Toxicological
Profile
for
CHLOROMETHANE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-07
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TOXICOLOGICAL PROFILE FOR
CHLOROMETHANE
Prepared by:
Syracuse Research Corporation
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990
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DISCLAIMER
The use of company or product name(s) is for identification only and
does not imply endorsement by the Agency for Toxic Substances and Disease
Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental Response,
Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public
law (also known as SARA) directed the Agency for Toxic Substances and
Disease Registry (ATSDR) to prepare toxicological profiles for hazardous
substances which are most commonly found at facilities on the CERCLA
National Priorities List and which pose the most significant potential
threat to human health, as determined by ATSDR and the Environmental
Protection Agency (EPA). The list of the 200 most significant hazardous
substances was published in the Federal Register on April 17, 1987 and on
October 20, 1988.
Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a
toxicological profile for each substance on the list. Each profile must
include the following content:
(A) An examination, summary and interpretation of available
toxicological information and epidemiological evaluations on the
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the associated
acute, subacute, and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, or chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and health effects information for the hazardous substance
being described. Each profile identifies and reviews the key literature that
describes a hazardous substance's toxicological properties. Other
literature is presented but described in less detail than the key studies.
The profile is not intended to be an exhaustive document; however, more
comprehensive sources of specialty information are referenced.
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
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iv
presents levels of significant human exposure and, where known, significant
health effects. The adequacy of information to determine a substance's
health effects is described in a health effects summary. Data needs that
are of significance to protection of public health will be identified by
ATSDR, the National Toxicology Program of the Public Health Service, and
EPA. The focus of the profiles is on health and toxicological information-
therefore, we have included this information in the front of the document
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public. We plan to
revise these documents in response to public comments and as additional data
become available; therefore, we encourage comment that will make the
toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed
by scientists from ATSDR, EPA, the Centers for Disease Control, and the
National Toxicology Program. It has also been reviewed by a panel of
nongovernment peer reviewers and was made available for public review.
Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR.
William L. Roper, M.D., M.P.H.
Acting Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS CHLOROMETHANE? 1
1.2 HOW MIGHT I BE EXPOSED TO CHLOROMETHANE? 2
1.3 HOW CAN CHLOROMETHANE ENTER AND LEAVE MY BODY? 2
1.4 HOW CAN CHLOROMETHANE AFFECT MY HEALTH? 2
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH
EFFECTS? 3
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO CHLOROMETHANE? 8
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? 8
1 .8 WHERE CAN I GET MORE INFORMATION? 8
2. HEALTH EFFECTS 9
2.1 INTRODUCTION 9
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 9
2.2.1 Inhalation Exposure 10
2.2.1.1 Death 10
2.2.1.2 Systemic Effects 25
2.2.1.3 Immunological Effects 29
2.2.1.4 Neurological Effects 29
2.2.1.5 Developmental Effects 31
2.2.1.6 Reproductive Effects 32
2.2.1.7 Genotoxic Effects 32
2.2.1.8 Cancer 33
2.2.2 Oral Exposure 3 3
2.2.2.1 Death 33
2.2.2.2 Systemic Effects 33
2.2.2.3 Immunological Effects 33
2.2.2.4 Neurological Effects 33
2.2.2.5 Developmental Effects 33
2.2.2.6 Reproductive Effects 33
2.2.2.7 Genotoxic Effects . 33
2.2.2.8 Cancer 33
2.2.3 Dermal/Ocular Exposure .... 34
2.2.3.1 Death 34
2.2.3.2 Systemic Effects 34
2.2.3.3 Immunological Effects 34
2.2.3.4 Neurological Effects 34
2.2.3.5 Developmental Effects 34
2.2.3.6 Reproductive Effects 34
2.2.3.7 Genotoxic Effects 34
2.2.3.8 Cancer 34
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2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
2.3.1.2 Oral Exposure . . .
2.3.1.3 Dermal Exposure . .
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
2.3.2.2 Oral Exposure . . .
2.3.2.3 Dermal Exposure . .
2.3.3 Metabolism
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
2.3.4.2 Oral Exposure . . .
2.3.4.3 Dermal Exposure . .
RELEVANCE TO PUBLIC HEALTH
BIOMARKERS OF EXPOSURE AND EFFECTS.
2.5.1 Biomarkers Used to Identify or Quantify Exposure
to Chloromethane
2.5.2 Biomarkers Used to Characterize Effects Caused
by Chloromethane
INTERACTIONS WITH OTHER CHEMICALS
POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
ADEQUACY OF THE DATABASE
2.8.1 Existing Information on Health Effects of
Chloromethane
2.8.2 Identification of Data Needs
2.8.3 On-going Studies
2.4
2 . 5
2.6
2.7
2.8
3. CHEMICAL AND PHYSICAL INFORMATION. .
3.1 CHEMICAL IDENTITY
3.2 PHYSICAL AND CHEMICAL PROPERTIES
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION. .......
4.2 IMPORT • • . . .
4.3 USE • • . . .
4.4 DISPOSAL. ... • • ¦ . .
POTENTIAL FOR HUMAN EXPOSURE .
5-1 reSIsEs'TO THE ENVIRONMENT
5.2.1 Air. . .
5.2.2 Water. .
5.2.3 Soil . .
ENVIRONMENTAL FATE. ... ...
5 3.1 Transport Partitioning . .
TransforrtlSt^ori and Degradation
c i i * ~-
5.2
5.3
5.3.2
5.3.2.1
5.3.2.2
5.3.2.3
Air
Water-
Soil,
5.4
LEVELS MONITORED OR EstjmatpA
5.4.1 Air. . . . . _ IIMATED IN THE ENVIRONMENT.
34
34
34
35
35
35
35
36
36
36
37
37
39
39
39
k 9
50
50
50
51
52
52
54
60
61
61
61
65
65
66
66
67
69
69
69
69
71
72
72
72
73
73
74
75
75
75
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5.4.2 Water 77
5.4.3 Soil 80
5.4.4 Other Media 80
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 81
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 84
5.7 ADEQUACY OF THE DATABASE 84
5.7.1 Identification of Data Needs 84
5.7.2 On-Going Studies 87
6. ANALYTICAL METHODS 89
6.1 BIOLOGICAL MATERIALS 89
6.2 ENVIRONMENTAL SAMPLES 89
6.3 ADEQUACY OF THE DATABASE 92
6.3.1 Identification of Data Needs 92
6.3.2 On-going Studies 93
7. REGULATIONS AND ADVISORIES 95
8. REFERENCES 97
9. GLOSSARY 123
APPENDIX 127
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LIST OF FIGURES
2-1 Levels of Significant Exposure to Chloromethane - Inhalation. ... 22
2-2 Proposed Scheme for the Metabolism of Chloromethane 38
2-3 Existing Information on Health Effects of Chloromethane 53
5-1 Frequency of Sites With Chloromethane Contamination 70
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LIST OF TABLES
1-1 Human Health Effects from Breathing Chloromethane 4
1-2 Animal Health Effects from Breathing Chloromethane 5
1-3 Human Health Effects from Eating or Drinking Chloromethane 6
1-4 Animal Health Effects from Eating or Drinking Chloromethane .... 7
2-1 Levels of Significant Exposure to Chloromethane - Inhalation. ... 11
2-2 Genotoxicity of Chloromethane In Vitro 46
2-3 Genotoxicity of Chloromethane In Vivo 47
3-1 Chemical Identity of Chloromethane 62
3-2 Physical and Chemical Properties of Chloromethane 63
5-1 Detection of Chloromethane in Air 76
5-2 Detection of Chloromethane in Water and Sediments 78
5-3 Occupational Monitoring of Chloromethane 82
5-4 Numbers of Workers Potentially Exposed to Chloromethane and
Industrial Classification 83
6-1 Analytical Methods for Determining Chloromethane in
Biological and Environmental Samples 90
7-1 Regulations and Guidelines Applicable to Chloromethane 96
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1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about chloromethane
and to emphasize the human health effects that may result from exposure to
it. The Environmental Protection Agency (EPA) has identified 1177 sites on
its National Priorities List (NPL). Chloromethane has been found at 18 of
these sites. However, we do not know how many of the 1177 NPL sites have
been evaluated for chloromethane. As EPA evaluates more sites, the number
of sites at which chloromethane is found may change. The information is
important for you because chloromethane may cause harmful health effects and
because these sites are potential or actual sources of human exposure to
chloromethane.
When a chemical is released from a large area, such as an industrial
plant, or from a container, such as a drum or bottle, it enters the
environment as a chemical emission. This emission, which is also called a
release, does not always lead to exposure. You can be exposed to a chemical
only when you come into contact with the chemical. You may be exposed to it
in the environment by breathing, eating, or drinking substances containing
the chemical or from skin contact with it.
If you are exposed to a hazardous substance such as chloromethane,
several factors will determine whether harmful health effects will occur and
what the type and severity of those health effects will be. These factors
include the dose (how much), the duration (how long), the route or pathway
by which you are exposed (breathing, eating, drinking, or skin contact), the
other chemicals to which you are exposed, and your individual
characteristics such as age, sex, nutritional status, family traits, life
style, and state of health.
1.1 WHAT IS CHLOROMETHANE?
Chloromethane is a clear, colorless gas (vapor) that is difficult to
smell. It has a faintly sweet, nonirritating odor at high levels in the
air. It is a naturally occurring chemical that is made in large amounts in
the oceans and is produced by some plants and rotting wood and when such
materials as grass, wood, charcoal, and coal burn. Chloromethane is also
produced industrially, but most of it is destroyed during use. It is used
mainly in the production of other chemicals such as silicones, agricultural
chemicals, and butyl rubber. Producers of the chemical supply the chemical
to their customers as a liquified gas in metal containers. Chloromethane
was used widely in refrigerators in the past, but generally this use has
been taken over by newer chemicals such as Freon. Some functioning
refrigerators more than about 30 years old may contain chloromethane.
Since chloromethane is continuously released into the atmosphere from oceans
and biomass, a very low concentration will always be present. When present
in water, chloromethane will evaporate rapidly. Chloromethane will
evaporate from the soil surface, but if present in a landfill or waste site,
it may move downward and get into well water. For more information, please
read Chapters 3, 4, and 5.
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1. PUBLIC HEALTH STATEMENT
1.2 HOW MIGHT I BE EXPOSED TO CHLOROMETHANE?
Because chloromethane is made in the oceans by natural processes, it is
present in air all over the world. In most areas, the outside air contains
less than 0.001 part of chloromethane in a million parts of air (ppm). In
cities, however, the air may contain up to 0.003 ppb. It is also present in
some lakes and streams and has been found in drinking water (including well
water) at very low levels in the ppb range. Chloromethane is also found in
tap water that has been chlorinated. If chloromethane is present at waste
sites, it may get into underground water as it passes downward through the
soil. Very low levels may be present naturally in the soil. There have
been no reports that chloromethane is found in food. You could be exposed
to levels somewhat higher than the background levels, although probably
still very low levels, if you live near a hazardous waste site or a source
of industrial release. The people most likely to be exposed to increased
levels of chloromethane in the air are those who work where it is made.
Other occupations or industries that present a higher risk of exposure to
chloromethane include building contracting, metal industries,
transportation, car dealers, and service - station attendants. In the past
(more than 30 years ago), chloromethane was widely used in refrigerators,
and people may still be exposed to it if these old refrigerators leak the
gas into their homes. Other consumer sources of chloromethane include
cigarette smoke; polystyrene insulation; aerosol propellents; home burning
of wood, grass, coal, or certain plastics; and the use of chlorinated
swimming pools. For more information, please read Chapter 5.
1.3 HOW CAN CHLOROMETHANE ENTER AND LEAVE MY BODY?
Chloromethane can enter your body through the lungs if you breathe it
in or through the digestive tract if you drink water containing it. Almost
all of the chloromethane that you breathe in or drink rapidly enters the
bloodstream from the lungs or the digestive tract. Chloromethane can also
enter your body through the skin if you come into contact with it, but the
amount that enters this way is not known. Breathing air that contains
chloromethane vapor is the most likely way you could be exposed if you live
near a hazardous waste site. Chloromethane goes rapidly from the lungs
into the bloodstream, and then it or its breakdown products go to organs
such as the liver, kidneys, and brain. The portion of the chloromethane
that does not get changed in your body leaves in the air you breathe out,
and the breakdown products of chloromethane formed in the body leave in the
urine. These processes take anywhere from a few hours to a couple of days.
For more information, please read Chapter 2.
1.4 HOW CAN CHLOROMETHANE AFFECT MY HEALTH?
If the levels are high enough (over a million times the natural level
in outside air), brief exposures to chloromethane can have serious effects
on the nervous system, including convulsions, coma, and death. Some people
have died from breathing chloromethane that leaked from refrigerators in
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1. PUBLIC HEALTH STATEMENT
rooms with little or no ventilation in their homes. Most of these cases
occurred more than 30 years ago, but exposure could still happen if you have
an old refrigerator that contains chloromethane as the refrigerant. Others
exposed to high levels this way or to leaks while they were repairing
refrigerators did not die but had effects such as staggering, blurred and
double vision, dizziness, fatigue, personality changes, confusion, tremors,
uncoordinated movements, nausea, and vomiting. These symptoms can last for
several months or more, but complete recovery is possible. Exposure to
chloromethane has also had harmful effects on the liver, kidney, heart rate,
and blood pressure. If you work in an industry that uses chloromethane to
make other products, you might be exposed to chloromethane levels that cause
some symptoms that resemble drunkenness and impaired ability to perform
simple tasks.
Harmful liver, kidney, and nervous system effects have developed after
animals breathed air containing high levels of chloromethane (100,000 times
higher than natural levels) for a few hours each day for 1 or more days.
Animals have also died from exposure to high levels of chloromethane. When
mice breathed the vapors for only several hours per day, they could be
exposed to higher levels of chloromethane before developing effects than if
they breathed the vapors all day for several days. The same effects
occurred in animals when they were exposed to lower levels of chloromethane
for longer periods. In long-term exposure experiments, animals that
breathed air containing chloromethane grew more slowly than animals that
were not exposed. Male rats that breathed air containing chloromethane
developed effects in their reproductive organs that made them less fertile
or even sterile. They also produced sperm that were damaged, causing female
rats that became pregnant by these exposed male rats to lose their fetuses.
Female rats that were exposed to chloromethane during pregnancy had smaller
than normal fetuses with underdeveloped bones. Female mice that are exposed
during pregnancy may produce fetuses with abnormal hearts, but this issue is
controversial. Male mice that breathed air containing chloromethane for 2
years developed tumors in their kidneys, but female mice and male and female
rats did not develop tumors. It is not known whether chloromethane could
cause sterility, miscarriages, birth defects, or cancer in humans. For more
information, please read Chapter 2.
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Tables 1-1 through 1-4 show the relationship between exposure to
chloromethane and known health effects. Minimal Risk Levels (MRLs) are also
included in Table 1-1. These MRLs were derived from animal data for both
short-term and long-term exposure, as described in Chapter 2 and in
Table 2-1. The MRLs provide a basis for comparison with levels that people
might encounter in air. If a person is exposed to chloromethane at an
amount below the MRL, it is not expected that harmful (noncancer) health
effects will occur. Because these levels are based on information currently
available, some uncertainty is always asssociated with them. Also, because
the method for deriving MRLs does not use any information about cancer, an
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing Chloromethane*
Short-term Exposure
(less than or equal to 14 days)
Levels in Air fppm)
Length of Exposure
Description of Effects**
0.46
200
29,000
3 hours
4 hours
Minimal Risk Level (based on
animal studies; see Section
1.5 for discussion).
Impaired ability to perform
simple tasks.
Serious nervous system
effeets,nausea, vomiting.
Long-terra Exposure
(greater than 14 days)
Levels in Air (ppra)
Length of Exposure
Description of Effects**
0.40
265
2-3 weeks
Minimal Risk Level (based on
animal studies; see Section
1.5 for discussion).
Nervous system effects,
blurry vision, dizziness,
staggering, confusion.
*See Section 1.2 for a discussion of exposures encountered in daily
life.
**These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Chloromethane
Short-term Exposure
(less than or equal to 14 days)
Levels
in Air
(ppm)
Lenpth of Exposure
Description of Effects*
100
11 days
Damage to brain cells in
mice.
150
11 days
Death, muscle incoordination,
liver damage, decreased
growth rate in mice.
500
1000
2-3 days
5 days
Damage to testes of rats.
Decreased fertility of rats.
1500
13 days
Underdeveloped bones in
3000
5 days
fetuses of pregnant rats.
Damaged sperm that cause
abortion in rats.
Long-term Exposure
(greater than 14 days)
Leve1s
in Air
(ppm)
Length of Exposure
Description of Effects'*
375
3 months
Decreased body weight in rats.
475
5 months
Decreased fertility in rats.
1000
6 months
Liver and nervous system
effects (tremors, paral-
ysis) in mice, damage to
testes of rats.
1000
12 months
Decreased survival and
kidney changes in mice.
1500
5 months
Sterility in rats.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking Chloromelhane*
Short-term Exposure
(less Chan or equal
to 14 days)
Levels
i n
Food
Leneth of Exposure
Descriotion of Effects
The health effects resulting
from short-term exposure of
humans to food containing
specific levels of chloro-
niethane are not known.
Levels
in
Water
The health effects resulting
from short-term exposure of
humans to water containing
specific levels of chloro-
methane are not known.
Long-term Exposure
(greater than 14
days)
Levels
in
Food
Length of Exposure
Description of Effects
The health effects resulting
from long-term exposure of
humans to food containing
specific levels of chloro-
methane are not known.
T.eve Is
in
Water
The health effects resulting
from long-term exposure of
humans to water containing
specific levels of chloro-
methane are not known.
*See Section 1.2 for a discussion of exposures encountered in daily
life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1
-4.
Animal
Health Effects from
Eating or Drinking Chioromethane
Short-term Exposure
(less than or equal
to 14 days)
Levels
in
Food
Length of Exposure
DescriDtion of Effects
The health effects resulting
from short-terra exposure of
animals to food containing
specific levels of chloro-
methane are not known.
Levels
in
Water
The health effects resulting
from short-term exposure of
animals to water containing
specific levels of chloro-
methane are not known.
Long-term Exposure
(greater than 14 days)
I.eve 1 s
in
Food
Length of Exposure
DescriDtion of Effects
The health effects resulting
from long-term exposure of
animals to food containing
specific levels of chloro-
methane are not known.
Levels
in
Water
The health effects resulting
from long-term exposure of
animals to water containing
specific levels of chloro-
methane are not known.
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1. PUBLIC HEALTH STATEMENT
MRL does not imply anything about the presence, absence, or ievels of ' W
for cancer. The exposure levels of chloromethane in air that resulted fS
refrigerator leaks and caused coma and death are likely to be relati 1 ^
high but are not known exactly, so they could not be listed in Table 1 1
People who have died in this way did not know that chloromethane was leak'
because it is difficult to smell. lnS
The mice referred to in Table 1-2 that died at 150 ppm were exposed
almost all day for 11 days. Mice that were exposed for only 6 hours per d
for 11 days died following exposure to much higher levels of chloromethan ^
As seen in Tables 1-3 and 1-4, the effects of eating food or drinking wate*
containing chloromethane are not known. Furthermore, the effects of ski C
contact with chloromethane are not known. For further information please
read Chapter 2.
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
CHLOROMETHANE?
There is no known reliable medical test to determine whether you have
been exposed to chloromethane. Symptoms resembling drunkenness and food
poisoning, along with a sweet odor of the breath, may alert doctors that
person has been exposed to chloromethane. For further information please
read Chapters 2, 3, and 6.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
HEALTH?
The Occupational Safety and Health Administration (OSHA) has set an
average permissible exposure limit of 50 parts of chloromethane per million
parts of workroom air (50 ppm) to protect workers during each 8-hour work
shift in a 40-hour workweek. The exposure limit recommended by the National
Institute for Occupational Safety and Health (NIOSH) is 100 ppm for each 8-
hour vorkshift in a 40-hour workweek. Further information on governmental"
recommendations can be found in Chapter 7.
1.8 WHERE CAN I GET MORE INFORMATION?
If you have any more questions or concerns not covered here, please
contact your State Health or Environmental Department or-
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
This agency can also give you information on the location of the
nearest occupational and environmental health clinics. Such clinics
specialize in the recognizing, evaluating, and treating illnesses that
result from exposure to hazardous substances.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
chloromethane. Its purpose is to present levels of significant exposure for
chloromethane based on toxicological studies, epidemiological
investigations, and environmental exposure data. This information is
presented to provide public health officials, physicians, toxicologists, and
other interested individuals and groups with (1) an overall perspective cf
the toxicology of chloromethane and (2) a depiction of significant exposure
levels associated with various adverse health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section are
organized first by route of exposure -- inhalation, oral, and dermal -- and
then by health effect -- death, systemic, immunological, neurological,
developmental, reproductive, genotoxic, and carcinogenic effects. These
data are discussed in terms of three exposure periods -- acute,
intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in figures.
The points in the figures showing no-observed-adverse-effect levels (NOAELs)
or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses
(levels of exposure) used in the studies. LOAELs have been classified into
"less serious" or "serious" effects. These distinctions are intended to
help the users of the document identify the levels of exposure at which
adverse health effects start to appear, determine whether or not the
intensity of the effects varies with dose and/or duration, and place into
perspective the possible significance of these effects to human health.
The significance of the exposure levels shown on the tables and figures
may differ depending on the user's perspective. For example, physicians
concerned with the interpretation of clinical findings in exposed persons or
with the identification of persons with the potential to develop such
disease may be interested in levels of exposure associated with "serious"
effects. Public health officials and project managers concerned with
response actions at Superfund sites may want information on levels of
exposure associated with more subtle effects in humans or animals (LOAEL) or
exposure levels below which no adverse effects (NOAEL) have been observed.
Estimates of levels posing minimal risk to humans (minimal risk levels,
MRLs) are of interest to health professionals and citizens alike,
Estimates of exposure levels posing minimal risk to humans (MRLs) have
been made, where data were believed reliable, for the most sensitive
noncancer end point for each exposure duration. MRLs include adjustments to
reflect human variability and, where appropriate, the uncertainty of
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2. HEALTH EFFECTS
extrapolating from laboratory animal data to humans. Although methods have
been established to derive these levels (Barnes et al. 1988; EPA 1989),
uncertainties are associated with the techniques. Furthermore, ATSDR
acknowledges additional uncertainties inherent in the application of these
procedures to derive less than lifetime MRLs. As an example, acute
inhalation MRLs may not be protective for health effects that are delayed in
development or are acquired following repeated acute insults, such as
hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds
of health effects data become available and methods to assess levels of
significant human exposure improve, these MRLs will be revised.
2.2.1 Inhalation Exposure
2.2.1.1 Death
Before its use as a refrigerant declined about 30 or more years pon
many human deaths were reported as a result of exnncv^ - v , y a£°-
vapors from leaks from home refrigerators and industrial cool in^and^*
refrigeration systems (Baird 1954; Borovska et al. 1976* Kerrl *r
McNally 1946; Thordarson et al. 1965). In some cases, the Individual« 1
found comatose or dead in their homes. In other caspc »-• were
hospitals with typical neurological signs and symptoms '
poisoning (confusion, staggering, slurred speech) eventually became
comatose, developed convulsions and died Th<= ,
of expose in these situation, were
concentrations of chloromethane can result in moderate to severf
neurological effects (see Section 2.2.1.4) but need »- i - ¦
exposure is discontinued and/or medical attention is received l^time^ ^
example, workers exposed to "^titrations as high as 600,000 ppm while
repairing refrigeration leaks developed neurological sWtMs, but did not
die (Morgan Jones 1942) • J ^ < UUL Uia not
In acute exposure situations, animals also rii.n ^ , •
signs of neurotoxicity- *n an extensive investigation " eveloPln8 severe
species including rats, mice. guinea '»'
were exposed to chloromethane until death rn j r°?S' cats. and monkeys
c!«.», I* Opftinpen 1947a.M el*"* (Dunn and Smith 1947; Smith 1947:
J
ueatn (Dunn and Smith 1947; Smith 1947:
j_ c cApua c ^ 1 947 vv „ »
Smith and von Oetting^n /a>D). Severe neurological effects, such as
paralysis convulsions. opisthotonos, developed before death. Although
limitations of these stu . such as unknown purity of chloromethane,
unconventional reporti?£ °d lethality data, and generally poor reporting of
details, preclude PreClS*- eterinination of concentration-duration-response
relationships, these s^Ut^f demonstrate the universal response of animals
to the neurotoxic and 1® a effects of chloromethane. As seen in Table 2-1
and Figure 2-1. death ot ats and mice from continuous exposure occurred at
lower concentrations X°"| intermittent exposure, and mice appear to be
more susceptible than j1Sweater susceptibility of mice has also
been demonstrated in i" on duration and chronic exposure studies
(CUT 1981)- No effe ? Vea Llty was seen in rats exposed intermittently
to 1000 ppm for up to 2 y ts; however, the same exposure of mice resulted
-------
TABLE 2-1- Levels of Significant Exposure to Chloremethane - Inhalation
Figure
Key Species
Exposure
Frequency/
Duration
Effect
NOAEL
(ppm)
LOAEL (Effect)
less Serious
(ppn)
Serious
(ppm)
Reference
ACUTE EXPOSURE
Death
1 Rat
2 Rat
3 Rat
4 House
House
Mouse
7 House
8 Mouse
Systemic
9 Hunan
10 Hunan
5
6
2 wk
4-5 d/wk
6 hr/d
2 or 3 d 500
24 hr/d
2 d
6 hr/d
11 d
5.5 hr/d
12 d 500
6 hr/d
1 d
6 hr/d
11 d 100
22 hr/d
2 wk
5 d/wk
6 hr/d
1-2 wk Resp 150
2-5 d/wk Cardio 150
1, 3 or 7.5 Hemato 150
hr/d
3500 (killed in extremis)
1000
7500 (8/12 deaths)
2400 (killed in extremis)
1000
2200 (LCca)
1500
150a (killed in extremis)
1500 (2/10 deaths)
1 d
Gastro
39,000 (nausea, vomiting)
Morgan et a I.
