EPA 560/2-75-006 TR-75-561
INVESTIGATION OF SELECTED
POTENTIAL ENVIRONMENTAL CONTAMINANTS;
HALOETHERS
Patrick R. Durkin
Philip H. Howard
Jitendra Saxena
September 1975
Final Report
Contract No. 68-01-2202
Project L1256-05
Project Officer
Frank Kover
Prepared for
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
Document is available to the public through the
National Technical Information Service, Springfield,
Virginia 22151
-------
BIBLIOGRAPHIC DATA 1. Report No. 2.
SHEET EPA 560/2-75-J006
'. Title and Subtitle
Investigation of Selected Potential Environmental
Contaminants: Haloethers
. Author(s)
i Patrick R. Durkin, Philip H. Howard, Jitendra Saxena
9. Performing Organization Name and Address
Life Sciences Division
Syracuse University Research Corporation
Merrill Lane, University Heights
Syracuse. New York 13210
2. Sponsoring Organization Name and Address
f Office of Toxic Substances
1 U.S. Environmental Protection Agency
Washington, B.C. 20460
3. Recipient's Accession No.
nn ? i\ A 356
5. Report Date Published ,
September. 1975
6.
8. Performing Organization Rept.
N°- TR-75-561
10. Project/Task/Work Unit No.
11. Contract/Grant No.
EPA 68-01-2996
13. Type of Report & Period
Covered
Final Technical Report
14.
15. Supplementary Notes
T.
16, Abstracts Th±g report review8 the potential environmental hazard from the commercial use
ot haloether compounds. The fluorinated anesthetic ethers, methoxyfurane (2,2-dichloro-
1,1-difluoroethyl methyl ether) and fluroxene (2,2,2-trifluoroethyl vinyl ether), are
jonly peripherally treated. Major focus is on the a-chloroethers, bis(chloromethyl)-
I ether ^nd chloromethyl methyl ether, and the B-chlorotithers, bis (2-chloroisopropyl)-
ather, bis(2-chloroethyl)ether, and bis(2-chloroethoxy)methane. The a-chloroethers
are used as chemical intermediates for production of ion exchange resins while the
|6-chloroethers are used mostly for solvents but have some chemical intermediate uses.
Information on physical and chemical properties, production methods and quantities,
commercial uses and factors affecting environmental contamination, as well as infor-
mation related to health and biological affects, are reviewed.
I 17. Key Words and Document Analysis. I7a. Descriptors
Haloethers
bis(chloromethyl)ether
I chloromethyl methyl ether
chlorex
bis(2-chloroethyl)ether
• bis(2-isopropyl)ether
I toxicology
pollution
chemical marketing information
17b. Identifiers /Open-Ended Terms
Pollution
I Environmental effects
Carcinogens
Solvents
17e. COSATI Field/Group
118. Availability Statement
Document is available to public through
The National Technical Information Service,
j Springfield, Virginia 22151
19. Security Class (This
Report)
UNCL/
121. No. of Pages
Class (Thi:
ZOTSecurity Class (This
Page
UNCLASSIFIED
FORM NTI«-»» (HEV. io-7s> ENDORSED BY ANSI AND UNESCO.
THIS FORM MAY BE REPRODUCED
USCOMM-DC 5Z85-P74
-------
NOTICE
The report has been reviewed by the Office of Toxic Substances, EPA,
and approved for publication. Approval does not signify that the contents
necessarily reflect the views and policies of the Environmental Protection
Agency, nor does mention.of trade names or commercial products constitute
endorsement or recommendation for use.
ii
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TABLE OF CONTENTS
Page
Executive Summary 1
I. Physical and Chemical Data 3
A. Structure and Properties 3
1. Chemical Structure 3
2. Physical Properties 3
3. Principal Contaminants in Commercial Products 5
B. Chemistry 9
1. Reactions Involved in Uses 9
2. Hydrolysis 11
3. Oxidation and Photochemistry 21
4. Other 23
II. Environmental Exposure Factors 25
A. Production and Consumption 25
1. Quantity Produced 25
2. Producers, Major Distributors, Importers, Sources 29
of Imports, and Production Sites
3. Production Methods and Processes 30
4. Market Prices 43
5. Market Trends 44
B. Uses 44
1. Major Uses 44
2. Minor Uses 49
3. Discontinued Uses 49
4. Projected or Proposed Uses 49
5. Possible Alternatives to Use 51
C. Environmental Contamination Potential 53
1. General 53
2. Production 53
3. Transport and Storage 54
4. Uses 54
5. Disposal 55
6. Potential Inadvertent Production of Haloothera tn 55
Other Industrial Processes
7. Potential Inadvertent Production in the Environment 63
iii
-------
Table of Contents
(continued)
D. Current Handling Practices and Control Technology 63
1. Special Handling 63
2. Methods of Disposal and Storage 64
3. Accident Procedures 64
4. Current Controls 64
E. Monitoring and Analysis 65
1. Analytical Methods 65
2. Monitoring 72
III. Health and Environmental Effects 76
A. Environmental Effect 76
1. Persistence 76
a. Biological Degradation 76
b. Chemical Degradation in the Environment 73
2, Environmental Transport 79
3. Bioaccumulation and Biomagnification 80
B. Biology 83
C. Toxicity - Humans 86
1. Epidemiology 86
2. Occupational Exposure 97
3. Controlled Human Exposures 98
4. Chemical Warfare Agents 99
D. Toxicity - Birds and Mammals 100
1. Acute Toxicity 100
a. Acute Oral Toxicity 100
b. Acute Dermal Toxicity 101
c. Eye Injury 103
d. Acute Inhalation Toxicity 104
(i) Chloroalkyl Ethers 104
(ii) Fluorinated Ethers 112
(iii) ToxicOlogical Relationships Between the 115
Chloroalkyl Ethers and Fluorinated Ethers
iv
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Table of Contents
(continued)
2. Chronic Toxicity 116
a. Chronic Oral Toxicity 116
b. Chronic Dermal Toxicity 117
c. Chronic Toxicity of Haloethers in Subcutaneous 118
Injection
d. Chronic Inhalation Toxicity 119
3. Sensitization 125
4. Teratogenicity 125
5. Mutagenicity 125
6. Carcinogenicity 126
a. Screening Tests 126
(i) Dermal Application 126
(ii) Subcutaneous Injection 133
(iii) Inhalation 137
(iv) Ingestion 143
b. Biochemical Studies Related to Carcinogenicity 145
7. Behavioral Effects 147
8. Possible Synergisms 147
E. Toxicity - Invertebrates 147
F. Phytotoxicity 148
G. Toxicity - Microorganisms 148
IV. Regulations and Standards 149
A. Current Regulations 149
B. Concensus and Similar Standards 149
V. Summary and Conclusions 150
REFERENCES 157
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Number
LIST OF TABLES
Page
1 Physical Properties of Haloethers *
2 Solubility of Fats, Oils, Waxes, Resins, Balsams, and 6
Dyes in Commercial Isopropyl Ether, Dichloroethyl
Ether, and Ethylene Dichloride
3 Isomers of Chloroisopropyl Ethers Found as By-Products 8
of Propylene Chlorohydrin
4 Rate of Hydrolysis of Chloroethers in H20-DMF (3:1) 13
5 Hydrolysis of B-, Y~» 6-Chloroethers in 20 M Water in 14
Dioxane Solution at 100°C
6 Solvolysis of Chloromethyl Ethers in Dioxane 15
7 Hydrolysis Rate Constants for Chloromethyl Methyl Ether in 17
95% Aqueous Acetone at 0.0°C
8 Solvolysis Rates of Chloromethyl Methyl Ether 18
9 Hydrolysis of Bis(Chloromethyl)ether in Water and 19
Aqueous HC1 and NaOH
10 Vapor Phase Reactivity (25°C) 20
11 Surface Effect on the Gaseous Hydrolysis Rates of 22
Chloromethyl Methyl Ether (A) and Bis(chloromethyl)-
ether (B) Near Ambient Temperature
12 Production of Haloethers (10 Ibs) 26
13 Past and Present Manufacturers of Haloethers 31
14 Capacities and Production Sites of Haloether Manufacturers 32
15 Reactants and Products of the Ethylene Oxide Chlorohydrin 35
Process
16 Products and Reactants of a Typical Propylene Chlorohydrin 39
Plant
17 Price of Bis(2-chloroethyl)ether 43
18 Prices of Haloethers 43
19 Major Uses of Haloethers 45
20 Principle Ion Exchange Resin Producers 46
21 Minor Uses of Haloethers 50
22 Amount of BCME Formed at 40% Relative Humidity and 26°C 56
at Various CH 0 Concentrations
23 Applications of Formaldehyde 58
24 Producers of Epichlorohydrin 62
vi
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List of Tables
(continued)
Number _aSe
25 Haloethers Detected in Industrial Raw and Finished Waters 74
26 Lung Cancer in Workers Exposed to Chloromethyl Methyl 89
Ether and Bis(chloromethyl)ether
27 Respiratory Cancer Deaths Among the Heavy Exposure Group 91
Workers Exposed to "Chloromethyl Ethers" in Firm-one
by Duration of Maximum Exposure
28 Death from Lung Cancer in German Workers Associated with 93
Bis(chloromethyl)ether Exposure
29 Deaths from Respiratory Cancer in Japanese Workers 94
Associated with Bis(chloromethyl)ether Exposure
30 A comparison of Epidemiological Studies Associating 96
Bis(chloromethyl)ether and/or Chloromethyl Methyl Ether
with Respiratory Cancer
31 Acute Oral Toxicity of Various Haloethers 101
32 Acute Dermal Toxicity of Haloethers 102
33 Acute Inhalation Toxicity of Haloethers 105
34 Mortality and Lung-to-Body Weight Ratios After Single 108
Seven Hour Exposures to (A) Chloromethyl Methyl Ether
and (B) Bis(chloromethyl)ether
35 Median Life Span and Lung-to-Body Weight Ratio After a 109
Single Seven Hour Exposure to Bis(chloromethyl)ether
36 Effects of Bis(2-chloroethyl)ether on Guinea Pigs 111
37 Chronic Inhalation Toxicity of Haloethers 120
38 Median Life Span of Rats and Hamsters After Multiple Exposures 121
to 1 ppm Bis(chloromethyl)ether
39 Tumor Induction in Mice Involving Dermal Application of 128
Various Haloethers
40 Tumor Induction Associated with Subcutaneous Injection of 134
Various Haloethers into Mice and Rats
41 Pulmonary Tumors in Male Mice After Inhalation of 138
Bis(chloromethyl)ether, Chloromethyl Methyl Ether,
and Urethane
42 Cancer in Rats Following Exposure to 0.1 ppm 141
Bis(chloromethyl)ether for Periods of Two to
Twenty Weeks
43 Tumors in Mice Associated with Oral Administration 144
of Bis(2-chloroethyl)ether
-------
LIST OF FIGURES
1 Chloromethylation with Chloromethyl Methyl Ether 10
2 Formation of Polysulfides 10
3 Minor Chemical Intermediate Applications of Haloethers 11
4 Hydrolysis of Chloroacetals 15
5 S,,l and Sx,2 Mechanisms for the Hydrolysis of 16
N N
Chloromethyl Ethers
6 Photolysis Mechanism of an Oxygen-Saturated Solution 23
of Ethyl Ether
7 Formation of Bis(2-chloroethyl)ether During 33
Chlorohydrin Synthesis of Ethylene Oxide
8 Chlorohydrin Process for Manufacturing Ethylene Oxide 34
9 Formation of Bis(2-chloroisopropyl)ether and Related 36
Ethers During Chlorohydrin Synthesis
10 Diagram of a Typical Chlorohydrin Propylene Oxide Plant 38
11 Suggested Mechanism for the Formation of Bis(chloromethyl)- 41
ether
12 Formation of Chloroethers During Chlorohydrination 60
13 Production of Epichlorohydrin by Allyl Chloride Route 62
14 Potential Chloroethers from Epichlorohydrin Manufacturer 62
15 Bis(chloromethyl)ether Hydrolysis Apparatus 71
16 Postulated Pathway of Fluroxene Metabolism in Mice 84
17 Proposed Pathway for the Metabolism of Methoxyflurane 85
Based on Studies of Human and Rat Liver Microsomes
18 Cumulative Mortality - Corrected Probabilities of Lung 90
Cancer Death in Bis (chloromethyl)ether [BCME] Exposed
and Non-exposed Workers
19 Mortality of Rats Following Chronic Exposures to 0.1 ppm 122
Bis(chloromethyl)ether
20 Mortality of Hamsters Following Chronic Exposure to 122
0.1 ppm Bis(chloromethyl)ether
21 Cumulative Percent Mortality of Male Mice Exposed to 123
Bis(chloromethyl)ether
22 Incidence of Respiratory Tract Cancer in Rats Following 140
Exposures to 0.1 ppm Bis(chloromethyl)ether
23 The Effect of Bis(chloromethyl)ether on Various 146
Incorporation Patterns in Mouse Skin Preparations
viii
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Executive Summary
Chloroethers appear to be the most important commercial haloethers. In
terms of environmental hazard, the chloroethers can be divided in two cate-
gories, (1) a-chloroethers and (2) non-a-chloroethers. These two groups differ
drastically in terms of uses, environmental stability and contamination, and
toxicity.
Chloromethyl methyl ether (CMME), which usually contains a small amount
of bis(chloromethyl)ether (BCME), is the only commercial a-chloroether. It is
used as a chemical intermediate in the synthesis of strong base ion exchange
resins, but the quantities used and the losses to the environment are unknown.
Ion exchange resins have important applications in water conditioning and as a
method of separation for chemical processes. The two compounds are very reactive
and have extremely short half-lives in water (< 1 second for CMME and < 1 minute
for BCME), although they are more stable in the vapor phase (tj > 390 minutes for
•"5
CMME and > 25 hours for BCME). Normally, compounds that are used as chemical
intermediates and are relatively non-persistent would have little environmental
significance. However, BCME has been demonstrated to be one of the most carcin-
ogenic compounds known (6 hour inhalation exposure to 0.1 ppm induces respiratory
tract cancer in rats). Industrial exposure to the CMME-BCME combination has led
to at least 47 human deaths from respiratory cancer. Because of the extreme
toxicity, it would seem worthwhile to determine if sizable quantities of CMME and
BCME are being released to the environment, especially the atmosphere. However,
due to the high reactivity of a-chloroethers, they would appear to be mure of an
occupational, rather than an environmental problem.
-------
In contrast, f3-chloroethers are widespread environmental contaminants.
Contamination of raw and drinking water by bis(2-chloroethyl)ether and
bis(2-chloroisopropyl)ether is well documented by monitoring, and the B-
chloroethers are considerably more chemically stable than the a-chloroethers.
However, the sources of contamination are not well understood [although the
propylene chlorohydrin process for producing propylene oxide (capacity - 900
million pounds a year) is implicated], nor is the available production and use
information very exact. These two g-chloroethers are less corrosive than the
a-chloroethers [fatal inhalation concentration above 100 ppm for bis(2-chloro-
ethyl)ether] and have not been as intensively screened for carcinogenicity.
Nevertheless, one study has demonstrated the apparent oral carcinogenicity of
bis(2-chloroethyl)ether. By other routes of administration, g-chloroethers show
no marked carcinogenic activity. Since the g-chloroethers are (1) produced or
may be formed as by-products in sizable quantities, (2) are released to and
appear to persist in the environment, (3) can pass through drinking water treat-
ment plants, and (4) may be carcinogenic, it is suggested that intensive research
and study of these compounds be undertaken.
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Investigation of Selected Potential Environmental Contaminants: Halocthers
I. Physical and Chemical Data
A. Structure and Properties
1. Chemical Structure
Haloethers are compounds which contain an ether moiety
(R-O-R) and a halogen atom attached to the alkyl or aryl substituent. When
the compound is named as an ether, the numbering or lettering of the carbons
begins at the carbon next to the oxygen. Thus, for example, an a-haloalkyl
(or 1-halo) ether has at least one halogen attached to the carbon next to
the oxygen. 3
C2
Y 3 a 2
6 a
This review has considered only ethers which have a halogen
substituted on an alkyl chain; aryl halogen substituted ethers were
excluded. The review focuses upon compounds that appeared to have commercial
or environmental significance. The compounds which received the most
attention during the literature search are listed in Table 1. These com-
pounds were chosen because they appeared either in the U.S. Tariff Commission
(1972) reports of commercial synthetic organic chemicals, the Directory of
Chemical Producers (S.R.I., 1974), or the Kirk-Othmer Encyclopedia of Chemical
Technology (Lurie, 1965; Krantz, 1963). A considerable amount of information
on bis (chlorome thy 1) ether and chloromethyl methyl ether has been reviewed in this
report; for brevity, these compounds have been assigned the acronyms BCME and
CMME, respectively.
2. Physical Properties
Non-halogenated ethers are pleasant smelling, colorless
liquids with densities of less than 1.0. They are neutral, volatile,
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flammable compounds, which have little or no solubility in water but
are miscible with most organic liquids (Lurie, 1965).
The majority of the compounds listed in Table 1 are chloro-
ethers. Chlorine substitution on ethers has a tendency to increase the
density, boiling point, and odor, decrease the flatnmability, and alter
the solubility properties. For example, diethyl ether has a density of
0.714 and boiling point of 34.5?C, a pleasant odor, and is very flammable
(flash point, closed-cup; -49°C).- In contrast, bis(2-chloroethyl)ether
has a density of 1.219 and boiling point of 178°C, a pungent odor, and is
much less flammable (flash point, open cup; 84°C). The fluorine substituted
compounds (last two compounds in Table 1), which find commercial applications
as anesthetics, are much more volatile than their chlorinated analogues.
Other general physical properties for the haloethers are listed in Table 1.
Some of the commercial applications of the haloethers
are dependent upon the solubility of the compounds. For example,
bis(2-chloroethyl)ether has been used to separate lubricating stocks
into paraffinic and naphthenic fractions. A comparison of the solubility
of bis(2-chloroethyl)ether with two other solvents is presented in Table 2.
3. Principal Contaminants in Commercial Products
Of the haloethers that have been reviewed, only six,
including the two anesthetics, appear to be produced in commercial
quantities (see Section II-A, p.25). The two anesthetics, methoxyfurane
(CHC£2CF2OCH3) and fluroxene (CF3CH2OCH=CH2), are probably highly purified
before use since they are meant for human consumption. However, information
-------
Table 2. Solubility of Fats, Oils, Waxes, Resins, Balsams, and Dyes
in Commercial Isopropyl Ether, Dichloroethyl Ether, and
Ethylene Dichloride (Fife and Reid, 1930)
Iso- Dtchloro- Ethylene
Propyl Ethyl Dlchio-
Solute Ether Ether ride
Crlsco
Vaseline
Mazola
Wesson oil
Mineral oil
Cttronella
Juniper
Coriander
Sweet birch
Menthol
Castor oil
Linseed oil
Cottonseed oil
Venetian
turpentine
Japan wax
Carnauba wax
Beeswax
Paraffin wax
Amberol
Albertol
Aroclar 1254
Rezyl balsam
Rezyl resins
Varnish-type
glyptals
Sarpee
East India
Bakelite R. 352
Gum- Lac
Coumarone
Cumar
Manilla
Ester gum
Ester gum
(oxidized)
Rosin
AbH'ttc acid
(purified)
Beckacite
G. P. 0. Resin
Ester gum
(acetylated)
G.E, Realn
(Bakelite type)
Manta gum
Dammar
Congo
S
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IHO- Dit.hloro-
Propyl Ethyl
Solute Ether Ether
Kauri
Zopal
Zinc resinate
Larulohe (A)
Gllsonlte
Sandarac
Montol resin
Ponti anac
Gum mastic
Benzyl abietate
Shellac
Vlnylite 80
Vinylite A
Casein (rennet)
Nitrocellulose
Cellulose
acetate
Benzyl cellulose
Ethyl cellulose
Camphor
Spirit-soluble
yellow
Spirit-soluble
red
Spirit-soluble
nlgrosene
Water-soluble
nlgrosene
Oil-soluble
nigrosene
Oil-soluble
blue
Oil-soluble
yellow
Oil-soluble
black
tndigosol
Spirit-soluble
black
Spirit-soluble
blue
Oil-soluble
green
Ind 1 |^o
Bfnzo brown
36A
Alizarine aky
blue
Victoria blue B
Diazo brown
Scarlet S B A
SH
S
S
PSH
I
SSH
S
I
1
S
SSH
I
I
SSH
1
I
I
S
S
S
S
I
S
S
S
S
S
I
I
PS
I
S
PSH
ss
ss
SH
S
S
SH
S
PSH
S
SH
S
S
PSH
PSH
I
SSH
SS
SH
SH
S
S
PSH
PSH
S
I
S
SH
S
S
PSH
SH
S
PS
S
PSH
S
S
Ethylene
Dichlo-
ride
PSH
S
S
PSH
S
SSH
S
PSH
S
S
SSH
S
S
SSH
I
I
S
S
S
PSH
PSH
S
I
S
SH
S
S
I
SH
S
I
S
PSH
S
S
SSH
PSH
S " Soluble at room temperature
SS " Slightly soluble at room temperature
SH - Soluble hot
PS - Partially soluble
PSH - Partially soluble hot
I • Insoluble
-------
on the analysis of the commercial products for trace contaminants is not
available. With fluroxene, a non-volatile stabilizer is added (0.01% of
N-phenyl-l-n«.phthylamine) to prevent polymerization and hydrolysis (Ohio
Medical Products, 1972).
As with the anesthetics, the other commercial haloethers —
bis(chloromethyl), chloromethyl methyl, bis(2-chloroethyl) , and bis(2-chloro-
isopropyl) ethers — have not been extensively analyzed for trace contaminants.
In fact, in many instances these compounds may be trace contaminants in other
commercial products (e.g. bis(2-chloroethyl) and bis(2-chloroisopropyl) ethers
in ethylene and propylene chlorohydrins) (see Section II-C-7, p. 63 ). However,
Collier (1972) has reported that bis (chloromethyl) ether (BCME) is typically
found as several percent (1 to 7%, Figueroa ejt^ al . , 1973) of commercial
chloromethyl methyl ether (CMME) , which is made by reacting gaseous HC£
with a heated solution of formaldehyde and methanol.
The other commercial chloroethers are also not produced by
direct chlorination and, therefore, probably have little chloroether by-
products. For example, bis(2-chloroethyl)ether is formed during the synthesis
of ethylene chlorohydrin.
- +
HOC&
CH2 = CH2 - +
However, with propylene chlorohydrin two chlorohydrins are possible which
result in three possible ethers (see Figure 9, p. 36). Two isomer ratios have
been reported, suggesting that the quantities of chloroether isomers noted
in Table 3 would be found in the commercial product.
-------
CH3CH-0-CHCH3
di I
CH2C£CH2C£
Table 3. Isomers of Chloroisopropyl Ethers
Found as By-Products of Propylene Chlorohydrin
Ratio of Attack at Secondary
__ vs. Primary Carbon _
3:1 9:1
56% 81%
CH3-CH-CH2-0-CHCH3 38%
Cl CH2CJl
CH3CHCH2-0-CH2CHCH3 6%
ca en
When bis(2-chloroethyl)ether is heated during use as an
extraction solvent, traces of hydrochloric acid are formed resulting in a
corrosion problem. In order to reduce this problem, inhibitors are added
to the solvent. Pollard and Lawson (1955) have evaluated a number of
inhibitors, such as ammonia, diethyl aminoethanol, tri-cresyl phosphate,
tertiary heptyl me reaptan, and two commercial amine-type inhibitors, for use
with bis(2-chloroethyl)ether and, therefore, these additives might be found
in commercial formulations.
-------
B. Chemistry
1. Reactions Involved in Uses
There is considerable difference between the reactivity of
a-haloalkyl ethers and ethers in which the halogen is substituted on a carbon
that is not attached to the ether oxygen. The high reactivity of the a-halo-
ethers is a result of the two electronegative atoms, oxygen and halogen, which
are bonded to the same carbon (Summers, 1955). This difference in reactivity
is particularly evident in the different rates of hydrolysis (see Section I-B-2,
p. ID.
The major application of CMME, the only a-haloether that is used
in substantial commercial quantities, is as a chloromethylating agent in the
production of anion exchange resins. The compound is used as the swelling
solvent as well as the reactant, and the reaction takes place under Fiedel-
Crafts conditions (see Figure la). Chloromethylation using a-haloethers
is somewhat Unusual because most displacement reactions of ot-halcethers,
whether under basic or acidic conditions, result in products in which the halogen
rather than the oxygen is displaced (Summers, 1955). This reactivity of the
chlorine atom has been attributed to the possibility for resonance stabilization.
+ " +
R'-CH-0-R« 1- R'-CH=0-R
Under proper Fiedel-Crafts conditions, both the chloromethyl
derivative and the benzyl ether can be formed (Figure lb,c). However, the
chloromethylation product always predominates, and the benzyl ether yields
are always very low (Summers, 1955). In contrast, a-haloethers under Fiedel-
Crafts conditions add across the double bond of olefins (Figure Id).
-------
(a)
(b)
(c)
(d)
C1CH2OCH3
catalyst
CX,CH2OR
C1CH2OCH
CS2
ZnC£2, etc.
ZnC£2
Figure 1 . Chloromethylation with Chloromethyl
Methyl Ether (Wheaton and Seamster,
1966; Summers, 1955)
CH-,C£
CH2OR
The other principal chemical intermediate application of haloethers
is the manufacture of polysulfides from bis(2-chloroethoxy)methane (Berenbaum and
Johnson, 1968). Figure 2 illustrates the chemical reaction involved in the poly-
merization process.
C«,CH2CH2OCH2OCH2CH2CJ!, + H2S
•t-S-SCH2CH2OCH2OCH2CH24
Figure 2. Formation of Polysulfides
10
-------
Other minor chemical intermediate applications have been noted
in the available literature. Some of these are summarized in Figure 3 (see
Table 21, p. 50, for a full list of minor chemical intermediate uses).
C£CH2CH2OCH2CH2CJl
Chemical Process
3HH"3
Reference
Nieneker (1967)
AKOH
NH2NH2
+ 2NHi+C«,
CH2=CHOCH=CH2 Ruigh and Major (1931)
RNHCH2CH2OCH2CH2NHR Fife and Reid (1930)
Farrar (1956)
0 l
Figure 3. Minor Chemical Intermediate Applications of
Haloethers
2. Hydrolysis
As noted above, there is a considerable difference between the
reactivity of a-haloethers and ethers with halogens on carbon atoms not connected
to the ether function. However, this difference cannot be demonstrated with the
two commercial fluorinated haloethers, mostly because of a lack of information.
No information was obtained on the hydrolytic stability of methoxyflurane (CHC£2-
CF2OCH3>. Since two fluorine atoms are substituted in the a-position, it might
11
-------
be suspected that the compound would hydrolyze rapidly. However, because
fluorine is a poor leaving group and the C-F bond is extremely strong (C-F =
i 116 Kcal/mole compared to C-H * 99 Kcal/mole) , hydrolysis of methoxyf lurane is
probably quite slow. The other commercial fluoroether, fluroxene (CF3CH2-
OCH=CH2) , does not contain an a-halogen. It does not hydrolyze in solutions
buffered between pH 2.0-11.0 when incubated for 3 hrs at 38°C (Ohio Medical
Products, 1972). Because of its stability, fluroxene can be used in a closed
circuit anesthesia system with carbon dioxide absorption with a 70-100°C soda
lime solution. However, the commercial product usually contains a stabilizer
to prevent polymerization and hydrolysis, which may take place in the presence
of moisture and air,
0
II
CF3CH2OCH=CH2 - >- CF3CH20H + CH3CH
Salomaa and coworkers (1966) have also indicated that under acidic conditions
vinyl ethers are readily hydro lyzed to an aldehyde and alcohol.
