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Description of key information

Absorption of chloromethane in humans likely occurs almost exclusively after inhalation. 
Most inhaled chloromethane is metabolized and metabolites are rapidly excreted/catabolized; Chloromethane is not stored in the body and does not accumulate. Tissue distribution is similar across all tested species (rats, dogs, humans) (Dekant and Colnot, 2013).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - inhalation (%):

Additional information

The toxicokinetics, metabolism and distribution pattern of chloromethane was thoroughly summarized in the peer reviewed CICAD 28 (2000) and OECD SIDS (2004). Moreover, absorption, distribution, biotransformation and excretion of chloromethane was summarized in the expert reviews by Dekant and Colnot (2013) and by Dekant (2015):


Inhalation is the only likely route of exposure of humans to chloromethane. Most inhaled chloromethane is metabolized and excreted. As part of the detoxification process chloromethane is readily conjugated to glutathione and may be excreted in the urine, the metabolites being undistinguishable from other metabolites. In addition, some chloromethane may be metabolized and excreted as one-carbon fragments.



In humans as well as in experimental animals, chloromethane 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 chloromethane/m³ (10 or 50 ppm) for 6 h or to 21 mg/m³ (10 ppm) for 2 h, steady state (for blood and expired air concentrations) 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).



After rats were exposed to 14C-labelled chloromethane 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 and Gowenlock, 1971; Kornbrust et al., 1982; Landry et al., 1983). The presence of residues was, however, attributed to the metabolism of chloromethane to formaldehyde and formate and subsequent incorporation of the radiolabelled carbon atom into tissue macromolecules through single-carbon anabolic pathways (Kornbrust and Bus, 1982; Kornbrust et al., 1982). Chloromethane may also bind to macromolecules, especially protein, and to a minimal extent probably also to DNA (Kornbrust et al., 1982; Vaughan et al., 1993).



The metabolism of chloromethane involves conjugation with glutathione to yield S-methylglutatione, S-methylcysteine and other sulfur-containing compounds (Kornbrust and Bus, 1983). The compounds can be excreted in the urine, and S-methylglutathione may be further metabolized to methanethiol. While conjugation with glutathione is the primary metabolic pathway in rodents and humans, a minor oxidative pathway catalyzed by the cytochrome P450 enzyme 2E1 (CYP2E1) in mice yields formaldehyde and formic acid (Dekant and Colnot, 2013). These compounds enter the one-carbon pool for incorporation into macromolecules or formation of CO2. Formaldehyde may also be a direct product of chloromethane via oxidative dechlorination.  

Inhalation of chloromethane 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 207 mg/m³ (100 ppm) decreased the glutathione level by 45%, and exposure to 5163 mg/m³ (2500 ppm) reduced the glutathione content to 2% of control levels (Kornbrust and Bus, 1984).


Methanethiol and formaldehyde, as well as chemically reactive lipid peroxidation products formed in increased concentrations due to glutathione depletion after inhalation of high concentrations of chloromethane have been suggested as the toxic intermediates initiating the mechanism responsible for the toxicity of chloromethane (Dekant and Colnot, 2013).



The biochemical effects of chloromethane were investigated (Jäger et al., 1988) in tissues of F-344 rats and B6C3F1 mice (both sexes). Activities of glutathione-S-transferase (GST) were 2-3 times higher in livers of male B6C3F1 mice, compared with those of female mice, and with rats of both sexes. In kidneys GST activities of (male) mice were about 7 times lower than those found in livers. The activity of formaldehyde dehydrogenase (FDH) was higher in livers of mice (both sexes) than in those of rats. No obvious sex difference was found in livers of rats and mice with respect to FDH. In kidneys, however, (minor) differences in FDH activities occurred between male and female B6C3F1 mice (4.7 vs. 3.1 nmol/min per mg). Sex differences of FDH activity in kidneys were not observed in F-344 rats. The microsomal transformation (by cytochrome P-450) ofchloromethaneand S-methyl-L-cysteine to formaldehyde in tissues of B6C3F1 mice occurred preferentially in the liver. More formaldehyde was produced in liver microsomes of male, compared to those of female mice. Kidney microsomes metabolized chloromethane to formaldehyde much less than liver microsomes. However, the rate of oxidation of chloromethane by CYP2E1 was approximately four times higher in kidney microsomes from male mice as compared to female mice and in rats of both sexes (Dekant and Colnot, 2013).


