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Chloromethyl methyl ether (CMME) (CASRN 107-30-2)

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0245

Chloromethyl methyl ether (CMME); CASRN 107-30-2


Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.

STATUS OF DATA FOR CMME

File First On-Line 09/30/1987

Category (section)
Status
Last Revised
Oral RfD Assessment (I.A.) no data  
Inhalation RfC Assessment (I.B.) no data 01/01/1992
Carcinogenicity Assessment (II.) on-line 12/01/1989*

* A comprehensive review of toxicological studies was completed (07/28/05) - please see section II.D.2. for more information.

_I.  Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Chloromethyl methyl ether (CMME)
CASRN — 107-30-2

Not available at this time.

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_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — Chloromethyl methyl ether (CMME)
CASRN — 107-30-2

Not available at this time.

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_II.  Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Chloromethyl methyl ether (CMME)
CASRN — 107-30-2
Last Revised — 12/01/1989

Section II provides information on three aspects of the carcinogenic assessment for the substance in question; the weight-of-evidence judgment of the likelihood that the substance is a human carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. The quantitative risk estimates are presented in three ways. The slope factor is the result of application of a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m air breathed. The third form in which risk is presented is a drinking water or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods used to develop the carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the publication of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment also utilize those Guidelines where indicated (Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for information on long-term toxic effects other than carcinogenicity.

_II.A. Evidence for Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

Classification — A; human carcinogen

Basis — The observation of an increased incidence of respiratory cancer in exposed workers and the observation of respiratory tumors in mice, rats, and hamsters exposed by inhalation forms the basis for this classification.

__II.A.2. Human Carcinogenicity Data

Sufficient. Commercial grade CMME is always contaminated with 1 to 8% bis(chloromethyl)ether (BCME), a known human carcinogen. CMME has an extremely short half-life in aqueous solution (estimated to be less than one- half second), but may be converted to BCME through hydrolysis (Nelson, 1976).

Numerous case reports (Bettendorf, 1976; Reznik et al., 1977) and epidemiologic studies (Figueroa et al., 1973; DeFonso and Kelton, 1976; Lemen et al., 1976; Nelson, 1976; Weiss et al., 1980) have reported respiratory cancer associated with exposure to CMME. There are four studies of workers exposed to technical grade CMME with 1 to 8% of BCME as a contaminant. All studies observed statistically significant excesses in the incidence of lung carcinomas, predominantly of the oat-cell type. The age range in the study populations was 35 to 54 years, with a latency period of 8 to 16 years. In a retrospective cohort mortality study of 1827 workers exposed to CMME for up to 19 years and 8870 controls, 26 cases of respiratory cancer were reported (9.3 expected, SMR=278) (Pasternack et al., 1977). This increased incidence was statistically significant. Exposure was not quantifiable. A statistically significant dose-response relationship was observed for duration and intensity of exposure (Pasternack, 1977; Albert et al., 1975). The observed number of lung carcinomas was higher than expected in the workers exposed to CMME contaminated with BCME (technical grade CMME) by comparison to unexposed workers, but was lower than the observed numbers in workers who were exposed to BCME alone. Hence the observed lung carcinomas in the CMME-exposed workers may be due to the contaminant BCME, which is a known human carcinogen. Therefore, despite the limitations of these studies, the human evidence for the carcinogenicity of technical grade CMME is considered to be sufficient.

__II.A.3. Animal Carcinogenicity Data

Leong (1971) administered 2 ppm CMME by inhalation to 50 A/Heston strain male mice for 6 hours/day, 5 days/week for 101 days. An increased incidence of lung adenomas with increasing proportions of BCME was seen compared with controls but was not statistically significant. Newborn ICR Swiss mice injected with 125 uL/kg CMME subcutaneously had an increased incidence of pulmonary tumors, but the increase was not statistically significant (Gargus et al., 1969).