1982
Burek et al.
1981
Chellman et al.
1986a
Landry et al.
1985
Morgan et al.
1982
Chellman et al.
1986b
Landry et al.
1985
Jiang et al.
1985
Stewart et al.
1980
Morgan Jones
1942
t"
H
se
m
T!
175
O
•H
00
-------
Exposure
Figure Frequency/
Key Species Duration Effect NOAEL
(ppm)
Systemic
11 Hunan
12 Rat
13 Rat
1 d
4 hr/d
2 uk
4-5 d/wk
6 hr/d
2 or 3 d
24 hr/d
Gastro
Hepatic
Renal
Resp 2000
Hemato 2000
Hepatic 500
Renal
Other
500
200
14
15
16
Rat
House
House
5 d
6 hr/d
I d
6 hr/d
II d
22 hr/d
Renal
Hepatic
Hepatic 100
Other
17
18
Mouse
Mouse
2 wfc
5 d/wk
6 hr/d
11 d
5.5 hr/d
Renal
Hemato
Renal
1600
Other
TABLE 2-1 (Continued)
LOftEl (Effect?
Iw; Serious Serious Reference
(ppm) (ppm)
29,000 (nausea, vcmiting)
Battigelli and
Perini 1955
2000 (moderate lesions)
2000 (degeneration and
necrosis of tubules
Morgan et al.
1982
1000 (fatty infiltration
of tiver)
500 (reversible weight
I oss )
5000 (necrosis)
1500 (increased SGPT)
1000 (kidney failure)
Burek et al.
1981
Chellman et al.
1986a
Chellman et al.
1986b
¦X
£
r1
H
X
P3
*7)
•D
tn
o
H
trs
150a (necrosis)
150a (decreased body
weight gain)
Landry et al.
1985
1500 (increased DNA
synthesi s,
bnsophilia)
Chellman et al.
1986b
2400 (enlarged spleen)
2400 (degeneration and
regeneration of
tubules)
2400 (decreased body
weight gain)
Landry et al.
198 5
-------
TABLE 2-1 (Continued)
Exposure
Figure Frequency/ LOAEL (Effect)
Key Species Duration Effect NOAEl Less Serious Serious Reference
(pprn) (ppm) (ppm)
Systemic
19 Mouse
20 Dog
21 Cat
Neurological
22 Hunan
23 Hunan
24 Hunan
12 d
6 hr/d
3 d
23.5 hr/d
3 d
23.5 hr/d
1 d
1-2 wk
2-5 d/ufc
1,3 or 7.5
hr/d
1 d
3 hr/d
Hepat i c
Renal
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Derm/Oc
Other
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Derm/Oc
Other
1000
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
150
2000 (degeneration,
necrosis)
1000 (basophilia,
regenerati on)
Morgan et al.
1982
McKenna et al.
1981a
McKenna et al.
1981a
39,000 (convulsions, ataxia,
staggering, double
vision)
200 (4X decrement in
performance)
Morgan Jonesa
1942
Stewart et al.
1980
Putz-Anderson
et al. 1981a
r
H
a
tn
•*1
pi
o
H
v>
-------
TABLE 2-1 (Continued)
Exposure
Figure Frequency/ LOAEL (Effect)
Key Species Duration Effect NOAEL Less Serious Serious Reference
(ppm) (ppm) (ppm)
Neurological
25 Human
26 Rat
27 Rat
28 Rat
29 Mouse
30 House
31 House
32 House
33 Dog
Developmental
34 Rat
1 d
4 hr/d
2 or 3 d
24 hr/d
5 d
6 hr/d
2 wfc
4-5 d/wk
6 hr/d
12 d
6 hr/d
11 d
5.5 hr/d
11 d
22 hr/d
2 wfc
5 d/wk
6 hr/d
3 d
23.5 hr/d
13 d
6 hr/d
Gd 7-19
500
3500
150
50
200
29000 (vertigo, confusion,
tremors, weakness)
1000 (withdrawn appearance,
lethargy)
5000 (tremors, ataxia)
5000 (hindlinto paralysis,
forelinto incoordi-
nation, cerebellar
lesions)
1000 (severe cerebellar
degeneration, ataxia)
400 (degeneration in
cerebellar!)
100a (cerebellar degenera-
tion)
1500 (motor incoordination,
degeneration)
500 (neuropathy,
histological lesions)
1500 (delayed development)
Battigelli and
Perini 1955
Burek et al.
1981
ChelIman et al.
1986a
Morgan et al.
1982
Morgan et al.
1982
Landry et al.
1985
Landry et at.
1985
Jiang et at.
1985
McKenna et al.
1981a
Wolkowski-Tyl
et al. 1983a
5
i
P3
PJ
O
H
W
-------
TABLE 2-1 (Continued)
Exposure
Figure Frequency/ LOAEL (Effect)
Key Species Duration Effect NOAEl Less Serious Serious Reference
(ppm) (ppm) (ppm)
Developmental
35 House
36 House
Reproductive
37 Rat
38 Rat
39 Rat
40 Rat
41 Rat
42 Rat
43 Rat
44 Rat
45 Rat
12 d
6 hr/d
Gd 6-17
12 d
6 hr/d
Gd 6-17
5d
6 hr/d
5 d
6 hr/d
9 d
4-5 d/uk
6 hr/d
5 d
6 hr/d
2 or 3 d
24 hr/d
5 d
6 hr/d
5 d
6 hr/d
5 d
6 hr/d
2 wk
4-5 d/uk
6 hr/d
250
200
500 (heart defects in
fetuses)
500 (heart defects in
fetuses)
3500 (irreversible lesions
in testes)
3000 (reversible dis-
ruption of sperma-
togenesis)
3000 (sperm toxicity)
500 (degeneration of
epididymides)
5000 (testicular lesion,
granuloma epididymis)
3000a (post implantation
loss)
1000a (decreased fertility) 3000 (severely reduced
fertility)
2000 (testicular
degeneration)
Wolkowski-Tyl
et al. 1983a
Wolkowski-Tyl
et al. 1983b
3000 (persistent decreased Working et al.
fertility) 1985a
Working et al.
1985b
Chapin et al.
1984
Che11man et al.
1987
Burek et al.
1981
Chellman et al.
1986a
Chellman et al.
1986c
Working and Bus
1986
Horgan et a I.
1982
f
H
se
m
T)
m
o
H
cn
-------
Exposure
F i gure f requency/
Key Species Duration
Effect MORE I
(ppm)
Reproductive
46 Dog
47 Cat.
INTERMEDIATE
Death
A3 Rat
49 House
50 House
51 Dog
Systemic
52 Rat
3 d
23.5 hr/d
3 *1
23.5 hr/d
EXPOSURE
J2 mo
5 d/wfc
6 hr/d
6 mo
5 d/wk
6 hr/d
12 mo
5 d/wk
6 hr/d
90 d
5 d/wk
6 hr/d
90 d
5 d/wk
6 hr/d
500
500
WOO
1000
225
400
Resp 1500
Csrdio 1500
Hemeto 1500
Hepatic
Renal 1500
Derm/Oc 1500
Other
TABI.E 2-1 (Continued)
LOAEL (Effect)
Less Serious Serious Reference
Ippn) (ppm)
MeKenna et al.
1981a
McKenna et al.
1981a
CUT 1981
CUT 1981
1000a (increased mortality) ClIT 1981
HcKenna et al
1981b
Mitchell et a
1979
1500 (increased liver
weight, infarct)
375a (decreased body
weight)
-------
TABLE 2-1 (Continued)
Exposure
Figure Frequency/ LQAEL (Effect)
Key Species Duration Effect NOAEl Less Serious Serious Reference
(ppm) (ppm) (ppm)
Systemic
53
Rat
6 mo
Other
1000 (decreased body
CIIT 1981
5 d/wk
weight gain)
6 hr/d
54
Rat
12 mo
Hepatic
1000
CUT 1981
5 d/wk
Renal
1000
6 hr/d
Derm/Oc
1000
Other
225
1000 (decreased body
weight gain)
55
Mouse
6 no
Hepatic
10003 (necrosis)
CUT 1981
5 d/wk
Renal
1000
6 hr/d
Derm/Oc
1000 ,
Other
225
1000 (decreased body
weight gain
56
Mouse
12 mo
Hepatic
225
1000 (necrosis)
CUT 1981
5 d/wk
Renal
225
1000® (hyperplasia)
6 hr/d
Other
225
1000 (decreased body
weight gain)
57
Mouse
90 d
Resp
1500
Mitchell et al
5 d/uk
Cardio
1500
1979
6 hr/d
Hemato
1500
Hepatic
750
1500 (vacuolization)
Renal
1500
Other
1500 (decreased body
weight gain)
58
Dog
90 d
Resp
400
McKenna et al.
5 d/wk
Cardio
400
1981b
6 hr/d
Castro
400
Hemato
400
Hepatic
400
Renal
400
Derm/Oc
400
Other
400
a:
f
H
X
w
T)
Tl
W
O
H
CO
-------
TABLE 2-1 (Continued)
Exposure
figure Frequency/ LOAEL (Effect)
Key Species Duration Effect NOAEL Less Serious Serious Reference
(ppm) (ppm) (ppnt)
Immunological
59 Mouse
Neurological
60 Hunan
61 House
62 Mouse
63 Mouse
Reproductive
(A Rat
65 Rat
66 Rat
6 mo
5 d/wk
6 hr/d
2-3 wk
or more
5 d/wk
8-16 hr/d
(occup)
6 mo
5 d/wk
6 hr/d
12 mo
5 d/wk
6 hr/d
90 d
5 d/uk
6 hr/d
6 mo
5 d/wk
6 hr/d
20 wk
5-7 d/wk
6 hr/d
12 mo
5 d/wk
6 hr/d
400
225
1000 (lymphoid depletion
of spleen)
265^ (neurological
symptoms)
475 (reduced fertility)® 1500 (sterility)
CUT 1981
Scharnweber
et al. 1974
1000® (tremor, paralysis) CUT 1981
1000 (tremor, paralysis) CUT 1981
McKerma et al.
1981b
1000a (testicular atrophy) CUT 1981
Ham et a(. 1985
r1
H t->
ZC 00
tn
o
H
C/3
1000 (testicular atrophy) CUT 1981
-------
TABLE 2-1 (Continued)
Exposure
Figure Frequency/ LOAEl (Effect)
Key Species Duration Effect NOAEL Less Serious Serious Reference
(ppn) (ppm) (ppm)
Reproductive
67 Mouse
68
Dog
CHRONIC EXPOSURE
Death
69 Rat
70
71
House
House
Systemic
72 Rat
12 mo
5 d/wk
6 hr/d
90 d
5 d/wk
6 hr/d
24 mo
5 d/uk
6 hr/d
24 mo
5 d/uk
6 hr/d
18 mo
5 d/wk
6 hr/d
24 mo
5 d/wk
6 hr/d
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Derm/Oc
Other
1000
400
1000
225
1000
1000
1000
1000
1000
1000
1000
225
CIIT 1981
HcKerma et al.
1981b
CIIT 1981
1000 (increased mortality) CUT 1981
1000 (increased mortality) CIIT 1981
CUT 1981
5
X
PI
~n
pi
n
H
t/l
1000 (decreased body
weight gain)
-------
TABLE 2-1 (Contirued)
Exposure
Figure Frequency/ LOAEL (Effect)
Key Species Duration Effect NOAEL Less Serious Serious Reference
(ppn) (ppm) (ppm)
Systemic
73 Rat
74 Mouse
75 House
I mmjno logical
76 Mouse
Neurological
77 Rat
78 Mouse
79 Mouse
18 mo
Other
1000
(decreased bod/
CUT
1981
5 d/wk
weight gain)
6 hr/d
18 mo
Hepatic
1000
(degeneration)
CUT
1981
5 d/wk
Renal
1000
(hyperplasia)
6 hr/d
Other
1000
(decreased body
weight gain)
24 mo
Resp
1000
CUT
1981
5 d/wk
Cardio
1000
6 hr/d
Hemato
1000
Hepatic
225
1000
(degeneration)
Renal
225
1000
(Hyperplasi a)
Derm/Oc
1000
Other
225e
1000
(decreased bode
18 no
5 d/wk
6 hr/d
24 mo
5 d/wk
6 hr/d
24 no
5 d/wk
6 hr/d
18 «*o
5 d/wk
6 hr/d
weight gain)
1000 (splenic atrophy)
1000
225
1000 (neurotoxicity,
cerebellar lesions)
1000 (neurotoxicity,
cerebellar lesions
CUT 1981
CUT 1981
CUT 1981
CUT 1981
a:
ID
>
t-1
H
SI
m
~n
m
Ci
H
to
CO
o
-------
TABLE 2-1 (Continued)
Exposure
Figure Frequency/ LOAEL (Effect)
Key Species Duration Effect NOAEL Less Serious Serious Reference
(ppm) (ppm)
-------
ACUTE
(<14 Days)
tjOOO
0.1
(ppm) ^
100,000 r-
10400
/ /
/
/
j-
/
&
f
£
J
/
/
A'o
An
•r.
O"
o>*
- • s« •»
Olkn
Oiam O
Oi«
®1tm
«» ®l»m Ol!, _ ®ir
19m (ft ™Tm
19m O ®!3r
frftm
~?2
~25
#271. Mr
o»
•32m
•3*
•7m
— o«
O OricOMd O^'Om OneOm OicOod oo™ O'* O OOOm O OOJieO»i9i» •xm
21c 2ic 20d 11m
O'* 0*M
A*
L*
A»
9l«m
O1®"1
&
0» • Sfcn.Sfrn
0*ti
®»* |]i>
•m.o.Mt 33#r. 4Ci
Cfca.
Om,
OtcOM ®«1r
On
i Mm
3fm
%.
(J)3lm
Key
r B*
¦
LC50
1 Mtfumftlrvfc
ImI for
m Moum
•
LOAEL tar aanoua
¦Aacta faramafa)
1
tt«ncanc»r
d Dog
9
LOAEL tor toaa wi
~ua aflact» (an ma Is)
1
w
c Cat
O
NOAEl (animate)
' ~
UMakrHRu
¦Had (human*)
A
LOAEL tor laaa wi
aua allacl (lumana)
A
NOACL (lunn]
DmuitoMltoatfipM
oomapondalo anlrti
r
H
a:
m
n
n
H
CO
ho
ro
FIGURE 2-1. Levels of Significant Exposure to Chloromethane - Inhalation
-------
INTERMEDIATE
(15 • 364 Days)
////
~ s
1M.0M —
10.000 -
100
10
0.1
Ww ITM
•.«. * oo» oo»
h O • O
Stm
oo» w
J®Mr O
®Wm®OMr OsS7m
9n*,Hn Olt.W 9i*m ••Im.ttm
•Mr
Of™ •**.
0»w
Own
Ow On
Om Om Om
OMn
Om
OS4ffl
OM
Os»
0*3"
Om
Om.
QUm OHm 0&*
AM
o»
K«v
r m
•
tOAELfcr MrioiatflKK (MOnMl)
•
1 MMmel iMt tmvl lor
¦i Moum
LCMEL t«r l*H aaitoM aHMM (anfcnafc)
| efleeli otef then cwte
4 0«0
o
NOAEL film Hi)
A
UMB. ta miIm •Hack fwwra)
ThefMnberoearieea
cmapon* to Mfea In J-1.
FIGURE 2-1. Levels of Significant Exposure to Chloromethane - Inhalation
(Continued)
•x
r-
si
rn
w
o
H
to
N3
It*
-------
CHRONIC
(> 365 Days)
tax")
100.000 r-
/ /
/ /
/ /
/
/ /
/
¦» O 70m. 71m 0»» OtVi 0T2r O^Vn CO O7* O"™07f ®7*n. 7lm Q?!r ®7«m. 75m O7^ OiyiO" ®Mm 7Sm &T*.n 371m ~7«m.7»m O™ Ow>-«>" •«*. lit ~
Q?0m
OTSm Ots™
Qts™ 0™
C)7»m
0«Jm 0«>
K.y
f R«t
•
IOAEL for Mf«ui vtac*
* MrtimAt m
ik tow fo»
m Uoum
LOAEL for t»w Mnou*
IkU
«r man eanc*'
O
NOA£L (wwr**)
t
~
Cf l-Cancmr £%cf
7>* nunMf n*f
itemed
poM eeffMpomfe to antri*
• tn Tatofe?-1.
FIGURE 2-1. Levels of Significant Exposure to Chloromethane - Inhalation
(Continued)
3T
m
>
r
H ?o
ac ¦*>
n
-n
m
o
H
00
-------
25
2. HEALTH EFFECTS
in significantly increased mortality after exposure for 1 year. This
became so dramatic that the 1000 ppm exposure groups were terminated at 21
and 22 months of exposure. No deaths occurred in male dogs (four per group)
exposed to 400 ppm chloromethane or greater for 90 days (McKenna et al.
1981b) . Female dogs were not tested. The highest levels that did not cause
death and all reliable levels that caused death in each species and duration
category are recorded in Table 2-1 and plotted in Figure 2-1.
2.2.1.2 Systemic Effects
Respiratory Effects. Case reports generally have not described
respiratory effects in humans exposed to chloromethane. No effects on
pulmonary function were observed in volunteers who participated in a study
of neurological and neurobehavioral effects of acute inhalation exposure of
up to 150 ppm chloromethane (Stewart et al. 1980). This study, however, had
several limitations such as small sample size, multiple dosing schemes, and
confusing protocol. Specifically, groups of two to four men and two to four
women were exposed to 20, 100, or 150 ppm or to concentrations that were
increased from 50 to 150 ppm in the same group for 1, 3, or 7.5 hours/day
for 2-5 days/week for 1 or 2 weeks. Several subjects, both male and female,
dropped out of the study before some of the experiments were completed, and
other subjects were added. Furthermore, the same subjects were used for
different protocols during different weeks of the study. Despite the
limitations, however, chloromethane exposure did not appear to have any
effect on pulmonary function.
Acute exposure of dogs to 15,000 ppm caused an initial rise in heart
rate and blood pressure, followed by markedly reduced respiration, decreased
heart rate, and a progressive fall in blood pressure until the dogs died
within 4-6 hours (von Oettingen et al. 1949, 1950). These effects may have
resulted from vasodilation due to depression of the central nervous system.
Pulmonary congestion was a common finding among the various species exposed
to chloromethane until death (Dunn and Smith 1947; Smith and von Oettingen
1947a). As discussed above in Section 2.2.1.1, however, limitations of
these reports preclude precise determination of concentration-duration-
response relationships. Furthermore, more recent studies using very pure
chloromethane (99.5-99.9%) failed to find any exposure-related
histopathological lesions in the lungs of male dogs and male cats exposed
acutely to 500 ppm chloromethane (McKenna et al. 1981a), rats exposed
acutely to 2000 ppm (Burek et al. 1981), male dogs exposed to 400 ppm and
rats and mice exposed to up to 1500 ppm chloromethane for intermediate
durations (CUT 1981; McKenna et al. 1981b; Mitchell et al. 1979), or rats
and mice exposed chronically to up to 1000 ppm (CUT 1981). The highest
NOAEL values for respiratory effects in each species and duration category
are recorded in Table 2-1 and plotted in Figure 2-1.
Cardiovascular Effects. Cardiovascular effects of chloromethane have
been described in case reports of humans exposed to chloromethane
occupationally or accidentally due to refrigerator leaks (Gummert 1961;
-------
26
2. HEALTH EFFECTS
r a1 1953 Keeel et al. 1929; McNaily 1946; Spevak ft al. 1976;
Hansen e ' ' 1949). These effects include electrocardiogram
\J prT*16TT6 3DG »SCu6Z i-' ' _i
tachycardia and increased pulse rate, and decreased blood
pressure The precise concentrations and durations of exposure are not
P i rpfrn«ective epidemiological study of workers exposed to
k"°WI1, rh„n. in a butyl rubber manufacturing plant found no statistical
Chlorome ^ ^ ^ ^ diseaSes of the circulatory system
8 MC(irl in the exposed population when compared with U.S. Mortality
was incr 1986) In a study of neurological and neurobehavioral
effHti of'cute inhalation exposure in volunteers, no abnormalities of
cardiac function or electrocardiograms were found at concentrations up to
150 ppm (Stewart et al. 1980).
Dops exposed acutely to 15,000 ppm had an initial rise in heart rate
and blood pressure, followed by markedly reduced respiration, decreased
rt rate and a progressive fall in blood pressure uniil death, which
occurred within 4-6 hours (von Oettingcn et al. 1949. 1950). These effects
mav have resulted from vasodilation due to depression of the central nervous
system. C^l05°mf^^0^PinhedheLr\rdemLstrrted by'acute studies in
^tr^ranrrats1::^^ - 300 ppm Chloromethane (HcKenna et
hv intermediate duration studies in male dogs exposed to 400 ppm and in
rats and mice exposed to up to 1500 ppm chloromethane (McKenna et al 1981b;
M-r hell et al 1979) and by chronic studies in rats and mice exposed to up
to 1000 ppm (C1IT 1981). The highest NOAEI. values for cardiovascular
effects in each species and duration category are recorded n, Table 2-1 and
plotted in Figure 2-1.
Gastrointestinal Effects. Numerous case reports of humans exposed to
chloromethane vapors as a result of industrial leaks and defective
refrigerators have described symptoms of nausea and vomiting (Baird 1954;
Raker 1927 • Battigelli and Perini 1955; Borovska et al. 1976; Hansen et al.
?qSV Keeel et al 1929; Mackie 1961; Morgan Jones 1942; Raalte and van
Jelzen 1945" Spevak et al. 1976; Verriere and Vachez 1949). In all cases,
these symptoms were accompanied by central nervous system toxicity, which
«« usually severe. It is not clear, therefore, if the nausea and vomiting
3ere secondary to the neurotoxic effects of chloromethane. Two of the
reports (Battigelli and Perini 1955; Morgan Jones 1942) provided exposure
concentration data. The LOAELs for gastrointestinal effects in humans are
recorded in Table 2-1 and plotted in Figure 2-1.
Histopathologic^ examination of animals exposed to various
of chloromethane for acute, intermediate, or chronic
concentrations of ch^ of gastrolntestinal damage (CIIT 19B1;
durations highest NOAELs for gastrointestinal effects in
SSS: "e'recjrded'in Table 2-1 and plotted in Figure 2-1.
Hematological Effects. No henatological effects »ere foundin
volunteers who participated in a study of neurological and neurobehavioral
-------
27
2. HEALTH EFFECTS
effects of acute inhalation exposure of up to 150 ppm chloromethane
(Stewart et al. 1980). Case reports of human overexposure have also
generally been negative for hematological effects.
