UNITED STATES EPA/600/a-9i/083
...- ENVIRONMENTAL PROTECTION JUNE 1988
P-p/\ AGENCY FINAL
RESEARCH AND
DEVELOPMENT
EVALUATION OF THE POTENTIAL CARCINOGENICITY OF
BIS(CHLOROMETHYL)ETHER
(542-88-1)
IN SUPPORT OF REPORTABLE QUANTITY ADJUSTMENTS
PURSUANT TO CERCLA SECTION 102
PREPARED FOR
OFFICE OF EMERGENCY AND REMEDIAL RESPONSE
OFFICE OF SOLID WASTE AND EMERGENCY RESPONSE
PREPARED BY
CARCINOGEN ASSESSMENT GROUP
OFFICE OF HEALTH AND
ENVIRONMENTAL ASSESSMENT
WASHINGTON, D.C. 20460
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental
V
Protection Agency policy and approved for publication. Mention of trade names
or commercial products does not constitute endorsement or recommendation for
use.
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PREFACE
This report summarizes and evaluates information on the potential
carcinogenicity of a substance designated as hazardous under Section 101 (14)
of the Comprehensive Environmental Response, Compensation and Liability Act of
1980 (CERCLA). Pertinent epidemiologic and toxicologic data were obtained
through on-line searches and from hard-copy sources. On-line searches were
extended as far back as the data bases-would allow. Retrieval of historical
data was accomplished through searches of hard-copy sources and bibliographies
of relevant publications. Every attempt has been made to rely upon primary
publications as opposed to data summaries or abstracts contained in. secondary
sources such as monographs, surveys, review articles, criteria documents, etc.
The on-line data bases that were searched included CHEMLINE (National Library
of Medicine [NLM]) , RTECS (NLM), Toxicology Data Bank (NLM) , TOXLINE,' (NLM) ,
CANCERLINE (NLM), and Chemical Abstracts (DIALOG Information Services).
Unpublished data were not used in this evaluation. .
The Agency's Methodology for obtaining, evaluating, and ranking CERCLA
potential carcinogens is described in the Technical Background Document to
Support Rulemaking Pursuant to CERCLA Section 102, Volume 3, April 26, 1988
(EPA/600/8-89/053). This document revises the previous methodology document
of 1986 according to the public comments received on the March 16, 1987 Notice
of Proposed Rulemaking (52 FR 8140). The Methodology for Adjusting reportable
quantities is described in the Technical Background Document to Support
Rulemaking Pursuant to CERCLA Section 102, Volume 1, March, 1985, and is also
summarized in Volume 2, August, 1986, and. Volume 3, December, 1986. The EPA's
Office of Emergency and Remedial Response (OERR) has considered this
evaluation in adjusting reportable quantities pursuant to CERCLA Section 102.
This report is consistent with the revised methodology. It draws largely on
information supplied by the Syracuse Research Corporation in 1984 under EPA
Contract No. 68-03-3112. Due to the amount of time elapsed between the
original work performed by Syracuse Research Corporation and the present
ill
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effort to produce this document, Environmental Monitoring & Services, Inc.,
under EPA Contract No. 68-03-3182, has been involved in an extensive review of
all the Syracuse documents. In some cases, this review involved updating the
information provided but it was primarily a quality assurance effort. The
present document is a result of this effort.
IV
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ABSTRACT
Bis(chloromethyl)ether is a human carcinogen, classified as weight-of-evidence
Group A under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA,
1986a). Evidence on potential carcinogenicity from animal studies is
"Sufficient," and the evidence from human studies is "Sufficient."
The potency factor (F) for bis(chloromethyl)ether is estimated to be 10,377
(mg/kg/day)"^-, placing it in potency group 1 according to the CAG's methodology
for evaluating potential carcinogens (U.S. EPA, 1986b).
t
Combining the weight-of-evidence group and the potency group, bis(chloro-
methyl) ether is assigned a "HIGH" hazard ranking for the purposes of RQ
adjustment.
