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W4236063183 abstract "Free Access Methyl chloride [MAK Value Documentation, 1996] 1996. Documentations and Methods First published: 31 January 2012 https://doi.org/10.1002/3527600418.mb7487e0007 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Published in the series Occupational Toxicants, Vol. 7 (1996) The article contains sections titled: Toxic Effects and Modes of Action Pharmacokinetics Effects in Man Effects on Animals Reproductive and Developmental Toxicity Genotoxicity in vitro in vivo Carcinogenicity Mechanistic studies of renal tumour development in male mice Manifesto (MAK value, classification) Classification/MAK value: 50 ml/m3 (ppm) 105 mg/m3 see Section IIIB MAK List 1992 MAK value dates from: 1984 Classification dates from: 1984 Synonyms: monochloromethane Chemical name (CAS): chloromethane CAS number: 74–87–3 Structural formula: Molecular formula: CH3Cl Molecular weight: 50.49 Melting point: − 97.4 °C Boiling point: − 23.7 °C 1 ml/m3 (ppm) = 2.09 mg/m3 1 mg/m3 = 0.477 ml/m3 (ppm) 1 Toxic Effects and Modes of Action Methyl chloride, like methyl bromide, is not a typical halogenated aliphatic hydrocarbon. It produces only slight central nervous depression (Merzbach 1928); the narcotic concentration for the mouse is 6.5 % v/v (65000 ppm); for comparison, that of chloroform is 0.44 % v/v (Meyer and Gottlieb-Billroth 1920). The brief prenarcotic phase involves inebriation with severe gastrointestinal symptoms (nausea and vomiting). After a latent period of several hours, characteristic sequelae develop with delayed illness and death, sometimes without previous signs of severe intoxication. Circulatory and metabolic organs and especially the nervous system are affected with haemorrhage, inflammation and degeneration. Death comes suddenly in deep coma and is caused by respiratory failure; delayed deaths result from degenerative changes in the brain. The substance does not cause severe mucosal irritation. When liquid methyl chloride comes into contact with the skin, chilling can produce blisters. Negative results were obtained with methyl chloride in studies of reproductive toxicity in the rat; higher doses caused heart anomalies in the progeny of mice. Short-term tests with methyl chloride yielded positive results in vitro (Section 6); in vivo, positive results were only obtained after exposure of the animals to extremely high and toxic concentrations. In a carcinogenicity study, exposure to methyl chloride resulted in the development of renal tumours in male mice but not in female mice nor in rats. A number of factors specific to these study conditions are necessary for the production of the renal tumours so that it may not be concluded that such tumours could develop in persons exposed to methyl chloride. 1.1 Pharmacokinetics Methyl chloride is readily taken up via the lungs and rapidly metabolized in the organism (Andersen et al. 1980). Most elimination does not take place via the lungs; in man 29 % of the absorbed substance is exhaled during the first hour (Morgan et al. 1970). During 120 to 135 minutes after subcutaneous injection of the substance into rats, about 27 % is exhaled unchanged; 70 % is metabolized within 20 to 330 minutes (Soucek 1961). In dogs, 80 % of a dose administered by intravenous injection disappears from the blood very rapidly and a total of 90 % within the first hour (Sperling et al. 1950). More recent metabolic studies have demonstrated that methyl chloride is broken down to yield formate (Kornbrust and Bus 1982) and CO2 (Kornbrust and Bus 1982, Landry et al. 1983); some of the carbon enters the C1 pool (tetrahydrofolic acid) of intermediary metabolism and is built into biological macromolecules. Thus it is not unexpected that formaldehyde appears as an intracellular intermediate (Bus 1982). The main metabolic pathway begins with the enzymatic conjugation of methyl chloride with glutathione (Dodd et al. 1982, Landry et al. 1983). A later metabolite, S-methylcysteine, has been identified in the urine of persons exposed to methyl chloride (Van Doom et al. 1980). In rats, not only S-methylcysteine but also