Spleen enlargement, suggestive of extramedullary hematopoiesis, and
hemoglobinuria, suggestive of intravascular hemolysis, were found in female
mice exposed intermittently to a high concentration (2400 ppm) of
chloromethane for 11 days (Landry et al. 1985). These effects were not seen
when female mice were exposed continuously to a lower concentration
(150 ppm) (Landry et al. 1985). Male mice were not used in this study. No
exposure - related effects on hematological parameters were found in male dogs
or cats exposed continuously for 3 days to 500 ppm (McKenna et al. 1981a),
or in rats exposed continuously for 3 days to 2000 ppm (Burek et al. 1981).
In addition, male dogs exposed to 400 ppm and rats or mice exposed to 1500
ppm for 90 days (McKenna et al. 1981b; Mitchell et al. 1979), and rats and
mice exposed for 6, 12, 18, or 24 months to up to 1000 ppm (CUT 1981) did
not have hematological effects. LOAEL and NOAEL values for spleen
enlargement, and the highest NOAEL values for hematological effects in each
species and duration category are recorded in Table 2-1 and plotted in
Figure 2-1.
Hepatic Effects. Case reports of humans exposed to chloromethane have
described clinical jaundice (Kegel et al. 1929; Mackie 1961; Weinstein
1937). A case of jaundice and cirrhosis of the liver was attributed to
chloromethane exposure in a man who had been a refrigeration engineer for
10 years and had frequently been exposed to chloromethane vapors (Wood
1951). There was no reason to believe that these liver effects were due to
other causes such as infective hepatitis or to alcohol consumption.
Hepatic effects have also been observed in animals exposed to
chloromethane, and mice appear to be more susceptible than rats. Rats
exposed to 1000-1500 ppm for acute, intermediate, or chronic durations had
either no liver effects or relatively mild to moderate changes, such as
loss of normal areas of basophilia, cloudy swelling, increased liver weight,
fatty infiltration, and increased levels of SGPT, SGOT, and serum bilirubin
(Burek et al. 1981; Chellman et al. 1986b; CUT 1981; Mitchell et al. 1979;
Morgan et al. 1982). No necrosis was seen. Acute, intermediate, or chronic
exposure of mice to 1000-1500 ppm generally resulted in necrosis and
degeneration (CUT 1981; Landry et al. 1985; Mitchell et al. 1979; Morgan
et al. 1982). Female mice exposed acutely to a relatively high intermittent
concentration (2400 ppm) had milder liver effects than those exposed to a
continuous lower concentration (150 ppm) (Landry et al. 1985). Although no
liver effects were observed in male dogs and cats (McKenna et al. 1981a,b),
the exposure concentrations (400 or 500 ppm) may not have been high enough
to produce liver toxicity in these species. The highest NOAEL values and
all reliable LOAEL values for liver effects in each species and duration
category are recorded in Table 2-1 and plotted in Figure 2-1.
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28
2. HEALTH EFFECTS
Renal Effects. Case reports of humans exposed to chloromethane have
described such indicators of renal toxicity as albuminuria, increased serum
creatinine and blood urea nitrogen, proteinuria, and anuria (Kegel et al
1929; Mackie 1961; Spevak et al. 1976; Verriere and Vachez 1949). Exposure
concentrations at which these effects occur are not known.
Effects on the kidney have also been observed in rats and mice. In
acute studies, rats exposed intermittently to 2000-2500 ppm had degeneration
and necrosis of the proximal convoluted tubules (Chellman et al. 1986a;
Morgan et al. 1982), while rats exposed continuously to 1000 ppm had
evidence of renal failure (Burek et al. 1981). In intermediate and chronic
studies in which rats were exposed intermittently to <1500 ppm, however no
effects on the kidneys were observed (CUT 1981; Mitchell et al . 1979-
McKenna et al. 1981b). Areas of basophilia, which wore interpreted as
evidence of regeneration, were found in kidneys of mice exposed acutely to
1000 ppm (Morgan et al. 1982) and 1500 ppm (Chellman et al. 1986b). An
extensive study by CUT (1981) did not find kidney lesion?; in mice killed
after 6 months of exposure, but hyperplasia and kidney tumor.s were observed
after 12, 18, and 24 months of exposure. The highest NOAEL values and all
reliable LOAEL values for kidney effects in each species and duration
category are recorded in Table 2-1 and plotted in Figure 2-1.
Dermal/Ocular Effects. Case reports of humans exposed to
chloromethane have described such symptoms as blurred and double vision
(Baker 1927; Borovska et al. 1976; Gummert. 1961; Kegel et al . 1929; Mackie
1961). These symptoms probably reflect effects on the nervous system rather
than effects on the eye itself.
Ophthalmological examination of male cats and doys exposed to 500 ppm
continuously for 3 days (McKenna et al. 1981a), male dogs exposed to 400 ppm
for 90 days (McKenna et al. 1981b), or of rats and mice exposed to 1000 ppm
for up to 24 months (CUT 1981) failed to reveal eye lesions. However
mucopurulent conjunctivitis with total destruction of the eye in some cases
was found in mice exposed to >375 ppm for 90 days (Mitchell et al. 1979).
These lesions were attributed to exposure because no lesions were found in
controls; however, the failure of longer-term studies to detect eye lesions
at higher concentrations makes the findings of Mitchell et al. (1979)
questionable. If the eye lesions were due to chloromethane exposure, the
effect was probably due to direct contact of the vapor with the eye, rather
than a consequence of inhalation. The highest NOAEL values for
dermal/ocular effects in each species and duration category are recorded in
Table 2-1 and plotted in Figure 2-1.
Other Systemic Effects. Other than neurological effects, which are
discussed in a separate section, studies and case reports of humans exposed
to chloromethane have not described other systemic effects.
The only other consistent systemic effect of chloromethane exposure in
animals is reduced body weight gain, which was observed in rats and mice
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29
2. HEALTH EFFECTS
exposed to chloromethane for acute, intermediate, and chronic durations
(Burek et al. 1981; CUT 1981; Landry et al. 1985; Mitchell et al. 1979).
The highest NOAEL values and all reliable LOAEL values for other systemic
effects in each species and duration category are recorded in Table 2-1 and
plotted in Figure 2-1. The highest NOAEL in both intermediate and chronic
duration studies, below which no LOAEL exists, is 225 ppm in the CUT (1981)
study. Based on the NOAEL of 225 ppm, intermediate and chronic duration
inhalation MRLs of 0.40 ppm were calculated as described in the footnote in
Table 2-1. The MRL is presented in Table 1-1.
2.2.1.3 Immunological Effects
No studies were located regarding immunological effects in humans
after inhalation exposure to chloromethane.
In animals, the only effects that could possibly be considered
immunological effects were lymphoid depletion of the spleen and splenic
atrophy observed in mice exposed to 1000 ppm chloromethane for up to 2 years
(CUT 1981) . The lymphoid depletion was first observed in mice killed after
6 months of exposure, while the splenic atrophy was observed in mice killed
after 18 months. This LOAEL value for immunological effects in mice is
recorded in Table 2-1 and plotted in Figure 2-1 for both intermediate and
chronic duration categories. The lower exposure level in this study (225
ppm) cannot be considered a NOAEL for immunological effects, however,
because more sensitive tests for immune function were not conducted. In
addition, cats exposed continuously to chloromethane for 3 days had higher
incidences of brain lesions than did control cats (McKenna et al. 1981a).
The lesions, however, were consistent with infection or post-vaccinal
reaction (the cats were vaccinated for panleukopenia by the supplier).
Exacerbation of viral-induced central nervous system disease could not be
ruled out. It is not known whether the exacerbation would represent an
immunological effect.
2.2.1.4 Neurological Effects
Numerous case reports of humans exposed to chloromethane vapors as a
result of industrial leaks and defective refrigerators have described
neurological effects (Baird 1954; Baker 1927; Battigelli and Perini 1955;
Borovska et al. 1976; Gummert 1961; Hansen et al. 1953; Hartman et al. 1955;
Kegel et al. 1929; MacDonald 1964; McNally 1946; Morgan Jones 1942; Raalte
and van Velzen 1945; Spevak et al. 1976; Wood 1951). In addition, a couple
who had stored insulated boards made of polystyrene foam in the basement of
their home had symptoms of neurotoxicity (Lanham 1982). (Chloromethane is
used in the production of some polystyrene foam, from which it is slowly
emitted.) In general, symptoms develop within a few hours after exposure
and include fatigue, drowsiness, staggering, headache, blurred and double
vision, mental confusion, tremor, vertigo, muscular cramping and rigidity,
sleep disturbances, and ataxia. These symptoms may persist for several
months, and depression and personality changes may develop, although
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30
2. HEALTH EFFECTS
complete recovery generally occurs eventually. In of mote severe
ooisonine convulsion, coma, and death may ensue. Microscopic examination
of the brain of an individual who died revealed accumulation of lipoid-
filled histiocytes in the leptomeninges of the hemispheres, hyperemia of the
cerebral cortex, and lipoid droplets in the adventitia cells of the
capillaries throughout the brain (Kegel et al. 1929).
Although the precise concentrations and durations of exposure
resulting in neurological effects were generally not known a few reports
were able to define exposure concentrations. In cas.-s in which workers were
pmosed acutely to leaks while repairing refrigeration systems, exposures
tfere >29 000 ppm (Battigelli and Perini 1955; Morgan Jones 194?). In a
report of six cases, workers were exposed occupationally to relatively low
levels (TWA 265 ppm) for 2-3 weeks before the onset of typical symptoms
(Scharnweber et al 197U) . In addition, the concentrat ion of chloromethane
in the home of the couple who stored polystyrene- foam insulation boards in
their basement was in excess of 200 ppm (Lanh.-.ra et al . 198?). In a study of
volunteers no exposure - related neurological abnormalities or abnormal EEGs ,
and no effects on cognitive tests or subjective- response were found at acute
exposures of up to 150 ppm (Stewart et al. 1980), while, although not
statistically significant, a hi decrement in performance in behavioral tests
was found at an acute exposure level of 200 ppm (Putz-Anderson et al.
1981a) Although some of these studies had limitations, taken as a whole
they indicate that the threshold for neurological and behavioral effects in
humans appears to be about 200 ppm.
Chloromethane exposure also results in neurological effects in
animals Rats, mice, rabbits, guinea pigs, dogs, cats, and monkeys exposed
to chloromethane until death all displayed signs of severe neurotoxicity,
including paralysis and convulsions (Smith and von Oettingen 194/a,b). As
discussed in Section 2.2.1.1, these studies have several limitations that
preclude determination of concentration-duration-response_relationships, but
are useful for demonstrating the universal response of animals to the
neurotoxic effects of chloromethane. More recent studies using very pure
chloromethane have also demonstrated neurotoxic effects of acute inhalation
chlorometnane ek et q1 19 chellman et al.
SKI"! al 198?; Landry Jt al. 1985; Morgan et al. 1982; McKenna
et al 1981a) Effects include ataxia, tremors, limb paralysis and
incoordination, and cerebellar lesions consisting of degeneration of the
eranular layer. Mice appear to be more sensitive than rats, developing
similar but ©ore severe effects at lower exposure concentrations (Morgan
r al 1982). In addition, under identical exposure conditions, male dogs,
which developed hind limb stiffness and tremors and had brain and spinal
cord lesions appeared to be more sensitive than male cats, which had brain
Wons consistent with viral-induced central nervous system disease
fMcKenna et al. 1981a). Neurotoxic effects occurred at lower
concentrations in continuously exposed mice than in intermittently exposed
mice (Landry et al. 1985).
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31
2. HEALTH EFFECTS
Mice exposed to 1000 ppm for 6 or 12 months developed signs of
neurotoxicity (tremor and paralysis) but had no histopathological lesions
(CIIT 1981). After exposure for 18 or 24 months, however, reduced numbers
of neurons in the granular cell layer of the cerebellum and degenerative
changes in the spinal cord were observed. This study also demonstrates the
greater sensitivity of mice to the neurotoxicity of chloromethane, as no
clinical signs or histological evidence of neurotoxicity were observed in
rats similarly exposed.
The highest NOAEL values and all reliable LOAEL values in each species
and duration category are recorded in Table 2-1 and plotted in Figure 2-1.
The 50 ppm concentration in mice exposed continuously for 11 days (Landry et
al. 1985) is the highest NOAEL below which no LOAEL exists. At 100 ppm, the
mice had cerebellar lesions. Based on the NOAEL of 50 ppm, an acute
inhalation MRL of 0.46 ppm was calculated as described in the footnote in
Table 2-1. This MRL is presented in Table 1-1.
2.2.1.5 Developmental Effects
No studies were located regarding developmental effects in humans
after inhalation exposure to chloromethane.
Maternal toxicity, evidenced by decreased body weight gain and retarded
development of fetuses, was observed in rats exposed to 1500 ppm
chloromethane for 6 hours/day during gestational days 7-19 (Wolkowski-Tyl
et al. 1983a). The fetal effects consisted of reduced fetal body weight and
crown-rump length and reduced ossification of metatarsals and phalanges of
the anterior limbs, thoracic centra in the pubis of the pelvic girdle, and
metatarsals of the hind limbs. Concentration-related higher incidences of
heart malformations were also found among fetuses of mice exposed to
chloromethane for 6 hours/day during gestational days 6-17 (Wolkowski-Tyl
et al. 1983a,b). The heart malformations consisted of absence or reduction
of atrioventricular valves, chordae tendineae, and papillary muscles. The
heart anomaly may have been an artifact of the sectioning technique, due to
the examination of fixed as opposed to unfixed fetal tissue, or a
misdiagnosis, as suggested by John-Greene et al. (1985), because they
failed to find the defect when they attempted to increase the incidence of
heart malformations by continuously exposing the dams to a higher
concentration, but only during gestational days 11.5-12.5. They also found
much interanimal variability in the appearance of the papillary muscles in
control mice. This period (gestational days 11.5-12.5) was chosen as the
critical period for development of the embryonal heart (John-Greene et al.
1985). However, Wolkowski-Tyl (1985) countered that the inability of John-
Greene et al. (1985) to detect the abnormality was due to the different
exposure protocol and that the critical period is more appropriately
gestational day 14. Until the controversy is resolved, it is prudent to
consider chloromethane a developmental toxicant in mice. NOAEL and LOAEL
values for developmental effects in mice are recorded in Table 2-1 and
plotted in Figure 2-1.
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32
2. HEALTH EFFECTS
2.2.1.6 Reproductive Effects
No studies were located regarding reproductive effects in humans after
inhalation exposure to chloromethane.
Chloromethane is a reproductive toxicant in male rata. In acute
exposure experiments (Burek et al. 1981; Chapin et al. 1984; Chellman et al
1986a, 1987; Morgan et al. 1982; Working et al. 1985a,b; Working and Bus
1986), inhalation exposure of male rats resulted in disruption of
spermatogenesis (delayed spermiation, disorganization of the seminiferous
epithelium, decreased mid and late spermatids, increased abnormal sperm,
decreased fertility), inflammation of the epididymides, and sperm granulomas
in the epididymides. Inhalation exposure of male rats also resulted in
pre implantation and postimplantation loss (see Section 2.2.1.7 on Genotoxic
Effects below) in unexposed females mated to the exposed males (Chellman
et al. 1986c; Rushbrook 1984; Working et al. 1985a). In a 20-week
reproduction study in rats, reduced fertility was found in males at 475 ppm
and complete sterility was found at 1500 ppm (Hanim et al. 1985). Germinal
epithelial degeneration and atrophy of the seminiferou.s tubules was found in
male rats exposed to 1000 ppm chloromethane at the 6-month interim kill
(CUT 1981). The incidence of these lesions increased at later kills such
that all males exposed to 1000 ppm had lesions at 18 months. Testicular
lesions were also found in mice similarly exposed for 18 months. No
testicular effects were found in cats or dogs exposed acutely for 3 days or
in dogs exposed for 90 days (McKenna et al. 1981a,b). It is possible that
male dogs and male cats are not sensitive to the reproductive effects of
chloromethane, but the concentrations may not have been high enough to
produce the effect. The highest NOAEL values and all reliable L0AE1. values
in each species and duration category are recorded in Table 2-1 and plotted
in Figure 2-1.
2.2.1.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans after
inhalation exposure to chloromethane.
In animals, chloromethane exposure has resulted in dominant lethal
mutations in the sperm of male rats (Chellman et al. 1986c; Rushbrook 1984;
Working et al. 1985a). Experiments on the mechanism of the
postimplantation loss observed in the females mated to the exposed males
indicated that the dominant lethal effect may be secondary to epididymal
inflammation, rather than a direct genotoxic effect of chloromethane itself
(Chellman et al. 1986c). Chloromethane did not result in unscheduled DNA
synthesis in hepatocytes, spermatocytes, or tracheal epithelial cells when
male rats were exposed to 3500 ppm, 6 hours/day for 5 days, but did produce
a marginal increase in unscheduled DNA synthesis in hepatocytes when rats
were exposed to 15,000 ppm for 3 hours (Working et al. 1986).
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33
2. HEALTH EFFECTS
2.2.1.8 Cancer
A retrospective epidemiology study of 852 male workers exposed to
chloromethane in a butyl rubber manufacturing plant produced no statistical
evidence that the rates of deaths due to cancer at any site were increased
in the exposed population when compared with U.S. Mortality rates (Holmes
et al. 1986). The subjects had worked in the plants for at least 1 month
from 1943. No specific exposure levels were given in this study.
A high incidence of renal tumors was found in male mice that were
exposed to 1000 ppm chloromethane and died or were killed from 12 months on
(CIIT 1981). Tumors consisted of renal cortex adenomas and
adenocarcinomas, papillary cystadenomas, tubular cystadenomas, and papillary
cystadenocarcinomas. No evidence of carcinogenicity was found in male mice
exposed to 50 or 225 ppm or in female mice or male and female rats exposed
to any concentration (1000 ppm or less) in this study. The cancer effect
level is recorded in Table 2-1 and plotted in Figure 2-1.
2.2.2 Oral Exposure
Only one animal study was located in which chloromethane was
administered orally. In this study, the hepatotoxic effects of chloroform,
carbon tetrachloride, dichloroethane, and chloromethane were compared
(Reynolds and Yee 1967) . Rats were given chloromethane in mineral oil by
gavage at a single dose of 420 mg/kg. Only the livers were examined for
effects, but no liver necrosis was found in the rats given chloromethane.
Higher doses of chloromethane were not administered because of the known
anesthetic and lethal effects of the compound.
Other than the study described above, no studies were located
regarding the following health effects in humans or animals after oral
exposure to chloromethane.
2.2.2.1
Death
2.2.2.2
Systemic Effects
2.2.2.3
Immunological Effects
2.2.2.4
Neurological Effects
2.2.2.5
Developmental Effects
2.2.2.6
Reproductive Effects
2.2.2.7
Genotoxic Effects
2.2.2.8
Cancer
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34
2. HEALTH EFFECTS
2.2.3 Dermal/Ocular Exposure
Other than the study by Mitchell et al. (1979) described in Section
2.2.1.2 above, in which possible ocular effects were observed in mice
following exposure to chloromethane vapors, no studies were located
regarding the following effects in humans or animals after dermal/ocular
exposure.
2.2.3.1 Death
2.2.3.2
Systemic Effects
2.2.3.3
Immunological Effects
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genotoxic Effects
2.2.3.8 Cancer
2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
Chloromethane is absorbed readily from the lungs of humans following
inhalation exposure. Alveolar breath levels of chloromethane reached
equilibrium within 1 hour during a 3- or 3.5-hour exposure of men and women
(Putz-Anderson et al. 1981a,b). Mean ± SD alveolar breath levels were
63+23 6 ppm in 2U men and women exposed to 200 ppm and 36112 ppm in 8 men
women exposed to 100 ppn, for 3 hours . Mean ± SD blood levels were
11 5+12 3 ppm for the 200 ppm exposed group and 7.7±6.3 ppm for the 100 ppm
exoosed croup. The results suggest that uptake was not proportional to
exposure concentration, but individual levels were quite variahle based on
the standard deviations. A high correlation between alveolar air and blood
levels (r-0.85, p<0.01) was found.
Blood and alveolar air levels of chloromethane also reached
equilibrium during the first hour of exposure in six men exposed to 10 or 50
Z for 6 hours (Nolan et al. 1985). The levels in blood and expired air
were proportional to the exposure concentrations Based on elimination
Til rhe ^ubiects were divided into two groups, fast and slow metabolizers.
?he difference between inspired and expired chloromethane concentrations
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35
2. HEALTH EFFECTS
indicated that the fast metabolizers absorbed 3.7 ng/min/kg and the slow
metabolizers absorbed 1.4 /ig/min/kg.
In experiments in rats, uptake of chloromethane reached equilibrium
within 1 hour and was proportional or nearly proportional to exposure
concentrations of 50-1000 ppm for 3-6 hours (Landry et al. 1983a,b).
Absorbed doses were calculated to be 67 mg/kg for rats exposed to 1000 ppm
and 3.8 mg/kg for rats exposed to 50 ppm (ratio of 17.6 compared to
predicted ratio of 20 if proportional to exposure concentration). The rate
of uptake was 165 mg/min/kg for 1000 ppm and 10 mg/min/kg for 50 ppm (ratio
of 16.5). Where the uptake was not completely proportional to exposure, the
difference in the ratio of absorbed doses from the predicted ratios may be
due to the lower respiratory minute volume in the rats exposed to 1000 ppm
and to different amounts remaining in the body at the end of exposure and
the amounts metabolized (Landry et al. 1983b). Blood chloromethane
concentrations also reached equilibrium within 1 hour and were proportional
to exposure concentration in dogs exposed to 50 or 1000 ppm (Landry et al.
1983a) or 15,000 or 40,000 ppm (von Oettingen et al. 1949, 1950) for 6
hours.
At relatively low exposure concentrations, absorption of chloromethane
from the lungs appears to be proportional to exposure concentration in rats
and humans, but at higher concentrations, some process, such as metabolism
or excretion, becomes saturated, limiting the rate of uptake. In dogs,
however, it appears that absorption is proportional to exposure
concentration through a wide range of exposure levels.
2.3.1.2 Oral Exposure
No studies were located regarding absorption in humans or animals
after oral exposure to chloromethane.
2.3.1.3 Dermal Exposure
No studies were located regarding absorption in humans or animals
after dermal exposure to chloromethane.
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
No studies were located regarding distribution in humans after
inhalation exposure to chloromethane.
After absorption of chloromethane, distribution of chloromethane
and/or its metabolites is extensive in animals. Total uptake of
radioactivity (as /imol [14C]-chloromethane equivalents/g wet weight) in
whole tissue homogenates following exposure of rats to 500 ppm for 6 hours
was 1.21 for lung, 4.13 for liver, 3.43 for kidney, 2.29 for testes, 0.71
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36
2. HEALTH EFFECTS
for muscle, 0.57 for brain, and 2.42 for intestine (Kornbrust et al. 1982).
Little difference in the pattern of distribution was found at an exposure
concentration of tissue homogenate ixiacromolecules 1500 ppm as compared with
500 ppm. Upon acid precipitation of protein, 80% of the radioactivity
present was found in the acid soluble (unbound) fraction. The remainder was
found to have been metabolically incorporated into lipid, RNA, DNA, and
protein, rather than bound to the macromolecules as a result of direct
alkylation. Tissue levels of chloromethane (in mgX) in dogs exposed to
chloromethane for 6 hours were A.5 in liver, 4.1 in heart, and 3.7 in brain
at 15,000 ppm and 9.3 in liver, 8.1 in heart, and 9.9 in brain at 40,000 ppm
(von Oettingen et al. 1949, 1950).
2.3.2.2 Oral Exposure
No studies were located regarding distribution in humans, or animals
after oral exposure to chloromethane.
2.3.2.3 Dermal Exposure
No studies were located regarding distribution in humans or animals
after dermal exposure to chloromethane.
2.3.3 Metabolism
Information regarding metabolism of chloromethane in humans is
limited. In a group of six workers exposed to TWA 8-hour workroom
concentrations of 30-90 ppm, the urinary excretion of S-methylcysteine.,
which is formed as a result of conjugation of chloromethane with
glutathione, showed wide variations, with little correlation to exposure
levels (van Doom et al. 1980). In four of the workers all values were
higher than in controls, and appeared to build up during the course of the
week. Two of the workers had only minor amounts of S-methylcysteine in the
urine, but these workers experienced the highest exposure concentrations.
It appeared that two distinct populations of individuals exist: fast
metabolizers with lower body burdens and higher excretion, and slow
metabolizers with higher body burdens and lower excretion (van Doom et al.