H30+ 0
C£CH2CH2OCH»CH2 - * CHCH2CH2OH + CH3CH(K = 0. leSM^sec"1)
25°C
For the chloroethers , the contrast between hydrolysis reactivity
for a-chloroethers compared to other chloroethers is best demonstrated in the
work of VanDuuren and coworkers (1972) . These researchers investigated the
kinetics of hydrolysis by placing known quantities (10-50 y&) of the chloroethers
in a 10 ml solution of water-dimethylformamide (3:1). By titrating the hydrochloric
acid formed with an automatic recording titrator (pH maintained at 7.0), the
pseudo first-order rate constants were calculated. The results are tabulated
in Table 4. All compounds containing an a-chloro substituent have a half life of
less than 2 minutes ; compounds with no chlorine atom in the a-position have half-
!
lives greater than one day .
12
-------
Table 4. Rate of Hydrolysis of Chloroethers in
H.O-DMF (3:1) (Van Duuren et al. , 1972)
2
Chemical
Formula
Temperature Rate
(°C) (mirTJ
(min)
Bis(l-chloroethyl)
ether
Chloromethyl methyl
ether
Bis(chloromethyl )
ether
1,l-Dlcltloroim'tliy I
methyl ether
Bis(2-chloroettiyl)
ether
Octachloro-di-n-
propyl ether
(CH3CH)20
30
30
>3.5 x 10
-1
>3.5 x 10
>3.5 x 10
-1
>3.5 x 10
<5.0 x 10
-4
<5.0 x 10
-4
<2
<2
<2
<2
>23 hr
>23 hr
The rates of hydrolysis of the non-a-chloroethers are very similar
to the hydrolysis rate of simple alkyl halides. This is illustrated by the work
of BBhme and Sell (1948), who studied the hydrolysis of $, y, and 6-chloroethers
and chlorothioethers and several alkyl chlorides in a dioxane-water mixture
(20 M water in dioxane). The kinetics were run at a temperature of 100°C. Table 5
presents the measured hydrolysis rates of reaction and half-lifes for the chloro-
ethers and alkyl chlorides. The only compound studied by both Van Duuren et al.
(1972) and BOhme and Sell (1948) is bis(2-chloroethyl)ether. Considering that
the studies were done in different solvents and at different temperatures, the
rates obtained seem to be reasonable (t, =* > 24 hr compared to 12.8 days).
*
13
-------
Table 5. Hydrolysis of 0-, Y~» 6-Chloroethers in
20 M Water in Dioxane Solution at 100°C
(Bo'hme and Sell, 1948)
Compound
C£CH2CH2OCH2CH3
C£CH2CH20 -/O/
(C£CH2CH2)20
C«,CH2CH2CH2OCH2CH3
C£CH2CH2CH20 -/O/
C£CH2CH2CH2CH20 -\Q/
CH3CH2CH2CH2C£
C£CH2CH2CH2CH2C£
CH3CH2CH2CH2CH2CH2C£
K (min"1)
0.000011
0.0000056
0.000015
0.000048
0.000023
0.000052
0.000062
0.000089
0.000053
ti (days)
17.5
34.3
12.8
4.0
8.3
3.7
3.1
2.1
3.6
Interestingly enough, the thioether analogue of bis(2-chloroethyl)ether, com-
monly referred to as mustard gas, hydrolyses approximately 4000 times as fast
as the ether.
As noted earlier, Salomaa et_ al. (1966) have studied the hydrolysis
of vinyl ethers under acid conditions. These authors have also demonstrated
that chlorine substituted acetals are readily hydrolyzed under acid conditions
(see Figure 4).
14
-------
CS,CH2CH2OCH2 • OCH2CH 3
H
•+ C«,CH2CH20*=CH2 + HOCH2CH
i H" +
C«,CH2CH20»CH2OCH2CH3 > C£CH2CH2OH + CH2=OCH2CH3
Figure 4. Hydrolysis of Chloroacetals (Salomaa et _al., 1966)
The instability of a-haloethers under hydrolysis conditions has
been recognized for some time. For example, in 1941, Bohme (see Summers,
1955) showed that the hydrolysis rate constant for 1-chloroethyl ethyl ether was
only approximately 20 times less than the rate constant for acetyl chloride
(very violent reaction with water). Bohme and Dorries (1956) examined the hydrol-
ysis and alcoholysis rates of a variety of chloromethyl ethers in dioxane. The
results are summarized in Table 6. These results demonstrate that with aryl
chloromethyl ethers hydrolysis is very slow. In fact, chloromethyl phenyl ether
may be washed with water or aqueous sodium biocarbonate during preparation
(Summers, 1955).
Table 6. Solvolysis of Chloromethyl Ethers in Dioxane
(Bohme and Dorries, 1956)
Compound 1%
«,CH2OC6H5
C«,CH2OCH2C6H5
C£CH2OCH3
C£CH2OCH2CH3 0.013
Water
2%
0.000035
0.015
0.038
0.14
kdnliT1)
3% 5% 10%
0.00041 0.0019
0.046
Methanol
20% 5%
0.012 0.000019
0.0060
0.0073
0.022
15
-------
The more recent studies on haloether hydrolysis have concen-
trated on determining the stability of C.MME and BCME in water (and other
solvolysis media) and in humid atmospheres. The studies of the rates of
hydrolysis in these two environments will be discussed separately.
Ribar and Glavas (1968) studied the rate of hydrolysis of
CMME in 95% aqueous acetone at 0°C in an attempt to clarify the mechanism
of reaction. They concluded that the reaction was not autocatalyzed by
the hydrogen chloride that is generated by hydrolysis, as had previously been
reported, and that the reaction may proceed by either an Si or S 2 mechanism
(see Figure 5). The experimental results are presented in Table 7.
-a
ROCH2C£ >•
R-0-CH-,
R-0+=CH2
HO
R-OCH2OH
ROCH2Cfc
Figure 5.
H?0 II20 C Ci -HC&
0
I
R
HO-CH2
0
R
SN! and S 2 Mechanisms for the Hydrolysis
of Chlororaethyl Ethers
16
-------
Table 7. Hydrolysis Rate Constants for Chloromethyl
Methyl Ether in 95% Aqueous Acetone at 0.0°C
(Ribar and Glavas, 1968)
"1 * (min)
Added salt (mol/ liter) K x lOec")
5.38 ± 0.10 21
2.50 x 10~3 LiC£ 9.82 ± 0.13 11
5.00 x 102 LiN02 7.58 ± 0.09 15
4.0 x 10~3 HC£ 6.68 ± 0.21 17
5.40 x 10~2 HC£ 7.82 ± 0.16 15
1.45 ± 0.30 (-20°C) 80
Jones and Thornton (1967) also studied the solvolysis mechanism
of CMME. They concluded that "the solvolysis of methyl chloromethyl ether
is S^l like, resembling _t-butyl chloride in spite of the steric possibility
of a tight, 5^2-like transition state." Some of the reported solvolysis rates
are listed in Table 8.
Tou and coworkers (Tou and Kallos, 1974a, Tou, £t al. , 1974) have
examined the hydrolysis rates of BCME in aqueous systems. During a study of
the possible formation of BCME in aqueous HC& and HCHO mixtures, Tou and
Kallos (1974a) determined the rate of hydrolysis of BCME at ambient
17
-------
Table 8. Solvolysis Rates' of Chloromethyl Methyl Ether
(Jones and Thornton, 1967)
Solvent
2-propanol
2-propanol
2-propanol
95.2% acetone KLO
95% dioxaneH20
90% dioxaneH20
ethanol
methanol
Temperature (°C)
24.87
0.0
15.1
24.87
24.87
24.87
24.87
24.87
K x 102 ( sec 1)
4.791
0.738
2.486
0.4198
0.3402
3.507
13.305
135 (extrapolated)
t| (sec)
14
94
28
165
203
20
5.2
0.5
temperature in five acidic solutions [(1) 1 ppm HC£ and 1 ppm HCHO, (2) 10 ppm
HC£ and 10 ppm HCHO, (3) 100 ppm ECU and 100 ppm HCHO, (4) 250 ppm HC£ and 250 ppm
HCHO, (5) 1000 ppm ECU and 1000 ppm HCHO] and in deionized water. The hydrolysis
rate constant was k = 0.050 sec (tt=14 sec) in all cases, and was independent
^
of the HC£ and formaldehyde concentrations. In a more intensive study of BCME
hydrolysis rates and mechanism of reaction, Tou £t_ al. (1974) studied the
hydrolysis of BCME under both acidic and basic conditions. Their reaction vessel
is depicted in Figure 15 (see p. 71). The rates of hydrolysis measured at 1 ppm
of BCME are presented in Table 9.
18
-------
Solution
Table 9. Hydrolysis of Bis(chloromethyl)ether in Water
and Aqueous HCfc and NaOH (Tou et etl. , 1974)
0°C 20°C 40°C
Rfsec"1)
Rfsec
j (sec)
2N NaOH
IN NaOH
H20
IN HC£
3N HC£
0.0079
0.0064
0.0025
0.0019
0.0011
88
108
277
365
630
0.024
0.032
0.018
0.018
0.011
29
22
38
38
63
0.064
0.13
0.10
0.12
0.088
11
5
7
6
8
From the measured energy of activation and entropy of activation,
these researchers concluded that the hydrolysis of BCME "is SI in character
in basic solutions and shifts to an S 2-like mechanism in acidic solutions." It
([O.CH-OCH ]C£-«
was postulated that carbonium ion stabilization by charge delocalization
+
£C£CH20=CH2]Cfc ) is not possible under acidic conditions
because of the protonation of the ether oxygen atom.
The hydrolysis of CMME in water has not been measured
because of its high reactivity. Tou and Kallos (1974b) have estimated
that the half-life is less than 1 second based on extrapolations of the
solvolysis study of Jones and Thorton (1967) . Nichols and Merritt (1973) demon-
strated that the solvolysis rate of CMME is orders of magnitude greater than BCME.
19
-------
In aqueous methanol at 45°C, they found a rate ratio of -1:5,000, and they
estimated a rate ratio of CMME:BCME at 0°C in 25% DMF - 75% H20 (solvent system
used by VanDuuren et^ al., 1972) to be approximately 1:1.5 x 106. With these
relative rates in mind and the hydrolysis data of Tou ejt al. (1974) for BCME,
a half-life of less than 1 second seems reasonable for CMME.
This difference between the reactivity of BCME and CMME is also
noticeable in vapor phase studies. Collier (in Nichols and Merritt, 1973) deter-
mined the reactivity of the two compounds in 70% relative humidity at 25°C.
These results are presented in Table 10. Frankel e_t al. (1974) also noted the
stability of BCME in recovery studies of 1, 5, and 12 ppb BCME in Saran bags main-
tained for 18 hr at 26°C and 40% relative humidity.
Table 10. Vapor Phase Reactivity (25°C)
(L. Collier as reported in Nichols and
Merritt, 1973)
Concentration
100 ppm CMME
1000 ppm CMME
10 ppm BCME
(percent)
70
70
70
t^(min)
6
3.5
No reaction
18 hours
100 ppm BCME
70
* 1 mole CMME/100 moles
20
-------
In a much more detailed study, Tou and Kallos (1974b) examined
the vapor phase reactivity of BCME and CMME using different water concentrations
and reactor material. Their results are presented in Table 11.
The results of Tou and Kallos (1974b) strongly suggest a surface
catalyzed reaction for CMME, thus suggesting that both BCME and CMME may persist
in the atmosphere for extended periods of time. These researchers concluded
that "stability data on CMME cannot be extrapolated from a glass system to
atmospheric environment" and that even the results that were obtained with the
Saran reactor material should only be considered as the upper limits of the rate
of hydrolysis. Therefore, the upper limits of the rate of hydrolysis taking
place in the gas phase were 0.0018 min~ (or t,>390 min) and 0.00047 min~
*2
(or t, >25 hr) for CMME and BCME, respectively, under the temperature and
water concentration conditions used.
3. Oxidation and Photochemistry
No studies have been located concerning the oxidative or photo-
lytic reactivity of the haloethers of interest to this report. However,
ethers in general are very stable compounds. Upon prolonged exposure to air,
some ethers will autooxidize to peroxides (Lurie, 1965). This does not appear
to occur with trifluoroethyl vinyl ether (Ohio Medical Products, 1972). Strong
oxidizing conditions tend to cleave unsubstituted ethers to yield the corresponding
aldehyde and carboxylic acid (Lurie, 1965). Whether haloethers react in a
similar way is unknown.
21
-------
§
1-1
o
rfl
vii
CO
•H
TJ
i
j(
v-/
cu
4J
M
rH
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33
rH
t
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o
w
rl R
>J Cd rH
0) U 0
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cd n
5 5 *
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ti
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CU
H
3 /— ^
cd u
rl 0
(1) v_,
I-
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"it
»r"
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0)
4J
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M
C
C
cd
a
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1
^-N ^
'M' 'M x JK
OO 00 CO J3 J2
• • «OOOOOcg
10 m 10 ooo ooo r^cs oo o^o _/ rH V^ v^ s_^
ON oo oo co m i^» co vo
00 lA-d-lArHinvOCN O -~T rH rH
«S«S CM OrHCO OOO -*rH O O O O
OrH H OOO OOO OCO O O O O
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CO{J\ f-« CNOIO CjNCM^ 1/">CS t~~ rH CN rH
irivo «* -»\ovo covoin cor-- vo oo •* oo
f^eN vO lOCTirH VOOCM •— |rO CN vO CN CO
rHcM rH rHrHCM rHCMCN rHCM CM CM rH CN
W^ to ^D P*- if) lO ON ^O ON U") LO to m CO CO
CMCM CM CMCMCM CMCMCM CMCM CM CM CM CM
i
fi m ^ 1 a! cci
9 flj n 3 -a M
ow s* oco^cd
oo cd ^ &o cd a.
rH C ^ TJ rH 13
CO TJOOO C .-CUt/) 1300 coal
CO 01 rH Ct) .T'WCfl CU O-U
cd en u-i »-i °,cdcd co CN«
H 3 CU Cd 5^ O rH 3 CUO
CJ fa H to Qjcjcj fn faO
•< m
22
-------
Alkyl ethers, even halogenated ones, are not stronj/, al)norl>ers
of ultraviolet light, and, therefore, if they are to react photochemically, they
must derive energy from light indirectly (e.g., sensitization). No studies are
available on the photolysis of the alkyl haloethers being reviewed in this report.
However, a study by Stenberg e_t _al. (1967) provides some insight into possible
photochemical reactions. These researchers photolyzed an oxygen-saturated
ethyl ether solution with Vycor filtered (>218 nm) and Pyrex filtered (>278 nm)
light. The oxygen-saturated solution had a wavelength maximum at longer
wavelength (X - 210 nm) than a nitrogen-saturated solution, which was
tuclX
attributed to a charge-transfer complex. The mechanism and product formed
from photolysis with the Vycor filter is depicted in Figure 6. No reaction took
place when the Pyrex filter was used.
?2
1 hv |2
02 >
^
CH3CH20-CCH3 -« CH3CH20-CHCH3«- CH3CH2OCHCH3
+
Figure 6. Photolysis Mechanism of An Oxygen-Saturated
Solution of Ethyl Ether (Stenberg e^t al. , 1967)
4. Other
The chemical difference between a-haloethers and non-a-haloethers
is also apparent in the difference in thermal stability. When a-haloalkyl
23
-------
ethers are capable of undergoing dehydrohalogenation, the compounds readily de-
compose with evolution of hydrogen halide. However, the chloromethyl ethers,
since they cannot undergo dehydrohalogenation, are relatively stable compounds,
given the exclusion of water (Summers, 1955). Nevertheless, the chloromethyl
ethers will decompose at elevated temperatures to yield the aldehyde and an
alkyl chloride.
The g-chloroethers will also decompose at elevated temperatures.
For example, Pollard and Lawson (1955) found that when solutions of bis(2-chloro-
ethyl)ether and oil are heated, hydrochloric acid is formed. Barton et_ al. (1951)
compared the thermal decomposition of ji-propyl chloride and bis(2-chloroethyl)-
ether. Bis (chloroethyl) ether decomposed at a slightly lower temperature (373-
429 °C) than n-propyl chloride (420-478°C) and yielded a complex mixture including
divinyl ether.
Chlorination of ethers initially takes place at the a-carbon. For
example, direct chlorination of ethyl ether yields 1-chloroethyl ethyl ether and
then 1,2-dichloroethyl ethyl ether.
K:X.CH2CH«,OCH2CH3
Both CMME and BCME can be produced in this manner under photochemical con-
ditions (Summers, 1957).
For other chemical properties of haloethers see the review by
Summers (1955) (a-haloalkyl ethers only) and the review of ethers in general by
Lurie (1965).
24
-------
II. Environmental Exposure Factors
A. Production and Consumption
1. Quantity Produced
Very little information is available on the quantities
of haloethers that are produced. Of the ten compounds that have appeared
in the U.S. Tariff Commission reports over the years 1959-1972 (criteria
require that the chemical be produced in a quantity of 1000 Ibs or have a
•
value of $1000), only production and sales figures for bis(2-chloroethyl)ether
during the late 1950'a and early 1960's have been published. These quantities
are depicted in Table 12. However, since bis(2-chloroethyl)ether and bis(2-
chloroisopropyl)ether are produced as by-products in the chlorohydrin synthesis
of ethylene and propylene oxide, respectively (see Section II-A-3, p. 30),
estimates of the quantities of the two compounds produced can be determined.
These estimates are also depicted in Table 12 with the references to the factors
and data used in the calculations. Comparison of the 1959 and 1960 published
production and the calculated production for bis(2-chloroethyl)ether indicates
that the calculations provide only an order of magnitude reliability. The
factor reported by Horsley (1968) (100 Ibs oxide = 2 Ibs ether) seems to be
quite different than the effluent monitoring data of Kleopfer and Fairless
(1972), thus suggesting that only a protion of the by-product that is produced
is released from production facilities. The latter authors reported that approx-
imately 150 Ibs/day of bis(2-chloroisopropyl)ether was being discharged by a
glycol plant 150 river miles upstream from Evansville, Ind. (probably the Olin
25
-------
CO
vO
O
-co
(U
X!
O
H
d)
M-l
O
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II. Environmental Exposure Factors
A. Production and Consumption
1. Quantity Produced
Very little information is available on the quantities
of haloethers that are produced. Of the ten compounds that have appeared
in the U.S. Tariff Commission reports over the years 1959-1972 (criteria
require that the chemical be produced in a quantity of 1000 Ibs or have a
value of $1000), only production and sales figures for bis(2-chloroethyl)ether
during the late 1950's and early 1960's have been published. These quantities
are depicted in Table 12. However, since bis(2-chloroethyl)ether and bis(2-
chloroisopropyl)ether are produced as by-products in the chlorohydrin synthesis
of ethylene and propylene oxide, respectively (see Section II-A-3, p. 30),
estimates of the quantities of the two compounds produced can be determined.
These estimates are also depicted in Table 12 with the references to the factors
and data used in the calculations. Comparison of the 1959 and 1960 published
production and the calculated production for bis(2-chloroethyl)ether indicates
that the calculations provide only an order of magnitude reliability. The
factor reported by Horsley (1968) (100 Ibs oxide = 2 Ibs ether) seems to be
quite different than the effluent monitoring data of Kleopfer and Fairless
(1972), thus suggesting that only a protion of the by-product that is produced
is released from production facilities. The latter authors reported that approx-
imately 150 Ibs/day of bis(2-chloroisopropyl)ether was being discharged by a
glycol plant 150 river miles upstream from Evansville, Ind. (probably the Olin
25
-------
(U
4-1
0)
o
u
3
T3
O
CN
>pyl)ether
H
bis(2-chloroiso
M
2
0>
rH
.c
4J
01
o
o
rH
U
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W
•H
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-product of propylene c
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-ohydrin
roduct of ethylene chloi
a
.£
g
•H
ffi
V.
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produced
i oxide -
ether)
;y, 1968)
M * * H
V iH »H
Production
.
3-sJ-fnfncM
OOCrlCSOO(Nl-^1f*1OS(SCM\OiO-JfOrOfMfl>4fNlCMf>tyl
i— 1 CN vO f— 1 iH ^D O
00 n f*l CM ^ CT* CM
fH 00 fH t^- 00 *A Is*-
rH rH
%O CN
CM ^
°" o^oOr^vom-*roeNrHOc>
26
-------
Mathieson propylene oxide plant at Brandenburg, Kentucky). The Olin plant has
a capacity of 130 million Iba/year, and propylene oxide plants were operated
at about 90% of capacity in 1972 (Blackford, 1973b). Using Horsley's (1968)
factor, this plant would produce 2.34 million Ibs of by-product bis(2-chloro-
isopropyl)ether a year. The estimated annual discharge of 54,750 Ibs does
not correlate well with the calculated production. The difference may be
attributed to sizable quantities being recovered, although Olin is not
listed as a producer of bis(2-chloroisopropyl)ether. Dow Chemical stated
that they collect and burn most of their bis(2-chloroisopropyl)ether that is
formed as a by-product in their propylene chlorohydrin process, and this may
be the explanation for the difference at the Olin Mathieson plant (Otis, 1975).
Dow Chemical also indicated that the amount of by-product bis(2-chloroisopropyl)-
ether is approximately equal to 2 Ibs per 100 Ibs of propylene oxide produced
and that there are no regular uses or sales for bis(2-chloroisopropyl)ether,
except that in the past some material has been exported to Japan. In 1975,
there have been no sales to Japan (Otis, 1975).
Other indirect methods are available for estimating the pro-
duction of some of the other haloethers. For example, the anesthetics, fluroxene
(CF3CH20CH=CH2) and methoxyfurane (CHC£2CF2OCH3), are probably produced in
relatively small quantities since their application requires only small amounts.
A chemical produced by Aldrich Chem. Co., 2,2-dichloroethyl methyl ether, has
never appeared in the U.S. Tariff Commission reports and, therefore, is probably
produced in extremely low quantities. Similarly, chloromethyl phenyl ether has
only recently appeared in the U.S. Tariff Commission reports, thus indicating
relatively small amounts. Polychlorinated propyl ether, a compound produced by
27
-------
the Jefferson Chemical Co. in 1963-1966, is no longer being manufactured in
sufficient quantity for inclusion in the U.S. Tariff Commission reports
(probably not produced at all). 2-chloroethyl vinyl ether is probably
synthesized from bis(2-chloroethyl)ether (Lurie, 1965) and, therefore, the
vinyl ether production has probably declined similar to the bis(2-chloro-
ethyl)ether production (Union Carbide, r.he major manufacturer of the vinyl
ether, reports that they are no longer making any haloethers.
Both bis(2-chloroethoxy)methane and 2-(2-chloroethoxy)ethyl
2-chloroethyl ether are produced from ethylene chlorohydrin (C£CH2CH2OH).
Blackford (1973a) estimated that only about 20 million Ibs of ethylene oxide
(produced by direct oxidation) are consumed in the production of ethylene
chlorohydrin. The chlorohydrin is used as an intermediate in the production
of many chemicals besides the ethers, such as indigo and thiodiethyleneglycol.
In addition, bis(2-chloroethoxy)methane is principally consumed in the synthesis
of polysulfide polymers which are produced in approximately 11.5 million Ib
quantities (1.5 million, solid elastomers; 10 million, liquid polymers)
(Berenbaum and Johnson, 1968).
In 1965, BCME was produced by General Aniline in large enough
quantities to be listed in the U.S. Tariff Commission reports, but is no longer
being produced. However, in the past, sizable quantities of BCME were produced;
for example, between September 1917 and May 1918, 466,000 Ibs of BCME were
produced by the Germans for use as a war gas and chemical intermediate (Lurie,
1965). CMME, which contains a small amount of BCME (Collier, 1972), is used
as a chloromethylating agent in the production of strong-base anion-exchange
resins and ionic bactericides (Marceleno and Bierbaum, 1974). The quantity of
CMME used is unknown, but is entirely consumed in internal use.
28
-------
The quantities of haloethers and ethers in general that
are imported or exported are considered to be very small due to high
transportation costs (U.S. Tariff Commission, 1969). The costs can be
attributed to the high volatility of the compounds which results in special
shipping considerations.
2. Producers, Major Distributors, Importers, Sources of Imports,
and Production Sites
Haloether compounds as a group are somewhat unusual due to the
fact that many of the commercially important compounds are only found in large
commercial quantities because they are inadvertent by-products of other major
commercial products. Thus many of the haloethers are produced at sites and
with equipment meant for an entirely different purpose. This is the case with
bis(2-chloroethyl)ether and bis(2-chloroisopropyl)ether, both of which are
found as by-products from the chlorohydrin synthesis of the corresponding
epoxlde. Complicating this situation is the fact that presently direct
oxidation of ethylene to ethylene oxide is economically more attractive
than the chlorohydrin route and, therefore, all of the chlorohydrin ethylene
oxide facilities have either been closed or converted to propylene oxide. In
addition, some manufacturers are beginning to use a direct oxidation process
for propylene oxide. Thus the producers and sites of production, at least
for some of the major haloethers, appear to be in a continuous state of change.
29
-------
This continually changing picture is reflected in Table
13 which lists some of the past and present manufacturers of haloethers.
Where the information is available, the sites and capacities of the plants
are noted in Table 14.
3. Production Methods and Processes
The two major commercial haloethers, bis(Z-chloroethyl)-
ether and bis (2-chloroisopropyl) ether, are in most instances produced
as by-products in the chlorohydrin synthesis of ethylene oxide or propylene
oxide. The chlorohydrin approach is economically attractive when a good
supply of captive low-cost chlorine and lime or caustic soda as well as
a market for the by-products, 1,2-dichloroethane or propane and the halo-
ethers, are available (Schultz, 1965). Both chlorohydrin processes will
be reviewed, although chlorohydrin synthesis of ethylene oxide has not
been used since 1972.
Ethylene oxide was initially produced commercially by
reacting ethylene with hypochlorous acid to yield the ethylene chloro-
hydrin followed by treatment with base to provide ethylene oxide. The
hypochlorous acid can be formed in two ways: (1) by mixing a slurry of
hydrated lime with a stream of chlorine to yield the unstable calcium
oxy chloride which decomposes to give hypochlorous acid and calcium
chloride, or (2) by dispersing chlorine in water.
(1) CaO + C£2 ------ *
CaC«,(OC«.) + CJi2 + H20
(2) HOH + C£2 " - y HCK. + HOC&
30
-------
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31
-------
Table 14. Capacities and Production Sites of Haloether Manufacturers
(SRI, 1974; Blackford, 1973a,b).
Capacity (106lbs)
(in terms of oxide
produced by chloro-
Chemical Cony any Location hydrin route)
Remarks
(C1CH2CH2)20
CH3
1
1
(C1CH2CH)20
C1CH2CH2-0
CH2=CH
C1CH2OCH3
(C1CH2CH20)CH2
C12CHOCH3
CHC12CF2OCH3
CF.qCH?OCH=CH?
Buckman Labs.
