United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-030
October 1980
C-l
rxEPA
Ambient
Water Quality
Criteria for
Chloroalkyl Ethers
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AMBIENT WATER QUALITY CRITERIA FOR
CHLOROALKYL ETHERS
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train. 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
Donald J. Hansen, ERL-Gulf Breeze
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects.
Yin Tak Woo
Joseph Arcos (author)
Tulane Medical Center Donald Barnes
East Carolina University
Michael L. Dourson (doc. mgr.)
ECAO-Cin
U.S. Environmental Protection Agency
Robert D. Lingg
U.S. Environmental Protection Agency
Donna Sivulka (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Robert Bruce, ECAO-RTP
U.S.Environmental Protection Agency
Stephen Hecht
American Health Foundation
Robert E. McGaughy, CAG
U.S. Environmental Protection Agency
Martha Radike
University of Cincinnati
James Withey
Health and Welfare, Canada
R.K. Boutwell
University of Wisconsin
Herbert Cornish
University of Michigan
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Albert Munson
Medical College of Virginia
Steven Tannenbaum
Massachusetts Institute of Technology
Roy E. Albert, CAG*
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J-Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, R. Rubenstein, C. Russom.
*CAG Participating Members: Elizabeth L. Anderson, Larry Anderson, Ralph Arnicar,
Steven Bayard, David L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard Haberman,
Charalingayya Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dharm V. Singh, and Todd W. Thorslund.
IV
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxicity B-l
Chronic Toxicity B-l
Plant Effects B-2
Residue B-2
Miscellaneous B-2
Summary B-2
Criteria B-2
References B-7
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-5
Ingestion from Water C-5
Ingestion from Food C-l3
Inhalation C-16
Dermal C-18
Pharmacokinetics C-19
Effects C-22
Acute, Subacute and Chronic Toxicity C-22
Subacute Toxicity to Experimental Mammals C-22
Chronic Toxicity to Experimental Mammals C-25
Effect on Humans C-27
Synergism and/or Antagonism C-28
Teratogenicity C-30
Mutagenicity C-31
Carcinogenicity C-34
Criterion Formulation C-57
Existing Guidelines and Standards C-57
Current Levels of Exposure C-58
Special Groups at Risk C-59
Basis and Derivation of Criteria C-60
References C-66
Appendix C-82
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CRITERIA DOCUMENT
CHLOROALKYL ETHERS
CRITERIA
Aquatic Life
The available data for chloroalkyl ethers indicate that acute toxicity
to freshwater aquatic life occurs at concentrations as low as 238,000 u9/l
and would occur at lower concentrations among species that are more sensi-
tive than those tested. No definitive data are available concerning the
chronic toxicity of chloroalkyl ethers to sensitive freshwater aquatic life.
No saltwater organism has been tested with any chloroalkyl ether and no
statement can be made concerning acute or chronic toxicity.
Human Health
For the protection of human health from the toxic properties of bis(2-
chloroisopropyl) ether ingested through water and contaminated aquatic orga-
nisms, the ambient water criterion is determined to be 34.7 yg/1.
For the protection of human health from the toxic properties of bis(2-
chloroisopropyl) ether ingested through contaminated aquatic organisms
alone, the ambient water criterion is determined to be 4.36 mg/1.
For the maximum protection of human health from the potential carcino-
genic effects due to exposure of bis(chloromethyl) ether through ingestion
of contaminated water and contaminated aquatic organisms, the ambient water
concentrations should be zero based on the non-threshold assumption for this
chemical. However, zero level may not be attainable at the present time.
Therefore, the levels which may result in incremental increase of cancer
risk over the lifetime are estimated at 10~5, 10"6, and 10~7. The
VI
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corresponding recommended criteria are 37.6 x 10" n9/l, 3.76 x 10
yg/1, and 0.376 x 10"6 yg/1, respectively. If the above estimates are
made for consumption of aquatic organisms only, excluding consumption of
water, the levels are 18.4 x 10~3 yg/1, 1.84 x 10~3 yg/1, and 0.184 x
10~3 wg/l, respectively.
For the maximum protection of human health from the potential carcino-
genic effects due to exposure of bis(2-chloroethyl) ether through ingestion
of contaminated water and contaminated aquatic organisms, the ambient water
concentrations should be zero based on the non-threshold assumption for this
chemical. However, zero level may not be attainable at the present time.
Therefore, the levels which may result in incremental increase of cancer
risk over the lifetime are estimated at 10~5, 10"6, and 10" . The
corresponding recommended criteria are 0.30 yg/1, 0.030 yg/1, and 0.003
wg/l, respectively. If the above estimates are made for consumption of
aquatic organisms only, excluding consumption of water, the levels are 13.6
ug/l, 1.36 pg/1, and 0.136 yg/1, respectively.
vn
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INTRODUCTION
The chloroalkyl ethers have been widely used in laboratories and in
industrial organic synthesis, textile treatment, preparation of ion exchange
resins, and pesticide manufacture. They also have been used as solvents for
polymerization reactions (Summers, 1955).
The chloroalkyl ethers are compounds with the general structure RClx-
0-R1 Clx, where x may be any positive integer, including zero, and R and R'
are aliphatic groups. The chemical reactivity of these compounds varies
widely, depending on the placement of chlorine atoms and the nature of the
aliphatic groups involved. Chloromethylmethyl ether, bis(chloromethyl)
ether, 1-chloroethylethyl ether, and 1-chloroethylmethyl ether decompose in
water (Hampel and Hawley, 1973). Tou and Kallos (1974) calculated a half-
life of 14 seconds for bis(chloromethyl) ether in aqueous solution. Chloro-
methylmethyl ether undergoes decomposition in water to form methanol, for-
maldehyde, and hydrochloric acid. Bis(chloromethyl) ether will form spon-
taneously in the presence of hydrogen chloride and formaldehyde (Frankel, et
al. 1974).
The general physical properties of bis(2-chloroisopropyl) ether are as
follows.
Molecular weight 171.07
(Weast, 1977)
Melting point -97°C
(Verschueren, 1977)
Boiling point at 760 torr 189'C
(Verschueren, 1977)
Vapor pressure at 20°C 0.85 torr
(Verschueren, 1977)
A-l
-------
Solubility in water* i ynn ma/i
(Verschueren, 1977) ' UU mg/'
Log octanol/water partition coefficient 2 58
(Leo, et al. 1971)
The general physical properties of bis(2-chloroethyl) ether are as fol-
lows.
Molecular weight 143 n?
(Weast, 1977) 143'°2
Melting point _46 gec
(Weast, 1977)
Boiling point at 760 torr 178'C
(Weast, 1977)
Vapor pressure at 20*C 0.71 torr
(Verschueren, 1977)
Solubility in water* 10,200 mg/1
(Verschueren, 1977)
Log octanol/water partition coefficient l 53
(Leo, et al. 1971)
*Experimental data generated at room temperature; no specific tempera-
ture reported.
The general physical properties of bis(chloromethyl) ether are as fol-
lows.
Molecular weight 114 gg
(Weast, 1977) U4'96
Melting point _41 cv
(Weast, 1977)
Boiling point at 760 torr 104°C
(Weast, 1977)
Vapor pressure at 22*C 30 torr
(Dreisbach, 1952)
Solubility in water at 25°C 22,000 mg/1
(calc. by method of Moriguchi,
1975 using the data of Quayle, 1953)
Log octanol/water partition coefficient -0.38
(calc. by Radding, et al. 1977)
A-2
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The general physical properties of 2-chloroethyl vinyl ether are as fol-
lows.
Molecular weight 106.55
(Weast, 1977)
Melting point No data found
Boiling point at 760 torr 108*C
(Heast, 1977)
Vapor pressure at 20°C 26.75 torr
(calc. from Dreisbach, 1952)
Solubility in water at 25°C 15,000 mg/1
(calc. by method of
Moriguchi, 1975)
Log octanol/water partition coefficient 1.28
(calc. by method of Leo, et al. 1971)
The general physical properties of bis(2-chloroethoxy) methane are as
follows.
Molecular weight 173.1
(Webb, et al. 1962)
Melting point No data found
Boiling point at 760 torr 218.1°C*
(Webb, et al. 1962)
Vapor pressure at 20°C <0.1 torr
(calc. from Dreisbach, 1952 based
on the data of Webb, et al. 1962)
Solubility in water at 25°C 81,000 mg/1
(calc. by method of
Moriguchi, 1975)
Log octanol/water partition coefficient 1.26
(calc. based on method of Leo, et al. 1971)
*The boiling point at 760 torr has been reported as 105 to 106° by
Durkin, et al. (1975). Based on the detailed study of Webb, et al.
(1962) on the properties of this pollutant and other compounds in this
series, the value reported by Durkin, et al. (1975) is incorrect.
A-3
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REFERENCES
Dreisbach, R.R. 1952. Pressure-Volume-Temperature Relationships of Organic
Compounds. Handbook Publishers, Inc., Sandusky, Ohio.
Durkin, P.R., et al. 1975. Investigation of selected potential environ-
mental contaminants: Haloethers. EPA 560/2-75-006. Off. Toxic Subst., U.S.
Environ. Prot. Agency, Washington, D.C.
Frankel, L.S., et al. 1974. Formation of bis-(chloromethyl) ether from
formaldehyde and hydrogen chloride. Environ. Sci. Technol. 8: 356.
Hampel, C.A. and G.G. Hawley. 1973. Encyclopedia of Chemistry. Van Nos-
trand Reinhold Co., New York.
Leo, A., et al. 1971. Partition coefficients and their uses. Chem. Rev.
71: 525.
Moriguchi, I. 1975. Quantitative structure activity studies. Parameters
relating to hydrophobicity. Chem. Pharmacol. Bull. 23: 247.
Quayle, O.R. 1953. The parachors of organic compounds. Chem. Rev.
53: 439.
Radding, S.B., et al. 1977. Review of the environmental fate of selected
chemicals. EPA 560/5-77-003. Off. Toxic Subst., U.S. Environ. Prot.
Agency, Washington, D.C.
A-4
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Summers, L. 1955. The haloalkyl ethers. Chem. Rev. 55: 301.
Tou, J.C. and G.J. Kallos. 1974. Study of aqueous HC1 and formaldehyde
mixtures for formation of bis-(chloromethyl) ether. Jour. Am. Ind. Hyg.
Assoc. 35: 419.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York.
Weast, R.C. 1977. CRC Handbook of Chemistry and Physics. 58th ed. CRC
Press, Inc., Cleveland Ohio.
Webb, R.F., et al. 1962. Acetals and oligoacetals. Part I. Preparation
and properties of reactive oligoformals. Jour. Chem. Soc. London, p. 4307.
A-5
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Aquatic Life Toxicology*
INTRODUCTION
The data base for freshwater organisms and chloroalkyl ethers is limit-
ed to a few toxicity tests with bis(2-chloroethyl) ether and one with 2-
chloroethyl vinyl ether. No LC5Q or EC50 values were observed below
238,000 ug/1. Bioconcentration of bis(2-chloroethyl) ether by the bluegill
was low.
No appropriate data are available for saltwater organisms and any chlo-
roalkyl ether.
EFFECTS
Acute Toxicity
A 48-hour EC5Q value for Daphnia magna was determined to be 238,000
ug/l for bis(2-chloroethyl) ether (Table 1).
No 96-hour LC^g value for the bluegill could be determined for bis-
(2-chloroethyl) ether in a test with exposure concentrations as high as
600,000 wg/l (Table 4).
The 96-hour LC5Q for the bluegill and 2-chloroethyl vinyl ether is
354,000 wg/l (U.S. EPA, 1978) (Table 1).
Chronic Toxicity
An embryo-larval test has been conducted with bis(2-chloroethyl) ether
and the fathead minnow (U.S. EPA, 1978). No adverse effects were observed
at test concentrations as high as 19,000 yg/1 (Table 2).
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of toxi-
city as described in the Guidelines.
R-1
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Plant Effects
No data are available on the effects of any chloroalkyl ether on aquat-
ic plants.
Residues
Using 1 C-bis(2-chloroethyl) ether and thin layer chromatography
(U.S. EPA, 1978), a steady-state bioconcentration factor of 11 was deter-
mined during a 14-day exposure of bluegill (Table 3). The half-life was ob-
served to be between 4 and 7 days.
Miscellaneous
The only datum in Table 4 has been discussed previously.
Summary
Only a few tests have been conducted with freshwater organisms and
chloroalkyl ethers. Results for 2-chloroethyl vinyl ether and bis(2-chloro-
ethyl) ether suggest that acute and chronic toxicity occur at relatively
high concentration and that bioconcentration is low.
CRITERIA
Tha available data for chloroalkyl ethers indicate that acute toxicity
to freshwater aquatic life occurs at concentrations as low as 238,0090 ug/l
and would occur at lower concentrations among species that are more
sensitive than those tested. No definitive data are available concerning
the chronic toxicity of chloroalkyl ethers to sensitive freshwater aquatic
life.
No saltwater organism has been tested with any chloroalkyl ether and no
statement can be made concerning acute or chronic toxicity.
B-2
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Table 1. Acute values for chloroalkyl ethers (U.S. EPA, 1978)
LC50/EC50 Species Acute
(uo/l) Value (ug/l)
species
Cladoceran,
Daphnla magna
Blueglll,
Lepomls macrochlrus
FRESHWATER SPECIES
S, U Bis(2-chloro- 238,000
ethyl) ether
S, U 2-chloroethyl 354,000
vinyl ether
238,000
354,000
* S - static, U » unmeasured
No Final Acute Values are calculable since the minimum data base requirements are not
m met.
U)
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Table 2. Chronic values for chloroalkyl ethers (U.S. EPA, 1978)
Chronic
Limits Value
Species Method* Chemical (poyi) (|ig/l)
FRESHWATER SPECIES
Fathead minnow, E-L Bls(2-chloro- >19,000
Plmephales promelas ethyl) ether
* E-L = embryo-larva I
No acute-chronic ratio can be calculated since no acute toxic Ity data are
available for this species.
