a 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.).

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.

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 administra tion. 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 chlor ide in experimental animals are summarized.

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 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.

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).

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.

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 corrobor ated by either a 90-day or a 2-year study.

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 concen tration–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 statis tical significance, cortical adenoma was also 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 concentra tion–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.

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.

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]).

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 depen dent. A NOAEL of 206 mg/m³ (100 ppm) could be estimated from the developmental toxicity studies.

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.

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 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 poten tial sites of injury under chronic exposure conditions.

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.

A guidance value for indirect inhalation exposure to methyl chloride via the environment for the general population was estimated to be:

where:

• 103 mg/m³ (50 ppm) is the LOAEL,
• 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).

A guidance value for occupational inhalation exposure was estimated to be:

where:

• 103 mg/m³ (50 ppm) is the LOAEL,
• 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).

No correction was made for continuous exposure in the working environment.

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 maxi mum 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.

The quality of human exposure data in the present report is fairly poor, which will contribute to uncertain ties 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.

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 strato sphere, 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 consider ably. However, as estimated from figures presented by the WMO, methyl chloride contributes approximately 15% of the total equivalent effective stratospheric chlorine.³ The relative contribution from methyl chloride to the depletion of the ozone layer will probably increase in the future, as the use of chlorofluorocarbons and hydrochlorofluorocarbons is expected to decrease. The stratospheric ODP of methyl chloride has been deter mined 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 symp toms 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]).

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.

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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

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 Directorate-General 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.

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

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 from the ATSDR reviewed the peer reviewers’ comments and determined which ones to include in the profile.

The responsibility for the content of the profiles lies with the ATSDR.

Copies of the BUA report on chloromethane (ISBN 3-527- 28558-X [Weinheim] and 1-56081-734-8 [New York]) may be obtained from VCH in Weinheim, Basel, Cambridge, and New York.

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.

The version of HSDB used for this CICAD is included in the CD-ROM CHEM-BANK (July 1996), published by:

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.

The date for the last revision or modification of the record on methyl chloride was June 1996.

Copies of this report (ISBN 92-807-1449-X) for scientific users may be obtained from:

World Meteorological Organization

attn. Dr Rumen Bojkov

P.O. Box 2300

1211-Geneva

Switzerland

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.

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:

M. Baril, International Programme on Chemical Safety/ Institut de Recherche en Santé et en Sécurité du Travail du Québec, Montreal, Quebec, Canada

R. Benson, US Environmental Protection Agency, Denver, CO, USA

R. Cary, Health and Safety Executive, Bootle, United Kingdom

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

Mr H. Abadin, Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, GA, USA

Dr B. Åkesson, Department of Occupational and Environmental Health, University Hospital, Lund, Sweden

Dr T. Berzins (Chairperson), National Chemicals Inspectorate (KEMI), Solna, Sweden

Mr R. Cary, Health and Safety Executive, Bootle, Merseyside, United Kingdom

Dr R.S. Chhabra, General Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

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

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

Dr A. Poole (representing CEFIC), Dow Europe S.A., Horgen, Switzerland

Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Toxikologie, Neuherberg, Oberschleissheim, Germany

Dr A. Aitio, Programme for the Promotion of Chemical Safety, World Health Organization, Geneva, Switzerland

Ms M. Godden, Health and Safety Executive, Bootle, United Kingdom

Ms L. Regis, Programme for the Promotion of Chemical Safety, World Health Organization, Geneva, Switzerland

Dr P. Toft, Division of Health and Environment, World Health Organization, Regional Office for the Americas/Pan American Sanitary Bureau, Washington, DC, USA

Dr M. Younes, Programme for the Promotion of Chemical Safety, World Health Organization, Geneva, Switzerland

METHYL CHLORIDE ICSC:0419

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 écotoxicol ogiques 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 consul tation 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.

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 esti mations 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).

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 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.

Le chlorure de méthyle disparaît principalement de l’eau et du sol par évaporation. Dans les couches pro fondes 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.

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.

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.

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 gonfle ment 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.

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 vraisemblable ment 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 volon taires 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.

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.

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.

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 ambien tales en bases de datos pertinentes para el período 1989- 1997. La información relativa al carácter y a la disponi bilidad 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 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).

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 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 calentami ento mundial o a la contaminación fotoquímica del aire.

El mecanismo predominante de eliminación del cloruro de metilo en el agua y el suelo es la volatiliza ción. 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 embar go, 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 experi mentación, 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.

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, correspondi entes 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.

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 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 epididi males 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.

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.

    See Also:
       Toxicological Abbreviations
       Methyl chloride (ICSC)
       Methyl chloride (WHO Food Additives Series 14)
       Methyl chloride (PIM 339)
       Methyl Chloride (IARC Summary & Evaluation, Volume 71, 1999)