Dow Chemical
Union Carbide
Dow Chemical
Union Carbide
BASF Wyandotte
Jefferson Chem.
Olin Corp.
Union Carbide
Stauffer
Rohm and Haas
Diamond Shamrock
Dow Chemical
Thiokol Corp.
Aldrich Chem.
Dow Chemical
Airco Inc.
Cadet, MO
Memphis, TN
Freeport, TX 200
Institute and
South Charleston,
WV
Freeport, TX 600
Plaquemine, LA* 220
South Charleston, 220
WV
Wyandotte, MI* 175
Port Neches, TX* 150
Brandenburg, KY* 130
Institute and
South Charleston,
WV
Edison, NJ
Philadelphia, PA
Redwood City, CA
Midland, MI
Moss Point, MS
Milwaukee, WI
Midland, MI
Cleveland, OH
Converted to
propylene oxide
(1972)
No longer pro-
duces this
compound
Closed May, 1972
May have closed
in 1974
No longer pro-
duces this
compound
* Not listed as manufacturing site in SRI Directory of Chemical Producers, 1974.
32
-------
Two major by-products, 1,2-dichloroethane and bis (2-chloroethyl) ether ,
which are formed during the chlorohydrin formation are depicted below.
C1+
H
CH2=CH2 + HO Ci — •*• GH2-CH2 + OH~
,C\+
CH2CH2 + OH - >• HOCH2CH2C£
-OH, CH2OH
CHo ^"2
^V
CH2C£
CH2 HOCH2CH2C£ CH2CH2C£
iH2/C£ -- ' <
^ NCH2CH2C£
Figure 7. Formation of Bis(2-chloroethyl)ether During Chlorohydrin
Synthesis of Ethylene Oxide
From the equations above, it can be seen that the amount of 1,2-dichloro-
ethane formed is dependent upon the ethylene and chlorine gas concentrations
and that the amount of ether formed is dependent upon the ethylene chloro-
hydrin concentration. In most chlorohydrin processes ether formation is
minimized by avoiding hig'n chlorohydrin concentrations (Lichtenwalter
and Riesser, 1964).
A typical chlorohydrin process ethylene oxide plant is
depicted In Figuie U. Hie bisU~ chloroeLliyljeLliel would be found with llie
ethylene dichloride noted in the diagram. Table 15 notes the quantities of
reactants consumed aud products formed in the production of 1000 Ibs of
ethylene oxide in 80% yield.
33
-------
Water znc
caustic soda
scrubbers
Ethylene
Cnlorchydrin
reactor anc
conoenser
Hycroly:er
Ethylene oxide
distillation
system
Chlorine
Water
Water +
calcium
chloride
and some
ethylene
dichloride
Chlorinated
hydrocarbon
by-products
to recovery
unit
Refined
ethylene
oxide to
storage
Fig. 8. Chlorohydrin process for manufacturing ethylene oxide (Schultze, 1965)
LEGEND: FCV, flow-control-valve; LCV, liquid-control valve;
TCV, temperature-control valve.
(Reprinted with permission from Wiley - Interscience)
34
-------
Table 15. Reactants and Products of the Ethylene Oxide
Chlorohydrin Process (Schultze, 1965)
Reactants Products
Compound Quantity (Ibs) Compound Quantity (Ibs)
Ethylene 800 Ethylene oxide 1000
Chlorine 2000 Calcium chloride 3200
Lime (as CaO) 1600 1,2-dichloroethane 100-150
Bis(2-chloroethyl)ether 70-90
Acetaldehyde 5-10
As noted earlier, ethylene oxide is no longer commercially produced
by the chlorohyc'rin route. This is basically due to the fact that the
direct oxidation process has lower operating costs, although the capital
investment for direct oxidation is 50% higher than the chlorohydrin process.
(Schultze, 1965)
Bis(2-chloroethyl)ether can also be produced in high
yield by saturating an aqueous solution of ethylene chlorohydrin with
chlorine and ethylene or by heating ethylene chlorohydrin with sulfuric
acid (Tschamler, 1950).
The propylene chlorohydrin route to propylene oxide still
enjoys a competitive economic position. Approximately 70% of the capacity
is still based on chlorohydrination as opposed to peroxidation (direct
oxidation). The switch to the direction oxidation route to ethylene
oxide has freed paid-up ethylene chlorohydrin facilities for propylene
chlorohydrin manufacture, "posing stiff competition, indeed for direct
propylene oxide processes" (Sittig, 1968). This is especially true
35
-------
considering that chlorohydrin plants for ethylene oxide are readily
converted to propylene oxide in only 24-36 hr (Lapkin, 1965).
As with ethylene chlorohydrin, propylene chlorohydrin
is formed by reacting hypochlorous acid with propylene. However, unlike
the ethylene chlorohydrin process, two chlorohydrins are possible with
propylene chlorohydrin, and as a result three ethers may be formed (see
Figure 9).
HO+CJl~
CH3CH-CH2
+
\
CV
t . H20
CH2
CH3CHCH2
OHCJl
CH3CHCH2
CH3dH-CH2
CH3-CH-CH2
3 I I 4
OH CJl
a-chlorohydrin
CH3-CH-CH2
! "I 2
CJl OH
6-chlorohydrivi
CH3-CH-0-CH-CH3
CH2CJICH2CJI
CH3-CH-CH2OCHCH3
CJl
major ether
CH3-CH-CH2OCH2CHCH3
ca en
Figure 9. Formation of Bis(2-chloroisopropyl)ether and Related Ethers
During Chlorohydrin Synthesis
36
-------
The a-chlorohydrin is the major product, because of the stability of the
secondary carbon atom, but the isomer ratios has been reported to vary from
3:1 to 9:1 (Lapkin, 1965). The major ether isomer is the bis(2-chloro-
isopropyl)ether. As with the production of ethylene chlorohydrin, a major
by-product, which is formed in larger quantities than the ethers, is the
propylene dichloride.
A typical chlorohydrin reactor for manufacturing propylene
oxide is depicted in Figure 10. The haloethers would be found at the
same locations as crude propylene dichloride: (1) in the chilled caustic
soda wash of unreacted gases (sometimes a partial condenser is used to
remove propylene dichloride and bis(chloroisi3propyl)ether, Horsley, 1968)
and (2) in the aqueous effluent from the steam heated flash hydrolyzer.
Yields for hypochlorination of propylene are frequently
in the neighborhood of 90%, although the yield can be improved by reducing
the chlorohydrin concentration to less than 4% (Lapkin, 1965). For
every ton of oxide produced, 40 tons of aqueous effluent are generated
(Lapkin, 1965) which can present a major disposal problem. Depending
upon the location and local ordinances, the effluent may be simply dis-
charged or it may be treated by a sewage works before release. Table
16 shows the ratio of reactants to products in a typical propylene chlorohydrin
plant.
37
-------
Chlorohydrin
tower ,
Crude x-Sef
propylene f/\
'dichloride /^
propylene dichloride
Recycle gas/
booster
Figure 10. Diagram of a Typical Chlorohydrin Propylene Oxide Plant
(Fyvie, 1964)
(Reprinted with permission)
38
-------
Table 16. Products and Reactants of a Typical Propylene
Chlorohydrln Plant (Horsley, 1968)
Reactants Ib moles
propylene 94 2.24
chlorine 159 2.24
lime (as CaO) 109 1.95
Products
propylene oxide 100 1.72
propylene chloride 9 0.0796
dichloropropyl ethers 2 0.0117
CaCl2 brine (100% basis) 215 1.95
i ,•
As with bis (2-chloroethyl) ether, bis(2-chloroisopropyl)
ether can also be prepared by dehydration with sulfuric acid.
CJICH2CHOH — — ». CACH2CHOCHCH2CK.
CHj CHjCHj
Information on the commercial synthesis of the other
haloethers is not very detailed. The following will review some of the
processes that may be used in industry. However, although it is likely
that the basic chemistry may remain the same, the equipment and handling
may change considerably.
While CMME can be made by a variety of approaches
including direct chlorination of dimethyl ether (Hake and Rowe,
1963; Lurie, 1965), the most frequently used technique is to pass
gaseous hydrogen chloride through a heated solution of form-
aldehyde and methanol (Hake and Rowe, 1963; Summers, 1955; Fieser and
39
-------
Fieser, 1967; VEB Farbenfabrik Wolfen, 1967a,b; Cherepanova and Chereva,
1961). In this process, small amounts of BCME (several percent) are also
produced (Collier, 1972).
HCHO + CH3OH — > CACH2OCH3
In the past, CMME was produced in batches in loosely covered reaction kettles
(Figueroa et^ jtl. , 1973). However, because of occupational exposure, CMME is
now generated in batches in completely enclosed rooms (Rohm and Haas, personal
communication, 1975). The ether that is formed is reacted with the polymer chain
and any remaining ether is destroyed by hydrolysis workup. The source of
formaldehyde can be paraformaldehyde, poly(oxymethylene) , or tris(oxyinethylene) .
German patents by VEB Farbenfabrik Wolfen (1967a,b) suggest using a counter-
current reactor and an excess of paraformaldehyde (the latter increased the
yield). Yields can also be increased by passing a stream of inert gas (N. ,
air, or preferably HC&) through the aqueous waste acid and recovering the BCME
from the gas stream by cooling (Bachman et al. , 1966).
The methods for preparing BCME have been reviewed by
Buc (1956). For laboratory purposes, the most convenient procedure
is the reaction of paraformaldehyde and chlorosulfonic acid (source
of hydrochloric acid) .
2 CH20 + 2 CfcS03H + H20 - > (C1CH2>20 + 2 ^80,+
Evidence also suggests that BCME is formed whenever formaldehyde and a
chloride ion source are present (Frankel et al. , 1974; Marceleno and Bierbaum,
1974; Marceleno et al. , 1974a,b).
40
-------
At the present time, the exact path of formation for BCME using
formaldehyde and HC1 is unknown. Solomon (1975) suggested that it can take
path & (see Figure 11) which involves the intermediacy of a formaldehyde dimer
HOCH2OCH2+ or path b_ which involves the intermediate formation of chloromethanol.
He quoted Olah and Yu (1975) as demonstrating that the hydroxycarbonium ion gives
chloromethyl alcohol with HC1 and that this exists as an intermediate in acid
medium as the chloromethyloxonium ion. Combination of the species with pro-
tonated formaldehyde followed by attack of chlorine leads to the direct form-
ation of BCME. Although both paths may be involved in the formation of BCME,
path b_ is likely to predominate. These and other processes are presently under
investigation by the National Institute for Occupational Safety and Health (NIOSH)
through contract with the Bendix Corporation which is also evaluating existing
BCME analytical and sampling protocols.
path a
_..- path b_
C1-H2C-0-CH2
HC -0-CH-OH
Cl-H.C-0-CH OH
• A I "
T1-
Cl
C1-H2C-0-CH2-C1
C1-CH2-0-CH2
C]
C1-CH2-0-CH -Cl
Figure 11. Suggested Mechanism for the Formation of Bis(chloromethyl)ether
41
-------
The synthetic route used for commercial synthesis of
methoxyfurane (CHCX,2CF2OCH3) ia unknown. However, a patent by Hudlicky
(1965) suggests the following approach.
CH3ONa
CH3OH + F2C»CC£2 - »- CH3OCF2CHC£2
or KOH
In order to synthesize 2-chloroethyl vinyl ether,
a dehydrochlorination approach from the bis(2-chloroethyl)ether may
be used (Lurie, 1965).
CX,CH2CH2OCH2CH2Cfc & & "* CiCH2CH2OCII-CH2
Bis(2-chloroethoxy)methane has been produced for many years
for consumption in polysulfide polymers. It is prepared by condensation of
ethylene chlorohydrin with anhydrous formaldehyde. An azeotroping agent
is used to drive the reaction to completion by removing the water formed in
the process (Berenbaum and Johnson, 1968).
2 C£CH2CH2OH + CH20 — + CX-CH2CH20CH2OCH2CH2CX. + H20
42
-------
4. Market prices
Recent information on the markat price of commercial haloethers
is not available. However, some historical information is available on bis
(2-chloroethyl)ether and bis(2-chloroisopropyl)ether. Lurie (1965) reported
that the ethers, when shipped in 55 gallon drums, were sold for $0.13-15/lb.
The price of bis(2-chloroethyl)ether during the early 1960's is listed in Table 17,
Table 17. Price of Bis (2-chloroethyl)ether
(U.S. Tariff Commission)
Year 1959 1960 1961 1962 1963 1964 1965
Price($/lb) 0.07 0.02 0.02 0.02 0.02 0.02 0.09
Table 18 lists the prices of a variety of haloethers when they
are sold in laboratory quantities. Although the prices are far removed from
the value of large commercial quantities of the chemicals, they are somewhat
indicative of the relative value.
Table 18. Prices of Haloethers (Aldrich, 1975-76)
Ether Price $
Bis(2-chloroethyl)ether 6.00/500g
Bis (2-chloroisopropyl)ether 15.75/4kg
2-Chloroethyl vinyl ether 24.90/500g
Chloromethyl methyl ether 17.35/500g
ot,a-Dichloromethyl methyl ether 23.50/100g
43
-------
5. Market Trends
Use of haloethers in large commercial quantities appears to be
declining. Bis(2-chloroethyl)ether, which was produced in 26 million Ibs in
1960, is no longer produced in large quantities due to the change over to direct
oxidation production of ethylene oxide. Direct oxidation is also beginning
to infringe on chlorohydrin synthesis of propylene oxide, thus leveling off
the availability of by-product bis(2-chloroisopropyl)ether. Use of CMME
in the production of ion exchange resins seems to be continuing, although
large investments are being incurred in order to prevent occupational
exposure to the chemical (Dr. E. Beavers, Rohm and Haas, cited in Hricko and
Pertschuk, 1974). The anesthetics will probably continue to be used in small
quantities and the acetal, bis(2-chloroethoxy)methane, will continue to be
consumed as the principal monomer in the production of polysulfides.
B. Uses
1. Major Uses
The major commercial applications of haloethers can be grouped
into three general areas: (1) anesthetics - usually fluorinated ethers, (2)
chemical intermediates - mostly the a-haloethers because of their reactivity,
and (3) solvent use - usually the (3-haloethers due to their stability, low
price, high boiling points, and unique solubility properties. These uses are
summarized in Table 19.
The two commercial haloethers which contain fluorine substituents
are exclusively used as general anesthetics. Fluroxene (CF3CH2-OCH=CH2) is
44
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Table 19. Major Uses of Haloethere
Compound
Fluroxene
Me thoxyflurane
Bis(2-chloroethoxy)methane
Chloromethyl methyl ether
Bis(2-chloroethyl)ether
Bis(2-chlorois:opropyl) -
ether
Structure
CF3CH2OCH=CH2
CH«,2CF2OCH3
(C£CH2CH20)2CH2
CfcCH2OCH3
(C£CH2CH2)20
CH3
(C£CH2CH)20
Use
General anesthetic
General anesthetic
Principal monomer in the pro-
duction of polysulfides
Chloromethylating agent for
anion exchange resins, membranes,
and other aromatic products
Dewaxing agent for lubricating
oils - Solvent, pentrant, and
wetting agent in the textile
industry - Chemical intermediate
Solvent in paint and varnish
removers, spotting agents, and
cleaning solutions - Soap addi-
tive in textile industry -Chemical
intermediate
usually administered by inhalation using onen, semi-aloqpH, or closer)
(Ohio Medical Products, 1972). It has the advantage of rapid induction of
anesthesia at comparatively low levels in inspired air and yet recovery is rapid
due to low solubility of the compound in blood. Methoxyflurane (CHC£2CF2OCH3)
is an excellent volatile anesthetic which has a slow induction time, but good
relaxation of skeletal musculature (Krantz, 1963).
45
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Bis(2-chloroethoxy)methane (C1CH2CH20CH2OCH2CH2C1) finds its major
application as the principal monomer in polysulfide polymers (Berenbaum and Johnson,
1968). The chemical is manufactured by Thiokol at their Moss Point, Mississippi,
plant and is totally consumed in the production of polysulfides. These specialty
polymers are used as room temperature curing liquid polymers in the sealant and
adhesives market because of their good solvent resistance, good low-temperature
performance, and good weathering and ozone resistance. There is also a limited
market (-1.5 million Ibs/year, 1968) for the solid elastomers in printing rolls,
paint spray hoses, and solvent resistant gaskets and diaphragms. The polymers
are formed by polycondensation of the bis(2-chloroethoxy)methane with an aqueous
polysulfide solution. Frequently, 1,2,3-trichloropropane is added for cross-
linking and in some instances bis(4-chlorobutoxy)methane or bis(4-chlorobutyl)ether
are used in minor amounts to improve low temperature performance (Berenbaum and
Johnson, 1968).
Since the ct-haloethers are very reactive, they constitute a useful
class of intermediates (Lurie, 1965; Summers, 1955). Of this group of chemicals,
CMME is the most important commercially. It is generally used as a chloro-
methylating agent in many synthetic processes, the most important being the
chloromethylation step in the production of strong-base anion exchange resins.
The companies and their plant locations which use CMME for producing ion exchange
resins are listed in Table 20.
Table 20. Principle Ion Exchange Resin Producers
(Wheaton and Seamster, 1966)
Company Location Trademark
Diamond Shamrock Redwood City, Calif. Dualite
Dow Chemical Co. Midland, Mich. Dowex
Rohm and Haas Co. Philadelphia, Pa. Amberlite
lonac Chemical Corp. Birmingham, N.J. lonac
46
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The strong-base anion exchange resins are made by attaching a quarternary ammonium
group to a poly(styrene-divinylbenzene)matrix. The chloromethylation is accom-
plished by placing the copolymer beads in the ether (beads become fully swollen)
with a Friedel-Crafts condensation catalyst (e.g. A1C13, SnCl^, FeCl3 or ZnCl2).
-CH - CH2 - CH - CH2-
,..-,.
Catalyst
-CH - CHo -
— CH "~ CH 2 ~~ CH — CH 9 ~~
-CH - CH2 - ' ' '
+ CH3OH
the chloromethylated polymer is then reacted with various tertiary amines to form
the quaternary ammonium salt.
-CH2C1 + NR3
-CH2NRljci~
The two tertiary amines which are used most commonly are trimethylamine (Amberlite
IRA-400, Amberlite IRA-401, Amberlite IRA-402, Amberlite IRA-900, Duolite A-101-D,
Duolite ES-111, Dowex 1, Dowex 11, Dowex 21K, and lonac A-540) and dimethylethanol-
amine (Amberlite IRA-410, Amberlite IRA-911, Dowex 2, Duolite A-102-D, lonac A-542,
and lonac A-550) (Wheaton and Seamster, 1966).
The commercial uses of the two B-haloethers, bis(2-chloroethyl)ether
and bis(2-chloroisopropyl)ether, are extremely similar. The ethyl ether, which is
frequently identified by the Union Carbide tradename Chlorex (Lurie, 1965), was
first recognized as an effective, low-cost solvent (Fairhall, 1949). In the past,
its principal use was as a dewaxing agent for lubricating oils because it is a
47
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powerful solvent for naphthenic components but a poor solvent for paraffin com-
ponents (Fairhall, 1949; Jacobs and Scheflan, 1953; Pollard and Lawson, 1955;
Mervart jat _al., 1960). After separation, the solvent is recovered by distillation
(Pollard and Lawson, 1955). The chloroethyl ether has also been used to separate
butadiene from butylene (Lurie, 1965). The second major use of bis(2-chloroethyl)
ether is in the textile industry as: (1) a solvent to remove paint and tar brand
marks from raw wool and oil and grease spots from cloth, and for use in scouring
and fulling soaps where low solvent loss at elevated temperatures is required
(sometimes used to replace sodium hydroxide in kier boiling), and (2) as a wetting
agent and penetrant in combination with diethylene glycol, sulphonated oils, etc.
(Browning, 1953; Jacobs and Scheflan, 1953; Allen, 1956). The compound generally
is a good solvent for tars, fats, waxes, oils, resins, pectins, and will dissolve
cellulose esters when used with 10-30% ethanol (Fife and Reid, 1930). The ether
also finds some application as a chemical intermediate. The quantities of bis-
(2-chloroethyl)ether used in these applications is unknown but is expected to be
very low based on the fact that the two major manufacturers (Dow Chemical and
Union Carbide) are no longer producing the compound.
Bis(2-chloroisopropyl)ether is also an excellent solvent and
extractant for fats, waxes, and greases and finds some use as a cleaning and
spotting agent as well as an additive to paint and varnish removers (Hake and
Rowe, 1963; Lurie, 1965). However, its use in dewaxing lubricating oils is not
as common as it is with Chlorex. Similar to the chloroethyl ether, the chloro-
isopropyl ether is used to assist the action of hot soap solutions used in textile
processes. The ether is also used as a chemical intermediate where a more oil
soluble product than formed with the chloroethyl ether is desired (dyes, resins
and Pharmaceuticals - Hake and Rowe, 1963).
48
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2. Minor Uses
A number of miscellaneous applications of haloethers have bt>t:u
reported in the literature. These are summarized in Table 21 with the appropriate
references. Some of the compounds in Table 21 were not discussed in the previous
section because they are used in such small quantities.
3. Discontinued Uses
The available information on the uses of haloethers is not very
up-to-date or quantitative. However, one compound that is being used less and
less is bis(2-chloroethyl)ether. The two major manufacturers no longer make the
chemical, and the chlorohydrin process to ethylene oxide, which produces bis (2-
chloroethyl)ether as a by-product, has not been used since 1972. When bis(2-
chloroethyl)ether was a relatively cheap, unwanted by-product of another large
commercial process, it had numerous applications. However, now that the compound
is relatively expensive, it probably finds little application, especially in its
solvent applications. Even when it was relatively inexpensive, Mervart et al.
(1960) concluded that aqueous acetone was less expensive than bis(2-chloroethyl)-
ether for the isolation of 1,3-butadiene from 1-butene.
4. Projected or Proposed Uses
Table 21 lists a number of minor applications of haloethers that
might be potential major uses. In many cases, the more recent references are
patent applications and, therefore, possible growth applications. Of the compounds
cited, 2-chloroethyl vinyl ether appears to have the greatest potential for growth.
Its successful use as a copolymer would substantially increase the amount of com-
pound being produced.
49
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Table 21. Minor Uses of Haloethers
Compound
(C1CH2CH2)20
CH3
i
(C1CH2CH)20
(C1CH2CH2CH2CH2)20
C1CH2CH2OCH"CH2
C1CH2OCH3
C1CH2OCH2C1
Us.
IX H20 suspension-lniectlcldal soil fumlgant
dry-cleaning agent
insecticide, acaricide, and soil fumigant
gasoline additive to scavenge lead deposits
synthesis of morpholine, N-substitute morphollne, and
divinyl ethyl
synthesis of plasticiters, synthetic rubbers,
Pharmaceuticals and resins
aqueous solution - soil disinfectant against Japanese
beetle grubs and wire grubs
synthesis of amino ethers (inhibitors, antloxldants,
and antiknock compounds)
one of three ways to synthesize morpholine
synthesis of 4-aminomorpholine (reaction with hydrazine)
synthesis of divinyl ether
used with 1,3 dichloropropene and 1,2-dichloro-
propane in microcapsules as a nematocide
used to prepare good impact resistance styrene copolymers
synthesize 8-(B-chloroethoxy)phenetole analogues of DDT
synthesis of surfactants
low-temperature dewaxing of oils
used in wood preservative formulation with pentachloro-
phenol Na salt
used in minor amounts as monomer in polysulfides to
improve low-temperature performance
oil and water repelling copolymer for cotton
copolymer with acrylic elastomers
copolymer beads
synthesis methoxymethyl ethers of phenols
crosslinking polystyrene
surface treatment of vulcanized rubber to increase
adhesion of epoxy resin or polyurethane elastomers
crosalinking cellulose
preparation of three-block styrene-butadiene-styrene
polymers
surface treatment of vulcanized rubber to increase
adhesion of epoxy resin and polyurethane elastomers
Reference
Hake and Rowe (1963)
Lurie (1965)
Fairhall (1949)
Fife and Reid (1930)
Nieneker (1967)
Farrar (1956)
Ruigh and Major (1931)
Siebel (1972)
Ihouchi (1974)
Omarov e_t al. (1966)
Anon (1975)
Seleznev and Stepuro (1962)
Ishii et^ a^. (1974)
Berenbaum and Johnson (1968)
Klrimoto and Hayashi (1974)
Kaendler ejt al. (1973)
Cohen (1970)
Fieser and Fieser (1967)
Peyrot (1971)
Honda e_t aJL. (1974)
Guthrie and Heinzelman (1972)
Bebb and Carr (1971)
Honda et al. (1974)
50
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5. Possible Alternatives to Use
The uses of haloethers can be divided into two broad categories •
(1) applications that use the chemicals as intermediates, and (2) applications
that make use of the physical properties (e.g., solubility) of the chemicals.
Alternatives to the latter uses are easier to find since other chemicals can
often be used. However, with chemical intermediate applications, few alternatives
are possible unless a new synthetic route is developed.
Of the major haloethers (Table 19), CMME and bis(2-chloroethoxy)-
methane are used exclusively as chemical intermediates. CMME is used in the
manufacture of anion-exchange resins. The resins find applications in deionizing
water and as a method of separation in many industrial chemical processes
(e.g., recovering uranium from sulfuric acid leach liquors) (American Chemical
Society, 1973). The occupational difficulties encountered with CMME (see
Section III-C-1, p. 86) have provided considerable incentive to review alter-
native synthetic approaches. Whether possible alternatives were seriously
considered is unknown, but the fact that the anion exchange resins are still
being produced by the CMME route even with costly modifications of the pro-
duction facilities suggests that alternatives to this use of CMME are limited.
However, an alternative approach to the benzyl chloride function through side-
chain chlorination of polyvinyltoluene has been reported (McMaster et al., 1953) .
Bis (2-chloroethoxy)methane is the principal monomer in the
production of polysulfides. The polysulfides are commercially modest, specialty
polymers which are used mostly for their solvent resistance. Other dihalide
monomers might be used, but whether they would provide the same desired proper-
ties is unknown. Other compounds such as silicones might be used, but such
alternatives require considerably more review than is possible here.
51
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The two fluorinated haloethera are used exclusively as general
inhalation anesthetics. Other inhalation anesthetics that might be used as
alternatives include nitrous oxide, ether, chloroform, ethylene, cyclopropane,
vinyl ether, ethyl vinyl ether, ethyl chloride, trichloroethylene and halothane
(CF3CHBrCl) (Krantz, 1963).
The two remaining commercial haloethers, bis(2-chloroethyl)ether and
bis(2-chloroisopropyl)ether, are mostly used as solvents. The uniqueness of their
solvent properties is difficult to assess, but it appears, at least for bis(2-
chloroethyl)ether, that its use was more dependent upon its price than on its
solubility properties. Presently, little bis(2-chloroethyl)ether is used in
solvent applications, so some alternatives must have been devised. As noted earlier,
Mervart ejt a_l. (1960) concluded that aqueous acetone was cheaper for the
separation of 1,3-butadiene from 1-butene. The chemical intermediate applications
of the two compounds would be much more difficult to replace. Contamination from
the chemical intermediate use of bis(2-chloroethyl)ether may be quite signi-
ficant (Anon., 1975).