Laskin et al. (1975) reported two respiratory carcinomas in 74 male Sprague-Dawley rats and two in 90 male Syrian golden hamsters with lifetime exposures to 1 ppm CMME for 6 hours/day, 5 days/week. CMME administered by subcutaneous injection (1/week for 30 days) to 20 female Sprague-Dawley rats, and female ICR/Ha Swiss mice produced encapsulated nodules and injection site sarcomas (Van Duuren et al., 1969, 1971, 1972). Dermal application of CMME to mice has not resulted in tumors (Van Duuren et al., 1969; IARC, 1974). CMME has been shown to initiate skin tumorigenesis in initiation/promotion assays with phorbol ester in mice (IARC, 1974).

BCME has been found to be a skin carcinogen and to induce respiratory tract tumors in rodents when administered by inhalation (Van Duuren et al., 1968; Leong et al., 1971; Drew et al., 1975; Kuschner et al., 1975).

__II.A.4. Supporting Data for Carcinogenicity

CMME is mutagenic to E. coli and S. typhimurium in the absence of exogenous metabolism (Mukai and Troll, 1969; Mukai and Hawryluk, 1973). Cytogenetic analysis of peripheral lymphocytes in workers exposed to CMME and BCME showed 6.7% aberrant cells compared with 2% in controls (Zudova and Landa, 1977).

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_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

Not available. Risk is likely to be no more than that of BCME, a contaminant of CMME.

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_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

Not available.

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_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)

__II.D.1. EPA Documentation

Source Document — U.S. EPA, 1980, 1977

The 1980 Ambient Water Quality Criteria for Chloroalkyl Ethers has received internal and external review.

__II.D.2. EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 05/13/1987

Verification Date — 05/13/1987

A comprehensive review of toxicological studies published through July 2005 was conducted. No new health effects data were identified that would be directly useful in the revision of the existing carcinogenicity assessment for Chloromethyl methyl ether and a change in the assessment is not warranted at this time. For more information, IRIS users may contact the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

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_III.  [reserved]
_IV.  [reserved]
_V.  [reserved]


_VI.  Bibliography

Substance Name — Chloromethyl methyl ether (CMME)
CASRN — 107-30-2
Last Revised — 07/01/1993

_VI.A. Oral RfD References

None

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_VI.B. Inhalation RfC References

None

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_VI.C. Carcinogenicity Assessment References

Albert, R.E., B.S. Pasternack, R.E. Shore, M. Lippmann, N. Nelson and B. Ferris. 1975. Mortality patterns among workers exposed to chloromethyl ethers - a preliminary report. Environ. Health Perspect. 11: 209-214.

Bettendorf, U. 1976. Gwerblich induzierte Lugenkarzinome nach Inhalation alkylierender verbindungen (Bischlormethylather und Monochlormethylather). Zbl. Arbeitsmed. 27: 140-142. (Ger.)

Defonso, L.R. and S.C. Kelton, Jr. 1976. Lung cancer following exposure to chloromethyl methyl ether. An epidemiological study. Arch. Environ. Health. 31: 125-130.

Drew, R.T., S. Laskin, M. Kuschner and N. Nelson. 1975. Inhalation carcinogenicity of alpha halo ethers. I. The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl) ether. Arch. Environ. Health. 30: 61-69.

Figueroa, W.G., R. Raszkowski and W. Weiss. 1973. Lung cancer in chloromethyl methyl ether workers. New England J. Med. 288: 1096-1097.

Gargus, J.L., W.H. Reese and H.A. Rutter. 1969. Induction of lung adenomas in newborn mice by bis(chloromethy)ether. Toxicol. Appl. Pharmacol. 15: 92-96.

IARC (International Agency for Research on Cancer). 1974. Monographs on the evaluation of the carcinogenic risk of chemicals to man. Vol. 4. Some aromatic amines, hydrazine and related substances, N-nitroso compounds and miscellaneous alkylating agents. Lyon, France. p. 239-245.

Kuschner, M., S. Laskin, R.T. Drew, V. Cappiello and N. Nelson. 1975. Inhalation carcinogenicity of alpha halo ethers: III. Lifetime and limited period inhalation studies with bis(chloromethyl)ether at 0.1 ppm. Arch. Environ. Health. 30(2): 73-77.

