This report contains the collective views of an international group of experts and does not
necessarily represent the decisions or the stated policy of the United Nations Environment
Programme, the International Labour Organization, or the World Health Organization.
Concise International Chemical Assessment Document 28
METHYL CHLORIDE
Note that the layout and pagination of this pdf file are not identical to those of the printed
CICAD
First draft prepared by
Agneta Löf, National Institute of Working Life, Solna, Sweden
Maria Wallén, National Chemicals Inspectorate (KEMI), Solna, Sweden, and
Jonny Bard, Åseda, Sweden
Published under the joint sponsorship of the United Nations Environment Programme, the
International Labour Organization, and the World Health Organization, and produced within the
framework of the Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 2000
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purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating
Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human
health and the environment.
WHO Library Cataloguing-in-Publication Data
Methyl chloride.
(Concise international chemical assessment document ; 28)
1.Methyl chloride - toxicity 2.Risk assessment 3.Environmental exposure
I.International Programme on Chemical Safety II.Series
ISBN 92 4 153028 6
ISSN 1020-6167
(NLM Classification: QV 633)
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TABLE OF CONTENTS
FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.
EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.
IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.
ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.
SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5.
ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . . . . 7
6.
ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
6.1
6.2
7.
COMPARATIVE KINETICS AND METABOLISM IN LABORATORY MAMMALS AND
HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
7.1
7.2
7.3
7.4
8.
Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Metabolism and elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Genetic polymorphism and sex, strain, organ, and species differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
11
11
11
EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
9.
Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Medium-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Long-term exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.1
Studies in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.2
Studies in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.1
Effects on fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7.2
Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
13
13
15
16
18
18
18
20
20
22
22
EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
9.1
9.2
9.3
Studies in volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
10.1
10.2
Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
iii
Concise International Chemical Assessment Document 28
11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
11.1
11.2
Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.2 Criteria for setting tolerable intakes or guidance values for methyl chloride . . . . . . . . . . . . . . . . . . . . . .
11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
24
26
27
27
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
APPENDIX 1 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
iv
Methyl chloride
While every effort is made to ensure that CICADs
represent the current status of knowledge, new
information is being developed constantly. Unless
otherwise stated, CICADs are based on a search of the
scientific literature to the date shown in the executive
summary. In the event that a reader becomes aware of
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IPCS to inform it of the new information.
FOREWORD
Concise International Chemical Assessment
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The primary objective of CICADs is
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The second stage involves international peer
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Risks to human health and the environment will
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1701 for advice on the derivation of health-based
tolerable intakes and guidance values.
The CICAD Final Review Board has several
important functions:
–
–
–
International Programme on Chemical Safety (1994)
Assessing human health risks of chemicals: derivation
of guidance values for health-based exposure limits.
Geneva, World Health Organization (Environmental
Health Criteria 170).
1
–
to ensure that each CICAD has been subjected to
an appropriate and thorough peer review;
to verify that the peer reviewers’ comments have
been addressed appropriately;
to provide guidance to those responsible for the
preparation of CICADs on how to resolve any
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author has not adequately addressed all comments
of the reviewers; and
to approve CICADs as international assessments.
Board members serve in their personal capacity, not as
representatives of any organization, government, or
1
Concise International Chemical Assessment Document 28
CICAD PREPARATION FLOW CHART
SELECTION OF PRIORITY CHEMICAL
SELECTION OF HIGH QUALITY
NATIONAL/REGIONAL
ASSESSMENT DOCUMENT(S)
FIRST DRAFT
PREPARED
PRIMARY REVIEW BY IPCS
( REVISIONS AS NECESSARY)
REVIEW BY IPCS CONTACT POINTS/
SPECIALIZED EXPERTS
R E V I E W O F C O M M E N T S ( PRODUCER/RESPONSIBLE OFFICER),
PREPARATION
OF SECOND DRAFT 1
FINAL REVIEW BOARD
FINAL DRAFT
2
3
EDITING
APPROVAL BY DIRECTOR, IPCS
PUBLICATION
1 Taking into account the comments from reviewers.
2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments.
3 Includes any revisions requested by the Final Review Board.
2
Methyl chloride
industry. They are selected because of their expertise in
human and environmental toxicology or because of their
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chosen according to the range of expertise required for a
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Observers may participate in Board discussions only at
the invitation of the Chairperson, and they may not
participate in the final decision-making process.
3
Concise International Chemical Assessment Document 28
1. EXECUTIVE SUMMARY
CFC-11, which has an ODP of 1. Methyl chloride is not
thought to contribute significantly to either global
warming or photochemical air pollution.
The assessment of human health aspects in this
CICAD on methyl chloride was based primarily on a
review prepared by the Nordic Expert Group in
collaboration with the Dutch Expert Committee for
Occupational Standards (Lundberg, 1992). Relevant
databases covering the years 1992–1999 were searched
to identify additional data. For the environmental and
ecotoxicological aspects of methyl chloride, BUA (1986),
ATSDR (1990), WMO (1994), and HSDB (1996) were
used as primary sources. ATSDR (1990) was updated in
1998; where ATSDR (1998) provided new information,
this has been taken into account. Additional data on
environmental issues were identified in relevant
databases covering the years 1989–1997. Information
concerning the nature and availability of the source
documents is presented in Appendix 1. Information on
the peer review of this CICAD is presented in Appendix
2. This CICAD was approved as an international
assessment at a meeting of the Final Review Board, held
in Stockholm, Sweden, on 25–28 May 1999. Participants
at the Final Review Board meeting are listed in Appendix
3. The International Chemical Safety Card (ICSC 0419) for
methyl chloride, produced by the International
Programme on Chemical Safety (IPCS, 1999), has been
reproduced in this document.
The dominant loss mechanism for methyl chloride
in water and soil is volatilization. Slow hydrolysis and
possibly biotic degradation may contribute to the loss in
deeper soil layers and in groundwater. However, little
information is available concerning biodegradation.
The most important route of exposure of methyl
chloride in humans is via the respiratory pathway. In
humans as well as in experimental animals, methyl
chloride is readily absorbed through the lungs following
inhalation. Following exposure to 14C-radiolabelled
methyl chloride, the radioactivity is found throughout
the body. Although a large portion of the radiolabelled
substance is incorporated into protein through the onecarbon pool, methyl chloride may also bind to protein by
direct alkylation. However, if methyl chloride is an
alkylating agent, it is so to a very small extent. Methyl
chloride is metabolized in mammals either by conjugation
with glutathione or, to a lesser extent, through oxidation
by cytochrome P-450; the glutathione pathway yields
methanethiol, and both pathways yield formaldehyde
and formate. Metabolites from methyl chloride are
excreted via the urine and by exhalation. Methyl chloride
is also exhaled unmetabolized.
In humans, there are large interindividual differences in the uptake and metabolism of methyl chloride.
These differences depend on the presence or absence of
the enzyme glutathione transferase T1 (GSTT1), which
displays genetic polymorphism. Humans can be phenotyped as high conjugators, low conjugators, or nonconjugators of GSTT1. However, as it is not evident if
high conjugators or non-conjugators incur the highest
risk, one must consider all phenotypes as sensitive to
methyl chloride exposure.
Methyl chloride (CAS No. 74-87-3) is released
mainly to air during its production and use and by
incineration of municipal and industrial wastes. However, natural sources, primarily oceans and biomass
burning, clearly dominate over anthropogenic sources.
The total global release of methyl chloride from all
sources is estimated to be about 5 × 106 tonnes per year.
The contribution from natural sources has been
estimated to be well over 90%, and perhaps as much as
99%, of the total release. Methyl chloride is present in
the troposphere at a concentration of approximately 1.2
µg/m3 (0.6 ppb).
The acute inhalation toxicity of methyl chloride in
rats and mice seems to be fairly low, with an LC50 value
above 4128 mg/m3 (2000 ppm). No data on irritation or
sensitizing properties were located in the literature.
The principal sink for methyl chloride in the troposphere is chemical reaction with hydroxyl radicals, and
the atmospheric lifetime is estimated to be 1–3 years. A
certain amount of methyl chloride reaches the stratosphere; there, photodissociation generates chlorine radicals, which contribute to ozone depletion. Estimates of
the amount of methyl chloride reaching the stratosphere,
and thus depleting ozone, vary widely. As estimated
from figures presented by the World Meteorological
Organization (WMO), methyl chloride contributes
approximately 15% of the total equivalent effective
stratospheric chlorine. The stratospheric ozone
depletion potential (ODP) of methyl chloride has been
determined to be 0.02 relative to the reference compound
The main target organs after short-term inhalation
exposure to methyl chloride seem to be the nervous
system, with functional disturbances and cerebellar
degeneration in both rats and mice, as well as testicles,
epididymis, and kidneys in rats and kidneys and liver in
mice.
In a 2-year inhalation study in mice, axonal swelling and degeneration of lumbar spinal nerves were
observed at 103 mg/m3 (50 ppm) in exposed animals
compared with controls, but without an apparent
4
Methyl chloride
2. IDENTITY AND PHYSICAL/CHEMICAL
PROPERTIES
dose–response relationship. At the end of the study,
cerebellar degeneration in mice of both sexes and renal
adenocarcinomas in male mice were observed at
2064 mg/m3 (1000 ppm). These effects were not observed
in the rat at 2064 mg/m3 (1000 ppm).
Methyl chloride (CAS No. 74-87-3; CH3Cl; chloromethane) is a colourless gas at ambient temperatures. It
can be compressed to a liquid, which has a weak ethereal
smell. The odour threshold has been estimated to be 21
mg/m3 (10 ppm) (ASTM, 1973). Methyl chloride
decomposes in water with a half-time of 4.66 h at 100 °C
(IARC, 1986).
Methyl chloride is clearly genotoxic in in vitro
systems in both bacteria and mammalian cells. Although
the positive effects seen in a dominant lethal test most
likely were cytotoxic rather than genotoxic, methyl
chloride might be considered a very weak mutagen in
vivo based on some evidence of DNA–protein crosslinking at higher doses.
Methyl chloride is marketed as a liquefied gas
under pressure. The purity of a representative technical
grade of methyl chloride is close to 100%. Impurities
include water, hydrochloric acid, methyl ether, methanol,
and acetone (Holbrook, 1992).
Testicular lesions and epididymal granulomas
followed by reduced sperm quality lead to reduced
fertility in rats at 980 mg/m3 (475 ppm) and to complete
infertility at higher doses.
Methyl chloride has a very high vapour pressure
and a high solubility in water. The value of its Henry’s
law constant is high, which suggests that volatilization
of methyl chloride will be significant in surface waters.
The calculated octanol/water partition coefficient (log
Kow) is low, indicating a low potential for bioaccumulation and low tendency of adsorption to soil and
sediment.
Methyl chloride induced heart defects in mouse
fetuses when dams were exposed to 1032 mg/m3
(500 ppm) during the gestation period.
Effects on humans, especially on the central
nervous system, can be clearly seen after accidental
inhalation exposure. In short-term exposure of
volunteers to methyl chloride, no significant effects were
seen that could be attributed to the exposure. There are
insufficient epidemiological data available to assess the
risk for humans to develop cancer as a result of methyl
chloride exposure.
Some relevant physical and chemical properties of
methyl chloride are listed in Table 1. Additional
physical/chemical properties are presented in the
International Chemical Safety Card, reproduced in this
document.
In conclusion, the critical end-point for methyl
chloride inhalation toxicity in humans seems to be
neurotoxicity. Guidance values of 0.018 mg/m3
(0.009 ppm) for indirect exposure via the environment
and 1.0 mg/m3 (0.5 ppm) for the working environment
were derived. Although the nerve lesions were seen at
lower exposure levels than those at which infertility in
rats (980 mg/m3 [475 ppm]) and renal tumours in male
mice (2064 mg/m3 [1000 ppm]) occurred, emphasis should
also be laid on these very serious effects in a qualitative
risk characterization of methyl chloride.
3. ANALYTICAL METHODS
In air, methyl chloride can be analysed by Method
1001 of the US National Institute for Occupational Safety
and Health (NIOSH, 1994). Analysis is performed by gas
chromatography (GC), and the sample detection limit is
3.1 µg/m3 (1.5 ppb). Using the method of Oliver et al.
(1996), the detection limit is 1.1 µg/m3 (0.53 ppb).
Few data were found on the short-term toxicity of
methyl chloride to both aquatic and terrestrial organisms.
No data were found on long-term toxicity. The existing
data indicate that methyl chloride has a low acute
toxicity to aquatic organisms. The lowest LC50 value for
fish is 270 mg/litre. As measured concentrations of
methyl chloride in surface waters are generally several
orders of magnitude less than those demonstrated to
cause effects, it is likely that methyl chloride poses a low
risk of acute effects on aquatic organisms. Only very
limited data are available on the effects of methyl
chloride on terrestrial organisms.
The use of carbon disulfide at dry ice temperature
for desorbing the analyte has also been described, as
well as a thermal desorption technique as an alternative
(Severs & Skory, 1975). A thermally desorbable diffusional dosimeter for monitoring methyl chloride in the
workplace has also been described (Hahne, 1990). Very
low concentrations (0.006–0.1 µg/m3 [0.003–0.05 ppb]) of
methyl chloride (in ambient air) can be analysed by the
use of photoionization, flame ionization, and electron
capture detectors in series (Rudolph & Jebsen, 1983).
5
Concise International Chemical Assessment Document 28
!160 °C, thermal desorption, separation on a GC capillary column, and detection with ion trap MS. The detection limit is about 0.06 µg/m3 (0.03 ppb) for methyl
chloride.
Table 1: Identity and physical/chemical properties of methyl
chloride.
Property
Value
Relative molecular mass
50.49
Melting point
!97.7 °C
!97.1 °C
Holbrook,
1992
Weast, 1988
Boiling point
!23.73 °C
!24.2 °C
Holbrook,
1992
Weast, 1988
0.920 g/ml
2.3045 g/litre
Holbrook,
1992
Holbrook,
1992
Density
liquid at 20/4 °C
gas at 0 °C, 101.3 kPa
Specific gravity
1.74 (air = 1)
Holbrook,
1992
Solubility in water at 25 °C
5.325 g/litre
4.800 g/litre
Horvath, 1982
Holbrook,
1992
3.04 × 10 5 Pa
5.75 × 10 5 Pa
BUA, 1986
BUA, 1986
0.1977 ± 1.4%
Moore et al.,
1995
BUA, 1986
Vapour pressure at
5.5 °C
25 °C
Henry’s law constant at
3 °C (seawater, salinity
30.4‰)a
25 °C
a
Reference
4.15–6.05
kPa@m 3/mol
Log K ow
0.91
Hansch & Leo,
1985
Conversion factor ppm (v/v)
to mg/m 3 in air at 25 °C
1 ppm =
2.064 mg/m 3
1 mg/m 3 =
0.4845 ppm
ATSDR, 1990
In water, methyl chloride can be analysed by EPA
Method 502.2 at a detection limit of 0.1 µg/litre (US EPA,
1986b). Other methods for the detection of volatile
organic substances in water are EPA Method 502.1,
which has a detection limit of 0.01 µg/litre (US EPA,
1986b), and EPA Method 524.2, with a detection limit of
0.05 µg/litre (US EPA, 1986b). Another method involving
a solid-phase micro-extraction technique has a detection
limit of <25 µg/litre (Shirey, 1995).
EPA Method 601 (purgeable halocarbons) is suitable for measuring methyl chloride in wastewater. The
detection limit is 0.06 µg/litre (US EPA, 1982; CFR, 1990).
A similar method is EPA Method 624 (purgeables), with
a detection limit of 2.8 µg/litre (US EPA, 1982; CFR,
1991). A third method used for analysis of wastewater is
EPA Method 1624, with a minimum detection level of 50
µg/litre (CFR, 1991).
In soil and solid waste, EPA Method 5030 (US
EPA, 1986a) may be used to analyse methyl chloride.
Analysis is performed by different EPA methods. In
Method 8010B, the limit of detection is 12.5 µg/kg for
high-concentration soils and sludges (US EPA, 1986a).
Gomes et al. (1994) describes another method to collect
and analyse methyl chloride, which can also be used to
analyse contaminants in groundwater.
4. SOURCES OF HUMAN AND
ENVIRONMENTAL EXPOSURE
Henry’s law constant is defined as the concentration in air
divided by the concentration in water at equilibrium; unit of
Henry’s law constant: dimensionless (Moore et al., 1995).
Exposure to methyl chloride can also be monitored
in air by a direct-reading infrared analyser, at minimum
detectable concentrations of 800–3100 µg/m3 (390–
1500 ppb) (IARC, 1985).
Natural sources of methyl chloride dominate over
anthropogenic sources. The major source appears to be
the marine/aquatic environment, likely associated with
algal growth. Other sources are biomass burning (forest
fires), degradation of wood by fungi, and direct and
indirect anthropogenic sources.
Stratospheric air samples are often concentrated by
a cryogenic procedure, at liquid nitrogen or argon temperature, followed by GC analysis employing electron
capture detection (Rasmussen et al., 1980; Singh et al.,
1983, 1992; Rudolph et al., 1992, 1995; Khalil &
Rasmussen, 1993; Fabian et al., 1996) or with GC/mass
spectrometry (MS) (Schauffler et al., 1993). The GC may
be equipped with a flame ionization detector (Evans et
al., 1992) or a mass selective detector (Atlas et al., 1993).
Almasi et al. (1993) described a modified version of a
method commonly used by the US Environmental
Protection Agency (EPA) to analyse low levels of
volatile organic compounds in air (EPA Method TO-14).
It includes sample concentrations on glass beads at
Methyl chloride is produced industrially by reaction of methanol and hydrogen chloride or by chlorination of methane (Key et al., 1980; Edwards et al., 1982a;
Holbrook, 1992). In almost all of the commercial uses,
methyl chloride is reacted to form another product
(ATSDR, 1998). The current principal uses are in the
production of silicones and also as a general methylating
agent. The use of methyl chloride in the manufacture of
synthetic rubber, its refrigerant and extractant applications, and its use as a tetramethyllead intermediate now
have secondary importance (Holbrook, 1992).
6
Methyl chloride
Indirect sources of methyl chloride are tobacco
smoke, turbine exhaust (Wynder & Hoffmann, 1967;
Graedel, 1978; Häsänen et al., 1990), incineration of
municipal and industrial waste (Graedel & Keene, 1995),
chlorination of drinking-water, and sewage effluent
(Abrams et al., 1975).
(Isidorov, 1990). Estimates of the global yearly release of
methyl chloride from marine sources are in the range 1–8
× 106 tonnes (Watson et al., 1980; Singh et al., 1983;
Isidorov, 1990).
Terrestrial species also produce methyl chloride.
The activity of methyltransferases, believed to be
responsible for methyl chloride production, has been
observed in several herbaceous species (Saini, 1995).