52
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C. Environmental Contamination Potential
1. General
The potential for environmental contamination from haloethers
varies considerably with the different compounds and applications. The greatest
potential appears to be from the inadvertent production of these chemicals in
other industrial processes such as the chlorohydrin processes. These potential
sources will be discussed in greater detail in the following subsections. Other
sources are also briefly discussed when information is available.
2. Production
CMME containing a few percent of BCME is produced by Rohm and
Haas in a plant building where the chemicals are isolated from the workers by
closed partitions and the area is maintained at negative pressure. A trailer
located just outside the building routinely draws air samples from eight differen:
locations in the plant. This monitoring assures that the workers are not ex-
posed to more than 1 ppb of BCME (limits of detection of the dual gas-chromato-
graphic technique). In addition, "procedures have been developed for decon-
taminating all waste streams, both gaseous and liquid, that might contain bis-
CME" and these procedures have been instituted in the Rohm and Haas Philadelphia
plant (statement of Dr. E. Beavers, Rohm and Haas, cited in Hricko and Pertschuk,
1974). The above information is all that was available in the reviewed liter-
ature. Whether the plants and analytical sampling systems are similar in other
companies that produce CMME (i.e., Stauffer, Diamond Shamrock, and Dow Chemical),
is unknown.
53
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3. Transport and Storage
The quantities of haloethers lost during transport and storage
are unknown. CMME and BCME are produced and consumed at the same location and,
therefore, no loss during transport and storage is likely. Similar reasoning
applies to bis(2-chloroethoxy)methane which is produced and probably used at the
same plant by Thiokol in the synthesis of polysulfides. Bis(2-chloroethyl)ether
and bis(2-chloroisopropyl)ether are available in 55-gal drums (Lurie, 1965),
and fluroxene (CF3CH20CH»CH2) is packaged in amber bottles containing 125 ml
(Ohio Medical Products, 1972).
4. Uses
The possibility of loss of CMME and traces of BCME during their
use as chloromethylating agents in the production of anion exchange resins seems
rather remote. After the chloromethylation step, the polymer is reacted with a
tertiary amine in a polar solvent such as water (Wheaton and Seamster, 1966). The
half-lifes of these two compounds in aqueous systems is a matter of seconds (see
Section I-B-2, p.11, on hydrolysis) and, therefore, all the material should be
destroyed. Rohm and Haas has ruled out the possibility of BCME remaining in the
anion-exchange resins by radiotracer experiments with C11+ BCME (statement of
Dr. E. Beavers, Rohm and Haas, cited in Hricko and Pertschuk, 1974).
In contrast to the a-chloroethers, some of the other chloroethers
are likely candidates for release to the environment. When bis(2-chloroethyl)-
ether is used to separate paraffins from lubrication stocks, the solvent is recovered
by distillation. In order to completely strip the solvent, live steam is introduced
54
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into the evaporator (Pollard and Lawson, 1955). This contact with water could
be a source of water contamination. Two 8-chloro compounds, bis(2-chloroethoxy?
methane and bis(2-chloroethyl)ether, have been detected in the treated wastes
from a synthetic rubber plant (140 mg/fc and 0.16 mg/£, respectively) (Webb et al.,
1973). In addition, just recently bis(2-chloroethyl)ether has been detected in
the effluent from the Rohm and Haas Philadelphia plant (Anon., 1975). Rohm and
Haas acknowledged that they were discharging up to 135 Ibs/day of the intermediate,
which is used in industrial surfactant production.
5. Disposal
No information was located on the disposal procedures for haloethers.
However, with the a-chloroethers, hydrolysis is an obvious choice because of the
rapid rate of reaction.
6. Potential Inadvertent Production of Haloethers in Other
Industrial Processes
Because BCME is a potent carcinogen, considerable attention
has been focused on possible inadvertent production of the chemical in various
industrial processes. BCME is produced in the laboratory by reacting formal-
dehyde with hydrochloric acid (Buc, 1956). However, until 1973, no one con-
sidered whether BCME would be formed when formaldehyde and hydrochloric acid
were present at low concentrations.
The Rohm and Haas Company (Anon., 1973) first announced that BCME
can form spontaneously in ordinary humid air. In a detailed study, Frankel et
al. (1974) studied a variety of concentrations of hydrogen chloride and formaldehyde
at room temperature and 40% relative humidity. The amount of BCME formed for each
concentration is presented in Table 22. The specificity and sensitivity of the
analytical methods used by Frankel £t al. (1974) and in other studies described
in this section are reviewed in Section II-E, p. 65.
55
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Table 22. Amount of BCME Formed at 40% Relative Humidity
.ind 2(>°C .-it. Various CII^O/IIC? Concentrations
(Frankel et al. , 1.974)
(Reaction times, 12-24 hr.)
CHoO/HCft, ppm BCME, ppb
4000/40,0005000
1000/10,000 730
1000/1000 130
300/300 23
100/100 3
20/20 <0.5 (limit of
detection)
Kallos and Solomon (1973) of Dow Chemical also conducted a
similar study on the formation of BCME in HCHO/HCK. simulated atmospheres. They
used both glass and Saran reactors, as did Frankel ejt jjul. (1974), and evaluated
different commercial sources of formaldehyde and hydrogen chloride. The yields of
BCME in this study were much less (largest - 48 ppb for 3000/10,000 ppm HCHO/HC&)
than those obtained by Frankel £t _al. (1974). At a concentration of 100/100 ppm
for HCHO/HC2, less than 0.1 ppb BCME (level of detection) was formed. Kallos and
Solomon (1973) concluded that "occupational health problems would not be expected
from hydrogen chloride and formaldehyde, since bis-chloromethyl ether is not formed
even at concentrations of these reactants significantly above that which humans
can tolerate" (TLV for HCHO=2 ppm; HCfc=5 ppm).
Tou and Kallos (1974a) have considered the possibility that BCME
might be formed in aqueous ECU and formaldehyde mixtures. Because the hydrolysis
56
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rate of BCME in aqueous media is very rapid (half-life ~ 10-40 seconds - see
Section I-B-2, p.11), it coult not exist in aqueous media for long periods of time.
However, BCME formed in aqueous media might escape to the atmosphere where it is
relatively stable (half-life greater than 25 hrs - see Section I-B-2, p.11). Tou and
Kallos (1974a) used five solutions of equal concentrations of 1 to 1000 ppm of
HCfc and HCHO. They monitored both the aqueous solution and the air left in the
reaction vessel. No BCME was detected in the aqueous media (limit of detection
9 ppb) or in the gas phase above the reaction mixture (limit of detection 1 ppb).
The studies by Frankel ejt al. (1974) and Kallos and Solomon (1973)
leave unresolved the question of occupational hazard from BCME possibly in mixtures
of formaldehyde and hydrogen chloride vapors at high concentrations (500-3000 ppm).
However, at lower concentrations, the studies agree that BCME formation seems
unlikely. The study by Kallos and Solomon (1973) would suggest that BCME is not
formed in aqueous solutions containing low concentrations of hydrochloric acid
and formaldehyde. However, Frankel et al.. (1974) have monitored the vapors above
formalin slurries of Friedel-Crafts chloride salts and detected varying concen-
trations from 210 ppb with FeCl3 to 1500 ppb with A1C13. Marceleno e± al. (1974)
also found BCME in solutions containing MgCl2 catalysts.
Solutions which have been used to prepare BCME include: hydrogen
chloride and aqueous formaldehyde; hydrogen chloride and sulfuric acid solution of
paraformaldehyde; paraformaldehyde in concentrated hydrochloric acid with chloro-
sulfonlc acid; hydrogen chloride and hexamethylenetetramine; and phosphorus tri-
chloride, zinc chloride, and papaformaldehyde (Frankel e£ al., 1974). Goodson
(1974) noted that hexamethylenetetramine, a once widely used urinary antiseptic,
might form BCME in the acid environment of the stomach. However, Harris (1974)
57
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pointed out that hexamethylenetetramine has been administered as 1% in drinking
water to mice and rats for 60 and 104 weeks, respectively, with no evidence of
carcinogenicity.
From the available information, it appears that whenever formalde-
hyde is used in the presence of ionic chloride compounds, BCME may be formed. Whether
it is formed in a particular situation needs to be determined by monitoring. This
approach has been used by NIOSH (Marceleno and Bierbaum, 1974; Marceleno et al.,
1974a,b).
Formaldehyde is produced in about 6 billion Ibs a year. Table 23
lists the various applications of formaldehyde.
Table 23. Applications of Formaldehyde
(Chemical Marketing Reporter, 1975)
Use Percent
Urea-formaldehyde resins 25
Phenolic resins 21
Polyacetal 8
Pentaerythritol 7
Hexamine 5
Melamine-formaldehyde resins 3
Tetrahydrofuran 3
Acetylenics 3
Export 2
Other 23
58
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Marceleno and Bierbaum (1974) have considered the possibility of BCME formation
from formaldehyde use in: (1) the paper industry, (2) the textile industry, and (3)
medical and scientific applications. In the paper industry, it was found by
walk-through surveys that formaldehyde and hydrochloric acid were stored separately
and, in most cases, used separately. When they are used together (formaldehyde
treated fibers immersed in a solution treated with hydrochloric acid), a basic
condition prevails. In evaluating the medical application!?, Marceleno and
Bierbaum (1974) monitored BCME in the vicinity where the following histological
techniques were being performed: Hematoxylin and Eosin Stain; Colloidal Iron-
Periodic Acid; Schiff-Bismark Brown Technique; and Snook's Reticulum Stain. No
BCME was detected with a limit of detection of 0.1 ppb.
With a textile pilot plant using formaldehyde resins and magnesium
chloride and zinc nitrate catalysts in the permanent press process, some samples
contained BCME, but the results were inconclusive (Marceleno and Bierbaum, 1974).
Further monitoring of two textile concerns, Springs Mills, Inc., and Burlington
Industries, by Marceleno and coworkers (1974a,b), provided several samples con-
taining low ppb concentrations of BCME (highest concentration 2.7 ppb). No BCME
was found in the Springs Mills plant and this was attributed to a switch from
high chloride containing catalysts prior to the survey. NIOSH through the Bendix
Corporation, is continuing to monitor selected work environments for BCME (Nat.
Inst. Occup. Safety and Health, 1974).
a-chloroethers may also be produced by direct chlorination.
For example, the reaction of 2000 g of chloromethyl methyl ether and 1100 g of
chlorine at 18-25° with stirring and ultraviolet irradiation for 7 hrs yielded
376 g C12CHOCH3, 1174 g C1CH2OCH2C£, and 36 g C12CHOCH2C£ (Rieche and Gross, 1958).
59
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The possibility of this reaction taking place commercially or without irradiation
is unknown, but considering the toxicity of the products, an investigation seems
worthwhile.
Another inadvertent source of production of haloethers, which has
been shown to be an environmental contamination source, is the commercial chloro-
hydrin process. This source of production for bis(2-chloroethyl)ether and bis (2-
chloroisopropyl) ether has been considered in some detail in Section II-A, p. 25.
This discussion will focus on environmental contamination from chlorohydrin
processes in general.
There are three major groups of commercial chlorohydrins : ethylene
chlorohydrin, propylene chlorohydrin, and glycerol chlorohydrins (Lichtenwalter and
Riesser, 1964). The haloether is formed during the chlorohydrination reaction
as depicted in Figure 12.
HOC J, ' * HO
R-CH-CH2 - * R-CH-CH2 - — - »• RCHCH2« + RCH-CH2OH
OH C£
major
product
RCH-CH2CJl - 2— »• R-CHO-C-R + other isomers
OH CH2«CH2«
major product
Figure 12. Formation of Chloroethers During Chlorohydrination
(Lapkin, 1965; Schultze, 1965)
Formation of the chloroether during chlorohydrination has been demonstrated with
ethylene chlorohydrin (Sherwood, 1949; Silov, 1945; Schultze, 1965) and propylene
chlorohydrin (Lapkin, 1965; Blackford, 1973b). However, the ethylene chlorohydrin
route to ethylene oxide is no longer used commercially (Blackford, 1973a). In
00
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fact, most ethylene chlorohydrin that is produced now is mace by hydrochloric acid
reaction with ethylene oxide, the latter being made by the direct oxidation route.
On the other hand, 70% of the propylene oxide capacity (1275 million Ibs) is still
based upon the chlorohydrin process. Horsley (1968) estimates that a typical
propylene chlorohydrin plant produces approximately 2 Ibs of dichloropropyl
ethers [three isomers - major one is bis(2-chloroisopropyl)ether] for every
100 Ibs of propylene oxide, and this has been confirmed by Dow Chemical
(Otis, 1975). Kleopfer and Fairless (1972) have detected 0.5 - 35 mgA of
bis(2-chloroisopropyl)ether in an industrial outfall 150 river miles upstream
from Evansville, Indiana (probably Olin propylene oxide plant at Brandenburg,
Kentucky - annual capacity 130 million Ibs). If one assumes a daily discharge
of 150 Ibs (Kleopfer and Fairless, 1972), production at 90% of capacity, and
similar losses at other plants, an annual loss of approximately 47,000 Ibs per
100 million Ibs of propylene oxide produced by chlorohydrination is possible. In
1973, this could amount to a loss of 600,000 Ibs. However, Dow Chemical indicated
that they collect and burn most of their by-product bis(2-chloroisopropyl)ether,
although they' do emit about 20 Ibs/day of bis(2-chloroisopropyl)ether in the
air effluent from their chlorohydrin oxide plants (Otis, 1975). Whether this
practice is used in other propylene chlorohydrin plants is unknown. Dow's water
effluents contain 3-5 ppm bis(2-chloroisopropyl)ether before bioxidation treat-
ment and no detectable chloroether after treatment. Bis(2-chloroisporpyl)ether
has also been detected in an unspecified glycol plant's thickening and sedi-
mentation pond (Webb ejt _al. , 1973). Propylene glycol is made from propylene
oxide.
Another potential, but unconfirmed, source of chloroethers is the
chlorohydrination route to epichlorohydrin. Epichlorohydrin is produced by
chlorohydrination of allyl chloride followed by base cyclization to the epoxide
(see Figure 13).
61
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H2OCHCH2C£ + HOC£ »• C£CH2CH«CH2OH
Figure 13. Production of Epichlorohydrin by Allyl Chloride
Route (Oosterhof, 1970)
Some of the crude epichlorohydrin is further hydrolyzed to synthetic glycerin,
and the rest is refined by a two-column distillation in which some light and heavy
ends are removed. The ethers that could be formed are similar to the propylene
chlorohydrln ethers, except that they contain two extra chlorine atoms (see
Figure 14). Because they are not a-chloroethers, they should be fairly stable
in water. Table 24 lists the producers, capacities, and plant locations of
epichlorohydrin manufacturers where these chloroethers might be formed.
C£CH2CHOCHCH2C«. C«,CH2CHCH2OCH2CH2C£
CACH2CH2C£ C£ CH2C£
major isoner
C1CH2CHCH2OCH2CHCH2C£
Cl C£
Figure 3.4. Potential Chloroethers From Epichlorohydrin
Manufacture
Table 24. Producers of Epichlorohydrin (SRI, 1975)
;
Company Location Capacity
> (millions of Ibs)
Dow Chemical Freeport, TX 275
Shell Chem. Co. Deer Park, TX 160
Norco, LA 60
495
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7. Potential Inadvertent Production in the Environment
Recent contamination problems from halogenated hydrocarbons in
drinking water (e.g., Dowty ej: al. , 1975) have raised the question of the possible
formation of chlorinated compounds in water due to chlorination. Chlorination
of ethers in water at low concentrations has not been studied. However, the first
chlorination step, if it occurs, is probably substitution of a chlorine atom on
the ex-position of the ether (Summers, 1955). Since a-chloroalkyl ethers hydrolyze
very rapidly in water, the possibility of chloroethers being a drinking water
contaminant seems fairly remote.
D. Current Handling Practices and Control Technology
Information in this category is very limited and applies mostly to BCME
and CMME in the occupational environment. The available information is briefly
reviewed below and in Section IV-A, p. 149) (Current Regulations).
1. Special Handling
Both BCME and CMME are regulated under Occupational Safety and
Health Standards (OSHA, 1973; OSHA, 1974a,b). This requires that the materials
be handled only in "closed system" operations where containment prevents the
release of the chemical into regulated areas, non-regulated areas, or the external
environment. Employees engaged in transfer operations must wear full-face, sup-
plied-air respirators and full-body protective clothing.
63
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With bis(2-chloroethyl)ether, Allen (1956) has suggested that
workers be provided with activated charcoal respirator canisters where high con-
centrations are encountered.
2. Methods of Disposal and Storage
No information on recommended disposal methods was located in the
available literature. However, the instability of BCME and CMME in water make
it likely that water hydrolysis is used at least with these two compounds. Also,
Dow Chemical states that they burn any bis(2-chloroisopropyl)ether that is rormed
as a by-product from their propylene chlorohydrin process (Otis, 1975).
3. Accident Procedures
When accidents occur with BCME and CMME, the affected area
should be evacuated as soon as possible and the following actions undertaken:
(1) the hazardous condition should be eliminated before resumption of normal
procedures, (2) special medical surveys should be instituted, and (3) employees
having contact with the chemical should shower as soon as possible (OSHA, 1974a,b).
4. Current Controls
Controls on the non-a-haloethers were not noted in the available
literature. However, with the effluent from propylene oxide and glycol plants,
Lapkin (1965) suggests that:
"Plant location and local ordinance restrictions determine
the method of disposal. Whenever local conditions permit, the
effluent is simply discharged into a sufficiently large body of
water flowing to the sea. In some cases, the effluent is treated
by a sewerage works before it is directed to a water tributary."
Current controls for BCME and CMME have been preventive in nature.
For example, the National Institute of Occupational Safety and Health (1974)
64
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has recommended that textile manufacturers change their processes to use resins
low in free formaldehyde and substitute catalysts low in ionic chloride (e.g., use
zinc nitrate instead of magnesium chloride). Also, they recommended that continuous
ventilation be supplied in areas where formaldehyde and ionic chloride might come
in contact.
E. Monitoring and Analysis
1. Analytical Methods
In the last several years, considerable research activity has been
devoted to analytical methods development for non-anesthetic haloethers. This
activity has been directed at techniques that are sensitive and specific for halo-
ethers at ppb concentrations. However, the techniques that have been used with
the anesthetic gases are not as sensitive or specific,
Kelley (1967) has reviewed the techniques available for fluroxene
(CF3CH2OCH-CH2) and methoxyflurane (CHC£2CF2OCH3)- Methoxyflurane can be
determined by assaying for fluorine (not very sensitive). Volatile impurities
in methoxyflurane can be determined by gas chromatography. Fluroxene can also
be determined by fluorine assay, but a more sensitive technique (good to 1 mg of
fluroxene/100 ml blood), devised by Linde (1956), consists of passing the blood
distillate through a methanol solution containing a known amount of bromine.
The bromine quantitatively reacts with the vinyl group and the amount of fluroxene
is determined by titrating the remaining bromine with thiosulfate. Kelly (1967)
also noted a direct injection gas chromatographic technique for analyzing 0-160 yg
of fluroxene in 25 y£ of blood.
65
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A number of techniques besides those noted above have also
been used to determine methoxyflurane. For example, Chenoweth £jt al. (1962)
used infrared spectrometry for the quantitation of methoxyflurane in blood, tissue,
and exhaled air samples. The air samples were placed in a gas cell and concen-
trations down to 0.28% were determined. The blood and tissue samples were extracted
with carbon disulfide before infrared quantitation, and the lowest concentration
measured was 28 ppm by weight. Gelb and Steen (1969) have used a dielectric
analysis technique to continuously monitor methoxyflurane in an oxygen-nitrous
oxide stream. By measuring the capacity change which results from the difference
in dielectric constants between the methoxyflurane gas and the oxygen-nitrous
oxide gases, concentrations down to 3yg/cm3 could be continuously detected.
Both Santo (1966) and Jones et. al. (1972) have used gas chromato-
graphy for analysis of methoxyflurane in biological samples. Santo (1966) used
C1 -labelled methoxyflurane and a gas radio-chromatographic system to determine
tetrachloroethylene-extracted methoxyflurane in samples of blood, plasma, urine,
spinal fluid, etc. The sensitivity of the technique is probably quite high, al-
•
though it was not reported. However, the method does require the synthesis or
purchase of radiolabelled compounds.
Jones et al. (1972) noted that a number of techniques including
gas equilibration, distillation, and chemical extraction have been used to extract
anesthetics from blood before analysis. The last technique has the advantage that
it can be commenced as soon as the sample is taken, therefore, reducing the risk
66
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of leakage from the sample. However, most of the available volatile commercial
solvents interfered with subsequent gas chromatographic analysis. Therefore, Jones
and coworkers (1972) chose a non-volatile liquid (silicone fluid) that could be
directly injected into a gas chromatograph after the extraction of methoxyflurane
by equilibration. The technique provided linear response and good reproducibility
at concentrations of 1-20 mg/100 mH of blood.
The discovery of the carcinogenic properties (see p. 86) of BCME
has stimulated analytical development efforts at two major chemical companies;
Rohm and Haas and Dow Chemical. The techniques were developed for measuring
BCME or CMME at low concentrations in order to analyze air samples, as well as
to determine the rate of formation (from formaldehyde and chloride ion) or
hydrolysis of BCME. Collier (1972) devised a method for measuring BCME at the
0.1 ppb level in air samples. The technique consisted of adsorbing the compound
on an aromatic copolymer in bead form (Porapak Q) followed by thermal elution
directly into a mass spectrometer. The mass spectrometer is set to measure ions
at m/e 78.9950 (CS,CH2-0-CH2+) with a resolation of 1/3500.
Shadoff and coworkers (1973) used the same trapping technique
(Porapak Q), but selected gas chromatography-mass spectrometry (GC-MS) for analysis.
The sensitivity was 1 Vppb (4.7 ng/£ of air). GC-MS analysis was selected in
order to achieve three ways of specificity: (1) characteristic retention time on gas
chromatography, (2) most intense ion at m/e 79 and 81 (loss of one chlorine acoui I .a
the molecular ion, and (3) the relative ratio of m/e 79 to 81 must be 3:1 due to
the chlorine isotopic abundance. The authors felt that the added specificity of
the gas chromatograph was required for monitoring BCME in air samples which containec
67
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large excesses of CMME (this is quite likely since BCME is an impurity in CMME).
The mass spectrometry technique of Collier (1972) would have serious interference
problems caused by the ion, CJ,CH20CH2 , which is found in the mass spectrum of
CMME (m/e 79 is 0.14% of the major peak at m/e 45).
In order to obtain even more specificity and sensitivity, Evans
and coworkers (1975) have combined gas chromatography with high resolution mass
spectrometry. Monitoring the ion m/e 78.9950 (C2^OC!L ) from BCME, they were
able to measure down to levels of 0.1 ppb v/v BCME on a 1 I air sample and 0.01 ppb
v/v BCME with a 10 Si air sample. Poropak Q was used for pre-concentration.
Marceleno and coworkers (Marceleno and Bierbaum, 1974; Marceleno
ej: jal. , 1974a,b) have used Poropak Q, Tenax, and Chromosorb 101 as absorbers in
the analysis of BCME in occupational situations (textile plants and medical
laboratories). Drying tubes were employed ahead of the Poropak Q samples in
areas in the textile plants where excessive heat and moisture would hinder BCME
uptake by the absorber. Considerable effort was expended to overcome tube in-
line resistance so as to utilize portable low flow samplers. The samples were
submitted to Rohm and Haas and to Dow Chemical for analysis.
Soloman and Kallos (1975) concluded that although GC-MS techniques
were very specific and sensitive, they did not lead themselves to on-site plant
monitoring because of the sophisticated equipment required. Therefore, they used
a derivative approach with gas chromatography for detecting BCME or CMME at low ppb
68
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concentrations. The air sample being examined was drawn through two impingers
containing a methanolic solution of the sodium salt of 2 ,4,6-trichlorophenol. The
derivatives I and II were identified for CMME and BCME, respectively.
OCH2OCH3
OCH2OCH2OCH3
I II
Because these derivatives are chlorinated aromatic compounds, they are well suited
for detection by electron capture.
Kallos and Solomon (1973) used the GC-MS technique of Shadoff et_
al. (1973) to detect the possible formation of BCME in simulated hydrogen chloride-
formaldehyde atmospheres. However, they used Chromosorb 101 rather than Poropak Q
for adsorptive concentration. A detection limit of 0.1 ppb was reported when 15
liters of air were sampled.
Frankel £t al. (1974) also studied the formation of BCME from
formaldehyde and hydrogen chloride in moist air. They used three different analytic
methods, all of which were sensitive to <0.5 ppb with 15 liters samples. Each method
required a concentration step (Poropak Q). Quantitation was provided by: (1) high
resolution mass spectrometry (Collier, 1972), (2) GC-MS [similar to Shadoff et al.
(1973)], and (3) dual column chromatography. The dual column chromatographic system
69
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consisted of two temperature-programmed gas chromatographic columns connected in
series. Connecting the columns was a valve that allowed the BCME fraction from
the first column to be transferred to the second column. Quantitation was pro-
vided by a flame ionization detector.
Westover and coworkers (1974) have devised a rather novel method
of direct sampling of volatile organics in both aqueous solution and air. Hollow
fiber probes, usually constructed of silicone rubber, are placed directly into the
medium to be analyzed and connected to a mass spectrometer. The probe provides the
pressure reduction required by the mass spectrometer and also enriches the concen-
tration of the material to be analyzed. In order to demonstrate the usefulness of
hollow fiber probes in direct monitoring, Westover et al. (1974) embedded a probe
in the venous blood stream of a rat. When the rat was exposed to methoxyflarane
(CHCX.2CF20CH3) , response in the mass spectrometer was noted approximately 0.5 min.
after the start of exposure and reached a maximum at 1.5 min.
Because the hollow fiber probe - mass speci:rometry technique is
capable of continuous analysis, it is the method of choice for kinetic studies.
Tou et al. (1974) used the technique in order to determine aqueous hydrolysis rates
of BCME under both basic and acidic conditions (see Figure 15 for the apparatus).
The rate determinations were carried out at approximately 1 ppm. Tou and Kallos
(1974a) used the method to study the possible formation of BCME in aqueous solutions
of HC£ and formaldehyde.
70
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Figure 15. Bis(chloromethyl)ether Hydrolysis Apparatus
(Tou et al., 1974)
(Reprinted with permission from American Chemical Soceity)
They monitored both the aqueous phase and the gas phase above the reaction mixture
(limits of detection were 9 ppb and 1 ppb, respectively). The same technique was
also used by Tou and Kallos (1974b) to determine the stabilities of CMME and BCME
in humid air.
The previously described analytical methods have all been used in
clinical and laboratory studies or in occupational environments. They have not been
used to analyze ambient air or water samples. However, haloethers have been detected
in river water and municipal drinking water. The most frequently used technique for
isolating the compounds is to filter large volumes of water with a carbon filter
followed by extraction of the organics from the carbon by chloroform extraction
(carbon chloroform extract, CCE). This isolation technique has been used for years,
and haloethers have been detected as early as 1963 using the procedure (Rosen et
al., 1963). Usually enough material is isolated to allow conventional identification
techniques (e.g., infrared spectrometry) to be used. The carbon chloroform isolation
71
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technique has also been used in a number of recent studies (Friloux, 1971; Kleopfer
and Fairless, 1972; and the U.S. Environmental Protection Agency, 1972, 1974). A
disadvantage of the technique is that only qualitative concentrations can be reported
when the efficiencies of the isolation process are not determined. For example,
researchers examining water supplies in the New Orleans area (U.S. Environmental
Protection Agency, 1974) reported their results in terms of "highest measured con-
centration." By knowing the quantity of water sampled and by assuming efficiencies
for the isolation technique, a qualitative concentration can be estimated. However,
in order to determine quantitative concentrations, "the efficiency of the carbon
adsorption from water, losses incurred in carbon drying, efficiency of desorption
by solvent from the carbon, and losses incurred in concentrating the solvent to a
lew /olume" (U.S. Environmental Protection Agency, 1974) would have to be determined
Cor each compound detected.