03
I
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Table 3. Residues for chloroalkyl ethers (U.S. EPA, 1978)
Bloconcentration Duration
Species Tissue Chemical Factor (days)
FRESHWATER SPECIES
to
I
en
Blueglll, whole body Bls(2-chloro- 11 14
Lepomls macrochlrus ethyl) ether
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Table 4. Other data for chloroalkyi ethers (U.S. EPA, 1978)
Result
Species Chemical Duration Effect (tig/1)
FRESHWATER SPECIES
Bluegill, Bls(2-chloro- 96 hrs LC50 >600,000
Lepomls macrochlrus ethyl) ether
Ed
I
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REFERENCES
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No.
68-01-4646.
B-7
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
The chloroalkyl ethers, a subclass of haloethers, are widely
used in industries and laboratories. Some of the members of this
subclass are potent carcinogens, and some have been found in the
aquatic environment. The chloroalkyl ethers discussed in this doc-
ument are listed in Table 1. Of these compounds, bis(chloromethyl)
ethe.. .BCME), chloromethy 1 methyl ether (CMME) , bis(2-chloroethyl)
ether (BCEE), and bis(2-chloroisopropyl) ether (BCIE) have received
the greatest attention because of their potential health hazards.
Comprehensive reviews on the physical and chemical properties and
biological effects of these chemicals have been published (Summers,
1955; Van Duuren, 1969; Int. Agency Res. Cancer, 1974, 1975;
Durkin, et al. 1975; Nelson, 1976; NAS, 1977). The physical con-
stants of the four environmentally important chloroalkyl ethers are
summarized in Table 2. This document will be primarily concerned
with the health effects of the chloroalkyl ethers listed in Table 2.
Because of their high reactivity, BCME and CMME have found
wide laboratory and industrial use as intermediates in organic syn-
thesis, in the treatment of textiles, for the manufacture of poly-
mers and insecticides, in the preparation of ion-exchange resins,
and in industrial polymerization reactions. Following recognition
of the high potency of these chemicals as carcinogens by inhalation
in animals, and various epidemiological evidence linking excessive
human respiratory cancer incidence to exposure, BCME and CMME have
been listed as two of the 14 carcinogens restricted by Federal
C-l
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TABLE 1
Chloroalkyl Ethers Covered in this Document
Names, Abbreviations, and Synonyms
Chemical Formula
Chloromethyl methyl ether (CMME)
other names: dimethyIchloroether;
methyl Chloromethyl ether
C1CH2OCH3
Bis(Chloromethyl) ether (BCME)
other names: Chloromethyl ether;
chloro(chloromethoxy) methane;
dichloromethyl ether;
dimethyl-l,l-dichloroether
C1CH2OCH2C1
°<, *<-Dichloromethyl methyl ether
other name: 1,1-dichloromethyl
methyl ether
C12CHOCH3
Bis(«<-chloroethyl) ether
other name: bis(l-chloroethyl)-
ether
CH3CHOCHCH3
Cl Cl
Bis(2-chloroethyl) ether (BCEE)
other names: l,l'-oxybis(2-chloro)-
ethane; bis(^-chloroethyl) ether;
l-chloro-2-(//-chloroethoxy)ethane;
etc.
C1CH2CH2OCH2CH2C1
Bis(2-chloroisopropyl) ether (BCIE)
other name: bis(2-chloro-l-methyl-
ethyl)ether
2-Chloroethyl vinyl ether
ClCH-CHOCHCH^Cl
I \
CH3 CH3
C1CH2CH2OCH=CH2
Octachloro-di-n-propyl-ether
C13CCHCH2OCH2CHCC13
Cl Cl
C-2
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TABLE 1 (Continued)
cc
2,3-Dichlorotetrahydrofuran \ ^^^(.l
2f3-trans-Dichloro-p-dioxane
Bis-1,2-(chloromethoxy)ethane C1CH2-0-CH2CH2-0-CH2C1
Bis-1,4-(chloromethoxy)butane C1CH2-O-CH2CH2CH2CH2-O-CH2C1
Bis-1,6-(chloromethoxy)hexane C1CH2-O-CH2CH2CH2CH2CH2CH2-O-CH2C1
CH2-0-CH2C1
Tris-1,2,3-(chloromethoxy)propane CH -O-CH2C1
CH2-O-CH2C1
Bis(2-chloroethoxy)methane (BCEXM) C1CH2CH2-O-CH2-O-CH2CH2C1
Bis-1,2-(2-chloroethoxy)ethane (BCEXE) C1CH2CH2-O-CH2-CH2-O-CH2CH2C1
C-3
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O
I
£>.
TABLE 2
Physical Constants of Four Environmentally Most Significant Chloroalkyl Ethers
Compound Mol. Wt. APPearance at
room temperature v'
CMME
BCME
BCEE
BCIE
(760'L Hg) Density
80.5 colorless liquid
115.0 colorless liquid
-51.9°Cb
171.07 colorless liquid
riARC (1975)
cSchrenk, et al. (1933)
n for refractive index
59°C dj°=1.0605
104°C
143.01 colorless liquid -24.5°Ca 176-178°C
dj5 =1.328
1.213
187-188°C
Solubility
1.3974 Immediately hydrolyze in
water; miscible with
ethanol, ether and many
other organic solvents.
1.435 Immediately hydrolyze in
water; miscible with ethanol,
ether and many other organic
solvents.
1.457
1.4474
Practically insoluble in water;
miscible with most organic
solvents (especially, benzene
and chloroform)
Practically insoluble in water;
miscible with most
organic solvents.
-------
regulations, effective February 11, 1974 (39 PR 3756; Anonymous,
1974). Realization of the potential hazard of BCME grew dramatical-
ly when it was reported that at high concentrations, vapors of HC1
and formaldehyde, two commonly used chemicals in many industries
and laboratories, can combine spontaneously to form BCME.
The concern over BCEE and BCIE arose mainly because of their
presence in river water and the drinking water of several U.S.
cities. These chemicals were found at high concentrations in waste
water from chemical plants involved in the manufacturing of glycol
products, rubber, and insecticides. As an end product, BCEE is an
excellent solvent for fats, waxes, and greases. It can be used as a
scouring agent for textiles and has also been employed as an insec-
ticide, ascaricide, and soil fumigant. The U.S. EPA has included
these two compounds in its National Organics Monitoring Survey
(NOMS) of U.S. drinking water (U.S. EPA, 1977).
EXPOSURE
Ingestion from Water
Chloroalkyl ethers do not occur as such in nature; their oc-
currence is entirely anthropogenic. Discharges from industrial and
manufacturing processes represent the major sources of these organic
pollutants in the aquatic environment. Chlorination of drinking
water could also be a potential source.
The stability of chloroalkyl ethers in aqueous systems plays a
crucial role in determining their persistence in the water. In
general, °t-chloroalkyl ethers have an extremely short lifetime
in aqueous solutions and are therefore not expected to persist for
any extended period of time in water. On the other hand, other
chloroalkyl ethers are quite stable and may persist in the aqueous
C-5
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environment. The rate of hydrolysis of a number of °<-chloroalkyl
ethers in an aqueous system has been measured by Van Duuren, et al.
(1972). In a solution of water-dimethylformamide (3:1) kept at 0°C,
the four o<-chloroalkyl ethers (BCME, CMME, bis( °<-chloroethyl)
ether, °( , °<-dichloromethylmethyl ether) tested were found to
have a rate constant greater than 0.35 min with a half-life of
less than two minutes. Kinetic studies of BCME hydrolysis by Tou
and coworkers confirmed the above finding. In neutral aqueous sol-
ution, the t^ was 280, 38, and 7 seconds at 0°C, 20°C, and 40°C,
respectively. The hydrolysis was faster in alkaline solution and
slower in acidic solution (Tou, et al. 1974). A comparably fast
rate of hydrolysis of BCME was observed in aqueous solutions con-
taining hydrochloric acid and formaldehyde (Tou and Kallos, 1974a)
or anion-exchange resins (Tou, et al. 1975). CMME is even more
reactive than BCME. Its half-life in aqueous solution cannot be
directly measured with accuracy. Jones and Thornton (1967) have
measured the hydrolysis rate of CMME in aqueous isopropanol. Extra-
polation of the data to pure water yielded a tu of less than one
second (Tou and Kallos, 1974b). In aqueous methanol at 45 C, the
hydrolysis rate of CMME was about 5,000 times faster than that of
BCME (Nichols and Merritt, 1973).
In contrast to o\-chloroalkyl ethers, the ^-chloro compounds
are much more stable. Van Duuren, et al. (1972) found that the
half-life of BCEE was more than 23 hours in water-dimethylformamide
(3:1) at 30°C. Bohme and Sell (1948) estimated the half-life of
BCEE to be 12.8 days in a mixture of water-dioxane solution at
100°C. Kleopfer and Fairless (1972) observed that BCIE appeared to
C-6
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be quite persistent in contaminated river water; there was no sign
of biodegradation.
The occurrence of chloroalkyl ethers in river water and fin-
ished drinking water has been reported by various investigators.
Among the chloroalkyl ethers covered in this document, BCEE and
BCIE have been consistently detected in some areas of the country
and quantitatively determined in some cases. Shackelford and Keith
(1976) have recently compiled information on the frequency of or-
ganic compounds identified in water from published literature and
unpublished survey analyses from U.S. EPA laboratories. Occurrence
of BCEE and BCIE in various types of water, has been reported 10 and
19 times, respectively. Other chloroalkyl ethers, occasionally
reported, included BCEXM, BCEXE, vinyl 2-chloroethyl ether,
2-chloroethyl methyl ether, BCME, and chloromethyl ethyl ether. In
view of the extremely short lifetime of "V-chloroalkyl ethers in
aqueous systems, reports of their presence in water are probably
erroneous. Schulting and Wils (1977) have noted that even the
sophisticated GC-MS selected ion monitoring (SIM) method may yield
false results. Using SIM on a SE-30 column, the authors demon-
strated that l-chloro-2-propanol could be mistaken for BCME. Re-
ports of occurrence of /^-chloroalkyl ethers in water appear to be
more reliable and in some cases quantified; the major findings of
these reports are summarized in Table 3.
Rosen, et al. (1963) were the first to detect BCEE and BCIE in
contaminated river water. Investigation of the cause of odor of
the Kanawha River at Nitro, West Virginia, led to the qualitative
identification of BCEE and BCIE as two of the pollutants. The
C-7
-------
TABLE 3
Occurrence of Principal Chloroalkyl Ethers in Various Types of Water
Reference
Rosen, et al. (1963)
Kleopfer and
Fairless (1972)
Webb, et al. (1973)
Webb, et al. (1973)
Keith, et al. (1976)
o
i
00
U.S. EPA (1975)
U.S. EPA (1975)
Manwaring, et al.
(1977)
Sheldon and Kites
(1978)
Location and
Source of Water
Nitro, W.Va.
Kanawha River
Evansville, Ind.
Ohio River
Effluent from
synthetic rubber plant
Glycol plant's thickening
and sedimentation pond
New Orleans, La.
Mississippi River:
Carrollton station
Jefferson station #1
Jefferson station #2
Unspecified
Philadelphia, Pa.
Delaware River
Philadelphia, Pa.
Delaware River
Philadelphia, Pa.
Delaware River
Type of
water
RW
RW
WW
RW
FDW
WW
WW
WW
FDW
FDW
FDW
FDW
FDW
FDW
FDW
FDW
FDW
WW
FDW
RW
RW
Compound .
identified
BCEE
BCIE
BCIE
BCIE
BCIE
BCEXM
BCEE
BCIE
BCEE
BCIE
BCEE
BCIE
BCEE
BCIE
BCIE
BCEE
BCEXE
BCEE
BCEE
BCEE
BCEXE
Cone.
(ug/l)c
n. q.
n.q.
500-35,000
2.0(0.5-5.0)
0.8
140,000
160
n.q.
0.04
0.18
0.16
0.08
0.12
0.03
1.58
0.42-0.5
0.03
0.23-41
0.04-0.6
n.d. -trace
15
For additional information see: Dressman, et al. 1977; U.S. EPA, 1977, Table 4 (following).
aRW = river
plant.
water; FDW = finished drinking water; WW = wastewater or effluent from chemical
BCEE = bis-(2-chloroethyl) ether; BCIE=bis-(2-chloroisopropyl) ether; BCEXM = bis-(2-chloroethoxy)-
methane; BCEXE = bis-(2-chloroethoxy)ethane.
:n.q. = not quantified; n.d. = not detectable.
-------
threshold odor concentrations for BCEE and BCIE were estimated to
be 360 jug/1 and 200 jug/1, respectively.
The presence of BCIE in river water and finished drinking
water at Evansville, Indiana, was noted by Kleopfer and Fairless
(1972). An industrial outfall, located about 150 river miles up-
stream from the Evansville water intake, was found to be the prob-
able source of the pollutant. Samples from this outfall were ana-
lyzed using flame-ionization and electron-capture detection gas
chromatography, verified by IR and mass spectrometry, on several oc-
casions during the fall of 1971. In each case BCIE was found in
concentrations ranging from 0.5 to 35 mg/1; the estimated discharge
was 68 kg/day. Concentrations of BCIE found in the Ohio River at
Evansville ranged from 0.5 to 5.0 jug/1. The conventional drinking
water treatment was capable of removing only 60 percent of BCIE
from the raw river water. BCIE concentration of 0.8 ug/1 was found
in the finished drinking water.
The detection of BCEE and BCEXM in the treated effluent from
synthetic rubber plants was reported by Webb, et al. (1973); the
concentrations were on the order of 0.16 mg/1 and 140 mg/1, respec-
tively. BCIE was also readily detected in a thickening and sedi-
mentation pond of glycol plants.
The lower region of the Mississippi River is well known for
being heavily contaminated with organic pollutants from industrial
discharges. Since 1969, the drinking water of the New Orleans area
has been closely monitored by the U.S. EPA with detection of vari-
ous pollutants frequently reported. Keith, et al. (1976) have
recently compiled detailed quantitative data from these studies.