According to Harper et al. (1988), 34 species of fungi are
also known to biosynthesize methyl chloride.
The current production capacity of methyl chloride
in the USA has been estimated to be about 0.417 × 106
tonnes per year (CMR, 1995). The production in Japan in
1996 was 0.13 × 106 tonnes (Chemical Daily Co. Ltd.,
1998).
Estimates of the global annual release of methyl
chloride from biomass burning are in the range 0.4–1.8 ×
106 tonnes (Watson et al., 1980; Andreae, 1991, 1993;
Lobert et al., 1991; Rudolph et al., 1994, 1995). The major
part of the methyl chloride released from biomass
burning originates from forest fires in the tropics
(Andreae et al., 1994). The estimated global release of
methyl chloride from temperate and boreal biomass fires
has been calculated to be 0.012 × 106 tonnes per year
(Laursen et al., 1992). Low-intensity, inefficient combustion and high chlorine content of the biomass promote
methyl chloride formation (Reinhardt & Ward, 1995).
It has been concluded that well over 90%, and
perhaps as much as 99%, of ambient air concentrations
on a global scale appear to originate from natural
sources rather than from anthropogenic sources
(ATSDR, 1998). Edwards et al. (1982b) estimated the
emissions of methyl chloride during production,
transport, storage, and use to be approximately 0.02 × 106
tonnes per year, corresponding to nearly 6% of the
amount produced. According to this estimate,
anthropogenic sources would account for 1–2% of the
total release, including natural sources. Other estimates
of the global yearly release from anthropogenic sources
are in the range of 0.024–0.6 × 106 tonnes (Watson et al.,
1980; Gribble, 1992; Dowdell et al., 1994), the higher
estimate including indirect anthropogenic sources and
possibly also biomass burning.
5. ENVIRONMENTAL TRANSPORT,
DISTRIBUTION, AND TRANSFORMATION
Methyl chloride, which is the most prevalent halogenated methane in the atmosphere, is present in the
troposphere at a concentration of about 1.2 µg/m3
(0.6 ppb) (WMO, 1994). It has been calculated that at a
production rate of about 3.5 × 106 tonnes per year, the
steady-state mixing ratio of 1.2 µg/m3 (0.6 ppb) is
maintained given an atmospheric lifetime in the order of 2
years (WMO, 1994). Estimates of the total global annual
release of methyl chloride from all sources are around 5 ×
106 tonnes (Rasmussen et al., 1980; Logan et al., 1981;
Edwards et al., 1982b; Dowdell et al., 1994; WMO, 1994;
Fabian et al., 1996). According to ATSDR (1998), the
total release from all sources amounts to approximately
3.2–8.2 × 106 tonnes per year.
Most methyl chloride discharged to the environment will be released to air. The principal sink for methyl
chloride in the troposphere is chemical reaction with
hydroxyl radicals (ASTDR, 1990; Graedel & Keene, 1995;
Fabian et al., 1996). The rate constant for this reaction is
approximately 4.3 × 10–14 cm3/s per molecule at 25 °C
(NASA, 1981; Atkinson, 1985). Atmospheric lifetime
estimates range from 1 to 3 years (Atkinson, 1985; BUA,
1986; Warneck, 1988; ATSDR, 1990; WMO, 1990, 1994;
Fabian et al., 1996; Houghton et al., 1996). Surface
deposition, rainout, and washout are unimportant sinks
for methyl chloride (Graedel & Keene, 1995).
Estimates of the amount of methyl chloride
reaching the stratosphere vary considerably. Borchers et
al. (1994) claim that the contribution of methyl chloride to
the stratospheric chlorine budget is significant. Crutzen
& Gidel (1983) estimated the flux of methyl chloride to
the stratosphere to be about 2 × 106 tonnes per year or
20–25% of the total annual stratospheric chlorine input.
According to Fabian et al. (1996), only a fraction (less
than 10%) of the amount of methyl chloride emitted
reaches the stratosphere. Edwards et al. (1982b) claim
that about 6% of the methyl chloride released reaches
the stratosphere (corresponding to 0.3 × 106 tonnes per
year). According to Graedel & Crutzen
Over the Pacific Ocean, the concentration of
methyl chloride is higher in the lower troposphere than
in the higher layers. However, over the continents, the
concentration is independent of the altitude. Thus, the
ocean seems to be a source of methyl chloride (Geckeler
& Eberhardt, 1995). In the oceans, algae, especially
planktonic algae, are considered to be responsible for
most of the methyl chloride production. However, this
has not been fully proven. Phytoplankton have been
shown to produce methyl chloride in laboratory studies
(Tait & Moore, 1995). An alternative model is that methyl
chloride is formed as a result of exchange processes
between methyl iodide and chlorine ions in seawater
7
Concise International Chemical Assessment Document 28
HO-reaction
4 ± 1 x 106 tonnes
Marine algae
4 ± 2 x 106 tonnes
Biomass combustion
0.5 ± 0.2 x 106 tonnes
CH3Cl
β= 3.7x106 tonnes
∆≈ 0
Industrial
0.3 ± 0.1 x 106 tonnes
Ocean hydrolysis
0.3 ± 0.6 x 106 tonnes
Transport to the stratosphere
0.03 ± 0.01 x 106 tonnes
Rainout/washout
≈ 0.0012 x 106 tonnes
β= Tropospheric burden
∆= Tropospheric growth rate
Figure 1. Global budget for tropospheric methyl chloride (as tonnes chlorine per year). The budget is based on an average
concentration of methyl chloride in the troposphere of 1.3 µg/m3 (0.62 ppb), a lifetime of 1.5 years, and a tropospheric burden of
about 3.7 × 106 tonnes chlorine per year (adapted from Graedel & Keene, 1995).
(1993) and Graedel & Keene (1995), only 0.8% (corresponding to 0.03 × 106 tonnes chlorine per year) is
expected to reach the stratosphere. A global budget for
tropospheric methyl chloride is shown in Figure 1.
dissociation rate of each compound involved in ozone
depletion.
A radiative forcing value of 0.0053 W/m2 per part
per billion has been determined for methyl chloride. This
value is about 2% of the forcing of CFC-11 and about
300 times the forcing of carbon dioxide, on a per
molecule basis (Grossman et al., 1994). Houghton et al.
(1996) gave the radiative forcing value as 0 W/m2 for
methyl chloride. The global warming potential (GWP)
has been calculated to be about 25, relative to carbon
dioxide (GWP = 1), at a time scale of 20 years (Grossman
et al., 1994).
The ability of the ozone layer to absorb ultraviolet
radiation shorter than 290 nm should exclude direct
photolysis in the troposphere, because methyl chloride
does not absorb any radiation above 290 nm (BUA,
1986). In the stratosphere, photodissociation will occur
at a rate approximately equal to its reaction with hydroxyl
radicals (Robbins, 1976). The chlorine radicals that are
generated contribute to ozone depletion. Methyl
chloride has been shown to photochemically decompose
at 185 nm. Photooxidation products in the gas phase
were carbon dioxide, carbon monoxide, formic acid,
formyl chloride, water, and hydrogen chloride (Gürtler &
Kleinermanns, 1994).
As the current concentration of methyl chloride
in the atmosphere is relatively low, approximately
1.2 µg/m3 (0.6 ppb), the contribution of this substance to
the greenhouse effect will not become a problem unless
large releases of this gas occur (Grossman et al., 1994).
WMO (1994) also considers that the contribution of
methyl chloride to climate forcing is minimal.
The stratospheric steady-state ODP of methyl
chloride has been determined to be 0.02 relative to CFC11 (ODP = 1) (Solomon et al., 1992; WMO, 1994; Fabian
et al., 1996). Estimates of the amount of methyl chloride
reaching the stratosphere, and thereby also its
contribution to ozone depletion, vary considerably.
However, as estimated from figures presented by WMO
(1994), methyl chloride contributes approximately 15%
(0.5 ppb) of the total (3.3 ppb) equivalent effective
stratospheric chlorine. The term “equivalent effective
stratospheric chlorine” includes both stratospheric
chlorine and bromine ("1 = 40) and also considers the
The contribution of methyl chloride to the creation
of photochemical air pollution is not significant because
of its relatively low reactivity and low amounts emitted.
The photochemical ozone creation potential (POCP)
of methyl chloride has been determined to be 3.5
(integrated ozone formation over 5 days) relative to that
of ethylene (POCP = 100) (Derwent et al., 1996).
Reactive chlorine in the lower atmosphere (as
distinguished from chlorofluorocarbon-derived chlorine
1
In the stratosphere, each bromine atom is assumed to
be 40 times more damaging to ozone than each chlorine
atom (WMO, 1994).
8
Methyl chloride
in the stratosphere) is supposed to be important in
considerations of precipitation acidity, corrosion of
metals and alloys, foliar damage, and chemistry of the
marine boundary layer. The tropospheric reactive
chlorine burden of approximately 8.3 × 106 tonnes
chlorine is dominated by methyl chloride (~45%) and
trichloroethane (~25%) (Graedel & Keene, 1995).
layers may to some extent leach into the groundwater, as
well as diffuse to the surface and volatilize (ATSDR,
1990; HSDB, 1996). In groundwater, methyl chloride is
expected to biodegrade or hydrolyse very slowly
(ATSDR, 1990; HSDB, 1996). The cumulative volatilization loss of methyl chloride, from a depth of 1 m
beneath ground, has been calculated to be at least 70%
and 22% in 1 year for a sandy soil and a clay soil,
respectively (Jury et al., 1990).
If methyl chloride is released into water, it will be
lost primarily by volatilization. The volatilization half-life
has been calculated to be 2.1 h in a model river (Lyman et
al., 1982). The volatilization half-lives of methyl chloride
in a pond and in a lake have been estimated to be 25 h
and 18 days, respectively, using the model EXAMS
(ATSDR, 1990). The low log Kow (0.91) of methyl chloride
indicates that the substance does not tend to
concentrate in sediments.
There are no experimental studies on bioaccumulation. However, only a minor accumulation in biota
would be expected on the basis of the low log Kow. A
bioconcentration factor of 2.9 has been calculated based
on the log Kow (ATSDR, 1990).
6. ENVIRONMENTAL LEVELS AND
HUMAN EXPOSURE
The transformation of methyl chloride by hydrolysis is probably negligible under acid and neutral conditions. Under basic conditions, slow hydrolysis takes
place, yielding methanol as a transformation product
(Simon, 1989). Hydrolytic half-lives range from 31 days
(pH 11) to 2.5 years (pH not given) at 20–25 °C (Zafiriou,
1975; Mabey & Mill, 1976, 1978; Simon, 1989). The
hydrolytic half-life of methyl chloride in seawater varies
with temperature (0–30 °C) from 0.5 to 77 years (Elliott &
Rowland, 1995). Laboratory data indicate that the
photochemical transformation of methyl chloride in water
is negligible (Mabey & Mill, 1976).
6.1
Environmental levels
Background concentrations of methyl chloride in
the troposphere are around 1.2 µg/m3 (0.6 ppb), ranging
from about 1.0 to 1.4 µg/m3 (from 0.5 to 0.7 ppb) (Cox et
al., 1976; Cronn et al., 1976, 1977; Pierotti & Rasmussen,
1976; Singh et al., 1977, 1979, 1983; Graedel, 1978; Khalil
& Rasmussen, 1981, 1993; Guicherit & Schulting, 1985;
Gregory et al., 1986; Warneck, 1988; Rudolph et al., 1992;
Singh et al., 1992; Atlas et al., 1993; WMO, 1994; Graedel
& Keene, 1995; Fabian et al., 1996). In the stratosphere,
the concentration of methyl chloride decreases with
altitude. Concentrations in the Arctic stratosphere in
March 1992 ranged from 0.60 to 0.082 µg/m3 (from 0.29 to
0.04 ppb) at altitudes of 11–22 km (von Clarmann et al.,
1995). In May 1985, at a latitude of 26–30 °N, Zander et
al. (1992) found methyl chloride concentrations ranging
from 0.12 to 0.050 µg/m3 (from 0.058 to 0.024 ppb) at
altitudes of 12–22 km. Near the tropical tropopause
(23.8–25.3 °N, 15–17 km altitude), the mean methyl
chloride concentration was measured to be 1.1 µg/m3
(0.531 ppb) during January–March 1992 (Schauffler et al.,
1993).
Methyl chloride was not readily biodegraded in a
standardized “closed bottle test” (MITI, 1992). However,
several isolated bacterial strains have been shown to
degrade methyl chloride under both aerobic (Stirling &
Dalton, 1979; Hartmans et al., 1986; Bartnicki & Castro,
1994; Chang & Alvarez-Cohen, 1996) and anaerobic
conditions (Traunecker et al., 1991; Braus-Stromeyer et
al., 1993; Dolfing et al., 1993; Leisinger & BrausStromeyer, 1995). A half-life of less than 11 days was
estimated for the anaerobic biodegradation of methyl
chloride in groundwater, based on laboratory data
obtained under conditions favourable for anaerobic
biodegradation (Wood et al., 1985).
The very low log Kow (0.91) of methyl chloride
indicates that it will not tend to adsorb to soil (Lyman et
al., 1982). The adsorption coefficient, Koc, has been
calculated to be 5, based on physical/chemical data
(ATSDR, 1990). The very high vapour pressure and low
adsorption to soil suggest that methyl chloride present
near the soil surface will rapidly be lost by volatilization
(ATSDR, 1990; HSDB, 1996). As it is not expected to
adsorb to soil, methyl chloride present in deeper soil
Numerous measurements of methyl chloride levels
in air have been performed, especially in the USA. The
mean or median concentrations of methyl chloride
measured in the air of rural/remote sites in the USA were
about 1.0–2.7 µg/m3 (0.5–1.3 ppb), with the majority of
the values below 2.1 µg/m3 (1.0 ppb); the maximum
concentration measured was 4.3 µg/m3 (2.1 ppb)
(Grimsrud & Rasmussen, 1975; Robinson et al., 1977;
9
Concise International Chemical Assessment Document 28
Singh et al., 1977, 1981b; Brodzinsky & Singh, 1983;
Rasmussen & Khalil, 1983; Shah & Singh, 1988). In
samples from urban/suburban areas in the USA, the
mean/median concentrations were in the range of 0.27–
6.2 µg/m3 (0.13–3.0 ppb), with the majority of the values
in the range 1.0–2.3 µg/m3 (0.5–1.1 ppb); the highest
concentration found was 25.0 µg/m3 (12.1 ppb) (Singh et
al., 1977, 1979, 1981a, 1982, 1992; Brodzinsky & Singh,
1983; Edgerton et al., 1984; Shah & Singh, 1988; Rice et
al., 1990; US EPA, 1991a, 1991b; Evans et al., 1992; Kelly
et al., 1994; Spicer et al., 1996). Methyl chloride
concentrations in three Japanese cities ranged from 4.5
to 35 µg/m3 (from 2.2 to 17 ppb) (Furutani, 1979). In Delft,
the Netherlands, and Lisbon, Portugal, concentrations of
6.2 µg/m3 (3.0 ppb) (Guicherit & Schulting, 1985) and 4.5
µg/m3 (2.2 ppb) (Singh et al., 1979), respectively, were
found.
methyl chloride was mostly found at 0.01–0.05 µg/litre
(Lovelock, 1975; Pearson & McConnell, 1975; NAS,
1978; Singh et al., 1979, 1983; Edwards et al, 1982b);
however, a higher concentration of 1.2 µg/litre was
reported from a measurement near the shore of California,
USA (Singh et al., 1979).
Methyl chloride was detected in soils at 34 waste
sites and in sediments at 13 waste sites in the USA
(HazDat, 1998) and in 1 of 345 sampling stations of the
US EPA STORET database, at a concentration of
<5 µg/kg (Staples et al., 1985). Methyl chloride was also
detected in soil at an electronic industrial site in São
Paulo, Brazil (Gomes et al., 1994). No data were found on
methyl chloride levels in sediment. According to the US
EPA STORET database, methyl chloride was detected in
1% of analysed samples of fish and seafood (Staples et
al., 1985).
From these data, it appears that the concentrations
of methyl chloride are slightly higher in the air of urban/
suburban sites than at rural/remote sites. However, a
direct comparison is difficult, because samples in urban/
suburban areas were probably often taken at ground
level, while several measurements of rural/remote areas
were made at higher altitudes.
6.2
Human exposure
Data given in section 6.1 suggest that humans are
exposed to methyl chloride in ambient air. Background
concentrations are around 1.2 µg/m3 (0.6 ppb). In urban
areas, mean and median concentrations generally seem
to be slightly higher, 1.0–2.3 µg/m3 (0.5–1.1 ppb). However, individual measurements may be much higher. The
highest value found in the literature was 35 µg/m3
(17 ppb).
Methyl chloride has also been occasionally
detected in water, soil, and biota. A few studies on
measurements of methyl chloride in drinking-water were
identified, most of them performed in the USA and
Canada (Abrams et al., 1975; Coleman et al., 1976;
Burmaster, 1982; Mariich et al., 1982; Otson et al., 1982;
Otson, 1987). A maximum concentration of 44 µg/litre
was measured in a drinking-water well (Burmaster, 1982).
Workplace concentrations have been measured in
four US chemical plants (NIOSH, 1980). Three of the
plants produced methyl chloride. The personal 8-h timeweighted average concentrations in the three plants
ranged from 18.4 to 25.6 mg/m3 (from 8.9 to 12.4 ppm),
from <0.4 to 15.5 mg/m3 (from <0.2 to 7.5 ppm), and from
<0.2 to 26.2 mg/m3 (from <0.1 to 12.7 ppm), respectively.
In the fourth plant, where methyl chloride was used as a
blowing agent in the production of polystyrene foam,
the personal exposures ranged from 6.2 to 44.2 mg/m3
(from 3.0 to 21.4 ppm). In a Dutch methyl chloride
production plant, individual 8-h time-weighted averages
of methyl chloride exposure in the air ranged from 62 to
186 mg/m3 (from 30 to 90 ppm) (van Doorn et al., 1980).
In measurements of groundwaters in the USA,
concentrations of methyl chloride ranged from not
detectable up to 100 µg/litre, found at a former waste site
of a chemical factory (Page, 1981; Burmaster, 1982;
Sabele & Clark, 1984; Lesage et al., 1990; Plumb, 1991;
Rosenfeld & Plumb, 1991). The substance was detected
in groundwaters at 20 of 479 waste disposal sites in 1991
(Plumb, 1991).
