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Bis(chloromethyl)ether (BCME)
CASRN 542-88-1
Contents
0375
Bis(chloromethyl)ether (BCME); CASRN 542-88-1
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR BCME
File On-Line 09/26/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) message 07/01/1991
Carcinogenicity Assessment (II.) on-line 01/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Bis(chloromethyl)ether (BCME)
CASRN -- 542-88-1
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Bis(chloromethyl)ether (BCME)
CASRN -- 542-88-1
The health effects data for bis(chloromethyl) ether were reviewed by the
U.S. EPA RfD/RfC Work Group and determined to be inadequate for the derivation
of an inhalation RfC. The verification status of this chemical is currently
not verifiable. For additional information on the health effects of this
chemical, interested parties are referred to the EPA documentation listed
below.
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.
Agency Work Group Review -- 03/28/1991
EPA Contacts:
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Bis(chloromethyl)ether (BCME)
CASRN -- 542-88-1
Last Revised -- 01/01/1991
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 CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- A; human carcinogen
Basis -- Statistically significant increases in lung tumors (oat cell
carcinomas) observed in six studies of exposed workers and bioassay data
from rats and mice.
___II.A.2. HUMAN CARCINOGENICITY DATA
Sufficient. There are six studies of workers exposed to BCME in which
statistically significant increases in lung tumors were found (Figueroa et
al., 1973; Sakabe, 1973; Thiess et al., 1973; Albert et al., 1975; Lemen et
al., 1976; Pasternack et al., 1977). In four studies, workers were primarily
exposed to CMME (technical-grade chloromethyl methyl ether) with 1-8% of BCME
as a contaminant in the remaining two studies, workers were exposed to BCME
alone. All six studies found statistically significant increases in the
incidence of lung carcinomas, predominantly of the oat-cell type which is
generally not associated with smoking. The observed numbers of lung
carcinomas were much higher in workers exposed to BCME alone than in workers
exposed to both BCME and CMME. The age range in the studies was from 35-54
years, with latency periods of 8-16 years. Despite a lack of information on
study designs and analytical techniques, the consistent finding of a high
incidence of oat-cell carcinoma of the lung in similar age groups after an
appropriate latency period in all studies provides sufficient qualitative
evidence of the carcinogenicity of BCME in humans. The data, however, were
not considered to be adequate for use in quantitative risk estimation.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Kuschner et al. (1975) conducted an inhalation study of male
Sprague-Dawley rats exposed to BCME at 0.1 ppm 6 hours/day, 5 days/week for
10, 20, 40, 60, 80, or 100 days, then observed for the remainder of their
lifetimes. There was a marked increase in the incidence of several types
respiratory tract tumors at this low dose in the treated animals as compared
with the controls. There was also a log-normal distribution of cancer
induction time, with a median of 440 days; The cancer incidence shows a
sigmoidal curve with time.
Several other investigators have demonstrated the ability of BCME to
induce respiratory tumors by the inhalation route. Leong et al. (1971)
reported a 34% increase in tumor incidence in A/Heston mice exposed 6
hours/day, 5 days/week for 6 months to CMME vapors at either 1 ppm or 2 ppm
with 0.3-2.6% BCME as an impurity. Drew et al. (1975) reported a skin tumor
on 1/25 Sprague-Dawley rat after one exposure to 0.7 ppm and a nose tumor on
1/50 Syrian golden hamster after three exposures to 1 ppm of BCME; both tumors
occurred more than 1 year after exposure.
BCME is a potent complete skin carcinogen in mice, producing both
papillomas and squamous cell carcinomas (Van Duuren et al., 1969). Pulmonary
tumors in newborn ICR Swiss mice have been induced by s.c. injection of BCME
(Gargus et al., 1969).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
BCME is a direct-acting mutagen for Salmonella typhimurium (Nelson, 1976).
BCME decreases the latency period of benzo[a]pyrene-initiated tumors, but does
not affect tumor yield (Van Duuren et al., 1968).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 2.2E+2 per (mg/kg)/day
Drinking Water Unit Risk -- 6.2E-3 per (ug/L)
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 1.6E-2 ug/L
E-5 (1 in 100,000) 1.6E-3 ug/L
E-6 (1 in 1,000,000) 1.6E-4 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Based on inhalation data in II.C.2.
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The unit risk should not be used if the water concentration exceeds 1.6
ug/L, since above this concentration the unit risk may not be appropriate.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
This oral estimate is derived from inhalation data. BCME is not likely to
be found in water since it rapidly hydrolizes.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 6.2E-2 per (ug/cu.m)
Extrapolation Method -- Linerarized multistage procedure, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 1.6E-3 ug/cu.m
E-5 (1 in 100,000) 1.6E-4 ug/cu.m
E-6 (1 in 1,000,000) 1.6E-5 ug/cu.m
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Tumor Type -- respiratory tract tumors
Test Animals -- rat/Sprague-Dawley, male
Route -- inhalation
Reference -- Kuschner et al., 1975
---- Dose ----- Tumor
Number Human Incidence
of 6-hour, Equivalent
0.1-ppm (mg/kg/day)
Exposures
--------- ----------- ---------
0 0 0/240
10 0.000270 1/41
20 0.000541 3/46
40 0.00105 4/18
60 0.00184 4/18
80 0.00347 15/34
100 0.00373 12/20
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
Tumor types observed were neuroepitheliomas, malignant olfactory tumors
(unclassified), ganglioneuroepitheliomas, squamous cell carcinomas of the
turbinates and gingiva, poorly differentiated epithelial tumors of the nose,
nasal cavity adenocarcinomas, and squamous cell carcinomas and adenocarcinomas
of the lung.
