chloromethane; methyl chloride

Endpoint summary

Description of key information

NOAEC systemic (rat and mouse, 2 a): 465 mg/m³ (CIIT, 1981)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

465 mg/m³

Study duration:

chronic

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score: 2) studies, which are sufficient to fulfil the standard information requirements set out in Annex VIII-X, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Under normal conditions chloromethane exists as a gas. Therefore the only relevant route of exposure is via inhalation.

Data on subacute, subchronic and chronic chloromethane exposure are available from experiments with mice, rats and dogs (CIIT, 1979 and 1981, Morgan et al., 1982; McKenna et al., 1981; Burek et al., 1981). The urogenital tract, the central nervous system (please also refer to Section Neurotoxicity) and the liver could be identified as target organs of chloromethane, as well as the testes and epididymis in rats. Species and sex differences in severity of chloromethane toxicity were reported by several authors. In general, B6C3F1 mice were much more severely affected than rats.

 

In a 2-year inhalation study equivalent to OECD Guideline 453 Fischer 344 rats were exposed to 103, 465 or 2065 mg/m³ chloromethane for 6 hours/days, 5 days/week (CIIT, 1981). Planned interim necropsies of experimental animals were completed at 6,12, 18 and 24 months following initiation of the exposure.

Mortality data indicated that rat survival was not affected by exposure to chloromethane. Total body weight gain was consistently reduced throughout the exposure period for male and female rats in the highest dose group. Although female rats in the 465 mg/m³ group had significantly decreased body weights, these occurred periodically and were not observed at the end of the study. Ophthalmologic examinations revealed corneal cloudiness or opacity in the rat, which were apparently due to a SDA virus infection and which were also found in control animals, although at a lower incidence. Lenticular changes, which appeared in rats only at 18 months, may have been related to exposure. Haematology, clinical chemistry and urinalysis were unaffected in all dose groups. No neurofunctional impairments were observed after exposure. Significant changes in organ weights were determined in rats exposed to 2065 mg/m³ chloromethane. Relative heart weight was increased in male rats at 12, 18 and 24 months and in female rats at 12 and 24 months. Males had increased relative liver weights, since females had decreased absolute liver weights at all times. Decreased absolute brain weights were generally observed at all time periods for both sexes. Relative lung weights were increased at all concentrations, but only at the 6-months sacrifices. The testes were the only organ of the rats considered to have significant chloromethane induced lesions. Bilateral and diffuse degeneration and atrophy of the seminiferous tubules of the testes were first noted in males exposed to 2065 mg/m³ for 6 months. The effect increased in degree and in number of animals affected until the 18-month sacrifice. By 24 months, the effects of normal ageing prevented interpretation. However, with increased exposure to chloromethane, the resultant significant decrease in bilateral compressive degeneration and atrophy and the significant increase in unilateral compressive degeneration and atrophy (caused by testicular tumors) correlated with a decrease in interstitial cell tumor size. This observation was supported by decreased testicular weights and testes/body weight ratios in rats exposed to 2065 mg/m³ chloromethane. No changes in the testes were detectable at either 103 or 465 mg/m³. Sperm granulomas were noted in three male rats at 2065 mg/m³: two at 6 months and one at 24 months. Their presence could not directly be attributed to chloromethane exposure.

On the basis of these results a NOAEC for systemic effects of 465 mg/m³ was derived from the 2-year inhalation study for rats.