1980). The difference may be due to a deficiency of the enzyme
glutathione-S-transferase that catalyzes the conjugation of chloromethane
with glutathione. Other possible reasons for the differences in
chloromethane elimination among subjects include differences in biliary
excretion and fecal elimination of thiolated conjugates. For the sake of
simplicity, however, the two distinct populations will be referred to as
fast and slow eliminators. Two distinct populations were also found based
on venous blood and expired concentrations of chloromethane in volunteers
(Nolan et al. 1985). The urinary excretion of S-methylcysteine in the
volunteers exposed to chloromethane was variable, was not significantly
different between pre- and post-exposure levels, and did not correlate with
exposure levels. Two distinct populations of slow and fast eliminators were
also identified. No change was detected in the S-methylcysteine
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37
2. HEALTH EFFECTS
concentration or in the total sulfhydryl concentration in the urine of four
workers before and after a 7-hour shift in a styrene production plant by De
Kok and Antheunius (1981), who concluded that S-methylcysteine is not a
human metabolite of chloromethane. It is possible, however, that the
workers examined by de Kok and Antheunius (1981) were slow eliminators.
The metabolism of chloromethane has been studied in rats, mice, and
dogs in vivo after inhalation exposure and in vitro. Based on these
studies, the metabolic pathway shown in Figure 2-2 was proposed (Kornbrust
and Bus 1983). According to this scheme, metabolism involves conjugation
with glutathione to yield S-methylglutathione, S-methylcysteine, and other
sulfur-containing compounds (Dodd et al. 1982; Kornbrust and Bus 1984;
Landry et al. 1983a,b; Redford-Ellis and Gowenlock 1971a,b). These
compounds can be excreted in the urine (Landry et al. 1983a), and
S-methylglutathione may be further metabolized to methanethiol. Cytochrome
P-450 dependent metabolism of methanethiol may yield formaldehyde and formic
acid, whose carbon atoms enter the one-carbon pool for incorporation into
macromolecules or formation of CO2 (Heck et al. 1982; Jaeger et al. 1988;
Kornbrust et al. 1982; Kornbrust and Bus 1983). Formaldehyde may also be a
direct product of chloromethane via oxidative dechlorination. Production of
methanethiol and formaldehyde, and lipid peroxidation due to glutathione
depletion have been suggested as possible mechanisms for the toxicity of
chloromethane, but the precise mechanisms are not known (Jaeger et al. 1988;
Kornbrust and Bus 1983, 1984).
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
Very little unchanged chloromethane is excreted in the urine. In
volunteers exposed to chloromethane, no chloromethane was found in the urine
in one study (Stewart et al. 1980), and urinary excretion was <0.01%/min in
another study (Morgan et al. 1970). The excretion patterns of chloromethane
following prolonged exposure will differ from those observed in these
experiments, which followed single breath exposure; therefore, these data
are not useful for monitoring occupational exposure. Volunteers exposed to
10 or 50 ppm eliminated chloromethane from blood and the expired air in a
biphasic manner when exposure ceased (Nolan et al. 1985). The half-life for
the ^-phase was 50-90 minutes, with differences possibly due to different
metabolic rates. These results suggest that chloromethane is unlikely to
accumulate in tissues during repeated intermittent exposures.
In rats exposed to chloromethane for 6 hours and dogs exposed for 3
hours at concentrations of 50 or 1000 ppm, blood levels rose rapidly and
reached equilibria proportionate or nearly proportionate to exposure levels
(Landry et al. 1983a). Blood concentrations declined rapidly in a biphasic,
nonconcentration-dependent manner when exposure was stopped. The
disappearance from blood was consistent with a linear 2-compartment open
model. Half-lives for the a-phase were 4 minutes in rats, and 8 minutes in
-------
38
2. HEALTH EFFECTS
ChUCI
GSH
glutathione
#
GS-CH
S-methylglutathione
I
NH2
I
CH,SCH,CHCOOH
S-methylcysteine
keto acid
amino acid
*CH3SCH2COCOOH
methylthiopyruvic
CO.
CH3SCH2COOH
methylthioacetic acid
?
~
~
ch3sh ¦
methanethiol
(P-450)
T
HaS
I
so4
¦ HCHO -
formaldehyde
HCOOH
formic acid
one
carbon
pool
incorporation Into
macromolecules
CO,
* Indicates the position of the radioactive label.
Source: Kornbrust and Bus, 1983
FIGURE 2-2. Proposed Scheme for the Metabolism of
Chloromethane
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39
2. HEALTH EFFECTS
dogs; half-lives for the ^-phase were 15 minutes in rats and 40 minutes in
dogs. The disappearance of chloromethane from blood probably represents
metabolism rather than excretion of parent compound. As discussed above in
Section 2.3.3 on metabolism, chloromethane is conjugated with glutathione
and cysteine, leading to urinary excretion of sulfur-containing compounds.
Further metabolism of the S-methyl cysteine metabolite of chloromethane
leads to formation of formaldehyde and formate, both of which are
metabolized by single-carbon metabolic pathways resulting in incorporation
into tissue macromolecules and production of carbon dioxide.
2.3.4.2 Oral Exposure
No studies were located regarding excretion in humans or animals after
oral exposure to chloromethane.
2.3.4.3 Dermal Exposure
No studies were located regarding excretion in humans or animals after
dermal exposure to chloromethane.
2.4 RELEVANCE TO PUBLIC HEALTH
Information regarding health effects of chloromethane in humans and
animals is available only for the inhalation route of exposure. Oral and
dermal routes of exposure are of concern because chloromethane is ubiquitous
in the environment. Because it is highly volatile, however, chloromethane
in water or soil will likely exist ultimately in the air (see Chapter 5).
The central nervous system is the major target of chloromethane
toxicity in both humans and animals, as demonstrated by such signs and
symptoms as dizziness, staggering, blurred vision, ataxia, muscle
incoordination, convulsions, and coma after acute exposure to high levels.
High acute exposures can also result in death of humans and animals. The
liver and kidney are also common targets of chloromethane toxicity in humans
and animals after acute or longer-term exposure. Toxic manifestations seen
in humans, but generally not in animals, include cardiovascular and
gastrointestinal effects, which may be secondary to the neurotoxicity.
Effects that have been observed in animals, but not reported in humans,
include testicular atrophy, infertility, and sterility of male rats, kidney
tumors in male mice, and possibly developmental effects (heart defects) in
mice.
Death. Case reports of humans who have died from exposure to
chloromethane involved the inhalation of fumes that leaked from home
refrigerators or industrial cooling and refrigeration systems (Baird 1954;
Borovska et al. 1976; Kegel et al. 1929; McNally 1946; Thordarson et al.
1965). Exposure concentrations were probably very high, perhaps >30,000
ppm, because the leaks occurred in rooms with little or no ventilation.
Exposure to high concentrations, even as high as 600,000 ppm, can result in
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AO
2. HEALTH EFFECTS
neurological effects (Morgan Jones 1942), but need not result in death if
exposure is discontinued and/or medical attention is received in time.
Since the use of chloromethane as a refrigerant in refrigeration devices has
declined, exposure from leaks is of less concern than in the past, although
some old refrigerators are probably still in use. Concentrations of
chloromethane in the environment, even at hazardous waste sites, are not
likely to be high enough to cause death.
Acute inhalation lethality data in animals indicate that high
intermittent concentrations can be tolerated better than lower continuous
concentrations (Burek et al. 1981; Jiang et al. 1985; Landry et al. 1985-
Morgan et al. 1982). This phenomenon may be related to the conversion of
chloromethane to a toxic metabolite or to diurnal susceptibility (Landry
et al. 1985). Acute and chronic inhalation studies also indicated that mice
are more sensitive than rats to the lethal effects of chloromethane
(Chellman et al. 1986a,b; CIIT 1981). The greater susceptibility of mice
may be due to differences in the ability of chloromethane to react with
glutathione in the two species. Chloromethane conjugated with glutathione
in liver, kidney, and brain to a much greater extent in mice than in rats
(Kornbrust and Bus 1984). Pretreatment of mice with buthionine-S,R-
sulfoximine (BSO), which depletes glutathione, thereby preventing its
reaction with chloromethane, protected mice from the lethal effects of
chloromethane (Chellman et al. 1986b). Thus, the reaction of chloromethane
with glutathione to produce S-methylglutathione appears to be a toxifying
rather than a detoxication mechanism (Chellman et al. 1986b). While the
exact mechanism for the lethal effects of chloromethane is unclear,
subsequent metabolism of S-methylglutathione may result in the formation of
methanethiol and formaldehyde (Kornbrust and Bus 1983), which have been
postulated to be toxic intermediates (Chellman et al. 1986b; Kornbrust and
Bus 1982). Alternatively, chloromethane can elicit lipid peroxidation as a
consequence of depletion of glutathione (Kornbrust and Bus 1984).
Conjugation of chloromethane with glutathione probably occurs in humans
because S-methylcysteine appears to be a human metabolite (see Section
2.3.3). No information was located regarding the extent to which
chloromethane reacts with glutathione in humans or the ability of
chloromethane to elicit lipid peroxidation in humans. The clinical signs
and histopathological lesions noted with death in humans are similar to
those in animals, suggesting a commonality of mechanism, but it is difficult
to determine which animal species best serves as a model for extrapolating
results to humans.
Systemic Effects. Cardiovascular effects, such as electrocardiogram
abnormalities, tachycardia and increased pulse rate, and decreased blood
pressure, and gastrointestinal effects such as nausea and vomiting, have
been described in case reports of humans exposed to chloromethane vapors
occupationally or accidentally due to refrigerator leaks (Baird 1954; Baker
1927; Battigelli and Perini 1955; Borovska et al. 1976; Gummert 1961; Hansen
et al. 1953; Kegel et al. 1929; Mackie 1961; McNally 1946; Morgan Jones
1942; Raalte and van Velzen 1945; Spevak et al. 1976; Verriere and Vachez
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41
2. HEALTH EFFECTS
1949). These case reports also describe neurological effects; therefore,
the cardiovascular and gastrointestinal effects may be secondary to the
neurotoxic effects of chloromethane. Exposure concentrations were probably
very high, perhaps >30,000 ppm, because the leaks occurred in rooms with
little or no ventilation.
Increased heart rate and blood pressure followed by decreased heart
rate and blood pressure, possibly due to vasodilation resulting from
depression of the central nervous system, occurred in dogs exposed by
inhalation to high concentrations of chloromethane (15,000 and 40,000 ppm)
(von Oettingen et al. 1949, 1950). The dogs died within 4-6 hours.
Cardiovascular effects have not been described in other species after acute,
intermediate, or chronic exposure by inhalation.
The only hematological effects described in animals were spleen
enlargement, suggestive of extramedullary hematopoiesis, and hemoglobinuria,
suggestive of intravascular hemolysis in mice exposed acutely to
chloromethane by inhalation (Landry et al. 1985). It is not clear if
similar hematological effects would occur in humans.
Case reports of humans exposed to chloromethane vapors have described
clinical jaundice and cirrhosis of the liver (Kegel et al. 1929; Mackie
1961; Weinstein 1937; Wood 1951), but exposure concentrations were not
known. Hepatic effects have also been observed in animals exposed by
inhalation to chloromethane at concentrations >1000 ppm in acute,
intermediate, and chronic duration experiments (Burek et al. 1981; Chellman
et al. 1986a; CUT 1981; Landry et al. 1985; Mitchell et al. 1979; Morgan
et al. 1982).
Milder liver effects occurred in mice exposed acutely to an
intermittent but relatively high concentration than to a low but continuous
concentration (Landry et al. 1985). The greater susceptibility to
continuous exposure may result from relatively greater metabolism to a toxic
intermediate or from diurnal susceptibility. Hepatic effects were more
severe in mice (necrosis and degeneration) than in rats (cloudy swelling,
fatty infiltration, increased SGPT and SGOT with no necrosis). Furthermore,
no hepatic lesions were observed in rats over the course of 2 years of
inhalation exposure to 1000 ppm, while mice similarly exposed had necrotic
lesions after 6 months (CUT 1981). The greater susceptibility of mice to
the hepatotoxic effects of chloromethane nay be related to the greater
ability of chloromethane to conjugate with hepatic glutathione in mice than
in rats (Dodd et al. 1982; Kornbrust and Bus 1984). The reaction of
chloromethane with glutathione appears to be a toxifying rather than a
detoxication mechanism (Chellman et al. 1986b). While the exact mechanism
for the hepatotoxic effects of chloromethane is unclear, chloromethane can
elicit lipid peroxidation as a secondary consequence of depletion of
glutathione (Kornbrust and Bus 1984). Comparison of lipid peroxidation in
the S-9 fraction from mouse and rat livers revealed Buch greater lipid
peroxidation in nouse liver than in rat liver. The findings that mice
-------
42
2. HEALTH EFFECTS
exposed to 2500 ppm chloromethane expired ethane to an extent comparable to
that produced by 2 mL/kg carbon tetrachloride, and developed moderate to
severe hepatocellular hydropic degeneration provide further evidence that
the mechanism of hepatotoxicity may involve lipid peroxidation.
Ind c a tor s of renal toxicity, such as albuminuria, increased serum
creatinine and blood urea nitrogen, proteinuria, and anuria have been
described in case reports of humans exposed to High levels of chloromethane
vapors due to refrigerator leaks (Kegel et al. 1929, Mackie 1961, Spevak
et al. 1976; Verriere and Vachez 1949).
Effects on the kidney have also been observed in animals exposed by
inhalation for acute, intermediate, and chronic durations. In acute
studies, rats developed more severe effects (evidence of renal failure) when
1000 ppm chloromethane was administered continuously (Burek et al. 1981)
than when a 2-fold higher concentration was administered intermittently
(degeneration and necrosis of convoluted tubules) (Morgan et al. 1982,
Chellman et al. 1986a). The greater susceptibility of mice to continuous
exposure than to intermittent exposure for lethal and hepatotoxic effects
(Landry et al. 1985), however, did not hold true for renal toxicity. Only
the mice exposed intermittently to the highest concentration had
degenerative and regenerative changes in the tubules. No explanation for
this apparent contradiction was offered. Degeneration and regeneration of
renal tubules were also found in other acute duration studies in mice (Jiang
et al. 1985; Morgan et al. 1982), and hyperplasia and kidney tumors were
found after 12 months of exposure and later in a 2-year study (CUT 1981).
The biological significance of the proliferative kidney lesions in mice is
discussed more fully in the subsection on Cancer below.
The possible relationship between the degenerative effects in the
kidneys of mice and granular layer lesions in the brain, which are also
observed in mice was discussed by Jiang et al. (1985). People who die of
renal insufficiency (not due to chloromethane exposure) often have granular
cell necrosis. Since the brain and kidney lesions in mice in this study
were unrelated in severity' however, the brain lesions were probably not a
direct consequence of chl°ron,e thane- induced kidney lesions. Although
chloromethane depleted glutathione in the kidney, comparison of lipid
peroxidation in the S-9 fjractions revealed much less lipid peroxidation in
kidney than in liver, suggesting that the mechanism for renal toxicity does
not involve stimulation of tissue lipid peroxidation (Kornbrust and Bus
1984).
Because some refrigerator's more than 30 years old are still in use,
leaks of chloromethane vap°r at concentrations high enough to produce
hepatic effects, renal eftectS) and neurotoxicity with consequent
cardiovascular and gastrointestinal effects in humans are possible. It is
not known whether exposure of humans to chloromethane outside or at
hazardous waste sites c°u result in hepatic and renal effects.
-------
A3
2. HEALTH EFFECTS
Immunological Effects. No studies were located regarding
immunological effects in humans after inhalation exposure to chloromethane.
The only effects in animals that could possibly be considered immunological
were lymphoid depletion of the spleen and splenic atrophy observed in mice
exposed by inhalation for up to 2 years (CUT 1981). Since more sensitive
tests for immune function were not conducted, the biological significance of
the splenic effects cannot be assessed. Furthermore, splenic alterations
were not observed in rats in the same study. In another study, cats exposed
continuously to chloromethane for 3 days had higher incidences of brain
lesions than the control (McKenna et al. 1981a). The lesions were
consistent with infection or post-vaccinal reaction (the cats were
vaccinated for panleukopenia by the supplier). Exacerbation of viral-
induced central nervous system disease, however, could not be ruled out. It
is not known whether the exacerbation would represent an immunological
effect.
Neurological Effects. Neurological effects have been described in
numerous case reports of humans exposed to chloromethane vapors as a result
of industrial leaks and leaks from defective home refrigerators (Baird 1954;
Hansen et al. 1953; Hartman et al. 1955; Kegel et al. 1929; MacDonald 1964;
McNally 1946; Morgan Jones 1942; Raalte and van Velzen 1945; Spevak et al.
1976; Wood 1951). Depending on the extent of exposure and the availability
of medical treatment, the signs and symptoms can range from staggering and
blurred vision to coma, convulsions, and death. Such effects as abnormal
gait, tremors, and personality changes may persist for several months or
more, but complete recovery may also occur eventually. In cases in which
exposure was quantitated, concentrations were generally >29,000 ppm
(Battigelli and Perini 1955; Morgan Jones 1942). Symptoms of blurred
vision, fatigue, vertigo, nausea, vomiting, tremor, and unsteadiness,
however, developed in a man and a woman a few days after they stored
insulated boards containing polystyrene foam in the basement of their house
(Lanham 1982) . The concentration of chloromethane in the house was found to
be in excess of 200 ppm (exact levels not reported). It should be noted,
however, that this exposure probably represented an unusual situation
because the rate of air turnover in the couples' home was an order of
magnitude lower than the typical rate. In addition, a small not
statistically significant decrement in performance in behavioral tests was
found in volunteers exposed to 200 ppm (Putz-Anderson et al. 1981a).
Severe neurological signs (ataxia, tremors, limb paralysis,
incoordination, convulsions) have been observed in rats, mice, rabbits,
guinea pigs, dogs, cats, and monkeys exposed acutely by inhalation to high
concentrations of chloromethane (Burek et al. 1981; Chellman et al.
1986a,b; Landry et al. 1985; McKenna et al. 1981a; Morgan et al. 1982; Smith
and von Oettingen 1947b). Signs of neurotoxicity developed after 6 and 12
months, and degeneration of the granular cell layer of the cerebellum was
observed after 18 months in mice exposed by inhalation for 2 years (CUT
1981). Cerebellar lesions have also been observed microscopically in guinea
pigs and rats (Kolkmann and Volk 1975; Morgan et al. 1982). Mice were more
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Uk
2. HEALTH EFFECTS
susceptible than rats (Morgan et al. 1982; CUT 1981), and dogs were more
susceptible than cats to the neurological effects of chloromethane (McKenna
et al. 1981a). Mice were more sensitive to neurological effects after
continuous exposure to low concentrations than after intermittent exposure
to higher concentrations of chloromethane (Landry et al. 1985). The greater
sensitivity of mice to continuous exposure may be a consequence of
metabolism of chloromethane to a toxic intermediate or diurnal
susceptibility.
The mechanism by which chloromethane produces neurological effects is
unclear. Pretreatment of mice with BSO to deplete glutathione protected
mice from cerebellar damage due to inhalation exposure to chloromethane
(Chellman et al. 1986b), suggesting that the reaction of chloromethane with
glutathione to form S-methylglutathione is required for the degenerative
changes in the brain to occur. In the metabolic scheme proposed by
Kornbrust and Bus (1983), subsequent metabolism of S-methylglutathione
produces methanethiol as an intermediate. Methanethiol produces signs and
symptoms of neurotoxicity (tremors, convulsions, coma) similar to those seen
in animals or humans acutely exposed to chloromethane (Chellman et al.
1986b). The possibility of a relationship between degenerative effects in
the kidneys and granular layer lesions in the brain, which were also
observed in mice was discussed by Jiang et al. (1985). Granular cell
necrosis is often seen in people who die of renal insufficiency (not due to
chloromethane exposure). Since the brain and kidney lesions in mice in this
study were unrelated in severity, however, Jiang et al. (1985) concluded
that the brain lesions were probably not a direct consequence of
chloromethane- induced kidney lesions.
Because refrigerators more than 30 years old are still in use, leaks of
chloromethane vapor at concentrations high enough to produce neurological
effects in humans are possible. These exposures have generally occurred in
rooms with poor ventilation. It is not known whether exposure of humans to
chloromethane in the outside environment or at hazardous waste sites could
result in neurological effects.
Developmental Effects. No studies were located regarding
developmental effects in humans exposed to chloromethane by any route.
Pregnant rats exposed to 1500 ppm chloromethane by inhalation during
gestation had decreased body weight gain and produced fetuses with delayed
development (Wolkowski-Tyl et al. 1983a). The investigators also found
increased incidences of heart malformations in the fetuses of mouse dams
exposed by inhalation to 500 ppm chloromethane during gestational days 6-17.
Heart malformations, however, were not found in fetuses of mouse dams
exposed to higher concentrations of chloromethane during gestational days
11.5-12.5, which was considered to be the critical period for development
of the embryonal heart (John-Greene et al. 1985). According to Wolkowski-
Tyl (1985), however, the critical period of embryonal heart development is
more appropriately gestational day 14. The developmental toxicity of
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45
2. HEALTH EFFECTS
chloromethane in mice is therefore controversial. It is not known whether
chloromethane could produce developmental effects in humans.
Reproductive Effects. No studies were located regarding reproductive
effects in humans exposed to chloromethane by any route. Acute,
intermediate, and chronic inhalation exposures of male rats to chloromethane
have resulted in such reproductive effects as inflammation of the epididymis
and sperm granuloma formation in epididymides, disruption of
spermatogenesis, and decreased fertility at about 500 ppm, and at higher
concentrations (1000 or 3000 ppm), sterility (Burek et al. 1981; Chapin
et al. 1984; Chellman et al. 1986a,b, 1987; CUT 1981; Hamm et al. 1985;
Morgan et al. 1982; Working et al. 1985a,b; Working and Bus 1986).
Testicular effects of chloromethane have been manifested as preimplantation
loss in unexposed female rats mated with males exposed to chloromethane
(Working et al. 1985a). Testicular lesions were also observed in mice after
18 months of exposure to chloromethane (CUT 1981). Studies on the
mechanism of chloromethane-induced testicular effects suggested that
preimplantation loss was due to cytotoxicity of chloromethane to sperm in
the testes at the time of exposure, rather than to a genotoxic effect on the
sperm (Chellman et al. 1986a,c, 1987; Working and Bus 1986; Working et al.
1985a,b).
Although testicular effects were observed in mice in the CUT (1981)
study, the incidence was much lower and occurred much later in mice than it
did in rats. The mechanism for testicular and epididymal effects has been
studied only in rats. It is not known whether chloromethane could produce
reproductive effects in humans.
Genotoxic Effects. Chloromethane has been tested for genotoxicity in a
number of in vitro and in vivo systems (Tables 2-2 and 2-3). Positive
results have generally been found in the reverse mutation assay in
Salmonella tvphimurium with and without metabolic activation (Andrews et al.
1976; DuPont 1977; Simmon et al. 1977). In addition, a positive result was
obtained in S. tvphimurium for 8-azaguanine resistance (Fostel et al.
1985) . Chloromethane gave positive results for gene mutation, sister
chromatid exchange, and transformation in cultured mammalian cells,
including human lymphoblast cells (Fostel et al. 1985; Hatch et al. 1982,
1983; Working et al. 1986). Chloromethane also produced recessive lethal
mutations in fruitflies (Valencia no date). Chloromethane, therefore,
appears to be a direct-acting genotoxicant in vitro. Although chloromethane
was positive for unscheduled DNA synthesis in rat hepatocytes,
spermatocytes, and tracheal epithelial cells in vitro, a marginally
positive response was found only in hepatocytes of rats exposed to
chloromethane in vivo, and only at very high concentrations (Working et al.