In surface water samples in North America, the
concentrations ranged from not detectable up to
224 µg/litre, the highest value reported from New Jersey,
USA, in the 1970s (Page, 1981; Otson et al., 1982; Great
Lakes Water Quality Board, 1983; Granstrom et al., 1984;
Staples et al., 1985; Otson, 1987). In the only European
study found (Hendriks & Stouten, 1993), a maximum
concentration of 12 µg/litre in the river Rhine was
reported. In seawater samples collected near the surface,
7. COMPARATIVE KINETICS AND
METABOLISM IN LABORATORY
MAMMALS AND HUMANS
The most important route of exposure of methyl
chloride in humans is via the respiratory pathway. Data
10
Methyl chloride
Metabolites from methyl chloride are excreted in
the urine and in the expired air. S-Methylcysteine has
been identified in the urine of occupationally exposed
humans and rats (van Doorn et al., 1980; Landry et al.,
1983), and formic acid has been found in rat urine
(Kornbrust & Bus, 1983). Further, carbon dioxide has
been shown to be the major final metabolite of methyl
chloride, accounting for nearly 50% of the radiolabelled
material recovered after a 6-h exposure of rats to methyl
chloride (Kornbrust & Bus, 1983). Methyl chloride is
also excreted unmetabolized via the lungs, as seen in
studies in volunteers (Stewart et al., 1980; Nolan et al.,
1985; Löf et al., 2000).
on methyl chloride toxicokinetics cover only inhalation;
no relevant information on other routes of administration
was located in the literature.
7.1
Absorption
In humans as well as in experimental animals,
methyl chloride is readily absorbed through the lungs
following inhalation (Andersen et al., 1980; Stewart et al.,
1980; Landry et al., 1983; Nolan et al., 1985; Löf et al.,
2000). In human volunteers exposed to 21 or 103 mg
methyl chloride/m3 (10 or 50 ppm) for 6 h or to 21 mg/m3
(10 ppm) for 2 h, steady state was reached during the
first exposure hour (Nolan et al., 1985; Löf et al., 2000). In
rats, equilibrium between uptake and elimination was
also obtained within 1 h (Landry et al., 1983).
7.2
The plausible metabolic pathways of methyl
chloride in mammals are shown in Figure 2.
Distribution
7.4
After rats were exposed to 14C-labelled methyl
chloride by inhalation, radioactivity was found to the
largest extent in the liver, kidneys, and testes and to a
smaller extent in the brain and lungs (Redford-Ellis &
Gowenlock, 1971; Kornbrust et al., 1982; Landry et al.,
1983). The presence of residues was, however, attributed
to the metabolism of methyl chloride to formaldehyde
and formate and subsequent incorporation of the radiolabelled carbon atom into tissue macromolecules through
single-carbon anabolic pathways (Kornbrust & Bus,
1982; Kornbrust et al., 1982). Methyl chloride may also
bind to macromolecules, especially protein, and to a
minimal extent probably also to DNA (Kornbrust et al.,
1982; Vaughan et al., 1993).
7.3
Genetic polymorphism and sex,
strain, organ, and species differences
In several studies in volunteers, large interindividual differences in concentrations of methyl
chloride in breath and blood and amounts of excreted
urinary metabolites have been observed (Stewart et al.,
1980; van Doorn et al., 1980; Putz-Anderson et al., 1981a;
Nolan et al., 1985; Löf et al., 2000).
One explanation for the large interindividual
differences in uptake and elimination of methyl chloride
in humans is the presence or absence of the enzyme
GSTT1 (Coles & Ketterer, 1990). The presence of the
GSTT1 gene leads to conjugation between glutathione
and methyl chloride (GSTT1+), and the absence of the
gene leads to no conjugation (GSTT1!) (Pemble et al.,
1994).
Metabolism and elimination
In humans as well as in animals, methyl chloride
is mainly metabolized by conjugation with glutathione.
S-Methylglutathione can then be further metabolized to
S-methylcysteine and methanethiol (Redford-Ellis &
Gowenlock, 1971; Bus, 1982; Landry et al., 1983). To a
lesser extent, methyl chloride is also metabolized microsomally via cytochrome P-450 in rat liver, resulting in the
formation of formaldehyde and formate (Kornbrust &
Bus, 1983). Formaldehyde and formate may also be
formed via the glutathione pathway (Kornbrust & Bus,
1983).
About 60% of blood samples from a German
population showed a significant metabolic elimination of
methyl chloride, whereas 40% did not (Peter et al., 1989).
In a Swedish population, Warholm et al. (1994) found a
large interindividual variation in the glutathione
transferase activity in erythrocytes treated with methyl
chloride, as 43% had a high activity, 46% had a medium
activity, and 11% lacked activity. Nelson and co-workers
(1995) mapped the ethnic differences in the prevalence of
the null genotype (GSTT1!) and found the highest
prevalence among Chinese (64%), followed by Koreans
(60%), African-Americans (22%), and Caucasians (20%),
and the lowest among Mexican-Americans (10%).
Warholm et al. (1994) concluded that the GSTT1
polymorphism leads to three different phenotypes in
humans — namely, non-conjugators (NC), low conjugators (LC), and high conjugators (HC). In a comparison
involving the three human phenotypes and experimental
animals, Thier et al. (1998) established that GSTT1
activity towards methyl chloride in human erythrocytes
Inhalation of methyl chloride by male B6C3F1 mice
resulted in a concentration-dependent depletion of
glutathione in liver, kidney, and brain. The depletion was
most pronounced in the liver, where a 6-h inhalation
exposure to 206 mg/m3 (100 ppm) decreased the glutathione level by 45%, and exposure to 5160 mg/m3
(2500 ppm) reduced the glutathione content to 2% of
control levels (Kornbrust & Bus, 1984).
11
Concise International Chemical Assessment Document 28
excretion of
CH3 Cl
in exhaled air
CH3 Cl
Methyl chloride
+ glutathione
+glutathione
transferase
+Cytochrome P450
GS CH3
S-Methylglutathione
NH2
CH3SCH2CHCOOH
S-Methylcysteine
CH3 SH
Methanethiol
alkylation of
macromolecules,
especially proteins
HCHO
Formaldehyde
HCOOH
Formic acid
one carbon
pool
CO2
H2S
Hydrogen
sulphide
incorporation
in the tissues
via metabolism
2-
SO4
Figure 2: Metabolic pathways for methyl chloride (slightly modified after Bus, 1982).
12
excretion
via urine
exhalation
Methyl chloride
(HC, LC, or NC) and in liver and kidney cytosol in
experimental animals decreased in the following order:
female mouse (B6C3F1) > male mouse (B6C3F1) > HC >
rat (Fischer 344) > LC > hamster (Syrian golden) > NC. In
animals, GSTT1 activity towards methyl chloride was 2–7
times higher in liver cytosol than in kidney cytosol
(Thier et al., 1998).
details. In another experimental series, where no clinical
acute toxicity symptoms except for lethality were
reported, five male B6C3F1 mice were exposed (whole
body) to methyl chloride at concentrations of 1032–
5160 mg/m3 (500–2500 ppm) in increments of 1032 mg/m3
(500 ppm) (Chellman et al., 1986a). The
6-h LC50 value was determined to be 4540 mg/m3
(2200 ppm). In this study, lethality as well as hepatotoxicity, renal toxicity, and cerebellar degeneration were
prevented in mice exposed to 5160 mg/m3 (2500 ppm) for
6 h by pretreatment with the glutathione synthesis
inhibitor L-buthionine-S,R-sulfoximine, indicating that
metabolism of methyl chloride by glutathione conjugation increases the toxicity.
The human GSTT1 polymorphism was illustrated in
a study on the toxicokinetics of methyl chloride in
volunteers phenotyped for GSTT1 activity (HC, LC, and
NC) (Löf et al., 2000). It was seen that conjugators with
the fast GSTT1 activity (HC) had the highest respiratory
net uptake (respiratory net uptake equals the difference
between the amount of methyl chloride in inhaled and
exhaled air during exposure) of methyl chloride, whereas
subjects with no GSTT1 activity (NC) had a smaller
respiratory net uptake. At the end of the exposure, the
concentration of methyl chloride in blood declined more
rapidly among volunteers with high (HC) and intermediate (LC) GSTT1 activity than in those with no activity
(NC). The area under the curve for NC was higher than
those for HC and LC, and the area under the curve for LC
was higher than that for HC. Further, the clearance of
methyl chloride by metabolism was high in fast conjugators (HC) and close to zero in subjects with no GSTT1
activity (NC).
Although other single-exposure inhalation toxicity
studies in small rodents exist, they are very old (published before 1950) and do not meet current standards,
and they are therefore not included in the present
evaluation on methyl chloride. In any case, the results
are similar to those reported here.
No single-exposure studies on methyl chloride
toxicity following other routes of administration were
located in the literature.
In conclusion, based on scarce data, the acute
inhalation toxicity in male mice seems to be fairly low,
with an LC50 value above 4128 mg/m3 (2000 ppm). In
mice, a sex difference in susceptibility to methyl chloride
was indicated.
In an investigation by Dekant et al. (1995), sex-,
strain-, and species-specific bioactivation of methyl
chloride by cytochrome P-450 2E1 (CYP2E1) was seen in
the liver and kidneys of rats and mice. In kidney
microsomes, the rate of oxidation of methyl chloride was
significantly higher in male mice than in female mice and
in rats of both sexes than in mice. It was also observed
that the rate of oxidation in kidney microsomes was
faster in CD-1 mice and NMRI mice than in C3H/He and
C57BL/6J mice. In erythrocytes from other species —
rats, mice, cows, pigs, sheep, and rhesus monkeys — no
conversion of methyl chloride was seen in erythrocyte
cytoplasm (Peter et al., 1989).
8.2
No data on irritation or sensitization were available.
8.3
Short-term exposure
The toxic response to methyl chloride was studied
in Fischer 344 rats (10 animals per sex per group)
exposed by inhalation to 0, 4128, 7224, or 10 320 mg
methyl chloride/m3 (0, 2000, 3500, or 5000 ppm) for
6 h/day for 9 days (5 days of exposure followed by a 2day break in exposure, then a further 4 days’ exposure)
and in C3H, C57BL/6, or B6C3F1 mice (5 animals per
strain per sex per group) exposed by inhalation to 0,
1032, 2064, or 4128 mg methyl chloride/m3 (0, 500, 1000, or
2000 ppm) for 6 h/day for 12 days (Morgan et al., 1982).
The animals were sacrificed 18 h after their last exposure
or immediately after the day’s exposure if they were
found to be moribund. Clinical observations and
histopathological investigations of the brain, liver,
kidneys, and adrenal glands in both species and of
testes and epididymis of rats were reported. As a result
of high intoxication, some rats from the two highest dose
groups were sacrificed in extremis (6 males, 5 females:
8. EFFECTS ON LABORATORY
MAMMALS AND IN VITRO TEST SYSTEMS
8.1
Irritation and sensitization
Single exposure
In B6C3F1 mice, the LC50 of methyl chloride via
inhalation for 6 h was reported to be 4644 mg/m3
(2250 ppm) in males and 17 544 mg/m3 (8500 ppm) in
females (White et al., 1982). The data on lethal doses
were obtained from an abstract without any further
13
Concise International Chemical Assessment Document 28
10 320 mg/m3 [5000 ppm]; 2 females: 7224 mg/m3 [3500
ppm]). No information was given on whether effects
were seen in animals with a fulfilled exposure scheme or
with an interrupted scheme.
cellular effects. A no-effect level could not be obtained
for either species.
The ultrastructure of the methyl chloride-induced
cerebellar lesions observed in mice and rats by Morgan
and co-workers (1982) and in guinea-pigs (reported
under section 8.4) by von Kolkmann & Volk (1975) was
further studied by Jiang et al. (1985) in female C57BL/6
mice. The mice were exposed for 6 h/day, 5 days/week,
for 2 weeks to 0 or 3096 mg methyl chloride/m3 (0 or 1500
ppm). In all treated mice, degenerative changes of
varying severity were observed in the granular cell layer
of the cerebellum. The lesions in the granular cells were
characterized by nuclear and cytoplasmic condensation
of scattered granule cells and also by watery swelling
and disruption of granule cell perikarya. From poorly
reported clinical observations, neurological deficiency in
motor coordination was seen. Few kidney abnormalities
were detected, indicating that the cerebellar degenerations were not secondary to kidney lesions.
Clinically, especially in the higher dose groups, the
rats were seriously affected by the exposure, and symptoms such as lack of coordination of the forelimbs, paralysis of the hindlimbs, convulsive seizures, perineal urine
staining, and diarrhoea were recorded. In the kidneys,
concentration-related degeneration and necrosis of the
proximal convoluted tubules could be seen (lowestobserved-adverse-effect level or LOAEL [males] =
4128 mg/m3 [2000 ppm]; LOAEL [females] = 7224 mg/m3
[3500 ppm]). Testicular degeneration in the seminiferous
tubules (LOAEL = 4128 mg/m3 [2000 ppm]) and adrenal
fatty degeneration (LOAEL [males and females] = 7224
mg/m3 [3500 ppm]) were also concentration related. Most
animals showed minimal hepatocellular response,
including loss of normal areas of cytoplasmic basophilia
and variable degeneration. Rats in the 10 320 mg/m3 (5000
ppm) group showed degeneration of the cerebellar
granular layer.
In a study primarily designed to investigate the
correlation between neurotoxicity and continuous
versus intermittent exposure to methyl chloride, Landry
et al. (1985) exposed female C57BL/6 mice for 11 days
either continuously (22.5 h/day) to 31, 103, 206, 310, or
413 mg/m3 (15, 50, 100, 150, or 200 ppm) or intermittently
(5.5 h/day) to 310, 826, 1651, 3302, or 4954 mg/m3 (150,
400, 800, 1600, or 2400 ppm). A quantitative relationship
between neurotoxicity and continuous and intermittent
exposure was not observed. The lowest effect level for
clinical observations, similar to those reported earlier by
Dunn & Smith (1947) and later by von Kolkmann & Volk
(1975), Morgan et al. (1982), and Jiang et al. (1985), was
206 mg/m3 (100 ppm) for continuous exposure and 3302
mg/m3 (1600 ppm) for intermittent exposure. Cerebellar
lesions were recorded at 206 and 826 mg/m3 (100 and 400
ppm) for continuous and intermittent exposure,
respectively. A statistically significant decrease was
observed in relative and absolute thymus weights at the
31, 103, and 310 mg/m3 (15, 50, and 150 ppm) exposure
levels (continuous exposure) and also at the 3302 and
4954 mg/m3 (1600 and 2400 ppm) levels (intermittent
exposure). Although the decrease in thymus weight at
31 mg/m3 (15 ppm) suggests that this level might be a
LOAEL, the absence of a methyl chloride-induced effect
on the thymus or its function in long-term studies
indicates that these weight decreases are of uncertain
significance. From the results, a LOAEL of 826 mg/m3
(400 ppm) for intermittent exposure (cerebellar lesions)
and of 206 mg/m3 (100 ppm) for continuous exposure can
be concluded.
All mice in the highest dose group died before or
were moribund at exposure day 5. No apparent strain
differences could be seen from available mortality data.
Prior to death, some of the animals developed moderate
to severe ataxia, and all females developed haematurea.
In the 2064 mg/m3 (1000 ppm) group, females developed
haematurea to a much larger extent than males. Cerebellar
degeneration of the same type as in rats was seen at the
2064 and 4128 mg/m3 (1000 and 2000 ppm) concentration
levels in female C57BL/6 mice only. The other two mouse
strains did not develop brain lesions. On the contrary, in
all three mouse strains, degeneration in the kidneys was
found at 4128 mg/m3 (2000 ppm), and basophilic renal
tubules were observed at 2064 mg/m3 (1000 ppm).
Hepatocellular necrosis was confined to the 4128 mg/m3
(2000 ppm) group in male C57BL/6 and B6C3F1 mice.
Hepatocellular degeneration was seen in lower dose
groups, mainly in the 1032 and 2064 mg/m3 (500 and 1000
ppm) groups of male and female C57BL/6 mice. Liver
damage in the low dose groups was considered mild and
consisted of, for example, variable degrees of glycogen
depletion and cytoplasmic vacuolization.
From these studies, which highlight species and
sex differences in methyl chloride-induced toxicity, a rat
LOAEL of 4128 mg/m3 (2000 ppm) could be derived from
the testicular, epididymal, renal, and to some extent
hepatocellular findings, and a mouse LOAEL of
1032 mg/m3 (500 ppm) could be derived from the hepato
To assess the role of inflammation in the toxicity of
methyl chloride, especially to sperm, Chellman et al.
14
Methyl chloride
No toxicity data for short-term exposures other
than those obtained from administration via the respiratory pathway were located in the literature.
(1986b) exposed male Fischer 344 rats for 5 days, 6 h/day,
to 0 or 10 320 mg methyl chloride/m3 (0 or 5000 ppm) with
and without the presence of the anti-inflammatory agent
3-amino-1-(m-[trifluoromethyl]phenyl)-2-pyrazoline
(BW755C), an inhibitor of leucotriene and prostaglandin
synthesis. Lesions that were induced by exposure to
methyl chloride alone were epididymal sperm
granulomas, degeneration of cerebellar granule cells,
necrosis of renal proximal tubules, cloudy swelling of
hepatocytes, and vacuolization of cell cytoplasm in the
outer region of zona fasciculata in the adrenal glands.
Virtually none of these effects was seen when BW755C
was given in parallel with methyl chloride, strongly
suggesting an inflammatory response.
8.4
Medium-term exposure
To investigate methyl chloride-induced neurotoxicity, von Kolkmann & Volk (1975) exposed 19 guineapigs to 41 280 mg methyl chloride/m3 (20 000 ppm; 2
vol% in a pressurized vessel) by inhalation for 61–
70 days (10 min/day, 6 times/week). Clinically, in
approximately half of the animals in the treated group,
ataxia, paresis of the hind legs, staggering, atactic
moving of the head, and retardation in spontaneous
reaction and mobility were observed. No animal died
during the exposure period. Histopathologically,
necroses were seen in the cerebellar cortex in the
granular cell layer. Further, Purkinje’s cell necrosis
occurred. Considering the extremely high exposure
concentrations, the study can be used for descriptive
purposes only.
The question as to whether methyl chlorideinduced renal tumours in male mice are evoked by the
metabolic intermediate formaldehyde was studied by
Jäger et al. (1988). Fischer 344 rats and B6C3F1 mice
of both sexes in groups of five were exposed to 0 or 2064
mg methyl chloride/m3 (0 or 1000 ppm) for 6 days, and
DNA lesions (cross-links and single-strand breaks),
glutathione transferase (GST) activity, and formaldehyde
dehydrogenase (FDH) activity were measured. It was
shown that the tumour formation in male mice is not
based on any obvious biochemical sex differences in
enzymatic transformation with respect to FDH. Neither is
the metabolically formed formaldehyde likely to be the
effective carcinogen, as the characteristic formaldehydeinduced genetic damage is absent. However, the significant species difference between mice and rats — in that
mice, due to higher GST activity, especially in the kidneys, seem to be more susceptible to methyl chloride
treatment — could not be ruled out. It was, for example,
not shown if toxicity caused by the glutathione conjugation pathway was due to a metabolite formed or to glutathione depletion, as suggested by Jäger et al. (1988).