The human equivalent dose was calculated from the animal dose, assuming
surface area equivalence. The animal dose was calculated from the air
concentration (0.1 ppm or 0.479 mg/cu.m.), an assumed breathing rate (0.283
cu.m./day) for 500-g rats (assumed), and from the number of exposures in each
group. Although the median life span of these animals (ranging from 483 to
497 days in the control and lowest two treated groups) was shorter than other
Sprague-Dawley colonies reported in the literature (Anver et al., 1982), the
response is still considered to represent a lifetime incidence. Since the
animals were allowed to live until natural death occurred, a correction factor
for estimating the lifetime incidence from less than lifetime studies was not
applied here, whereas the Ambient Water Quality Criteria Document (U.S. EPA,
1980) made such a correction. The customary 5/7 adjustment to convert from 5
to 7 days/week exposure in such studies was similarly unnecessary since the
actual number of days of exposure was provided by the authors. Also, a
mistake was found in the criteria document unit risk calculations, which were
a factor of 10 too high. The effect of these adjustments is to reduce the
unit risks by a factor of about 45 from that reported in the Ambient Water
Quality Criteria Document (U.S. EPA, 1980).
The unit risk should not be used if the air concentration exceeds 1.6E-1
ug/cu.m, since above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
Tumor incidence was shown to be dose-dependent in rats based on a time-
related exposure pattern. Human data do not corroborate the risk estimate.
Control data were pooled, not run concurrently.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1980, 1986
The 1980 Ambient Water Quality Criteria Document for Chloroalkyl Ethers has
received agency and external review. The 1986 evaluation of the potential
carcinogenicity of bis(chloromethyl)ether has received limited review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 07/23/1986, 05/04/1988
Verification Date -- 05/04/1988
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Bis(chloromethyl)ether (BCME)
CASRN -- 542-88-1
Last Revised -- 07/01/1991
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
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.
__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.
Anver, M.R., B.J. Cohen, C.P. Lattuada and S.J. Foster. 1982. Age-associated
lesions in barrier-reared male Sprague-Dawley rats: A comparison between hap:
(SD) and Crl:COBS(R)CD(SD) stocks. Exp. Aging Res. 8(1):3-24.
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 Engl. J. Med. 288: 1096-1097.
Gargus, J.L., W.H. Reese, Jr. and H.A. Rutter. 1969. Induction of lung
adenomas in newborn mice by bis(chloromethyl)ether. Toxicol. Appl. Pharmacol.
15: 92-96.
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: 73-77.
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.
NY Acad. Sci. 271: 71-80.
Leong, B.K.J., H.N. Macfarland and W.H. Reese, Jr. 1971. Induction of lung
adenomas by chronic inhalation of bis(chloromethyl)ether. Arch. Environ.
Health. 22: 663-666.
Nelson, N. 1976. The chloroethers - occupational carcinogens: A summary of
laboratory and epidemiology studies. Ann. NY 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.
Sakabe, H. 1973. Lung cancer due to exposure to bis(chloromethyl)ether.
Ind. Health. 11: 145-148.
Thiess, V.A.M., W. Hey and H. Zeller. 1973. Zur Toxikologie von
Dichlordimethylather - Verdacht auf kanzerogene Wirkung auch beim Menschen.
Zbl. Arbeitsmed. 23: 97-102.
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.
U.S. EPA. 1986. Evaluation of the Potential Carcinogenicity of
Bis(Chloromethyl)Ether. Draft RQ Document. Prepared by the Office of Health
and Environmental Assessment, Carcinogen Assessment Group, Washington, DC.
July 8.
Van Duuren, B., B. Goldschmidt, C. Katz, et al. 1968. Alpha-Haloesters: A
new type of alkylating carcinogen. Am. Med. Assoc. Arch. Environ. Health.
16: 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: 481-486.
_VII. REVISION HISTORY
Substance Name -- Bis(chloromethyl)ether (BCME)
CASRN -- 542-88-1
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/26/1988 II. Carcinogen summary on-line
04/01/1989 V. Supplementary data on-line
01/01/1990 II.A.4. Correct Van Duuren et al. citation year to 1969
01/01/1990 II.C.3. Correct Anver, 1982 to Anver et al., 1982
01/01/1990 VI. Bibliography on-line
02/01/1990 VI.C. Kuschner et al. 1975 citation clarified
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
01/01/1991 VI.C. van Duuren et al., 1968 reference added
05/01/1991 I.B. Inhalation RfC now under review
07/01/1991 I.B. Inhalation RfC message on-line
07/01/1991 VI.B. Inhalation RfC references added
01/01/1992 IV. Regulatory Action section on-line
VIII. SYNONYMS
Substance Name -- Bis(chloromethyl)ether (BCME)
CASRN -- 542-88-1
Last Revised -- 09/26/1988
542-88-1
BCME
Bis(chloromethyl)ether
BIS-CME
CHLORO(CHLOROMETHOXY)METHANE
CHLOROMETHYL ETHER
DICHLORDIMETHYLAETHER
1,1'-DICHLORODIMETHYL ETHER
sym-DICHLORO-DIMETHYL ETHER
sym-DICHLOROMETHYL ETHER
DIMETHYL-1,1'-DICHLOROETHER
ETHER, BIS(CHLOROMETHYL)
METHANE, OXYBIS(CHLORO-
OXYBIS(CHLOROMETHANE)
RCRA WASTE NUMBER P016
UN 2249
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0375.HTM
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