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TABLE OF CONTENTS
1.0 WEIGHT OF EVIDENCE . . 1-1
1.1 ANIMAL STUDIES . . . . 1-1
1.2 HUMAN STUDIES 1-3
1.3 WEIGHT-OF-EVIDENCE ASSESSMENT ....... 1-4
2.0 POTENCY . 2-1
3.0 HAZARD RANKING ........ .... 3-1
4.0 REFERENCES . 4-1
APPENDIX: SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
v ' "»
TABLES
Table 2-1. DERIVATION OF POTENCY FACTOR (F) 2-2
i
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1.0 WEIGHT OF EVIDENCE'
1.1 ANIMAL STUDIES
The effect of bis(chloromethyl)ether administered by inhalation has been
investigated in rats (Laskin et al., 1971; Kuschner et al., 1975; Leong et al.,
1981) and mice (Leong et al., 1971, 1981). Laskin et al. (1971) reported in a
preliminary study that 10 of 19 rats (Sprague-Dawley) exposed to 0.1 ppm
bis(chloromethyl)ether for 6 hours/day, 5 days/week (total of 101 exposures)
developed respiratory tumors (5 squamous-cell carcinomas of the lung; 5
aesthesioheuroepitheliomas of the nasal cavity). This study also indicates the
occurrence of lung and nasal cavity tumors in rats exposed for shorter periods,
but specific data are not reported. In a subsequent report, Kuschner et al.
(1975) reported a duration-response in rats exposed to 0.1 .ppm
bis(chloromethyl)ether for 6 hours/day, 5 days/week for 2, 4, 8, 12, 16, and
20 weeks (10, 40, 60, 80, and 100 exposure days, respectively). In groups of
rats exposed by inhalation for 80 or 100 exposure days, high incidences of
nasal cavity (12/50 and 5/30, respectively) and lung cancers (3/50 and 8/30,
respectively) were reported. A decreasing number of cancers was seen in groups
exposed for shorter periods. No tumors were reported in 240 control animals.
Leong et al. (1981) exposed rats by inhalation to several dose levels of
bis(chloromethyl)ether (1, 10, and 100 ppb) for 6 months (6 hours/day, 5 days/
week) and observations were made for the lifespan of the animals. A
significant increase in the incidence of tumors was seen only in the group
exposed to 100 ppb bis(chloromethyl)ether. Tumors were detected in the nasal
cavity (96/111, P<0.05), and lung (4/111, P-0.059), and metastases were,
detected in the lymphoreticular tissues. (5/111). No similar tumors were
reported in rats exposed to lower concentrations of bis(chloromethyl)ether or
in controls (0/112);
The effect of inhalation of bis(chloromethyl)ether at 1, 10, or 100 ppb was
also tested in mice (Ha/ICR) by Leong et al. (1981). Even though gross,
histological, and hematological examinations were conducted, no significant
1-1
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increase in tumors was reported for any treated group when compared with
controls. In an earlier study, Leong et al. (1971) administered 1 ppm
bis(chloromethyl)ether to mice (A/He) and reported a slight but insignificant
increase in the incidence of lung tumors (26/47 versus 20/49). It is noted
that it may be inappropriate to use these strains of mice (Strain A hybrid) for
pulmonary tumorigenesis testing.
A dose-response relationship was demonstrated for the progressive development
of hyperplasia and metaplasia in rats and hamsters (Drew et al., 1975). This
study also reported an ulcerating squamous-cell carcinoma in a rat following 3
exposures (6 hours each) to 1 ppm bis(chloromethyl)ether, and a malignant nasal
tumor in a hamster treated for a single 6-hour exposure to 1 ppm bis(chloro-
methyl)ether. .
Dermal application.of bis(chloromethyl)ether (2 mg/0.1 ml benzene, 3 times/
week) resulted in a high incidence of skin papillomas (13/20) and squamous-cell
carcinomas (12/20) in female mice (ICR/Ha Swiss). The control group, treated
with benzene (0.1 ml, 3 times/week) alone, developed no similar tumors (0/20)
. (Van Duuren et al., 1969). A progression from papillomas to carcinomas was
reported. The first papilloma was seen' at 161 days and the first carcinoma was
apparent at 231 days. . .