C-9
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At the Carrollton station and two sites in Jefferson Parish, the
finished drinking water was found to contain BCEE at levels of
0.04, 0.16, and 0.12 ug/1, respectively. The corresponding values
for BCIE were 0.18, 0.08, and 0.03 ug/1.
In a report to Congress, the U.S. EPA (1975) summarized the
findings of organics in U.S. drinking water. A number of chloro-
alkyl ethers were detected, with the highest reported concentra-
tions for BCEE, BCIE, and BCEXE being 0.42 ug/1, 1.58 jug/1, and
0.03 pg/lf respectively. In a study of 10 cities, the drinking
water of Philadelphia was found to contain 0.5 ug/1 BCEE and 0.03
pg/1 BCEXE. The drinking water of the other nine cities did not
contain these chloroalkyl ethers (U.S. EPA, 1975).
The discovery of BCEE in Philadelphia's drinking water initi-
ated a flurry of activity to determine the source and find means of
elimination (Manwaring, et al. 1977). A chemical manufacturing
plant located near the city's water intake admitted that it had
discharged approximately 61.4 kg/day of the compound into the river
(Anonymous, 1975). The effluent from the chemical plant contained
up to 41 ug/1 BCEE. Samples of the river adjacent to the discharges
showed the presence of up to 10 pg/1 of the chemical. Between
February and July of 1975, the city's finished drinking water con-
tained BCEE ranging from 0.04 to 0.6 pg/1. The chemical company
has since developed a BCEE destruction system for the treatment of
its effluent, and this system resulted in a greater than 99 percent
reduction in the discharge of BCEE into the river (Manwaring, et
al. 1977). In a more recent survey by Sheldon and Kites (1978),
BCEE was barely detectable (-—'O.Ol ug/1) in the river water.
C-10
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However, a high concentration of another chloroalkyl ether (BCEXE
(15 ug/1)) was detected in two of the five samples examined.
A National Organics Monitoring Survey of the U.S. drinking
water has recently been undertaken by U.S. EPA (1977). Three
phases of the study were carried out in March-April 1976, May-July
1976, and November 1976-January 1977. The drinking water of 113
cities has been analyzed for organic pollutants, including chloro-
alkyl ethers. In phase I, BCEE was not found in 112 cities at the
minimum quantifiable limit of 5 ug/1. In phases II and III, the
limit was lowered to 0.01 jag/1. In phase II, the drinking water of
13 of the 113 cities was found to contain BCEE, with a mean concen-
tration of 0.10 ug/1. BCIE was also found in 8 of the 113 cities.
The quantitative data of the phase II study have been published by
Dressman, et al. (1977) and are summarized in Table 4. In phase
III, 8 of 110 (7.27 percent) cities had BCEE, with a mean of
0.024 jag/1. For BCIE, 7 of 110 (6.36 percent) cities gave positive
results, with a mean of 0.11 jjg/1 (U.S. EPA, 1977).
BCME can be chemically produced by saturating a solution of
paraformaldehyde in cold sulfuric acid with HC1. Van Duuren, et
al. (1969) studied the reaction of BCME with deuterium oxide in
dioxane. Rapid disappearance of BCME was observed, with 70 percent
%
of the compound hydrolyzed within two minutes. However, after 18
hours, about 20 percent of BCME was still present. This suggested
a possible equilibrium between BCME and its hydrolysis products,
HC1 and formaldehyde, and further raised the question of whether
BCME could be formed spontaneously from HC1 and formaldehyde. This
question received great attention when the Rohm and Haas Company
C-ll
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TABLE 4
The Levels of BCEE and BCIE Detected in the Finished
Water of 113 Cities in the Phase II Study of
National Organics Monitoring Survey*
City
number**
17
18
32
40
56
60
65
67
75
77
80
88
102
109
121
122
BCEE
(ug/1)
0.19
0.14
0.02
0.01
0.17
0.13
0.01
0.30
0.06
0.06
0.36
0.02
0.01
BCIE
(ug/1)
0.03
0.03
0.14
0.17
0.09
0.09
0.55
0.02
— -
Mean cone. 0>10 0.17
of positives
Percent '
incidence
. . 11.5% 7.1%
among cities
surveyed
*Source: Dressman, et al. 1977
**To decode city number, please check with the source article or
U.S. EPA-NOMS data.
C-12
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disclosed that BCME could be detected in humid air and aqueous or
nonaqueous liquid-phase systems containing high concentrations of
HC1 and formaldehyde (Anonymous, 1972). However, more recent stud-
ies by Tou and Kallos (1974a, 1976) have indicated that, at least
for aqueous systems, there was no evidence of BCME formation from
HC1 and formaldehyde at a detection limit of an order of magnitude
of parts per trillion.
Ingestion from Food
There is no information on the possible human exposure to
chloroalkyl ethers via ingestion of food. The levels of chloro-
alkyl ethers in food have not been monitored, nor has there been any
attempt to study the bioaccumulation of chloroalkyl ethers. How-
ever, in view of their relative stability and low water solubility,
^-chloroalkyl ethers may have a high tendency to be bioaccumu-
lated.
Neely, et al. (1974) have noted a linear correlation between
the octanol/water coefficients (poctanol^ and bioconcentration
factors of chemicals in trout muscle. The relationship can be
expressed by the equation:
Log (bioconcentration factor) = 0.542 log (P . , ) + 0.124.
octanol
Tne Poctanol for cnloroalky1 ethers is not available. However,
Suffet and Radziul (1976) have published partition coefficients of
BCEE in a number of other organic solvents. Ether was the most
extensively used solvent; the average Petner calculated from their
data was 8.35. Using the solvent regression equation of Leo, et
al. (1971), pether may be converted to poctanol bY employing the
formula:
(Pether> = i-142 lo<3 -1'
C-13
-------
From these data, it can be calculated that the bioconcentration
factor of BCEE in trout muscle should be around 11.7.
Tne poctanol of c01010311^1 ethers may also be calculated
based on their solubility in water according to the method outlined
by Chiou and Freed (1977). Using the above method, the information
on water solubility of chloroalkyl ethers (Durkin, et al. 1975),
and the linear regression model (Neely, et al. 1974), the extrap-
olated bioconcentration factors for BCEE, BCIE and 2-chloroethyl
vinyl ether are 12.6, 56.2, and 34.2, respectively.
Another approach to calculating bioconcentration factors has
been recommended by the U.S. EPA1 s ecological laboratory in Duluth,
Minnesota. This approach states that a bioconcentration factor
(BCF) relates the concentration of a chemical in aquatic animals to
the concentration in the water in which they live. The steady-
state BCFs for a lipid-soluble compound in the tissues of various
aquatic animals seem to be proportional to the percent lipid in the
tissue. The per capita ingestion of a lipid-soluble chemical can
be estimated from the per capita consumption of fish and shellfish,
the weighted average percent lipids of consumed fish and shellfish,
and a steady- state BCF for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
C-14
-------
the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
A measured steady-state bioconcentration factor of 11 was
obtained for bis(2-chloroethyl)ether using bluegills (U.S. EPA,
1978). Similar bluegills contained an average of 4.8 percent
lipids (Johnson, 1980). An adjustment factor of 3.0/4.8 = 0.625
can be used to adjust the measured BCF from the 4.8 percent lipids
of the bluegill to the 3.0 percent lipids that is the weighted
average for consumed fish and shellfish. Thus, the weighted aver-
age bioconcentration factor for bis(2-chloroethyl)ether and the
edible portion of all freshwater and estuarine aquatic organisms
consumed by Americans is calculated to be 11 x 0.625 » 6.9.
No measured steady-state bioconcentration factor is available
for bis(chloromethyl)ether, 2-chloroethylvinyl ether, bis-
(2-chloroisopropyl)ether, or bis(2-chloroethoxy)methane, but the
equation "Log BCP - (0.85 Log P) - 0.70" can be used (Veith, et al.
1979) to estimate the BCF for aquatic organisms that contain about
7.6 percent lipids (Veith, 1980) from the octanol/water partition
coefficient (P). Since no measured log P values could be found,
log P values of 1.06, 1.00, 1.76, and 1.07 were calculated for
bis(chloromethyl)ether, 2-chloroethylvinyl ether, bis(2-chloro-
isopropyl)ether, and bis(2-chloroethoxy)methane using the method
described in Hansch and Leo (1979). The steady-state bioconcentra-
tion factors are estimated to be 1.59, 1.41, 6.25, and 1.62, re-
spectively. An adjustment factor of 3.0/7.6 = 0.395 can be used to
adjust the estimated BCF from the 7.6 percent lipids on which the
C-15
-------
equation is based to the 3.0 percent lipids that is the weighted
average for consumed fish and shellfish. Thus, the weighted
average bioconcentration factors for bis(2-chloromethyl)ether,
2-chloroethylvinyl ether, bis(2-chloroisopropyl)-ether and bis-
(2-chloroethoxy)methane and the edible portion of all freshwater and
estuarine aquatic organisms consumed by Americans are calculated to
be 0.628, 0.557, 2.47, and 0.64, respectively.
The use of aquatic organisms as a typical exposure factor
requires the quantification of pollutant residues in the edible
portion of the ingested species. For this reason, the U.S. EPA-recom-
mended calculations, based upon the percent lipids of aquatic
organisms, were used in the formulation of the criterion.
Inhalation
There is no evidence of occurrence of chloroalkyl ethers in
the atmosphere. Human exposure to compounds via inhalation appears
to be confined to occupational settings. It is important to note
that, in contrast to its instability in aqueous solution, BCME is
considerably more stable in humid air. Frankel, et al. (1974)
(?b
found that BCME introduced into a Saran w bag containing moist air
was stable for at least 18 hours. Tou and Kallos (1974b) have stud-
ied the stability of BCME and CMME in humid air. At an ambient
temperature with a relative humidity of 81 percent, the t^ of BCME
in the gaseous phase could be as long as 25 hours. The rate of
hydrolysis was dependent on the surface of the container. In a
ferric oxide-coated Saran® reactor, the t^ of BCME was on the
order of seven to nine hours. A similar surface effect on the
C-16
-------
hydrolysis of CMME in the gaseous phase was also observed. The t,
"i
of CMME in the gaseous phase ranged from 2.3 minutes to 6.5 hours.
The extreme potency of BCME and/or CMME as inhalation carcino-
gens has prompted industrial hygienists and researchers to closely
monitor the atmospheric level of these compounds in the work place.
Various such methods have been developed (e.g., Collier, 1972;
Solomon and Kallos, 1975; Sawicki, et al. 1976; Parkes, et al.
1976; Kallos, et al. 1977; Bruner, et al. 1978). The finding of
spontaneous formation of BCME from HC1 and formaldehyde vapors has
expanded the potential sites of BCME exposure to any place where
high atmospheric levels of these two reactants may co-exist. Rohm
and Haas Company first disclosed information on the spontaneous
formation of BCME from HC1 and formaldehyde (Anonymous, 1972). At
room temperature of about 71°F and with a 40 percent relative hu-
midity, a steady state level of BCME could be reached within one
minute. In general, ppm levels of the reactants yielded ppb levels
of BCME. This important finding has since been confirmed; however,
the yield in such a reaction is much lower than was previously
anticipated. Frankel, et al. (1974) reported that at 25°C and 40
percent relative humidity, fewer than 0.5 ppb of BCME was formed
from 20 ppm each of HC1 and formaldehyde. At 100 ppm or 300 ppm of
each reactant, the average yield was 2.7 or 23 ppb BCME, respec-
tively. The factors that affect the yield included the reactant
concentration, the surface of the reactor, the reaction time, the
humidity and temperature. A substantially lower yield was observed by
Kallos and Solomon (1973). At 100 ppm of each of the reactants, only
0.1 ppb BCME was detected. Nevertheless, with high concentrations
C-17
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of the reactants, substantial amounts of BCME could be detected.
The National Institute for Occupational Safety and Health (NIOSH) is
currently investigating the possible formation of BCME in various
work places where HC1 and formaldehyde may be used simultaneously
(Lemen, et al. 1976).
In addition to HC1 and formaldehyde, a number of other chemi-
cals are potential reactants for the formation of BCME. Gamble
(1977) reported that BCME could be detected in an animal room that
had been washed with a 15 percent hypochlorite solution followed by
routine gassing with formaldehyde. Duplicate air samples were
taken from both high levels (3 m) and low levels (1m). No BCME was
detected in the high-level sample whereas 0.2 ppb of BCME was found
in the low-level sample. The author recommended that chlorine-con-
taining disinfectants should not be used when animal rooms are
gassed with formaldehyde. Another possible source of BCME in the
work place was suspected to be from the reaction of dimethyl ether
and chlorine in air. Kallos and Tou (1977) have investigated this
possibility. The reaction was found to be photochemical in nature.
In ambient air BCME was barely detectable; the highest amount de-
tected was 2 ppb from 100 ppm each of chlorine and dimethyl ether.
However, it is interesting to note that as much as 1.5 ppm BCME was
found to be generated during the reaction of 100 ppm of each of the
reactants in dry nitrogen.
Dermal
There was no information available on the dermal exposure of
humans to chloroalkyl ethers; no evaluations can be made regarding
the relative importance of dermal exposure. One potential source
C-18
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of dermal exposure has, however, been investigated by Loewengart
and Van Duuren (1977). Tetra-bis(hydroxymethyl)phosphonium chloride
(THPC), a widely used flame retardant in children's sleepwear, is
synthesized from phosphine, hydrochloric acid, and formaldehyde and
may decompose thermally or chemically to these chemicals. Thus,
THPC is also a potential source of BCME reactants under the right
conditions. Because of the high add-on (up to 35 percent of the
final fabric weight) of the flame retardant, it seems likely that a
fraction of THPC may be loosely bound and that common solutions
such as sweat, urine, and saliva may be able to extract some free
THPC. A sample of commercial THPC was found to contain 4 to 14
percent (w/w) free formaldehyde. Gas chromatographic analysis of
aqueous commercial THPC did not reveal any peak characteristic of
BCME; however, the limit of detection of the study was only 0.1
ppm. THPC is also marginally active as a skin carcinogen and ac-
tive as a tumor promoter (Loewengart and Van Duuren, 1977).