1986). Chloromethane exposure consistently produced dominant lethal
mutations in the sperm of rats, as measured by postimplantation loss in
females mated to the exposed males (Chellman et al. 1986c; Rushbrook 1984;
Working et al. 1985a). Since concurrent exposure of male rats to
chloromethane and BW755C, an anti-inflammatory agent, did not result in
-------
TABLE 2-2. Genotoxicity of Chloronettiane In Vitro
Result
With Without
End Point Species (Test System) Activation Activation Reference
Prokaryotic organisms:
Gene nutation
Mamalian cells:
Gene nutation
Sister-chronatid exchange
DMA strand breaks
Unscheduled DMA synthesis
DMA viral transformation
Salmonella typhiwuriuni
(desiccator test for exposure to gases)
S. typhimuriun TA1535 (gas exposure)
S. typhimuriun (gas exposure)
TA1535
TA100
TA1537
TA18
S. typhimuriun TA677 (gas exposure)
Hunan lymphoblasts
Hunan lymphoblasts
Hunan lynfiioblasts
Rat hepatocytes
Rat spermatocytes
Rat tracheal epithelial cells
Primary hamster enbryocel Is
NO
ND
ND
ND
NA
ND
ND
NO
Simmon et al. 1977
Andrews et al. 1976
DiPont 1977
Fostel et al. 1985
Fostel et al. 1985
Fostel et al. 1985
Fostet et al. 1985
Working et al. 1986
Working et al. 1986
Working et al. 1986
Hatch et al. 1982, 1983
t-
H
ac
m
o
H
LO
•>
CT.
* = positive result; - = negative result; NO = no data; NA = not applicable.
-------
TABLE 2-3. Ototoxicity of Chloraaethane In Vivo
End Point
Species (Test System)
Results
Reference
Recessive lethal
Dominant lethal
Unscheduled DNA synthesis
Drosophila melanogaster (gas exposure)
Rat (inhalation)
Rat (inhalation)
Rat (inhalation)
Rat (inhalation)
hepatocytes
spermatocytes
tracheal epithelial cells
Valencia no date
Uorking et al. 1985a
Chellman et al. 1986c
Rushbrook 1984
(+) Working et al. 1986
Uorking et al. 1986
(+/¦) Working et al. 1986
~ * positive result; - = negative result; (+) = marginally positive result;
(~/-) = equivocal results.
£
£
re
M
~n
n
o
H
to
¦>
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48
2. HEALTH EFFECTS
postimplantation loss, it was suggested that the dominant lethal mutation
was probably due to chloromethane - induced epididymal inflammation, possibly
by production by inflammatory cells of a superoxide capable of damaging DNA
rather than by a genotoxic effect of chloromethane itself (Chellman et al.
1986c). The ability of inflammatory cells to produce superoxides capable of
genetic damage has been demonstrated (Weitzman and Stossel 1981) . Since
studies using chloromethane indicated that the carbon atom from
chloromethane becomes incorporated into normal macromolecules via the one-
carbon pool rather than binding to macromolecules as an alkylating agent
(Kornbrust et al. 1982; Peter et al. 1985), and since the dominant lethal
effect may be secondary to inflammation, it is possible that in vivo
genotoxicity may be secondary to other toxic effects of chloromethane.
Nevertheless, the in vitro studies demonstrate the direct genotoxicity of
chloromethane. Although chloromethane produced genotoxic effects in human
lymphocytes in culture, it is not known whether chloromethane could produce
dominant lethal mutations or other genotoxic effects in humans exposed by
any route.
Cancer. The only information regarding carcinogenicity in humans
after exposure to chloromethane comes from a negative epidemiological study
of butyl rubber workers which showed no statistically significant increase
in the rate of death due to cancer in this population (Holmes et al 1986)
Chloromethane has been tested for carcinogenicity in animals only by
the inhalation route. No evidence of a carcinogenic effect was found in
rats or in female mice (CUT 1981). In a 2-year inhalation study, a
statistically significant increased incidence of kidney tumors developed in
1000 ppm-exposed B6C3F1 male mice. Renal hyperplasia was also observed
after 12 months of exposure. In an acute study, significant increases in
cell proliferation occurred in the kidneys of male B6C3F1 mice, as measured
by incorporation of tritiated thymidine into DNA of the kidneys (Chellman
et al. 1986b). Such proliferation may be involved in the development of
kidney tumors, a hypothesis supported by the evidence that chloromethane is
probably not an alkylating agent but acts by an epigenetic mechanism
(Kornbrust et al. 1982; Peter et al. 1985). Female B6C3F1 mice exposed to
1500 ppm chloromethane also had increased cell proliferation in the kidney
(Chellman et al. 1986b), but did not develop kidney tumors in the CUT
(1981) study; however, the exposure concentrations in the CUT (1981) study
were lower than in the study by Chellman et al. (1986b). In addition,
greater evidence of regeneration of renal tubular cells, presumably in
response to cell death, was found in B6C3F1 males than in females of the
same strain exposed to 500 and 1000 ppm chloromethane for 12 days (Morgan
et al. 1982). In mice exposed to 2000 ppm, however, there was no sex
difference. It is possible, therefore, that at relatively low
concentrations, female mice are less sensitive than male mice to the renal
toxicity of chloromethane.
Since data that chloromethane exposure was associated with tumors were
found in only one sex of one species in only one study, the evidence that
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49
2. HEALTH EFFECTS
chloromethane is a carcinogen is limited. It is not known whether cancer
could develop in humans exposed to chloromethane by any route.
2.5 BIOMARKERS OF EXPOSURE AND EFFECTS
Biomarkers are broadly defined as indicators signaling events in
biologic systems or samples. They have been classified as markers of
exposure, markers of effect, and markers of susceptibility (NAS/NRC, 1989).
A biomarker of exposure is a xenobiotic substance or its metabolite(s)
or the product of an interaction between a xenobiotic agent and some target
molecule or cell that is measured within a compartment of an organism
(NAS/NRC 1989). The preferred biomarkers of exposure are generally the
substance itself or substance - specific metabolites in readily obtainable
body fluid or excreta. However, several factors can confound the use and
interpretation of biomarkers of exposure. The body burden of a substance
may be the result of exposures from more than one source. The substance
being measured may be a metabolite of another xenobiotic (e.g., high urinary
levels of phenol can result from exposure to several different aromatic
compounds). Depending on the properties of the substance (e.g., biologic
half-life) and environmental conditions (e.g., duration and route of
exposure), the substance and all of its metabolites may have left the body
by the time biologic samples can be taken. It may be difficult to identify
individuals exposed to hazardous substances that are commonly found in body
tissues and fluids (e.g., essential mineral nutrients such as copper, zinc
and selenium). Biomarkers of exposure to chloromethane are discussed in
Section 2.5.1.
Biomarkers of effect are defined as any measurable biochemical,
physiologic, or other alteration within an organism that, depending on
magnitude, can be recognized as an established or potential health
impairment or disease (NAS/NRC 1989). This definition encompasses
biochemical or cellular signals of tissue dysfunction (e.g., increased liver
enzyme activity or pathologic changes in female genital epithelial cells),
as well as physiologic signs of dysfunction such as increased blood pressure
or decreased lung capacity. Note that these markers are often not substance
specific. They also may not be directly adverse, but can indicate potential
health impairment (e.g., DNA adducts). Biomarkers of effects caused by
chloromethane are discussed in Section 2.5.2.
A biomarker of susceptibility is an indicator of an inherent or
acquired limitation of an organism's ability to respond to the challenge of
exposure to a specific xenobiotic. It can be an intrinsic genetic or other
characteristic or a preexisting disease that results in an increase in
absorbed dose, biologically effective dose, or target tissue response. If
biomarkers of susceptibility exist, they are discussed in Section 2.7,
"POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE."
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50
2. HEALTH EFFECTS
2.5.1 Biomarkers Used to Identify or Quantify Exposure to Chloromethane
Several studies have unsuccessfully attempted to correlate exposure
levels of chloromethane in air with urinary excretion of S-methylcysteine
In a group of six workers exposed to TWA 8-hour workroom concentrations of
30-90 ppm, the excretion of S-methylcysteine in urine showed wide
variations, with little correlation with exposure levels (van Doom et al.
1980). On the basis of variable excretion of S-methylcysteine in six male
volunteers exposed to 10 or 50 ppm chloromethane for 6 hours, Nolan et al
(1985) concluded that measurement of S-methylcysteine in urine is not a
valid method for monitoring exposure to chloromethane.
In an evaluation of the use of blood and breath analysis of
chloromethane to monitor exposure in volunteers exposed to up to 150 ppm
chloromethane, breath levels immediately after exposure to 20 or 100 ppm
correlated with exposure, but subsequent samples were difficult to
interpret (Stewart et al. 1980). Exposure to 100 ppm could not be
distinguished from exposure to 150 ppm. The excretion patterns following
prolonged exposure will differ from those observed in these experiments
(Morgan et al. 1970), which followed single breath exposure (see Section
2.3.4.1); therefore, the data are not useful for monitoring occupational
exposure. This conclusion probably applies to prolonged environmental
exposure as well. Symptoms resembling drunkenness and food poisoning, along
with a sweet odor of the breath, may alert physicians that a person has been
exposed to chloromethane.
2.5.2 Biomarkers Used to Characterize Effects Caused by Chloromethane
Attempts to correlate blood levels and expired air concentrations of
chloromethane with health effects of occupational and experimental
inhalation exposure have been unsuccessful. In a study of 73 behavioral
measures of task performance, 4 indices of exposure and 8 indicators of
neurological function in workers exposed to a mean concentration of 34 ppm
chloromethane, effects on cognitive time-sharing and finger tremor were
found, but correlation coefficients indicated that chloromethane in breath
was not a sensitive indicator of performance (Repko et al. 1977). A 4X
decrement in performance of behavioral tests was found in volunteers exposed
to 200 ppm chloromethane for 3 hours, but blood and alveolar air levels of
chloromethane were highly variable (Putz-Anderson et al. 1981a).
Furthermore, the decrement in performance was small and not statistically
significant.
2.6 INTERACTIONS WITH OTHER CHEMICALS
Inhalation exposure of volunteers to 200 ppm chloromethane along with
oral dosing with 10 mg diazepam produced an additive impairment in
performance on behavioral tests (Putz-Anderson et al. 1981a). Since both
of these compounds are known to be central nervous system depressants,
workers who are exposed to chloromethane in industry or during cleanup of
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51
2. HEALTH EFFECTS
hazardous waste sites, or people who live near hazardous waste sites where
chloromethane is present and are treated with diazepam or exposed to other
central nervous system depressants, including alcohol, may have aggravated
symptoms. The only other studies that show an effect of other compounds on
the toxicity of chloromethane are those in which the effects of BW755C, an
anti- inflammatory agent, and BSO, a depletor of glutathione, were
administered to rats or mice exposed to chloromethane by inhalation to study
the mechanism of chloromethane-induced toxicity (Chellman et al. 1986a,b).
These studies are discussed in Section 2.2. It is unlikely that these
compounds would be found with chloromethane at hazardous waste sites.
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Two distinct populations of humans with differences in elimination of
chloromethane have been identified. Some volunteers exposed by inhalation
to chloromethane had distinctly higher chloromethane concentrations in
alveolar breath samples than others (Stewart et al. 1980). In humans
exposed to chloromethane by inhalation, the chloromethane was eliminated
from the blood and expired air more slowly by the subjects who had higher
venous blood and expired air concentrations than by those who had lower
concentrations (Nolan et al. 1985). This finding was believed to be due to
differences in metabolic rate. In six workers exposed to chloromethane
occupationally, the excretion of S-methylcysteine showed wide variations,
and there was little or no correlation between exposure levels and excretion
(van Doom et al. 1980). In four of the workers, all concentrations of
S-methylcysteine were higher than In controls, and appeared to increase
during the course of the week. The other two workers had only small amounts
of S-methylcysteine in the urine, but these workers had experienced the
"highest exposure concentrations. These results support the speculation that
there are two distinct populations: fast eliminators, with lower body
burdens and higher excretion, and slow eliminators, with higher body burdens
and lower excretion. Because chloromethane is eliminated relatively
rapidly, the observation of two distinct populations may have no
toxicological significance (Nolan et al. 1985). Based on studies in mice,
the reaction of chloromethane with glutathione, however, may lead to the
formation of toxic compounds in humans that exert their action before they
are eliminated. If slow eliminators have a deficiency of glutathione-
s-transferase, the enzyme that catalyzes the conjugation of glutathione with
chloromethane, or low levels of glutathione, they would be expected to be
less susceptible to the toxic effects of chloromethane. The extent to which
chloromethane reacts with glutathione in humans, however, is not known.
As discussed in Section 2.7, workers treated with diazepam and exposed
to chloromethane had an additive impairment In performing behavioral tests
(Putz-Anderson et al. 1981a). These results imply that people who are
occupationally exposed to chloromethane and treated with diazepam, or
perhaps other drugs that depress the central nervous system, may have
aggravated symptoms.
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52
2. HEALTH EFFECTS
2.8 ADEQUACY OF THE DATABASE
Section 104
-------
53
2. HEALTH EFFECTS
SYSTEMIC
Inhalation
Oral
Derma!
HUMAN
SYSTEMIC
it-
Inhalation
Oral
Dermal
ANIMAL
^ Existing Studies
FIGURE 2-3. Existing Information on Health Effects of Chloromethane
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54
2. HEALTH EFFECTS
• , »vi«, rfPVPloTMnental, reproductive, and genotoxic effects,
neurological, Pos*lb^. deve p chloromethane for 2 years resulted ln
Inhalation exposure of m tumors. The only oral study i" aniffials
increased incidences of kidn y ± of chloroniethane with Carbon
attempted to compare t e e chloromethane administerecj
tetrachloride and chloroform^ The ^ ^ >dmlnlstratlon of
however, was too lo„ tNeurotoxicity.
higher doses was precluded due
2.8.2 Identification of Data Needs
. f sinele dose oral study, no information was
With t e excep effects of chloromethane in huifl^ns or animals
located regarding the health ett^ ^ ^ ible cq predict whether
after oral or erma exp ^ exp0sure to chloromethane would be similar
effects following oral or dermal e P all because tbe
to those following ^^iot^.B*£loronethane has not been compared for the
pharmacokinetic disposition of^clU^ ^ absorptlon, distribution, and
three routes o exp • differences in toxic response and different
metabolic pat ways c°u three routes of exposure. Therefore, studies
target organs fo ow ng exposure would provide information regarding
using oral and dermal routes of g an/re5ponses seen following
possible similarities e we following oral and dermal exposures.
inhalation exposure an Pvnosure are of concern because chloromethane
The oral and dermal routes of exp chloromethane -s Mghly volatile,
is ubiquitous in t e enviro ater or soil will likely volatiae to the air
however, and chloromethane in wate
(Chapter 5).
Case reports of humans exposed acutely to
Acute-Duration f^hToromethane have described severe neurological
, high concentrations oc death. Effects on the cardiovascular system,
effects, sometimes o owe described in case reports of humans exposed
liver, and kidney ave prolonged periods occupationally. Acute
for brief periods , £ chloromethane causing death in animals are
atfuSr^rS ann^e. S-erous acute inhalation studies have
identified the liver and kidney as target organs in rats and mice . the
T „ „ orcran in mice, the central nervous system as a target
system in rats mice, and dogs, and the testes and epididymides as target
roans in rats In addition, the respiratory and cardiovascular systems
° *c Ancs These studies have shown that species differences i
be ^fibilit, eflst and that generally animals are more susceptible to
S ? continuously than to relatively^
exDOSures given intermittently- Some studies provide information on the
mechanism of hepatic, renal, and neurolQgicai effects in mice and
rnductive effects in mice. The data for acute inhalation exposures in
animals were sufficient to derive an acute inhalation URL for chloromethane
based on a NOAEL for neurological effects in mice. Only one acute oral
study was conducted. In this study ,rats were dosed orally with
chloromethane, and livers were *>' pathology (Reynolds and Yee
1967). The administered dose was too lGw t0 cause hepatic effects, and
may
in
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55
2. HEALTH EFFECTS
higher doses were not administered because of the neurotoxic effects of
chloromethane. Therefore, an acute oral MRL can not be derived. No studies
were located regarding effects in humans or animals after dermal exposure to
chloromethane. Pharmacokinetic data are insufficient to identify target
organs of chloromethane after oral and dermal exposure. As discussed above,
although the potential for humans to be exposed to chloromethane is greater
for the inhalation route than for the oral and dermal routes, chloromethane
is ubiquitous in the environment. Therefore, acute studies in animals
exposed by oral or dermal routes would provide information to identify
target organs and dose-response relationships for these routes. This
information is important because there are populations surrounding hazardous
waste sites that might be exposed to chloromethane for similar durations.
Intermediate-Duration Exposure. Information regarding effects in
humans after intermediate-duration exposure to chloromethane is limited to
findings of neurological symptoms in humans occupationally exposed.
Inhalation studies have been conducted in rats, mice, and dogs, and have
identified the liver as a target organ in rats and mice, the testes as a
target organ in rats, and the kidney, spleen, and central nervous system as
targets in mice. The data were sufficient to derive an intermediate-
duration inhalation MRL. No studies were located regarding effects in
humans or animals after intermediate-duration oral or dermal exposure, and
pharmacokinetic data are insufficient to identify or predict target organs
of chloromethane for these routes of exposure. As discussed above,
although the potential for humans to be exposed to chloromethane is greater
for the inhalation route than for the oral and dermal routes, chloromethane
is ubiquitous in the environment. Therefore, intermediate-duration studies
in animals exposed by oral or dermal routes would provide information to
identify target organs and dose-response relationships for these routes.
This information is important because there are populations surrounding
hazardous waste sites that might be exposed to chloromethane for similar
durations.
Chronic Exposure and Cancer. No information was located regarding
effects of chloromethane in humans after chronic exposure by any route.
A 2-year inhalation study has been conducted that exposed both sexes of rats
and mice to several concentrations of chloromethane and comprehensively
examined endpoints of toxicity (CUT 1981). The liver, kidney, spleen, and
brain were identified as target organs in mice, and the testes were
identified as target organs in rats and mice. Data were sufficient to
derive a chronic inhalation MRL. No studies were located regarding effects
in humans or animals after chronic oral or dermal exposure to chloromethane,
and pharmacokinetic data are insufficient to identify or predict target
organs of chloromethane for these routes of exposure. As discussed above,
although the potential for humans to be exposed to chloromethane is greater
for the inhalation route than for the oral and dermal routes, chloromethane
is ubiquitous in the environment. Therefore, chronic-duration studies in
animals exposed by oral or dermal routes would provide information to
identify target organs and dose-response relationships for these routes.
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56
2. HEALTH EFFECTS
This information is important because there are populations surrounding
hazardous waste sites that might be exposed to chloromethane for similar
durations.
The carcinogenic effects of chloromethane were also examined in this
study. Male mice, but not female mice nor rats of either sex, developed
increased incidences of kidney tumors at the highest exposure level, The
rats and mice were exposed to the same concentrations, but differences in
ventilation rate, the ability to conjugate chloromethane with glutathione
and to further metabolize the glutathione conjugate, and body weight make
it probable that mice received a higher internal dose than rats. It is
possible, therefore, that the exposure concentration was not high enough in
rats to produce kidney tumors. Additional chronic inhalation studies in
rats using concentrations that would result in internal doses similar to
those received by the mice might show that chloromethane can induce tumors
in rats. No studies were located regarding the carcinogenic effects of
chloromethane in animals after oral and dermal exposure, and pharmacokinetic
data are insufficient to support the carcinogenic potential across routes of
exposure. As discussed above, although the potential for humans to be
exposed to chloromethane is greater for the inhalation route than for the
oral and dermal routes, chloromethane is ubiquitous in the environment.
Additional chronic studies in rats, mice, and other species would reduce
uncertainties in extrapolating information from animal studies to humans.
Genotoxicity. The available genotoxicity studies for mutation in
S almone11a tvnh imur iura. for mutation, sister - chromatid exchange, and DNA
strand breaks in human lymphoblasts, for unscheduled DNA synthesis in rat
hepatocytes, spermatocytes, and tracheal epithelial cells, for DNA viral
transformation in primary hamster embryo cells, and for recessive lethal
mutation in Drosophila melanoeaster indicate that chloromethane is
genotoxic. Studies of the mechanism of dominant lethal mutations in rat
sperm resulting from inhalation exposure of male rats to chloromethane
suggest that the dominant lethal effects may be secondary to inflammation of
the epididymis. Because the dominant lethal effect may have been secondary
to inflammation and because chloromethane does not appear to be an
alkylating agent, some investigators have suggested that chloromethane is
only a weak direct-acting genotoxicant. Further genotoxicity studies might
resolve this issue.
Reproductive Toxicity. No information was available regarding
reproductive effects of chloromethane in humans, but several inhalation
studies have demonstrated that chloromethane is a reproductive toxicant in
male rats. In addition, the mechanism of the reproductive effects has been
studied in rats. The reproductive effects of chloromethane have been
studied extensively only in rats because testicular lesions in mice occurred
at lower incidences and later time periods than in rats in the 2-year
inhalation study by CUT (1981). Testicular effects were not observed in
male dogs and cats exposed to chloromethane by inhalation, but the exposure
concentrations may not have been high enough. Species differences in
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57
2. HEALTH EFFECTS
sensitivity exist for other end points; therefore, testing for reproductive
effects in other species at higher exposure levels might provide information
on whether reproductive effects are confined to rats and mice or apply to
other species, even humans. No studies were located regarding the
reproductive effects of chloromethane in animals after oral and dermal
exposure, and pharmacokinetic data are insufficient to support the potential
for reproductive effects across routes of exposure. As discussed above,
although the potential for humans to be exposed to chloromethane is greater
for the inhalation route than for the oral and dermal routes, chloromethane
is ubiquitous in the environment.
Developmental Toxicity. No information was located regarding
developmental effects in humans after exposure to chloromethane by any
route. The teratogenicity of inhalation exposure to chloromethane has been
studied in rats and mice. In rats, delayed fetal development was found at
the same concentration that resulted in maternal toxicity. The results in
mice are controversial. Additional studies in mice and other species might
resolve the controversy and provide information on the possible
developmental effects of chloromethane in other species.
No studies were located regarding the developmental effects of
chloromethane in animals after oral and dermal exposure, and
pharmacokinetic data are insufficient to support the potential for
developmental toxicity across routes of exposure. As discussed above,
although the potential for humans to be exposed to chloromethane is greater
for the inhalation route than for the oral and dermal routes, chloromethane
is ubiquitous in the environment.
Immunotoxicity. The only effects that could be possibly considered
immunological effects were lymphoid depletion of the spleen and splenic
atrophy observed in mice, but not rats exposed by inhalation to
chloromethane for 2 years (CUT 1981). In addition, cats exposed
continuously to chloromethane for 3 days had higher incidences of brain
lesions than the control (McKenna et al. 1981a). The lesions, however, were
consistent with infection or post-vaccinal reaction (the cats were
vaccinated for panleukopenia by the supplier). Exacerbation of viral-
induced central nervous system disease could not be ruled out. It is not
known whether the exacerbation would represent an immunological effect.
More sensitive measures of immunotoxicity could be studied to determine
whether exposure to chloromethane by any route produces immunological
effects.
Neurotoxicity. The neurotoxic effects of inhalation exposure to
chloromethane are well defined in animals and humans, but the mechanism is
unclear. No studies were located regarding the neurotoxic effects of
chloromethane in animals after oral and dermal exposure, and
pharmacokinetic data are insufficient to support the potential for
neurological toxicity across routes of exposure. As discussed above,
although the potential for humans to be exposed to chloromethane is greater
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58
2. HEALTH EFFECTS
for the inhalation route than for the oral and dermal routes, chloromethane
is ubiquitous in the environment. The mechanism for the induction of
cerebellar lesions in mice exposed by inhalation may involve conjugation of
chloromethane with glutathione, with further metabolism leading to
production of methanethiol. Methanethiol produces similar central nervous
system effects as seen in animals and humans exposed Co chloromethane. The
relative importance of conjugation with glutathione in other species has not
been determined. As S-methylcysteine appears to be a metabolite in humans
conjugation with glutathione probably operates in humans. In addition
sensitive neurobehavioral toxicity studies in monkeys may provide valuable
information for determining the threshold for the neurotoxic effects and in
elucidating the possible mechanism of action of chloromethane-induced
neurotoxicity. Monkeys represent a better model than do rodents for
extrapolating animal data on neurobehavioral effects to human5;
Epidemiological and Human Dosimetry Studies. A retrospective
epidemiological study was conducted in workers exposed to chloromethane in a
butyl rubber manufacturing facility (Holmes et al.. 1986). No association
was found between chloromethane exposure and death due to cardiovascular
disease or cancer at any site. In a study of workers from fabricating
plants, occupational exposure to chloromethane below 100 ppm produced
subtle, quantifiable behavioral effects, but the threshold for changes in
functional capacity could not be determined precisely (Repko et al. 1977)
An experimental study by Stewart et al. (1980) found no effects on pulmonary
function, cardiac function or ECG, and no hematological, neurological, or
behavioral effects in volunteers exposed by inhalation to chloromethane but
the protocol was too confusing to clearly define the exposures. A slight
decrement in performance of behavioral tasks was found in volunteers exposed
to 200 ppm for 3 hours (PutE-Anderson et al. 1981a). Further
epidemiological studies could be conducted to confirm or refute the lack of
an association between increased cancer risk and occupational exposure and
to better define the threshold for neurobehavioral effects.