Besides using the CCE procedure, Kleopfer and Fairless (1972) also
developed a direct extraction procedure for determining bis(2-chloroisopropyl)ether
in cap and raw unfinished water. The procedure consisted of extraction with 5%
ethyl ether in hexane, concentrating the solvent, and quantitation by gas chromato-
graphy with flame ionization and electron capture detection. The lowest concentration
reported was 0.2 yg/£ (ppb).
2. Monitoring
The available information on monitoring of haloethers in water is
difficult to assess due to a confusing use of nomenclature. Also, some of thp
72
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compounds which have been reported have such a fast rate of hydrolysis (see Section
I-B-2, p.11) that it would appear very improbably that they would be detected in raw or
finished (drinking) water. The available information is summarized in Table 25.
The confusing nomenclature (e.g., is bis-chloroethyl ether the
same as dichloroethyl ether) and instability of some of the compounds (e.g., chloro-
methyl ether and chloromethyl ethyl ether) raises questions about the reliability
of the Friloux (1971) and U.S. Environmental Protection Agency (1972) data. However,
»
the rest of the studies rather convincingly indicate that bis(2-chloroethyl)ether
and bis(2-chloroisopropyl)ether are wide-spread water contaminants.
The major source of bis(2-chloroisopropyl)ether contamination, at
least for the Evansville drinking water, appears to be an industrial outfall about
150 river miles upstream from the Evansville water intake. Kleopfer and Fairless
(1972) detected concentrations of bis(2-chloroisopropyl)ether in the outfall
ranging from 0.5-35 pg/£ (estimated discharge of 150 Ibs/day). By assuming a dis-
charge of 150 Ib/day, a river flow of 50,000 ft3/sec, no biodegradation, and
perfect mixing, the authors calculated a concentration at Evansville of 1.8 yg/£.
In August-September 1971, the measured concentration in the Ohio River at Evans-
ville ranged from 0.5-5 yg/A. Above the industrial outfall, the concentration in
the Ohio River was less than 0.2 pg/£. From their experience with bis(2-chloro-
isopropyl) ether, Kleopfer and Fairless (1972) concluded that "the compounds
[bis(2-chloroisopropyl)ether and bis(2-chloroethyl)ether] are by-products in
the manufacturer of propylene glycol and ethylene glycol, respectively". Webb
e_t ail. (1973) have also detected bis(2-chloroisopropyl)ether in the thickening
and sedimentation pond of a glycol plant.
73
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07140
aajoft 8 until JQ 8TTTA»u»Aa
X ""» 0')
puoj
8ufU»5p7»U «,
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vr bo - oo
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'A'tt
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Z#
U03J10I1B3
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74
-------
Kleopfer and Fftirleas (1972) also examined whether conventional
drinking water treatment would remove bis(2-chloroisopropyl)ether. When the con-
centration in the raw intake water was 2.0 ug/Jl, the concentration in the Evansville
tap water was 0.8 vg/fc.
The earlier study of drinking water in the New Orleans area (U.S.
EPA, 1972) also examined a number of industrial outflows going into the Mississippi
River. No haloethers were detected, but it is unclear whether any of the plants
examined were manufacturing glycols.
Some sizable concentrations of bis(2-chlordethoxy)methane (140 mg/£)
and bis(2-chloroethyl)ether (0.16 mg/£) have been detected in treated waste from
synthetic rubber plants (Webb ejt a_l. , 1973). This is not unexpected for bis (2-
chloroethoxy)methane, since it is used as the principle monomer of polysulfide
rubbers.
Recently, bis (2-chloroethyl)ether has been detected in the effluent
from Philadelphia's Northeast treatment plant (10 ppb) and in the city's Deleware
River intake (0.4 - 0.5 ppb) (Anon., 1975). Rohm and Haas has acmitted that it has
been discharging up to 135 Ibs/day into the city sewer system. The company, which
uses bis(2-chloroethyl)ether as an intermediate in surfactant production, plans to
make process alterations to eliminate the chemical from the plant effluent.
N10SH (Marceleno and Bierbaum, 1974; Marceleno et _al., 1974a,b)
has monitored the air inside one pilot and two full-scale textile plants, all of
which used formaldehyde (a source of BCME) (these studies are reviewed in more
detail in Section II-C-7, p. 63). In a number of the samples taken, BCME was
detected at very low concentrations (1-2 ppb). This included one stack sample
of gases being emitted into the ambient air from a textile plant tenter frame.
75
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III. Health and Environmental Effects
A. Environmental Effect
1. Persistence
a. Biological Degradation
Very little information is available in the literature con-
cerning the environmental fate of haloethers. BCME is known to hydrolyze rapidly
in water; subsequently, its breakdown by microorganisms has not received any
attention. The only haloethers which have been studied to some extent are
bis(2-chloroethyl)ether and bis(2-chloroisopropyl)ether, the reason probably
being that both of these compounds have been recognized as surface water poilutants
(Rosen £t al., 1963; Kleopfer and Fairless, 1972).
Ludzack and Ettinger (1963) studied the breakdown of bis(2-
chloroethyl)ether (21.1 mg/£) to C02 in Ohio River water buffered to a pH of 7.2
and supplemented with settled sewage (1% by volume was added weekly to the test
medium). The authors found extensive degradation of the chloroether after
25-30 days lag period; about 85% of the theoretical C02 was recovered after 65 days
of incubation. Upon redosing the biodegradation test medium with the chemical,
C02 evolution occurred at rates several fold higher than the first time (indicating
the necessity for acclimation of microorganisms to the haloether). The investigate]
did not attempt to identify the form in which the remaining 15% carbon was present.
The reported C02 evolution data was determined by subtracting
the C02 evolved in the river water control from the C02 evolved in the test
sample containing the ether. In river water supplemented weekly by the addition
76
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of settled sewage, the control rates may be expected to be fairly high; this
questions the reliability of the calculated value of C02 evolved from the
haloather. Unfortunately, the amounts of C02 evolved in the control and in
the test sample were not reported. The test was run at a temperature close
to that of summer (22-26°C) and, therefore, persistence under winter conditions
is not known (Ludzack and Ettinger, 1963).
The fate of bis(2-chloroisopropyl)ether in river water has
been briefly studied by Kleopfer and Fairless (1972). These researchers in-
cubated the chloroether in raw Ohio River water in the laboratory and found no
degradation after 5 days. Since the incubation period was restricted to only
5 days, no definitive conclusions can be drawn concerning the biodegradability
of this compound. A long acclimation period is sometimes required before deg-
radation can occur, as noted by Ludzack and Ettinger (1963) with bis(2-chloro-
ethyl)ether. For this reason, the possibility that the degradation of bis(2-
chloroisopropyl)ether would have occurred upon prolonged incubation cannot be
excluded. Also, since the concentration of chloroether used in the study was
considerably higher (33 mg/£) than the concentrations detected in the Ohio River
water (0.5-5 yg/£), a question can be raised about the possible inhibitory action
of the test haloether on the microorganisms responsible for its degradation.
Bis(2-chloroisopropyl)ether does appear to biodegradate
under activated sludge waste water treatment conditions. Dow Chemical reports
that water effluents from their chlorohydrin oxide plants contain 3-5 ppm bis(2-
chloroisopropyl)ether before bioxidative treatment and no detectable amounts
(limit of detection unknown) after treatment (Otis, 1975).
Extrapolation of the laboratory results to the biodegradability
of haloethers in nature is difficult. From the studies described above, it
77
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may be tempting to conclude that bis(2-chloroethyl)ether is extremely bio-
degradable, whereas bis(2-chloroisoprop}il)ether is persistent. The widespread
occurrence of these chemicals in the natural waters of the United States (see
Section II-E-2, p. 72 on Monitoring) might suggest, however, that both bis(2-
chloroisopropyl)ether and bis(2-chloroethyl)ether persist in the aquatic environ-
ment for extended periods of time. The monitoring data of Kleopfer and Fairless
(1972) may help to resolve this question at least with bis(2-chloroisopropyl)ether.
These researchers found that the concentration of bis(2-chloroisopropyl)ether in
the industrial outfall located 150 miles upstream (on the Ohio River) from Evans-
ville, Indiana, was in the range of 0.5-35 mg/£. Assuming a discharge of 150 lb/da]
a river flow of 50,000 ft^/sec, no biodegradation, and perfect mixing,
Kleopfer and Fairless (1972) calculated the expected concentration of the haloether
at Evansville to be 1.8 yg/fc. The actual concentration found in the Ohio River
at Evansville was 2.0 yg/£ in August, 1971 (concentration range 0.5-5 pg/A, August-
September, 1971). These findings suggest that bis(2-chloroisopropyl)ether remained
relatively unaltered, at least during the time period required for transport of
the haloether 150 river miles. Unfortunately, similar monitoring information is
not available for bis(2-chloroethyl)ether, and, thus, no definitive conclusions
can be drawn concerning its fate in the environment.
b. Chemical Degradation in the Environment
Information pertinent to determining the possibility of
chemical degradation of haloethers is reviewed in Sections I-B-2, p. 11, and
I-B-3, p. 21. From that information, it is apparent that a-haloethers will
hydrolyze very rapidly (t,<2 min), while the non-a-chloroethers hydrolyze
very slowly. BCME would form hydrochloric acid and formaldehyde and CMME
would degrade to hydrochloric acid, formaldehyde, and methanol. The chloroethers
78
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that are not susceptible to hydrolysis also appear to be relatively stable
under photolytic and oxidative conditions.
2. Environmental Transport
No work has been reported concerning the transport of haloethers
in the environment. However, some predictions can be made based on the physical
properties of haloethers. The vapour pressure of a chemical determines to a
great extent the possibility of the compound vaporizing into the atmosphere. The
high vapour pressure of bis(2-chloroethyl)ether (0.73 mm Hg at 20°C; 1.6 mm Hg
at 25°C; Hake and Rowe, 1963) and bis(2-chloroisopropyl)ether (0.71 - 0.85 mm Hg
at 25°C; Hake and Rowe, 1963) suggests that these compounds are volatile enough
to enter and distribute through the atmosphere. Mackay and Wolkoff (1973) have
developed an approach to predict the rate of evaporation of compounds from water
bodies to the atmosphere using the water solubility and vapor pressure of the
compound. The equation for predicting residence time is based on the assumptions
that the water column undergoes continuous mixing and that the compound is
present in true solution and not adsorbed, complexed, etc. Using this approach,
the calculated half-life for bis(2-chloroethyl)ether and bis(2-chloroisopropyl)-
ether at less than saturation concentrations in a square meter of water would be
5.78 days and 1.37 days, respectively (for comparison, DDT's half-life is 3.7
days, dieldrin's, 723 days).
In view of their appreciable water solubility (10.7 g/Jl for bis(2-
chloroethyl)ether, and 1.7 g/£ for bis(2-chloroisopropyl)ether, it appears likely
79
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that these ethers will be washed out of the atmosphere with rain. Thus, a con-
tinuous cycling of the haloethers between air and water is likely. Because of
their high water solubility, the haloethers can also be expected to migrate
through soil and eventually make their way to ground water.
The mobility of bis(2-chloroisopropyl)ether in the aquatic environ-
ment has been examined in an indirect way by Kleopfer and Fairless (1972). These
investigators monitored the concentration of bis(2-chloroisopropyl)ether in the
Ohio River 150 miles from an industrial outfall, and found that the pollutant was
present at approximately the level calculated theoretically by taking into account
the dilution factor (see Section III-A-1, p. 76). This suggests a fairly high
mobility of bis(2-chloroisopropyl)ether in the aqueous environment and that
appreciable loss of the haloether due to adsorption to hydrosoil, evaporation, or
degradation does not occur during transport, at least over 150 river miles in the
Ohio River.
In summary, although sufficient information is not available to
allow any definite conclusions about environmental transport and distribution of
haloethers, the physical properties indicate that bis(2-chloroethyl)ether and
bis(2-chlorolsopropyl)ether should be quite mobile in the environment.
3. Bioaccumulation and Biomagnification
No experimental data could be located in the literature concerning
the bioaccumulation and biomagnification potential of haloethers. However, to some
extent, it may be possible to predict their behavior from their physical and
chemical properties. Accumulation of a chemical occurs when the chemical is
80
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taken into biological material and accumulated faster than it is eliminated.
Kenaga (1972) suggested that the characteristics of a molecule which will
affect Its bioaccumulation potential will be solubility, partition coeffIcipnt ,
latent heat el solution, and polarity. However, it a compound la leadilv tit-
composed in the environment, it will be less likely to bioaccumulate. in
assessing the bioaccumulation potential of the haloethers, their solubility,
partition coefficient, and environmental persistence have been considered.
The available information on biodegradability, although it does
not allow any definite conclusions, suggests that haloethers, such as bis(2-
chloroethyl)ether and bis(2-chloroisopropyl)ether, are not rapidly attacked by
microorganisms, and, therefore, may be expected to come in contact with food
chain organisms. On the other hand, the a-chloroethers (e.g., BCME and CMME)
hydrolyze rapidly in water (see Section I-B-2, p.11) and, therefore, are not
likely to be around to be taken up by organisms. Thus, it seems highly unlikely
that BCME or CMME would bioaccumulate.
The partition coefficient (ratio of the equilibrium concentration
of the chemical between polar and non-polar solvent) has been used in assessing
a chemical's bioconcentration potential. Neely jet _al. (1974) have reported a
linear relationship between octanol-water partition coefficients and bioconcentration
of chemicals in trout muscle. Using the equation of the straight line of best
fit, derived by Neely elt _al. (1974), the bioconcentration factor of diethyl ether
81
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(octanol-water partition coefficient, 25°C - 5.9, Leo et^ al., 1971) is calculated
to be approximately 3.5. Since the substitution of chlorines on ether tends to
reduce its water solubility (e.g., the solubility of bis(2-chloroethyl)ether in
water is one-sixth that of ethyl ether) and increase the lipid solubility, the
bioconcentration factor for bis(2-chloroethyl)ether will probably be somewhat
higher.
Biomagnification refers to concentration of a compound through
the consumption of lower organisms by higher food chain organisms with a net
increase in tissue concentration (Isensee £it jil. , 1973). The biomagnification
potential of haloethers has not been studied. To some extent, the water solu-
bility of haloethers may be helpful in predicting their biomagnification po-
tential. Metcalf and Lu (1973) have found that ecological magnification of
several chemicals (concentration in organisms/concentration in water) in their
model aquatic ecosystem follows a straight line relationship with water solu-
bility. Using this relationship, the ecological magnification for bis(2-
chloroethyl)ether and bis 2-(chloroisopropy1)ether is calculated to be approx-
imately 1 and 5, respectively (for comparison, DDT is approximately 17000). From
this calculation, it appears that the haloethers, bis(2-chloroethyl)ether and
bis(2-chloroisopropyl)ether will not biomagnify to a significant extent in the
food chain organisms.
82
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B. Biology
Specific information on the absorption, distribution, metabolism, and
elimination of the chloroethers is not available in the published literature. Un-
published sources of this information or current research in this area have not
been encountered.
For the a-chloroethers, BCME and CMME, this is neither surprising nor
particularly disturbing. These a-haloethers, as previously discussed, are powerful
alkylating agents and are subject to rapid hydrolysis. Thus, by environmentally
feasible routes of entry - i.e. oral, dermal, or inhalation - these agents would
either hydrolyze to simple organic compounds and hydrochloric acid or be alkylated
by any number of reactive sites in the biological material. As a result, they
would not be expected to undergo biological transport and modification in the
usual sense. At the cellular level, these compounds are stable enough to interact
with receptor sites and cause cancer. This aspect of a-chloroether biology is
discussed in detail below (see Section III-D-6, p. 126). In addition, one study
indicates that BCME is stable enough to be injected subcutaneously into the
middorsal area of mice and cause lung tumors (Gargus et al., 1969). Nevertheless,
these compounds are so unstable that their residence time in the body is probably
extremely short.
The same cannot be said for the 8-chloroethers. These compounds are
much more chemically stable and may be expected to be absorbed, transported, and
metabolized to a significant extent. The lack of data in this area will be referred
to repeatedly in discussing the known or potential toxic effects of these compounds.
83
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The biological behavior of other ethers is, of course, relatively
well characterized. Most notable, in this respect, are the anesthetics diethyl
ether, fluroxene (2,2,2-trifluoroethoxy ethene), and methoxyflurane (2,2-dichloro-
1,1-difluoro-methoxy ethane). Any attempt to extrapolate in detail the pharma-
cological characteristics of the &-chloroethers based on the behavior of these
anesthetics would be tenuous at best. Nevertheless, some basic patterns are
evident in the anesthetics, at least in their metabolism, which could conceivably
apply to the 0-chloroethers.
First, the ether bond can be cleaved by drug metabolizing enzymes.
In mice exposed to diethyl ether, the ether bond is cleaved forming acetaldehyde
and ethanol which are subsequently metabolized to carbon dioxide (Geddes, 1971).
Cascorbi and Singh-Amaranath (1973) have recently shown that mice also cleave
the ether linkage in fluroxene. The pathway which they propose for fluroxene
biotransformation is given in Figure 16.
Figure 16. Postulated Pathway of Fluroxene Metabolism in Mice
(Cascorbi and Singh-Amaranath, 1973)
CC>2 to Glucuronide
CF3CH2-0-CH-CH2 - »• CF3CH2OH - > CF3CHO - >• CF3COOH
Fluoroxene Trif luoroethanol Trifluoroacetaldehyde Trifluoroace
acid
84
-------
Secondly, both defluorination and dechlorination have been demon-
strated in the metabolism of methoxyflurane. Based on in vitro studies of human
and rat liver microsomes, VanDyke and Wood (1973) have postulated the pathway
shown in Figure 17 for methoxyflurane involving both ether cleavage and dehalogen-
ation.
r -^tCH3—0—CF - CC12] + F~
, Urinary Product
I.
H+
CH3—0—CF2—CC12H >- CH3—0—CF2—COOH + 2C1
HCHO + 2F + HCC12—COOH
1 1 HCHO + 2F + HOOC—COOH
C02 Urinary Product j
Urinary Product
Figure 17. Proposed Pathway for the Metabolism of Methoxyflurane
Based on Studies of Human and Rat Liver Microsomes
(VanDyke and Wood, 1973)
In vivo studies with humans are consistent with this proposed pathway (Holaday
jat al. , 1970).
None of this, of course, has any definite relevance to the 3-chloroethers,
However, it does suggest, based on structural similarities, that the (3-chloroethers
m^y be subject to metabolic degradation. Given the complete absence of hard data,
further speculation does not seem indicated. The potential-relevance of the
toxic effects of the fluorinated ethers to those of the chloroethers is discussed
below (see Section III-D-1-d, p. 104).
85
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C. Toxicity - Humans
1. Epidemiology
The consequences of occupational exposure to BCME and CMME
have been examined in several recent epidemiological studies. The results
clearly indicate that workers exposed to these chemicals have a markedly in-
creased risk of developing respiratory cancer. Most studies indicate that
one specific type of cancer, oal cell carcinoma, is prevalent. However, all
of these studies are limited in two respects. First, quantitative levels of
haloether exposure are not available. As indicated previously (see Section II-
E, p. 65), reliable methods for monitoring these chemicals have only recently
been developed and were generally not available to the epidemiologists involved
in these investigations. Secondly, occupational exposure to CMME cannot occur
without presuming simultaneous exposure to BCME, which is a contaminant (1-8%)
in the synthesis of CMME. Consequently, in the following discussion, the term
"chloromethyl ethers" is used to describe exposure to both BCME and CMME. The
reverse, however is not the case. Exposure to BCME may occur without exposure
to the monochloro analogue.
The initial indication that BCME caused cancer in man appeared
in the literature in 1972. This report discussed the deaths of four male
workers, ages 32 to 48, involved in the production of ion exchange resins using
the chemical intermediate, CMME, with BCME being a minor contaminant in the CMME.
All four deaths were due to lung cancer, with the youngest worker having been
employed for only two years. Of the 100 workers in this plant (Diamond Sham-
rock Co., Redwood City, California), two more males subsequently developed lung
cancer (Anon., 1972).
86
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These findings prompted a more extensive study at this plant
by Lemen and coworkers (1975) using both sputum cytology and retrospective
analysis of the incidence of lung cancer in exposed workers. Sputum samples
were obtained from both production workers exposed to the chloromethyl ethers
and from office workers with no record of exposure. These samples were ex-
amined for atypia as an early indicator of bronchial epithelial damage caused
by carcinogens.
When compared to the results of a similar survey of age-sex
cigarette matched uranium surface employees as a negative control group, workers
involved in the production of the chloromethyl ethers for more than five years
showed a significant (p<0.025) increase in moderate and marked atypia. Workers
exposed for less than five years and office employees with no record of haloether
exposure had no significant increase in atypia.
Similar results were obtained in the retrospective analysis of
lung cancer incidence. Using data on white Connecticut males between 1960
and 1962 to estimate an expected incidence of respiratory cancer, workers with
probable exposure to the chloromethyl ethers for five or more years had an in-
cidence of lung cancer more than nine times greater than expected (5/0.54,
p<0.01). Four of the five cancers consisted of oat cell carcinomas. The mean
exposure period for these cancer cases was 10 years with a mean induction -
latent period oT 15 years (Lemon ej^ n^.. , 1975).
Figueroa and coworkers (1973) published the first detailed report
implicating BCME and CMME as human carcinogens. This study involved employees
of the Rohm and Haas Co. chemical plant in Philadelphia, producing the chloro-
methyl ethers, and included both prospective and retrospective investigations.
87
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In the prospective study, a group of 111 workers potentially
exposed to the chloromethyl ethers were observed over a five year period.
During this time, four men developed oat cell carcinoma of the lung (cases
4-7, in Table 26). Because all four of these men were in the age range of
35 to 54 - which comprised 88 of the 111 men in the study group - the five
year lung cancer incidence was calculated as 4/88 or 4.!i4%. An expected
incidence of lung cancer from a group not exposed to haloethers was based
on data from the Philadelphia Pulmonary Neoplasm Research Project, which
included 2804 men, ages 45 to 54, with smoking habits similar to the haloether
exposed workers. This group had a five year lung cancer incidence of 0.57%.
Thus, Figueroa and coworkers (1973) concluded that the risk of lung cancer
development was about eight-fold greater in the chloromethyl ether exposed
groups (4.54/0.57 or 7.96, p<0.0017).
This part of the study has been criticized for not including
all 111 workers on the calculation of cancer incidence and for having a
control group that underestimates the actual degree of risk involved. Brown
and Selvin (1973), in correcting for these supposed errors, indicate that
the actual increased risk due to haloether exposure may have been underestimated
by a factor of 5.5, bringing the actual relative risk to 44.39. Although
the original investigators disagree with the above criticisms, they do agree
that the eight-fold increase in relative risk may be an underestimate, but
for different reasons. First, the exact number of men examined in the prospect-
ive study who were actually exposed to haloethers could not be determined.
Thus, the number of men at risk may have been overestimated. Secondly,
oat cell carcinoma, which appeared in all four of the haloether exposed
workers who developed cancer, comprised only 10% of the cancers in the control
group (Weiss and Figueroa, 1973).
88
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In the retrospective investigation, Figueroa and coworkers (1973) ex-
amined the available information on fourteen cases of lung cancer diagnosed
in workers from the same plant. This information is summarized in Table 26.
Table 26. Lung Cancer in Workers Exposed to Chloromethyl Methyl
Ether and Bis(chloromethyl)ether (Figueroa jet a_l. , 1973)
Case
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Age
yr.
37
33
39
47
52
47
43
53
48
50
55
43
37
44
Smoking
History*
None
lppd/20
lppd/20
lppd/20
lppd/10
lppd/21
lppd/20
2ppd/20
lppd/33
lppd/30
lppd/40
Pipe only
None
None
Duration
of
Exposure
yr.
7
8
8
10
4
3
14
10
5 t
1?T
12
12
14
12
Date of
Diagnosis
1962
1962
1962
1963
1964
1964
1966
1969
1970
1970
1970
1970
1971
1971
His to logic
Type
Unknown
Oat cell
Oat cell
Oat cell
Oat cell
Oat cell
Oat cell
Oat cell
Oat cell
Squamous
Oat cell
Oat cell
Oat cell
Oat cell
Survival
mo.
Unknown
7
6
18
11
8
4
4
11
24
4
20
5
10
*Packages/day (ppd) smoked/no, of yr. tl mo. according to fellow worker
^Estimates of exposure based solely on the memory of Case 14.
The prevalence of oat cell carcinoma in this group is particularly striking in
view of its limited incidence <10% of respiratory cancers) in the control populatio*
Albert and coworkers (1975) have recently completed a similar retrospective
survey of mortality data from 1948 to 1972 on workers in six firms producing the
chloromethyl ethers. Causes of death were determined for about 1800 workers
89
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exposed for five or more years, and 8000 non-exposed workers (controls). The
types of respiratory cancers found, however, are not specified. Between the two
groups, yearly death rates did not vary significantly with the exception of
deaths due to respiratory tract cancer. Here, age-adjusted yearly death rates
were 1.48 per thousand for the exposed workers and 0.59 per thousand for the
non-exposed workers. This represents an increased relative risk adjusted for age
of 2.53 in the haloether exposed workers.
More detailed information is presented for one of the production
plants studied, designated "Firm-one" by Albert and coworkers (1973). The
probability of death due to respiratory cancer as a function of age is illustrated
in Figure 18 for three groups: (1) workers in Firm-one exposed to the chloromethyl
ethers for more than five years (2) non-exposed workers from Firm-one, and
(3) Unites States white males between 1950 and 1967 [data for U.S. white
males taken from Burbank, 1971].
2001-
•"Tt '
£ 10.0
8 5.0
3
I 20
"5 1.0
f 0.5
1 0.2
0.1
10
Figure 18.
20 40
Age lyeors)
60 80
Cumulative Mortality - Corrected Probabilities
of Lung Cancer Death in Bis(chloromethyl)ether
[BCME] Exposed and Non-exposed Workers
(Albert elt al., 1975) Permission granted by
author.
90
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Comparing the data on the chloromethyl ether exposed and
non-exposed workers In Figure 18, it is evident that comparable rates of
death due to lung cancer occurred at a 15-20% earlier age in exposed workers,
and at any given age exposed workers experienced a 3-4 fold increase in
the rate of lung cancer death (Albert £t _al. , 1975).
For workers in Firm-one, additional qualitative estimates
were made of the relative intensities of maximum exposure to chloromethyl
ethers - based on the type of job held by the worker - and the total duration
of such exposure. Intensities of maximum exposure were then classified
as low, medium or heavy. All 19 cases of lung cancer from this plant occurred
in the heavy exposure group. [Since the report by Albert e_t al. (1975)
has been drafted, the number of cases has increased to 25 (Shore, 1975).]
Details for this group are presented in Table 27.