CH2OH
HOCH2-P+-CH2OH
CH2OH
Cl -> PH3 + V4HCHO
J f
C1CH2OCH2C1
PHARMACOKINETICS
No information is available on the pharmacokinetics of chloro-
alkyl ethers in humans; animal data are also rather scanty. The
e*-chloroalkyl ethers, by virtue of their high reactivity and
short lifetime in aqueous systems, are not expected to persist in
C-19
-------
the body. Nonetheless, Gargus, et al. (1969) observed a signifi-
cant increase in the incidence of lung tumors after s.c. injection
of BCME to newborn mice. This finding may indirectly indicate that
BCME may be absorbed from the subcutaneous tissue and induce tumors
at a site remote from the site of injection.
Smith, et al. (1977) have recently published detailed pharma-
cokinetic data on BCIE in female rats and monkeys. The BCIE was
believed originally to be labeled with 14C at the ^-position.
However, subsequently it was ascertained that labeling actually
occurred in the ^-position (Lingg, personal communication). After
single oral doses, BCIE appeared to be readily absorbed by both
species. In the monkey, the blood radioactivity level reached a
high peak within two hours and then declined in a biphasic manner
with a t, of about five hours and greater than two days for the
T
first and second phases, respectively. In the rat, the blood radio-
activity level reached a maximum between two and four hours after
dosing and then slowly declined with a t^ of two days. There was a
substantial difference in the tissue distribution and excretion
pattern seven days after a single parenteral dose of 30 mg/kg of
14C-BCIE. The monkey retained substantially higher amounts of
radioactivity in the liver (equivalent to 28.8 ug/g BCIE) than did
the rat (3.2 jug/g). Higher quantities were also found in the mus-
cle and brain of the monkey. On the other hand, with respect to the
percentage of administered dose recovered in the tissues and ex-
creta, higher amounts of radioactivity were found in the fat (1.98
percent), urine (63.36 percent), feces (5.87 percent), and expired
air (15.96 percent) of the rat. The corresponding figures in the
C-20
-------
monkey were 0.78 percent, 28.61 percent, 1.19 percent, and 0 per-
cent. Metabolites of BCIE in the rat included l-chloro-2 propanol,
propylene oxide, 2-(l-methyl-2-chloroethoxy)-propionic acid and
carbon dioxide. Initial attempts to analyze the urinary metabo-
lites of BCIE in the monkey had been inconclusive because of the
presence of interfering substances.
The fate of BCEE in rats after acute oral administration has
been studied by Lingg, et al. (1978). Bis((l-14C)chloroethyl)-
ether (40 rag/kg) was administered to male Sprague-Dawley rats by
intubation. Preliminary results showed that virtually all of the
BCEE was excreted as urinary metabolites with more than 60 percent
of the compound excreted within 24 hours. One major metabolite was
thiodiglycolic acid. A lesser metabolite was identified as 2-
chloroethanol-^-D-glucuronide. The presence of these two metabo-
lites suggests that cleavage of the ether linkage is a major step
in the biotransformation of BCEE. The products of this cleavage
then conjugate with nonprotein-free sulfhydryl groups or with glu-
curonic acid, with the former as the major route of conjugation in
the rat.
The metabolic fate of other chloroalkyl ethers is not known.
However, it is interesting to note that cleavage of the ether link-
age also appears to be a route of metabolism for diethyl ether in
mice (Geddes, 1971). For p-dioxane, a cyclic ether, ring hydroxy-
lation has been postulated as the first step of metabolism in the
rat (Woo, et al. 1977). The major urinary metabolite has been
identified as 2-hydroxyethoxyacetic acid (Braun and Young, 1977) or
C-21
-------
p-dioxane-2-one (Woo, et al. 1977) which are readily interconver-
tible depending on the pH of the system.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Animal Studies: The acute toxicity of a variety of chloro-
alkyl ethers has been studied in different animal species. Tables
5 and 6 summarize the acute toxicity data. It is apparent from
Table 5 that the route of exposure may play a determining factor in
the acute toxicity of chloroalkyl ethers. In the rat, the inhala-
tional toxicity follows the order, BCME > CMME > BCEE > BCIE; by
oral administration, however, the order is changed to BCEE ">
BCIE > BCME > CMME. Apparently, the extremely short lifetime of
BCME and CMME in aqueous solution significantly reduces their toxic
potential by oral administration. It is also of interest to note
the dramatic enhancement of toxicity of p-dioxane after chlorina-
tion. The acute LD5Q of p-dioxane has been reported as 5.3 g/kg
(Woo, et al. 1978). Chlorination of p-dioxane increases the toxi-
city by 10- to 1,000-fold. The stereochemistry of the compound also
plays a significant role; the 2r,3t,5t,6c-tetrachloro isomer was
found to be 80 times more toxic than its 2r,3c,5t,6t-stereoisomer
(Woo, et al. 1979).
The acute physiological response of the guinea pig to air con-
taining toxic concentrations of BCEE has been studied by Schrenk,
et al. (1933). The primary action was the irritation of the res-
piratory passages and the lungs. In the order of their appearance,
the symptoms produced were nasal irritation, eye irritation, lacri-
mation, disturbances in respiration, dyspnea, gasping, and death.
C-22
-------
O
KJ
CO
TABLE 5
Acute Toxicity of Chloroalkyl Ethers
Compound
Chloromethylmethyl ether,
CMME
Bis(chloromethyl)ether,
BCME
Bis(2-chloroethyl)ether,
BCEE
Bis(2-chloroisopropyl)ether ,
BCIE
2-Chloroethylvinyl ether
LD50=lethal dose for 50% kill
LC50=lethal concentration for
Test Species
Rat
Hamster
Rat
Mouse
Rabbit
Hamster
Rat
Guinea Pig
Rat
Rabbit
Rat
Rabbit
50% kill
Route
Oral
Inhalation
Inhalation
Oral
Inhalation
Inhalation
Skin
Inhalation
Oral
Inhalation
Skin
Inhalation
Oral
Inhalation
Skin
Oral
Inhalation
Skin
Lethal Dose or Concentration
LD50=817 mg/kg
LC5fl=55 ppm for 7 hr
LC5Q=65 ppm for 7 hr
LD5fl=0.21 ml/kg*
LC5fl=7 ppm for 7 hr
LCc«=25 mg/mj for 6 hr***
LD^"=0.28 ml/kg**
LCgQ=7 ppm for 7 hr
LD5fl=75 mg/kg
LC =1000 ppm for 45 min
or 250 ppm for 4 hr
LD 50=300 mg/kg
LCLo=105 ppm for 250 min
LD50=240 mg/kg
LC, =700 ppm for 5 hr
LDj^SOOO mg/kg
LD5fl=250 mg/kg
LC =250 ppm for 4 hr
LD5fl=3200 mg/kg
Reference
NIOSH (1974)
Drew, et al. (1975)
Drew, et al. (1975)
Smyth, et al. (1969)
Drew, et al. (1975)
Leong, et al. (1971)
Smyth, et al. (1969)
Drew, et al. (1975)
Smyth and Carpenter (1948)
Smyth and Carpenter (1948)
Carpenter, et al. (1949)
Smyth and Carpenter (1948)
Schrenk, et al. (1933)
Smyth, et al. (1951)
Gage (1970)
Smyth, et al. (1951)
Smyth, et al. (1949)
Carpenter, et al. (1949)
Smyth, et al. (1949)
LCLo=lowest lethal concentration published
•equivalent to 278 mg/kg
"equivalent to 370 mg/kg
***equivalent to 5.3 ppm
-------
TABLE 6
Acute Toxicity of Chloro-cycloalkyl Ethers
o
1
KJ
*»
Compound
2-Chloromethyltetrahydro-
fucan
Trans-2,3-dichloro-p-
d ioxane
2,3, 5-Tr ichloro-p-d ioxane
(isomer !*)("». p. 41 C)
2,3, 5-Tr ichloro-p-d ioxane
(isomer II*)(m.p. 71 C)
2r,3t,5t,6c-Tetrachloro-
p-dioxane (m.p. 99 C)
2r,3c,5t,6t-Tetrachlorg-
p-dioxane (m.p. 141 C)
Test Species
Mouse
Rat
Rabbit
Rat
Rat
Rat
Rat
Route
i.P-
oral
i.p.
skin
i.p.
i.p.
i.p.
i.p.
Lethal Dose
LDLo=250 ng/kg
LD5fl=1.41 ml/kg
LD50-435 mg/kg
LD50=0.44 ml/kg
LD50=83.2 mg/kg
LD50=146 mg/kg
LD5fl=5.3 mg/kg
LD5Q=424 mg/kg
Reference
NIOSH
Smyth
Woo,
Smyth
Woo,
Woo,
Woo,
Woo,
(1974)
, et al
et al.
, et al
et al.
et al.
et al.
et al.
. (1969)
(1979)
(1969)
(1979)
(1979)
(1979)
(1979)
LD5Q=lethal dose for 50% kill
LD. ^lowest lethal dose published
I.ft
The exact stereochemistry of the isomers has not been determined
-------
The principal gross pathology findings were congestion, emphysema,
edema, and hemorrhage of the lungs.
Gage (1970) exposed rats to eight, 5-hour exposures of 350 ppm
BCIE in air; the toxic sign observed included respiratory diffi-
culty, lethargy, and retarded weight gain. Histological examina-
tion of liver and kidneys revealed signs of congestion. Lethargy
and retarded weight gain were also observed in a group exposed 20
times, six hours each, to 70 ppm of BCIE in air. The highest con-
centration with no toxic signs was 20 ppm.
The National Cancer Institute (NCI) unpublished results of a
recently completed chronic toxicity study of BCIE has been summar-
ized according to the observations of nontumor pathology in Table
7. The most significant change in the mouse appeared to be an in-
creased incidence of centrilobular necrosis of the liver. However,
the effect was inexplicably higher in the low-dose group than in
the high-dose group. In the rat, the major effect of BCIE was on
the lungs, causing congestion, pneumonia, and aspiration.
A detailed study of the inhalational toxicity of BCME and CMME
has recently been carried out by Drew, et al. (1975) with Sprague-
Dawley rats and Syrian golden hamsters as the test species. The
most characteristic acute toxic effect of both compounds was the
irritation of the respiratory tract manifested by congestion,
edema, and hemorrhage (mainly of the lungs) and acute necrotizing
bronchitis. The lung-to-body weight ratios, which were used as an
objective criterion for the evaluation of lung damage, in animals
exposed to CMME were elevated in a dose-related fashion. Multiple
exposures of animals to subacutely toxic concentrations of BCME or
C-25
-------
TABLE 7
Summary of Nontumor Pathology in Mice and Rats After Repeated Oral Doses of DCIE
O
I
to
a\
Animal/Sex
Rats, male
Rats, female
Mice, male
Mice, female
Pathology
Lungs, congestion
pneumonia, aspiration
Liver, centrilobular necrosis
Esophagus, hyperkeratosis
Lungs, congestion
pneumonia, aspiration
Liver, centrilobular necrosis
Esophagus, hyperkeratosis
Adrenal cortex, angiectasis
Lung, hemorrhage
Liver, centrilobular necrosis
Esophagus, inflammation
Liver, centrilobular necrosis
Untreated
Control
2
0
8
0
0
0
0
0
10
0
0
0
0
Vehicle
Control
2
4
10
18
0
2
2
26
4
6
2
0
0
Incidence
100 mg/kg/day (rats)
10 mg/kg/day (mice)
0
14
4
20
2
33
2
20
1
'2
27
2
19
(%)
High Dose
200 mg/kg/day (rats)
25 mg/kg/day (mice)
14
24
22
82
15
46
15
65
27
14
0
5
6
"""source: NCI, unpublished results.
'Animals dosed 5 days/week for total of 728 days
-------
CMME resulted in severe shortening of lifespan and a variety of
regenerative, hyperplastic, and raetaplastic alterations of trachea
and bronchi, which were often histopathologically atypical (such as
nuclear abnormality). Incidences of mucosal changes were generally
increased in a dose-related manner in both species. Similar chang-
es were observed in studies of the long-term effects of single
exposure to BCME or CMME. For animals surviving beyond the median
life span, pathological alterations of respiratory epithelium,
abnormality of alveolar lining cells, and bronchoalveolar squamous
metaplasia were also occasionally noted.
Human Studies: The effect of brief exposures of man to BCEE
vapor was studied by Schrenk, et al. (1933). Concentrations of
greater than 260 ppm were found to be very irritating to the nasal
passages and eyes with profuse lacrimation. Deep inhalations were
nauseating in effect. The highest concentration with no noticeable
sign of irritation was 35 ppm. For comparison, BCME was reported
(Flury and Zernik, 1931, cited in Schrenk, et al. 1933) to be dis-
tinctly irritating at a concentration of 3 ppm. A concentration of
100 ppm would incapacitate a person under chemical warfare condi-
tions in a few seconds, and an exposure of 1 to 2 minutes might
produce a fatal lung injury. A fatal case of accidental, acute
poisoning of a research chemist by BCME has been reported (Thiess,
et al. 1973).
The respiratory effects of chronic exposures of industrial
workers to CMME (contaminated with BCME) have been extensively
investigated by Weiss and coworkers. Symptoms of chronic bronchi-
tis were noted more often among exposed men, and a dose-response
C-27
-------
relationship was apparent with smoking as a cofactor. There was no
demonstrable chemical effect on the ventilatory function, as mea-
sured by the forced vital capacity (FVC) and the 1-second forced
expiratory volume (FEVL), suggesting the absence of abnormality in
the large airways (Weiss and Boucot, 1975). The small airways
were, however, noticeably affected by the chemical exposure. The
end-expiratory flow rate (EEFR) was below 60 percent of the pre-
dicted value in one-third of the exposed men compared to only three
percent of the unexposed men. There was a dose-response relation-
ship between chemical exposure and the frequency of low EEFR
(Weiss, 1977).