N-acetyl-S-methylcysteine, methylthioacetic acid sulfoxide and N-(methylthioacetyl)glycine have been identified as metabolites of 14C-methyl chloride; all of these can be considered to arise as a result of primary glutathione conjugation (Landry et al. 1983). The oxidative conversion of methyl chloride to formaldehyde (via cytochrome P450) is considered to be a minor metabolic pathway (Bus 1982, Hallier et al. 1990, Kornbrust and Bus 1982). That formaldehyde is produced as an intermediate in the metabolism of methyl chloride may be concluded from the results of another research group (Kornbrust and Bus 1982) who investigated the liver, kidneys, lungs and testes of rats exposed to 14C-methyl chloride, also after pretreatment with cyclohexamide, methotrexate and methanol. The results suggest that most if not all of the protein-bound radioactivity derived from 14C-methyl chloride enters the protein during metabolic incorporation of formic acid arising in C1 metabolism. In the metabolic scheme illustrated in Figure 1 (Bus 1982), the postulated metabolite methanethiol (methyl mercaptan) plays a central role; it has been proposed that it is the metabolite responsible for the neurotoxic effects of methyl chloride (Korn-brust and Bus 1984). It was shown to be formed in incubations of rat intestinal contents with S-methyl-glutathione and S-methylcysteine (Peter et al. 1989b) and thus could be formed in vivo in the intestine after biliary excretion of such metabolites. Figure 1Open in figure viewerPowerPoint Metabolism of methyl halides (Bus 1982) Exposure of rats or mice to a methyl chloride concentration of 2500 ml/m3 for 1 to 6 hours results in a marked dose-dependent and time-dependent glutathione depletion in a number of organs (Bolt et al. 1988, Kornbrust and Bus 1984). Exposure of mice to methyl chloride concentrations of 2000–2500 ml/m3 for 6 hours resulted in a marked increase in lipid peroxidation, determined as ethane exhalation and as levels of thiobarbituric acid reactive material in the liver, kidneys and brain (Kornbrust and Bus 1984). In man there appear to be genetic differences in the capacity for methyl chloride metabolism, differences which are not known to exist in this form in experimental animals. Assay of S-methylcysteine in the urine of 6 individuals who were exposed to very similar methyl chloride levels showed that two persons, unlike the other four, excreted practically no S-methylcysteine (Van Doom et al. 1980). In a laboratory investigation, 6 male test persons were exposed to methyl chloride concentrations of 50 or 10 ml/m3 for 6 hours and the levels of the substance in blood and alveolar air determined during and after the exposures (Nolan et al. 1985). In two of the 6 persons, the blood levels were markedly higher (by a factor of 2 to 3) during the exposure and decreased very much more slowly after the exposure than in the rest of the collective; these results also suggest the existence in the human population of two groups differing in their capacity for methyl chloride metabolism. Incubation of methyl chloride with human haemolysate revealed in about 60 % to 70 % of the population (metabolizers) enzymatic conversion to S-methylglutathione which was absent in the remaining 30 % to 40 % (non-metabolizers) (Peter et al. 1989 a). Erythrocytes from rats, mice, cattle, pigs, sheep and rhesus monkeys did not carry out this conjugation step. Other studies (Schröder et al. 1992) showed that the erythrocytes from persons who carry out the conjugation contain an isoenzyme of GSH transferase with high specificity for C1 and C2 substrates such as methyl halogenides and ethylene oxide. These studies, together with those of Van Doom et al. (1980) and Nolan et al. (1985), demonstrate that the human population can be divided into two genetically different groups on the basis of their glutathione-dependent methyl chloride metabolism. 