Table 27. Respiratory Cancer Deaths Among the Heavy Exposure Group
Workers Exposed to "Chloromethyl Ethers" in Firm-one by
Duration of Maximum Exposure (modified from Albert et al., 1975)
Total Duration Years Elapsed Since First Exposure Total* for Age-Adj.
of Maximum
Exposure (years)
fc
1-5
<1
0-4
years
0
0
0
5-9
years
1/1*
2/3
0/8
10-14
years
1/1
4/15
0/27
15-25
vears
1/10
6/73
4/153
5 Elapsed
Years
3/12
12/91
4/188
Rate/ 1000 /
Year**
23.0
B.7
1.5
Number of deaths due to respiratory cancer/cumber of workers exposed
** Adjusted to the total exposed group in Firm-One. The control group had
an adjusted rate of 0.97/1000/yr.
91
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The increase in lung cancer death rate with increased duration of
maximum exposure clearly suggests a causative role for these chloromethyl ethers
as human respiratory carcinogens. For workers subject to heavy exposure for
over five years, the relative risk of lung cancer death was increased by a factor
!
of 23.7 (23/0.97) over the control population. Noting the increased latent period
(15-20 years) seen in those heavily exposed workers with a total exposure period
of under one year, Albert and coworkers (1975) indicate that the lack of abnor-
mally high rates of respiratory cancer in the low and medium exposure groups
may be due to an inverse relationship between dose and length of latent period.
Dow Chemical has recently furnished a report (Holder, 1973) on the
cancer incidence in workers exposed to CMME and BCME. The degree of exposure
was estimated only in total number of years worked in the exposure area. Age-
specific mortality rates of a group of Dow Midland hourly employees (control)
were used to estimate the number of expected deaths. Of the 104 men considered
at risk, two deaths occurred from malignant neoplasms. One death involved a
squamous cell carcinoma of the left lung which appeared 19 years after the
beginning of a three year exposure period. The primary site of the other cancer
case was not identified and death was attributed to generalized carcinomatosis.
This occurred in an individual with seven years exposure who died fourteen years
after exposure began. Based on the expected number of deaths from the control
group, those exposed to the chloromethyl ethers for over one year with less
than fifteen years since the first exposure have a 3.3-fold increase in total
number of malignancies (1 observed/0.3 expected), but no increase in respiratory
malignancies (0 observed/0.1 expected). Those exposed for over one year with
92
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more than fifteen years since the first exposure have a 10-fold increase in
total malignancies (1 observed/0.1 expected) and an apparently significant
increase in respiratory malignancies (1 observed/0 expected).
Further, though, less detailed reports implicating the chloromethyl
ethers as human carcinogens come from Germany (Thiess et al., 1973) and Japan
(Sakabe, 1973). In Germany, six of eighteen employees of a research institute,
and two of fifty employees in a production plant all involved in the handling
of BCME, died of lung cancer. Available details of exposure are summarized in
Table 28 for the eight cases.
Table 28. Death from Lung Cancer in German Workers Associated
with Bis(chloromethyl)ether Exposure (adapted from
Thiess et al., 1973)
Case No.
1
2
3*
4*
5
6
7
8
Period of
Exposure (yrs )
6
6
8
9
6
6
6
6
Latent Period to
Cancer Development
(yrs )
8
10
8
9
15
16
16
16
Age at
Death
59
53
31
52
65
42
58
60
Smoking Habits
+
+
-H-
7
+
None
+
+
^Employees at production facility. All others employed at research institute.
93
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Of the eight cases of lung cancer cited, five were oat cell carcinomas. This
is similar to the preponderence of oat cell carcinoma associated with chloro-
methyl ether exposure found by American investigators (Archer e_t ai. , 1975, and
Figueroa £t al., 1973). That these lung cancers may have been caused by exposure
to very low concentrations of BCME is indicated by the fact that the production
facility presumably utilized elaborate worker-production measures involving pro-
tective clothing, whole head fresh air masks, and exhaust equipment (Thiess et
al. , 1973).
Sakabe (1973) presents similar data on five cases of lung cancer which
developed in a Japanesse dyestuff factory in which 32 employees were exposed to
BCME between 1955 and 1971. Although the employees were exposed to over thirty
different chemicals, BCME was assumed to be the most probable causative agent
because of its known carcinogenicity in other mammals. Relevant details of
these five cases are presented in Table 29.
Table 29. Deaths from Respiratory Cancer in Japanese Workers
Associated with Bis(chloromethyl)ether Exposure
(data from Sakabe, 1973).
Total Time to
Duration of Death After Age
Case Exposure Initiation of at Death
No.?. (years) Exposure (years) (years)
8.5
12
47
38
Estimate of
Smoking
Habits
Moderate
Moderate
3
4
5
9
5
4
12.5
8
13
41
38
45
Moderate
Heavy
Moderate
Typjg Cancer
Simple carcinomas
of bronchia
Oat cell cancer of
bronchia
Pancoast lung cancer
Lung cancer (type
not determined)
Anaplastic adeno-
carcinoma papillo-
tubulare
94
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Baaed on the death rate due to respiratory cancer for the general population in
Japan, the expected respiratory cancer mortality for a group of 32 peaple over
the period in question was calculated to be 0.024. The five cases in this group
of 32 workers thus amount to increased relative risk of 20.8[p<0.001] (Sakabe, 1973).
It might be well argued that this study does not clearly implicate BCME as the
causative agent in these cases of respiratory cancer. First, the workers were
exposed to a variety of other chemicals (e.g., nitrobenzene and nitrophthalimide),
which may have contributed to the development of respiratory cancer. Second, no
estimates can be made of the degree of exposure to chloromethyl ethers. Lastly,
oat cell cancer appeared in only one of the five cases. However, in view of the
other epidemiological studies presented above and the detailed information on
the carcinogenic effects of BCME on other mammals (see Section III-D-6, p. 126),
such criticisms would be academic.
A summary of some of the more salient points in the epidemiological
surveys discussed above is provided in Tablti 30.
Including the six most recent deaths reported by Shore (1975),
a total of 47 deaths due to respiratory cancer have been associated with occu-
pational exposure to the chloromethyl ethers. The increased risk of respiratory
cancer deaths in exposed workers varies from about 2.5 to over 20. Albert and
coworkers (1975) have demonstrated that this risk is dose-related to both the
intensity and duration of exposure. The type of cancer associated with these
exposures seems relatively specific, respiratory oat cell carcinomas. In view
of all the epidemiological findings and the supportive laboratory data discussed
95
-------
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96
-------
below, there can be no serious doubt that BCME is a potent human carcinogen.
Lassiter (1973) has described it as possibly "one of the most potentially
hazardous carcinogens found in the workplace". More recent data lend support
to this assessment.
2. Occupational Exposure
Besides the rather extenstive epidemological surveys discussed
above, few cases of occupational injury resulting from exposure to the chloroethers
are encountered in the literature. All the reported cases give little detail, but
do cite or imply chemical irritation to the respiratory tract as the primary
toxic effect. This is consistent with the known toxicity of these compounds in
acute exposures to other mammals (see Section III-D-1, p.100). The available
information on human occupational exposures is summarized below by chemical.
CMME; A report by Dow Chemical (no date) indicates that two
workers were exposed to higher than normal concentrations of this a-haloether
for a presumably short period. One worker was exposed to "rather high con-
centrations" while the other "received only very slight exposure". Both workers
experienced respiratory difficulty. The most severely exposed individual could
not work for eight days because of sore throat, fever, and chills. The other
worker "had difficulty in breathing for several days".
1,2-Dichloroethyl ethyl ether; Jordi (1948a) describes three
cases of bronchial asthma induced in workers after repeated exposures to "rather
high" concentrations of this haloether. Initially, the workers developed head-
aches followed by irritation of the eyes and throat, and a painful cough. These
symptoms disappeared during weekends and vacation periods. After several months
of this exposure, all three workers developed severe bronchitis which was re-
lieved by a stay in a sanitorium. On return to work, all three patients ex-
perienced attacks of bronchial asthma. In one worker, these attacks were
97
-------
experimentally induced by direct exposure to 1,2-dichloroethyl ethyl ether. A
more severe attack was induced by an unspecified methyl derivative while bis-
(2-chloroethyl)ether had no effect. The major toxic effects seemed limited
to the respiratory tract with liver function being unaffected.
Bis(1-chloroethyl) ether; In anpther report, Jordl (1948b) also
states that this ot-haloether does not cause bronchial asthma but "has only a
general toxic effect." No details are igiven.
Bis(2-chloroethyl) ether; This B-chloroether is generally
regarded as less toxic than the a-chloroethers, but the type of overt hazard posed
by vapor exposure is the same, chemical irritation of the respiratory tract and
the eyes (Allen, 1956; Hake and Rowe, 1963). This assessment is based primarily
on the work of Schrenk and coworkers (1933) which is summarized in the following
section. Bell and Jones (1958) report than an occupational exposure to 2.5 ppm
bis(2-chloroethyl)ether and unspecified amounts of chlordane and kerosene caused
minor eye irritation. This chloroether may also have been a factor in the death
of a worker exposed to an unspecified concentration of vapor from a solution
containing bis(2-chloroethyl)ether. However, conclusive evidence indicating that
this haloether was the cause of death is not presented (Elkins, 1959).
3. Controlled Human Exposures
In an evaluation of potential occupational hazard, Schrenk and
coworkers (1933) have briefly exposed males to various concentrations of bis (2-
chloroethyl)ether. Concentrations of 1000 ppm and 550 ppm were considered intol-
erable and caused extreme irritation of eyes and nasal passages. Deep inhalations
caused nausea. Similar but less severe effects were caused at 260 ppm. This
98
-------
concentration was unpleasant but not intolerable. A concentration of 100 ppm
caused only slight irritation and nausea. At 35 ppm, irritation was negligible,
but the haloether was readily detected by its odor. Post-exposure respiratory
difficulty was not noted.
4. Chemical Warfare Agents
Bis(2-chloroethyl)ether is the oxygen analog of Mustard Gas, 2,2'
dichloroethyl sulfide. Both this latter chemical and its nitrogen analog are
severe respiratory and dermal irritants (Allen, 1956; Jordi, 1948). The oxygen
ether is, of course, much less reactive than either the nitrogen or sulfur analog
and has never been developed as a chemical warfare gas. Norris (1919), however,
reports that BCME was produced as a potential warfare agent during World War I.
While this chemical was apparently never used in the war, Flurry and Zamik (1931)
indicate that 3 ppm is very irritating to humans, and that 100 ppm is incap-
acitating in a few seconds and may cause fatal lung damage in one or two minutes.
99
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D. Toxicity - Birds and Mammals
1. Acute Toxicity
a. Acute Oral Toxicity
Most of the information on the acute oral toxicity of
the haloethers comes from the range finding studies of Smyth, Carpenter, and
coworkers. These tests involve administering, by intubation, four dose levels
of a compound to different groups of five to six unfasted animals. Mortality
in the test animals is noted for fourteen days after exposure. Approximate
are calculated either graphically or by interpolation (Smyth jet^ al_. , 1949). No
pathological data are obtained, and no responses other than death are noted. Thus
these tests are neither designed nor intended to give a reliable estimate of
potential toxicity. Bather, they are used to estimate comparative hazard and
"...yield no more than an indication of the degree of care necessary ..." in
exposure to humans (Smyth je_t al^. , 1969).
The available data on chloroethers are summarized in Table
31. The sources cited other than Smyth and Carpenter give few experimental
details but would appear to pose limitations similar to those discussed above.
Given the sparsity of detail and the few species tested, the differences in
lethal dosages do not seem appreciable with one possible exception, bis (2-
chloroethyl)ether. The LDso values for this compound presented by Spector
(1956) for rats, mice, and rabbits are somewhat lower than those for the other
haloethers, and the value given by Smyth and Carpenter (1948) is well below. The
significance of this observation, however, is dubious — especially in view of
the complete lack of information on metabolism.
100
-------
Table 31. Acute Oral Toxicity of Various Haloethers
ng/kg
Done(11. jfi S.I).) R«»pon«e „ Reference
tli (chloromethy 1 ) ether
Chloronathyl Methyl
Ether
•l«(2-chloroethyl)ether
lUte, Male, (5),
Carworth-Wl«t«t,
4-5 weeks, 90-120 g.
Rats
Rats, (6), Sherman
Rat
Mouse
Rabbit
300(172-530)
300
500
1000
75
105
136
126
LD50 in 14 day observation period
No death
Approximate LD50
Lethal
LD50
LD50
LD50
LD50
Smyth jet j
al., 1969+
Dow Chemical, no date
Smyt.i and
Spector,
Carpenter,
1956
Bis(2-chloroisopropyl)- Rats, (6) 240(220-270) LD50 Smyth et al., 1951
Ether Rats, (5) 200 No death Dow Chemical, no date
(6) 400 4/6 rats died
(5) 800 5/5 rats died
Guinea Pigs 450 LDso Spector, 1956
2-chloroethyl vinyl Rats, (6), Sherman 250 LD50 Smyth et, al., 1949
Ether
Bis(2-chloroethoxy)- Rat, Male, (5), 310(240-400) LD50 Smyth et_ al., 1969
methane Carworth-Wistar,
4-5 weeks, 90-120 g.
* The following data is Included when given in reference:
Animal, Sex, (Number),
Strain
Age, Weight
+ Cited as chloromethyl ether
I Cited as dichloroethyl ether
b. Acute Dermal Toxicity
Two types of dermal toxicity tests have been
conducted with the haloethers: One measures lethal response and the
other determines primary skin damage. The results of the studies measuring
lethal response are given in Table 32. These studies are similar both in
design and limitations to the acute oral administrations. In the work of
Smyth, Carpenter, and coworkers, the test chemical is held in contact
with the shaven skin of an immobilized animal for twenty-four hours either
by cuff or poultice. Smyth and Carpenter (1948) indicate that the exposures
using the poultice may prevent complete contact of the dose with the skin
101
-------
because much of the dose is absorbed by the saturated pad. In any event,
because detailed information on time to death or blood levels is not given,
the relative importance of rate of absorption as opposed to potency cannot
be assessed. All that can be concluded with confidence is that lethal amounts
of the specified chloroethers may penetrate the skin.
Table 32. Acute Dermal Toxicity of Haloethers
Compound
Bli(chloronethyl)
-------
however, caused "severe hyperemia, edema, denaturation, and even complete
destruction of skin" when applied undiluted (Dow Chemical, no date). Sim-
ilarly, BCME caused necrosis when applied undiluted (Smyth jit al. , 1969).
Smyth and coworkers (1969) also indicate that BCME applied as a 10% solution
in acetone caused "no reaction more severe than edema". However, because the
haloether is unstable in acetone (Van Duuren £t_ a^., 1968), Smyth and coworkers
(1969) may have underestimated its irritant properties.
c. Eye Injury
Eye irritation is occasionally cited as one of the effects
of vapor exposure to the haloethers. No cases, however, note that these com-
pounds cause severe eye injury. Carpenter and Smyth (1946) have developed a
rather elaborate method for evaluating eye injury from direct contact with liquid
solutions and subsequently tested five haloethers. Chemicals are ranked by
«
injury grades of one to ten, ten being the most severe. Three of the B-chloro-
ethers — bis(2-chloroisopropyl)ether, bis(Z-chloroethoxy)methane, and 2-chloro-
ethyl vinyl ether cause damage approaching severe injury in rabbit eyes when
0.5 ml is applied undiluted [injury grade of 2] (Smyth e_t a^. , 1949, 1951, 1969).
Bis(2-chloroethyl)ether, which has been reported to irritate eyes in humans at
vapor concentrations of 2.5 ppm, causes damage approaching severe injury in
rabbit eyes when 0.02 ml is applied undiluted and consistently causes severe
injury when 0.1 ml is applied [injury grade of 4] (Carpenter and Smyth, 1946).
BCME, the only a-chloroether tested, was by far the most damaging, causing
103
-------
severe injury when a 1% solution is applied to rabbit eyes [injury grade of
10] (Snyth t£ al., 1969). The solvent used in this test was not specified,
but propylene glycol is the preferred solvent (Carpenter and Smyth, 1946).
These results seem to indicate that direct eye contact with any of the chloro-
ethers would be irritating and possibly damaging. As in skin irritation tests,
the a-chloroethers are probably more potent than the B-chloroethers.
d. Acute Inhalation Toxicity
i) Chloroalkyl Ethers
Information on the acute inhalation toxicity
of various haloethers is summarized in Table 33. The studies of Smyth,
Carpenter, and coworkers are analogous to the oral and dermal exposures dis-
cussed above. The test animals are exposed once at a given concentration/
duration, and mortality is noted over a two week observation period. Unlike
the oral and dermal exposures, however, results from these acute inhalation
studies do seem to present a gradient in terms of relative toxicity among the
haloethers. With a single four hour inhalation exposure to rats, the ct-
haloethers are clearly more potent than the g-haloethers. Of the a-haloethers,
BCME is about ten times more acutely toxic than its monofunctional analogue,
CMME. A similar potency pattern is seen in inhalation carcinogenicity studies
between these two compounds (see Section III-D-6, p. 126). Of the 3-
haloethers, bis(2-chloroethyl)ether and 2-chloroethyl vinyl ether seem
about equally toxic. The somewhat disparate dose-response data for 2-
chlorovinyl ether presented by Carpenter and coworkers (1949) and Smyth
104
-------
Table 33. Acute Inhalation Toxicity of Haloethers
Reference
V— 1»V*H"
111 (chloraaethyDather
"-—— m
ute. (6).
Csrworth-Wlstar,
8 ppm
16 ppm
4 hre.
4 hre.
1/6 rate died In 14 dey observation period
6/6 rate died In 14 day observation period
Smith et al. ,
1969
4-5 weeks, 90-120 g
Rats, Male, (10),
Sprague Dewley,
8 weeks
0.94 ppn
Raster* , (tale, (10),>4.6 ppm
Chloroaethyl methyl ether
Bls(2-chloroethyl)ether
111 (2-chloroisopropyl)
ether
2-Chloroethyl vinyl ether
Bis (2-chloroethoxy)Bethane*
Fluroxene(2 , 2 , 2-trif luoro-
ethoxy ethane)
Methoxyflurane (2 , 2-dichloro-
1,1-dlfluoro-l-methoxy ethane)
Ooldn Syrian,
6 weeks
R«t«
Rats, Mala,
Spraguc Dawley,
8 veeke
Haiutara, Hale,
Golden Syrian,
6 weeks
Kate, (6),
Shenun
Hat, (6),
Shenun, 100-129 g
Guinea Pig*
tats, (6)
Rate
Rate
Rat., (5)
Rate, (10)
R«ta, (4)
Rate, (6), Sherman
100-150 g
Rate, (6), Shenun
Rate, (6),
Carwor th-Wlit»r ,
4-5 weeks, 90-120
Mice, Male, (15),
Swiss Weber,
25-30 g
Ibid. (51)
(15)
Race, Male, (6),
ri.cher 344,
6 no., 276-326 g
7 ppa
100 ppm
100 ppa
2000 ppm
55 ppn
65 ppm
1000 ppm
250 ppm
35 ppm
105 ppm
260 ppm
550 ppm
1000 ppm
1000 ppm
120,000 ppm
120,000 ppm
700 ppm
350 ppm
350 ppm
175 ppm
250 ppm
500 ppm
concentrated
vapor
I
45,000 ppm
45,000 ppm
45,000 ppm
7,500 pp.
7 hre.
7 hrs.
7 hre.
1/2 hr.
4 hrs.
1/2 hr.
7 hra.
7 hra.
3/4 hrs.
4 hrs.
13.5 hra.
13.5 hrs.
7.5 hrs.
* hrs.
4 hre.
4 hre.
immediate
>1 hr.
6 hrs.
8 hrs.
6 hrs.
8 hra.
4 hrs.
4 hra.
>1 hr.
0.5 hr.
1 hr.
2 hrs.
6 hra.
1 hamster and 4 rats with elevated lung-to-
body weight ratios
Elevated lung-to-body weight ratios In 90%
or more at rats and hamsters
LCjo In 14 day observation period for
rats and hamsters
[see text for details]
Highly Irritating tumerous membranes
"dangerous to life". Delayed death
(days-weeks) usually from pneumonia
" " " "
LCs(lafter 14 day observation period
LC50 after 14 day observation period
[aee text for details]
3/6 rats died in 14 days observation period
2-4/6 rats died in 14 day observation
period
Masai Irritation only
Respiratory depression and loss of motillty.
Death In 4/6 animals by 4 hrs. after ex-
posure was terminated.
Caused death In some animals
Caused death in some animals
Caused death In some animals
[see text for details]
1/6 rata died in 14 day observation period
Eye irritation and some Incoordinatlon
Death In some animals
Lethal' dose; alight lung irritation and
moderate to aevere liver damage
2/5 rats died. Moderate lung congestion
and necroais of the liver
No deaths
1/4 rats died
2-4/6 rats died In 14 day observation
period
1/6 rata died in 14 day observation period
Cause death in some animals
No mortality
8 mice (16X) died 16-30 hrs. after
exposure
100X mortality 16-30 hrs. after exposure
[see text for details]
Immediate gross hematurla in 4/6 rats
Acute tubular necroais In 2/6 rats
[see text for details]
Drew et al. ,
1975
Dow Chemical,
no date
Drew et al, ,
1975
Smyth and Carpenter,
1948
Carpenter et al.,
1949
Schrenk et al. ,
1933
Smyth et al. ,
1951
Dow Chemical,
no date
Carpenter et al . ,
1949
Smyth et al.,
1949
Smyth et al..
1969
Csscorbi and
Singh-Amaranath ,
1972
Maize et al.,
1972
* Cited M Di(2-chloroethyl)acetal
105
-------
and coworkera (1949) cannot be attributed to any obvious differences in
experimental detail and, given the limited numbers of animals tested,
may not be significant. In any event, the bis(2-chloroisopropyl)ether
requires a two to four fold higher concentration to elicit a lethal
response in rats comparable to either bis(2-chloroethyl)ether or 2-
chloroethyl vinyl ether. Unlike bis(2-chloroethyl)ether, bis(2-chloro-
isopropyl)ether seems to have its primary effect on the liver rather
than the respiratory tract. This distinction, however, is based on
rather limited data. The concentrated vapor exposure to bis(2-chloro-
ethoxy)methane is not readily compared to any of the above exposures
because the actual concentration to which the animals were exposed is
uncertain.
The much more detailed studies of Drew and
coworkers (1975) and Schenk and coworkers (1933) are in approximated
quantitative agreement with other corresponding studies summarized in
Table 33 and support the general order of haloether inhalation potency
outlined above.
Unlike the studies by Smyth, Carpenter, and
coworkers which were designed to approximate relative orders of occupa-
tional hazard for a variety of synthetic chemicals, Drew and coworkers
(1975) specifically addressed the acute toxicity of a-haloethers in
conjunction with carcinogenicity testing. Single seven-hour exposures
of both rats and hamsters to BCME or CCME resulted in similar pathological
106
-------
changes in the lungs of both species: i.e. congestion, edema, and hemorrhage.
In addition single exposures to 12.5 - 255 ppm COME produced dose-related
increases in lung-to-body weight ratios, indicative of lung damage. Mortality
at 14 days was also dose related. These details are summarized in Tables
34A and 34B.
•In additional studies on BCME, both rats and
hamsters were exposed to varying concentration for seven hours and observed
until death. As in the above exposures, elevated lung-to-body weight ratios
accompanied by congestion, edema, and hemorrhage were noted. The median life
span of both species decreased in proportion to the haloether concentration
(see Table 35).
107
-------
Table 34. Mortality and Lung-to-Body Weight Ratios After Single
Seven Hour Exposures to (A) Chloromethyl Methyl Ether
and (B) Bis(chloromethyl)«ther (Drew et al., 197b)
A: Chloromethyl methyl ether
Rats (10)
Concentration ,
ppm
225
141
70
54
42
26
12.5
% Mortality
at 14 Days
loot
100
100
43
25
10
0
% Increased*
Lung-to-Body
Weight Ratio
80
80
90
67
55
20
0
Hamsters (10)
% Mortality
at 14 Days
100A
70
60
33
0
0
0
% Increased*
Lung-to-Body
Weight Ratio
90
80
100
63
60
10
0
* Greater than control mean plus 3 SD
t All animals dead after four hours of exposure
A Two animals dead during the exposure period
IJ: Bis (Chloromethyl)ether
Rats (90)
Concentration,
ppm
74
19
9
7.3
6.2
4.6
0.94
% Mortality
at 14 Days
100
100
100
60
30
0
0
% Increased*
Lung- to-Body
Weight Ratio
100
100
100
90
100
100
40
Hamsters (10)
% Mortality
at 14 Days
100
100
100
60
10
10
0
% Increased
Lung-to-Body
Weight Ratio
100
100
100
90
90
100
10
*Greater than control mean plus 3 SD
108
-------
Table 35. Median Life Span and Lung-to-Body Weight Ratio after
a Single Seven Hour Exposure to Bis(Chloromethyl)ether
(Drew e£ al., 1975)
Rats
Hamsters
Lung/Body
Lung/Body
uuncen—
tration,
ppm
9.5
6.9
2.1
0.7
Control
median
Life Span,
Days
2
2
36
420
462
Mean
1.7
1.6
2.7
2.2
0.6
% Above
Normal*
93
88
100
96
...
Vjonceu—
tration,
ppm
9.9
5.6
2.1
0.7
Control
neu-Lciii
Life Span,
Days
4
16
68
657
675
Mean
1.2
1.4
1.8
1.2
0.6
% Above
Normal*
68
100
100
100
. . .
Greater than control mean plus 3 SD
In this series of exposures, Drew and coworkers
(1975) noted the relatively high mortality in rats at 6.9 ppm (median
life span, 2 days) in contrast to the 14-day LCs0 value of 7 ppm. This
was attributed to the limited reliability of the calculated 14-day LC50
values because of the narrow range between no mortality (4.6 ppm) and
complete mortality (9 ppm). Exposures of 2.1 ppm and above resulted in
marked histopathological changes including tracheal and bronchial
hyperplasia and squamous metaplasia without atypia. At 0.7 ppm, rats
showed increases over controls in tracheal epithelial hyperplasia (36%
in controls to 69% in exposed) and hamsters had increased pneumonitis
(23% in controls to 67% in exposed). One hamster, dying at 770 days,
had a focus of alveolar squamous metaplasia. In general, pathological
damage was more severe in the longer surviving animals.
109
-------
These single exposure studies thus indicate
not only acute chemical irritation (edema, hemorrhage, and conjestion)
but also epithelial changes perhaps related to ot-haloether carcinogenicity
(Drew et^ al., 1975).
Bis(2-chloroethyl)ether inhalation toxicity
has been examined in some detail by Schrenk and coworkers (1933), with
results in approximate agreement with those of Smyth and Carpenter
(1948) and Carpenter and coworkers (1949). Here, it should be emphasized
that Schrenk and coworkers (1933) present data on mortality occurring
during exposure, unless otherwise specified, while the other investigators
give mortality figures over a two week period after exposure. This
difference may be particularly critical with the haloethers in that
these chemicals seem to cause progressive damage over a prolonged
period after exposure. This was noted above for the a-haloethers (Drew
et al., 1975), and was also noted for the 6-haloether. Gross pathological
damage was similar to that caused by a-haloether exposure: lung conjestion,
edema, and hemorrhage. In fatally exposed animals the degree of such
damage was proportional to the length of time the animals survived,
indicating progressive post-exposure damage. Conjestion of the kidney,
liver, and brain was also noted but was perhaps secondary to lung damage.