After single exposure of mice of both sexes to 2065 mg/m³ (1000 ppm) chloromethane no elevation in formaldehyde concentrations was observed in livers and kidneys ex vivo. The determination of DNA lesions, using the alkaline elution technique, revealed no DNA-protein crosslinks in kidneys of male B6C3F1 mice after exposure to chloromethane (2065 mg/m³ (1000 ppm), 6 h day-1, 4 days) and gave only minor evidence of single-strand breaks. Lipid peroxidation (production of thiobarbituric acid (TBA) reactive material), induced by single exposure to chloromethane (2065 mg/m³ (1000 ppm), 6 h), was very pronounced in livers of male and female mice.Smaller increases in peroxidation were observed in the kidneys of exposed mice (Jäger et al., 1988).


In humans (Warholm et al., 1994), interindividual variation in the in vitro conjugation of chloromethane with glutathione by erythrocyte glutathione transferase was investigated in healthy males and females from the southern and central parts of Sweden. It was found that 11.1% of the individuals lacked this activity, whereas 46.2% had intermediate activity and 42.8% had high activity. This distribution of three phenotypes (non-conjugators (NC), low conjugators (LC) and high conjugators (HC)) is compatible with the presence of one functional allele with a gene frequency of 0.659 and one defect allele with a gene frequency of 0.341. The proportion of non-conjugators in this Swedish material was considerably smaller than that previously found in Germany (Peter et al., 1989). The polymorphic distribution of another glutathione transferase, GST mu, was determined in the same individuals with a PCR method. No connection between the genotype for GST mu (GSTM1) and the glutathione conjugation with chloromethane in erythrocytes was found.


In a comparison involving the three human phenotypes and experimental animals, Thier et al. (1998) established, that glutathione transferase (GSTT1) activity towards chloromethane in human erythrocytes (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.


The human GSTT1 polymorphism was illustrated in a study on the toxicokinetics of chloromethane 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 chloromethane in inhaled and exhaled air during exposure) of chloromethane, whereas subjects with no GSTT1 activity (NC) had a smaller respiratory net uptake. At the end of the exposure, the concentration of chloromethane 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 chloromethane by metabolism was high in fast conjugators (HC) and close to zero in subjects with no GSTT1 activity (NC).


A specific mode of action to explain formation of renal tumors by chloromethane in male mice has been developed based on the observation that male mice express a specific cytochrome P450 enzyme in kidney proximal tubules cells (Dekant, 2015). In mouse kidney, this P450 enzyme, which is immunochemically similar to hepatic cytochrome P450 2E1 and shares a preference for low molecular weight compounds, is regulated by testosterone. This cytochrome P450 is not present in the kidney of female mice norin the kidney of both sexes of rats. Presence of this enzyme could also not be detected in human kidney samples (Dekant, 2015).

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 chloromethane was seen in erythrocyte cytoplasm (Peter et al., 1989).

Dekant (2015) further reviewed, that the male mouse specific cytochrome P450 oxidizes chloromethane to formaldehyde (Dekant et al., 1995). Likely, this reaction only occurs to a relevant extent when glutathione is depleted due to high concentrations, causes cell death in the proximal tubule epithelium with ensuing compensatory cell proliferation finally resulting in male mouse specific renal tumor induction. A high incidence of renal tubular damage has been observed in the two year bioassay with chloromethane in the kidney of male mice supporting this mode-of-action. Toxicity of chloromethane in the kidney of male mice may be further enhanced due to glutathione depletion resulting in a decreased capacity for detoxification of formaldehyde and reactive oxygen species formed by inflammatory processes. The kidney has a high capacity for compensatory cell proliferation and several non-genotoxic agents have been demonstrated to induce renal tumor formation due to recurrent cytotoxicity and cell proliferation (Dekant and Vamvakas, 1992).