Synergism and/or Antagonism
There is very little information available on the synergistic
or antagonistic interaction of chlorc*lkyl ethers with other types
of chemical carcinogens in experimental animals. Promotion of
tumorigenesis after initiation by chloroalkyl ethers has, however,
been extensively studied. In two-stage mouse skin carcinogenesis
studies, the following compounds have been considered as "incom-
plete" carcinogens (i.e., active only as "initiators"): CMME, octa-
chlorodi-n-propyl ether, and oCX-dichloromethyl ether (Van Duuren,
et al. 1969, 1972). Induction of papillomas was also observed
after promotion of the initiation by BCEE, bis( o<-chloroethyl)-
ether, or 2,3-dichlorotetrahydrofuran; whether these compounds are
"complete" carcinogens or not is not known (Van Duuren, et al.
1972). Chloroalkyl ethers capable of inducing papillomas or car-
cinomas on mouse skin without promotion include BCME (Van Duuren,
et al. 1969) and 2,3-trans-dichloro-p-dioxane (Van Duuren, et al.
C-28
-------
1974); the carcinogenic activity of these compounds can be substan-
tially enhanced by promoters (Van Duuren, 1969; Van Duuren, et al.
1969, 1974; Slaga, et al. 1973). The details of these carcinogen-
icity data will be presented in the Carcinogenicity section. The
promoters used included croton oil, croton resin, or the pure phor-
bol myristate acetate. The tumor-promoting activity of several
chloroalkyl ethers has been tested using benzo(a)pyrene as the ini-
tiator. BCME was found to decrease the latent period for induction
of benign and malignant tumors but did not affect the tumor yield
(Van Duuren, et al. 1968, 1969). CMME and octachlorodi-n-propyl
ether were marginally active as promoters (Van Duuren, et al.
1969).
The ability of chloro derivatives of p-dioxane to modify
microsomal drug-metabolizing enzyme activity has been studied by
Woo, et al. (1979). Of the compounds tested (listed in Table 6),
only 2r,3c,5t,6t-tetrachloro-p-dioxane was found to have a signifi-
cant effect. The activities of microsomal aryl hydrocarbon hy-
droxylase and dimethylnitrosamine-demethylase were decreased by 44
percent and 61 percent, respectively.
Cigarette smoking has been found to act synergistically with
CMME to produce chronic bronchitis and small airway disorders among
exposed industrial workers (Weiss and Boucot, 1975; Weiss, 1976,
1977). In sharp contrast, however, there was an unexpected inverse
relationship between smoking and the induction of lung cancer by
CMME (Weiss and Boucot, 1975; Weiss, 1976). The reason for this
apparent antagonism is not known. Self-selection by the workers
has been suggested as a possible factor. Heavy cigarette smokers
C-29
-------
might have tended to avoid heavy chemical exposure because chronic
cough was directly related to both CMME exposure and cigarette
smoking, and simultaneous exposure might produce a greater effect
than either one alone. However, no data on smoking habit changes
were available to verify the self-selection hypothesis. Another
possible factor was the protective action of bronchorrhea associat-
ed with chronic bronchitis. The excessive discharge from bronchial
mucous membrane may protect against the carcinogenic effect of CMME
or its contaminant BCME by reducing the residence time of these
chemicals because of their instability in aqueous systems. Final-
ly, it is conceivable that some component of cigarette smoke may
neutralize the carcinogenicity of CMME. It is not known whether
the apparent antagonism observed by Weiss may be a general phenome-
non. In reviewing the case reports of four different groups of
workers, Lemen, et al. (1976) expressed the view that smoking may
provide a promotional or synergistic effect on the induction of
lung cancer by BCME.
Teratogenicity
The teratogenicity of the chloroalkyl ethers covered in this
document has not been studied. It is relevant to note, however,
that there is some epidemiological evidence that anesthetic gases
(including methoxyflurane) may lead to congenital abnormalities.
Although the evidence has been considered less than unequivocal,
there is little doubt that these gases are teratogenic in experi-
mental animals when administered in relatively high doses (Smith,
1974; Corbett, 1976; Ferstandig, 1978). A detailed discussion of
this subject is beyond the scope of this document. However, in
C-30
-------
view of the fact hat methoxyflurane can actually be classified as
a chloroalkyl ether, the teratogenicity of other chloroalkyl ethers
(especially the environmentally important and stable BCEE and BCIE)
should be critically studied.
Cl F H
I 1 I
H-C—C-O-C-H
Cl F H
methoxyflurane
Mutagenicity
The mutagenicity of chloroalkyl ethers has been investigated
in bacterial, eukaryotic, and mammalian systems. Table 8 compares
the carcinogenicity data to the mutagenicity data in microbial sys-
tems for a variety of chloroalkyl ethers. With a few exceptions,
there is a relatively good correlation between mutagenicity and
carcinogenicity. For most of these studies, E. coli and S_. typhi-
murium were used as the test organisms, and the test was designed
for direct-acting mutagens that do not require metabolic activa-
tion.
There are some disagreements regarding the mutagenicity of
BCEE. Shirasu, et al. (1975) have found BCEE to be a direct-act-
ing, base-change mutagen using different tester strains of E. coli,
£3. typhimurium, and B. subtilis. It was also reported by
Fishbein (1977) that BCEE, when tested in a desiccator containing
the vapor, was mutagenic to S_. typhimurium strains TA 1535 and TA
100 and weakly mutagenic to strains TA 1538, TA 98, and E. coli WP2.
In suspension assays, BCEE also proved to be mutagenic toward
strain TA 1535. BCEE was not mutagenic in host-mediated assays
C-31
-------
TABLE 8
Comparison of Carcinogenic and Mutagenic (in Microbial
A System) Activity of Chloroalkyl Ethers
Compound
Mutagenicity
Carcinogenicity
CMME
BCME
BCIE
o^X-Dichloromethylmethyl ether
Bis(*K-chloroethyl)ether
BCEE
Octachloro-di-n-propyl ether
2,3-Dichlorotetrahydrofuran
2,3-trans-Dichloro-p-dioxane
b
-,+
not tested
not tested
a,
.The mutagenicity data were mainly reported by Nelson, 1976.
Positive mutagenic activity of BCEE was observed by Shirasu, et
al. 1975, and the mutagenicity of BCEE and BCIE were reported in
Fishbein, 1977.
C-32
-------
when given as a single oral dose or when administered for two weeks
prior to the injection of S_. typhimurium into the peritoneal cavi-
ty.
In eukaryotic and nonmammalian systems, BCEE was reported to
be mutagenic to Saccharomyces cerevisiae D3 in suspension assay
(Fishbein, 1977). BCEE has been quoted as mutagenic to Drosophila
melanogaster (Fishbein, 1976, 1977); however, a careful examination
of the original publication of Auerbach, et al. (1947) failed to
confirm the quotation. It was bis-(2-chloroethylmercaptoethyl)
ether (not BCEE) that was mutagenic.
The mutagenic potential of BCEE and BCIE in mice has been
studied by Jorgenson, et al. (1977) using the heritable transloca-
tion test. Adult male mice were treated by gavage daily for three
weeks with three dose levels of BCEE or BCIE. They were then mated
to virgin females to produce an F^ generation. The FX males were
bred twice and examined cytogenetically. Preliminary evaluation of
the breeding and cytogenetic data suggests that BCEE and BCIE were
not mutagenic; no heritable translocations were observed.
The genetic risks of occupational exposures to CMME and BCME
have been evaluated by Zudova and Landa (1977). Cytogenetic analy-
sis of peripheral lymphocytes was performed. Scoring 200 cells per
person, the authors detected 6.7 percent of aberrant cells in ex-
posed workers while the corresponding value in the controls reached
only 2 percent. The frequency of aberrant cells in exposed workers
decreased toward the control value after the removal of exposure.
It was proposed that cytogenetic analysis of peripheral lymphocytes
C-33
-------
should become a part of a routine medical check-up of workers at
risk.
Carc i nogen ic i ty
Animal Studies: Van Duuren, et al. (1968) were the first to
demonstrate the carcinogenicity of chloroalkyl ethers. Application
of 2 mg BCME three times a week for 325 days led to the induction
of papillomas in 13/20 mice, 12 of which developed to squamous cell
carcinomas. A comparison with a number of other carcinogenic
alkylating agents (Table 9) indicated that BCME was, for the mouse
skin, more potent than the ^-lactones and epoxides listed in
terms of tumor yield, dose, and latency. In contrast, CMME was
found to be inactive as a complete carcinogen by skin application.
In an effort to delineate the structure-activity relationships
of chloroalkyl ethers, Van Duuren and coworkers have extended their
cutaneous carcinogenicity studies to a variety of compounds. The
test procedures used included s.c. injection in mice, repeated di-
rect application to mouse skin, and tests in mice by the initiation-
promotion procedure involving a single application of the test com-
pound followed by repeated applications of phorbol myristate ace-
tate. Table 10 summarizes the results of this extensive series of
studies. By skin application, BCME, trans-2,3-dichloro-p-dioxane,
bis-1,2-(chloromethoxy)ethane, and tris-1,2,3-(chloromethoxy) pro-
pane were found to be active as complete carcinogens. Most of
the other compounds tested were active as initiators. From these
studies, three salient features of structure-activity relation-
ships were observed. (1) The bifunctional o^-chloroalkyl ethers
(e.g., BCME) are more active than their monofunctional analogs
C-34
-------
TABLE 9
Comparison of Carcinogenic Potency
of Alkylating Agents on Mouse Skin3
Compound
BCME
Dose
(mg)
2.0
Days
to 1st
tumor
161
Mice with
carcinoma/ no.
of mice tested
12/20°
Median
survival
time (days)
313
^-Butyrolactone 10
252
15/30'
438
^-Propiolactone 2.5
9/30(
200
Glycidaldehyde
3.0
212
8/30*
496
D,L-l,2:3,4-Di-
epoxybutane
3.0
326
6/30(
475
^Source: Van Duuren, et al. 1968
Administered 3 times/week in 0.1 ml solvent; the solvents used
were benzene for the first 4 compounds and acetone for the last
compound, diepoxybutane.
^Female Swiss ICR/Ha mice
Male Swiss mice
C-35
-------
TABLE 10
O
I
U)
Carcinogenicity of Chloroalkyl Ethers by Skin Application or B.C. Injection*
Compound
CMME
BCME
c<,o<-Dichloromethylmethyl ether
Bis(
-------
(e.g., CMME). (2) The carcinogenic activity of chloroalkyl ether
decreases as chlorine moves further away from the ether oxygen.
Thus, ^-chloroalkyl ethers (e.g., BCEE) are substantially less
active than their «<-chloro isomers or analogs (e.g., bis(°*-
chloroethyl)ether). (3) The carcinogenic activity decreases as the
alkyl chain length increases. For example, if one considers BCME,
bis-1,2-(chloromethoxy)ethane, bis-1,4-(chloromethoxy)butane, and
bis-1,6-(chloromethoxy)hexane as a homologous series of di-e<-
chloro ethers of increasing length, it is clear that in general, the
longer the chain length, the lower the carcinogenicity.
The carcinogenicity of BCME and CMME in newborn ICR Swiss ran-
dom bred mice has been tested by Gargus, et al. (1969) by s.c.
injection. A single dose of 12.5 jul BCME/kg body weight was found
to increase the pulmonary tumor incidence after six months. In 50
males and 50 females injected with BCME, pulmonary tumors developed
in 45 percent of the animals, with a multiplicity of 0.64 tumors
per mouse. In addition, one mouse developed an injection site
papilloma and another a fibrosarcoma; such tumors were not seen in
control animals. In the vehicle (peanut oil) controls, the pul-
monary tumor incidence was 14 percent with a multiplicity of 0.14.
Mice receiving CMME (125 jil/kg) had an incidence of 17 percent with
a multiplicity of 0.21; these values were slightly higher but not
significantly different from the controls. It is of particular
interest to point out the high carcinogenic potency of BCME in this
study. A single, very small dose of 12.5 ul (equivalent to 0.017
nig/kg) was sufficient to induce pulmonary adenomas within six
months. Furthermore, this study indicated that, despite its short
C-37
-------
lifetime in an aqueous system, the biological effects of BCME were
not confined to the site of injection. On the other hand, using
rats, s.c. injection of BCME produced no increase in the incidence
of tumors remote from the injection site (Van Duuren, et al. 1969).
The tumor initiating ability of BCME and CMME has also been
studied by Slaga, et al. (1973) using female Charles River GDI
mice. A single dose of 9 jumoles (1.03 mg) BCME was sufficient to
induce papillomas within 15 weeks after promotion by croton oil.
CMME, up to a dose of 25 umoles (2.0 mg), was found to be a very
weak or inactive initiating agent.
The high vapor pressure of CMME (b.p. 59°C) and BCME (b.p.
104°C) at ambient temperatures and their extensive industrial uses
have prompted investigators to examine the inhalational carcinogen-
icity of these compounds. Leong, et al. (1971) were the first to
test the inhalational carcinogenicity of BCME and CMME in mice.
Strain A/Heston male mice, which are known to be highly responsive
to pulmonary tumor induction with a spontaneous incidence of about
40 percent were used in this study. The animals were exposed six
hours/day, five days/week to filtered room air (negative control),
aerosols of urethane (positive control), or vapors of BCME or CMME
for up to a maximum of six months. The CMME used contained 0.3 to
2.6 percent BCME as an impurity. The animals were sacrificed at
the end of the six-month period (Table 11 summarizes the results).