2 Effects in Man The inconspicuous odour of methyl chloride and the mild symptoms of acute toxicity provide little warning of the incipient intoxication which results after prolonged inhalation of the substance. In the literature, several hundred descriptions of cases of methyl chloride poisoning and more than 30 deaths are described. The prenarcotic symptoms (headaches, dizziness, confusion, marked sleepiness) and gastrointestinal disorders (nausea and vomiting) are followed by a symptom-free interval of 0 to 2 days. The subsequent illness is characterized clinically by neurotoxic symptoms. Personality changes originating in organic changes in the brain, tremor, tonic clonic spasms, hiccough and transient paralysis are observed. The eyes can also be affected. The symptoms (amblyopia, strabismus, double vision, accommodation disorders and ptosis) are like those of methanol intoxication. The effects on parenchymatous organs are seen in the heart as myocardial damage with characteristic ECG changes (Gummert 1961, Walter and Weis 1951), in the liver as enlargement (Roche et al. 1956), icterus (Weinstein 1937), pathological liver function parameters (Chalmers et al. 1940, Sayers et al. 1929) and focal parenchymal degeneration (Kegel et al. 1929), in the kidney as symptoms of nephritis (Mendeloff 1952, Roche et al. 1956, Verriere and Vachez 1949) and histopathological changes such as congestion, haemorrhage, focal degeneration and tubulus necrosis (Dunn and Smith 1947, White and Somers 1931) and in the lungs as hyperaemia, congestion and haemorrhage, most clearly in animal studies (Nuckolls 1933, Schwarz 1926, White and Somers 1931). When the methyl chloride intoxication is not lethal, the lesions in the central nervous system and parenchymatous organs can regress completely. Frequently, however, there are permanent defects. Most of the numerous occupational intoxications were acute; measurements of workplace concentrations were not carried out. There are only few reports of chronic intoxications (Mackie 1961, Noetzel 1952, Roche and Bouchet 1948) and details of exposure concentrations are not available for these either. The odour threshold is given as 10 ml/m3 (Leonardos et al. 1969). In a 4-month study, average workplace concentrations of methyl chloride were determined as 30 ml/m3 with peak concentrations up to 440 ml/m3. Symptoms of acute toxicity were not seen. In another factory where the workers were exposed to mixtures of methyl chloride with chlorofluorocarbons, 9 employees – at concentrations in the workplace air of 26 − 1500 ml/m3 – complained of symptoms such as weakness, inebriation, unsteadiness, lack of concentration and effects on the tongue. At concentrations between 2 and 500 ml/m3, 141 persons were said to be free of symptoms (Dow 1986). 3 Effects on Animals Different animal species differ markedly in their sensitivity to the effects of methyl chloride. Young animals are much more resistant than older animals (Smith and von Oettingen 1947 a, 1947 b). The results of studies of the acute inhalation toxicity of methyl chloride are shown in Table 2. Studies with repeated and prolonged exposure produced the results shown in Table 1. Table 1. Inhalation toxicity of methyl chloride after repeated exposure of experimental animals Species Concentration ml/m3 Exposure duration Observations References rabbit 250 − 465 5 days no corneal changes; reaction of the pupilla to light unaffected Grant 1962 6 different species 300 6 h/day 6 days/week 64 weeks no adverse effects Smith and von Oettingen 1947a dog 500 6 h/day 6 days/week after 4 weeks ataxia, later progressive spasticity; LC50/23 days (adults), LC50/211 days (juveniles) Smith and von Oettingen 1947a guinea pig 500 6 h/day 6 days/week 73 % of juvenile animals survived; LC50/71 days (adults) Smith and von Oettingen 1947a mouse 500 6 h/day 6 days/week LC50/82 days (juveniles), LC50/143 days (adults) Smith and von Oettingen 1947a dog 500 6 h/day 6 days/week LC50/211days (juveniles), LC50/23 days (adults) Smith and von Oettingen 1947a monkey 500 6 h/day 6 days/week LC50/110days Smith and von Oettingen 1947a rabbit 500 6 h/day 6 days/week LC50/192 days Smith and von Oettingen 1947a rat 500 6 h/day 6 days/week no effects Smith and von Oettingen 1947a guinea pig 1000 6 h/day 6 days/week LC50/25 days (juveniles), LC50/4 days (adults) Smith and von Oettingen 1947a mouse 1000 6 h/day 6 days/week LC50/48 days LC50/5 days (adults) Smith