Gargus et al. (1969) treated neonatal (24-72 hrs) ICR-Swiss mice with a single
subcutaneous injection of bis(chloromethyl)ether (12.5 ul of 0.05% solution/
kg). The incidence of lung adenomas after 6 months was 45/100 in treated
animals and 7/50 in vehicle controls. Injection site tumors have been reported
following the subcutaneous injection of bis(chloromethyl)ether in mice (Gargus
et al., 1969) and rats (Van Duuren et al., 1969), while similarly treated
controls showed no injection site tumors.
1.2 HUMAN STUDIES
There are six studies of workers exposed to bis(chloromethyl)ether (BCME). In
three studies, workers were primarily exposed to CMME (technical-grade
chloromethyl methyl ether) with 1% to 8% BCME as a contaminant.
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Thiess et al. (1973) reported that 6/18 testing laboratory workers exposed to
bis(chloromethyl)ether for 6-9 years developed lung cancer. Two additional
lung cancer deaths were reported in a group of 50 production workers.
Predominantly, oat-cell carcinomas developed with a latent period of 8-16
years.
Sakabe (1973) reported five cases of lung cancer among 32 dyestuff employees
exposed to bis(chloromethyl)ether. Workers exposed to bis(chloromethyl)ether in
the chemical manufacture of anion-exchange resiri were studied by Lemen et al.
(1976). This follow-up study revealed 5 cases of bronchogenic cancer in 136
exposed workers. Based on mortality statistics of white males in Connecticut,
only 0.54 deaths would be expected (P<0.01). Small-cell, undifferentiated
(oat-cell) carcinoma was the predominant malignancy.
In a chemical plant where workers were exposed to chloromethyl ether and
bis(chloromethyl)ether as a contaminant, Figueroa et al. (1973) reported 14
lung cancer cases. Four cases of lung cancer occurred in 88 men aged 35-54
years while only about 0.50 cases would be expected from the reference group
(2804 men 45-54 years of age from Pulmonary Neoplasm Research Project .study).
Epidemiological studies to evaluate workers exposed to chloromethyl ether and
bis(chloromethyl)ether in six of the major chemical companies that use these
chemicals have been conducted by Albert et al. (1975) and Pasternack et al.
(1977). Albert et al. (1975) reported on 1794 exposed workers and emphasized
700 who were employed by one chemical firm. Of these 700 workers, 19 developed
respiratory tract cancer while 8 cases would be expected from the control
group. Subsequently, Pasternack et al. (1977) reported 26/1827 respiratory
cancers in the same six chemical industries, and only 9.3 would be expected
(P<0.05). The single chemical firm now posted 23/721 deaths due to respiratory
cancer. The number of expected cases was reported as 4.5 (P<0.05). Once again'
it was noted that predominantly oat-cell carcinomas were seen in these workers
exposed to bis(chloromethyl)ether and chloromethyl ether.
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Despite a lack of information on adjustment of confounders, latency analysis,
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 causal evidence of the carcinogenicity of BCME in humans.
1.3 WEIGHT-OF-EVIDENCE ASSESSMENT
Bis(chloromethyl)ether is carcinogenic in rats when administered by inhalation
or subcutaneous injection. It is carcinogenic in mice following inhalation and
skin application, and tumors develop in neonatal mice given a single
subcutaneous injection of bis(chloromethyl)ether.
Several studies in addition to those reviewed by IARC (1974) indicate that
exposure to bis(chloromethyl)ether and mixtures of bis(chloromethyl)ether and
chloromethyl ether results in a high incidence of respiratory cancers.
Predominantly oat-cell carcinomas of the lung are seen. Thus, using the EPA
Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a) for evaluating the
overall weight of evidence to humans, bis(chloromethyl)ether is most
appropriately classified as a Group A chemical. The appendix contains
summaries of the significant human and/or animal studies cited in this review.
1-4
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2.0 POTENCY
The potency factor (F) for bis(chloromethyl)ether is estimated to be 10,377
(ing/kg/day) , placing it in potency group 1 under the CAG's methodology for
evaluating potential carcinogens (U.S. EPA, 1986b). Table 2-1 contains data
from the selected study used to derive the potency factor (F) for bis(chloro-
methyl)ether.