 

B6C3F1 mice were exposed to chloromethane under the same conditions as the Fischer 344 rats in a 24-months inhalation study (CIIT, 1981). Mice survival was adversely affected at the 2065 mg/m³ exposure concentration. As a result of high mortality in the mouse high-dose group, the scheduled 24-months sacrifice was carried out after 21 or 22 months of exposure. In addition, during the first six months substantial mouse mortality resulted from fighting for dominance among the group-caged (4 per cage) male mice in all dose groups and controls. Clinical signs suggesting disturbance of the central nervous system, such as tremors and paralysis, were observed in mice at 2065 mg/m³. Growth of only the male mice exposed to 2065 mg/m³ was depressed during the first 18 months. No chloromethane-related changes were observed in mice during ophthalmic examinations, in haematology and in urinalysis. Neurofunctional impairment (loss of clutch response) was observed in the 2065 mg/m³ group at 18 and 21 months in males and at 22 months in females. These statistically significant observations were supported by histopathological findings. Relative heart weight was increased in the 2065 mg/m³ exposure group in female mice. Additionally, an increase in the relative heart weight of female mice exposed to 465 mg/m³ for 24 months were observed. Decreased absolute brain weights were observed at all time periods in both sexes in the highest dose group and absolute and relative testicular weights were decreased at 18 and 24 months. Statistically significant hepatocellular changes (vacuolization, karyomegaly, cytomegaly, multinucleated hepatocytes and degeneration) were seen in male and female (to a lesser degree) mice exposed to 2065 mg/m³ chloromethane. In male mice of the 2065 mg/m³ dose group significantly elevated SGPT values occurred, coupled with histopathological findings in the liver. Increased SGPT were also observed in the lower dose groups and in female mice, but did not correlate with any histopathological alterations. Renal tubuloepithelial hyperplasia and karyomegaly were seen in male mice exposed to 2065 mg/m³ for 12 months and progressed in severity and prevalence throughout the study. A significant increase in renal tumors was noted in 2065 mg/m³ male mice sacrificed or dying between 12 and 21 months, including renal cortical adenoma, renal cortical adenocarcinoma, papillary cystadenoma, papillarx cystadenocarcinoma, and tubular cystadenoma. The only renal neoplasm noted at concentrations less than 2065 mg/m³ occurred in two 465 mg/m³ male mice at the 24-month terminal sacrifice. Although this increase was not statistical significant, the adenomas were similar to those that occurred in the 2065 mg/m³ group. Renal cortical cysts were predominantly seen in mice in the 2065 mg/m³ group, whereas microcysts were noted most frequently in the 103 mg/m³ at 24 months compared with the control males. According to Johnson (1988) the microcystes were likely considered as procedural artefact due to multiple pathologists examining the tissues and using different nomenclature. At exposure to 2065 mg/m³ chloromethane degeneration and atrophy of the seminiferous tubules were seen in mice, as well as lypmphoid depletion and splenic atrophy. Cerebellar lesions first appeared in male and female mice at the 18-month sacrifice from the 2065 mg/m³ group. The lesion, which was characterized by degeneration and atrophy of the cerebellar granular layer, did not appear in mice from any other exposure group or in the controls. At the 22-months sacrifice, similar but more extensive observations in 16/18 females were reported from 2065 mg/m³ group. At 18 months, axonal swelling and degeneration of minor severity were observed in the spinal nerves and cauda equina associated with the lumbar spinal cord. These effects were observed in all mice groups, including at a low incidence in the control group, and no dose-response relationship was established.

In conclusion, significant findings from the 2-year inhalation study in mice were disturbances of the nervous system and the occurrence of renal tumours. Neoplasia was not found at any other site in the male B6C3F1 mouse nor at any site in female mice. Therefore, on the basis of these results the NOAEC for systemic effects (not tumour formation) was considered to be 465 mg/m³ in the 2-year inhalation study in mice.

 

In a subchronic pilot study for the combined chronic toxicity/carcinogenicity study Fischer 344 rats and B6C3F1 mice were exposed 6 hours/day, 5 days/week for 13 weeks to exposure concentrations of 774, 1549 or 3098 mg/m³ chloromethane (CIIT, 1979). Both male and female rats of the highest dose group had significantly lower body weights when compared to controls at the end of the exposure period. In addition, female rats of the 1549 mg/m³ dose group showed significantly decreased body weights from week 6 through week 12.