Detailed dose response data on bis(2-chloroethyl)ether is presented in
Table 36.
110
-------
Table 36. Effects of Bis(2-chloroethy1)ether on Guinea Pigs
(Schrenk et al., 1933).
Response
Nasal irritation:
Scratching at nose. . . .
Eye irritation:
Disturbance in respiration.
Animals on slides; unable
to stand; quiet; dyspnea;
gasping respiration . . .
Period of
1000
(b)
(b)
1-2
90
180-300
230-330
exposure
com
550
(b)
(b)
1-2
180
240-480
360-500
causing
lentratio
260
1
1
3
310
445-600
450-740
respons
n (a)
105
2
20
c(810)
450
525-810
(d)
B with vapor
35
3-10
c(810)
c(810)
c(810)
c(810)
c(810)
a Concentration of vapor in ppm by volume; time in minutes
b Occurs immediately after start of exposure
c Not observed in the maximum exposure period given in parentheses
d Four died within a period ranging from immediately after to 250 minutes
after exposure. IWo survived 8 days and were killed for autopsy.
Besides the obvious difference in potency
from the a-haloethers, the time course of post-exposure damage with
bis(2-chloroethyl)ether may be different from that of the a-haloethers.
For the a-haloethers (Drew e£ a±., 1975), no amelioration of lung damage,
based on lung-to-body weight ratios, is noted even at low single dose
levels after prolonged post-exposure observations (see Table 35). With
bis(2-chloroethyl)ether, however, Schrenk and coworkers (1933) noted
that the degree of conjestion from exposures not causing death initially
increased but then markedly lessened eight days after exposure.
Ill
-------
ii) Fluorinated Ethers
Along with information on the chloroalkyl
ethers, Table 33 also summarizes two studies on the fluorine-containing
ethers, fluroxene and methoxyflurane. Both of these fluorinated ethers,
as indicated previously, are produced in relatively small quantities and
used exclusively as anesthetics. Because of their medical applications,
the pharmacology of these fluoroethers has undergone extensive investigation.
Some of this information has already been discussed with reference to
haloether metabolism. The development of these drugs and the continuing
research on the anesthetic properties of other fluorinated ethers have
generated biological data on scores of additional haloethers (e.g.
Robins, 1946; Van Poznak and Artusio, 1960; Speers et^ aj^., 1971; Terrell
et al., 1971). Krantz and Rudo (1966) provide a detailed review of much
of this literature. While the biological effects of these fluorinated
compounds are of undoubted interest to the medical community, a thorough
review of this topic would not seem justified in an evaluation of the
environmental threat posed by the commercially important haloethers. A
cursory examination of the toxicity of fluroxene and methoxyflurane will
illustrate this point.
Fluroxene was the first fluorinated anesthetic
to be used in humans (Krantz and Rudo, 1966). As an anesthetic agent,
its potency is similar to that of diethyl ether in dogs, producing
satisfactory surgical anesthesia at 0.65 - 1.11 mg/kg and respiratory
112
-------
failure at 1.52 - 2.50 mg/kg with a mean anesthetic index of 2.35.
After one hour exposures to anesthetic concentrations of fluroxene, dogs
evidenced no change in liver function as measured by urinary elimination
of brotnosulfalein (Krantz et_ ai_. , 1953). More recently, however, delayed
death has been seen in dogs, cats, rabbits, and mice exposed to anesthetic
concentration for more prolonged periods (Johnston and Thomas, 1971;
Cascorbi and Singh-Amaranath, 1972). Cascorbi and Singh-Amaranath
(1972) have shown that the duration exposure is critical to the number
of delayed deaths in mice (see Table 33). These workers also found that
no mortality was produced in mice given a dose schedule of 4.5% fluroxene
x 1/2 hr./day x 3 days, whereas 50% mortality was elicited in mice given
two exposures of 4.5% fluoroxene x 1 hr. with 48 hours between exposures.
In addition, inhibition of drug metabolizing enzymes with carbon tetrachloride
eliminated delayed death from an otherwise lethal dose of fluroxene.
Conversely, stimulation of drug metabolizing enzymes with phenobarbital
resulted in 95% mortality after exposure to an otherwise nonlethal dose
of fluroxene. These observations indicate that a metabolite of fluroxene
is the toxic agent (Cascorbi and Singh-Amaranath, 1972). As previously
discussed (see Section III-B, p. 83), this agent may be trifluoroacetic acid
(Cascorbi and Singh-Amaranth, 1973).
Although the precise nature of the toxic
response was not determined in the above studies, Harrison and Smith
(1973) have demonstrated that a normally nonlethal 3 hour exposure to
113
-------
fluroxene results in massive lethal hepatic necrosis in rats whose liver
cytochrome P-450 levels had been increased with phenobarbital. Thus,
fluroxene toxlcity may be similar to halothane (CF3-CCX,BrH) — which is
also metabolized to trifluoroacetic acid — and hepatotoxicity is
probably the primary adverse effect (Van Dyke, 1973).
Methoxyflurane, on the other hand, primarily
affects the kidneys. Mazze and coworkers (1972) have shown that methoxy-
flurane affects rat kidney function and histology in a dose-related
manner. At the highest dose level tested (0.75% x 6 hrs, see Table 33),
four of six rats developed gross hematuria attributable to severe hemorrhagic
and ulcerative cystitis of the bladder, and one rat developed polyuria
followed by oliguric renal failure. Histological examinations of the
renal cortices of these rats revealed dilation of the convoluted tubles,
reduced height of littoral cells, deposits of calcium oxalate crystals,
and foci of increased eosinophil leukocytes, fragmented or condensed
nuclei, and intraluminal slough of necrotic tubular epithelial cells.
Two of the six rats had acute tubular necrosis. As with fluroxene,
metabolites of methoxyflurane are the toxic agents. Of these, inorganic
fluoride is probably the most nephrotoxic (Van Dyke, 1973), while oxalic
acid may cause renal inflammation and scarring due to crystal formation
(Mazze et^ aju , 1972). Also like fluroxene, stimulation of liver cytochrome
P-450 with phenobarbital potentiates the toxic action of methoxyflurane
(Cousins et al., 1973).
114
-------
ill) Toxicological Relationships between the
Chloroalkyl Ethers and Fluorinated Ethers
As indicated previously, the metabolism
of the chloroalkyi ethers is poorly understood. As should be apparent
from the above discussion on acute toxicity, the mechanism of action of
these chloroethers has received little attention. In contrast, the
fluorinated ethers have been examined in detail. Thus, a detailed
comparison of these two groups of chemicals is neither warranted nor
possible. However, a few elementary points deserve emphasis.
Fluorination radically alters the chemical
and toxicological properties of aliphatic compounds (Clayton, 1966;
Howard et al., 1974). While both diethyl ether and fluoroxene may have
similar anesthetic potencies and while both may cause death due to
respiratory failure at high concentrations, only fluroxene is specifically
hepatotoxic. Similarly, while further toxicological testing might
conceivably demonstrate hepato- or nephrotoxicity for some of the chloroalkyi
ethers, this would not be directly related to fluroxene or methoxyflurane
toxicity as currently understood.
Based on available information, the biological
activity of the ot-chloromethyl ethers has no relationship to the fluorinated
ethers. The former are highly reactive and corrosive respiratory irritants
and carcinogens. It seems probable that they alkylate or hydrolyze in
the respiratory tract and are not subject to absorption as such, and
115
-------
hence would not directly effect internal organs other than the respiratory
tract itself. The 0-chloroethers may be similar to the fluorinated
ethers only in that they are stable enough to be absorbed, metabolized,
and cause organ specific effects. In acute inhalation exposures, they
act primarily as respiratory irritants like the a-chloroethers. Their
biological effects under other conditions are discussed in appropriate
sections. Thus, because information on these fluoroethers is of negligible
use in understanding the biological effects of the commercially significant
chloroalkylethers, the abundant toxicological data on these fluorinated
compounds are not reviewed in detail in this report.
2. Chronic Toxicity
a. Chronic Oral Toxicity
Only two haloethers have been tested in repeated
oral administration, bis(2-chloroethyl)ether and bis(2-chloroisopropyl)-
ether. The maximum dose of bis(2-chloroethyl)ether causing no mortality
to male and female one-week old mice after nineteen daily doses by
stomach tube was determined as part of a carcinogenicity screening
program (see Section III-D-6, p. 126), and was found to be 100 mg/kg (Innes
ejt jal. , 1969). This daily dose is only slightly less than the single oral
dose (136 mg/kg) found to be lethal to half the exposed mice over a two week
observation period after administration (Spector, 1956; Table 31).
Similar results are evident with bis(2-chloro-
isopropyl)ether. Twenty-two doses over a thirty one day period at 200
116
-------
rag/kg administered to rats by stomach tube reduced growth rates, increased
the weight of liver, kidney, and spleen relative to total body weight,
but had no effect on hematology and caused no deaths. Administration of
10 mg/kg on the same schedule caused only a reduced growth rate (Dow
Chemical, no date).
As indicated in Table 31, this same study,
presumably using the same strain rats under similar conditions, found that
a single administration of 400 mg/kg was lethal to four of six rats tested.
Further, Smyth and coworkers (1951) note that a single administration of
240 mg/kg bis(2-chloroisopropyl)ether causes death in half the exposed rats
over a two week observation period.
Because of the lack of detail in both the acute
and chronic studies, these results are difficult to interpret. From the
available data, these 3-chloroethers seem to have a relatively narrow
range between concentrations causing death and concentrations causing
no marked effects. The chloroethyl ether seems somewhat more toxic than
the chloroisopropyl ether, and the concentration seems more critical than
the frequency of exposure. This pattern is consistent with a chemical that
is readily absorbed and then rapidly detqxified and/or eliminated.
b. Chronic Dermal Toxicity
All repeated dermal applications of halo-
ethers have been conducted by Van Duuren and coworkers (1968 and 1969)
In setting dose levels for long term carcinogenicity screening tests.
117
-------
These dose setting tests involved applying varying amounts of the halo-
ethers to the shaven dermal skin of eight week old female mice (ICR/Ha
Swiss) three times a week for two weeks. The maximum tolerated dose was
established as the highest dose producing no adverse effects (e.g. ulcerative
lesions). Four haloethers were thus tested: BCME, CMME, a,a-dichloro-
methyl methylether, and bis(2,3,3,3-tetrachloro-n-propyl)-ether. For all
of these compounds, the maximum tolerated dose was determinec1 to be 2 mg
haloethers in 0.1 ml of benzene.
All of these haloethers were subsequently applied
at the same level and frequency over prolonged periods, BCME and CMME for
325 days and the other haloethers for 540 days. In these exposures, BCME
resulted in epilation and edema of subcutaneous tissue. This is apparently
similar to the effect on rabbits noted for a single application for un-
specified quantity of undilute chloromethyl ether (see Table 32). In these
long term studies on mice, however, only the BCME produced obvious skin
damage.
c. Chronic Toxicity of Haloethers in Subcutaneous
Injection
Multiple subcutaneous injections of haloethers
parallel the chronic dermal exposures both in purpose and methodology.
Maximum tolerated doses of 3 mg (Per animal per injection) were determined
for BCME and CMME using six week old female rats (Sprague Dawley). However,
neither the frequency nor duration of these "short term" toxicity tests
are noted. As in the dermal studies, prolonged exposure [3 mg/injection, 1
injection/week x 114 days] to BCME resulted in severe ulceration at the
118
-------
injection site. This effect persisted and was accompanied by significant
weight loss even after the dose was dropped to 1 mg/injection and the
frequency reduced to thrice monthly. The total treatment period lasted
about 300 days. CMME [3 mg/injection, 1 injection/week x ^ 300 days]
produced similar but less pronounced effects (Van Duuren et al., 1968).
Analogous tests have been conducted using
CMME, bis(1-chloroethyl)ether, and bis(2-chloroethyl)ether on six week
old female mice (ICR/HA Swiss). Again, frequency and duration of injection
for the "short term" toxicity tests are not specified. In these tests,
the highest dose which caused minimum cytotoxic effects was determined to
to be 0.3 mg for both CMME and bis(l-chloroethyl)ether, and 1 mg for bis(2-
chloroethyl)ether (Van Duuren e_t _al. , 1972). Presumably, these tests
involved only histological examination at the injection site. The lower
toxicity of bis(2-chloroethyl)ether by this route is consistent with the
much greater chemical reactivity of the a-haloethers as opposed to the 0-
haloethers and with the premise that the mode of action, both in skin
irritation and carcinogenicity, is related to the alkylating ability of
these compounds.
d. Chronic Inhalation Toxicity
Multiple inhalation exposures reflect the
recent concern with the occupational carcinogencity hazard posed by
119
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BCME and CMME. Both of these a-haloethers have been tested in some detail.
Of the g-haloethers, only bis(2-chloroethyl)ether has been examined. All of
these exposures are summarized in Table 37 and agree with the view of haloether
toxlcity presented in the previous section — i.e. that the u-haloethers are
more chemically reactive and hence more corrosive and toxic than the g-
haloethers.
Table 37. Chronic Inhalation Toxicity of Haloethers
Confound
_£onc.
Expo* art
Duration Raippnae
Rpferenre
Bis(chloroacthyl)ether Rats, Male, 120 0.01 and 6hr/day
Sprague Dawley 0.001 ppm
0.1 ppm 6hr/day
Mice, Male, 0.01 and 6hr/day
144-160, 0.0001 ppn
Swigs Webster
0.1 ppm 6hr/day
Chloromethyl methyl
ether
Bis(2-chloroethyl)-
ether
Rats, Male,
20-50,
Sprague Daw ley
0.1 ppm
Rats, Male, 50 1 ppm
Sprague Dawley,
8 weeks
Hamsters, Male, 1 ppm
50, Golden
Syrian, 6 weeks
Mice, Male, 50 1 ppm
A/Heston
20-25 g.
Rats, Male, 25 1 ppm
Sprague Dawley
8 weeks
10 ppi"
Mice, Male, 50 2 ppm
A/Heston,
20-25 g.
Rats and
Guinea Figs
6hr/day
6hr/day
6hr/day
6hr/day
7hr/day
/hr/day
6hr/day
Sdays/ 6 months no increased mortality Leong e_t^ a\_. , 1975
week
Sdays/ 6 months increased mortality
veek [see text]
Sdays/ 6 months apparent increase in
week mortality [see text]
Sdays/ 6 months
week
increased mortality
[see text]
10-100 decreased median life
exposures span in rats receiving
80 and 100 exposures
[see text for details]
Kuschnet e_t ^1. , 1975
3, 10, i 100% mortality after 30 Drew
30 exposures exposures
Rats and Hamsters: In-
crease in broncheal and
tracheal hyperplasia and
squamous metaplasia. De-
creased median life span
[see text for details]
3, 10, i
30 exposures
al. , 1975
•eong e± al. , 1971
Sdays/ 82 expo- 37 mice died. LOBS of :
week sures in body weight, respira-
27 weeks tory distress; hemor-
rhage, and patchy consol-
idation of lungs
30 2 rats died on days 16th Drew et al., 1975
exposures and 22nd exposures
30 22 rats died on pay
exposures from 3rd to 30th
exposures
[see text for details]
Sdays/ 101 expo- mortality, body weight, Leong ejt al. , 1971
week sures in and demeanos not sig-
21 weeks nificantly different
from controls
69 ppm 7hr/day Sdaya/ 93 expo- significant growth de- Dow Chemical, no
week sures In pression noted in males
130 days of both species. No
other adverse effects
noted in appearance,
behavior, mortality,
hematology, and gross
or microhistology
date
120
-------
As in acute inhalation exposures, BCME is clearly
the most toxic of the haloethers. As indicated in Table 37, multiple
exposures to BCME have been conducted at 1 ppm and 0.1 ppm, six hours per
day. Of the mammals tested, the mice used by Leong and coworkers (1971)
seem the most resistant showing only 74% mortality after 82 exposures over
2.7 weeks. Both rats and hamsters, however, reached 100% mortality prior
to ten weeks after only 30 exposures to 1 ppm. As illustrated in Table 38,
rats seem more severely effected than hamsters in terms of decreased longevity.
Table 38. Median Life Span of Rats and Hamsters After Multiple Exposures
to 1 ppm Bis (chloromethyl) ether (modified from Drew et^ al^., 1975)
Rats
Hamsters
Number of
Exposures
30
10
3
0
Median
Life Span
(days)
23
21
168
462
% of Control
5%
4.5%
36%
100%
Median
Life Span
(days)
42
137
471
675
% of Contro:
6.2%
20%
70%
100%
Even at a ten-fold liver concentration, both rats
and hamisters experience decreased median life spans. As partially summarized
in Table 37, rats exposed to 0.1 ppm BCME for six hours per day for 80 and
100 exposures had median life spans of forty-three and fifty weeks,
respectively (median life span of control group was sixty-six weeks). In
addition, both rats and hamsters show markedly increased mortality over
control groups during life time exposures to 0.1 ppm BCME for six hours per
121
-------
day (see Figures 19 and 20).
100
o 80-
60-
40-
20-
80 Exposure::
.Colony Control
±2SX
10
80
20 30 40 50 60 70
Weeks Alter First Exposure
Figure 19. Mortality of Rats
Following Chronic Exposures
to 0.1 ppm Bis(chloromethyl)-
ether (Kuschner et al., 1975)
10
70 8O
20 30 40 50 60
Weeks After First Exposure
Figure 20. Mortality of Hamsters
Following Chronic Exposures to
0.1 ppm Bis(chloromethyl)ether
(Kuschner et al., 1975)
Leong and coworkers (1975) examined the effects on
rats and mice of repeated exposures of 0.1, 0.01, and 0.001 ppm BCME. Similar
to the results of Kuschner and coworkers (1975), rats exposed to 0.1 ppm
BCME for 6 hours/day, 5 days/week x 6 months showed a marked increase in
mortality starting one month after exposure terminated. By the eleventh
month after exposure terminated, virtually all of the 0.1 ppm exposed rats
had died while the control group had only 26% mortality. Rats exposed to
0.01 and 0.001 ppm BCME had mortality patterns similar to the control group
throughout the twenty-seven month study period. Both the control and exposed
mice in this study suffered from ascending urinary tract infection which
appeared to be the direct cause of death in most mice. Thus, while the
mortality patterns of the various exposure groups did show an apparent con-
centration related effect (see Figure 21), the precise role of BCME is un-
certain.
122
-------
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The lung pathology in mice after multiple
exposure Co BCME noted In Table 37 Is similar to that seen in rats and
hamsters after acute exposures (see Table 37) and is indicative of the
corrosive effects of this chemical (Leong et^ jiJL., 1971). In rats, multiple
exposures to BCME evidenced dose related increases in bronchial tracheal
hyperplasia and bronchial squamous metaplasia. Atypias, mostly abnormal
nuclei, were noted in all of these pathological changes but were not dose
related. Similar pathology was seen in hamsters with dose related increases
in bronchial hyperplasia with and without atypia. Extreme irritability,
subarachnoid hemorrhage, and other signs of central nervous systems effects
were seen in animals of both species exposed ten or more times to BCME.
At exposure conditions under which BCME causes
marked lethality, CMME has a much less pronounced effect. As indicated in
Table 37, CMME at 1 ppm, 7 hrs/day x 30 exposures resulted in only 8%
mortality in rats while a nearly identical exposure to BCME caused 100%
ijiortality. Only at 10 ppm did CMME cause deaths in nearly all test rats
(Drew et al., 1975). This agrees well with acute inhalation data previously
cited indicating that BCME is about ten times as toxic as CMME, by this
route. Mice respond similarly to CMME, as compared to BCME, showing no
gross toxic response to 101 exposures to the monochloroether at 2 ppm,
whereas the dichloroether produced 74% mortality with fewer exposures and
at one half the concentration (Leong e_t al., 1971, see Table 37).
Lung pathology is similarly less severe with
CMME. In the 1 ppm exposure to rats (Drew e_£ ajL., 1975), only one in five
rats examined immediately after the thirtieth exposure had slight hemorrhage
124
-------
of both lungs, the remaining four having no lung abnormalities. Even in
the 10 ppm exposure, the only common change noted was regenerative bronchial
hyperplasia which was seen in 40% of the rats. As in acute exposures,
deaths in this group were associated with increased lung-to-body weight ratios.
Of the mice repeatedly exposed to 2 ppm CMME, the lungs of eleven animals
had pin-point hemorrhage or patchy consolidation (Leong et al., 1971).
No details are given for the exposure of rats
and guinea pigs to bis(2-chloroethyl)ether other than those noted in
Table 37. As in acute exposures, the 3-haloether seems much less toxic than
either of the a-haloethers.
3. Sensitization - No studies encountered.
4. Teratogenicity
The commercially important chloroethers have not been tested
for teratogenicity. The anesthetic haloether methoxyflurane, however, has
been found to induce congenital abnormalities in C57 black mice. When exposed
to 0.3% methoxyflurane, three hours per day, on days 10-12 of gestation, 45%
of the surviving group had skeletal abnormalities. The release of free fluoride
ions is thought to be the causative factor (Smith, 1974). Thus, this effect
cannot be considered indicative of the chloroethers.
5. Mutagenicity
None of the chloroethers have been tested as mutagens in mam-
mals. However, BCME and CMME have been cited as mutagens in bacteria (see
Section III-G, p. 148 ).
125
-------
6. Carcinogeniclty
a. Screening Tests
Since the initial indication by Van Duuren and coworkers
(1968) that BCME exposure leads to an increased incidence of carcinoma in mice,
a variety of haloethers and related compounds have been screened for carcin-
ogenicity. Although some studies have involved oral administration or inhala-
tion, most of the screening tests have utilized dermal application or sub-
cutaneous injection. Because the experimental design varies considerably with
the mode of exposure, the results of the various investigations are detailed
by route of administration.
(i) Dermal Application
The greatest number of haloethers have been tested
for carcinogenicity by applying solutions of haloethers in an appropriate
solvent to the shaven backs of mice. Because the haloethers degrade when
dissolved in .acetone, benzene has been used as the haloether solvent in
all dermal applications (e.g., Van Duuren e_t al., 1969). Three types
of carcinogenic activity have been examined: complete carcinogenesis,
initiating activity, and promoting activity. Tests for complete carcinogene-
sis simply consist of exposure to the test compound at regular intervals -
usually three times each week - over a relatively prolonged period - approxi-
mately one year. Initiating and promoting activity refers to the process
of two-stage carcinogenesis. In tests for two-stage carcinogenesis, the
animal is exposed once to the initiating agent; after a period of usually two
weeks, the animal is exposed repeatedly (usually three times per week) to
the promoting agent. A compound may be classified as an initiating agent if a
126
-------
single application of the compound followed by repeated applications of a known
promoting agent leads to significant increase in tumor production. Conversely,
a compound is classified as a promoting agent if repeated applications of the
compound, after previous exposure to a known initiating agent, lead to a
significantly increased incidence of tumors. The criteria for "significant increasi
production by haloethers is usually based on a comparison to known carcinogenic
alkylating agents (certain epoxides or lactones) or to a positive control (known
initiating agent and promoting agent) and negative control. The critical i
aspect of two-stage carcinogenesis testing is that neither the initiating ajjent
nor the promoting agent, when used alone at test doses, results in an appreciable
incidence of tumor production.
In evaluating the effects of dermal exposure, two types
of neoplasms are noted: squamous papillomas and squamous cell carcinomas.
Squamous papillomas are benign growths on the epidermis which may either regress,
persist, or become malignant. Squamous cell carcinomas are malignant growths
which infiltrate into the dermis and/or metastasize. Histologically, both
neoplasms evidence epidermal hyperplasia and hyperkeratosis (Van Duuren e_t al. ,
1968). The results of dermal application of various haloethers are summarized
in Table 39.
Of the haloethers tested as whole carcinogens -
promoting agent with no initiating agent in Table 39 - only BCME shows any
positive activity. This compound is carcinogenic under test conditions, pro-
ducing papilloma in thirteen of twenty mice, twelve of which subsequently
developed squamous cell carcinomas (Van Duuren ejt al., 1969). Similarly, in
127
-------
Table 39. Tumor Induction in Mice Involving Dermal Application of Various Haloethers
jjtynjtni *m[_
None
Danto(a)
pyrena 0*A___>aUULi
ll.(ohlor«oethyl)- I* 1 32)
uthflr
" ' In* 1 123
fhorbel eater ).023», 3 540
Acetone (eolvent O.lmJ ) 340
control)
None
Croton oil O.OSal 2 210
Croton oil O.OSnl 2 210
Mont -
ChloroMthyl 2mg 3 325
methyl ether
Chloromethyl 2mg 3 32S
Mthyl ether
Phorbol eeter 0.025«t 3 340
Phorbol eeter 0.025mg 3 540
Acetone (eolvent 0. lal 3 540
control)
None -
None -
Croton oil 0.05ml 2 210
Croton oil 0.05ml 2 210
Croton oil 0.05ml 2 210
Croton oil 0.05ml 2 210
Hone - -
"."-Dlcfcloro- 2m« 3 450
methyl Mthyl
• ther
-.--Dlchloro- 2mc 3 450
methyl Mthyl
eth«r
Phorbol eeter 0.023ng 3 450
Phorbol nyrl- 2.5ug 3 390
state acetate
Acetone (eolvent O.lml 3 590
control)
Phorbol nyrl-
atate acetate 2.5ug 3 590
Acetone (eolvent O.lml 3 590
control)
Octecliloro-dl- 2m« 3 450
n-propyl ether
Octachloro-dl- 2ng 3 450
n-propyl ether
Phorbol alter 0.023n| 3 450
Ibeervetlor NlaWier of
Period HIM Itrsin
(|g[|l M«. M»
340 20,tVR/KA
Svlta, FeMle,
9 «eeka
340 " "
540
340 ' "
540 " "
105 27, char lee
210 River CD1, Fe-
Mle, 7-9 like.
105 28, " "
210
105 30, " "
210
325 20, ICR/KA
Swlsi, Female,
8 weeks
540 " "
540 " "
540
540 " "
540
540
105 28, Char lea
210 River, CD1,
Female. 7-9
week a
105 30, " "
210
105 30, " "
210
105 30, "
210
105 29, " "
210
450 20, Swlae
Mlllertoti ,
Fenale, N.S.
450
450
590 20, ICR/BA
Swiss, female,
6 weeke
590 " '
590 20, ICR/HA
Swlits, Female,
6 weeks
590
450 20, Swim
HULenon,
Praalf, N.S.