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Table 2-1. Derivation of Potency Factor(F)
(Agent: Bis(chlorooethyl) ether
REFERENCE:
EXPOSURE ROUTE:
SPECIES:
STRAIN:
SEX:
VEHICLE OR PHYSICAL STATE:
BODY WEIGHT:9
DURATION OF TREATMENT:
DURATION OF STUDY:6
LIFESPAN OF ANIMAL:9
TARGET ORGAN:
TUMOR TYPE:
EXPERIMENTAL DOSES:C
NO. OF EXPOSURES:
TRANSFORMED DOSES:d
(mg/kg/day)
TUMOR INCIDENCE:
ANIMAL POTENCY:
(mg/kg/day)"1
HUMAN POTENCY:6
(mg/kg/day)"1
Kuschner et at ., 1975
-inhalation
rat
Sprague-Dawley
M
a i r
0.35 kg
0 hours 60 hours 120 hours 240 hours 360 hours 480 hours 600 hours
462 days 483 days 483 days 497 days 427 days 301 days 350 days
728 days
lung/nasal
carcinoma
0.1 ppm 0.1 ppm 0.1 ppm 0.1 ppra 0.1 ppm 0.1 ppm 0.1 ppm
0 10 20 40 60 80 100
0 0.001 0.002 0.004 0.006 0.008 0.010
0/240 1/41 3/46 4/18 4/18 15/34 12/20
363.1
10,377
8 Estimated
TK A /liirn^i/irt nf o * irl%* «!% + n * fc« A** A*4 «««* fr t« A *«M«J *»* It £&«««« a* A9*>K i-lnc* asi A 1 A WA 1 no rt i uar\ in f ti A o * i irlw
c 0.1 ppm for 6 hours/exposure
To derive the transformed dose from the experimental dose data: concentration (mg/nr) x breathing rate of rat (0.22 m3/day)/animal weight
(0.35 kg)/24~(hours/day) x total number of exposure hours/Iifespan of animal (728 days).
e Human potency = animal potency x (70 kg/0.35 kg)1^3
x (728 days/429 days) to adjust for the short study duration. The duration of study value used in this
calculation (429 days) was the average of the seven durations of study values given for the groups.
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3.0 HAZARD RANKING
Based on the weight-of-evidence Group A for bis(chloromethyl)ether, and the
potency factor (F) of 10,377 (mg/kg/day)'1, bis(chloromethyl)ether receives a
hazard ranking of "HIGH."
3-1
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4.0 REFERENCES
Albert, R.E., B.S. Pasternack, R.E. Shore, N.N.. Lippmann and B. Ferris, 1975.
Mortality Patterns Among Workers Exposed to Chloromethyl Ethers - A preliminary
report. Environ. Health Perspect. 11: 209-214.
Drew, R.T., S. Laskin, M. Kuschner and N. Nelson, 1975. Inhalation Carcino-
genicity of Alpha Halpethers. I. The Acute Inhalation Toxicity of Chlororaethyl
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.
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. Inhala-
tion Careinogenieity of Alpha Haloethers. III. Lifetime and Limited Period
Inhalation Studies with Bis(chloromethyl)ether at 0.1 ppm. Arch. Environ.
Health. 30: 73-77.
Laskin, S., M. Kuschner, R.T. Drew, V.P. Cappiello and N. Nelson, 1971. Tumors
of Respiratory Tract Induced by Inhalation of Bis(chloromethyl)ether. Arch.
Environ. Health.. 23: 135-136.
Lemen, R.A., W.M. Johnson, J.K. Wagoner, V.E. Archer and G. Saccomanno, 1976,
Cytologic Observations and Cancer Incidence Following Exposure to Bis(chloro-
methyl)ether. 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.
4-1
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Leong, B.K.J., R.J. Kociba and G.C. Jersey, 1981. A Lifetime Study of Rats and
Mice Exposed to Vapors of Bis(chloromethyl)ether. Toxicol. Appl. Fharmacol.
58(2): 269-281.
Pasternack, B.S., R.E. Shore and R.E; Albert, 1977. Occupational Exposure to
Chloromethyl Ethers. J. Occup. Med. 19: 741-746.
Sakabe', H. , 1973. Lung Cancer Due to Expo.sure to Bis (chloromethyl) ether. Ind.
Health. 11: 145. (Cited in Lemen et al., 1976).