Significant increases in SGPT activity were examined in male mice in the 3098 mg/m³ dose group. These increases may be explained by the presence of histological hepatic changes. Cytoplasmic vacuolization of hepatocytes occurred in the two highest dose groups in mice, the female mice were even more affected as males at 1549 mg/m³. One male mouse and one female rat exposed to 3098 mg/m³ had evidence of hepatic infarction. Increased relative liver weights were observed at the 3098 mg/m³ dose level. No compound-related lesions were reported from gross pathology or histopathology on kidneys, heart or testes. The absence of recorded organ lesions could be due to a high incidence of mortality in mice especially of the highest dose group. The NOAEC for this subchronic study was considered to be 1549 mg/m³ for both species.

 

In a subchronic multi-species study with CD-1 mice, Sprague-Dawley rats and Beagle dogs no specific target organ toxicity or unequivocal toxic manifestations of chloromethane were observed at exposure concentrations as high as 826 mg/m³ (6 hours/day, 5 days/week for 93-95 days). The exposure concentration in this study was too low to identify a LOAEC (McKenna et al., 1981).

 

In a subacute inhalation study by Morgan et al. (1982) Fischer 344 rats and three different mice strains (C3H; C57/BL/6 and B6C3F1) were exposed 6 hours a day up to 12 days to chloromethane at concentrations of 4130, 7228 or 10325 mg/m³ (rats) and 1033, 2065 or 4130 mg/m³ (mice), respectively.

All mice of the 4130 mg/m³ group were dead or moribund by day 5. Prior to death many of the mice exhibited ataxia and hematuria. Focal areas of necrosis of the internal granular layer of the cerebellum was seen at the 2065 and 4130 mg/m³ concentration levels in female C57BL/6 mice, the other two mouse strains did not develop brain lesions. Degeneration in the kidneys was found at 4130 mg/m³ and basophilic tubules in the renal cortex at 2065 mg/m³ in all three mice strains. Further treatment associated lesions in mice included hepatocellular necrosis in the highest dose group and hepatocellular degeneration in the lower dose groups, mainly in mice exposed to 1033 and 2065 mg/m³ chloromethane.

Rats, especially in the higher dose group, were seriously affected by the exposure; approximately 50% of the rats exposed to 10325 mg/m³ were killed in extremis on day 5. Symptoms such as lack of coordination of the forlimbs, paralysis of the hindlimbs, convulsive seizures, diarrhoe and convulsions were recorded in the 10325 and 7228 mg/m³ dose group. Cerebellar degeneration was seen in rats of the highest dose group, which resembled those observed in mice. In most rats lesions were seen in the liver, including loss of normal areas of cytoplasmic basophilia and variable degeneration. In the kidneys dose-dependent degeneration and necrosis of the proximal convoluted tubules were observed. All groups of rats had testicular degeneration in seminiferous tubules with a clear exposure-concentration related response.

Based on the hepatocellular effects the LOAEC for mice was considered to be 4130 mg/m³. Due to the renal, testicular, epididymal findings and to some extent to the hepatocellular responses a rat LOAEC of 4130 mg/m³ was derived. No-effect levels could not be obtained for the two species.

Continuous exposure for 2-3 days to chloromethane at concentration of 413, 1033, 2065 or 4130 mg/m³ were examined in Sprague-Dawley rats. All rats of the highest dose group died. Exposure to 2065 mg/m³ for 48 or 72 hours resulted in some mortality after exposure. The primary cause of death appeared to be kidney toxicity and subsequent renal failure. Kidneys were frequently dark and displayed varying degrees of renal tubular necrosis, degeneration, cytoplasmic heterogeneity, regeneration and epithelial cell lipid accumulation. In addition, a low degree of liver toxicity was observed in a dose-dependent manner in the 2065 and 4130 mg/m³ dose group. The epididymides were affected in male rats exposed to > 1033 mg/m³ and in those males surviving the recovery period. Testicular atrophy was also present apparently occurring secondarily to the epididymal alterations (Burek et al., 1981).

