bus 1979) measured radioactivity retained in some
organs and the carcass following exposure to -^CHoCl. in rats at
the end of a 48 hour period following 6 hours of exposure to 100/
375 or 1500 ppm of the gas, there was no increase in the amount
of associated radioactivity between the 375 and 1500 ppm groups
(e.g., for liver at 100 ppm, tissue radioactivity equalled 52.3
umole of l^C-chloromethane equivalents/g wet weight, while at 375
ppm, the radioactivity was 325.2, and at 1500 ppm, it was 265.2),
which may indicate a saturation of available binding sites. Of
the amount retained following a 6 hour exposure, 22.5 percent of
the radioactivity was associated with the tissues at 100 ppm,
21.4 percent at 375 ppm and 17.3 percent at 1500 ppm. Although
neither the form nor the type of binding in the tissues was
specified by CUT, the retention of such a high proportion of
radioactivity after two days indicates a fairly strong binding
capacity. At all dosages, retention was lowest, by a factor of
three, in the brain, highest in the liver at 375 and 1500 ppm and
highest in fat at 100 ppm. In mice following a similar exposure
regimen at 1500 ppm, only 8.3 percent of the total recovered was
associated with the tissues, and while the brain again had the
lowest value, liver and kidney had the highest.
f. Binding
Morgan et al. (1970) postulated that chloromethane acts like
iodomethane, reacting rapidly with sulfhydryl groups in an
enzyme-catalyzed methylation process. Redford-Ellis and
Gowenlock (1971a,b) studied the reaction of l^C-chloromethane
with human blood in_ vitro. In serum or plasma, about 65 percent
of the radioactive uptake was associated with plasna protein but
only about 2-3 percent covalently bound to the plasma protein
(specifically albumin), producing primarily S-methylcysteine,
although minor radioactive components of 1-methyl- and 3-methyl-
histidine were also found. In erythrocytes, uptake was
independent of dose over the range used (600-1000 mg/ml
61
-------
erythrocyte), being a constant 357 mg/ml erythrocyte after 80
minutes, of which 58-130 mg was bound covalently to GSH.
However, in studies on red cells, after uptake was complete, no
radioactivity was lost by hemolysis or by washing, and no
radioactivity could be detected bound to other components of the
erythrocyte, so there appears to be some discrepancy between
uptake and binding. Heating the blood before adding the
chloromethane reduced binding by over 90 percent, indicating a
probable enzyme-catalyzed reaction. Redford-Ellis and Gowenlock
(1971b) continued their researches by studying chloromethane's
binding to rat brain, liver and kidney hornogenates in vitro, as
these are the organs primarily associated with chloromethane
toxicity. In all these tissues, the primary products are 14CH
S-Cys and ^CHo-S-GSH, while in the kidney additional traces of
radioactivity were found in methionine. The formation of these
compounds in tissue homogenates also appears to be partially
enzyme-dependent, as heating the tissues reduced the level of
binding.
As part of the CUT study, Dodd et al. (1979) looked at
alterations in tissue sulfhydryl concentrations in rats after
acute inhalation exposure to 1500 ppm chloromethane for 6
hours. They found that although changes in total tissue sulfhy-
dryl groups were minimal at all times (0,1,2,4,8,18 hours) after
exposure, non-protein sulfhydryl content was reduced in liver,
kidney, lung and blood (most to least) indicating a decrease in
free, reactive, -SH groups. At eighteen hours after exposure
non-protein sulfhydryl content had returned to control values.
However, earlier work by the same group (Bus 1979) reported that
radioactivity was still present in these tissues 48 hours after
exposure. It appears to the EPA. that either: 1) significant
amounts of CH^Cl or a metabolite are reacting with non-sulfhydryl
groups or 2) rearrangemeat is occurring.
2. Current and Planned Testing
CUT has informed the EPA that they have not finished their
total planned metabolism studies on chloromethane. It is
62
-------
believed that these additional tests will substantially add to
the corpus of knowledge of the compound.
3. Conclusions
The EPA is not proposing metabolism studies. Although
information is incomplete, it is felt that the additional testing
being done by CUT is sufficient to aid the Agency in assessing
chloromethane.
G. Epidemiology
In the case of chloro.nethane, the Yevtushenko study (1976)
and the epidemiologic study of Repko et al. (1976) indicate that
chronic inhalation of chloromenthane by hurnans at the present TLV
(100 ppm) may result in impaired neurologic functions. The SPA
believes that an epidemiologic study would clarify the relation-
ship between chronic exposure to chloromethane at 100 ppm and
neurologic impaimerit. At this time, however, the EPA is not in
a position to develop a test rule for such a study because of its
current inability to identify suitable cohorts. NIOSH has
attempted to locate a cohort for chloromethane and has thus far
been unsuccessful (SRI 1979d). The EPA is proposing a rule under
Section 8(a)(2)(F) of TSCA for chloromethane as well as other ITC
chemicals. Under Section 8(a), the EPA may obtain readily
accessible information from the files of manufacturers,
processors and importers on the use, production and worker
exposure from specified chemicals. The Agency will carefully
evaluate the information received to determine if a cohort can be
identified and if additional testing would then be considered
necessary.
63
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IV. Summary
A. Exposure
In 1979 approximately 497 million pounds of chloromethane
were produced in the United States solely for domestic consump-
tion. Hydrochlorination of methanol is the process used for
greater than 98 percent of production. Chloromethane is used
almost exclusively as an intermediate, primarily in the
manufacture of silicones and tetramethyllead. Although
chloromethane is present in the atmosphere in parts per trillion
levels from natural sources, and in the parts per billion range
from anthropogenic sources other than manufacturing, processing
and use, high concentrations at the parts per million level have
been found in occupational settings.