Mice in the BCME exposed group had a 34 percent increase in the
incidence of lung tumors and a 3.3-fold enhancement in the average
number of tumors/animal/treatment group. The corresponding figures
in the CMME exposed group were 21 percent and 1.75-fold. It was
C-38
-------
TABLE 11
Pulmonary Tumors in Strain A/Heston Mice Following
Inhalation Exposures to BCME, CMME and Urethane*
Cone.
Compound (ppm)
Control
o
i
Exposure
duration
(days)
130
Incidence of lung
tumor (no. tumor-
bearing animals/
no. examined)
20/49 (41%)
Average number of
tumors/animal/treatment
group
0.87
138
130
46/49 (94%)
BCME
82
26/47 (55%)
2.89
CMME
101
25/50 (50%)
1.53
*Source: Leong, et al. 1971
-------
concluded that BCME was a potent inhalational carcinogen. CMME was
also, for practical purposes, carcinogenic although it was not cer-
tain whether the effect was exerted by CMME itself or its contami-
nant, BCME.
An extensive series of inhalational carcinogenicity studies of
BCME and CMME in rat and hamster has been carried out by Laskin, et
al. (1971, 1975), Drew, et al. (1975), and Kuschner, et al. (1975).
Table 12 summarizes the results of their findings. BCME was found
to be an extremely potent respiratory carcinogen in the rat. Lim-
ited exposures (no more than 100 daily exposures of six hours each)
of 200 rats to 0.1 ppm BCME led to the induction of respiratory can-
cers in 40 animals. The type of tumors induced and the time re-
quired for the induction are summarized in Table 13. Twenty-six
rats had tumors of the nose with esthesioneuroepithelioma as the
major histological type. Fourteen rats had tumors of the lung, 13
of them squamous cell carcinomas. The carcinogenic effect of BCME
was clearly dependent on the number of exposures (see Table 14)
showing an excellent dose-response. The exposure-response curve
(probit vs. log dose) showed a sigmoid type of relationship, and a
linear relationship was obtained by plotting log probit vs. log
dose. The number of exposures at 0.1 ppm required to induce tumors
in 50 percent of the rats was calculated to be 88. In experiments
designed for subacute toxicity study, exposure of rats to 1 ppm
BCME for three days (6 hours/day) led to the induction of squa-
mous cell carcinoma of skin in 1 of the 50 animals. Syrian golden
hamsters appeared to be very resistant to carcinogenesis by BCME.
Lifetime exposure of hamsters to 0.1 ppm BCME resulted in only one
C-40
-------
TABLE 12
Inhalational Carcinogenic!ty of BCME and CMME in Rats and Hamsters
Species &
Compound strain
BCME Sprague-
Dawley
male rats
Syrian
O golden
I male
*| hamsters
CMME Sprague-
Dawley
male rats
Syrian
golden
male
hamsters
ute auction animals with turaors< type period (days) Reference
0.1 10 to 100 exposures 200 26 nasal tumorsb 253-852
14 lung tumors 215-877
1.0 3 exposures 50 1 squamous cell 570
carcinoma of skin
0.1 lifetime exposure 100 1 undif ferentiated 501
carcinoma of lung
1.0 1 exposure 50 1 undif ferentiated 1000
malignant tumor
of the nose
1.0 3 exposures 50 1 esthesioneuro- 756
epithelioma of nose
1.0 lifetime exposure 74 1 squamous cell 700
carcinoma of lung
1 esthesioneuroepi- 790
thelioma of
olfactory epithelium
1.0 lifetime exposure 90 1 adenocarcinoma 134
of lung
1 squamous papilloma 683
of trachea
Kuschner, et al. (1975)
Drew, et al. (1975)
Kuschner, et al. (1975)
Drew, et al. (1975)
Drew, et al. (1975)
Laskin, et al. (1975)
Laskin, et al. (1975)
Animals were exposed 6 hr/day, 5 days/week for the number of exposures indicated; they were then kept for lifetime.
See Table 13 for detail.
-------
TABLE 13
Cancers and Induction Times Seen in 200 Rats Following
Limited Exposures to 0.1 ppm BCME*
n
i
Origin and type of cancer
Nose
Esthesioneuroepithelioma
Malignant olfactory tumor (unclassified)
Ganglioneuroepithelioma
Squamous cell carcinoma involving
turbinates and gingiva
Poorly differentiated epithelial tumors
Adenocarcinoma (nasal cavity)
Lung
Squamous cell carcinoma
Adenocarcinoma
Total no.
of cancers
17
1
1
1
4
2
13
1
Mean latent
period (days)
447
405
334
594
462
696
411
877
Range,
days
266-853
405
334
594
253-676
652-739
215-578
877
*Source: Kuschner, et al. 1975
-------
TABLE 14
Incidence of Tumors of Respiratory Tract in Rats
Following Limited Exposures to 0.1 ppm BCME*
Cancer incidence
(no. of tumor-bearing
No. of animals/no, of
exposures animals observed3)
100 12/20 (60.0%)
80 15/34 (44.1%)
60 4/18 (22.2%)
40 4/18 (22.2%)
20 3/46 (6.5%)
10 1/41 (2.4%)
*Source: Kuschner, et al. 1975
Animals surviving beyond 210 days
C-43
-------
undif ferentiated carcinoma of the lung in 1 of the 100 animals,
whereas limited exposures(one or three exposures) brought about one
tumor of the nose in one of each of the two groups of 50 animals.
The inhalational carcinogenic!ty of commercial grade CMME,
which is usually contaminated with 1 to 7 percent BCME, has also
been tested in rats and hamsters. Lifetime exposure to 1 ppm CMME
led to the induction of one pulmonary and one nasal tumor in 74
exposed rats or two respiratory tumors in 90 exposed hamsters.
Thus, in practical terms, commercial grade CMME must be considered
as a respiratory carcinogen, although of a lower order of activity
than BCME.
The carcinogenicity of BCEE by oral administration has been
evaluated by Innes, et al. (1969); more recently, in view of its
frequent occurrence in finished drinking water, further evaluations
have been undertaken by Theiss, et al. (1977) and in the National
Cancer Institute (Ulland, et al. 1973; Weisburger, personal commu-
nication). The major findings of these studies are summarized in
Table 15. Two strains of mice of both sexes were used by Innes, et
al. (1969). They received 100 mg/kg/day of BCEE for 80 weeks,
first by intubation for three weeks followed by ingestion of food
containing 300 ppm BCEE (estimated to be equivalent to daily intake
of 100 mg/kg). The most significant finding was a substantially
increased incidence of hepatoma, especially in male mice. The
incidence of hepatomas in male and female controls of the strains
were 8/79 and 0/87 in (C57BL/6X CSH/Anf^ mice and 5/90 and 1/82
in (C57BL/6XAKR)F, mice. The incidence of hepatomas in male treat-
ed mice was significantly different from that in controls at the
C-44
-------
TABLE 15
Carcinogenicity of BCEE in Mice and Rats by Oral or i.p. Administration
Species & strain
Treatment
Carcinogenic response8
Reference
O
•u
01
7-day-old
(C57BL/6XC3H/Anf)F,
mice
7-day-old
(C57BL/6XAKR)Fj
mice
6-8 weeks old,
male
Strain A/St
mice
Charles River CD
rats
oral, 100 mg/kg/day for 80 weeks
(BCEE given by intubation for the
first 21 days followed by 300 ppro
in diet), mice sacrificed at the
end of treatment
oral, 100 mg/kg/day for 80 weeks
(BCEE given by intubation for the
first 21 days followed by 300 ppm
in diet), mice sacrificed at the
end of treatment
i.p., 3x/week to a maximum of
24 injections} 3 dose levels:
4 x 40 mg/kg, 24 x 20 rag/kg,
24 x 8 mg/kgj mice sacrificed 24
weeks after the first injection
oral, 50 mg/kg/day or
25 mg/kg/day, 5 days/week
for two years
Male; 14/16 hepatoma(p 0.01)
2/16 Lymphoma
Female: 4/18 hepatoma
Male: 9/17 hepato»a(p 0.01)
2/17 pulmonary tumor
Female: 1/17 lymphoma
Pulmonary tumor response
not significantly different
from that of the control
animals
Preliminary analyses suggest
no significant increase in
the development of tumors
Innes, et al. (1969)
Innes, et al. (1969)
Theiss, et al. (1977)
Ulland, et al. (1973)
Weisburger (personal
communication)
No. of tumor-bearing animals/no, of animals observed at the end of experiment.
-------
p = 0.01 level. In contrast to the above study, Theiss, et al.
(1977), using strain A mice (which have a high spontaneous pulmon-
ary tumor incidence), were unable to detect any enhancement of pul-
monary tumor incidence after repeated i.p. injections of BCEE. The
average number of lung tumors/mouse was actually smaller in the
treated group (0.11 to 0.15) than that in the tricaprylin vehicle
controls (0.39). In the study by the National Cancer Institute on
the oral carcinogenicity of BCEE, Charles River CD rats of both
sexes were used. Although detailed statistical analyses have not
yet been completed, preliminary analyses suggest that BCEE did not
cause any significant increase in the tumor incidence in the rat
(Ulland, et al. 1973; Weisburger, personal communication).
The oral carcinogenicity of BCIE, another compound detected in
the finished drinking water, has also been recently evaluated by
the National Cancer Institute (NCI, unpublished). Mice of both
sexes were intubated with BCIE at doses of 10 mg or 25 mg/kg/day,
five days a week, for two years. Rats were similarly treated at
doses of 100 or 200 mg/kg/day. The results of this study are sum-
marized in Tables 16 and 17. Although these data have not yet been
fully analyzed, they suggest that no marked increase in tumor in-
cidence is induced by BCIE exposure.
The carcinogenicity of BCME and a number of other chloroalkyl
ethers in mice by i.p. administration has been studied by Van
Duuren, et al. (1974, 1975). The results are summarized in Table
18. In general, these compounds led to the induction of local
tumors. However, papillary tumors of the lung were observed in 12
of the 30 animals treated with 2,3-trans-dichloro-p-dioxane.
C-46
-------
TABLE 16
Summary of Total Tumor Incidence in Rats After Repeated Oral Doses of BCIE*
o
i
Untreated
Control
RATS, MALE:
Animals Initially in Study
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors**
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors
Total animals with secondary tumors
Total secondary tumors
Total animals with tumors uncertain-
benign or malignant
Total uncertain tumors
RATS, FEMALE:
Animals Initially in Study
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors**
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors
Total animals with secondary tumors
Total secondary tumors
50
50
50
50
102
47
67
29
35
1
1
50
50
49
36
59
29
43
14
16
3
4
Vehicle
Control
50
50
50
45
84
43
56
22
27
1
1
50
50
50
39
62
31
47
13
15
1
1
Low Dose
100 mg/kg/day
50
50
50
47
82
46
63
17
18
4
6
1
1
50
49
49
32
51
28
39
12
12
1
1
High Dose
200 mg/kg/day
50
50
50
34
48
30
38
8
8
1
1
2
2
50
48
48
15
22
11
15
7
7
1
1
*Source: NCI, unpublished.
**Primary Tumors: All tumors except secondary tumors.
Secondary Tumors: Metastatic tumors or tumors invading into an adjacent organ.
-------
o
I
*»
00
TABLE 17
Summary of Total Tumor Incidence in Mice After Repeated Oral Doses of BCIE*
Untreated
Control
MICE, MALE:
Animals Initially in Study
Animals Missing
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors**
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors +
Total animals with secondary tumors
Total secondary tumors
MICE, FEMALE:
Animals Initially in Study
Animals Missing
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors**
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors
50
50
50
13
13
3
3
10
10
50
50
50
6
6
1
1
5
5
Vehicle
Control
50
50
50
11
11
4
4
7
7
1
1
50
1
49
49
5
5
2
2
3
3
Low Dose
10 mg/kg/day
50
50
50
10
10
2
2
8
8
50
49
48
4
4
1
1
3
3
High Dose
25 mg/kg/day
50
1
49
49
12
12
3
3
9
50
r f\
50
50
4
4
2
2
2
* Source: NCI, unpublished.
**Primary Tumors: All tumors except secondary tumors.
+ Secondary Tumors: Metastatic tumors or tumors invading into an adjacent organ.
-------
TABLE 18
Carcinogenicity of Chloroalkyl Ethers in Mice3 by i.p. Administration*
Compound
Dose regime
and duration
Carcinogenic response
Median survival
time (days)
o
**
IO
BCME
2,3-trans-Dichloro-
p-dioxane
l,2-Bis-(chloro-
methoxy)ethane
l,4-Bis-(chloro-
methoxy)butane
1,6-Bis(chloro-
methoxy)hexane
l,2,3-Tris-(chloro-
methoxy)propane
0.02 mg, once/week
for 424 days
0.5 mg, once/week
for 450 days
0.3 mg, once/week
for 546 days
0.1 mg, once/week
for 567 days
0.3 mg, once/week
for 567 days
0.3 mg, once/week
for 532 days
4/30 local sarcoma 287
12/30 papillary tumor of lung
1/30 local undifferentiated
malignant tumor
2/30 local sarcoma 481
2/30 undifferentiated malignant
tumor at injection site
no tumor response 473
no tumor response 472
5/30 local sarcoma 428
*Source: Van Duuren, et al. (1974, 1975)
f*The mice were 6-8 weeks old ICR/Ha Swiss female mice.
No. of tumor-bearing animals/no, of animals tested.
-------
Human Data: There is now sufficient epidemiological evidence
to indicate unequivocally that BCME and, for practical purposes,
CMME are human respiratory carcinogens. Including other important
research, a total of at least 47 cases of respiratory cancer deaths
in association with occupational exposure to these compounds has
been observed (Nelson, 1976). A German report (Bettendorf, 1976)
has placed the total figure at a minimum of 60 cases. Table 19
summarizes the published case reports of respiratory cancer deaths
among exposed workers. These cases were observed in the United
States, Germany, and Japan among exposed workers in the chemical
manufacturing plants and laboratories. It is important to point
out the relatively short latency for the induction of respiratory
cancers by these chemicals. The latency period may be as short as
eight years. Short durations of exposures may be sufficient to
initiate carcinogenesis. Respiratory cancers occurred among cigar-
ette smokers, cigar or pipe smokers, and ex-smokers as well as non-
smokers. The average age of cancer death was around 42. The pre-
dominant histologic type of cancer was small-cell-undifferentiated
carcimona. The calculated increased risk factors of cancer due to
chemical exposure are summarized in Table 20.