and von Oettingen 1947a dog 1000 6 h/day 6 days/week LC50/6 days Smith and von Oettingen 1947a rabbit 1000 6 h/day 6 days/week LC50/51 days Smith and von Oettingen 1947a rat 1000 6 h/day 6 days/week 67 % survived for more than 175 days Smith and von Oettingen 1947a guinea pig 2000 6 h/day 6 days/week LC50/3 days Smith and von Oettingen 1947 a mouse 2000 6 h/day 6 days/week LC50/3 − 11 days Smith and von Oettingen 1947a dog 2000 6 h/day 6 days/week LC50/4 days Smith and von Oettingen 1947 a monkey 2000 6 h/day 6 days/week LC50/10 days Smith and von Oettingen 1947a rat 2000 6 h/day 6 days/week LC50/27 days (juveniles), LC50/15 days (adults) Smith and von Oettingen 1947a rabbit 2000 6 h/day 6 days/week LC50/23 days Smith and von Oettingen 1947a cat 2000 6 h/day 6 days/week LC50/27 days Smith and von Oettingen 1947a hen 2000 6 h/day LC50/38 days Smith and von Oettingen 1947a frog 2000 6 h/day 6 days/week no effects Smith and von Oettingen 1947a mouse guinea pig 3000 6 h/day 6 days/week LC50/1 day Smith and von Oettingen 1947a dog 3000 6 h/day 6 days/week LC50/3 days Smith and von Oettingen 1947a rat 3000 6 h/day 6 days/week LC50/5 days Smith and von Oettingen 1947a rat 4000 6 h/day 6 days/week LC50/4 days Smith and von Oettingen 1947a rabbit 4000 6 h/day 6 days/week LC50/13 days Smith and von Oettingen 1947a a In rats it was demonstrated that the composition of the diet affected the survival of the animals. After exposure to 2000 ml/m3, the LC50 increased by a factor of three when the casein level in the diet was increased from 20 % to 35 %. Addition of cysteine or methionine increased the LC50 by a factor of 14 even with the low casein diet (Smith and von Oettingen 1947a). The mechanism of toxic action of methyl chloride differs in different animal species. In rats, N-acetyl cysteine serves as an antidote against acute methyl halogenide poisoning so that reduction in the glutathione level seems to amplify the acutely lethal effects (Peter et al. 1985 a). In addition, pretreatment of rats with the non-steroid antiinflammatory agent BW755C, prevents the death of animals acutely exposed to otherwise lethal concentrations of methyl chloride (Working and Bus 1986a). In mice (B6C3F1), however, depletion of glutathione with L-buthionine-S,R-sulfoximine (BSO) protects the animals from the lethal effects of acutely toxic doses of methyl chloride (Chellman et al. 1986). 4 Reproductive and Developmental Toxicity Groups of 25 female F344 rats were exposed to methyl chloride concentrations of 100, 500 or 1500 ml/m3 for 6 hours daily from day 7 to day 19 of gestation. In the groups exposed to 1500 ml/m3, body weight development of dams and foetuses was delayed as was ossification in the foetuses. In the groups exposed to 100 or 500 ml/m3, no evidence of maternal or embryonal toxic effects was seen. Teratogenic effects were not observed in any of the dose groups (Wolkowsky-Tyl et al. 1983 a). Groups of 40 male and 80 female F344 rats were exposed to methyl chloride concentrations of 150, 475 or 1500 ml/m3, 6 hours daily for 10 weeks before mating, 7 hours daily during the mating interval and for the females also until day 18 of gestation and 6 hours daily from day 4 to day 28 post partum (Hamm et al. 1985). Ten males from each group were killed on day 28 post partum and subjected to gross pathological examination. Regression of the lesions at various times after the end of exposure was studied with the remaining 30 males per group. The progeny were treated in the same way as the animals of the parent generation. The results demonstrated delays in body weight gain in the males and females of the 475 ml/m3 and 1500 ml/m3 groups. All males exposed to 1500 ml/m3 were infertile. The pathological examination of the gonads revealed testis atrophy in all 1500 ml/m3 group males and granulomas in the epididymis in about 30% of the animals. In the 475 ml/m3 group, fertility disorders were detected in 57 % of the males. The fertility of the male animals in the 150 ml/m3 group was not different from that of the controls. Ten weeks after the end of exposure, the fertility disorder had regressed in 25 % of the males in the 1500 ml/m3 