Laskin, S., R.T. Drew, V. Cappiello, M. Kuschner and N. Nelson. 1975. Inhalation carcinogenicity of alpha halo ethers. II. Chronic inhalation studies with chloromethyl methyl ether. Arch. Environ. Health. 30(2): 70-72.

Lemen, R.A., W.M. Johnson, J.K. Wagoner, V.E. Archer and G. Saccomanno. 1976. Cytologic observations and cancer incidence following exposure to BCME. Ann. N.Y. Acad. Sci. 271: 71-80.

Leong, B.K.J., H.N. MacFarland and W.H. Reese. 1971. Induction of lung adenomas by chronic inhalation of bis(chloromethy)ether. Arch. Environ. Health. 22: 663-666.

Mukai, F.H. and I. Hawryluk. 1973. The mutagenicity of some halo-ethers and halo-ketones. Mutat. Res. 21: 228.

Mukai, F.H. and W. Troll. 1969. The mutagenicity and initiating activity of some aromatic amine metabolites. Ann. N.Y. Acad. Sci. 163: 828-836.

Nelson, M. 1976. The chloroethers - Occupational carcinogens: A summary of laboratory and epidemiology studies. Ann. N.Y. Acad. Sci. 271: 81-90.

Pasternack, B.S., R.E. Shore and R.E. Albert. 1977. Occupational exposure to chloromethyl ethers. A retrospective cohort mortality study (1948-1972). J. Occup. Med. 19: 741-746.

Reznik, G., H.H. Wagner and Z. Atay. 1977. Lung cancer following exposure to bis(chloromethyl)ether: A case report. J. Environ. Pathol. Toxicol. 1: 105-111.

U.S. EPA. 1977. Potential Industrial Carcinogens and Mutagens. Office of Toxic Substances, Washington, DC. EPA 560/5-77-005.

U.S. EPA, 1980. Ambient Water Quality Criteria Document for Chloroalkyl Ethers. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA 440/5-80-030. NTIS PB 81-117418.

Van Duuren, B.L., B.M. Goldschmidt, L. Langseth, G. Mercado and A. Sivak. 1968. Alpha-haloethers: A new type of alkylating carcinogen. Arch. Environ. Health. 16(4): 472-476.

Van Duuren, B.L., A. Sivak, B.M. Goldschmidt, C. Katz and S. Melchionne. 1969. Carcinogenicity of halo-ethers. J. Natl. Cancer Inst. 43(2): 481-486.

Van Duuren, B.L., S. Melchionne, R. Blair, B.M. Goldschmidt and C. Katz. 1971. Carcinogenicity of isoesters of epoxides and lactones: Aziridine ethanol, propane sulfone, and related compounds. J. Natl. Cancer Inst. 46(1): 143-149.

Van Duuren, B.L., C. Katz, B.M. Goldschmidt, K. Frenkel and A. Sivak. 1972. Structure-activity relationships of analogs of bis(chloromethyl)ether. J. Natl. Cancer Inst. 48(5): 1431-1439.

Weiss, W., R.L. Moser and O. Auerbach. 1980. Lung cancer in chloromethyl ether workers. Am Rev. Respiratory Disease. 120: 1031-1037.

Zudova, Z. and K. Landa. 1977. Genetic risk of occupational exposures to haloethers. Mutat. Res. 46: 242-243.

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_VII.  Revision History

Substance Name — Chloromethyl methyl ether (CMME)
CASRN — 107-30-2

Date
Section
Description
12/01/1989 II. Citations clarified
12/01/1989 VI. Bibliography on-line
01/01/1992 I.B. Inhalation RfC now under review
01/01/1992 IV. Regulatory Action section on-line
07/01/1993 VI.C. EPA refs added; inadvertently omitted from biblio.
08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995.
04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information.
10/28/2003 II.D.2. Screening-Level Literature Review Findings message has been added.
08/15/2005 II.D.2. Screening-Level Literature Review Findings message has been removed and replaced by comprehensive literature review conclusions.

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_VIII.  Synonyms

Substance Name — Chloromethyl methyl ether (CMME)
CASRN — 107-30-2
Last Revised — 09/30/1987

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