In a subchronic toxicity study, 80 Fischer 344 rats
(40 per sex) and 80 B6C3F1 mice (40 per sex) were
exposed to methyl chloride by inhalation at concentrations of 0, 774, 1548, or 3096 mg/m3 (0, 375, 750, or 1500
ppm) for 90 days (CIIT, 1979). Clinical observations and
data on food consumption, body and organ weights,
haematology, clinical chemistry, urinalysis,
ophthalmoscopic examination, gross pathology, and
histopathology were recorded.
Female mice in the 3096 mg/m3 (1500 ppm) dose
group had significantly depressed total body weight at
the end of the exposure period. Absolute and/or relative
organ weights were increased for heart, brain, spleen,
liver, kidneys, and lungs in female mice (mainly in the
highest dose group) and in pancreas in male mice. Cytoplasmic vacuolization of hepatocytes occurred in the two
highest dose groups and was considered compound
related. In the 1548 mg/m3 (750 ppm) dose group, vacuolization was seen 5 times as frequently in females as in
males. Exposure-related fluctuations in haematology and
in clinical chemistry were observed but not considered
significant, as they were within the control range.
Further, the methyl chloride-exposed mice had a high
incidence of a mucopurulent conjunctivitis. However,
this effect was probably not related to methyl chloride
exposure, as it was seen mainly in the 774 mg/m3 (375
ppm) dose group. The available results indicate that
female mice are more sensitive than male mice to methyl
chloride exposure.
In conclusion, after short-term exposure, the target
organ in both rats and mice is the nervous system, with
functional disturbances and cerebellar degeneration. The
LOAELs in mice are 206 and 826 mg/m3 (100 and
400 ppm) upon continuous and intermittent exposure,
respectively. Higher levels of exposure caused toxicity in
the kidney and liver in mice and in the testes, epididymis,
and kidney in rats. A mouse LOAEL of 1032 mg/m3 (500
ppm) could be derived from liver toxicity data. The
decrease in thymus weight, unaccompanied by
histopathological changes, in mice exposed to 31 mg/m3
(15 ppm) was not corroborated by either a 90-day (CIIT,
1979) or a 2-year study (CIIT, 1981) (reported in sections
8.4 and 8.5, respectively). Because of this lack of
corroboration, the decrease in thymus weight will not be
forwarded to the sample risk characterization.
Male rats in all dose groups and females in the two
highest dose groups showed significantly decreased
absolute body weight. In rats (males and/or females;
mainly in the highest dose group), absolute and/or rela-
15
Concise International Chemical Assessment Document 28
Total body weight gain was significantly reduced
throughout the exposure period for male and female rats
in the 2064 mg/m3 (1000 ppm) exposure group. Although
female rats in the 464 mg/m3 (225 ppm) group and female
mice in the 2064 mg/m3 (1000 ppm) group also had
significantly decreased growth rates, these occurred
periodically and were not observed at the end of
exposure. The relative heart weight was increased in
female mice and male and female rats at 2064 mg/m3 (1000
ppm). Otherwise, changes in relative or absolute organ
weights were seen at the 2064 mg/m3 (1000 ppm)
exposure level for kidney, liver, heart, and brain in both
species and in testes in rats. For comparison with the
short-term exposure study by Landry et al. (1985),
thymus weight was not affected by methyl chloride
exposure in the 2-year study.
tive organ weights were increased for heart, brain, testes,
ovaries, spleen, liver, kidney, pancreas, and adrenals.
In the 1979 CIIT study (which served as a pilot for
the 2-year chronic toxicity/carcinogenicity study by CIIT
[1981]), no compound-related lesions were reported from
gross pathology or histopathology on kidneys, heart, or
testes. The absence of recorded organ lesions in mice
could be due to a fairly high mortality, especially in the
highest dose group, in combination with the histological
examination applied. In the histopathological
examination, as a first step, the highest dose group was
compared with the control group. In the case of positive
findings, the control animals were thereafter compared
with the 1548 mg/m3 (750 ppm) dose group and then the
375 ppm (774 mg/m3) dose group. This procedure might
suffer from a high mortality in the 3096 mg/m3 (1500 ppm)
dose group and give rise to false negatives. No similar
explanation could be given for rats, as the mortality
during the exposure period was low.
8.5
Clinical observations on toxicity to the central
nervous system (hunched posture, tremor, and
paralysis) were seen in mice in the highest dose group
but not in rats.
Long-term exposure and
carcinogenicity
In mice, statistically significant hepatocellular
changes (vacuolization, karyomegaly, cytomegaly, and
degeneration) were seen in male and female mice from
the 2064 mg/m3 (1000 ppm) group. In male mice exposed
to 2064 mg methyl chloride/m3 (1000 ppm), significantly
elevated serum glutamic–pyruvic transaminase (SGPT)
values were seen, coupled with histopathological
findings in the liver. Elevated SGPT values were also
observed in the lower dose groups but were not
correlated with any histopathological findings.
In a 2-year inhalation study, Fischer 344 rats and
B6C3F1 mice (120 animals per sex per group) were
exposed to 0, 103, 464, or 2064 mg methyl chloride/m3 (0,
50, 225, or 1000 ppm) for 6 h/day, 5 days/week, with the
objective of determining the potential toxicological and
oncogenic effects (CIIT, 1981). Planned interim
necropsies of the experimental animals were completed at
6, 12, 18, and 24 months following initiation of exposure.
As a result of high mortality in the mouse high-dose
group, the scheduled 24-month sacrifice was carried out
after 21 or 22 months of exposure. After 6 or 12 months,
10 rats per sex per dose group were scheduled to be
sacrificed, and after 18 or 24 months, 20 and 80 rats per
sex per dose group, respectively. Mice were scheduled
for sacrifice in groups of 10 per sex per dose group after
6, 12, or 18 months and in groups of 90 per sex per dose
group after 24 (or 21, 22 months). Data on body weights,
clinical signs of toxic effects, clinical chemical analyses,
gross pathology, and histopathology were recorded.
In the 2064 mg/m3 (1000 ppm) dose group in male
mice, a large, statistically significant increase (P > 0.05)
in the development of renal tubuloepithelial hyperplasia,
hypertrophy, and/or karyomegaly, with onset at
12 months, was observed. Further, in the same group,
significant exposure-related increases (P < 0.05) in
numbers of observed renal cortical adenomas as well as
renal adenocarcinomas (including those designed as
renal cortical adenocarcinomas and renal cortical
papillary cystadenocarcinomas) were noted in animals
sacrificed or dying between 12 and 21 months (incidences of cortical renal lesions are found in Table 3).
Cortical adenomas were also seen in two male mice in the
464 mg/m3 (225 ppm) group. Although this increase was
not of statistical significance, the adenomas were similar
to those that occurred in the 2064 mg/m3 (1000 ppm)
group and were therefore judged to be associated with
the methyl chloride exposure. In the 103 mg/m3 (50 ppm)
group, there was a slightly increased incidence of renal
cortical microcysts in male mice sacrificed at 24 months
compared with the control males (6/32 vs. 1/20). Renal
microcysts were also observed in the 464 mg/m3 (225
ppm) group; the
During the exposure period, rat survival was not
affected by methyl chloride exposure. However, mouse
survival was low in the 2064 mg/m3 (1000 ppm) dose
group compared with the control animals. The high
mortality occurred predominantly during the first
6 months and was attributed by CIIT (1981) to fighting
for dominance. The number of rats and mice that died
during the 2-year study for reasons other than planned
sacrifice is given in Table 2.
16
Methyl chloride
Table 2: Number of rodents that died during the exposure period for reasons other than scheduled sacrifice.
Number of rodents that died
0 ppm
Species
50 ppm
225 ppm
1000 ppm
male
femal
e
male
female
male
female
male
female
Rats
15
23
12
19
12
23
14
19
Mice
75
33
62
34
62
25
93
73
Table 3: Total number of significant cortical renal lesions (malign and benign) observed in male B6C3F1 mice
exposed to methyl chloride for 2 years.
Number of renal lesions/number of animals necropsied
0 ppm
Renal lesions
50 ppm
225 ppm
1000 ppm
m
f
m
f
m
f
m
f
Cortex, adenocarcinoma
0/120
0/120
0/118
0/100
0/117
0/123
5/120
0/109
Cortex, papillary cysts,
adenocarcinoma
0/120
0/120
0/118
0/100
0/117
0/123
1/120
0/109
Cortex, adenoma
0/120
0/120
0/118
0/100
2/117
0/123
12/120
0/109
Cortex, papillary cysts, adenoma
0/120
0/120
0/118
0/100
0/117
0/123
2/120
0/109
Cortex tubuloepithelium, hypertrophy,
hyperplasia, and/or karyomegaly
0/120
0/120
0/118
0/100
0/117
0/123
44/120
0/109
2064 mg/m3 [1000 ppm]: 3/7 males and no data on
females). The effects at each exposure level were
significantly increased in each dose group as compared
with control animals. However, no concentration–
response relationship could be established. In the
2064 mg/m3 (1000 ppm) dose group sacrificed at
22 months, minimal to moderate swelling and degeneration of the lumbar spinal nerves were recorded in 13 of
18 female mice. Twelve of 18 females had similar lesions
in the thoracic spinal cord, and 6/18 females in the
cervical spinal cord. Histopathological examinations of
mice in the 2064 mg/m3 (1000 ppm) dose group with
unscheduled death showed high incidences of cerebellar
lesions and axonal degeneration of lumbar spinal nerves,
lesions similar to those found at the 18-month sacrifice.
increase, as compared with the control group, was not,
however, significant in either males or females. The
incidence of renal cortical microcysts was not reported in
animals from the highest dose group. Since the microcysts appear to be variations of the same lesion
observed at higher exposure levels, they should be
considered to be related to methyl chloride, although no
concentration dependence could be established.
Further, at 2064 mg/m3 (1000 ppm), degeneration
and atrophy of the seminiferous tubules were seen, as
well as lymphoid depletion and splenic atrophy.
At the 18-month sacrifice, cerebellar lesions
(degeneration and atrophy of the cerebellar granular
layer) were noted in male and female mice at the
2064 mg/m3 (1000 ppm) level. Mice from the control, low,
and intermediate exposure groups did not have lesions
in the granular cell layer of the cerebellum. At the 22month sacrifice, similar but more extensive observations
in 17/18 females were reported from the 2064 mg/m3 (1000
ppm) group (the only group examined at this time
period).
In rats, exposure to methyl chloride at 2064 mg/m3
(1000 ppm) caused testicular lesions (bilateral, P > 0.05,
and unilateral, P > 0.05, diffuse degenerations and
atrophies of the seminiferous tubules). These lesions
were statistically significant as compared with the
control group and were first observed at the 6-month
sacrifice. Sperm granulomas were noted in three male rats
at 2064 mg/m3 (1000 ppm). No statistically significant
changes other than the effects on body weight gain were
seen in female rats. This indicates that the maximum
tolerated dose used in the CIIT (1981) study might have
been too low to induce toxicity in female rats.
At the 18-month sacrifice, axonal swelling and
degeneration of minor severity were observed in the
spinal nerves and cauda equina associated with the
lumbar spinal cord. The effects occurred in most treated
animals in all dose groups (controls: 1/5 males and 2/10
females; 103 mg/m3 [50 ppm]: 4/5 males and 10/10
females; 464 mg/m3 [225 ppm]: 5/5 males and 5/5 females;
Significant findings from the long-term studies in
mice are disturbances of the nervous system and
17
Concise International Chemical Assessment Document 28
In vitro, 1–10% methyl chloride caused induction
of unscheduled DNA synthesis (UDS) in rat spermatocytes and hepatocytes (Working et al., 1986).
induction of tumours and microcysts in male mice.
Axonal swelling and degeneration of spinal nerves in all
exposure groups suggest a LOAEL of 103 mg/m3
(50 ppm). This LOAEL is forwarded to the sample risk
characterization. The observation of renal microcysts in
the 103 mg/m3 (50 ppm) dose group (although not concentration related) supports the LOAEL of 103 mg/m3
(50 ppm). Further significant findings are the testicular
lesions in rats. In male rats, testicular lesions occurred at
2064 mg/m3 (1000 ppm). No toxic effects in females were
reported.
Methyl chloride was shown to directly bind to
bovine serum albumin. No further details were available
(Kornbrust et al., 1982).
In TK/6 human lymphoblasts, methyl chloride
induced a statistically significant concentration-related
induction of sister chromatid exchange (SCE) frequency
as well as significantly declined mitotic index and a
significant concentration-related increase in seconddivision metaphases (Fostel et al., 1985).
No toxicity data from long-term exposure to methyl
chloride other than those obtained from administration
via the respiratory pathway were located in the literature.
8.6.2
8.6
In vivo, methyl chloride did not cause induction of
UDS in rat spermatocytes, hepatocytes, or tracheal
epithelial cells at exposure concentrations of 6192–
7224 mg/m3 (3000–3500 ppm) for 6 h/day for 5 days.
However, exposure to 30 960 mg/m3 (15 000 ppm) for 3 h
did cause a marginal increase in UDS in hepatocytes
(Working et al., 1986). The doses used were considered
below, but close to, the maximum tolerated dose.
For an overview of, and details on, the genotoxicity studies, see Table 4. In all studies referred to
below, methyl chloride was administered by inhalation,
unless otherwise noted.
8.6.1
Studies in vivo
Genotoxicity and related end-points
Studies in vitro
Using the Ames assay, methyl chloride was shown
to induce gene mutations in Salmonella typhimurium
TA100 (Simmon et al., 1977) and in S. typhimurium
TA1535 (Andrews et al., 1976) in both the presence and
absence of metabolic activation. Further, a concentration-related increase in the 8-azaguanine-resistant
fraction in S. typhimurium was observed (Fostel et al.,
1985).
In a macromolecular binding study, male rats were
exposed to 14C-labelled methyl chloride (specific activity
25–70 dpm/nmol = 11.2–31.4 × 10–3 mCi/mmol), and
accumulation of 14C was measured in lipid, RNA, DNA,
and protein from isolated liver, kidneys, lungs, and
testes (Kornbrust et al., 1982). Radiolabelled carbon was
found in all tissues and fractions studied; however,
methylation was not found. Pretreatment with the protein
synthesis inhibitor cycloheximide or the folic acid
antagonist methotrexate, which interferes with singlecarbon metabolism, to a large extent inhibited most of the
14
C-incorporation in proteins and macromolecules,
respectively. Further, the extent of incorporation of
methyl chloride into proteins and lipids was consistent
with the rates of turnovers in these macromolecules.
Therefore, the most likely mechanism for uptake of
methyl chloride into macromolecules is via the onecarbon pool. However, this does not exclude the
possibility that methyl chloride might bind directly to
macromolecules to a lesser extent.
Methyl chloride induced the adaptive response to
alkylation damage in Escherichia coli regulated by the
ada protein, which suggests that methyl chloride is a
direct DNA-alkylating agent (Vaughan et al., 1993).
Methyl chloride caused gene mutations in vitro in
TK6 human lymphoblasts, as shown by a dose-related
increase in the mutant fraction (Fostel et al., 1985).
In the study by Fostel and co-workers (1985), no
increase in DNA strand breaks as measured by alkaline
elution was observed. However, the outcome from the
positive control (methyl methane sulfonate [MMS]) was
questionable, as unexpectedly high doses were needed
for a positive result. Thus, the mutagenic lesions produced by methyl chloride might be either different from
those produced by MMS or formed at a level below the
threshold of detection of alkaline solution.
In a DNA binding assay, in which Peter et al.
(1985) exposed rats and mice to 14C-labelled methyl
chloride, no methylation of guanine in DNA at N7 and/or
O6 in liver and kidneys by methyl chloride was found.
The specific activity in this study (13 mCi/mmol = 2.9 ×
104 dpm/nmol) was about 3 orders of magnitude higher
than that used by Kornbrust et al. (1982).
DNA damage following methyl chloride exposure
was shown as a statistically significant enhanced
transformation of Syrian hamster embryo cells by SA7
adenovirus (Hatch et al., 1983).
18
Methyl chloride
Table 4: Genotoxicity of methyl chloride and related end-points.
Table 4 (contd)
Species
Protocol
Result
Reference
Gene mutation in vitro; bacteria
S. typhimurium TA100
Ames test
2.5–20%; 8 h; ± S9 mix
positive
Simmon et
al., 1977
S. typhimurium TA1535
Ames test
0.5–20.7%; ± S9 mix
positive
Andrews et
al., 1976
S. typhimurium TM677
(8-azaguanine
resistance)
bacterial forward mutation assay
0, 5, 10, 20, or 30%; 3 h; strain deficient in metabolizing
xenobiotics; no metabolizing system was added
positive
adaptive response to alkylation damage (ada gene)
positive
Vaughan et
al., 1993
positive
Fostel et al.,
1985
Fostel et
al.,
1985
DNA damage in vitro; bacteria
E. coli B F26
Gene mutation in vitro; mammalian cells
human lymphoblasts
TK6 (trifluorothymidine
resistance)
gene mutation
0, 1, 2, 3, 4, or 5%; 3 h
positive controls: ethyl methane sulfonate (EMS) or methyl
methane sulfonate (MMS)
DNA damage in vitro; mammalian cells
human lymphoblasts
TK6
alkaline elution
0, 1, 3, or 5%
positive controls: EMS or MMS
negative
Fostel et al.,
1985
Syrian hamster embryo
cells (primary SHE cells)
DNA damage and repair assay
(DNA adenovirus SA7 transformation)
0, 6000, 12 000, 27 000, 52 000, or 103 000 mg/m 3 (0,
3000, 6000, 13 000, 25 000, or 50 000 ppm); 2–20 h
positive
Hatch et al.,
1983
rat, F-344
hepatocytes
spermatocytes
unscheduled DNA synthesis
1–10%
positive
Working et
al., 1986
bovine serum albumin
protein binding assay
positive
Kornbrust et
al., 1982
positive
Fostel et al.,
1985
Working et
al., 1986
Chromosomal effects in vitro; mammalian cells
human lymphoblasts
TK6
sister chromatid exchange assay
0, 0.3, 1.0, or 3.0%
positive control: EMS
DNA damage in vivo; mammals
rat, F-344
hepatocytes
spermatocytes
tracheal epithelial cells
unscheduled DNA synthesis
6192–7224 mg/m 3 (3000–3500 ppm), 5 days, 6 h/day
negative
unscheduled DNA synthesis
30 960 mg/m 3 (15 000 ppm); 3 h
weakly
positive
rat, F-344, males
3 or 6 animals per group
(no further information
on groups was available)
DNA binding study
1032, 3096 mg/m 3 (500, 1500 ppm); 6 h + 24 h
postexposure
specific radioactivity: 25–70 dpm/nmol = 11.2–31.4 × 10 –3
mCi/mmol
liver, kidney, lung, testes
negative
Kornbrust et
al., 1982
mouse, B6F3C1, males
and females
6 animals per group
DNA–protein cross-links
0 or 2064 mg/m 3 (0 or 1000 ppm); 8 h
indications
(male
mice)
Ristau et al.,
1989
19
Concise International Chemical Assessment Document 28
Table 4 (contd)
Species
Protocol
Result
Reference
rat, F-344, males and
females
5 animals per group
DNA binding study
exposure for 4 h of rats in a closed chamber; initial
concentration approximately 2064 mg/m 3 (1000 ppm)
(reading off from graphs)
specific radioactivity: 13 mCi/mmol = 2.9 × 10 4 dpm/nmol
negative
Peter et al.,
1985
mouse, B6C3F1, males
and females
25 animals per group
DNA binding study
exposure for 4 h of rats in a closed chamber; initial
concentration approximately 2064 mg/m 3 (1000 ppm)
(reading off from graphs)
specific radioactivity: 13 mCi/mmol = 2.9 x 10 4 dpm/nmol
ngative
Peter et al.,
1985
rat, F-344, males and
females
5 animals per group
DNA–protein cross-links
2064 mg/m 3 (1000 ppm)
approximately 6 h/day for 6 days
indication
Jäger et al.,
1988
mouse, B6F3C1, males
and females
5 animals per group
2064 mg/m 3 (1000 ppm)
approximately 6 h/day for 6 days
animals sacrificed 6 h postexposure
Chromosomal effects in vivo; mammals
rat, Fischer 344,
males
80 animals per group
dominant lethal test
6 h/day for 5 days + 17 exposure-free weeks
0, 2064, 6192 mg/m 3 (0, 1000, 3000 ppm) + positive
control triethylenemelamine (TEM)
Using the alkaline elution technique, no cross-links
in male mouse kidneys could be detected after exposure
to 2064 mg methyl chloride/m3 (1000 ppm) for 6 days, but
some indications of DNA single-strand breaks were
obtained (Jäger et al., 1988). However, when mice were
exposed to 2064 mg/m3 (1000 ppm) for 8 h only, DNA
cross-links were seen in renal tissue of male mice but not
in female mice or in hepatic tissues (Ristau et al., 1989).