The five cases of lung cancer reported in Japan (Sakabe, 1973)
occurred among 32 employees exposed to BCME and many other noxious
chemicals in a dyestuff factory. Four of the workers exposed were
involved in the synthesis of dyestuffs; the fifth case was exposed
only in the laboratory. This represents a very high increased lung
cancer risk.
C-50
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en
I-1
Sakabe
(1973)
Thiess, et
al. (1973)
Pigueroa,
et al.
(1973)
Weiss and
Figueroa
(1976)
Kelton
(1976)
Bettendorf
(1976)
Reznik, et
al. (1977)
TABLE 19
^"^^.-P.-o., C.no,,s ^ng Bork8[5 E,_d ^ ^ and/ot ^
14
n
20
3i-
c a
6"9
8-16
33-55 1-14
3fi_q«; 011
5 2-a-
33-66 0.
10-24
42
12-13
Chemical plant
(Germany)
Chemical plant
(Philadelphia)
Chemical plant
(Philadelphia)
Chemical plant
(Philadelphia
Anion-exchange
resin plant
(California)
Research chemist
(Germany)
Research chemist
(Germany)
All moderate
to heavy
smokers
6 moderate
to heavy
smokers
2 unknown
3 nonsmokers
1 pipe smoker
10 smokers
3 nonsmokers
1 cigar smoker
2 ex-smokers
5 smokers
4 smokers
1 unknown
nonsraoker
1 oat cell
1 adenocar-
carcinoma
3 unspecified
5 small cell-
undiffer-
entiated
3 unspecified
12 small cell-
undiffer-
entiated or
oat cell
1 epidermal
1 unknown
10 small cell-
undiffer-
entiated
1 oat cell
4 small cell-
undiffer-
entiated
1 large cell-
undiffer-
entiated
adenocarcinoma
adenocarcinoma
-------
TABLE 20
O
I
ui
to
Increased Risk
No. of population
cases at risk
Sakabe (1973)
Figueroa, et al. (1973)
prospective study
Lemen, et al. (1976)
*
Albert, et al. (1975J
total of 6 U.S. firms
heavy exposure foe
more than 5 yrs.
heavy exposure for
1-5 yrs.
heavy exposure for
less than 1 yc-
DeFonso and Kelton
(1976)
'age-adjusted rate
19
699
0.001
4
^1
5
22
A*
3
12
4
88
136
1800
12
91
188
4.54/100/5 yes
5/136/18 yis
l.48/1000/yr
23/1000/yr.
8.7/1000/yr.
1.5/1000/yr.
0.57/100/5 yrs.
0.54/136/18 yrs.
0.59/1000/yr.
0.97/1000/yr.
0.97/1000/yr.
0.97/1000/yr.
7.96
9O 4
. **
2.53
Ol *J
/3» 1
8.97
1.56
0.0017
0.01
0.01
-------
o£ CMME in the U.S. has been carried out by
Albert, et al. (1975) and Pasternack, et al. (1977). The cohort
chosen included 1,827 exposed workers and 8,870 controls. The age-
adjusted respiratory cancer death rate for the exposed group as a
whole was found to be 2.53 times that in the control group, whereas
death rates due to other causes were comparable. Most of the CMME-
related deaths were associated with one of the six industrial firms
in which heavy exposures occurred. Among workers who were reported
to be heavily exposed for more than five years, a 23.7-fold in-
crease in the respiratory cancer risk was observed (Albert, et al.
1975). The increased risk was clearly dependent on the duration
and intensity of exposure. Based on job description, personnel
records, and information supplied by the supervisory personnel,
Pasternack, et al. (1977) estimated the duration (years) and cumu-
lative weighted exposure index (duration of exposure X intensity)
of workers and compared with their relative respiratory cancer
risk. As shown in Table 21, there was a clear dose-response rela-
tionship. The linear trend % tests gave a highly significant
C-54
-------
with u
In the United States, two of the best-known groups of
occurred in an anion-exchange resin plant in California and a chem-
ical manufacturing plant in Philadelphia. In the anion-exchange
resin plant, five cases occurred among 136 manufacturing employees.
Only 0.54 cases were expected among them if they were not exposed;
thus, a 9.24-fold increase in the respiratory cancer risk was ob-
served. The average age of cancer death was 47, and the mean induc-
tion time was 15 years (Lemen, et al. 1976). Heavy exposures to
CMME, contaminated with BCME, occurred among workers in the
Philadelphia chemical plant. In 1962, the management became aware
that an excessive number of workers who were suspected of having
lung cancers were reported in one area of the plant where CMME was
used. Extensive prospective and retrospective studies have since
been carried out independently by several groups of investigators
(Figueroa, et al. 1973; Weiss and Figueroa, 1976; Weiss and Boucot,
1975; Weiss, 1976; DeFonso and Kelton, 1976). The latest figure
C-53
-------
Thiess, et al. (1973) reported eight cases of respiratory can-
cer deaths in a chemical plant in Germany, six of the cases occur-
red among 18 experimental technical department workers, a group
known to experience very high exposures. In contrast, among the
manufacturing workers, only two cases were observed among 50.
Heavy exposures to BCME and CMME have been attributed as the cause
of induction of lung adenocarcinomas in two research chemists in
Germany (Bettendorf, 1976; Reznik, et al. 1977). One of the chem-
ists was exposed for only two years; this individual was not in-
volved with other known pulmonary carcinogens, although his contact
with unspecified agents cannot be excluded (Reznik, et al. 1977).
In the United States, two of the best-known groups of cases
occurred in an anion-exchange resin plant in California and a chem-
ical manufacturing plant in Philadelphia. In the anion-exchange
resin plant, five cases occurred among 136 manufacturing employees.
Only 0.54 cases were expected among them if they were not exposed;
thus, a 9.24-fold increase in the respiratory cancer risk was ob-
served. The average age of cancer death was 47, and the mean induc-
tion time was 15 years (Lemen, et al. 1976). Heavy exposures to
CMME, contaminated with BCME, occurred among workers in the
Philadelphia chemical plant. In 1962, the management became aware
that an excessive number of workers who were suspected of having
lung cancers were reported in one area of the plant where CMME was
used. Extensive prospective and retrospective studies have since
been carried out independently by several groups of investigators
(Figueroa, et al. 1973; Weiss and Figueroa, 1976; Weiss and Boucot,
1975; Weiss, 1976; DeFonso and Kelton, 1976). The latest figure
C-53
-------
shows that a total of 20 cases of respiratory cancer deaths had
occurred (DeFonso and Kelton, 1976). In one of the prospective
studies including 88 exposed workers, an increased risk of 7.96 was
observed (Figueroa, et al. 1973). A more recent analysis on an
age-specific basis revealed an increased risk of lung cancer 3.8
times higher in 669 exposed compared to 1,616 unexposed workers
(DeFonso and Kelton, 1976).
An extensive retrospective cohort mortality study of the res-
piratory cancer death among employees of six of the seven major
users and producers of CMME in the U.S. has been carried out by
Albert, et al. (1975) and Pasternack, et al. (1977). The cohort
chosen included 1,827 exposed workers and 8,870 controls. The age-
adjusted respiratory cancer death rate for the exposed group as a
whole was found to be 2.53 times that in the control group, whereas
death rates due to other causes were comparable. Most of the CMME-
related deaths were associated with one of the six industrial firms
in which heavy exposures occurred. Among workers who were reported
to be heavily exposed for more than five years, a 23.7-fold in-
crease in the respiratory cancer risk was observed (Albert, et al.
1975). The increased risk was clearly dependent on the duration
and intensity of exposure. Based on job description, personnel
records, and information supplied by the supervisory personnel,
Pasternack, et al. (1977) estimated the duration (years) and cumu-
lative weighted exposure index (duration of exposure X intensity)
of workers and compared with their relative respiratory cancer
risk. As shown in Table 21, there was a clear dose-response rela-
tionship. The linear trend X2 tests gave a highly significant
C-54
-------
TABLE 21
Relationship of Respiratory Cancer Mortality to Duration
and Intensity of Exposure to BCME and/or CMME*
Duration of
Exposure
(years)
10-19
5-9.9
2-4.9
0.1-1.9
Control
Cumulative
Weighted
Exposure
Index**
20-50
10-19.9
5-9.9
0.1-4.9
Control
Observed
Deaths
3
7
10
3
18
Observed
Deaths
8
8
4
3
18
Expected
Deaths
0.2
1.9
2.8
6.7
29.4
Expected
Deaths
0.9
2.4
1.6
0.7
29.4
Relative
Risk
26.6
6.0
5.7
0.7
1.0
Relative
Risk
14.5
5.4
4.2
0.7
1.0
Man-year-
at-risk
97
1,024
1,981
5,591
21,909
Man-year-
at-risk
482
1,398
1,176
5,637
21,909
* Source: Pasternack, et al. (1977)
**CWEI = Duration of Exposure x Intensity (varying across ex-
posure periods)
C-55
-------
p-value of less than 0.00001. Similar dose-response relationships
were reported by DePonso and Kelton (1976), and Weiss and Pigueroa
(1976). Thus, there is no doubt that BCME and CMME are potent human
respiratory carcinogens.
C-56
-------
CRITERION FORMULATION
Existing Guidelines and Standards
Both BCME and CMME have been recognized as human carcinogens;
all contact with them should be avoided. In 1973, these two chlo-
roalkyl ethers were listed as 2 of the 14 carcinogens restricted by
Federal regulation. Emergency temporary standards were established
for limiting occupational exposure. These regulations applied to
all preparations containing 1 percent (w/w) or more of the chloro-
alkyl ethers. The use, storage, or handling of these chemicals
must be limited to a "controlled area" in which elaborate precau-
tions were specified to minimize worker exposure. Decontamination,
waste disposal, monitoring, and medical surveillance programs were
also required (38 FR 10929). More detailed regulations have re-
cently been established; they apply to all preparations containing
0.1 percent of the chloroalkyl ethers by volume or weight (39 FR
3756; Anonymous, 1974). Based on the known carcinogenicity of BCME
in animal inhibition studies, the American Conference of Governmen-
tal and Industrial Hygienists (ACGIH, 1978) has recommended a
threshold limit value (TLV) of 1 ppb (4.71 ug/m3) for BCME. This
value is for the time-weighted average (TWA) concentration for a
normal 8-hour workday or 40-hour workweek, to which nearly all
workers may be repeatedly exposed, day after day, without adverse
effect.
The Federal standard for BCEE is 15 ppm (90 mg/m3) (Tabershaw,
et al. 1977). The ACGIH has recommended a time-weighted-average
threshold limit value (TLV-TWA) of 5 ppm (30 mg/m3) for BCEE. For a
short-term exposure limit, the tentative value (TLV-STEL) suggested
C-57
-------
is 10 ppm (60 rag/m ). These values are based on the irritant prop-
erties of the chemical to the eye and the respiratory tract. It is
also recommended that appropriate measures should be taken for the
prevention of cutaneous absorption (ACGIH, 1978). The guideline
level adopted by the Philadelphia regional office of U.S. EPA for
BCEE level permitted in Philadelphia's drinking water is 0.02 jag/1.
This value is based on an evaluation of the available toxicological
data for BCEE by the National Environmental Research Center; a
safety factor of 500,000 has been applied in the calculation
(Manwaring, et al. 1977).
The TLVs for the other chloroalkyl ethers are not available.
The provisional operational limit suggested for BCIE was 15 ppm
(Gage, 1970). The value was based on the irritant properties of
the compound to the eye and respiratory tract.
Current Levels of Exposure
There is no information available on the levels of chloroalkyl
ethers in food or in the atmosphere; hence, no estimates can be
made of the extent of human exposures to these compounds via these
two routes. Information on the dermal exposure is also virtually
nonexistent. Only incomplete data are available for the calcula-
tion of exposure via ingestion of drinking water; therefore, only
rough estimates can be made. The highest concentration of BCEE,
BCIE, and BCEXE in drinking water reported by U.S. EPA (1975) was
0.5, 1.58 and 0.03 jug/1, respectively. Assuming that (1) these
values are representative of yearly averages, (2) the average daily
intake of water is 2 liters, and (3) the average body weight is 70
kg, then the maximum possible daily exposure from water to BCEE,
C-58
-------
BCIE, and BCEX2 would be 14.3, 45.1, and 0.86 ng/kg. These values
are, of course, the upper limits and are based on the dubious assump-
tion that the highest value is representative of the yearly average
and that they only apply to specific contaminated areas. For na-
tional averages, the data of Dressman, et al. (1977) and U.S. EPA
(1977) may be used. The national average concentration of BCEE or
BCIE in drinking water is calculated as the mean concentration mul-
tiplied by the percent incidence of occurrence. Thus, the average
concentration in drinking water of BCEE and BCIE was respectively
11.5 ng/1 (0.1 ug/lxll.5 percent), and 12.1 ng/1 (0.17 ug/lx7.1
percent) in phase II and 1.7 ng/1 (0.024 jug/lx7.27 percent) and 7.0
ng/1 (0.11 ;ig/lx6.36 percent) in phase III. Using the same three
assumptions mentioned above, the estimated daily exposure to BCEE
and BCIE would be, respectively, 0.33 ng/kg and 0.35 ng/kg in phase
II and 0.05 ng/kg and 0.20 ng/kg in phase III.