On the basis of chloromethane's almost exclusive use as an
intermediate, reports prepared for NIOSH, and various reports of
exposure found in the literature, the EPA staff concludes that
the maximum potential for the possible risk associated with
direct exposure to chloromethane exists during its manufacture,
processing and use.
B. Health Effects
1. Systemic Effects
Chloromethane exposure has been reported to result in a wide
range of systeaic toxicity following both acute and chronic
exposure. Although effects on the liver, kidney, heart and
hematopoietic system have been demonstrated in both humans and
animals, the most sensitive organ seems to be the CNS. The
available animal studies appear to be adequate for determining
chronic toxicity in systems other than the CNS.
2. Ne urpt o x i c i ty
Chloromethane is a non-specific CNS depressant. There are
human case reports, several animal studies, and controlled human
laboratory studies that document its acute and chronic
neurotoxicity. Chloromethane intoxication produces neurologic
64
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signs, mood changes, and cognitive and intellectual deficits, as
well as other symptoms. Chronic neurotoxicity, with a potential
for permanent effects, is indicated by the evidence to be a risk
to human health that cannot be assessed at this time without
additional data, acquired by testing.
3. Mutagenicity
Chloromethane has been reported to possess mutagenic
activity in bacterial systems that detect gene mutations and to
cause chromosomal aberrations in higher plants. However, the
evidence for chloromethane mutagenicity from this series of
experiments is insufficient to permit a mutagenicity hazard
assessment for chloromethane.
4. Oncogenicity
Neither epidemiology, other systemic human studies nor any
animal assays have been reported which are sufficient to evaluate
the oncogenic potential of chloromethane. However, there is
substantial information suggesting that this chemical may possess
oncogenic potential. This information includes evidence of its
mutagenic activity, its in vitro and in vivo alkylating
~~ "^"**J • "~~" ~~ ~
capabilities, and its structural relationship to known or
suspected oncogens.
5. Teratogenicity
Because of the biologic activity of chloromethane in adults
and its probable accessibility to the fetus, the EPA. believes
that chloromethane may present an unreasonable risk of teratogen-
icity. With regard to the teratogenic potential of chloromethane,
the EPA is concerned with the danger of both structural
malformations and behavioral alterations.
6. Metabolism
Although fragmentary research has been conducted in several
areas of chloromethane metabolism, insufficient information
exists to give a complete characterization. Tt is known that
65
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chloromethane is absorbed through the airways and skin, that
radioactivity can be detected to varying degrees in all tissues
tested following inhalation of *-^C-chl orome thane, and that
excretion of unchanged compound is through the lungs, urine and
feces, while possible metabolites also appear in the expired air
and urine. A fraction of the inhaled radioactivity is retained
by the organism following administration of 14CH^C1, and appears
to be primarily bound to tissue sulfhydryl groups. Known
metabolic products include rnethanol, formaldehyde, and formate.
Although the EPA feels that metabolism studies on chloromethane
are not complete, the Agency believes that the data available are
sufficient at this time to assist in evaluating the risk of
exposure to chloromethane.'
7. Ep i d em i o1ogy
The EPA has determined that at ths time a suitable cohort
for epidemiology studies cannot be identified and, therefore, is
not requiring such studies. However, if information becomes
available to the Agency through TSCA Section 8(a)(2)(F) leading
to the identification of a suitable cohort, the Agency may
reexamine this conclusion.
66
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83
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TECHNICAL REPORT DATA
read lailructions on 'ne re\erse jei'orc completing)
\O
•3. RECIPIENT'S ACCESSION-NO.
EPA-560/11-80-015
4 TITLE AND SUBTITLE
Support Document Health Effects Test Rule:
Chloromethane
6. PERFORMING ORGANIZATION CODE
5, REPORT DATE
.Tune ] 980 (annrnvedl
7 AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO
9 PERFORMING ORGANIZATION \A.\lc AND ADDRESS
Assessment Division
Office of Pesticides and Toxic Substances
401 M Street, SW
Washington, DC 20460
110. PROGRAM ELEMENT NO.
11 CONTRACT GRANT NO
I
'13. T'-'PE OF REPORT AND PERIOD COVERED
U. S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
,14 SPONSORING AGENCY CODE
15 SUPPLEMENT.^ y .NOTES
16 ABSTRACT
In 1979 approximately 497 million pounds of chloromethane were produced in the
United States solely for domestic consumption. It is used almost exclusively as an
intermediate, primarily in the manufacture of silicone and tetramethyllead.
Chloromethane exposure has been reported to result in a wide range of systemic
toxicity following both acute and chronic exposure. Although effects on the liver,
kidney, heart, and hematopoietic system have been demonstrated in both humans and
animals, the most sensitive organ seems to be the central nervous system (CNS).
Chloromethane has been reported to possess mutagenic activity in bacterial
systems that detect gene mutations and to cause chromosomal aberration.
Evidence of its mutagenic activity, its in vitro and in vivo alkylating
capabilities, and its sturctural relationship to known or suspected oncogens
suggest that chloromethane may possess oncogenic potential.
EPA is also concerned with the danger of both structural malformation and
behavioral alterations that may be posed by chloromethane.
Bibliography included.
17
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