In an attempt to investigate the time-course of the DNA
lesions, Ristau et al. (1990) again exposed male mice to
2064 mg methyl chloride/m3 (1000 ppm) for 8 h. In renal
tissue, it was observed that DNA–protein cross-links
were removed at a fast rate, whereas single-strand breaks
appeared to accumulate. At 48 h postexposure, all
lesions had disappeared.
negative
(probably a
cytotoxic
effect)
Working et
al., 1985a
origin. However, a genotoxic effect should not be totally
excluded.
The role of epididymal inflammation in the induction of lethal mutations was studied by Chellman et al.
(1986c) in an assay with a test protocol similar to the
OECD test guideline for dominant lethal mutations. Rats
were exposed to methyl chloride in the presence or
absence of the anti-inflammatory agent BW755C.
BW755C was effective against the postimplantation
losses induced by methyl chloride, but not against preimplantation losses. The authors’ conclusions, based on
unpublished data mentioned in Chellman et al. (1986c),
are that the increase in preimplantation losses might be a
consequence of testicular lesions caused by methyl
chloride and that BW755C is effective against
epididymal injuries only, thus indicating that epididymal
inflammation has a role in the induced infertility.
In a dominant lethal assay, performed according to
Organisation for Economic Co-operation and Development (OECD) test guidelines, male rats were exposed to
methyl chloride (Working et al., 1985a). The numbers of
live and total implants were decreased, there was an
increase in the percentage of preimplantation loss at
weeks 2, 4, 6, and 8 postexposure, and there was an
increase in the percentage of postimplantation loss at
week 1 postexposure. The changes observed were not
concentration related. A true dominant lethal effect of
genetic origin could be questioned, as the time-courses
of the pre- and postimplantation losses after methyl
chloride exposure were not the same as those obtained
after administration of the positive control, triethylenemelamine (TEM). The development of sperm granulomas
in the epididymis, the effects seen in the dominant lethal
assay, seems to be cytotoxic rather than genotoxic in
In conclusion, methyl chloride is clearly genotoxic
in in vitro systems, in both bacteria and mammalian cells.
Methyl chloride binds to protein. Methyl chloride is
possibly an alkylating agent; however, the available
studies do not allow any quantification. Although the
positive effects seen in a dominant lethal test were most
likely cytotoxic rather than genotoxic, methyl chloride
might be considered a very weak mutagen in vivo based
on some evidence of DNA–protein cross-linking at
higher doses.
20
Methyl chloride
8.7
Reproductive and developmental
toxicity
8.7.1
Effects on fertility
Chapin et al. (1984) investigated the development
of lesions induced in testes and epididymis and effects
on reproductive hormones in F-344 rats after exposure to
0 or 6192 mg methyl chloride/m3 (0 or 3000 ppm) for a
total of 9 days (6 h/day; approximately 60 exposed animals and 16 control animals). Testicular lesions in the
form of delay in spermiation, germinal epithelial vacuolization, and cellular exfoliation as well as bilateral epididymal granulomas were seen. The effects were observed
in most animals, with the onset at day 9 or 11 after the
beginning of the exposure. In general, lesions seen in
In the 1981 CIIT study, referred to in section 8.5,
exposure to methyl chloride at 2064 mg/m3 (1000 ppm)
caused testicular lesions in rats. The lesions seen were
bilateral and consisted of diffuse degeneration and
atrophy of the seminiferous tubules.
Table 5: Breeding results in rats in the F0 and F2 generations after methyl chloride exposure.
Breeding results
0 ppm
150 ppm
475 ppm
1500 ppm
F0 generation: number of exposed males proven
fertile when mated to exposed females
18/40 (45%)
20/39 (51%)
12/40 (30%)
0/40 (0%)
F0 generation: number of exposed males proven
fertile when mated to unexposed females
23/28 (82%)
21/28 (75%)
12/28 (43%)
0/26 (0%)
F1 generation: number of exposed males proven
fertile when mated to exposed females
31/40 (78%)
26/40 (65%)
14/23 (61%)
–
animals at day 19 were of higher severity than those
seen earlier. In rats killed 70 days or more after the onset
of the exposure, 70–90% of the seminiferous tubules
lacked any germinal cells; in 10–30% of the tubules,
varying degrees of recovery of spermiation were
observed. The LOAEL in this study must be set at
6192 mg/m3 (3000 ppm).
size, sex ratio, pup viability, or pup growth were found
among the 980 mg/m3 (475 ppm) and 310 mg/m3 (150 ppm)
groups compared with the control F0 group. A trend
towards decreased fertility was also found in the 980
mg/m3 (475 ppm) dose group in the F1 generation. A
LOAEL of 980 mg/m3 (475 ppm) (infertility) was derived
from the two-generation study. Breeding results in rats
in the F0 and F2 generations after methyl chloride
exposure are shown in Table 5.
In a dominant lethal assay in rats exposed to
methyl chloride for 5 days, described in section 8.6,
visible sperm granulomas in the epididymis were present
in the 6192 mg/m3 (3000 ppm) group 17 weeks postexposure but not in the 2064 mg/m3 (1000 ppm) group or
in the control group. After exposure to 6192 mg/m3 (3000
ppm), the number of live and total implants was
decreased, and there was an increase in postimplantation
loss. In both treated groups, there was an increase in
preimplantation losses (Working et al., 1985a). The
LOAEL for preimplantation loss was 2064 mg/m3
(1000 ppm).
A two-generation inhalation study in Fischer 344
rats was carried out at methyl chloride concentrations of
0, 310, 980, or 3096 mg/m3 (0, 150, 475, or 1500 ppm)
(Hamm et al., 1985). The F0 generation (40 males and 80
females per exposure group) was exposed for 10 weeks
and during a 2-week mating period (6 h/day,
5 days/week, and 6 h/day, 7 days/week, respectively). A
similar exposure schedule was used for the F1 generation, with the exclusion of the 3096 mg/m3 (1500 ppm)
exposure level. In the high-dose F0-generation males
sacrificed immediately after 12 weeks of exposure,
treatment-related lesions were found, consisting of
minimal to severe atrophy of the seminiferous tubules
(10/10 males examined) and granulomas in the epididymis
(3/10). Severely affected tubules were lined by Sertoli’s
cells and by occasional stem cell spermatogonia. In the
less affected tubules, decreased numbers of
spermatogonia, primary spermatocytes, and/or
secondary spermatocytes were found.
In a subsequent study, Working et al. (1985b)
characterized the effect of methyl chloride exposure on
sperm quality and histopathology in rats in more detail.
Male Fischer 344 rats (80 animals per group) were
exposed to 0, 2064, or 6192 mg methyl chloride/m3 (0,
1000, or 3000 ppm) for 5 days, 6 h/day. Besides significantly decreased testis weights in the high-dose group
3–8 weeks postexposure and the findings that more than
50% of the treated animals showed sperm granulomas in
the epididymis in the same dose group, observations
indicating cytotoxic effects on sperm quality were made.
Further, in the F0 generation, no litters were born
when high-dose males were mated to exposed or unexposed females, and significantly fewer litters were born
to unexposed females mated to the males in the
980 mg/m3 (475 ppm) dose group. No differences in litter
21
Concise International Chemical Assessment Document 28
Observations made at the 6192 mg/m3 (3000 ppm) level
included significant decreases in testicular spermatid
head counts, delay in spermiation, epithelial vacuolization, luminal exfoliation of spermatogenic cells, and
multinucleated giant cells. Further, sperm isolated from
the vasa deferentia had significantly depressed numbers
and an elevated frequency of abnormal sperm head
morphology by week 1 postexposure and significantly
depressed sperm motility and increased frequency of
headless tails by week 3 postexposure. These changes
were all within or close to the normal range by week 16
postexposure. A LOAEL of 6192 mg/m3 (3000 ppm) could
be derived based on the histopathological findings.
In parallel with the rat study, Wolkowski-Tyl et al.
(1983a) also evaluated teratogenicity in pregnant
C57BL/6 mice (33 mice per dose group) carrying B6C3F1
fetuses exposed through gestation days 6–17 following
the same exposure schedule as the rats. Dams in the 3096
mg/m3 (1500 ppm) group died or were killed in extremis
due to very high toxicity (tremor, hunched appearance,
difficulty in righting, vaginal bleeding, bloody urine,
cerebellar granular cell necrosis and degeneration, etc.).
No other maternal toxicity was observed in the other
exposure groups. In the 1032 mg/m3 (500 ppm) group, the
fetuses (male and female) had a small but significant
increase in heart defects (reduction or absence of the
atrioventricular valves, chordae tendineae, and papillary
muscles). In both the 1032 and 206 mg/m3 (500 and 100
ppm) groups, a significant increase in degree of
ossification in the hindlimbs was seen as compared with
control animals. A LOAEL for heart defects in fetuses of
1032 mg/m3 (500 ppm) was obtained.
The cause of preimplantation loss induced by
methyl chloride was further investigated in rats by
Working & Bus (1986). Fischer 344 rats (10–30 animals
per group) inhaled 0, 2064, or 6192 mg methyl chloride/m3
(0, 1000, or 3000 ppm) 6 h/day for 5 days or received a
single injection of TEM as a positive control for
genotoxicity. At weeks 1–3 postexposure in the
6192 mg/m3 (3000 ppm) group, preimplantation losses did
not exceed unfertilized ova, which was the case for the
positive control. From these data, the authors suggested
that preimplantation losses are due to a failure in
fertilization rather than to an increase in embryonal
deaths.
In a subsequent study, Wolkowski-Tyl et al.
(1983b) again exposed pregnant C57BL/6 mice carrying
B6C3F1 fetuses with the aim of confirming the earlier
findings, elucidating the nature of the heart defects more
clearly, and establishing a concentration–effect relationship. Approximately 75 mice per dose group were
exposed to 0, 516, 1032, or 1548 mg methyl chloride/m3 (0,
250, 500, or 750 ppm) for 6 h/day during gestation days
6–18. In the 1032 and 1548 mg/m3 (500 and 750 ppm)
groups, an exposure-related increase in heart defects
(involving effects on the atrioventricular valves, chordae
tendineae, and papillary muscles) was observed. Dams
were affected at the 1548 mg/m3 (750 ppm) exposure level
(decrease in body weight and body weight gain). No
maternal toxicity, embryotoxicity, fetotoxicity, or
teratogenicity was associated with exposure to methyl
chloride at 516 mg/m3 (250 ppm). In this study, the
LOAEL for heart defects was 1032 mg/m3 (500 ppm), the
NOAEL was 516 mg/m3 (250 ppm), and the maternal
LOAEL was 1548 mg/m3 (750 ppm).
In conclusion, testicular lesions and epididymal
granulomas followed by reduced sperm quality lead to
reduced fertility as well as complete infertility in rats. A
LOAEL of 980 mg/m3 (475 ppm) and a no-observedadverse-effect level (NOAEL) of 310 mg/m3 (150 ppm)
were identified from the two-generation study of Hamm
et al. (1985).
8.7.2
Developmental toxicity
In a study designed to study structural teratogenicity, pregnant Fischer 344 rats (25 rats per dose group)
were exposed to 0, 206, 1032, or 3096 mg methyl chloride/
m3 (0, 100, 500, or 1500 ppm) for 6 h/day through
gestation days 7–19 (Wolkowski-Tyl et al., 1983a). In the
highest dose group, significant reductions in fetal body
weight and female crown–rump length were observed.
Further, skeletal immaturities such as reduced
ossification (metatarsals and phalanges of the anterior
limbs, thoracic vertebral centra, pubis of pelvic girdle,
and metatarsals of the hindlimbs) were seen. Although
these findings were seen in the presence of significantly
decreased maternal food consumption, body weight, and
weight gain in the same dose group, they should be
considered as serious and exposure related. A fetal
LOAEL for skeletal immaturities as well as a maternal
LOAEL for effects on body weight and food consumption of 3096 mg/m3 (1500 ppm) were obtained. No other
effects, including heart defects, were reported from the
206 and 1032 mg/m3 (100 and 500 ppm) dose groups.
In a number of different experiments on small
numbers of animals, pregnant C57BL/6 mice carrying
B6C3F1 fetuses were exposed to methyl chloride at
concentrations of 516, 619, or 2064 mg/m3 (250, 300, or
1000 ppm) for 12–24 h during gestation day 11.5–12.5
(John-Greene et al., 1985). The exposure time was chosen
as a critical period in development of cardiac defects.
The authors found heart defects when the test was nonblind but not when the technician was unaware of which
fetuses were exposed. Further, John-Greene et al. (1985)
had concerns regarding the technique used by
Wolkowski-Tyl et al. (1983a). However, the investigation
by John-Greene et al. (1985) is difficult to evaluate, as a
small number of animals were used and as the exposure
period was not similar to those in the Wolkowski-Tyl et
al. (1983a, 1983b) studies. No LOAEL could be
established.
22
Methyl chloride
disturbances, mental confusion, and paraesthesis.
Neurotic and depressive symptoms are also described.
Further, gastrointestinal symptoms (nausea, vomiting,
abdominal pain, etc.) have been observed, as well as
jaundice. In general, the symptoms seem to develop
soon after the exposure. However, recovery periods vary
to a large extent; for example, in seamen highly exposed
to methyl chloride, effects on the nervous system were
observed 13 years after the accident (Gudmundsson,
1977).
In conclusion, from the studies by Wolkowski-Tyl
and co-workers (1983a, 1983b), it seems that methyl
chloride could induce heart defects in mice exposed to
1032 mg/m3 (500 ppm) when dams were exposed through
gestation days 6–18. A NOAEL of 206 mg/m3 (100 ppm)
was established from the developmental toxicity studies.
8.8
Immunological and neurological
effects
9.3
No specific reports on immunological or neurological effects caused by methyl chloride were found in
the literature.
Performance and cognitive functions were
adversely affected in workers manufacturing foam
products. There was also an increase in the magnitude
of finger tremors. The workers were exposed for 2 years
to approximately 72 mg methyl chloride/m3 (35 ppm), as
well as other chemicals (NIOSH, 1976). However,
insufficient information was available on exposure to the
other chemicals and lifestyle factors, and no relationship
could be established between methyl chloride exposure
and the various psychological and personality tests
employed.
9. EFFECTS ON HUMANS
9.1
Studies in volunteers
In order to monitor the physiological response to
methyl chloride in healthy volunteers (eight men and
nine women) with no previous methyl chloride exposure,
Stewart et al. (1980) exposed the volunteers to methyl
chloride at concentrations of 0, 41, 206, or (men only) 310
mg/m3 (0, 20, 100, or [men only] 150 ppm), 1, 3, and 7.5
h/day, 5 days/week, for 6 weeks in an exposure chamber.
Using a wide battery of behavioural, neurological,
electromyographic, and clinical tests, no significant
decrements were found in the exposed volunteers as
compared with controls. For interindividual differences
in methyl chloride concentrations in blood and expired
air, see section 7.
A mortality follow-up study was conducted of
852 male workers employed for at least 1 month between
the years 1943 and 1978 in a butyl rubber manufacturing
plant using methyl chloride (Holmes et al., 1986). For
each cohort member, complete work history and death
information were obtained. No information on lifestyle
factors was reported. The exposure to methyl chloride
and other compounds used in the butyl rubber manufacturing plant was estimated in three categories (high,
medium, and low). No detectable excess mortality from
any specific cause of death including all cancers was
found in the study population after analysis by level
and duration of exposure.
In volunteers, Putyz-Anderson and co-workers
(1981a, 1981b) found minimal or no effects on
performance after exposure to methyl chloride at 206 or
413 mg/m3 (100 or 200 ppm) for 3h (n=56) and at 413
mg/m3 (200 ppm) for 3.5 h (n=84), respectively
9.2
Epidemiological studies
In a 32-year follow-up study by Rafnsson &
Gudmundsson (1997), indications of elevated mortality
from cardiovascular disease after high accidental methyl
chloride exposure were seen in Icelandic seamen (deckhands: relative risk [RR] = 3.9, 95% confidence interval
[CI] = 1.0–14.4; officers: RR = 1.7, 95% CI = 0.3–6.4). The
small number of observed cancers (all cancers and lung
cancers) in the exposed group provides an insufficient
basis for assessing the cancer risk in humans. The
reference group used was controlled for age,
occupation, social class, and lifestyle factors.