group. In the males of the 475 ml/m3 group 10 weeks after the end of exposure, fertility was no longer different from that of the controls. The progeny of fertile males from the 150 ml/m3 and 475 ml/m3 groups were exposed in the same way as their parents from birth until 10 weeks after weaning and then were mated. In the 475 ml/m3 group, the fertility of the F1 males was slightly impaired and the postnatal development of the F2 generation was delayed. The authors considered 150 ml/m3 to be the no effect level. Table 2. Acute inhalation toxicity of methyl chloride in experimental animals Species Concentration ml/m3 Exposure duration (continuous) Observations References guinea pig 49 72 h all animals survived White and Somers 1931 guinea pig 77 77 h 9/18 animals died White and Somers 1931 guinea pig 140 72 h all animals died; pulmonary oedema, brain lesions White and Somers 1931 guinea pig 400 10 h tolerated without severe damage Sayers et al. 1929 guinea pig 1200 − 1500 270 min some animals died after 2 − 3 days Smith and von Oettingen 1947a guinea pig 1200 − 1500 540 and 810 min all animals died Smith and von Oettingen 1947a guinea pig 3000 6 h no signs of toxicity during exposure; 15 to 20 animals died within 6 h of end of exposure Smith and von Oettingen 1947a guinea pig 3000 810 min no symptoms apart from rapid breathing and slight weakness Sayers et al. 1929 guinea pig 3000 540 min all animals died within 1- 3 days Sayers et al. 1929 guinea pig 3000 815 min animals died after 8 h to 2 days Sayers et al. 1929 mouse 3146 7h lethal for 50 % of animals von Oettingen et al. 1949 guinea pig 5000 − 5600 120 and 170 min all animals died within 1–2 days Sayers et al. 1929 guinea pig 5000 − 5600 540 min all animals died within 2½ − 15h Sayers et al. 1929 guinea pig 5000 − 10000 2 h first excitement, then depression; slow recovery Nuckolls 1933 cat 6160 240 min unsteady gait after 3 − 5 min; animals prostrate after 150 min Lehmann and Schmidt-Kehl 1936 cat 10860 190 min shallow narcosis after 150 − 155 min, deep narcosis after 180 − 190 min Lehmann and Schmidt-Kehl 1936 cat 13420 42 min shallow narcosis after 12 − 15 min, deep narcosis after 38 − 41 min Lehmann and Schmidt-Kehl 1936 cat 14050 60 min shallow narcosis after 13 − 15 min, deep narcosis after 52 − 55 min Lehmann and Schmidt-Kehl 1936 dog 15000 - died after 354 min; preterminal adverse effects on breathing and circulation von Oettingen et al. 1949 cat 16810 48 min shallow narcosis after 12 − 14 min, deep narcosis after 42 − 45 min Lehmann and Schmidt-Kehl 1936 dog 17000 30 min ataxia before narcosis Baker 1927 cat 17780 9 min shallow narcosis after 4 − 4.5 min, deep narcosis after 6 min Lehmann and Schmidt-Kehl 1936 guinea pig 21000 − 25000 2 h lethal for all animals Nuckolls 1933 guinea pig 27500 1–5 min 1 animal died after 30 min Sayers et al. 1929 dog 37000 10 min agitation, vomiting after 18 min, dyspnoea after 25 min Baker 1927 dog 40000 - animals dead after 240 min; preterminal ECG changes von Oettingen et al. 1949 rabbit 40500 5 min narcosis, respiratory depression and reduced blood pressure, effects less marked than with chloroform Kionka 1900 guinea pig 50000 − 60000 20–30min unsteady gait, no other symptoms Sayers et al. 1929 guinea pig 50000 − 60000 50 min unable to walk; animals died Sayers et al. 1929 guinea pig 60000 20 min occasional late deaths after 23 days Sayers et al. 1929 mouse 65000 − 70000 - narcosis after 30 − 45 min Schwarz 1926 guinea pig 95000 12 min inebriation, animals unable to walk after 2 min, late deaths after 1 − 4 days Sayers et al. 1929 guinea pig 143000 10–20 min late deaths Sayers et al. 1929 guinea pig 415000 - loss of balance after 30 s, dyspnoea after 8 min Sayers et al. 1929 In a test for dominant lethal mutations, groups of 40 male F344 rats were exposed to methyl chloride concentrations of 1000 or 3000 ml/m3, 6 hours daily for 5 days and then mated with untreated females 2 weeks after the last exposure. Fertility was significantly reduced in the males of the 3000 ml/m3 group. In addition, preimplantation and postimplantation losses were increased. The authors suggested that the high methyl chloride