 

Neurotoxicity

For further repeated dose toxicity studies with a special focus on neurotoxicity please refer to Section Neurotoxicity. In this Section a summary is given on observed neurological impairments and an assessment of neurotoxicity data (expert review) by Dekant and Colnot (2013) is included.

 

 

Human data

In humans, chloromethane acts principally as a depressant of the CNS. After single or repeated exposures states described asdrunkenness, although more persistent were described. Typical signs and symptoms of intoxication are staggering gait, weakness, double vision, headache, apathy, anorexia, nausea, vomiting, abdominal pain, diarrhea, personality changes, muscle spasms, tremors of the hands, loss of memory, paralysis and confusion have been observed. In general, the symptoms seem to develop soon after exposure. Effects of longer-term “low-level” exposure are thought to be generally mild and reversible after a recovery period (Gudmundsson, 1977; Ellenhorn and Barceloux, 1988; Sittig, 1991).

Other organ systems can be affected in persons showing marked central nervous system changes, these include the kidneys, liver, and particularly the lungs (von Oettingen, 1955). Changes reported in other systems are less certain and may be secondary or coincidental to chloromethane exposure. Although recovery appears to be complete, it is often prolonged and at least one report indicates adverse effects may be permanent (Gudmundsson, 1977). Permanency may depend upon the degree of injury and the ability of the subject to compensate for the injury.

 

 

 

References

Burek, J.D. et al. (1981) Methyl Chloride: 48 and 72 Hour Continuous InhalationExposurein Rats Followed by up to 12 Days of Recovery, Toxicology Research Laboratory, Health & Environ. Sciences, The Dow Chemical Company, Midland, Michigan (Final Report February 1981) [as cited in: OECD SIDS Chloromethane, 2004].

Ellenhorn, M.J. and Barceloux, D.G. (1988).Medical toxicology. Diagnosis and treatment of human poisoning. Elsevier Science Publishing Company, Inc., 982 - 983 [as cited in: US EPA, Toxicological review of methyl chloride, 2001].

Gudmundsson, G. (1977). Methyl chloride poisoning 13 years later. Archives of envrionmental health 32:236 - 237 [as cited in: OECD SIDS Chloromethane, 2004]

Johnson, K. A. (1988). Personal Communication to Methyl Chloride Industry Association. personal communication [as cited in: OECD SIDS Chloromethane, 2004].

Morgan, K.T. et al.(1982). Histopathology of acute toxic response in rats and mice exposed to methyl chloride by inhalation. Fundamental and Applied Toxicology, 2:293-299 [as cited in: OECD SIDS Chloromethane, 2004]

Sittig, M. (1991). Handbook of toxic and hazardous chemicals and carcinogens (3rd edition). Noyes Publication, 1086 -1088 [as cited in: US EPA, Toxicological review of methyl chloride, 2001].

von Oettingen, W.F. (1955) Public health services publications no. 414.Department of Health, Education and Welfare [as cited in: OECD SIDS Chloromethane, 2004].

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
No study was selected, since the life-time studies performed with the common rodent species rat and mouse (CIIT, 1981) are adequate and reliable and resulted both in an effect level of 465 mg/m³.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The life-time studies performed with the common rodent species rat and mouse (CIIT, 1981) do not reveal local effects.

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver; neurologic: behaviour; neurologic: spinal cord (3 levels); urogenital: epididymides; urogenital: kidneys; urogenital: testes

Justification for classification or non-classification

STOT‐RE classification is given due to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation), Table 3.1 (CLP classification) and Table 3.2 (DSD classification) (Index No. 602-001-00-7):

CLP: STOT RE 2; H373 - May cause damage to organs through prolonged or repeated exposure

DSD: Xn; R48/20 - Harmful: danger of serious damage to health by prolonged exposure through inhalation

For further discussion on the STOT-RE classification please refer to Section Neurotoxicity.