Case reports
Available information related to the toxic effects on
humans exposed to high concentrations of methyl
chloride is mainly derived from accidental exposures in
connection with the use of methyl chloride in the
production of polystyrene foams and also from
refrigerator leakages. Among symptoms described in
case reports (see, for example, MacDonald, 1946;
McNally, 1946; Hansen et al., 1953; Thordarson et al.,
1964; Scharnweber et al., 1974; Spevak et al., 1976;
Gudmundsson, 1977; Lanham, 1982) are effects on the
nervous system, such as dizziness, weakness, blurred
vision, muscular incoordination, drowsiness, sleep
In conclusion, effects on humans, especially on
the central nervous system, can clearly be seen after
accidental (mostly high) exposure or after normal work
exposure levels. A rough estimation of the degree of
exposure from case reports might be in the order of
approximately 200–2000 mg/m3 (100–1000 ppm). In shortterm exposure of volunteers, no significant effects were
23
Concise International Chemical Assessment Document 28
Table 6: Short-term toxicity to aquatic organisms.
Organism
End-point
Toxicity (mg/litre)
Reference
Cyanobacteria
Microcystis aeruginosa
Toxicity threshold, EC3
(cell multiplication inhibition test)
550
Bringmann & Kühn,
1976
Toxicity threshold, EC3
(cell multiplication inhibition test)
1450
Bringmann & Kühn,
1980
Toxicity threshold, EC5
(cell multiplication inhibition test)
>8000
Bringmann & Kühn,
1980
Green algae
Scenedesmus quadricauda
Protozoa
Entosiphon sulcatum
Fish
Bluegill sunfish (Lepomis macrochirus)
96-h LC50
550
Dawson et al., 1977
Tidewater silverside (Menidia
beryllina)
96-h LC50
270
Dawson et al., 1977
Table 7: Short-term toxicity to terrestrial organisms.
Organism
End-point
Toxicity
Reference
Bacteria
Methanogenic bacteria (35 °C,
pH 7, anaerobic conditions)
48-h IC50
(inhibition of gas production)
50 mg/litre
Blum & Speece, 1991
Nitrobacter
(25 °C, pH 9.1)
24-h IC50
(inhibition of NO 2-N production)
2010 mg/litre
Tang et al., 1992
Pseudomonas putida
Toxicity threshold, EC3
(cell multiplication inhibition
test)
500 mg/litre
Bringmann & Kühn,
1976
Higher plants
Several speciesa
(3-h exposure in gas phase)
a
5000–10 000 mg/m 3 (2400–4800
ppm)
>5000 mg/m 3 (>2400 ppm)
>5000 mg/m 3 (>2400 ppm)
Visible symptoms
Photosynthesis
Transpiration
Christ, 1996
Tested plant species were tomatoes (Lycopersicum esculentum Miller), sunflower (Helianthus annuus L.), bush bean (Phaseolus
vulgaris L.), nasturtium (Tropaeolum majus L.), sugar-beet (Beta vulgaris L.), soya bean (Glycine maxima (L.) Merill), and wheat
(Triticum aestivum L.).
seen. There are insufficient data available to assess the
risk for humans to develop cancer as a result of methyl
chloride exposure.
(see Table 6). The acute toxicity to the two fish species
was determined under static conditions, and the concentration of the test substance was not measured. This
means that the toxicity may have been underestimated
by the test, if significant amounts of the test substance
volatilized during the test. The 96-h LC50 values for the
freshwater species, bluegill sunfish (Lepomis macrochirus), and the saltwater species, tidewater silverside
(Menidia beryllina), were determined to be 550 and
270 mg/litre, respectively (Dawson et al., 1977).
10. EFFECTS ON OTHER ORGANISMS IN
THE LABORATORY AND FIELD
10.1
Aquatic environment
10.2
Few data were found on the short-term toxicity of
methyl chloride to aquatic organisms, and no data were
found on long-term toxicity. The existing data for a
cyanobacterium, a green alga, a protozoan, and two fish
species indicate a low acute toxicity to aquatic species
Terrestrial environment
Data on the short-term toxicity of methyl chloride
were found only for three species of bacteria and some
higher plants (see Table 7). No chronic toxicity data were
found for terrestrial organisms.
24
Methyl chloride
Table 8: Summary of animal inhalation toxicity studies with relevance for risk characterization.
Study
duration
Species
End-point
LOAEL,
mg/m3 (ppm)
NOAEL,
mg/m3 (ppm)
Reference
Short-term exposure
mouse, C3H,
females;
C57BL/6,
males and
females
12 days
hepatocellular necrosis and
degeneration
1032 (500)
–
Morgan et al., 1982
mouse,
C57BL/6,
females
11 days,
continuous
exposure
cerebellar lesions
206 (100)
–
Landry et al., 1985
826 (400)
–
intermittent
exposure
Long-term exposure
rat, F-344
2 years
testicular lesions
2064 (1000)
464 (225)
CIIT, 1981
mouse,
B6C3F1
2 years
renal tumours in males; significant
increase at 2064 mg/m 3 (1000 ppm)
2064 (1000)
464 (225)
CIIT, 1981
development of renal microcysts in
males; also seen at 464 mg/m3 (225
ppm); no dose–response
103 (50)
nerve axonal swelling and
degeneration; seen in all treated
groups; effects significant as compared
with control
103 (50)
Reproductive toxicity — fertility
rat, F-344
9 days
testicular lesions and epididymal
granulomas
6192 (3000)
–
Chapin et al., 1984
rat, F-344
twogeneration
infertility; dose dependence or trend
980 (475)
310 (150)
Hamm et al., 1985
rat, F-344
5 days
preimplantation loss
2064 (1000)
–
Working et al., 1985a
rat, F-344
5 days
effects on sperm quality
6192 (3000)
2064 (1000)
Working et al., 1985b
Reproductive toxicity — development
rat, F-344
gestation
days 7–19
skeletal immaturities in the presence
of effects of maternal body weight and
food consumption
3096 (1500)
1032 (500)
Wolkowski-Tyl et al.,
1983a
mouse,
B6C3F1
gestation
days 6–17
heart defects in fetuses; significant
increase as compared with control
animals
1032 (500)
206 (100)
Wolkowski-Tyl et al.,
1983a
mouse,
B6C3F1
gestation
days 6–18
heart defects in fetuses; dose
dependence
1032 (500)
516 (250)
Wolkowski-Tyl et al.,
1983b
administration. However, as the major route of human
exposure to methyl chloride seems to be by the
respiratory pathway, the lack of data from other routes of
administration is of minor concern. It should be pointed
out that there are surprisingly few recent investigations
of methyl chloride toxicity for all end-points except
genotoxicity. In Table 8, data from inhalation toxicity
studies on methyl chloride in experimental animals are
summarized.
11. EFFECTS EVALUATION
11.1
Evaluation of health effects
11.1.1
Hazard identification and
dose–response assessment
The database for methyl chloride risk assessment
is in general acceptable in terms of toxicity after
inhalation exposure. Few data could be located in the
literature on methyl chloride toxicity after dermal or oral
Considering the human GSTT1 polymorphism and
the suggested metabolic pathways of methyl chloride
(Figure 2), it is not possible to conclude whether a rapid
metabolic clearance of methyl chloride as in high
25
Concise International Chemical Assessment Document 28
seen at 464 mg/m3 (225 ppm). Development of renal
cortical microcysts in mice was seen in the 103 mg/m3 (50
ppm) dose group and to some extent in the 464 mg/m3
(225 ppm) group (CIIT, 1981); however, no concentration–response relationship could be established
Although there are indications of low CYP2E1 activity in
male human kidney microsomes as compared with male
CD-1 mice, as shown by Speerschneider & Dekant
(1995), the presence of human renal CYP2E1 cannot be
excluded. Further, the presence of CYP2E1 in human
tissues other than kidneys might lead to the induction of
tumours in other organs. Therefore, the findings of renal
tumours in male mice should be considered as relevant
for humans.
conjugators (HC) leads to a higher or lower risk than a
longer retention of methyl chloride in the body as in low
conjugators (LC) or non-conjugators (NC). Further, as
the GSTT1 activity decreases in the order mouse liver
and kidney cytosol > HC > rat > LC > hamster > NC, it is
impossible to select one species of experimental animal
as preferable in the risk assessment of methyl chloride
when extrapolating animal effects data to humans.
Because of these uncertainties, no species of
experimental animal can be ruled out in favour of
another, and human high conjugators, low conjugators,
and non-conjugators must be considered as sensitive to
methyl chloride. Consequently, the lowest appropriate
LOAEL or NOAEL from any species could be chosen for
further risk characterization.
Methyl chloride is clearly genotoxic in in vitro
systems in both bacteria and mammalian cells. Methyl
chloride can bind to protein. However, if methyl chloride
is an alkylating agent, it is so to a very small extent.
Further, methyl chloride might be considered only a very
weak mutagen in vivo.
Data on single exposures are poor for methyl
chloride, and no firm conclusions can be drawn.
However, the acute inhalation toxicity in rats and male
mice after single exposure seems to be fairly low, with an
LC50 value above 4128 mg/m3 (2000 ppm). In mice, there
might be a sex difference in susceptibility to methyl
chloride, as the LC50 value obtained for female mice was
17 544 mg/m3 (8500 ppm).
Testicular lesions and epididymal granulomas
followed by reduced sperm quality lead to reduced
fertility as well as complete infertility in rats. A LOAEL of
980 mg/m3 (475 ppm) could be derived from the reproductive toxicity data where a concentration–response
could be established (NOAEL = 310 mg/m3 [150 ppm]).
No data on irritation and sensitization were
available. However, from short- and long-term exposure
data, no indications of respiratory irritation caused by
methyl chloride exposure have been reported. Thus,
methyl chloride is probably not a strong respiratory
irritant.
It seems from the Wolkowski-Tyl et al. (1983a,
1983b) studies that methyl chloride could induce heart
defects in mice exposed to 1032 mg/m3 (500 ppm) when
dams are exposed through gestation days 6–18. The
development of heart defects was concentration dependent. A NOAEL of 206 mg/m3 (100 ppm) could be
estimated from the developmental toxicity studies.
The principal target in both rats and mice upon
short-term exposure is the nervous system, with animals
exhibiting functional disturbances and cerebellar
degeneration. The LOAEL (based on cerebellar
degeneration) in mice is 206 mg/m3 (100 ppm) upon
continuous exposure. Higher levels of exposure caused
toxicity in the kidney and liver in mice and in the testes,
epididymis, and kidney in rats. The decrease in thymus
weight, unaccompanied by histopathological changes, in
mice exposed to 31 mg/m3 (15 ppm) was not corroborated
by either a 90-day or a 2-year study.
Effects on humans, especially on the central
nervous system, can clearly be seen after accidental or
normal work exposure levels. A rough estimation of the
degree of exposure from case reports might be in the
order of approximately 200–2000 mg/m3 (100–1000 ppm).
In short-term exposures of volunteers, no significant
effects on the nervous system were seen. There are
insufficient data available to assess the risk for humans
to develop cancer as a result of methyl chloride
exposure.
In the long-term studies, exposure to 103 mg/m3 (50
ppm) caused nerve lesions, such as axonal swelling and
degeneration. The effects at each exposure level were
significantly increased in each dose group as compared
with control animals. However, no concentration–response relationship could be established.
Significant degenerative effects on nerve fibres were
also seen at higher doses, although the observations
were not concentration related. Further, testicular lesions
in rats and renal lesions in male mice were important
findings obtained from the 2-year toxicity study. Renal
tumours as well as testicular lesions were seen at the
2064 mg/m3 (1000 ppm) exposure level, and, although not
of statistical significance, cortical adenoma was also
11.1.2
Criteria for setting tolerable intakes or
guidance values for methyl chloride
Human data supplemented by data from short-,
medium-, and long-term studies in laboratory animals,
principally the mouse, clearly indicate that the nervous
system is a particularly vulnerable target of methyl
chloride exposure. Histopathological effects in spinal
cord nerves were observed in a 2-year exposure of mice
(CIIT, 1981) at a LOAEL of 103 mg/m3 (50 ppm), in the
26
Methyl chloride
absence of renal and hepatic effects. At 2064 mg/m3
(1000 ppm), cerebellar degeneration was noted. This
latter lesion, which appears to be of a progressive and
persistent nature, has also been observed in mice
exposed in other studies (e.g., Landry et al., 1985) for
much shorter periods of time. In addition, evidence of
functional impairment noted in short-term studies is
consistent with the spinal cord and the brain being
potential sites of injury under chronic exposure conditions.
11.1.3
Sample risk characterization
Based on the sample estimate of exposure, indirect
exposure via the ambient air, 0.0012 mg/m3 (0.6 ppb), is 15
times below the guidance value of 0.018 mg/m3 (0.009
ppm). Also, the sample median exposure estimate for
urban air, 0.0010–0.0023 mg/m3 (0.5–1.1 ppb), is 18 to 8
times below the guidance value. Finally, the maximum
value obtained from individual measurements in urban
air, 0.035 mg/m3 (17 ppb), is 2 times above the guidance
value. From the available exposure data, a risk was
identified from exposure in urban air but not ambient air.
Consequently, the LOAEL of 103 mg/m3 (50 ppm),
derived from the 2-year study by CIIT (1981) for effects
on the nervous system, was chosen to be used in the
risk characterization.
As no estimation from the available exposure
database can be made on the allocation of the tolerable
intake from environmental air and from air in the working
environment, two separate guidance values were
derived.
The quality of human exposure data in the present
report is fairly poor, which will contribute to uncertainties in the outcome of the sample risk characterization for
occupational exposure. However, when more applicable
exposure data can be used, the quality of the risk
assessment will improve.
The range of the sample estimate of workplace
exposure, 0.2–186 mg/m3 (0.1–90 ppm), is 5 times below
and 180 times above the guidance value of 1.0 mg/m3 (0.5
ppm), respectively. Thus, a comparison of the available
methyl chloride exposure concentrations in the working
environment and the guidance value derived from effects
on the nervous system leads to the identification of a
risk. Although the nerve lesions were seen at lower
exposure levels than those at which infertility in rats (980
mg/m3 [475 ppm]) and renal tumours in male mice (2064
mg/m3 [1000 ppm]) occurred, emphasis should also be
laid on these very serious effects in a qualitative risk
characterization of methyl chloride.
A guidance value for indirect inhalation exposure
to methyl chloride via the environment for the general
population was estimated to be:
(103 mg/m3 × 1.0 × 6/24 × 5/7) / 1000
= 0.018 mg/m3 (0.009 ppm)
where:
• 103 mg/m3 (50 ppm) is the LOAEL,
• 1.0 refers to 100% allocation of the tolerable intake to
intake via the environmental air,
• 6/24 and 5/7 are the conversion of 6 h/day and 5
days/week to continuous exposure, and
• 1000 is the uncertainty factor (×10 for intraspecies
variation, ×10 for interspecies variation, and ×10 for
the poor database and the use of a LOAEL instead of
a NOAEL).
11.2
Evaluation of environmental effects
The troposphere, where methyl chloride reacts
with hydroxyl radicals, is the main environmental sink for
the chemical. A certain amount of the tropospheric
methyl chloride reaches the stratosphere. In the stratosphere, photolysis produces chlorine radicals, which in
turn will react with ozone. Estimates of the amount of
methyl chloride reaching the stratosphere, and thereby
also its contribution to ozone depletion, vary considerably. However, as estimated from figures presented by
the WMO, methyl chloride contributes approximately
15% of the total equivalent effective stratospheric
chlorine.1 The relative contribution from methyl chloride
to the depletion of the ozone layer will probably increase
A guidance value for occupational inhalation
exposure was estimated to be:
(103 mg/m3 × 1.0) / 100 = 1.0 mg/m3 (0.5 ppm)
where:
• 103 mg/m3 (50 ppm) is the LOAEL,
• 1.0 refers to 100% allocation of the tolerable intake to
intake via workplace air, and
• 100 is the uncertainty factor (×10 for interspecies
variation and ×10 for the poor database and the use of
a LOAEL instead of a NOAEL).
1
The term “equivalent effective stratospheric chlorine”
includes both stratospheric chlorine and bromine and
also considers the dissociation rate of each compound
involved in ozone depletion (e.g., chlorofluorocarbons).
In the stratosphere, each bromine atom is assumed to be
40 times more damaging to ozone than each chlorine
atom.
No correction was made for continuous exposure in the
working environment.
27
Concise International Chemical Assessment Document 28
in the future, as the use of chlorofluorocarbons and
hydrochlorofluorocarbons is expected to decrease. The
stratospheric ODP of methyl chloride has been determined to be 0.02 relative to that of CFC-11 (ODP = 1).
Methyl chloride is not thought to contribute
significantly to global warming or to the creation of
photochemical air pollution.
The dominant loss mechanism for methyl chloride
in water and soil is volatilization. Slow hydrolysis and
possibly biotic degradation may contribute at deeper soil
depths and in groundwater. However, little information is
available concerning biodegradation.
Data on short-term toxicity to both aquatic and
terrestrial organisms are sparse. No information was
found on long-term toxicity. The available data show
that methyl chloride has a low acute toxicity to tested
aquatic organisms (e.g., protozoa, green algae, and fish).
The lowest LC50 value for fish is 270 mg/litre. As concentrations of methyl chloride in surface waters (maximum
0.22 mg/litre) are generally several orders of magnitude
less than those demonstrated to cause effects, it is likely
that methyl chloride poses a low risk of acute effects on
aquatic organisms. Data on terrestrial organisms are
even more sparse than data on aquatic organisms. The
only information found shows that methyl chloride
causes acute effects (i.e., visible symptoms and effects
on photosynthesis and transpiration) on higher plants at
concentrations above 5000 mg/m3 (2400 ppm), which is
about 105 times higher than the highest concentration
found in urban air (i.e., 0.035 mg/m3 [0.017 ppm]).
12. PREVIOUS EVALUATIONS BY
INTERNATIONAL BODIES
In its series of monographs, the International
Agency for Research on Cancer (IARC, 1986) has
evaluated methyl chloride. Based on the data available,
the Task Group concluded that there is inadequate
evidence for the carcinogenicity of methyl chloride to
experimental animals and to humans. In the overall
assessment of data from short-term tests, the Task
Group concluded that there is sufficient evidence for
genotoxic activity. In the overall evaluation (IARC,
1987), methyl chloride was placed in group 3 as being
not classifiable as to its carcinogenicity to humans.
28
Methyl chloride
Bartnicki EW, Castro CE (1994) Biohalogenation: rapid oxidative
metabolism of mono- and polyhalomethanes by Methylosinus
trichosporium OB-3b. Environmental toxicology and chemistry,
13(2):241–245.
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S-methylcysteine in urine of workers exposed to methyl chloride.
International archives of occupational and environmental health,
46:99–109.
Working PK, Bus JS, Hamm TE (1985b) Reproductive effects of
inhaled methyl chloride in the male Fischer 344 rat. II.
Spermatogonial toxicity and sperm quality. Toxicology and
applied pharmacology, 77:144–157.