Thiess, A.M., W. Hey and H. Zeller, 1973. Zur Toxlkologie von Dichloromethyl-
ather-Verdacht auf Kangerogene Wirkung auch beim Menschen. Zbl. Arbeitsmed.
23: 97. (Cited in IARC, 1974).
\
U.S. EPA (Environmental Protection Agency), 1986a. Guidelines for Carcinogen
Risk Assessment, 51 FR 33992-34003, September 24, 1986
f . '
U.S. EPA (Environmental Protection Agency), 1986b. Methodology for Evaluating
Potential Carcinogenicity in Support of Reportable Quantity Adjustments
Pursuant to CERCLA Section 102, OHEA-C-073, December 1986. Available from
CERCLA Docket 102RQ-273C. The public document for RQ rulemaking is located in
room M2427, U.S. Environmental Protection Agency, 401 M Street, SW, Washington,
DC 20460. It is available for inspection Monday through Friday excluding
Federal holidays, between the hours of 9:00 a.m. and 4:00 p.m.
U.S. EPA (Environmental Protection Agency). 1988. Technical Background
Document to Support Rulemaking Pursuant to CERCLA Section 102, Volume 3, Draft,
Appendix A, April 26, 1988.
Van Duuren, B.L., A. Sivak, B.M. Goldschmidt, C. Katz and S. Melchionne, 1969.
Carcinogenicity of Halo-ethers. J. Nat. Cancer Inst. 43: 481.
4-2
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APPENDIX
SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
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Table A. An
Agent: Bis(chtoromethyl)ether
Reference: Gargus et al., 1969
Exposure
Route
sc
sc
Species/
Strain Sex
mouse3/ H,F
ICR-Swiss
mouse/ M,F
ICR-Swiss
Dose
or
Exposure
12.5 ug/kg
0.0 ml/kg
*
Duration
of
Treatment
si'ngte
injection
single
injection
Duration
of
Study
6 months
6 months
Purity
of
Compound
industrial
grade
NA
. Vehicle or
Physical
State
peanut oil
(0.05X
solution)
0.5 mg
peanut oil
only
Target
Organ Tumor Type
lung . adenoma
lung adenoma
Tumor
Incidence
(P value)
45/100
7/50
* )
Strengths of Study:
Weaknesses of Study:
OveralI-Adequacy:
Comments:
QUALITY OF EVIDENCE
Appropriate vehicle control animals were used. Bis(chloromethyl)ether was tested near the maximum tolerated dose.
The duration of study was short. Neonatal mice were given a single subcutaneous dose.
Adequate
Due to the sensitivity of neonatal animals, the induction of tumors is circumspectly viewed.
a Newborn (24-72 hours) mice were injected.
NA = Not applicable
O
CD
O
CD
O
rv>
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Table A. A
Agent: Bis(chloromethyl)ether
Reference: Kuschner et al., 1975
Exposure
Route
i
i
i
i
i
i
NA
Species/
Strain
rat/
Sprague-
Dawley
rat/
Sprague-
Dawley
rat/
Sprague-
Oawley
rat/
Sprague-
Dauley
rat/
Sprague-
Dauley
rat/
Sprague-
Oawley
rat/
Sprague-
Oawley
Dose
or
Sex Exposure
H 0.1 ppm,
6 hrs/day,
5 days/week
H 0.1 ppm, ,
6 hrs/day,
5 days/week
H 0.1 ppm,
6 hrs/day,
5 days/week
M 0.1 ppm,
6 hrs/day,
5 days/week
M 0.1 ppm,
6 hrs/day,
5 days/week
H 0.1 ppm,
6 hrs/day,
5 days/week
H 0.0 ppm
Duration Duration
of of
Treatment Study3
20 weeks 50 weeks
(100 expo-
sures)
16 weeks 43 weeks
(80 expo-
sures)
12 weeks 61 weeks
(60 expo-
sures)
8 weeks 71 weeks
(40 expo-
sures) .
4 weeks 69 weeks
(20 expo-
sures)
2 weeks 69 weeks
(10 expo-
sures)
NA 66 weeks
Purity Vehicle or
of Physical Target
Compound State Organ
NR . air nasal
cavity
lung
NR air nasal
cavity
lung
NR air nasal
cavity .
lung
NR air nasal
cavity
lung
NR air nasal
cavity
lung
NR air nasal
cavity
lung
NA control nasal
cavity
lung
Tumor Type
various
various0
various
various6
various'*
various0
various
various0
various
various0
various
various0
various
various
Tumor
Incidence
(P value)
5/30
8/30
12/30
3/30
2/20
2/20
3/20
1/20
3/50
0/50.