Metabolites from chloromethane 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 and Bus, 1983). Further, carbon dioxide has been shown to be the major final metabolite of chloromethane, accounting for nearly 50% of the radiolabelled material recovered after a 6-h exposure of rats to chloromethane (Kornbrust and Bus, 1983). Chloromethane is also excreted unmetabolized via the lungs, as seen in studies with volunteers (Stewart et al., 1980; Nolan et al., 1985; Löf et al., 2000).

Following intravenous injection into the bloodstream and injection into the peritoneal cavity, only a small amount is excreted in the breath. 80% disappeared from the blood almost immediately and an additional 10% in the first hour. Pulmonary excretion of unchanged chloromethane following i.v. injection accounted for only 5% of the total (Sperling et al, 1950).




Andersen, M. E. et al. (1980). Determination of the kinetic constants of metabolism of inhaled toxicants in vivo using gas uptake measurements. Toxicology and Applied Pharmacology, 54:100-116 [as cited in: CICAD 28, Methyl Chloride, 2000].

Dekant, W. and Colnot, T. (2013) Expert Review: Can the German OEL-value (MAK) for Chloromethane (MeCl) be considered to be equivalent to a DNEL within the REACH-framework?

Dekant, W. (2015) Expert Review: Additional comments on mutagenicity and carcinogenicity of chloromethane: Human relevance of male mouse-specific renal tumors

Dekant, W. et al. (1995). Sex, organ and species specific bioactivation of chloromethane by cytochrome P4502E1. Xenobiotica, 25(11):1259 -1265[as cited in: CICAD 28, Methyl Chloride, 2000].

Jäger, R. et al. (1988) Biochemical effects of methyl chloride in relation to its tumorigenicity. Journal of cancer research and clinical oncology, 114(1):64-70 [as cited in: OECD SIDS, Chloromethane, 2004].

Kornbrust, D.J. and Bus, J.S. (1984) Glutathione depletion by methyl chloride and association with lipid peroxidation in mice and rats. Toxicology and applied pharmacology, 72:388-399 [as cited in: CICAD 28, Methyl Chloride, 2000].

Löf A., et al. (2000). Glutathione transferase T1 phenotype affects the toxicokinetics of inhaled methyl chloride in human volunteers. Pharmacogenetics, 10:645-653 [as cited in: CICAD 28, Methyl Chloride, 2000].

Nolan, R. J. et al.(1985) Pharmacokinetics of inhaled methyl choride (CH3Cl) in male volunteers. Fundamental and applied toxicology 5:361-369 [as cited in: CICAD 28, Methyl Chloride, 2000].

Peter, H. et al. (1985) DNA-binding assay of methyl chloride. Archives of toxicology, 57:84-87 [as cited in: OECD SIDS, Chloromethane, 2004].

Redford-Ellis, M. and Gowenlock, A.H. (1971) Studies on the reaction of chloromethane with preparations of liver, brain and kidney. Acta Pharmacologica et Toxicologica, 30:49-58 [as cited in: CICAD 28, Methyl Chloride, 2000].

Sperling, F. et al. (1950) Distribution and excretion of intravenously administered methyl chloride. Archives of Industrial Hygiene and Occupational Medicine, 1(2): 215-224 [as cited in: OECD SIDS Chloromethane, 2004]

Stewart, R. D. et al. (1980). Methyl chloride: Development of a biological standard for the industrial worker by breath analyses.,, National Insitute for Occupational Safety and Health (NTIS PB 81-167686) [as cited in: CICAD 28, Methyl Chloride, 2000].

Thier, R. et al. (1998) Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloromethane in liver and kidney. Archives of toxicology, 72:622-629 [as cited in: CICAD 28, Methyl Chloride, 2000].

van Doorn, R. et al. (1980) Detection and identification of S-methylcysteine in ruine of workers exposed to methyl chloride. International archives of occupational and environmental health, 46:99-109 [as cited in: CICAD 28, Methyl Chloride, 2000].

Vaughan, P. et al. (1985). Induction of the adaptive response of Escherichia coli to alkylation damage by the environmental mutagen, methyl chloride. Mutation Research; 293:249-257[as cited in: CICAD 28, Methyl Chloride, 2000].

Warholm, M. et al. (1994) Polymorphic distribution of glutathione transferase activity with methyl chloride in human blood. Pharmacogenetics, 4:307-311 [as cited in: OECD SIDS, Chloromethane, 2004].