Vaughan P, Lindahl T, Sedgwick B (1993) Induction of the
adaptive response of Escherichia coli to alkylation damage by
the environmental mutagen, methyl chloride. Mutation research,
293:249–257.
Working PK, Doolittle DJ, Smith-Oliver T, White RD, Butterworth
BE (1986) Unscheduled DNA synthesis in rat tracheal epithelial
cells, hepatocytes and spermatocytes following exposure to
methyl chloride in vitro and in vivo. Mutation research, 162:219.
von Clarmann A, Linden A, Oelhaf H, Fisher H, Friedl-Vallon F,
Piesch C, Seefeldner M (1995) Determination of the
stratospheric organic chlorine budget in the spring arctic vortex
from MIPAS B limb emission spectra and air sampling
experiments. Journal of geophysical research, 100(D7):13
979–13 997.
Wynder EL, Hoffmann D, eds. (1967) Tobacco and tobacco
smoke: Studies in environmental carcinogenesis. New York, NY,
Academic Press, p. 454.
Zafiriou OC (1975) Reaction of methyl halides with seawater and
marine aerosols. Journal of marine research, 33(1):75–81 [cited
in BUA, 1986; HSDB, 1996].
von Kolkmann FW, Volk B (1975) Über Körnerzellnekrosen bei
der experimentellen Methylchloridvergiftung des
Meerschweinchens. Experimentelle Pathologie, 10:298–308.
Zander R, Gunson MR, Farmer CB, Rinsland CP, Irion FW,
Mahieu E (1992) The 1985 chlorine and fluorine inventories in
the stratosphere based on ATMOS observations at 30° north
latitude. Journal of atmospheric chemistry, 15:171–186.
Warholm M, Alexandrie A-K, Högberg J, Sigvardsson K, Rannug
A (1994) Polymorphic distribution of glutathione transferase
activity with methyl chloride in human blood.
Pharmacogenetics, 4:307–311.
Warneck P (1988) Chemistry of the natural atmosphere . London,
Academic Press, pp. 267–272.
Watson AJ, Lovelock JE, Stedman DH (1980) The problem of
atmospheric methyl chloride. In: Nicolet M, Aikin AC, eds. NATO
Advance Study Institute on Atmospheric Ozone: Its variation and
human influence. Washington, DC, Department of
Transportation, pp. 365–373 (Report No. FAA-EE-80-20).
Weast RC (1988) CRC handbook of chemistry and physics, 69th
ed. Boca Raton, FL, CRC Press [cited in ATSDR, 1998].
White RD, Norton R, Bus JS (1982) Evidence for S-methyl
glutathione metabolism in mediating the acute toxicity of
methyl chloride (MeCl). Pharmacologist, 24:172.
WMO (1990) Scientific assessment of stratospheric ozone: 1989.
Geneva, World Meteorological Organization, p. 158 (Global
Ozone Research and Monitoring Project Report No. 20).
35
Concise International Chemical Assessment Document 28
from the ATSDR reviewed the peer reviewers’ comments and
determined which ones to include in the profile.
APPENDIX 1 — SOURCE DOCUMENTS
The responsibility for the content of the profiles lies with
the ATSDR.
Lundberg P (1992) Methyl chloride. NEG and
DECOS basis for an occupational standard.
Solna, National Institute of Occupational
Health, Nordic Council of Ministers (Arbete och
Hälsa 27)
BUA (1986) Chloromethane. GDCh-Advisory
Committee on Existing Chemicals of
Environmental Relevance (BUA). Weinheim,
VCH Verlagsgesellschaft mbH; and New York,
NY, VCH Publishers, Inc. (BUA Report 7)
Copies of the Arbete och Hälsa document on methyl
chloride (ISSN 0346-7821; ISBN 91-7045-179-6) may be
obtained from:
National Institute for Working Life
Publications Department
S-171 84 Solna
Sweden
Copies of the BUA report on chloromethane (ISBN 3-52728558-X [Weinheim] and 1-56081-734-8 [New York]) may be
obtained from VCH in Weinheim, Basel, Cambridge, and New
York.
The document, which is focused on health effects only,
was prepared in the series of criteria documents from the Nordic
Expert Group for Documentation of Occupational Exposure
Limits (NEG) in collaboration with the Dutch Expert Committee
for Occupational Standards (DECOS) of the Dutch DirectorateGeneral of Labor. The draft was reviewed by the Dutch Expert
Committee as well as by the Nordic Expert Group. The reviewers
were industrial and academic specialists who were chosen either
because they have an extended knowledge of methyl chloride
itself or because they are specialists in the critical effect area of
the chemical.
BUA reports are written by the largest German producer of
the chemical. The draft is examined by BUA (GDCh-Advisory
Committee for Existing Chemicals of Environmental Relevance),
which consists of representatives from government agencies,
industry, and the scientific community. Resulting questions are
clarified by the authors as well as by further research (resulting in
updated reports). After an average of two readings in the work
group and discussions with experts, the BUA plenum debates the
report before it is published. More detailed information on the
BUA reports is found in Assessment of existing chemicals. A
contribution toward improving the environment, a 1993 report by
BUA.
ATSDR (1990) Toxicological profile for
chloromethane. Atlanta, GA, US Department of
Health and Human Services, Public Health
Service, Agency for Toxic Substances and
Disease Registry (Report No. TP-90-07)
HSDB (1996) Hazardous substances data bank.
Bethesda, MD, US National Library of Medicine
The version of HSDB used for this CICAD is included in
the CD-ROM CHEM-BANK (July 1996), published by:
ATSDR (1998) Toxicological profile for
chloromethane (update). Atlanta, GA, US
Department of Health and Human Services,
Public Health Service, Agency for Toxic
Substances and Disease Registry (Report No.
205-93-0606)
Silver Platter Information Inc.
100 River Ridge Drive
Norwood, MA 02062-5043
USA
HSDB is also available on CD-ROM from the Canadian
Centre for Occupational Health and Safety (CCINFOdisc 2) and
on-line by Data-Star, DIMDI, STN International, Toxicology Data
Network (TOXNET). HSDB is built, reviewed, and maintained on
the National Library of Medicine’s TOXNET. HSDB is a factual
data bank, referenced and peer reviewed by a committee of
experts (the Scientific Review Panel). All data extracted from
HSDB for use in this CICAD were preceded by the symbol
denoting the highest level of peer review.
Copies of the ATSDR Toxicological profile for
chloromethane may be obtained from:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road NE, E-29
Atlanta, Georgia 30333
USA
The date for the last revision or modification of the record
on methyl chloride was June 1996.
A peer review panel was assembled for the Toxicological
profile on chloromethane (1990), including Dr Anthony DeCaprio
and Dr Nancy Reiches (private consultants), Dr Theodore Mill
(SRI International), and Dr Nancy Tooney (Department of
Biochemistry, Polytechnic University). A joint panel of scientists
from ATSDR and EPA reviewed the peer reviewers’ comments
and determined which ones to include in the profile.
For the updated profile (1998), the panel consisted of Dr
Herbert Cornish (private consultant), Dr Anthony DeCaprio
(Associate Professor, State University of New York at Albany), Dr
Theodore Mill (Senior Scientist, SRI International), and Dr
Nancy Tooney (Associate Professor, Brooklyn, NY). Scientists
36
Methyl chloride
APPENDIX 2 — CICAD PEER REVIEW
WMO (1994) Montreal protocol on substances
that deplete the ozone layer — Scientific
assessment of ozone depletion: 1994. Geneva,
World Meteorological Organization (Global
Ozone Research and Monitoring Project Report
No. 37)
The draft CICAD on methyl chloride was sent for review to
institutions and organizations identified by IPCS after contact
with IPCS national Contact Points and Participating Institutions,
as well as to identified experts. Comments were received from:
Copies of this report (ISBN 92-807-1449-X) for scientific
users may be obtained from:
M. Baril, International Programme on Chemical Safety/
Institut de Recherche en Santé et en Sécurité du Travail
du Québec, Montreal, Quebec, Canada
World Meteorological Organization
attn. Dr Rumen Bojkov
P.O. Box 2300
1211-Geneva
Switzerland
R. Benson, US Environmental Protection Agency, Denver,
CO, USA
R. Cary, Health and Safety Executive, Bootle, United
Kingdom
The WMO (1994) report was the latest in a series of
scientific assessments of ozone depletion, prepared under the
auspices of WMO and UNEP, that was available during the
preparation of the CICAD on methyl chloride. The genesis of the
WMO (1994) report occurred at the 4th meeting of the
Conference of the Parties to the Montreal Protocol held in
Copenhagen, Denmark, in 1992, at which the scope of the
scientific needs was defined. In 1993, an international steering
group outlined the report and suggested scientists to serve as
authors. The first draft was examined by the authors and a small
group of experts, and the second draft was sent to a large
number of scientists worldwide for review. At a Panel Review
Meeting in July 1994, final changes were discussed and decided
upon. The scientists who prepared the report (230) and
participated in the peer review process (147) are listed in the
report.
R. Chhabra, Department of Health and Human Services,
National Institute of Environmental Health Sciences,
Research Triangle Park, NC, USA
P. Edwards, Department of Health, Protection of Health
Division, London, United Kingdom
M. Greenberg, US Environmental Protection Agency,
Research Triangle Park, NC, USA
Martin Matisons Environmental Health Service, Health
Department of Western Australia
H. Nagy, National Institute for Occupational Safety and
Health, Cincinnati, OH, USA
W. Rawson and L. Neuwirth, Methyl Chloride Industry
Association, Washington, DC, USA
M. Warholm, Institute of Environmental Medicine,
Karolinska Institute, Stockholm, Sweden
P. Yao, Ministry of Health, Institute of Occupational
Medicine, Chinese Academy of Preventive Medicine,
Ministry of Health, Beijing, People’s Republic of China
K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt
und Gesundheit, Neuherberg, Oberschleissheim,
Germany
37
Concise International Chemical Assessment Document 28
Dr A. Poole (representing CEFIC), Dow Europe S.A., Horgen,
Switzerland
APPENDIX 3 — CICAD FINAL REVIEW
BOARD
Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und
Gesundheit, Institut für Toxikologie, Neuherberg,
Oberschleissheim, Germany
Stockholm, Sweden, 25–28 May 1999
Members
Secretariat
Mr H. Abadin, Agency for Toxic Substances and Disease
Registry, Centers for Disease Control and Prevention, Atlanta,
GA, USA
Dr A. Aitio, Programme for the Promotion of Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr B. Åkesson, Department of Occupational and Environmental
Health, University Hospital, Lund, Sweden
Ms M. Godden, Health and Safety Executive, Bootle, United
Kingdom
Dr T. Berzins (Chairperson), National Chemicals Inspectorate
(KEMI), Solna, Sweden
Ms L. Regis, Programme for the Promotion of Chemical Safety,
World Health Organization, Geneva, Switzerland
Mr R. Cary, Health and Safety Executive, Bootle, Merseyside,
United Kingdom
Dr P. Toft, Division of Health and Environment, World Health
Organization, Regional Office for the Americas/Pan American
Sanitary Bureau, Washington, DC, USA
Dr R.S. Chhabra, General Toxicology Group, National Institute
of Environmental Health Sciences, Research Triangle Park, NC,
USA
Dr M. Younes, Programme for the Promotion of Chemical
Safety, World Health Organization, Geneva, Switzerland
Dr S. Dobson (Rapporteur), Institute of Terrestrial Ecology,
Monks Wood, Abbots Ripton, Huntingdon, Cambridgeshire,
United Kingdom
Dr H. Gibb, National Center for Environmental Assessment, US
Environmental Protection Agency, Washington, DC, USA
Dr R.F. Hertel, Federal Institute for Health Protection of
Consumers and Veterinary Medicine, Berlin, Germany
Dr G. Koennecker, Chemical Risk Assessment, Fraunhofer
Institute for Toxicology and Aerosol Research, Hannover,
Germany
Dr A. Nishikawa, National Institute of Health Sciences, Division
of Pathology, Tokyo, Japan
Professor K. Savolainen, Finnish Institute of Occupational
Health, Helsinki, Finland
Dr J. Sekizawa, Division of Chem-Bio Informatics, National
Institute of Health Sciences, Tokyo, Japan
Ms D. Willcocks (Vice-Chairperson), Chemical Assessment
Division, National Occupational Health and Safety Commission
(Worksafe Australia), Sydney, Australia
Professor P. Yao, Institute of Occupational Medicine, Chinese
Academy of Preventive Medicine, Ministry of Health, Beijing,
People’s Republic of China
Observers
Dr N. Drouot (representing ECETOC), Elf Atochem, DSE-P
Industrial Toxicology Department, Paris, France
Ms S. Karlsson, National Chemicals Inspectorate (KEMI), Solna,
Sweden
Dr A. Löf, National Institute of Working Life, Solna, Sweden
38
METHYL CHLORIDE
0419
March 1999
CAS No: 74-87-3
RTECS No: PA6300000
UN No: 1063
EC No: 602-001-00-7
TYPES OF
HAZARD/
EXPOSURE
Chloromethane
Monochloromethane
CH3Cl
Molecular mass: 50.5
ACUTE HAZARDS/SYMPTOMS
PREVENTION
FIRST AID/FIRE FIGHTING
FIRE
Highly flammable. Heating will
cause rise in pressure with risk of
bursting.
NO open flames, NO sparks, and
NO smoking.
Shut off supply; if not possible and
no risk to surroundings, let the fire
burn itself out; in other cases
extinguish with water spray.
EXPLOSION
Gas/air mixtures are explosive.
Closed system, ventilation,
explosion-proof electrical equipment
and lighting. Use non-sparking
handtools.
In case of fire: keep cylinder cool by
spraying with water. Combat fire
from a sheltered position.
EXPOSURE
STRICT HYGIENE!
Inhalation
Staggering gait. Dizziness.
Headache. Nausea. Vomiting.
Convulsions. Unconsciousness.
See Notes.
Ventilation, local exhaust, or
breathing protection.
Fresh air, rest. Artificial respiration if
indicated. Refer for medical
attention.
Skin
MAY BE ABSORBED! ON
CONTACT WITH LIQUID:
FROSTBITE.
Cold-insulating gloves. Protective
clothing.
ON FROSTBITE: rinse with plenty
of water, do NOT remove clothes.
Eyes
(See Skin).
Safety goggles, face shield, or eye
protection in combination with
breathing protection.
Ingestion
SPILLAGE DISPOSAL
PACKAGING & LABELLING
Evacuate danger area! Consult an expert!
Ventilation. NEVER direct water jet on liquid. (Extra
personal protection: complete protective clothing
including self-contained breathing apparatus).
F+ Symbol
Xn Symbol
R: 12-40-48/20
S: (2-)9-16-33
UN Hazard Class: 2.1
EMERGENCY RESPONSE
STORAGE
Transport Emergency Card: TEC (R)-41/20G41
NFPA Code: H2; F4; R0
Fireproof. Ventilation along the floor.
IPCS
International
Programme on
Chemical Safety
Prepared in the context of cooperation between the International
Programme on Chemical Safety and the European Commission
© IPCS 2000
SEE IMPORTANT INFORMATION ON THE BACK.
0419
METHYL CHLORIDE
IMPORTANT DATA
Routes of exposure
The substance can be absorbed into the body by inhalation and
through the skin.
Physical State; Appearance
COLOURLESS LIQUEFIED GAS.
Physical dangers
The gas is heavier than air and may travel along the ground;
distant ignition possible, and may accumulate in low ceiling
spaces causing deficiency of oxygen. See Notes.
Inhalation risk
A harmful concentration of this gas in the air will be reached
very quickly on loss of containment.
Chemical dangers
The substance decomposes on burning producing toxic and
corrosive fumes including hydrogen chloride and phosgene.
Reacts violently with powdered aluminium, powdered zinc,
aluminium trichloride and ethylene causing fire and explosion
hazard. Attacks many metals in the presence of moisture.
Effects of short-term exposure
The liquid may cause frostbite. The substance may cause
effects on the central nervous system. Exposure may result in
unconsciousness. Exposure far above OEL may result in liver,
cardiovascular system and kidney damage. Medical
observation is indicated.
Occupational exposure limits
TLV: 50 ppm; (skin) (ACGIH 1998).
TLV (as (STEL) ): 100 ppm; (skin) (ACGIH 1998).
Effects of long-term or repeated exposure
The substance may have effects on the central nervous
system, resulting in effects measured using behavioural tests.
Animal tests show that this substance possibly causes toxic
effects upon human reproduction.
PHYSICAL PROPERTIES
Boiling point: -24.2°C
Melting point: -97.6°C
Relative density (water = 1): 0.92
Solubility in water, g/100 ml at 25°C: 0.5
Vapour pressure, kPa at 21°C: 506
Relative vapour density (air = 1): 1.8
Flash point: Flammable Gas
Auto-ignition temperature: 632°C
Explosive limits, vol% in air: 8.1-17.4
Octanol/water partition coefficient as log Pow: 0.91
ENVIRONMENTAL DATA
NOTES
Following intoxication patient should be observed carefully for 48 hours.
Check oxygen content before entering area.
ADDITIONAL INFORMATION
LEGAL NOTICE
Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible
for the use which might be made of this information
©IPCS 2000
Methyl chloride
RÉSUMÉ D’ORIENTATION
relatives à la proportion de chlorure de méthyle qui
atteint la stratosphère et contribue par là à la destruction
de la couche d’ozone, sont très variables. Selon les
chiffres donnés par l’Organisation météorologique
mondiale (OMM), le chlorure de méthyle contribue à
hauteur de 15 % à la teneur totale de la stratosphère en
chlore actif. Le chlorure de méthyle a un potentiel de
destruction de l’ozone stratosphérique de 0,02 par
rapport au composé de référence, le CFC-11 dont le
potentiel est égal à 1 par définition. On ne pense pas que
le chlorure de méthyle ait une influence sensible sur le
réchauffement climatique ou sur la pollution de l’air
d’origine photochimique.
L’évaluation des effets du chlorure de méthyle sur
la santé humaine qui figure dans le présent CICAD
repose principalement sur une mise au point rédigée par
le Groupe nordique d’experts en collaboration avec le
Comité néerlandais pour les normes d’hygiène sur les
lieux de travail (Lundberg, 1992). Un dépouillement des
banques de données couvrant la période 1992-1999 a été
effectué afin de compléter les données disponibles. En
ce qui concerne les effets environnementaux et
écotoxicologiques du chlorure de méthyle, les
principales sources d’information utilisées sont les
suivantes : BUA (1986), ATDSR (1990) et WMO/OMM
(1994). La banque de données ATDSR a été mise à jour
en 1998; chaque fois que cette banque de données
contenait de nouvelles informations, elles ont été prises
en compte. La consultation des banques de données
pertinentes couvrant la période 1989-1997 a permis
d’obtenir des données supplémentaires sur les
questions d’ordre écologique. On trouvera à l’appendice
1 des renseignements sur la nature des sources
documentaires existantes. Des informations sur l’examen
par des pairs du présent CICAD sont données à
l’appendice 2. Ce CICAD a été approuvé en tant
qu’évaluation internationale lors d’une réunion du
Comité d’évaluation finale qui s’est tenue à Stockholm
(Suède) du 25 au 28 mai 1999. La liste des participants au
Comité d’évaluation finale figure à l’appendice 3. La
fiche internationale sur la sécurité chimique (ICSC 0419)
du chlorure de méthyle, établie par le Programme
international sur la sécurité chimique (IPCS, 1999), est
également reproduite dans le présent document.