1/50
0/50
0/240d
0/240d .
o
CD
CD
CD
CD
LN
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Table A. Ar
Reference: Kuschner et al., 1975 (cont.)
Exposure
Route
Species/
Strain
Dose
or
Sex Exposure
Duration
of
Treatment
Duration
of
Study8
Purity
of
Compound
Vehicle or
Physical
State
Target
Organ Tumor Type
Tumor
Incidence
(P value)
QUALITY OF EVIDEMCE
Strengths of Study: Several different exposure levels were used to show a dose response. Animals were observed for their
lifespan. A large number of animals were used in each group. Microscopic examination of tumors was
performed.
Weaknesses of Study: Purity of the compound is not stated.
Overall Adequacy: Adequate
Comments: No tumors for the control group are reported but it is not specifically stated that there were none.
a Median lifespan
Esthesioneuroepitheliomas, unclassified malignant olfactory tumor, gangtioneuroepithelioma, squamous cell carcinoma, poorly
differentiated epithelial tumor, adenocarcinoma
0 Squamous ce.ll carcinoma, adenocarcinoma
No tumors were reported jn the control group.
NA = Not applicable; NR = Not reported
CD
O
O
O
O
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Table A.
Agent: Bis(chlororaethyl)ether
Reference: Laskin et al., 1971
Exposure
Route
i
Species/
Strain
rat/
Sprague-
Dawley
Dose Duration
or of
Sex Exposure Treatment
H 0.1 ppm, 20 weeks
6 hrs/day.
5 days/week .
Duration Purity Vehicle or
of of Physical
Study Compound State
659 days3 NR air
Target
Organ
lung ..
olfactory
epithelium
Tumor Type
squamous cell
carcinoma
esthesioneuro-
epitheliomas
Tumor
Incidence
(P value)
5/19
5/19
QUALITY OF EVIDEUCE
Strengths of Study: Low dose levels were tested by inhalation. Microscopic examination of animals was conducted.
Weaknesses of Study: Tumor incidences in an untreated group are not reported. The purity of compound is not reported.
Overall Adequacy: Limited
Comments: This is a preliminary report on rats exposed to the highest dose level tested. Tumors in rats exposed for
shorter periods are noted.
a Lifespan of oldest animal
NR = Not reported
O
o
O
o
o
en
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Table A. A
Agent: Bis(chloromethyl)ether
Reference:. Leong et al., 1971
Exposure
Route
i
Species/
Strain Sex
mouse/ H
A/Heston
Dose Duration
or of
Exposure Treatment
0.005 mg/l 82 days
(1 ppm),
6 hrs/day,
5 days/week
Duration
of
Study
189 days
Purity Vehicle or
of Physical
Compound ' State
industrial air
grade
Target
Organ Tumor Type
lung . pulmonary tumors
>Tumor
Incidence
(P value)
26/47a
mouse/
A/Heston
0 mg/l
130 days 196 days
NA
air
lung
pulmonary tumors
20/49b
QUALITY OF EVIDENCE
Strengths of Study: ' Biological study on chronic and acute inhalation conducted.
Weaknesses of Study: Only males used; only one dose level administered. Short study duration.
Overall Adequacy: Limited
8 .2 tumors per tumor-bearing animal, average; 55X incidence of lung tumors.
2.2 tumors per tumor-bearing animal, average; 41% incidence of lung tumors.
NA = Not applicable
O
O
O
CD
O
Os
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Table A.