Biomarkers of Exposure and Effect. A number of studies have
unsuccessfully tried to relate blood and alveolar air levels of
chloromethane and urinary levels of S-methylcysteine with exposure. The
blood and alveolar air levels of chloromethane and the urinary levels of
S-methylcysteine are highly variable. Symptoms resembling drunkenness and
food poisoning, along with a sweet odor on the breath, may al.ert a physician
that a person has been exposed to chloromethane, but such symptoms could
easily be mistaken for the conditions they resemble. Further studies
designed to identify a metabolite or biomarker that can be monitored for
exposure to chloromethane would facilitate future medical surveillance.
Attempts to correlate blood levels and expired air concentrations of
chloromethane with health effects of occupational and experimental
inhalation exposures of humans have also been unsuccessful. Blood and
alveolar levels are highly variable and are not sensitive indicators of
neurological function or behavior. Further studies designed to identify a
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59
2. HEALTH EFFECTS
metabolite or biomarker that can be correlated with the known subtle
neurological effects would facilitate future medical surveillance that could
lead to early detection and possible treatment.
Absorption, Distribution, Metabolism, and Excretion. Experimental
inhalation studies in animals and humans indicate that chloromethane is
rapidly taken up from the lungs into the "blood, widely distributed
throughout the body and extensively metabolized, with the carbon atom being
incorporated into natural biological macromolecules, CO2 being excreted in
the expired air, and other metabolites being excreted in the urine.
Differences in the rate and extent of absorption, metabolic pathways, and
disposition may result in differences in the toxic manifestations of a
chemical following exposure by oral or dermal routes. Thus, further studies
of the rate and extent of absorption, distribution, metabolism, and
excretion in animals following exposure by the oral and dermal routes, would
provide information to fully characterize the pharmacokinetics of
chloromethar.e in animals . Oral and dermal routes of exposure are of concern
because chloromethane is ubiquitous in the environment. Chloromethane is
highly volatile, however, and chloromethane in water or soil will likely
volatilize to the air (see Chapter 5).
Comparative Toxicokinetics. Studies on the pharmacokinetics of
chloromethane following inhalation exposure have been conducted in rats,
mice, dogs, and humans. Kinetics of chloromethane in humans were similar to
those in rats and dogs, with data for each species consistent with 2-
compartment models. The plateau concentrations of slow human metabolizers
were less than those in rats and dogs. The half-life for the beta phase of
excretion was 15 minutes for rats, 50 minutes for rapid human metabolizers
and dogs, and 90 minutes for slow metabolizers. Species difference can be
explained by differences in respiratory minute volumes and basal metabolic
rates (rat > dog > human). Studies in rats and mice indicate that
chloromethane conjugates with glutathione. Since S-methylcysteine is
probably a metabolite of chloromethane in humans, conjugation with
glutathione probably operates in humans. Glutathione reacts with
chlnrcmethane to a greater extent in mice than in rats, but the extent to
which chloromethane reacts with glutathione in humans is not known.
Although chloromethane reacts with glutathione in human erythrocytes
(Redford-Ellis and Gowenlock 1971b), determination of the extent of
glutathione depletion in human liver and/or kidney would probably involve
exposure of humans to chloromethane and invasive methods of investigation.
Information on the extent of glutathione depletion in humans is important
because the reaction of chloromethane with glutathione is believed to
represent a toxifying mechanism that leads to the formation of other toxic
compounds. Studies to determine the specific metabolites (or parent
compound) that are responsible for the neurotoxicity, testicular toxicity,
and kidney timorigenesis in animals and the identification of the same
metabolites in humans would help in the prediction of toxic effects in
humans and the identification of the appropriate animal model to further
study the effect. Identification of further similarities between animals
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60
2. HEALTH EFFECTS
and humans with respect to toxicokinetics would provide information to
identify the most appropriate species to serve as a model for predicting
toxic effects in humans.
2.8.3 On-going Studies
Very little on-going research was identified. As reported in a recent
abstract, the activity of glutathione transferase was determined in human
erythrocytes exposed to chloromethane in vitro (Hallier and Peter 1988).
The method may be useful for identifying the subpopulations of fast and slow
metabolizers. As reported in another recent abstract, a significant sex-
specific difference was found in the content of microsomal cytochrome P450
in kidneys (male>fe!nale), but not in livers, of mice of three different
strains (Jaeger 1988). Glutathione-S-transferase activities in liver and
kidney cytosol incubated with methyl chloride were greater in female mice
than male mice. These data may help to elucidate the reasons for the sex-
specific renal toxicity observed in mice.
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61
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Data pertaining to the chemical Identity of chloromethane are listed in
Table 3-1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The physical and chemical properties of chloromethane are presented in
Table 3-2.
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62
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Chloronethane
Value
Reference
Chemical name
Synonyms
T r ade name s
Chemical formula
Chemical structure
Chloromethane
Methyl chloride
monochlorome thane
Artie
R 40
Freon 40
CH3CI
H
I
H—c—CL
I
H
CAS 1988
CAS 1988; SANSS 1988
HSDB 1988; SANSS 1988
CAS 1988
SANSS 1988
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM-TADS
DOT/UN/NA/IMCO Shipping
HSDB
NCI
74-87-3
PA6300000
U045
7216794
UN 1063
883
No data
CAS 1988
RTECS 1988
HSDB 1988
OHM-TADS 1988
HSDB 1988; RTECS 1988
HSDB 1988
• i Services' EPA - Environmental Protection Agency;
.£ Transportation/United
DOT/UN/I^A/lnou uep ^ roH»' HSnR - Hazardous
National
Stitute for "occupational Safety and Health; OHM-TADS - Oil and Hazardous
Materials/Technical Assistance Data Systen,; RTECS - Reentry of Toxic
Data Bank; NCI - National Cancer Institute,
Materiais/T
Effects of Chemical Substances
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63
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Chloromethane
Property
Value
Reference
Molecular weight
50.49
Color
Colorless gas
Ahlstrom
and
Steele
1979
Physical state
Gas
Ahlstrom
and
Steele
1979
Melting point
-97.7°C
Ahlstrom
and
Steele
1979
Boiling point
-23.73°C
Ahlstrom
and
Steele
1979
Density:
Liquid at 20/4°C
0.920 g/mL
Ahlstrom
and
Steele
1979
Gas at 0°C, 1 atm
1.74 (air~l)
Ahlstrom
and
Steele
1979
Odor
Ethereal, nonirritating
Ahlstrom
and
Steele
1979
Odor threshold
Water
Air
Solubility:
Water at 25°C
Organic solvents3:
Benzene
Carbon tetrachloride
Glacial acetic acid
Absolute alcohol
Partition coefficients:
Log octanol/water
Log Koc
Log BCF
Vapor pressure:
at 20°C
at 25°C
Henry's law constant:
at 25°C
Autoignition temperature
Flashpoint, open cup
Flammability limits
Conversion factors:
ppm (v/v) to mg/ni3
in air at 25°C
mg/m3 to ppm (v/v)
in air at 25"C
No data
No data
5325 mg/L
4800 mg/L
4723
3756
3679
3740
0.91 (experimental)
0.7 (estimated)
0.46 (estimated)
3670 mmHg
4310 mmHg
8.82xl0"3 atm-m3/mol
632°C
<0"C
10.7-17.4 vol %
Horvath 1982
Ahlstrom and Steele 1979
Ahlstrom and Steele 1979
Ahlstrom and Steele 1979
Ahlstrom and Steele 1979
Ahlstrom and Steele 1979
Hansch and Leo 1985
PCGEMS equ 4-10
PCGEMS equ 5-5
Ahlstrom and Steele 1979
Riddick et al. 1986
Gossett 1987
Ahlstrom and Steele 1979
Ahlstrom and Steele 1979
Ahlstrom and Steele 1979
ppm (v/v) x 2.064 - mg/m3
mg/m3 x 0.4845 - ppm (v/v)
aGas, 20°C, 1 atm, mL CH3CI/IOO mL solvent.
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65
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
h.1 PRODUCTION
Chloromethane is both an anthropogenic and naturally occurring
chemical. Anthropogenic sources include industrial production, polyvinyl
chloride burning, and wood burning; natural sources include the oceans,
microbial fermentation, and biomass fires (e.g., forest fires, grass fires).
Chloromethane is produced industrially by either reaction of methanol and
hydrogen chloride (HC1) or by chlorination of methane (Ahlstrom and Steele
1979; Key et al. 1980; Edwards et al. 1982a). While the reaction of
methanol with HC1 is the most common method, the process chosen depends, in
part, on the HC1 balance at the site (the methane route produces HCl, the
methanol route uses it) (Ahlstrom and Steele 1979; Edwards et al. 1982a).
Typically, manufacturing plants that produce chloromethane also produce
higher chlorinated methanes (methylene chloride, chloroform, and carbon
tetrachloride).
The methanol-HCl process involves combining vapor-phase methanol and
HC1 at 180-200°C, followed by passage over a catalyst where the reaction
occurs (Ahlstrom and Steele 1979). Catalysts include alumina gel, gamma
alumina, and cuprous or zinc chloride on pumice or activated carbon. The
exit gases from the reactor are quenched with water to remove unreacted HC1
and methanol. The quench water is stripped of the dissolved methanol and
chloromethane and the remaining dilute HCl solution is used in-house or
treated and discharged (Ahlstrom and Steele 1979). The chloromethane is
then dried by treatment with concentrated sulfuric acid, then compressed,
cooled, and stored.
In the methane chlorination process, a molar excess of methane is mixed
with chlorine, and the mixture is then fed to a reactor, which is operated
at 400°C and 200 kPa pressure (Ahlstrom and Steele 1979; Key et al. 1980).
The exit gases can then be scrubbed with chilled chloromethanes (mono- to
tetrachloromethane) to remove most of the reaction chloromethanes from
unreacted methane and HCl. The by-product HCl is removed by water wash,
stripped of any chloromethanes, and either used in-house or sold; the
unreacted methane is recycled through the process. The condensed
chloromethanes are then scrubbed with dilute NaOH to remove any HCl, dried,
compressed, cooled, then fractionally distilled to separate the four
chloromethanes. While there are some variations to this process, including
the use of catalysts, the above description is a general overview of the
basic steps in the process.
Six domestic manufacturers of chloromethane are Dow Corning Corp.
(Carrollton, KY; Midland, MI), Dow Chemical Co. (Plaquemine, LA; Freeport,
TX), LCP Chemicals (Moundsville, WV), General Electric Co. Silicone Products
Division (Waterford, NY), Occidental Chemical Co. (Belle, WV), and Vulcan
Materials (Lake Charles, LA) (CMR 1986; USITC 1987). Vista Chemical Co.'s
plant in Geisman, LA, will be completed in 1991 (CMR 1989). LCP Chemicals
in Moundsville, WV, can use either process, and the others use the methanol
hydrochlorination process (Key etal. 1980). Total United States production
-------
66
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
of chloromethane was 373 million pounds (1.7X.1G11 g) in 1987 (USITC 1987),
which is less than the 1985 production of 511 million pounds (2.2X1011 g)
(CMR 1986) and the 1984 production of 482 million pounds (USITC 1985).
World-wide production was «790 million pounds (3.6xlOn g) in 1980 (Edwards
et al. 1982b). It is difficult to estimate the total production levels for
chloromethane because many of the producers consume their output internally
as a feedstock for other chemicals, including silicones and higher
chlorinated methanes. Total production, therefore, may be higher than the
above estimates.
In addition to direct manufacture, chloromethane is also produced
naturally and from a number of human activities. The amount of
chloromethane produced naturally far exceeds the amount manufactured (at
least by a factor of 10). Most chloromethane produced on earth comes from
the ocean; estimates of oceanic production volumes vary, but generally fall
within the range <3-5)xl012 g/year (6.6-11 billion pounds/year) (Fabian
1986; Rasmussen et al. 1980; Singh et al. 1979; Yung et al. 1975). Other
sources of natural chloromethane include biomass burning (both natural and
resulting from human activity, e.g., forest fires, wood burning, cigarette
smoking, volcanoes, burning plastic, coal burning), which accounts for (0.2-
0.4)xl0^ g/year (0.44-0.88 billion pounds/year) (Chopra 1972; Crutzen
et al. 1979; Edgerton et al. 1984, 1986; Fabian 1986; Kadaba et al. 1978;
Khalil et al. 1985; Kleindienst et al. 1986; Palmer 1976; Rasmussen et al.
1980; Tassios and Packham 1985), microbial activity (Fabian 1986; Harper and
Hamilton 1988; Harper 1985; Harper et al. 1988), chlorination of drinking
water and wastewater (Coleman et al. 1976; Lurker et al. 1983), and some
trees (Isidorov et al. 1985). Some controversy exists concerning wood
burning as a source of chloromethane (DeGroot 1989). The total production
of chloromethane from sources other than manufacture account for
approximately (3.2-8.2)xl012 g/year (7-18 billion pounds).
4.2 IMPORT
No information concerning the import of chloromethane in the United
States was located in the literature (chloromethane is not reported
separately by the U.S. International Trade Commission). Approximately 4X of
production is exported (CMR 1986).
4.3 USE
Chloromethane is used mainly (72X) in the production of silicones (CMR
1986) where it is used to methylate silicon. This process involves the
reaction of silicon with chloromethane and heat to form mono-, di-, and
trichlorosilicon (Browning 1985). Chloromethane is also used in the
production of agricultural chemicals (8X), methyl cellulose (62) , quaternary
amines (5%) butyl rubber (3X), and for miscellaneous uses including
tetramethyl'lead (2%) (CMR 1986). Virtually all of the uses for
chloromethane are consumptive in that the chloromethane is reacted to form
-------
67
A. PRODUCTION, IMPORT, USE, AND DISPOSAL
another product during use. Thus, chloromethane is consumed when used and
is no longer available for release, disposal, or reuse.
4.4 DISPOSAL
No information was located in the literature concerning the disposal of
chloromethane. Since most chloromethane is used consumptively, little
remains to be disposed of. Nonetheless, some chloromethane is present in
waste, since it has been detected in hazardous waste landfills. These
concentrations may result from the landfilling of still bottoms or other
residues from the manufacture and use of chloromethane. Its presence in
municipal waste landfills may suggest that consumer products containing
chloromethane are landfilled (e.g., propellants for aerosol cans, old
refrigerators). In a study of the products of initial combustion using
mixtures of chloromethane under simulated incinerator conditions,
chloromethane was destroyed under oxygen-rich conditions (Taylor and
Dellinger 1988). Under oxygen starved conditions, however, chloromethane
can combine with other components of the mixture to form, among other
compounds, chlorinated ethanes, hexachlorobenzene, and octachlorostyrene.
-------
69
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Chloromethane is a natural and ubiquitous constituent of the oceans and
atmosphere (both troposphere and stratosphere). It is a product of biomass
combustion, and is produced by wood rotting fungi. Chloromethane has been
detected in surface waters, drinking water, groundwater, and soil. It is
present in at least 18 out of 1177 hazardous waste sites on the National
Priorities List (NPL) in the United States (VIEW Database 1989). The
frequency of these sites in the United States can be seen in Figure 5-1.
Chloromethane is a constituent of municipal and industrial solid waste
leachate, and is a component of industrial waste discharges as well as being
present in the effluents of publicly owned treatment works (POTWs).
Chloromethane in air has an estimated half-life of =1.5 years and is the
dominant organochlorine species in the atmosphere. In water, chloromethane
is expected to volatilize rapidly from shallow bodies of water with a half-
life of 25 hours calculated for a pond and 18 days for a lake. It is not
expected to sorb to sediments or bioconcentrate. Chemical hydrolysis and
biodegradation are not expected to be significant processes. In soil,
chloromethane is expected to volatilize from the surface, but when present
in a landfill, will probably leach to groundwater. In groundwater,
hydrolysis may be the only removal mechanism available to chloromethane with
a half-life of =2 years. Air concentrations of chloromethane are generally
in the sub-ppb range, but urban locations appear to have elevated
concentrations when compared to background concentrations. Although
detailed information is lacking, water concentrations are likely to vary
considerably depending on the season and geographic location. Very little
information is available concerning chloromethane concentrations in soil.
The general population is not expected to be exposed to concentrations of
chloromethane much above 3 ppb in urban locations. In rural locations, the
exposure concentration will be =0.7-0.9 ppb. Occupational exposure to
chloromethane may result in exposures of up to "10 ppm based upon the
incomplete database; however, the database for occupational exposure is
dated (1980 or earlier) and not comprehensive enough to allow reliable
predictions of average or probable occupational exposure levels. The
population with the highest potential exposures probably would include those
people who work in chloromethane manufacturing or use industries.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
Most releases of chloromethane will be to air, since it is a gas at
ambient temperatures and manufacturing practices suggest that little will be
discharged by any other route. Chloromethane discharged to water will
volatilize rapidly, based on the Henry's law constant; however, the amount
volatilized will vary depending on a number of factors including the
temperature, turbulence, and depth of the receiving water. Chloromethane
will be released from both manufacturing and use (fugitive emissions) as
well as production resulting from human activities (e.g., grass and plastics
-------
-------
71
5. POTENTIAL FOR HUMAN EXPOSURE
burning, water chlorination) and natural production. All of the sources
amount to 7-18 billion pounds (3.2-8.2x10^ g) annually on a world-wide
basis and sources include the oceans, forest fires, wood burning, coal
burning, cigarette smoking, volcanos, burning plastic (Chopra 1972; Crutzen
et al. 1979; Edgerton et al. 1984, 1986; Edwards et al. 1982a, 1982b; Khalil
et al. 1985; Kleindienst et al. 1986; Palmer 1976; Rasmussen et al. 1980;
Singh et al. 1979, 1981a, 1981b, 1982, 1983; Tassios and Packham 1985; Yung
et al. 1975), fungal activity (Fabian 1986; Harper and Hamilton 1988; Harper
1985; Harper et al. 1988; Wuosmaa and Hager 1990), and some trees (Isidorov
et al. 1985). Chloromethane present in wastewaters also may be released to
air during aeration (Pincince 1988). By comparison, 1980 world-wide
production of chloromethane was =794 million pounds (3.6x10^ g) (Edwards
et al. 1982b), of which =-6% was released to the environment from production,
storage, transport, and use emissions (Edwards et al. 1982) or in other
words world-wide releases of 44 million pounds (2.0x10^ g) resulted from
manufacturing and use activities in 1980. United States production of
chlorome thane in 1987 was 373 million pounds (1.7x10^ g) , resulting in
estimated releases of 21 million pounds (9.5x10^ g). Thus, over 98% of
ambient air concentrations of chloromethane appear to come from releases
from natural sources rather than releases from manufacturing or use.
Chloromethane concentrations are elevated in the ambient air of cities in
the United States (Singh et al. 1982, 1983) (Section 5.4,1). The authors
suggested that this elevation may be the result of manufacturing and use
sources as well as combustion sources.
5.2.2 Water
Chloromethane is released to water from a number of sources including
industrial discharges and effluents from municipal waste treatment plants,
but insufficient information is available to quantify the releases. During
the manufacture of chloromethane, process water contacts the reaction
mixtures (see Section 4.1) (Ahlstrom and Steele 1979; Edwards et al. 1982a;
Key et al. 1980). This water is stripped during manufacture and treatment
to remove most of the dissolved chloromethane, then discharged (some
chloromethane manufacturing plants use the process water on-site as a source
of dilute hydrochloric acid rather than discharging it). Data regarding the
use and fate of process water in use applications were not found in the
available literature; however, spent process water is probably treated
(including aeration) prior to discharge. Nonetheless, chloromethane has
been found in wastewater effluents, possibly as a result of its formation
(Coleman et al. 1976; Gould et al. 1983) or incomplete removal during
industrial wastewater treatment (Snider and Manning 1982). Chloromethane
has been detected in the leachate of both municipal (Gould et al. 19B3;
Sabel and Clark 1984) and hazardous waste landfills (Brown and Donnelly
1988; Kosson et al. 1985; Venkataramani et al. 1984). It was reportedly
found in at least 18 of 1177 NPL hazardous waste sites (VIEW Database 1989)
in unspecified medium and in the water at 7 of 357 hazardous waste sites in
the Contract Laboratory Program Statistical Data Base at a concentration
range of 5.4-500 ppb (CLPSDB 1987).
-------
72
5. POTENTIAL FOR HUMAN EXPOSURE
5.2.3 Soil
Chloromethane is probably released to soil during the landfilling of
sludges and other wastes (e.g., still bottoms) generated from industrial
processes and municipal sewage treatment; however, no specific information
concerning chloromethane containing wastes was located in the literature
Chloromethane has been detected in the leachate of both municipal (Sabel and
Clark 1984) and hazardous waste landfills (Brown and Donnelly 1988- Kosson
et al. 1985; Venkataramani et al. 1984), indicating that disposal of these
materials apparently results in contamination of soila. The Contract.
Laboratory Program Statistical Data Base reports that chloromethane has been
detected in the soil at 8 of 357 hazardous waste sites at a concentra*i n f
5-500 ppb (CLPSDB 1987). ° °'
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
The physical properties of chloromethane that affect its transport and
partitioning in the environment are: water solubility, =*5000 ppm; log
octanol/water partition coefficient, 0.91; Henry's law constant, 8.82x10'^
atm-m-3 rnol; vapor pressure, 4310 mm Hg at 25C,C; log sediment sorption
coefficient =0.7; and log BCF =0.46 (see Table 3-2). Most chloromethane
discharged to the environment will be released to air where it will be
subjected to transport and diffusion into the stratosphere (Singh et al
1979, 1982, 1983). The relatively uniform concentration of chloromethane in
the northern and southern hemispheres (Singh et al. 1979, 1982, 1983)
indicates its widespread distribution and the importance of transport
processes in its distribution. The water solubility of chloromethane
indicates that small amounts may be removed from the atmosphere by
precipitation; however, no information confirming this was located in the
literature.
The dominant transport process from water will be volatilization The
results of two EXAMS model runs and the value of the- Honry's law constant
(calculated from the solubility and the vapor pressure) suggest that
volatilization will be significant in surface waters. EXAMS is an
environmental model that predicts the behavior of a chemical in surface
waters. Using the code test data developed by the Athens Environmental
Research Laboratory of the EPA for a pond, the half-life for volatilization
was calculated to be 25 hours. For a lake, the half-life was calculated to
be IB days. Input data included molecular weight, vapor pressure, Henry's
law constant, octanol/water partition coefficient, sediment sorption
coefficient, and water solubility. The volatilization rates predicted by
the EXAMS model appear to be in agreement with the observation of Lurker
et al. (1983) who reported chloromethane concentrations in wastewater and
in the air above the wastewater at the Memphis North Wastewater Treatment
Plant in Memphis, Tennessee. Based on the log octanol/water partition
-------
73
5. POTENTIAL FOR HUMAN EXPOSURE
coefficient arid the sorption coefficient and BCF calculated from it (see
Table 3-2), chloromethane is not expected to concentrate in sediments or in
biota.
In soil, the dominant transport mechanism for chloromethane that is
present near the surface probably will be volatilization (based on its
Henry's law constant, water solubility, and vapor pressure), but no
experimental information was located in the literature to confirm this.
The actual volatilization rate for a chemical in soil is influenced by a
number of factors including surface roughness, soil type, rainfall,
leaching, depth of incorporation, temperature, and ground cover (Jury et al.
1987). Since chloromethane is not expected to sorb to soils, any
chloromethane present in lower layers of the soil will be expected to leach
to lower horizons as well as diffuse to the surface and volatilize. The
presence of chloromethane in groundwater confirms the importance of leaching
as a transport route (Greenberg et al. 1982; Jury et al. 1987; Page 1981).