Le chlorure de méthyle disparaît principalement de
l’eau et du sol par évaporation. Dans les couches profondes du sol et dans les eaux souterraines, sa
disparition pourrait s’expliquer notamment par une lente
hydrolyse et éventuellement par une biodégradation. On
sait cependant peu de choses sur ce dernier point.
La voie la plus importante d’exposition humaine au
chlorure de méthyle est la voie respiratoire. Chez
l’Homme comme chez l’animal de laboratoire, il est
rapidement absorbé au niveau des poumons après
inhalation. Après exposition à du chlorure de méthyle
marqué au 14C, la radioactivité se répartit dans l’ensemble
de l’organisme. Le produit radiomarqué est incorporé en
grande partie aux protéines par le canal du pool des
substances à un atome de carbone, mais le chlorure de
méthyle peut également se fixer aux protéines par
alkylation directe. Toutefois, si le composé se comporte
comme un agent alkylant, c’est en très faible proportion.
Chez les mammifères, il est métabolisé par conjugaison
avec le glutathion et, dans une moindre mesure, par
oxydation au niveau du cytochrome P-450. La
conjugaison avec le glutathion conduit à la formation de
méthanethiol et les deux voies métaboliques ont pour
point d’aboutissement le formaldéhyde et le formiate.
Les métabolites du chlorure de méthyle sont excrétés
dans les urines ainsi que dans l’air expiré, qui contient
également une certaine proportion du composé initial.
Lorsque du chlorure de méthyle (No CAS 74-87-3) est
libéré dans l’atmosphère, c’est surtout au cours de sa
production, de son utilisation ou encore lors de
l’incinération de déchets municipaux ou industriels. Quoi
qu’il en soit, les sources naturelles de chlorure de
méthyle (en premier lieu les océans et la combustion de
la biomasse) l’emportent largement en importance sur les
sources d’origine humaine. On estime que l’ensemble de
ces sources libère chaque année quelque 5 × 106 tonnes
de chlorure de méthyle. La part des sources naturelles
dans ce bilan dépasse largement 90 % selon les estimations et pourrait même atteindre 99 %. Le composé est
présent dans la troposphère à une concentration
approximativement égale à 1,2 µg/m3 (0,6 parties par
milliard).
Chez l’Homme, on observe d’importantes
différences individuelles concernant l’absorption et la
métabolisation du chlorure de méthyle. Ces différences
sont dues à la présence ou à l’absence d’une enzyme, la
glutathion-transférase T1 (GSTT1), qui présente un
polymorphisme génétique. On distingue en effet 3
phénotypes chez l’Homme qui correspondent à une
conjugaison forte, faible ou nulle. De toute manière,
comme on voit pas très bien si le risque le plus élevé
correspond à une conjugaison forte ou à une
conjugaison nulle, il faut considérer que tous les
phénotypes ont la même sensibilité au chlorure de
méthyle.
Dans la troposphère, le piégeage du chlorure de
méthyle s’effectue principalement par sa réaction sur les
radicaux hydroxyle et l’on estime que sa demi-vie
atmosphérique est de 1 à 3 ans. Une fraction s’échappe
dans la stratosphère où le composé subit une
photodissociation donnant naissance à des radicaux
chlore qui attaquent la couche d’ozone. Les estimations
41
Concise International Chemical Assessment Document 28
La toxicité aiguë du chlorure de méthyle après
inhalation semble assez faible pour le rat et la souris,
puisque la CL50 est supérieure à 4128 mg/m3 (2000 ppm).
On n’a pas trouvé dans la littérature de données qui
indiquent que le composé soit irritant ou sensibilisant.
En conclusion, on peut dire que chez l’Homme, le
point d’aboutissement de l’action toxique du chlorure de
méthyle est vraisemblablement le système nerveux
central. On a pu en tirer des valeurs-guides de
0,018 mg/m3 (0,009 ppm) pour une exposition indirecte
dans l’environnement et de 1,0 mg/m3 (0,5 ppm) pour une
exposition sur le lieu de travail. Bien que les lésions
nerveuses aient été constatées chez le rat à des doses
plus faibles que celles qui provoquaient la stérilité des
mâles (980 mg/m3, soit 475 ppm) ou des lésions rénales
chez des souris mâles (à la concentration de 2064 mg/m3,
soit 1000 ppm), c’est ces très graves effets qui sont à
prendre en compte pour toute caractérisation qualitative
du risque que comporte une exposition au chlorure de
méthyle.
Il semble qu’après inhalation, les principaux
organes cibles du chlorure de méthyle soient le système
nerveux (avec des troubles fonctionnels ainsi qu’une
dégénérescence du cervelet chez le rat et la souris) ainsi
que les testicules, l’épididyme et le rein chez le rat ou
encore le rein et le foie chez la souris.
Lors d’une étude de 2 ans au cours de laquelle on
a fait inhaler du chlorure de méthyle à des souris, on a
constaté qu’à la concentration de 103 mg/m3 (50 ppm),
les nerfs rachidiens lombaires présentaient un gonflement de l’axone et des signes de dégénérescence par
comparaison aux animaux témoins, sans qu’on puisse
toutefois mettre en évidence une relation dose-réponse.
Au terme de cette étude, on a observé chez les souris
des deux sexes une dégénérescence du cervelet et chez
les mâles, des adénocarcinomes rénaux à la
concentration de 2064 mg/m3 (1000 ppm). Ces effets
n’ont pas été observés chez le rat à cette concentration.
On n’a guère trouvé de données sur la toxicité à
court terme du chlorure de méthyle pour les organismes
aquatiques ou terrestres. Dans le cas de la toxicité à long
terme, c’est même une absence totale. Les données
existantes indiquent que le composé n’a qu’une faible
toxicité aiguë pour les organismes aquatiques. Chez les
poissons, la plus faible valeur de la CL50qui ait été
obtenue est de 270 mg/litre. Comme les dosages donnent
pour les eaux de surface des concentrations de chlorure
de méthyle généralement inférieures de plusieurs ordre
de grandeur à celles qui produisent effectivement des
effets, il est vraisemblable que ce composé ne présente
pas de risque important d’intoxication aiguë pour les
organismes aquatiques. On ne possède que des données
très limitées concernant les effets du chlorure de méthyle
sur les organismes terrestres.
Le chlorure de méthyle se révèle nettement
génotoxique in vitro, tant vis-à-vis des bactéries que des
cellules mammaliennes. Même si les effets observés lors
d’un test de létalité dominante étaient très vraisemblablement plutôt cytotoxiques que génotoxiques, on pourrait
considérer le chlorure de méthyle comme très faiblement
mutagène in vivo, eu égard à certains signes témoignant
de la présence de pontages ADN–protéines aux doses
élevées.
Chez des rats soumis à une concentration de
980 mg/m3 (475 ppm), on a observé la présence de
lésions testiculaires et notamment de granulomes
épididymaires, puis une réduction de la vitalité des
spermatozoïdes qui a conduit à une baisse de la fertilité
aboutissant à une stérilité totale à plus forte dose.
Le chlorure de méthyle a produit des anomalies
cardiaques chez des foetus de souris dont la mère avait
été exposée à une concentration de 1032 mg/m3
(500 ppm) pendant la gestation.
Après inhalation accidentelle de chlorure de
méthyle, les effets sont nets chez l’Homme, notamment
au niveau du système nerveux central. Chez des volontaires brièvement exposés à du chlorure de méthyle, on
n’a pas constaté d’effets sensibles qui puissent être
attribués à ce composé. On n’a pas suffisamment de
données épidémiologiques pour évaluer le risque de
cancer chez l’Homme par suite d’une exposition au
chlorure de méthyle.
42
Methyl chloride
RESUMEN DE ORIENTACIÓN
equivalente total de cloro estratosférico efectivo. Se ha
determinado que el cloruro de metilo tiene un potencial
de destrucción del ozono estratosférico de 0,02 en
relación con el compuesto de referencia, el CFC-11, cuyo
potencial es igual a 1. No parece que el cloruro de metilo
contribuya de manera significativa al calentamiento
mundial o a la contaminación fotoquímica del aire.
La evaluación de los aspectos relativos a la salud
humana de este CICAD sobre el cloruro de metilo se
basó fundamentalmente en un estudio preparado por el
Grupo de Expertos Nórdicos en colaboración con el
Comité de Expertos Neerlandeses en Normas del Trabajo
(Lundberg, 1992). Se realizó una búsqueda en las bases
de datos pertinentes para el período de 1992-1999 con
objeto de obtener datos adicionales. Se utilizaron como
fuentes principales para los aspectos ambientales y
ecotoxicológicos del cloruro de metilo BUA (1986),
ATSDR (1990), WMO/OMM (1994) y HSDB (1996). La
publicación ATSDR (1990) se actualizó en 1998; cuando
esta versión actualizada proporcionaba información, se
ha tenido en cuenta. Se obtuvieron datos adicionales
sobre cuestiones ambientales en bases de datos
pertinentes para el período 1989-1997. La información
relativa al carácter y a la disponibilidad de los
documentos originales se presenta en el apéndice 1. La
información sobre el examen colegiado de este CICAD
figura en el apéndice 2. Este CICAD se aprobó como
evaluación internacional en una reunión de la Junta de
Evaluación Final, celebrada en Estocolmo (Suecia) del 25
al 28 de mayo de 1999. La lista de participantes en esta
reunión figura en el apéndice 3. La Ficha internacional de
seguridad química (ICSC 0419) para el cloruro de metilo,
preparada por el Programa Internacional de Seguridad de
las Sustancias Químicas (IPCS, 1999), se reproduce en el
presente documento.
El mecanismo predominante de eliminación del
cloruro de metilo en el agua y el suelo es la volatilización. La hidrólisis lenta y posiblemente la degradación
biótica pueden contribuir a su desaparición en las capas
más profundas del suelo y en el agua freática. Sin embargo, hay poca información sobre su biodegradación.
La ruta de exposición más importante del ser
humano al cloruro de metilo son las vías respiratorias. En
las personas, así como en los animales de experimentación, el cloruro de metilo se absorbe con rapidez a
través de los pulmones después de la inhalación. Tras la
exposición a cloruro de metilo marcado con 14C, se
detecta radiactividad en todo el organismo. Aunque una
gran parte de la sustancia marcada se incorpora a las
proteínas a través del “pool” de moléculas de un átomo
de carbono, el cloruro de metilo también se puede unir a
proteínas por alquilación directa. Sin embargo, si bien es
un agente alquilante, lo es en un grado muy pequeño. El
cloruro de metilo se metaboliza en los mamíferos por
conjugación con el glutatión, y en menor proporción
mediante oxidación por el citocromo P-450; la vía del
glutatión produce metanotiol y ambas vías dan lugar a
formaldehído y formato. Los metabolitos del cloruro de
metilo se eliminan con la orina y por exhalación. También
se exhala cloruro de metilo sin metabolizar.
El cloruro de metilo (CAS Nº 74-87-3) se libera
fundamentalmente en el aire durante su producción y
uso y por la incineración de residuos municipales e
industriales. Sin embargo, las fuentes naturales, en
particular los océanos y la combustión de biomasa,
predominan claramente sobre las fuentes
antropogénicas. La emisión mundial total de cloruro de
metilo de todas las fuentes se estima en alrededor de 5 ×
106 toneladas al año. Se ha calculado que la contribución
de las fuentes naturales es muy superior al 90%, y tal vez
hasta del 99%, de la emisión total. El cloruro de metilo
está presente en la troposfera en una concentración
aproximada de 1,2 µg/m3 (0,6 ppmm).
En las personas, hay grandes diferencias
individuales en la absorción y el metabolismo del cloruro
de metilo. Estas diferencias dependen de la presencia o
ausencia de la enzima glutatión transferasa T1 (GSTT1),
que presenta polimorfismo genético. Se distinguen en el
ser humano tres fenotipos, correspondientes a una
conjugación alta, baja o nula de la GSTT1. Sin embargo,
como no está claro si el mayor riesgo corresponde a una
conjugación alta o a una conjugación nula, hay que
considerar que todos los fenotipos son sensibles a la
exposición al cloruro de metilo.
El principal medio de absorción del cloruro de
metilo en la troposfera es la reacción química con los
radicales hidroxilo y su vida en la atmósfera se estima
que es de uno a tres años. Cierta cantidad de cloruro de
metilo llega a la estratosfera; allí, la fotodisociación
genera radicales de cloro, que contribuyen a la
destrucción de la capa de ozono. Las estimaciones de la
cantidad de cloruro de metilo que llega a la estratosfera y
destruye pues la capa de ozono varían ampliamente. A
partir de las cifras presentadas por la Organización
Meteorológica Mundial (OMM), se estima que el cloruro
de metilo contribuye con alrededor del 15% al
La toxicidad aguda por inhalación de cloruro de
metilo en ratas y ratones parece ser bastante baja, con
un valor de la CL50 superior a 4128 mg/m3 (2000 ppm). No
se han encontrado en la bibliografía datos indicativos de
que el compuesto sea irritante o sensibilizante.
Los principales órganos destinatarios tras una
exposición breve por inhalación al cloruro de metilo
parecen ser el sistema nervioso, con trastornos
funcionales y degeneración cerebelar tanto en las ratas
como en los ratones, así como los testículos, el
43
Concise International Chemical Assessment Document 28
Se encontraron pocos datos sobre la toxicidad a
corto plazo del cloruro de metilo para los organismos
acuáticos o terrestres. No se obtuvo ningún dato sobre
la toxicidad a largo plazo. Los datos disponibles indican
que el cloruro de metilo tiene una toxicidad aguda baja
para los organismos acuáticos. El valor más bajo de la
CL50 para los peces es de 270 mg/litro. Teniendo en
cuenta que las concentraciones de cloruro de metilo que
se han determinado en las aguas superficiales son
generalmente varios órdenes de magnitud inferiores a las
que se ha demostrado que son causantes de esos
efectos, es probable que el cloruro de metilo represente
un riesgo bajo de efectos agudos para los organismos
acuáticos. Solamente se dispone de datos muy limitados
sobre los efectos del cloruro de metilo en los organismos
terrestres.
epidídimo y los riñones en las ratas y los riñones y el
hígado en los ratones.
En un estudio por inhalación de dos años con
ratones se observaron inflamación y degeneración
axonal de los nervios de la médula espinal lumbar con
103 mg/m3 (50 ppm) en los animales expuestos en
comparación con los testigos, pero sin una relación
dosis-respuesta aparente. Al final del estudio se
detectaron degeneración cerebelar en los ratones de
ambos sexos y adenocarcinomas renales en los ratones
machos con 2064 mg/m3 (1000 ppm). Estos efectos no se
observaron en las ratas con 2064 mg/m3 (1000 ppm).
El cloruro de metilo es claramente genotóxico en
sistemas in vitro, tanto en bacterias como en células de
mamífero. Aunque los efectos positivos observados en
una prueba de dominancia letal fueron con toda
probabilidad citotóxicos más que genotóxicos, el cloruro
de metilo podría considerarse un mutágeno muy débil in
vivo sobre la base de algunos signos de
entrecruzamiento proteína-ADN a dosis más altas.
Las lesiones testiculares y los granulomas epididimales seguidos de una disminución de la calidad del
esperma dieron lugar a una reducción de la fecundidad
en las ratas con 980 mg/m3 (475 ppm) y a su pérdida
completa a dosis superiores.
El cloruro de metilo indujo afecciones cardíacas en
fetos de ratones cuyas madres estuvieron expuestas a
1032 mg/m3 (500 ppm) durante el período de gestación.
Se pueden observar claramente efectos en las
personas, especialmente en el sistema nervioso central,
tras la exposición accidental por inhalación. En la
exposición breve de voluntarios al cloruro de metilo no
se observaron efectos significativos que pudieran
atribuirse a ella. Hay pocos datos epidemiológicos que
permitan evaluar el riesgo de aparición de cáncer para las
personas como resultado de la exposición al cloruro de
metilo.
En conclusión, el efecto final crítico para la
toxicidad por inhalación de cloruro de metilo en las
personas parece ser la neurotoxicidad. Se obtuvieron
valores guía de 0,018 mg/m3 (0,009 ppm) para la
exposición indirecta a través del medio ambiente y de
1,0 mg/m3 (0,5 ppm) para el entorno de trabajo. Aunque
las lesiones nerviosas se observaron a niveles de
exposición inferiores a los que provocaron la pérdida de
fecundidad en las ratas (980 mg/m3 [475 ppm]) y los
tumores renales en los ratones macho (2064 mg/m3 [1000
ppm]), en la caracterización del riesgo cualitativo del
cloruro de metilo se debe hacer hincapié también en esos
efectos muy graves.
44
THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES
Azodicarbonamide (No. 16, 1999)
Benzoic acid and sodium benzoate (No. 26, 2000)
Benzyl butyl phthalate (No. 17, 1999)
Biphenyl (No. 6, 1999)
2-Butoxyethanol (No. 10, 1998)
Chloral hydrate (No. 25, 2000)
Crystalline silica, Quartz (No. 24, 2000)
Cumene (No. 18, 1999)
1,2-Diaminoethane (No. 15, 1999)
3,3'-Dichlorobenzidine (No. 2, 1998)
1,2-Dichloroethane (No. 1, 1998)
2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) (No. 23, 2000)
Diphenylmethane diisocyanate (MDI) (No. 27, 2000)
Ethylenediamine (No. 15, 1999)
Ethylene glycol: environmental aspects (No. 22, 2000)
2-Furaldehyde (No. 21, 2000)
HCFC-123 (No. 23, 2000)
Limonene (No. 5, 1998)
Manganese and its compounds (No. 12, 1999)
Methyl methacrylate (No. 4, 1998)
Mononitrophenols (No. 20, 2000)
Phenylhydrazine (No. 19, 2000)
N-Phenyl-1-naphthylamine (No. 9, 1998)
1,1,2,2-Tetrachloroethane (No. 3, 1998)
1,1,1,2-Tetrafluoroethane (No. 11, 1998)
o-Toluidine (No. 7, 1998)
Tributyltin oxide (No. 14, 1999)
Triglycidyl isocyanurate (No. 8, 1998)
Triphenyltin compounds (No. 13, 1999)
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