Agent: Bis(chloromethyl)ether
Reference: Leong et al., 1981
Dose Duration Duration Purity Vehicle or
Exposure Species/ or of of of Physical Target
Route Strain Sex Exposure9 Treatment Study Compound State Organ
i rat/
Sprague-
Dawley,
Spartan
substrain
i rat/
Sprague-
Dawley,
Spartan
substrain
i rat/
Sprague-
Dawley,
Spartan
substrain
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
M 100 ppb
10 ppb
1 ppb
0 ppb
M 100 ppb
10 ppb
1 ppb
0 ppb
H 100 ppb
10 ppb
1 ppb
0 ppb
6 months lifetime
6 months lifetime
6 months lifetime
NA lifetime
6 months lifetime
6 months
6 months
NA
6 months
6 months
6 months
NA
Complete histological,
each group
1 ifetime
lifetime
lifetime
lifetime
lifetime
lifetime
lifetime
NR air respiratory
system
NR air respiratory
system
NR air respiratory
system
NA air respiratory
system
NR air respiratory
system
NR air respiratory
system
NR air respiratory
system
NA air respiratory
system
NR air lymphor-
eticular
NR
NR
NA
QUALITY OF EVIDENCE
Tumor Type
neoplasm of
olfactory
neuroepi thet ioma
esthesioneuro-
epithelioma
pulmonary adenoma
pulmonary adenoma
pulmonary adenoma
pulmonary adenoma
metastasis of
esthesioneuro-
epithelioma of
regional lymph
nodes
hematological, and other examinations were conducted. The number of
was significant. The animals
Exposure was limited to
Adequate
only one quarter
Tumor
Incidence
(P value)
96/111
(P<0.05)
0/111
0/113
0/112
A/111
(P=0.059)
0/111
0/113
0/112
5/111
(P<0.05)
0/111
0/113
0/112
animals in
were exposed to a variety 'of dose levels.
of the animals' lifespan. Only
male rats were studied.
Exposure is for 6 hours/day, 5- days/week for 6 months.
NR = Not reported; NA = Not applicable
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Table A.
Agent: Bis(chloromethyl)ether
Reference: Leong et al., 1981
Exposure
Route
i
i
i.
j
Species/
Strain
mouse/
Ha/ICR
mouse/
Ha/ICR
mouse/
Ha/ICR
mouse/
Ha/ICR
Strengths of Study:
Weaknesses of Study:
Overal I
Adequacy:
Dose Duration Duration Purity Vehicle or
or of of of Physical Target
Sex Exposure3 Treatment Study Compound State Organ Tumor Type
M 100 ppb 6 months lifetime NR air respiratory pulmonary adenoma
10 ppb system
1 ppb
0 ppb
M 100 ppb 6 months lifetime NR air respiratory pulmonary adeno-
10 ppb system carcinoma
1 ppb
0 ppb
M 100 ppb 6 months lifetime NR air liver hepatocellular
10 ppb carcinoma
1 ppb
0 ppb
M 100 ppb 6 months lifetime NR air liver angioma
10 ppb
1 ppb
0 ppb
QUALITY OF EVIDENCE
Complete histological. hematological, and other examinations were conducted. The number of
each group was significant. The animals were exposed to a variety of dose levels.
The exposure was limited to only one quarter of the animals' lifespan. Only male mice were
Adequate
Tumor
Incidence
(P value)
7/144
2/143
4/138
6/157
8/U4
1/143
3/138
4/157
0/144
0/143
1/138
3/157
0/144
0/143
0/138
1/157
animals in
studied.
a Exposure is 6 hours/day, 5 days/week for 6 months.
NR = Not reported
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Table A.
Agent: Bis(chloromethyl)ether
Reference: Van Duuren et at., 1969
Exposure Species/
Route Strain
d mouse/
ICR/Ha
Swiss
sc rat/
Sprague-
Dawley
Strengths of Study:
Weaknesses of Study
Overall Adequacy:
Dose Duration Duration Purity Vehicle or
or of of of Physical Target
Sex Exposure Treatment Study Compound State Organ Tumor Type
f 2 mg/0.1 ml 311 days 325 days NR benzene skin papilloma
3 times/ week squamous-
carcinoma
0 mg/0.1 ml 526 days 540 days NA benzene skin NA
3 times/week
F 3 mg/0.1 ml8 300 days 515 days NR nujol injection fibrosarcoma
once/week site
connective fibroma
tissue
0 mg/0.1 ml 515 days 515 days NA nujol injection NA
once/week site
QUALITY OF EVIDENCE
Two species of animals were considered.
: Only females were studied. One dose level was given to the animals.