5.3.2 Transformation and Degradation
5.3.2.1 Air
The dominant tropospheric removal mechanism for chloromethane is
generally regarded to be hydrogen abstraction by hydroxyl radical (Dilling
1982; Fabian 1986; Gusten et al. 1984; Lovelock 1975; Rasmussen et al. 1980;
Robbins 1976; Singh et al. 1979). The hydroxyl radical reaction with
chloromethane has been experimentally determined in a number of studies
(Butler et al. 1978; Cox et al. 1976; Davis et al. 1976; Howard and Evenson
1976; Jeong and Kaufman 1980, 1982; Jeong et al. 1984; Paraskevopoulos
et al. 1981; Perry et al. 1976). The data of Howard and Evenson (1976)
[discharge flow-laser magnetic resonance], Perry et al. (1976) [flash
photolysis-resonance fluorescence], Davis et al. (1976) [flash photolysis-
resonance fluorescence], Paraskevopoulos et al. (1981) [flash photolysis-
resonance adsorption], and Jeong and Kaufman (1980, 1982) [discharge flow-
resonance fluorescence] are in agreement (Atkinson 1985; NASA 1981). The
recommended rate constants for the hydroxyl radical reaction are 4.36x10"^
and 4.3x10"^ cm^ molecule'^ sec"^, respectively, at 298 K (Atkinson 1985;
NASA 1981). The Arrhenius form recommended by Atkinson (1985) was:
k - (3.50?jJ-71) x 10"18T2exp[ (-585+59)/T] ,
where k is the rate constant in cw^ molecule"^- sec*^ and T is the Kelvin
temperature; that recommended by NASA (1981) based on the same data set
without the Paraskevopoulos et al. (1981) data was:
k - 3.49 x 10"18T2exp(-582/T)
over the range 247-483 K. The equations yield rate constants that vary <1%
over the valid temperature range of the equation.
-------
74
5. POTENTIAL FOR HUMAN EXPOSURE
The high quality of the early measurements of the rate constants for
the chloromethane reaction with hydroxyl radicals has allowe-d calculation of
tropospheric lifetimes by a number of researchers (Crutzen and Cidel 1983;
Dilling 1982; Fabian 1986; Khalil and Rasmussen 1981; Singh et al. 1979),
Using the most recent estimates of global hydroxyl radical concentrations
[(O.l-l)xlO6 molecules cm"3, Fabian (1986)], a half-life of =1.5 years has
been calculated, although estimates vary from 1-2 year.'; (Khalil and
Rasmussen 1981) to 2-3 years (Crutzen and Cidel 1983; Sin^h et al . 1979),
A complex atmospheric model, a hydroxyl radical concentration of (0.5-
3)xl06 molecules cm"^ in the troposphere, and UV absorption cross sections
[calculated by Robbins (1976)] for photochemical reactions have been used to
estimate the mixing height of chloromethane to be ~50 km. Another
atmospheric model (and probably high estimates of hydroxyl radical
concentrations) has been used to estimate the importance of the
stratospheric photochemical dissociation of chloromethane to chlorine and
methyl radicals (Robbins 1976). In this model, photochemical dissociation
will compete with hydroxyl radical reactions above 30 km, but photochemical
processes below 30 km will be insignificant compared to hydroxyl radical
reaction rates. The products of photochemical destruction have been
reported to be CHC10 and HC1 along with CO (Sanhueza and Heicklen 1975).
5.3.2.2 Water
In water, chloromethane can degrade either by hydrolysis or
biodegradation. Although few data are available on the biodegradation of
chloromethane in water, neither hydrolysis nor biodegradation in surface
appears to be rapid when compared with volatilization. Chloromethane
j-jycl^olysis proceeds via an Sj^2 mechanism (bimolecular) in which no
intermediate ions are formed and methanol and HC1 are the only products.
The kinetics of chloromethane hydrolysis have been measured by Heppolette
and Robertson (1959) and Laughton and Robertson (1956) by bubbling
chloromethane into water and following the reaction by measuring the
conductance of the water. The rate constant for hydrolysis of chloromethane
at 50°C was reported to be 7.6xl0"7 sec'1, which yields a half-life of 10.5
days. When extrapolated to 20°C and neutral conditions using the
thermodynamic constants calculated by Heppolette and Robertson (1959), a
rate constant of 1.04xl0*8 sec'1 and a half-life of =2 years are calculated.
This rate is expected to be unaffected by pH ranges normally encountered in
the environment. This hydrolysis half-life is too long to be of any
environmental significance in surface waters, especially considering the
rapid volatilization of chloromethane from surface water (Mabey and Mill
1978). In groundwater, however, hydrolysis may be the only degradation
mechanism available and, hence, may be a significant removal process under
these conditions. Biodegradation may also occur in groundwater, but rates
are highly variable.
Very little information is available concerning the biodegradation of
chloromethane in water. Both cell-free preparations of methane
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75
5. POTENTIAL FOR HUMAN EXPOSURE
monooxygenase, prepared from Methvlococcus capsulatus (Bath), and whole-cell
preparations oxidized chloromethane (Stirling and Dalton 1979).
Formaldehyde was the product of metabolism. In pure cultures of a
Hvohomicrobium sp., obtained by culturing with a chloromethane-minimal
medium, hydrolytic dehalogenation was not observed, but cell growth and
chloride formation occurred simultaneously (Hartmans et al. 1936). Strain
GJ10 of Xanthobacter autotronhicus could not use chloromethane in a growth
medium containing other carbon sources (Janssen et al. 1985). These reports
show that under pure culture conditions, some microbial strains can degrade
chloromethane. Since these conditions, however, do not occur in the
environment, these same species may not degrade chloromethane in the
environment. Biodegradation of chloromethane is not ruled out, however, by
the available information. Based on the reactions of other chloroalkanes,
chloromethane may degrade anaerobically via dechlorination to form methane
(Vogel et al. 1987). An estimated half-life of less than 11 days has been
predicted for anaerobic biodegradation of chloromethane in groundwater,
based upon laboratory data obtained under conditions favorable for anaerobic
biodegradation (Wood et al. 1985).
5.3.2.3 Soil
No information concerning soil transformation and degradation was
located in the literature. In lower soil horizons, hydrolysis may be a
significant process since no other removal mechanism has been identified.
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
Chloromethane has been the subject of numerous studies conducted to
determine the atmospheric chloride balance. In the development of a
database for ambient air monitoring, over 242 sites in the United States had
been monitored for chloromethane in a 5-year period (Eichler and Mackey
1986). Table 5-1 presents monitoring data for chloromethane for
urban/suburban and rural/remote air masses. The ranges and averages
presented in Table 5-1 cannot be compared directly since the measurements
taken at urban/suburban locations were all taken at ground level, while many
of the rural/remote analyses were made at higher altitudes. The volatile
organic carbon (VOC) database contained 706 data points (300 cities from 42
states) and further reported the following analysis of the data for
chloromethane (Shah and Singh 1988):
Average
740 ppt
Upper Quartile 721 ppt
Median
Lower Quartile
652 ppt
607 ppt
Since the average value, which is higher than the upper quartile (75% value)
may be skewed because of a few high values, the median may be a better
-------
TABLE 5-1. Detection of Chloraethane in Aira
Sampling # of Sample Analytical Concentration (ppt) %
Media Type/Location Dates Samples Type Method Range Mean Occurrence Reference
Urban/Suburban Air
Los Angeles, CA
4/9-21/79
NS
Cont i nuous
GC/ECD
1037-7761
3001
100
Singh
et
al. 1981
Phoenix, AZ
4/23/79-5/6/79
NS
Continuous
GC/ECD
1231-5685
2391
100
Singh
et
al. 1981
Oakland, CA
6/28/79-7/10/79
NS
Continuous
GC/ECD
483-5000
1066
100
Singh
et
al. 1981
Houston, TX
5/15-24/80
NS
Continuous
GC/ECD
531-2284
955
100
Singh
et
al. 1982a
St. Louis, NO
5/30/80-6/8/80
NS
Continuous
GC/ECD
531-1015
732
100
Singh
et
al. 1982a
Denver, CO
6/16-26/80
NS
Continuous
GC/ECD
519-1157
763
100
Singh
et
al. 1982a
Riverside, CA
7/2-12/80
NS
Continuous
GC/ECD
437-1593
703
100
Singh
et
al. 1982a
Staten Island, MY
3/27/80-4/5/80
NS
Continuous
GC/ECD
466-1280
701
100
Singh
et
al. 1982a
Pittsburgh, PA
4/8-16/80
NS
Continuous
GC/ECD
450-852
665
100
Singh
et
al. 1982a
Chicago, IL
4/21-30/80
NS
Cont i nuous
GC/ECD
575-1311
856
100
Singh
et
al. 1982a
Los Angeles, CA
4/29/76-5/4/76
NS
Grab
GC/ECD
708-944
834
100
Singh
et
al. 1977
Stanford Hills, CA
11/24-30/75
NS
Grab
GC/ECD
700-1700s
1022
100
Singh
et
al. 1977
Rural/Remote Air
Pullman, UA
12/74-2/75
t"
Grab
GC/MS
503-566
530
100
Grimsrud and Rasnussen 1975
Alaska
5/24-30/75
45c
Grab
GC/MS
505-970
NS
100
Robinson et al. 1977
Point Barrow, AK
5/7 & 13/82
51e
Grab
GC/ECD
634-660
647
100
Rasmussen arid Khali I 1983
Pacific Northwest
3/11/76
34c
Grab
Continuous
GC/ECD
428-611d
569
100
Cronn et al. 1977
Point Arina, CA
12/8/79-2/18/81
NS
GC/ECD
674-898
754
100
Singh et al. 1981b
Point Reyes, CA
12/2-12/75
NS
Grab
GC/ECD
680-1700a
1260
100
Singh et al. 1977
Yosemite, CA
5/12-17/75
NS
Grab
GC/ECD
654-999
713
100
S i righ et a 1. 1977
Palm Springs, CA
5/24-27/76
NS
Grab
GC/ECD
645-2128
1058
100
Singh et al. 1977
O
H
pi
z
H
~H
>
f
P!
O
po
2C
C
PI
X
~-e
Q
in
e
P3
PJ
a*
aMarine air may influence levels.
Samples were taken in downtown Pullman, Washington State University canpus, 1.2,
^Samples were taken at altitudes up to 14.5 km.
Tiead from a graphical presentation of the data.
^Samples Mere taken at altitudes ip to 4.3 km.
4-6 samples were taken in a 24-hour period on each of 17 sampling days.
1.8, 2.4, 3.0, and 3.6 km in altitude.
GC/ECD = gas chromBtography/electron capture detector; GC/MS = gas chromatography/mass spectroscopy; NO = not detected; NS = not specified.
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77
5. POTENTIAL FOR HUMAN EXPOSURE
representation of the database. The data by types of air mass were also
reported so that the influence of urban centers could be estimated (Shah and
Singh 1988):
Air Mass Median Concentration Data Points
Remote 713 ppt 5
Rural 923 ppt 2
Suburban 641 ppt 599
Urban 810 ppt 100
From these data and the data presented in Table 5-1, it appears that source
contributions from industrial processes do not significantly impact the
ambient concentration of chloromethane, although some elevation may occur.
There are many fewer data points, however, for rural/remote data than for
urban/suburban data so that a direct comparison is difficult. The ambient
air levels of chloromethane in cities in the United States are slightly
elevated above background levels, probably due to higher numbers of
combustion sources (Singh et al. 1982, 1983). Average urban levels
reported by these authors were 660-960 ppt, while background levels were
600-700 ppt.
5.4.2 Water
Chloromethane has been detected in surface water, groundwater,
drinking water, municipal and hazardous waste landfill leachate, and
industrial effluents (Table 5-2). When detected, concentrations appear to
be in the ppb-ppt range, possibly due to the rapid volatilization of
chloromethane. Chloromethane apparently is formed during the chlorination
of drinking water. It was 1 of 13 compounds found in the drinking water of
all five cities (Philadelphia, PA; Miami, FL; Seattle, WA; Ottumwa, IA;
Cincinnati, OH) studied as part of the EPA National Organics Reconnaissance
Survey (NORS) (Coleman et al. 1976). Most of the compounds detected were
reported to be highly specific to the locality and raw water supply. Those
compounds found in all supplies studied may be widespread.
No specific information concerning sources of chloromethane in fresh
surface water was located in the literature. Chloromethane concentrations
in surface water may be the result of rain out from the atmosphere as well
as the result of human activity (e.g., industrial effluents, chlorinated
secondary effluent from POTWs). Industrial effluents may be a significant
source. Seven positive detections of chloromethane in industrial effluents
out of over 4000 samples from 46 industrial categories and subcategories
were reported in the EPA database (Bursey and Pellizzari 1982).
Concentrations ranged from 6-4194 /Jg/L in these effluents. Thirty-four
species of fungi can produce chloromethane biosynthetically (Harper et al.
1988). The presence of these fungi near lakes and streams may be a source
of chloromethane. The significance of this source to surface water,
however, cannot be estimated.
-------
TABLE 5-2. Detection of Chlortmethane in Water and Scdiaents
Media Type/Location Sanpling # of Sample Analytical Concentration (ppb) %
Dates Samples Type Method Rnnge Mean Occurrence Reference
Surface Water
Delaware River and Raritan Canal NS
Lake Ontario 7/82-5/83
Lake Ontario NS
Surface Uaters in New Jersey NS
Groundwater
New Jersey NS
Minnesota0 NS
Minnesota NS
Massachusetts NS
Drinking Water
Miami, FL NS
Seattle, UA NS
Ottunwa, IA NS
Philadelphia, PA NS
Cincinnati, OH NS
Landf i11 Leachate
Minnesota'* NS
Wisconsin NS
Love Canal, NYe NS
Kin-Buc Landfill, NJe NS
Hazardous Waste Sites NS
11 National Priority List Sites NS
NS
10a
NS
605
1058
13
7
NS
NS
NS
NS
NS
NS
6
5
NS
NS
NS
NS
Grab
Grab
NS
NS
NS
NS
NS
NS
Grab
Grab
Grab
Grab
Grab
NS
NS
NS
NS
US
NS
NS
GC/MS
NS
NS
NS
NS
NS
NS
GC/MS
GC/MS
GC/MS
GC/MS
GC/MS
NS
NS
NS
NS
GC/MS
NS
ND
<1
Detected
<0.1-222
<0.1-6
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
170
180
3.1
5.4-500
Detected
NS
<1
NS
NS
NS
NS
NS
44
NS
NS
NS
NS
NS
NS
170
180
3.1
115
NS
0
0
NS
0.3
69
29
NS
NS
NS
NS
NS
NS
66
20
NS
NS
NS
NS
Granstrom et al.1984
Otson 1987
Great Lakes Water
Quality Board 1983
Page 1981
Page 1981;
Greenberg et al. 1982
Sabel and Clark 1984
Sabel and Clark 1984
Burmaster 1982
Coleman et
Coleman et
Coleman et
Coleman et
Coleman et
ICopf ler et al.
1976
1976
1976
1976
1976
1977
Sabel and Clark 1984
Sabel and Clark 1984
Shuckrow et al. 1982
Shuckrow et al. 1982
CLPSBD 1987
NPLTDB 1989
~n
O
H
m
z
H
t—i
>
t-
T!
0
73
1
G
£
•n
o
G
73
m
-j
oo
Urban Runoff
15 United States cities
NS
86
Grab
GC/MS
ND
ND
Cole et al. 1984
-------
TABLE 5-H (Continued)
Media Type/Location
Sampling
Dates
it of
Samples
Sample
Type
Analytical
Method
Concentration (ppb) X
Range Mean Occurrence
Reference
Effluents
Petroletm refinery effluents*
Petroleun refinery effluents9
NS
NS
17
17
Grab
Grab
GC/MS
GC/MS
<100->100 NS
<10 MS
NS Snider and Manning
1982
NS Snider and Manning
1982
®10 locations on Lake Ontario.
408 wells.
^Groundwater under municipal solid waste landfills.
cWrticipal solid waste leachate.
^Industrial landfill.
Biotreatment effluents.
9Final effluent.
GC/ECD = gas chrometography/electron capture detection; GC/MS = gas chromatography/mass spectroscopy; NO = not detected; NS = not specified.
o
H
m
H
M
>
f
o
TO
vo
s
*0
O
m
C
50
rn
-------
80
5. POTENTIAL FOR HUMAN EXPOSURE
The presence of chloromethane in groundwater may also result from both
natural and anthropogenic sources. Since chloromethane has been detected in
the groundwater near municipal waste sites containing the chemical (Sabel
and Clark 1984) , waste deposits of chloromethane on land may lead to
groundwater contamination. Chloromethane appears to be a constituent of
both municipal and industrial waste landfills. In these landfills,
volatilization may be hindered so that leaching to groundwater can become an
important transport pathway. Additionally, chloromethane may be the product
of anaerobic metabolism of higher chlorinated methanes also present in the
soil (Vogel et al. 1987).
5.4.3 Soil
The only information located in the literature concerning the presence
of chloromethane in soil was the natural formation of chloromethane by a
number of fungi (Harper et al. 1988) and its presence in both landfill
leachate and groundwater. Thus, chloromethane is present in soils, but no
concentrations can be inferred from these reports. The Contract Laboratory
Program Statistical Data Base reported that the soil at hazardous waste
sites contained chloromethane at mean concentrations ranging from 5-500 ppb
(CLPSDB 1987).
b.h.U Other Media
As presented in Section 5.2.1, chloromethane is present in wood
smoke, cigarette smoke, coal burning, volcanoes, and burning plastic
(Chopra 1972; Crutzen et al. 1979; Edgerton et al. 1984, 1986; Fabian 1986"
Kadaba et al. 1978; Khalil et al. 1985; Kleindienst et al. 1986; 1983;
Palmer 1976; Rasmussen et al. 1980' Singh et al. 1982; Tassios and Packbarn
1985). It was suggested that 1 cm3 of chloromethane gas (2.2 mg) was
produced for each gram of cellulose burned (glowing combustion) (Palmer
1976). Concentrations of chloromethane in smoke from combustion processes
however, are highly variable and depend on both the fuel (i.e., the amount1
of inorganic chlorine present in the fuel) and temperature of the burn.
Thus, quantification of chloromethane in these media will be representative
of the specific source and the exact conditions of the burn rather than
general emission levels. Chloromethane has not been detected in auto
exhaust (detection limit of 1 ppm) (Hasanen et al. 1979).
Chloromethane was present in 2 of 8 samples of mothers' milk from
Bayonne and Jersey City, NJ; Bridgeville, PA; and Baton Rouge, LA
(Pellizzari et al. 1982). No concentrations were reported and no
information was given concerning the source of the chloromethane in the
milk. Chloromethane was present in the expired air of all three tested
groups of 62 non-smoking adults, including a control, prediabetic, and
diabetic group (Krotoszynski and O'Neill 1982). Since chloromethane is a
ubiquitous constituent of air, it is reasonable that it would be found in
the expired air of virtually all humans. The chlorine used to chlorinate
-------
81
5. POTENTIAL FOR HUMAN EXPOSURE
drinking water did not contain chloromethane, but other higher
chloromethanes were present (Otson et al. 1986). Sources for the chlorine
included both mercury and diaphragm cells and contamination by higher
chloromethanes was uniform across several manufacturers.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Chloromethane is a ubiquitous constituent of air and probably drinking
water. As such, the general population will be exposed to background levels
at all times, while those living in urban centers will be exposed to
slightly higher levels.
According to one report, persons living in Los Angeles, CA, Phoenix,
AZ, and Oakland, CA, would have daily intakes of =120, 94, and 52 ^g/day,
respectively (Singh et al. 1981a). These intakes are based on a total
respirable air volume of 20 m^/day at 25°C and 1 atm pressure. Using the
data of Shah and Singh (1988) for remote, rural, suburban, and urban air
masses, daily intakes are estimated to be =31, 40, 28, and 35 /jg/day,
respectively. The intakes for rural and remote air masses are based on very
small sample sizes and may be inaccurate. Dermal exposure and exposures
from drinking water containing chloromethane are more difficult to estimate
from the available information. Drinking water concentrations are not well
described in the literature and may vary considerably both seasonally and
geographically.
Historically (30 years ago or longer), large exposures have been
associated with leaking refrigerators that used chloromethane as a
refrigerant. While refrigeration grade chloromethane is apparently still
available (Ahlstrom and Steele 1979), it is not known whether it is
currently used in refrigeration equipment. Without this information,
potential exposures cannot be estimated.
A large database of documented occupational exposure levels is
available for chloromethane manufacturing; however, the information is
dated (1980 and earlier) and may not represent current conditions. The
available data are summarized in Table 5-3. In general, the occupational
exposure data indicate that the majority of exposure concentrations are
below 50 ppm, but excursions as high as 300 ppm can occur. Most exposure
concentrations reported in the literature have occurred in the manufacturing
industry, with very few reported in use industries. Based on the major use
patterns (see Section 4.3), exposures in use industries will be similar to
those in manufacturing industries since similar storage and transfer
equipment is used and these are the major sources of leakage (Edwards et al.
1982a,b). NIOSH (1984) reported 30 industrial categories (SIC codes) where
exposures to chloromethane may occur. Table 5-4 presents these categories
along with the number of workers potentially exposed in each category.
These data are based on 1972-1974 surveys. The more recent National
Occupational Exposure Survey (NOES) reports much lower exposure incidents
than the 40,538 estimated by the 1972-1974 survey (NIOSH 1984). According
-------
TABLE 5-3. OccLfntianal Monitoring of Chi or one thane
Concentration (pcm) Number of X
Company Year Sampled Sample Type Range Mean Sanples Positive Reference
Conoco Chemicals
Conoco Chemicals
1978
1978
Area
Personal
0.8-5.9
<0.2-7.5
NS
1.1
16
16
94
81
Cohen 1979
Cohen 1979
DUPont Company
DUPont Conpany
1977
1977
Area
Personal
<1.0-75.1
<0.16-12.A
NS
NS
15
22
93
86
Koketsu 1979
Koketsu 1979
Diamond Shamrock Chemical
Diamond Shamrock Chemical
1975
1975
Area
Personal
0.14-101.7
0.04-34.7
NS
NS
9
53
100
100
Egan et al. 1976
Egan et al. 1976
Union Carbide
1976-1980
Personal
0.1-15
NS
NS
100
Gorman and Froneburg 1981
Foxboro Company
1976
Area
<0.001
NS
2
0
Ruhe 1976
UCARb
1978
Area
0.02-0.08
NS
5
100
BeIanger 1980
Cities Service Coapany
Cities Service Conpany
1980
1980
Area
Personal
52-313
1.45-166
NS
NS
2
11
100
100
Harkel and Froneburg 1983
Markel and Froneburg 1983
Dow Chemical Co.
Dow Chemical Co.
1979
1979
Area
Personal
1.47-19.8
0.35-39.6
NS
NS
16
50
100
100
Crandall et al. 1980
Crandall et al. 1980
Dow Chemical Co.
1975
Area
1 -120c
NS
75
100
Repko et al. 1977
Survey of 4 Plants
1979
Area and
Personal
<0.16-62.5
NS
82
82
Cohen 1980
^Geometric mean of the positive sanples.
University Corporation for Atmospheric Research, Mauna Loa, Hawaii.
cRange of average concentrations taken at various locations in the plant, concentrations measured with conductivity and infrared equipment.
T3
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M
Z
H
>
r1
•n
o
po
5C
C
m
X
T3
O
in
e
rn
00
ro
NS = not specified.
-------
83
5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-4. Numbers of Workers Potentially Exposed to Chloromethane
and Standard Industrial Classification (SIC)
Number of
Workers Potentially
SIC Code SIC Description Exposed
07
Agricultural services and hunting
647
13
Oil and gas extraction
24
15
General building contractors
1301
16
Heavy construction contractors
405
17
Special trade contractors
1143
20
Food and kindred products
2720
21
Tobacco manufacturers
90
22
Textile mill products
8
24
Lumber and wood products
112
27
Printing and publishing
212
28
Chemicals and allied products
980
29
Petroleum and coal products
16
31
Leather and leather products
85
33
Primary metal industries
1223
34
Fabricated metal products
238
35
Machinery, except electrical
1292
36
Electrical equipment and supplies
451
37
Transportation equipment
1660
38
Instruments and related products
453
39
Miscellaneous manufacturing industries
418
41
Local and interurban passenger transit
73
44
Water transportation
93
45
Transportation by air
1115
48
Communication
424
50
Wholesale trade
486
53
Retail general merchandise
402
55
Automotive dealers and service stations
14,734
73
Miscellaneous business services
8960
79
Amusement and recreation services
342
80
Medical and other health services
431
Total
40,538
Source: NIOSH 1984
-------
84
5. POTENTIAL FOR HUMAN EXPOSURE
to NOES, 8853 employees are exposed to chloromethane. Of these, 572 are
female. Fifty-six percent of the total exposures were to the actual
chemical, while 44% were to trade name products. Ninety-nine percent of the
exposures to female employees were to the actual chemical and 1% to trade
name products (NIOSH 1988).