Special Groups at Risk
Exposure to BCME and CMME appears to be confined to occupa-
tional settings. A partial list of occupations in which exposure
may occur includes: ion-exchange resin makers, specific organic
chemical plant workers, laboratory workers, and polymer makers
(Tabershaw, et al. 1977). Of these groups, workers in small noncom-
mercial laboratories should probably be particularly cautious be-
cause of the lack of monitoring and surveillance and because of the
fact that this group is more likely to be relatively more heavily
exposed. Potential exposure to BCME may also occur in workplaces
where vapors of hydrochloric acid and formaldehyde may coexist.
The National Institute for Occupational Safety and Health has
C-59
-------
already found trace levels of BCME in the textile industry. Other
such places include biological, medical and chemical laboratories,
and particle-board and paper manufacturing plants (Lemen, et al.
1976).
Exposure to ^-chloroalkyl ethers may occur in residents in
areas where the source of drinking water is from the contaminated
river water and the treatment of drinking water is inadequate to
remove the contaminants. Individuals consuming the water in these
areas may be at a greater risk than the general population. Occu-
pational exposure to BCEE may also occur. A partial list of occu-
pations in which exposure may occur includes: cellulose ester plant
workers, degreasers, dry cleaners, textile scourers, varnish work-
ers, and processors or makers of ethyl cellulose, fat, gum, lac-
quer, oil, paint, soap, and tar (Tabershaw, et al. 1977).
Basis and Derivation of Criteria
There is no empirical evidence that BCIE is carcinogenic.
However, because of its mutagenic activity and its close structural
similarity to BCEE - which some studies have shown to be carcino-
genic in mice - the possible carcinogenicity of BCIE is a matter of
concern. The National Toxicology Program is currently re-testing
this compound in mice by gavage and the results of this study
should be reviewed as soon as they become available.
In the interim, a toxicity based criterion can be derived from
the NCI bioassay using nontumor pathology which is summarized in
Table 7. The lowest dose tested which caused minimum adverse ef-
fects was 10 mg/kg/day for the mice. At this dose, there was an
increased incidence of centrilobular necrosis of the liver which
C-60
-------
was not seen in the high-dose group. Because of concern for poten-
tial carcinogenicity and the failure of this study to define a pos-
itive dose/response relationship, a safety factor of 1,000 would
seem justified. In addition, because the low dose group defines a
LOAEL rather than a NOAEL, an additional safety factor of 10 is re-
commended. Assuming a 70 kg body weight for humans, the ADI can be
calculated as:
ADI - 10 mg/kg/day x 70 kg/10,000 = 70 ug/day
Using the estimated bioconcentration factor of 2.47 for BCIE
and assuming a daily consumption of 0.0065 kg fish and 2 liters of
water, a criterion of 34.7 ug/1 may be calculated:
70 09 -
_ _
2+(0.0065 x 2.47) '
Because this criterion is based on a LOAEL and on a study in
which a positive dose/response relationship was not noted, it
should be regarded as a very imprecise approximation at best. The
criterion should be revised as soon as better data become avail-
able.
In summary, based on the use of chronic mouse toxicological
data and an uncertainty factor of 10,000, the criterion level of
bis(2-chloroisopropyl) ether corresponding to an acceptable daily
intake of 10 mg/kg is 34.7 ug/1. Drinking water contributes 99
percent of the assumed exposure, while eating contaminated fish
products accounts for 1 percent. The criterion level can similarly
be expressed as 4.36 mg/1 if exposure is assumed to be from the con-
sumption of fish and shellfish products alone.
The estimated safe level of BCEE in drinking water may be cal-
culated using the linearized multistage model as discussed in the
C-61
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Human Health Methodology Appendices to the October 1980 Federal
Register notice which announced the availability of this document.
The data of Innes, et al. (1969) on the carcinogenicity of this
compound by oral administration to male mice are used in the calcu-
lation. The bioaccumulation factor for BCEE is 6.9. Based on this
approach, the calculated water quality criterion for BCEE is 0.30
ug/1. Compliance to this level should limit human lifetime risk of
carcinogenesis from BCEE in ambient water to not more than 10
(one case in 100,000 persons at risk). It should also very ade-
quately protect against noncarcinogenic toxicity since the daily
dose of contaminant that would be absorbed from water containing
the criterion limit is many times less than the minimal daily oral
dose required to produce a detectable toxic response in animals.
The setting of drinking water standards for BCME and CMME
would be of academic interest only, since these °^ -chloroalkyl
ethers may not, under ordinary conditions, exist in water for per-
iods of time longer than a few hours. Carcinogenicity data gener-
ated by oral administration of these compounds are not available.
In the case of CMME, no criterion was calculated due to its
extremely short half-life in aqueous solution. Jones and Thornton
(1967) have measured the hydrolysis rate of CMME in aqueous isopro-
panol. Extrapolation of the data to pure water yielded a t^ of less
than one second. BCME has a slightly longer half-life. Therefore,
as a guideline, the safe level of BCME in drinking water may be cal-
culated using the tumor incidence data from chronic rat inhalation
studies (Kuschner, et al. 1975). In this study, Sprague-Dawley
rats were exposed to various doses of BCME six hours per day, five
Cr-62
-------
days per week throughout their lifetime. The validity of the in-
cidence rates for humans was established by evaluating the cancer
incidence in workers after accounting for their exposure
(Pasternack, et al. 1977).
Therefore, using the linearized multistage model as previously
described and a bioconcentration factor of 0.63, the recommended
maximum permissible concentration of BCME for the ingested water is
0.038 ng/1. Compliance to this level should limit human lifetime
risk of carcinogenesis from BCME in ambient water to not more than
ID'5.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." BCEE and
BCME are suspected of being human carcinogens. Because there is no
recognized safe concentration for a human carcinogen, the recom-
mended concentration of these chloroalkyl ethers in water for maxi-
mum protection of human health is zero.
Because attaining a zero concentration level may be infeasible
in some cases and in order to assist the Agency and states in the
possible future development of water quality regulations, the con-
centrations of BCEE and BCME corresponding to several incremental
lifetime cancer risk levels have been estimated. A cancer risk
level provides an estimate of the additional incidence of cancer
that may be expected in an exposed population. A risk of 10 , for
example, indicates a probability of one additional case of cancer
for every 100,000 people exposed, a risk of 10~ indicates one
C-63
-------
additional case of cancer for every million people exposed, and so
forth.
In the Federal Register notice of availability of draft am-
bient water quality criteria, the U.S. EPA stated that it is con-
sidering setting criteria at an interim target risk level of 10~5,
— 6 — 7
10 , or 10 as shown in the following table.
Exposure Assumptions
(daily intake)
2 liters of drinking
water and consumption
of 6.5 g of fish
and shellfish (2)
Bis(2-chloroethyl)ether
Bis(chloromethyl)ether
Consumption of fish and
shellfish only
Bis(2-chloroethyl)ether
Bis(chloromethyl)ether
Risk Levels
and Corresponding Criteria (1)
lO
'7
io
-6
ID
'5
0.003
0.376x10
-6
0.030
3.76x10
-6
0.30
37.6x10
-6
0.136
0.184x10
-3
1.36
1.84x10
-3
13.6
18.4x10
-3
(1) Calculated by applying a linearized multistage model as dis-
cussed in the Human Health Methodology Appendices to the
October 1980 Federal Register notice which announced the
availability of this document. Appropriate bioassay data used
in the calculation are presented in Appendix 1. Since the
extrapolation model is linear at low doses, the additional
lifetime risk is directly proportional to the water concentra-
tion. Therefore, water concentrations corresponding to other
risk levels can be derived by multiplying or dividing one of
the risk levels and corresponding water concentrations shown
in the table by factors such as 10, 100, 1,000, and so forth.
C-64
-------
(2) Two percent of BCEE exposure results from the consumption of
aquatic organisms which exhibit an average bioconcentration
potential of 6.9-fold. The remaining 98 percent of BCEE expo-
sure results from drinking water.
Two-tenths percent of BCME exposure results from the consump-
tion of aquatic organisms which exhibit an average bioconcen-
tration potential of 0.63-fold. The remaining 99.8 percent of
BCME exposure results from drinking water.
Concentration levels were derived assuming a lifetime exposure
to various amounts of BCIE, BCEE, and BCME, (1) occurring from the
consumption of both drinking water and aquatic life grown in water
containing the corresponding chloroalkyl ether concentrations and,
(2) occurring solely from consumption of aquatic life grown in the
waters containing the corresponding chloroalkyl ether concentra-
tions.
Although total exposure information for these chloroalkyl
ethers is discussed and an estimate of the contributions from other
sources of exposure can be made, this data will not be factored
into the ambient water quality criteria formulation because of the
tenuous estimates. The criteria presented, therefore, assume an
incremental risk from ambient water exposure only.
C-65
-------
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C-68
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* Off
. s
^
.
5"
- 1971
d
,
„„.
„,.
C-,
-------
OiS'V
3°
. jav^3
* ••
3°
• \jjXV V
o
10
uo
jau.
•£98*
-.68
jaftoc
3°
aUOC
086"1
as 3^
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no A01*'
-------
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C-71
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C-72
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C-73
-------
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C-74
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C-75
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C-76
-------
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APPENDIX I
Summary and Conclusions Regarding the
Carcinogenicity of Chloroalkyl Ethers*
Chloroalkyl ethers have a wide variety of industrial and lab-
oratory uses in organic synthesis, treatment of textiles, manufac-
ture of polymers and insecticides, and as degreasing agents. Bis-
(chloromethyl)ether (BCME) and chloromethylmethyl ether (CMME)
have been included in the Occupational Saftey and Health Admin-
istration's (OSHA) list of restricted chemicals (1974) based on
animal studies and human epidemiological evidence indicating that
these compounds are carcinogenic by inhalation. An additional
occupational hazard is the spontaneous combination at high concen-
trations of vapors of HCL and formaldehyde to form BCME. Bis(2-
chloroethyl)ether (BCEE) is present in rivers and drinking water
in several cities and is found in high concentrations in waste
water from chemical plants.
Several of the Chloroalkyl ethers including BCME, CMME, BCEE,
and BCIE were mutagenic in bacterial systems without metabolic
activation, indicating that they are direct-acting mutagens. Data
for BCME, CMME, and BCEE indicate furthermore, that these compounds
are both mutagenic and carcinogenic.
BCME has been shown to be carcinogenic in animals following
inhalation or dermal exposure. In an inhalation study by Kuschner,
et al. (1975), BCME induced malignant tumors of the respiratory
tract in male Sprague-Dawley rats. Application of BCME to mouse
*This summary has been prepared and approved by the Carcinogens
Assessment Group, EPA, on July 20, 1979.
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skin induced skin tumors (van Duuren, et al. 1968), while s.c.
injection of BCME to newborn ICR Swiss random-bred mice induced
pulmonary tumors (Gargus, et al. 1969). There were no studies re-
ported using oral administration of BCME.
The carcinogenicity of BCEE by oral administration was inves-
tigated by Innes, et al. (1969) in two strains of mice. There was a
statistically significant increase of hepatomas in the male mice of
both strains (C57BL/6 x C3H/Anf)P1 and (C57BL/6 x AKR^, respec-
tively, and in the female mice of one strain (C57BL/6 x C3H/Anf )F
Epidemiological studies of workers in the United States, Ger-
many, and Japan who were occupationally exposed to BCME and/or CMME
(chloromethylmethyl ether) have indicated that these compounds are
human respiratory carcinogens.
The water quality criterion for BCEE is based on the results
of the Innes study in which hepatomas were induced in mice given a
daily oral dose of 300 ppm (i.e., 39 mg/kg/day). The concentration
of BCEE in drinking water calculated to limit human lifetime cancer
risk from BCEE to less than 10~5 is 0.30 ug/1.
There is no carcinogenicity data from oral exposure to BCME.
The rapid hydrolysis rate of BCME in water precludes a realistic
exposure. However, a criterion is calculated in the event that
levels are monitored in the water. Since BCME is a locally acting
carcinogen and it is expected that the stomach would be the target
organ from oral exposure, the lung tumor data from the inhalation
study was accepted for estimating human risk, and 100 percent ab-
sorption of BCME was assumed. The water quality criterion was cal-
culated using data from the Kuschner, et al. inhalation study,
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where rats given 100 exposures of various doses of BCME for six
hours per day, five days per week, developed malignant respiratory
tract tumors. The concentration of BCME calculated to maintain
lifetime cancer risk below 10" is 0.038 ng/1.
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Bis(2-Chloroethyl)ether
The water quality criterion for BCEE is based on the induction
of hepatomas in male mice (strain C57BL/6 x GSR/Anf)?^ given a
daily oral dose of 300 ppm for 80 weeks (Innes, et al. 1969). The
criterion was calculated from the following parameters:
Dose Incidence
(mg/kg/day) (no. respond ing/no. tested)
0 8/79
39 14/16
le = 560 days w = 0.030 kg
Le = 560 days R = 6.9 I/kg
L = 560 days
With these parameters, the carcinogenic potency factor for
* -1
humans, q.^ , is 1.144 (mg/kg/day) . The resulting water concen-
tration of BCEE calculated to keep the individual lifetime cancer
risk below 10"5 is 0.30 jug/1.
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Bis(Chloromethyl)ether
The water quality criterion for BCME is based on the induction
of malignant respiratory tract tumors in male Sprague-Dawley rats
given 100 exposures of various doses of BCME by inhalation six
hours per day, five days per week (Kuschner, et al. 1975). The
criterion was calculated from the following parameters:
Dose Incidence
(mg x 10 /kg/day) (no. responding/no.tested)
0.0 0/240
0.35 1/41
0.70 3/46
1.4 4/18
2.1 4/18
2.8 15/34
3.5 12/20
le = 728 days w = 0.500 kg
Le = 728 days R - 0.63 I/kg
L = 728 days
With these parameters, the carcinogenic potency factor for
humans, qx*, is 9299.8 (mg/kg/day)"1. The resulting water concen-
tration of BCME calculated to maintain the individual lifetime can-
cer risk below 10"5 is 0.038 ng/1.
U. S GOVERNMENT PRINTING OFFICE • 1980 720-016/4371
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