Limited
Tumor
Incidence
(P value)
13/20b
12/20
0/20
5/20c
2/20
0/20
a 3 ma/0.1 ml dose reduced after 114 weeks to 1 mg/0.1 ml and subsequent injections reduced to 3 times/month.
b First papilloma was seen at 161 days; median survival was 313 days.
r_ c Confirmed in animals that died at 245 days
,j NA = Not applicable; NR = Not reported
O
vC
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Table B. Hu|
Agent: Bis(chlororaethyl)ether
Reference: Albert et al., 1975
Size of Size of
Exposure Exposed Control Level of Duration of Target Tumor
Route Population Population Sex Exposure . Exposure Organ Type
Number of Number of Relative
Tumors Tumors Risk
Observed Expected (P Value)
d+ i +o
700
1819
MR heavy3 >5 years
respiratory cancer
tract
19
NR
QUALITY OF EVIDENCE
Strengths of Study: A large population of exposed chemical workers was studied. The reference group was workers of the same
factories not exposed to chemicals. Analyses were conducted based on exposure level and duration of
exposure.
Weaknesses of Study: Exposure to many other chemicals is likely in a chemical plant. Exposure to bis(chloromethyl)ether and
chloromethyl methyl ether is reported.
Overall Adequacy: Adequate
Comments: . A dose-response relationship is reported by the authors.
8 Exposure was to bis(chloromethyl)ether (2-8X) and chloromethyl methyl ether.
Estimated, based on 21/1819 respiratory cancers in the control group.
NR = Not reported
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Table B. HU^^
Agent: Bis(chloromethyl)ether
Reference: Figueroa et al., 1973
Exposure
Route
d+i+o
Size of
Exposed
Population
111
Size of
Control
Population Sex
2804 H
Level of
Exposure
NRa
Duration of
Exposure
3-14 years
Target
Organ
lung
Tumor
Type
oat-cell
carcinoma
Number of
Tumors
Observed
4
Number of
Tumors
Expected
0.63
Relative
Risk
(P Value)
P<0.002
QUALITY OF EVIDENCE
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
This study was based on the Philadelphia Pulmonary Research Project and used 2804 men, 45-54 years of age,
as a reference group. Cigarette smoking in both groups was similar.
Exposure was to several chemicals within the factory.
Adequate
a Exposure was reported for chloromethyl ether and bis(chloromethyl)ether.
Predominant type of tumor
NR = Not reported
O
O
CD
CD
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Table B.
Agent: Bis(chloromethyl)ether
Reference: Lemen et al., 1976
Exposure
Route
d+i+o
Size of
Exposed
Population
136
Size of
Control
Population
Connecticut
white males
Level of
Sex Exposure
H NR
Duration of
Exposure
10.5 years
Target
Organ
respiratory
tract
Tumor
Type
bronchogenic
cancer8
Number of
Tumors
Observed
5
Number of
Tumors
Expected
0.54
Relative
Risk
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Table B. H
Agent: Bis(chloromethyl)ether
Reference: Pasternack et al., 1977
Size of Size of
Exposure Exposed Control Level of
Route Population Population Sex Exposure
Duration of Target
Exposure Organ
Number of Number of Relative
Tumor Tumors Tumors Risk -
Type Observed Expected (P Value)
d+i+o 1827
d+i+o 721
8870 NR various
a
<20 years respiratory cancer 26
tract
1815 NR all levels <20 years respiratory cancer
tract
9.3 P<0.05
26 4.5
P<0.05
QUALITY OF EVIDENCE
Strengths of Study:
Weaknesses of Study:
Overall Adequacy: Adequate
Analyses were conducted on a large population of exposed chemical workers. Statistics of observed versus
expected incidences of cancers are reported.
Increased cancers cannot be absolutely attributed to bis(chloromethyl)ether since exposure to many
chemicals is likely in a chemical plant.
a Exposure was generally not reported, but, where possible, estimates were made depending on job area, exposure to
bis(chloromethyl)ether and exposure to chloromethyl methyl ether. _
Exposure levels were denoted into four groups based on duration of exposure; exposure was to bis(chloromethyl)ether and
chloromethyl methyl ether.
c Predominantly oat-cell carcinoma
NR = Not reported '.'.-.-
O
o
O
CD
CM
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