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
All humans are probably exposed to low concentrations of chloromethane
because chloromethane is ubiquitous in the environment. Those with
potentially high exposures appear to be workers employed in the
manufacturing and use (by analogy) industries. Concentrations in these
industries may reach 100,000 times background concentrations, but can go up
to 1,000,000 times background concentrations. People with old refrigerators
in which chloromethane is used as a refrigerant are another population with
potentially high exposure. These refrigerators can leak and result in very
high air concentrations of chloromethane. This latter population should be
diminishing, since the number of refrigerators using chloromethane should be
decreasing.
The concentrations of chloromethane reported at hazardous waste sites
present in the Contract Laboratory Program Statistical Data Base are low
(CLPSDB 1987), and, if indicative of the concentrations at NPL sites, they
probably do not represent a source of potentially high exposures to those
populations surrounding the sites.
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of chloromethane is available. Where adequate information is not
available, ATSDR, in conjunction with the NTP, is required to assure the
initiation of a program of research designed to determine the health effects
(and techniques for developing methods to determine such health effects) of
chloromethane.
The following categories of possible data needs have been identified by
a joint team of scientists from ATSDR, NTP, and EPA. They are defined as
substance - specific informational needs that, if met would reduce or
eliminate the uncertainties of human health assessment. In the future, the
identified data needs will be evaluated and prioritized, and a
substance-specific research agenda will be proposed.
5.7.1 Identification of Data Needs
Physical and Chemical Properties. Data regarding physical and chemical
properties are essential for estimating the partitioning of a chemical in
the environment. Host of the necessary data on physical and chemical
-------
85
5. POTENTIAL FOR HUMAN EXPOSURE
properties are available for chloromethane, and many of these have
experimental descriptions accompanying them so that accuracy can be
evaluated. A property of chloromethane that has not been measured is the
odor threshold. The odor of chloromethane, however, is probably not a
sufficient warning property for humans because severe neurological effects
and death have occurred in people who were unaware of being exposed even to
high concentrations in confined spaces. The known physical and chemical
properties data form the basis of many of the input requirements for
environmental models that predict the behavior of a chemical under specific
conditions including hazardous waste landfills.
Production, Use, Release, and Disposal. Production methods for
chloromethane are well described in the literature (including the patent
literature) and there does not appear to be a need for further information.
Uses of chloromethane have been recently documented, although a detailed
description of all uses is not available. This information is useful for
estimating the potential for environmental releases from manufacturing and
use industries as well as the potential environmental burden; however, it is
difficult to obtain this information in the detail desired since generally
it is considered to be confidential business information for those
industries that manufacture chloromethane. Release information, which can
be used to estimate environmental burdens and potentially exposed
populations, is also not obtained easily.
According to the Emergency Planning and Community Right-to-Know Act of
1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries are
required to submit release information to the EPA. The Toxics Release
Inventory (TRI), which contains release information for 1987, became
available in May of 1989. This database will be updated yearly and should
provide a more reliable estimate of industrial production and emission.
Environmental Fate. The fate of chloromethane in air is well described
because extensive air photolysis and photooxidation studies are available
that characterize these processes. In water, biodegradation studies in
surface and groundwaters are lacking. Hydrolysis data are available, but
reliable data have not been obtained at environmentally relevant
temperatures. These kinds of studies are important because they would
provide information about fundamental removal mechanisms for chloromethane
in the environment and might aid in understanding the behavior of
chloromethane at hazardous waste sites. Data regarding biodegradation in
water may be difficult to obtain and may be irrelevant due to possible rapid
volatilization from the aqueous media used in the experiments. In addition,
transport mechanisms, particularly volatilization of chloromethane from soil
surfaces and leaching to lower soil horizons, are not well described. These
processes, however, are complex and unless theory for these improves, it is
likely that any data for chloromethane would apply only to the specific
sites where measurements are taken. The vapor pressure of chloromethane and
its presence in groundwater suggest that these processes are important,
-------
86
5. POTENTIAL FOR HUMAN EXPOSURE
particularly at hazardous waste sites, and may account for some of the
losses of chloromethane from the site.
Bioavailability from Environmental Media. Experimental inhalation
studies in animals and humans indicate that chloromethane is bioavailable
from the atmosphere. Although chloromethane in water or soil is likely to
end up in the air because of its volatility, studies using the oral and
dermal routes of exposure would help to determine the bioavailability of
chloromethane from water, soil, and other environmental media.
Food Chain Bioaccumulation. The log Kow for chloromethane is 0.91 and
the bioconcentration factor calculated from this value is 2.98 (PCGEMS)
indicating that chloromethane will not concentrate significantly in aquatic
organisms. No information was available concerning the bioaccumulation of
chloromethane at other trophic levels. Information concerning the
accumulation of chloromethane in several trophic levels would be useful in
estimating human dietary intake of chloromethane; however, based on the
calculated BCF, little intake is expected.
Exposure Levels in Environmental Media. Extensive environmental
monitoring data are available for air, while only some data are available
for drinking water, surface water and groundwater. The air monitoring data
describe the concentrations that populations are exposed to through
inhalation of ambient air. The data for water are not sufficient to
accurately characterize the concentrations of chloromethane present in
drinking water, surface water, and groundwater. Virtually no data are
available for soils. These data would be helpful in determining the ambient
concentrations of chloromethane so that exposure of the general population
as well as of terrestrial and aquatic organisms could be estimated.
Exposure Levels in Humans. The database for exposure levels in humans
is limited to determinations of chloromethane in breast milk. A more
complete database would be helpful in determining the current exposure
levels and thereby estimating the average daily dose associated with various
scenarios (e.g., living near a hazardous waste site). An environmental
media monitoring program may provide the necessary information for
estimating environmental exposures, while workplace monitoring at use sites,
using personal dosimeters and remote sensing devices, would probably provide
useful workplace information.
Exposure Registries. An exposure registry is not available. The
development of a registry of exposures would provide a useful reference
tool in assessing exposure levels and frequency. In addition, a registry
would allow assessment of variations in exposure resulting from such
variables as geography, season, regulatory actions, presence of hazardous
waste landfills, or manufacturing and use facilities. These assessments, in
-------
87
5. POTENTIAL FOR HUMAN EXPOSURE
turn, would provide a better understanding of the need for various types of
research or data acquisition.
5.7.2 On-Going Studies
No on-going studies were located in the literature.
-------
89
6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods that
are available for detecting and/or measuring and monitoring chloromethane in
environmental media and in biological samples. The intent is not to provide
an exhaustive list of analytical methods that could be used to detect and
quantify chloromethane. Rather, the intention is to identify well-
established methods that are used as the standard methods of analysis. Many
of the analytical methods used to detect chloromethane in environmental
samples are the methods approved by federal agencies such as EPA and the
National Institute for Occupational Safety and Health (NIOSH). Other
methods presented in this chapter are those that are approved by a trade
association such as the Association of Official Analytical Chemists (AOAC)
and the American Public Health Association (APHA). Additionally, analytical
methods are included that refine previously used methods to obtain lower
detection limits, and/or to improve accuracy and precision.
6.1 BIOLOGICAL MATERIALS
Methods used to analyze biological samples for chloromethane are
summarized in Table 6-1. S-Methylcysteine may be a metabolite of
chloromethane in some humans (Nolan et al. 1985; Van Doom et al. 1980).
S-methylcysteine can be analyzed by diluting urine with water and treating
the resulting solution with a buffer and a phthaldialdehyde solution to
derivatize the S-methylcysteine (De Kok and Antheunius 1981: van Doom
et al. 1980). Analysis is performed on a reversed phase high performance
liquid chromatography column using methanol sodium hydrogen phosphate
gradient elution and a fluorescence detector. The reported detection limit
is 1 mg/L.
Breast milk can be analyzed for chloromethane by expressing a 60 mL
sample into a wide mouth bottle followed by freezing (Pellizgari et al.
1982). Analysis was performed by warming the sample then purging with
helium flowing through a Tenax GC column to sorb the chloromethane and other
volatiles. The Tenax was thermally desorbed onto a GC column and analyzed
by mass spectrometry. No recoveries or accuracy information was reported.
6.2 ENVIRONMENTAL SAMPLES
In air, chloromethane can be analyzed by NIOSH Method 1001 (NIOSH
1987), which is suitable for air concentrations to *»1 ppm. The method
involves drawing a 0.4-3 L sample through a coconut charcoal tube followed
by methylene chloride desorption and analysis by GC-FID. The method has a
working range of 66-670 rng/rn^ for a 1.5 L sample and a detection limit of
0.01 mg/tube. Table 6-1 presents accuracy information for this method. For
lower concentrations, the analytical methods necessary are more specialized.
The use of coconut charcoal tubes preceded by an MgCl04 drying tube has been
described to measure chloromethane in air (Lindskog et al. 1988). From
1-2 L of air aredrawn through the tube then placed in dry ice. The
chloromethane is thermally desorbed onto a liquid nitrogen cooled capillary
column then flushed onto the GC column by warming the capillary column.
-------
TABLE 6-1. Analytical Methods for Determining Chlorwthane in Biological fnd Enrvirommtal Saftlo
Sample Matrix
Sanple Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Urine
Rat blood
Breast mi Ik
Expired air
Air
Water
Soi(/solid waste
Dilution with water followed
by derivatiiation with phthaldi-
aldehyde (method for S-methyl
cysteine)
Warming sample and immediate
analysis of headspace air
Warming sample then purging to
Tenax and thermal desorption
to GC colunn.
Expired air collected in a 10 l
gas sanple bag and analyzed with
added ethyl chloride or vinyl
chloride as an internal standard
Charcoal tii>e collection and
CHjClj desorption.
Charcoal tiise collection,
thermal desorption.
Purging sanple with inert gas
and trapping the chloromethane
on a colunn followed by desorp-
tion onto GC colum.
Same as above.
Purging sample with inert gas
and trapping the chloromethane
on a colunn followed by desorp-
tion onto GC colunn.
HPLC/FD
GC/ECD
GC/MS
GC/ECD
GC/FID
GC/FID
GCb
GC/MS
GCb
GC/MS
1 mg/l
MS
NS
NS
66 mg/m'
NS
10 |zg/l
7.4 ug/kg
f
NS
MS
NS
NS
95
NS
0.08 (ig/L 91.4
99±24e
MS
De Kok and Antheinius
1981
Landry et al. 1983a
Pellizzari et al. 1982
Nolan et al. 1985
NIOSH 1987
Lindskog et al. 1988
EPA 1982
EPA 1982; EPA 1988a
EPA
EPA 1988a
"Average percent recovery.
^ectrolytic conductivity or microcoulometric detector.
^laboratory water and effluents.
^Quantitation limit for Contract Laboratory Program.
^laboratory water.
Recoveries from solid sanp(es will vary depending on the particular matrix.
CCD « Electron capture detector; fD * fluorescence detection; FID a flame ionization detector; GC/MS = gas chromatography/mass
spectroscopy; HPLC s high performance liquid chromatography; US = not specified.
>
n
o
>
r
s
m
¦-5
•x
o
o
C/1
o
-------
91
6. ANALYTICAL METHODS
Analysis is performed by GC with flame ionization detection. For very low
concentrations, extreme care must be taken to ensure no contamination is
introduced into the sampling and analysis method.
Chloromethane can be analyzed in municipal and industrial wastewater by
EPA Test Method 601 - Purgeable Halocarbons or EPA Test Method 624 -
Purgeables (EPA 1982). The method is adequate for measuring chloromethane
in wastewaters; however, care must be taken in sampling the site since
chloromethane is volatile and some of the chemical may be lost during the
sampling process. Method 601 involves purging the sample with an inert gas
and passing the gas through a trap containing 2,6-diphenylene oxide polymer
(Tenax GC), silica gel, and coconut charcoal to adsorb the purged
chloromethane and other halocarbons. After the purging is complete, the
trap is heated to desorb the chloromethane from the trap. The desorbed
chloromethane is analyzed by gas chromatography (GC) using an electrolytic
conductivity or microcoulometric detector. Method 624 is similar to Method
601, but the trap material is made of 3% methyl silicone (OV-1) on packing
material, 2,6-diphenylene oxide polymer (Tenax GC), and silica gel; analysis
is made by gas chromatography/ mass spectroscopy (GC/MS). Over purging the
sample may result in loss of some chloromethane. The average recovery from
reagent water and effluents was 91.4±13.4% for Method 601 and 99+24X from
wastewater for method 624. The Contract Laboratory Program analytical
method involves screening the sample for component concentrations by rapidly
transferring the room temperature sample to a volumetric flask, adding
hexadecane and extracting the volatiles, including chloromethane, for
1 minute then qualitatively analyzing the sample by gas chromatography with
flame ionization detection (EPA 1988a). The quantitative analysis method
for the sample is by GC/MS and is essentially identical to EPA method 624
(EPA 1988a). Table 6-1 presents accuracy and detection limit data for the
methods.
In soil and solid waste, EPA Method 5030 for soil and solid waste
analysis of chloromethane (EPA 1986b) and the Contract Laboratory Procedure
for soil analysis (EPA 1988a] involve the direct purge and trap method for
low level samples or methanolic extraction for high level samples, based on
a hexadecane extraction as described above. For low level samples, the
soil/solid waste is placed in a purge impinger, mixed with water, purged
with an inert gas, and trapped on a Texax GC and silica gel (EPA 1988a) or
OV-1, Tenax GC, and silica gel column (EPA 1986b). The trap column is
heated and purged to desorb the chloromethane and other volatiles onto the
GC column. For medium level samples, the soil/solid waste is mixed with
methanol and shaken. An aliquot of the methanol is removed, diluted with
water and purged as described above for water samples. Over purging the
sample may result in loss of some chloromethane. Analysis is performed by
EPA Method 8000 (Gas Chromatography) and 8010 (Halogenated Volatile
Organics) or Method 8240 (Gas Chromatography/Mass Spectrometry for Volatile
Organics) (EPA 1986b), which is essentially identical to the Contract
Laboratory Program method. Method 8010 uses a GC with an electrolytic
-------
92
6. ANALYTICAL METHODS
conductivity detector. Table 6-1 presents the detection limit for this
method.
6.3 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of chloromethane is available. Where adequate information is not
available ATSDR, in conjunction with the NTP, is required to assure the
initiation of a program of research designed to determine the health effects
(and techniques for developing methods to determine such health effects) of
chloromethane.
The following categories of possible data needs have been identified by
a ioint team of scientists from ATSDR, NTP, and EPA. They are defined as
substance-specific informational needs that, if met would reduce or
eliminate the uncertainties of human health assessment. In the future, the
identified data needs will be evaluated and prioritized, and a
substance-specific research agenda will be proposed.
g.3.1 Identification of Data Needs
Methods for Biomarkers of Exposure and Effect. No biomarker that can
be associated quantitatively with exposure to chloromethane has been
identified (see Section 2.5). Methods are available for the analysis of
chloromethane in blood, expired air, and breast milk. In addition, a method
exists for analysis of the metabolite S-methylcysteme in urine.
Quantitative relationships have not been established between exposure and
measurement of chloromethane or 2-methylcysteine in these biological media.
The observed variability of metabolism (see discussion of metabolism of
chloromethane in Section 2.3.3) suggests that a correlation of chloromethane
1 Is in tissues with levels of chloromethane exposure is not likely to be
^unrt It mav be possible to use levels of yet unidentified metabolites in
blood or urTne as biomarkers of exposure. If reliable biomarkers of
pynosure were available, it would allow both investigators and reviewers to
Assess the accuracy and uncertainty of the methods used in toxicological
studies Furthermore, the ready availability of tested analytical methods
for the biomarkers, including ample preservation, would permit a
standardized approach to the analysis of biological materials tp assist in
measuring human exposure and monitoring effects in humans.
No biomarker that can be associated quantitatively with effect has been
irfpntified (see Section 2.5). Thus, there are no analytical methods for the
determination of biomarkers of effect for chloromethane.
Methods for Determining Parent Compound and Degradation Products in
, lWia Methods appear to be available for the analysis of
chTorome thane in .11 environmental media including groundwater, surface
-------
93
6. ANALYTICAL METHODS
water, waste water, soil, solid waste, and workplace and ambient air.
Chloromethane degrades to a number of products in the environment including
methanol and formaldehyde, both of which are natural products. While
analytical methods exist for these compounds, they cannot be used as
indicators of chloromethane degradation since methanol and formaldehyde have
large natural sources.
6.3.2 On-going Studies
No on-going studies were located regarding analytical method
development for chloromethane.
-------
95
7. REGULATIONS AND ADVISORIES
The International Agency for Research on Cancer (IARC) and National and
state regulations and guidelines pertinent to human exposure to
chloromethane are summarized in Table 7-1.
Chloromethane is regulated by the Clean Water Effluent Guidelines for
the following industrial point sources: electroplating, organic chemicals,
steam electric, asbestos, timber products processing, metal finishing,
paving and roofing, paint formulating, ink formulating, gum and wood, carbon
black (EPA 1988b) .
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96
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Chloroaethane
Agency
Description
Value
Reference
I ARC
Regulations:
a. Air:
OSHA
Carcinogenic classification
national
TWA
STEL
Group 3
50 ppm (8 hr)
100 ppm
1 ARC 1987
29 CFR 1910.1000
OSHA 1989
b. Nonspecific media:
EPA OERR
Reportable quantity (statutory)
1 lb
40 CFR 302.4
EPA 1987a, 1988c
Guidelines:
a: Air:
ACGIH
NIOSH
TLV TUA
STEL
TUA
Cei ling
Maxinun peak
50 ppm ACGIH 1988
100 ppm
100 ppm NIOSH 1985
200 ppm
300 ppm (5 min in 3 hr)
b. Other:
EPA
EPA
Carcinogenic classification
q^* for inhalation exposure (proposed)
q-j* for oral exposure (proposed)
State
Group C"
6.32x10 (mg/kg/d) ,
1.26x10 (mg/kg/d)'1
EPA 1987b
Regulat ions:
a. Air:
Connecticut
Kansas
Kentucky
Michigan
North Dakota
Nevada
New York
Pennsylvania
Virginia
b. Water
Arizona
Kansas
Accceptable artoient air concentrations
Drinking water
2100 ng/it? (8 hr)
74.12 jtg/m (annual)
52.5 mg/nr (8 hr)
1.6 ns/nr* (annual)
1.05 mg/nr (8 hr)
2.05 mg/nr (1 hr)
2.5 mgim5 (8 hr)
2100 Mg/"C (1 yr)
2520 (tg/nc (1 yr)
1750 ng/(ir (24 hr)
0.50 ng/l
0.19 U0/i
NATICH 1988
NAT1CH 1988
State of Kentucky
1986
NATICH 1988
NATICH 1988
NATICH 1988
NATICH 1988
NATICH 1988
NATICH 1988
NATICH 1988
NATICH 1988
*The agent is not classifiable as to its carcinogenicity to hunans.
"Possible human carcinogen.
ACGIH • American Confererwe of Governmental Industrial Hygienists; EPA « Envirocmental e
IMC * International Agency for Research on Cancer; NIOSK * Nat ionat .nstitute ToTo'L::?!!!?^/^;
Health; OERR « Office of Emergency and Remedial Response; OSHA . Occixwtional **'«y and
Adninistrat ion; STEL « Short-Term Exposure Limit; TLV « Threshold Limit Value- TUA ¦ Tim. u!I!!V _.,nd Me*lth
< ¦«" "wwetghted Average.
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9. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or less,
as specified in the toxicological profiles.
Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical
adsorbed per unit weight of organic carbon in the soil or sediment to the
concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or
soil (i.e., the solid phase) divided by the amount of chemical in the
solution phase, which is in equilibrium with the solid phase, at a fixed
solid/solution ratio. It is generally expressed in micrograms of chemical
sorbed per gram of soil or sediment.
Bioconcentration Factor (BCF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete time
period of exposure divided by the concentration in the surrounding water at
the same time or during the same period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or
group of studies, that produces significant increases in the incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen - - A chemical capable of inducing cancer.
Ceiling Value -- A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally to
the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the insult
occurred. The terms, as used here, include malformations and variations,
altered growth, and in utero death.
EPA Health Advisory --An estimate of acceptable drinking water levels for a
chemical substance based on health effects information. A health advisory
is not a legally enforceable federal standard, but serves as technical
guidance to assist federal, state, and local officials.
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9. GLOSSARY
Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental
concentration of a contaminant from which one could escape within 3o niin
without any escape-impairing symptoms or irreversible health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
days as specified in the Toxicological Profiles.
Immunologic Toxicity -- The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In Vitro -- Isolated from the living organism and artificially maintained,
as in a test tube.
In Vivo -- Occurring within the living organism.
Lethal Concentration/^) (LCjjO) " ^e lowest concentration of a chemical in
air which has been reported to have caused death in humans or animals.
Lethal Concentration/50) (L^o) "" A calculated concentration of a chemical
in air to which exposure for a specific length of time is expected to cause
death in 50% of a defined experimental animal population.
Lethal Doseflm (LD^) The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in humans
or animals.
Lethal Dose/50 (LD50) "" The d°Se °f a chemical which has been calculated to
cause death in 50% of a defined experimental animal population.
Lethal Time/50) (LT50) " A calculated period of time within which a
specific concentration of a chemical is expected to cause death in 50% of a
defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical
in a study, or group of studies, that produces statistically or biologically
significant increases in frequency or severity of adverse effects between
the exposed population and its appropriate control.
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level -- An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations. A mutation is a change in the
genetic material in a body cell. Mutations can lead to birth defects,
miscarriages, or cancer.
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9. GLOSSARY
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which
there were no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (KqW) -- The equilibrium ratio of the
concentrations of a chemical in n-octanol and water, in dilute solution.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-hour shift.
q^* -- xhe upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The qj* can be used to
calculate an estimate of carcinogenic potency, the incremental excess cancer
risk per unit of exposure (usually /ig/L for water, mg/kg/day for food, and
Mg/m^ for air).
Reference Dose (RfD) --An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious effects
during a lifetime. The RfD is operationally derived from the NOAEL (from
animal and human studies) by a consistent application of uncertainty factors
that reflect various types of data used to estimate RfDs and an additional
modifying factor, which is based on a professional judgment of the entire
database on the chemical. The RfDs are not applicable to nonthreshold
effects such as cancer.
Reportable Quantity (RQ) -- The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are (1) 1 lb or
greater or (2) for selected substances, an amount established by regulation
either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities
are measured over a 24-hour period.
Reproductive Toxicity -- The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
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9. GLOSSARY
excursions are allowed per day, and there must be at least 60 min between
exposure periods. The daily TLV-TWA may not be exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen - - A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) -- A concentration of a substance to which most
workers can be exposed without adverse effect. The TLV may be expressed as
a TWA, as a STEL, or as a CL.
Time-Weighted Average (TWA) --An allowable exposure concentration averaged
over a normal 8-hour workday or 40-hour workweek.
Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route
other than inhalation, which is expected to cause a specific toxic effect in
50% of a defined experimental animal population.
Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the variation
in sensitivity among the members of the human population, (2) the
uncertainty in extrapolating animal data to the case of human, (3) the
uncertainty in extrapolating from data obtained in a study that is of less
than lifetime exposure, anc* (4) the uncertainty in using LOAEL data rather
than NOAEL data. Usually each of these factors is set equal to 10.
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APPENDIX: PEER REVIEW
A peer review panel was assembled for chloromethane. The panel
consisted of the following members: Dr. Anthony DeCaprio, Private
Consultant; Dr. Theodore Mill, Physical Organic Chemistry Department, SRI
International; Dr. Nancy Reiches, private consultant; and Dr. Nancy Tooney,
Department of Biochemistry, Polytechnic University. These experts
collectively have knowledge of chloromethane's physical and chemical
properties, toxicokinetics, key health end points, mechanisms of action,
human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer review
specified in Section 104(i)(13) of the Comprehensive Environmental Response,
Compensation, and Liability Act as amended.
A joint panel of scientists from ATSDR and EPA has reviewed the peer
reviewers' comments and determined which comments will be included in the
profile. A listing of the peer reviewers' comments not incorporated in the
profile, with brief explanation of the rationale for their exclusion, exists
as part of the administrative record for this compound. A list of databases
reviewed and a list of unpublished documents cited are also included in the
administrative record.
The citation of the peer review panel should not be understood to
imply its approval of the profile's final content. The responsibility for
the content of this profile lies with the Agency for Toxic Substances and
Disease Registry.
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