concentration had produced dominant lethal mutations in the sperm in the vas deferens and epididymis and that these were responsible for the increase in postimplantation deaths. In the group exposed to 1000 ml/m3 there were no findings which could be ascribed to the methyl chloride exposure (Working et al. 1985 a). In an additional study which also treated groups of 40 males according to the above dose scheme, testis atrophy and unilateral and bilateral sperm granulomas were found in the cauda epididymidis in 50 % of the animals in the 3000 ml/m3 group (Working et al. 1985 b). There was also a significant reduction in testicular spermatid head counts two weeks after the last exposure. Characteristic symptoms of cytotoxicity were seen in the testes (delayed sperm maturation, vacuolation of the epithelia, polynuclear giant cells, etc.). Examination of the seminiferous tubules 7 weeks after the last exposure revealed that 60 % to 70 % of the spermatogonia had been killed during the methyl chloride exposure. This resulted in a reduced number of sperm. All other measured parameters had returned to normal. The authors considered that the high preimplantation losses seen after methyl chloride exposure are more likely to be the result of inflammatory changes than of direct genotoxic effects. Groups of 33 C57BL/6 mice were exposed to methyl chloride concentrations of 100, 500 or 1500 ml/m3, 6 hours daily from day 6 to day 17 of gestation. In the dams which inhaled 1500 ml/m3, marked signs of toxicity (vaginal bleeding, haematuria, neurotoxicity) developed after 6 to 9 days of treatment; these dams were therefore killed prematurely. Autopsy revealed selective necrosis of the neurones in the inner granular layer of the cerebellum in all animals. In the 500 ml/m3 group there were no signs of maternal toxicity. There were no externally visible effects on the foetuses. Visceral examination, however, revealed heart defects (reduced or absent atrioventricular and bicuspid valves) in 16.7% of the foetuses. In the 100 ml/m3 group, neither maternal nor embryonal toxic effects nor teratogenic effects were seen (Wolkowsky-Tyl et al. 1983 a). In an additional study, groups of 62 to 67 pregnant mice were exposed according to the same schedule to methyl chloride concentrations of 250, 500 or 750 ml/m3 (Wolkowsky-Tyl et al. 1983 b). Ataxia, tremor, convulsions, delayed body weight gain and deaths were observed from day 7 of exposure in the animals of the 750 ml/m3 group. Heart defects (absent or abnormal tricuspid valve, reduced number of papillary muscles and/or chordae tendineae on the right side of the heart, right ventricle reduced in size, heart spherical, white spots on the wall of the left ventricle) were significantly increased in the foetuses of the 500 and 750 ml/ m3 groups. No toxic effects were detected in either dams or progeny in the 250 ml/m3 group. Male F344 rats were exposed to a methyl chloride concentration of 3500 ml/m3, 6 hours daily for 5 days and then, after a 3 day pause, were exposed again for another 4 days. The exposure resulted in damage to the seminiferous epithelium, formation of inflammatory granulomas in the cauda epididymidis and marked reduction in plasma testosterone levels. Glutathione depletion was found in the tissues but was not correlated with the severity of the lesions (Chapin et al. 1984). A follow-up study (Working and Bus 1986b) with male Fischer 344 rats which inhaled methyl chloride in concentrations of 1000 or 3000 ml/m3, 6 hours daily for 5 days before mating revealed that the fertility of the higher dose group animals was markedly reduced. After carrying out comparative studies with triethylenemelamine, the authors concluded that the effects of methyl chloride result from non-genotoxic processes. 5 Genotoxicity 5.1 in vitro Methyl chloride is a direct mutagen in the Ames test (Andrews et al. 1976, Fostel et al. 1985, Simmon et al. 1977). This is to be expected because of its alkylating activity which is, however, relatively weak, markedly weaker than that of methyl bromide or methyl iodide (order of activity: methyl iodide > methyl bromide > methyl chloride). In plants (Tradescantia sp.), methyl chloride produced chromosomal aberrations (Smith and Lotfy 1954). Methyl chloride caused transformation of cultured Chinese hamster embryo cells (Hatch et al. 1983). Very high concentrations of methyl chloride, 1 % to 10 % in a closed container, caused unscheduled DNA synthesis (UDS) in rat hepatocytes and spermatocytes incubated for 18 and 3 hours, respectively, but not in primary cultures of rat tracheal epithelial cells (Working et al. 1986). In cultures of human lymphocytes, methyl chloride (in concentrations up to 5 % in the gas phase) induced sister chromatid exchange and mutations but no DNA strand breaks (Fostel et al. 1985). 5.2 in vivo In a dominant lethal test, male rats were exposed to a methyl chloride concentration of 3000 ml/m3 and then mated; in the females, preimplantation and postimplantation losses were increased (Section 5) (Working et al. 1985 a). In a subsequent publication, these effects were considered to be of non-genotoxic origin, an effect of failure of fertilization (Working and Bus 1986b). Inhalation of a methyl chloride concentration of 3000 to 3500 ml/m3, 6 hours daily for 5 days, did not result in DNA repair in hepatocytes, spermatocytes or tracheal epithelial cells in male F344 rats. In vivo exposure of rats to 15000 ml/m3 for 3 hours caused a slight increase in UDS in hepatocytes but not in spermatocytes or tracheal epithelial cells (Working et al. 1986). The available results of short-term studies suggest that methyl chloride has weak direct alkylating activity which can be demonstrated in vitro. It is weaker than that of methyl bromide or methyl iodide. In vivo, such effects are seen, if at all, only after extremely high and toxic doses of the substance (see also IARC 1986). This conclusion is supported by the results of two DNA binding studies. A DNA-binding study carried out in male Fischer 344 rats which inhaled 14C-methyl chloride demonstrated that radioactivity was incorporated into bases of the RNA and DNA but that methylated bases could not be detected in any of the tissues examined (liver, lung, kidneys, testes, brain, muscle, intestines) (Kornbrust et al. 1982). Another DNA-binding study (Peter et al. 1985b) in which Fischer 344 rats and B6C3F1 mice were exposed to 14C-methyl chloride also showed that no methylation of guanine at the positions O6 or N7 was detectable in liver or kidneys of the exposed animals. The association of radioactivity with the DNA, probably because of its incorporation into normal DNA bases, was most marked in the kidneys of B6C3F1 mice. These results are in contrast with the clear systemic DNA-methylating effects of methyl bromide (Gansewendt et al. 1991 a) and methyl iodide (Gansewendt et al. 1991b) in vivo. 6 Carcinogenicity The results of a 2-year inhalation study with rats (Fischer 344) and mice (B6C3F1, which was carried out for CIIT, raised the question of a potential carcinogenic activity of methyl chloride (Batelle Columbus 1982). In this study, groups of 120 rats or mice per sex and concentration were exposed to methyl chloride concentrations of 0, 50, 225 or 1000 ml/m3, 6 hours daily on 5 days per week. In the male mice of the highest exposure group and only in that group, the incidence of kidney tumours (cystadenomas, adenomas of the renal cortex and papillary cystadenomas) was increased significantly. In female mice or in rats of either sex, these lesions did not develop and no tumours were observed. Discussion of this study produced arguments against the applicability of these results to man; drawbacks of the study were pointed out. In particular, mortality was unusually high in all groups of male mice and highest in the group exposed to 1000 ml/m3. In the study protocol, this is ascribed to the fact that the animals were kept in groups so that fighting for dominance between the male mice was common, especially during the first 6 months. Bite wounds predominated in the genital area and led to frequent retrograde urinary tract infections. 6.1 Mechanistic studies of renal tumour development in male mice In recent years, studies have been carried out to" @default.
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