450 " '
450 " '
ftfLLI|OHMf ^AIIIllhnHAIf 1
W» I t
3 (0.63) 161
3 (0.63) 98
3 (0.23) 76
0 0
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1 (0.05) 392
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5 (0.25) 140
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laga et afr
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ii >,
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1973
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et «1. , 1969
„
Van Duuren
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Van Duuren
et aj.. , 1972
et al. , 19b9
Reproduced from |PP|
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t> M - nioetier of vice with papillo*a« or carcinomas
N • total nuAer of papillo.ua or carcino.ua
X - nu».b*r of paplllo-M* or carcinoaaa per Mouae. Hu«.b«r In ( .) aasune H-H
T • ti«* to firat papillOeMa or catoincr.ua
two wa*k period between, initiation end pro«0 tien unleaa otherwla* ep«cified
One **ek period baHiinti inltUtlo* aad promotion imleM otttervlae a
-------
those haloethers tested as promoting agents - using benzo(a)pyrene as ini-
tiating agent - BCME is again the only compound with clear carcinogenic
action. The only effect of the initiating agent for this haloether is to
decrease the period before neoplasms appear without altering the incidence
of papilloma and carcinoma development. CMME and octachloro-di-n-propyl
ether did result in papilloma development in one of twenty mice in each ex-
perimental group, but these papillomas did not develop into carcinomas and
the mean survival time of the experimental groups was not reduced. The
activity of these latter two haloethers is comparable to a control group using
benzo(a)pyrene as an initiator and acetone (a skin irritant but noncarcinogenic)
as the promoting agent, and, thus, they are not considered to be carcinogenic
promoting agents in this series of tests (Van Duuren e_t ail. , 1969).
As indicated in Table 39, the majority of dermal
exposures have tested haloethers as initiating agents. This method is par-
ticularly suitable for the more caustic haloethers (e.g., BCME and CMM"i)
which are not tolerated on repeated application (Van Duuren e_t al., 1969; also
see Section III-D-2-b, Chronic Dermal Toxicity, p. 117).
As in whole carcinogen and promoting tests, BCME
shows positive initiating activity. In the work of Van Duuren and coworkers
(1969), one treatment with BCME followed by phorbol ester promotion resulted
in papillomas in five of twenty exposed mice, two of which subsequently developed
squamous cell carcinomas with metastasis to the lung in one mouse. The first
129
-------
tumor in this group was observed after seventy-six days. In contrast, a neg-
ative control group of twenty mice receiving phorbol ester promotion without
an initiating agent developed only two papillomas, the first of which did not
appear until the three hundred and twenty second day of treatment, and neither
of which progressed to carcinomas. Conversely, the initiating activity of BCME
is well below that of the benzo(a)pyrene-phorbol ester (positive control) group
in which all twenty exposed mice developed papillomas (the first within seventy
days) and seven subsequently developed carcinomas. Thus, the initiating
activity of BCME is appreciably higher than the negative controls but only
moderate in comparison to the potent carcinogen benzo(a)pyrene. Further, as
indicated in Table 39, an initiating dose of BCME failed to produce any neo-
plasms in the absence of phorbol ester promotion.
These results are in substantial agreement with
the more recent work of Slaga and coworkers (1973) when differences in ex-
perimental technique are considered. Using a comparable initiating dose of
BCME followed by croton oil promotion, Slaga and coworkers (1973) note a 0.4
incidence of papilloma development per mouse at 105 days with 25% of these
regressing by 210 days. No carcinomas are noted. While these investigators
used a different strain of mice than that used by Van Duuren and associates
(1969), it seems probably that the papilloma regression is partially due to
the use of croton oil rather than phorbol esters as the promoting agent.
Although both promoting agents are derived from the seeds of Croton tigluim
JL_.. (Van Duuren and Orris, 1965) and have enjoyed wide used as promoting agents
in two-stage carcinogenesis testing, croton oil is a less refined extract which
130
-------
has been shown to result in more tumor regressions and fewer malignancies
than purified phorbol esters (see Van Duuren, 1969, for complete review of
croton-based promoting agents). This alone, however, may be too simplistic
an explanation. Using initiating doses (e.g., producing no tumor promotion)
of urethane with croton oil promotion, levels of papillomas at 105 days in mice
were about identical to those produced by BCME but increased rather than re-
gressed at 201 days (Slaga ejt _al., 1973). No carcinomas were noted in urethane
treated mice, although urethane is generally regarded as a potent carcinogen.
Thus, the tumor regression and lack of carcinoma development noted in BCME
' I
initiation is probably attributable to both the limited promoting activity
of croton oil and the moderate rather than potent initiating activity of the
haloether. The central point, however, is apparent: BCME has definite pro-
nounced initiating activity. This is demonstrated in the almost quantitative
increase in papilloma incidence at both 105 and 210 days when the initiating
dose of the haloether is doubled (see Table 39). As in the study by Van
Duuren and coworkers (1969), BCME failed to induce papillomas when the active
promoting agent was omitted (Slaga e_t ad. , 1973).
Similar to the above work on BCME, the same groups of
investigators have screened CMME as an initiating agent. Although inactive as
a whole carcinogen and promoting agent, CMME (>99.5% pure) showed definite
initiating activity with phorbol ester promotion when tested by Van Duuren
and coworkers (1969), producing a marked increase in papillomas over phorbol
ester control as well as leading to carcinomas - not found in phorbol ester
controls - in five of the forty mice tested at two dose levels (see Table 39).
131
-------
The total Incidence of tumor production was inversely related to haloether
dose, but the higher dose did result in a decreased latent period to papilloma
appearance. As with BCME, CMME was markedly less potent as an initiator than
benzo(a)pyrene and had no activity in the absence of an active promoting
agent (Van Duuren e_t a_l. , 1969). In the test conducted by Slaga and coworkers
(1973), CMME showed only slight initiating activity at doses two to ten times
higher than those used by Van Duuren and coworkers (1969). The difference
already discussed between these two series of tests may have contributed to
this disparity. Although the incidence of papillomas and the degree of
papilloma persistence is directly proportioned to the dose of CMME in the
study by Slaga and coworkers (1973), the investigators did not consider this
haloether to be an effective initiator. Control data on mice receiving croton
oil promotion alone is not given to support this conclusion, but supportive
biochemical evidence is detailed below (see Section III-D-6-b, p. 145).
None of the remaining haloethers listed in Table 39
can be considered as potent as BCME or CMME. Bis(l-chloroethyl)ether, however,
does shown some activity. Although no carcinomas were produced by this halo-
ether, nine papillomas were induced in seven of twenty mice, and most important,
the time to this appearance of the first papillomas was only sixty-one days.
This is appreciably higher than the phorbol myristate acetate (promoter) control
wihch produced only two papillomas in two mice, the first tumor appearing after
three hundred and forty seven days (Van Duuren e_t a_l. , 1972). In groups of
twenty mice exposed to bis(2-chloroethyl)ether, a,a-dichloromethyl methyl ether,
or octachloro-di-n-propyl ether, three mice in each group developed papillomas,
132
-------
and one mouse in each of the latter two groups developed carcinomas: this
activity, however, is considered negligible compared to promoter controls
and the relatively long latent periods to neoplasm appearance (Van Duuren
e_t al. , 1969 and 1972).
Cii) Subcutaneous Injection
Two types of studies have been conducted on the
effects of subcutaneous injection of haloethers in laboratory mammals. One
type (i.e., Gargus £t al., 1969) involves a single injection of the haloether
as the only treatment, followed by histological examination of the lungs and
any other grossly abnormal tissue after six months. In the other type (i.e.,
Van Duuren e_t al. , 1969 and 1972), the animals receive injections repeated
once weekly for a period of 300-658 days followed by histological examination
of the injection site and any abnormal tissues. Tumors associated with halo-
ether exposure are found only at the injection site or the lung. Both benign
fibroma, adenoma - and malignant - sarcoma, fibrosarcoma - tumors have been
induced. The results of these studies, along with other appropriate details,
are given in Table 40.
As in the dermal application studies, BCME shows
marked tumorogenic activity. On repeated injections, five of twenty exposed
rats developed fibrosarcomas at the injection site with two additional rats
developing fibromas. Of particular note is the short period, fifty-eight days,
before the first fibrosarcoma appeared. No tumors beyond the injection site
were associated with haloether exposure (Van Duuren ej: _al., 1969). The active
133
-------
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carcinogenicity of this haloether is also indicated in mice receiving only
a single injection. However, & different pattern is evident. Although one
papilloma and one fibrosarcoma were noted at injection sites, the great
majority of tumors appeared as lung adenomas (Gargus e_t aJL. , 1969). In
this study, positive carcinogenicity was defined as a mean number of adenomas
(column N, Table 40) in the experimental group at least double that of the
vehicle control groups. This criteria is adopted from Shimkin and coworkers
(1966) and Zweifel (1966). Applying this criteria to the total test group,
both males and females, a ratio of 0.64 (4.56) clearly indicated a positive
0.14
response. Most striking, however, is the marked differences in response between
males and females. These are summarized below from Table 40,
X N
Mean Number of Mice Mean Number of Tumors
With Tumors per Mouse Nexp/Ncontrol
Bis(chloromethyl)-
ether, Females 0.4 0.46 1.84
Bis(chloromethyl)-
ether, Males 0.5 0.82 11.70
Vehicle Control,
Females 0.25 0.25
Vehicle Control,.
Males 0.07 0.07
135
-------
Although the incidence of tumor development (X) is not significantly different
between males and females, BCME fails to meet the criteria for a positive
carcinogen in females but far exceeds the criteria In males.
Similar sex-related differences are seen in the
response of mice to a single injection of CMME (Gargus e_t al. , 1969). Here,
the ratio of the mean number of tumors in the haloether exposed group to the
control group is 1.5 (0.21/0.14) if males and females are considered together.
For females, however, the ratio is only 0.72 (0.18/0.25) - a tumor incidence
below the control level. Males, on the other hand, have a ratio of 3.3 (0.23/
0.07), which meets the criteria for carcinogenicity. Caution is required in
the interpretation of these results, however, because the CMME used was con-
taminated with 0.3-2.6% BCME.
The data presented by Van Duuren and coworkers (1968
and 1972) may indicate a differential response between species. In female
rats, repeated injections of CMME produced only marginal activity (Van Duuren
e_t al. , 1969). In female mice, however, at a comparable dose per unit body
weight, one-third of the animals developed sarcomas at the injection site
(Van Duuren et^ _al. , 1972). In addition, me^n survival time was not signi-
ficantly decreased in rats but did drop from 643 to 496 days for mice. Although
mice received injections for 685 days and rats were treated for only 300 days,
the appearance of the first mouse tumor at day 308 seems to indicate that the
greater response in mice is not entirely an artifact of the longer treatment
period. As noted in Table 40, no tumors appeared in the negative control group
of mice (nujol injections) over 643 days (Van Duuren £t al., 1972).
136
-------
Bis(1-chloroethyl)ether produced less than half
the number of sarcomas in mice at the injection site as did CMME but was
the only haloether tested by Van Duuren and associates (1972) that resulted
in an increased incidence of lung adenomas. Bis(2-chloroethyl)ether caused
no lung adenomas and only half as many injection site sarcomas as bis(l-
chloroethyl)ether. Neither of these ethyl ethers resulted in decreased median
survival time in mice (Van Duuren je_t _al. , 1972). Thus, by potency, the halo-
ethers tested by subcutaneous injection follow the same order as in dermal
application: BCME > CMME > bis(l-chloroethyl)ether > bis(2-chloroethyl)ether.
(iii) Inhalation
Inhalation carcinogenicity testing has been limited
to those haloethers which have been most strongly implicated as occupational
hazards (i.e., BCME and CMME). Parelleling the results of dermal and sub-
cutaneous applications, the symmetrical ether is by far the more potent.
The initial screening of these compounds was
performed by Leong and coworkers (1971) using male mice of a strain A/Heston,
known to be sensitive to the induction of pulmonary tumors. In addition
to two groups exposed to the haloethers, [BCME, i ppm; CMME, 2 ppm] bor.h neg-
ative and positive (urethane exposed) controls were adopted. In that the
experiment was designed to assess occupational hazard, the mice were exposed
for six hours per day over periods indicated in Table 41.
137
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As described previously, the criteria for carcin-
ogenicity is a two-fold increase in average number of tumors per animal in
the exposed group as compared to the negative control. Using this standard,
BCME shows definite carcinogenicity while CMME falls slightly short. Further,
the significance of the near doubling-tumor incidence with the CMME is ques-
tionable because the sample was contaminated with BCME (0.3-2.6%).
Drew and coworkers (1975) indicate that BCME at 1 ppm
may be carcinogenic after much more limited exposures. Of 50 hamsters exposed
once to 1 ppm BCME for six hours, one animal developed a malignant nasal tumor.
Of 50 rats subjected to three exposures, one rat developed an ulcerating squamous
cell carcinoma of the skin. Similar spontaneous tumors are not noted for the
negative control groups.
The carcinogenic potency of BCME has also been demon-
strated at 0.1 ppm by Laskin and coworkers (1971). In this preliminary report,
rats exposed to 0.1 ppm haloether for six hours per day, five days per week,
for up to 659 days, developed squamous cell carcinomas of the lung and esthesio-
neuroepitheliomas of the olfactory epithelium. Recently, these investigators
have published more detailed studies on both BCME (Kuschner jjit al. , 1975) and
CMME (Laskin e£ al., 1975) administered to rats - male Sprague-Dawley - and
hamsters - male Golden Syrian.
In the BCME study, rats and hamsters were exposed
to 0.1 ppm of the haloether for six hours peT day, five days per week. Fifty
139
-------
rats and one hundred hamsters received this treatment throughout their life-
time. As indicated previously (see Section III-D-2, Chronic Toxicity, Mammals,
p. 116), both groups approached 100% mortality after seventy weeks (350 exposures)
Of the one hundred hamsters, only one tumor was noted, an undifferential car-
cinoma of the lung (Kuschner et al. , 1975).
Because of the high mortality in these exposures,
groups of rats were exposed to BCME as above for periods of two to twenty weeks
(10-100 exposures), observed until death, and then examined for tumors of the
lung and nose. The results of these exposures are summarized in Table 42.
In calculating the incidence of cancer from these
exposures, corrections were made for animals that died early in the experiment
(i.e., before cancer could have developed, thus effectively lowering the number
of animals at risk). An analysis of induction time in these exposures indicated
that the chance of developing tumors before 210 days was 1%. Consequently,
cancer incidence was expressed as number of cancer bearing animals per number of
animals surviving beyond 210 days in each exposure group. As illustrated in
Figure 22, the respiratory tract cancers are clearly correlated to the number
of exposures.
60
50
Incidence of Cancer"
of the Respiratory Tract in Rats
• Following Limited Exposure to 0 1 ppm
Bis(Chloromethy!)Ether
8 20
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'Survivors Beyond 210 Days
20 40 60
No. of Exposures
80
100
Figure 22. Incidence of Respiratory Tract Cancer in Rats Following
Exposures to 0.1 ppm Bis(chloromethy1)ether (Kuschner et
al., 1975)
140
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141
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Leong and coworkers (1975) have examined the
inhalation carcinogenicity of BCME at levels of 0.1, 0.01, and 0.001 ppm
using rats and mice. The details of these exposures are summarized in
Table 37, p. 120. In repeated exposures to 0.1 ppm, 81.6% of the rats
developed nasal tumors with some metastasizing to the lungs or lymph nodes.
No primary lung tumors were found. Presently completed gross examinations
of the rats exposed to the lower levels have thus far revealed no nasal tumors
and no increase over controls in the total tumor incidence. Similar results
were found with mice. At 0.1 ppm, mice surviving the urinary tract infection
showed a significantly (p<0.005) increased incidence of lung nodules. This
was not found at the two lower levels tested. These results seem to indicate
that there is either a very steep concentration response curve or a threshold
concentration for BCME inhalation carcinogenicity under these test conditions
(Leong jet al., 1975).
Laskin and coworkers (1975) conducted similar inhalation
exposures to 1.0 ppm CMME. The haloether was not purified and probably con-
tained 1-7% BCME. Male Sprague-Dawley rats and Golden Syrian hamsters were ex-
posed for six hours per day, five days per week, throughout their lifetime (up
to 854 days, 565 exposures). Mortality rates in these groups have been discussed
previously (see Section III-D-2, Chronic Toxicity, Mammals, p. 116). Of the
seventy-four rats exposed, two respiratory tract cancers developed: a squamous
cell carcinoma of the lung invading blood vessels and with metastasis to kidney
and an esthesioneuroepithelioma of olfactory epithelium. These tumors were found
in rats dying at 700 and 790 days, respectively. An undifferentiated pituitary
tumor also found in one rat was not attributed to the haloether. Of the ninety
hamsters exposed, one hamster killed after 134 days had an adenocarcinoma of
142
-------
the lung and another, which died after 683 days, had developed a squamous
papilloma of the trachea.
(iv) Ingestion
Of the haloethers, only bis(2-chloroethyl)ether
has been tested for carcinogenicity by oral administration (Inne8 jsjt al.,
1969). However, because this relatively stable compound has been monitored
in environmental water samples, the results of Innes and coworkers (1969)
are particularly relevant and warrant detailed consideration. In this study,
two strains of mice were used and designated strain X (C57BL/6xC3H/Anf,F-)
and strain Y (C57BL/6xAKR,F ). Seven days after birth, the mice received
lOOmg/kg/day of bis(2-chloroethyl)ether in water by intubation until the mice
were four weeks old. The dose was calculated by the weight of the seven day
old mice and not adjusted for weight gain. At age four weeks, the haloether was
administered in the food at a concentration of 300mg/kg/day based on the weight
and food consumption at four weeks. This schedule was maintained for eighty
weeks, using thirty-six mice of each strain evenly divided by sex. The results
of this exposure are summarized in Table A3.
As in the subcutaneous administrations previously
cited, males of both strains are significantly more susceptible to the tumor-
igenic effect of the haloether. The only statistically significant increase
is in hepatomas of male mice of both strains, with strain X being by far the
more sensitive. In this study, hepatomas are classified as liver tumors which
have not metastasized. Such a classification does not imply "that these
tumors are benign. Indeed, it seems more reasonable to conclude that
143
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the great majority had malignant potential" (Innes £t al., 1969). The
positive control consisted of combined data from mice exposed to seven
known carcinogens: urethane, ethylene imide, amitrol, aramite, dihydro-
safrole, isosafrole, and safrole. Although the increased incidence of
hepatomas in male mice administered bis(2-chloroethy1)ether compared to the
positive control has no absolute definitive value, it is indicative of the
highly positive tumorigenie potential of this haloether that has shown only
marginal activity in other routes of administration.
b. Biochemical Studies Related to Carcinogenicity
Various attempts have been made to correlate the inter-
actions of haloethers and macromolecules to the carcinogenic activity of
these ethers. Van Duuren and coworkers (1972) were unable to demonstrate that
BCME, CMME, or a,
-------
mice (see Table 39), CMME did not induce incorporation patterns differing
significantly from control values. BCME, as illustrated in Figure 23, did
cause marked variations in all three incorporation patterns.
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123456
DAYS AFTER BIS(CHLOROMETHYL) ETHER
TREATMENT
Figure 23. The Effect of Bis(chloromethyl)ether on Various
Incorporation Patterns in Mouse Skin Preparations
(Slaga et al., 1973)
146
-------
These biochemical effects, however, may not relate solely to the carcinogenic
activity of BCME. The initial decrease in thymidine incorporation into
DNA, for instance, may in part be due to cell death, higher DNA turnover,
or an adverae effect on enzymes involved in thymidine incorporation.
Nevertheless, these results are consistent with the high tumor inducing
potential of BCME relative to its monochloro analogue (Slaga et al.,
1973).
7. Behavioral Effects - No studies encountered.
8. Possible Synergisms - No studies encountered.
E. Toxicity - Invertebrates
Little is known concerning the effect of the chloroethers in inver-
tebrates. Takizawa and Fujita (1974) report that a mixture of 25-90 parts
bis(2-chloroisopropyl)ether and 100 parts 0,0-diethyl-0-(2-isopropyl-4-methyl-
6-pyrimidinyl) phosphorothioate is effective in controlling Scarabaeidae larvae
in soil. The dose is not specified, but the chloroethers are synergistic with
the phosphorothioic acid.
i
Bis(2-chloroethyl)ether appears to have nematocidal properties. A
preparation of this ether, 1,3-dichloropropene, and 1,2-dichloropropane (50:30:
20) microencapsulated in a vapor permeable gelatin and applied to soil at a
2
concentration of 30-50 ml/m was effective against nematodes for over two weeks
(Siebel, 1972). However, bis(2-chloroethyl)ether used alone - concentration un-
specified - seemed to have only a slight effect in protecting sugar beets from
nematode attack (Saly et al., 1962).
147
-------
F. Phytotoxlcity
Only two reports concerning•the effects of haloethers in plants have
been encountered. Matsumoto and coworkers (197A) report that bis(2-chloroisopro-
pyl)ether, at an unspecified concentration, promotes root growth in tomatoes.
Bis(2-chloroethyl)ether, on the other hand, is highly toxic to sugar beets at
concentrations over 150 ml/m2 (Saly e_t _al. , 1962).
G. Toxicity - Microorganisms
Mukai and Hawryluk (1973) have found that BCME and CMME are muta-
genic to Escherichia coli and Salomonella typhimurium. Both chemicals produce
dose related increases in mutations in these species. Similar to their car-
cinogenic potencies, BCME induces mutations at yg levels while CMME produces
the same effects at 10 to 100 fold higher levels (Mukai, 1975).
A solution containing bis(2-chloroisopropyl)ether and sodium penta-
chlorophenol has been reported to be effective in protecting the Japanese cedar,
Cry ptoneria japonica, from the fungus, Poria vaporaria (Ishii jejt _al., 1974).
However, because the relative quantities of each of the two chemicals are not
given, and because pentachlorphenol is itself a potent fungicide (Howard and
Durkin, 1973), the actual fungicidal properties of the B-chloroethers cannot
be assessed.
148
-------
IV. Regulations and Standards
A. Current Regulations
Of the haloethers under review, only BCME and CMME are currently
under regulation. In 1973, both of these a-chloroethers were cited along
with twelve other chemicals as carcinogens and emergency temporary standards
were established for limiting occupational exposure (OSHA, 1973). These
initial standards limited the use, storage, or handling of the ethers to
"controlled areas" in which elaborate precautions were specified to minimize
worker exposure. In addition, decontamination, waste disposal, monitoring,
and medical surveillance programs were required. These regulations applied
to all preparations containing 1% or more of the haloethers. Recently, more
detailed regulations have been established for both BCME (OSHA, 1974a) and
CMME (OSHA, 1974b). While similar in scope to the emergency temporary standards,
these more recent regulations apply to all substances containing 0.1% of the
haloethers by volume or weight.
B. Concensus and Similar Standards
The American Conference of Governmental and Industrial Hygienists
(ACGIH, 1974) have established TLV's for BCME and bis(chloroethyl)ether.
The TLV for BCME is 1 ppb (about 5 yg/m3). This value is based
on the known carcinogenic activity of this a-chloroether as discussed pre-
viously.
The TLV for bis(chloroethyl)ether has recently been changed from
15 ppm (about 90 mg/m3) to 5 ppm (about 30 mg/m3). This value is based on
the irritant properties of the g-chloroether to the eye and respiratory tract
without reference to its potential oral carcinogenicity.
149
-------
V. Summary and Conclusions
The chloroethers appear to be the most important commercial haloethers.
In terms of environmental hazard, the chloroethers can be divided into two
categories, (1) a-chloroethers and (2) the non-a-chloroethers, because of the
drastic difference between these two categories in terms of uses, stability,
environmental contamination, and toxicity.
Of the a-chloroethers, bis(chloromethyl)ether (BCME) and chloromethyl methyl
ether (CMME) have received the most attention. CMME, containing a minor amount
• L-7%) of BCME, is used as a chemical intermediate in the production of strong base
anion exchange resins. The quantities used have not been reported. BCME can
also be formed whenever formaldehyde and a chloride source are present under
acidic conditions. The ion exchange resins find applications in deionizing water
and as a method of separation in many industrial chemical processes (e.g., re-
covering uranium from sulfuric acid leach liquors). The compounds are unstable
in water (t, = <1 sec and <1 min for CMME and BCME, respectively) , although they
*5
may be stable for relatively long periods of time in the vapor phase (tx >390
-5
dnutes and >25 hrs for CMME and BCME, respectively). Under both aqueous and
/apor phase conditions, BCME is more stable.
Past contamination of the working environment in the ion exchange manu-
facturing plants has been well documented. Presently, elaborate precautions
are taken to prevent exposure to workers and precautions appear to be taken to
prevent contamination of the external environment. However, the latter has not
been well documented. Inadvertent BCME contamination from contact between for-
maldehyde and hydrochloric acid has been considered and research is continuing
150
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in the textile and paper industries and medical research field. Monitoring in
a medical research laboratory resulted in no detection of BCME. However, low
concentrations (»2 ppb) of BCME have been detected in some textile plants. Con-
tamination of the external environment from this source may prove to be insig-
nificant. On the other hand, sizable concentrations (210-1500 ppb) have been
noted above formalin slurries of Friedel-Crafts chloride salts (chloromethylating
agent). No extensive monitoring of the air or water effluent from the ion exchange
plants or industries that possibly produce BCME inadvertently has been reported.
Detection of chloromethyl ethyl ether and chloromethyl ether in the drinking
water of the New Orleans area has been reported, but the studies are probably
in error considering the high rate of hydrolysis of a-haloethers.
The potential hazard posed by these a-chloroethers has been convincingly
demonstrated. At high levels, both BCME and CMME are extremely corrosive to
living tissue because of their chemical reactivity. Of greater concern, however,
is the inhalation carcinogenicity of these compounds in the low ppm range. BCME
is clearly the more potent. In six hour exposures to 0.1 ppm, this chloroether
has been shown to induce respiratory tract cancer in rats directly related to
the number of exposures. In rather extensive epidemiological investigations,
the incidence of respiratory tract cancer in men exposed to BCME has been shown
to be positively related to both the intensity and duration of exposure. The
carcinogenicity of pure CMME has not been demonstrated because of BCME con-
tamination of the CMME used in the tests. Commercial grade CMME (containing
1-7% BCME) at 1 ppm has been shown to induce respiratory cancers in rats after
multiple six hour exposures. Occupational exposure to CMME with concomitant
151
-------
BCME exposure has been associated with increased respiratory tract cancers
in man. Thus, exposure to either of these u-chloroethers may be regarded as
carcinogenic. '
In summary, the a-chloroethers appear to be, for the most part, occupational
hazards since they are carcinogenic, but seem to be unstable in the environment.
However, because they are extremely carcinogenic, some selective monitoring is
probably needed to insure that sizable quantities of these compounds, especially
BCME, are not reaching the external environment. Because these compounds are
relatively stable in the vapor phase, sources of atmospheric contamination are
particularly important to consider. Also, the researchers that have reported
detection of a-chloroethers in the New Orleans area drinking water should be
contacted to determine the validity of their results.
In contrast to the a-chloroethers, the 3-chloroethers are widespread
environmental contaminants. There are three 6-chloroethers that are used in
reasonably large commercial quantities: bis(2-chloroethyl)ether, bis(2-chloro-
isopropyl)ether, and bis(2-chloroethoxy)methane. The last compound is an acetal,
not an ether, but was considered because of its close chemical similarity.
Bis(2-chloroethyl)ether and bis(2-chloroisopropyl)ether have been used as
dewaxing agents for lubricating oils, solvents and penetrants in the textile
industry, and as chemical intermediates. Bis(2-chloroethoxy)methane is the
principal monomer in the production of polysulfides. The quantities of these
materials that are presently produced and used are unreported. Sizable quantities
152
-------
of bis(2-chloroethyl)ether were produced (26 million Ibs in 1960) and sold
(15 million Ibs in 1960) when the chemical was a cheap by-product in the
chlorohydrin synthesis of ethylene oxide. Since 1972, no ethylene oxide
has been synthesized by the chlorohydrin route. However, 70% of the propylene
oxide produced is manufactured using th-e ohlorohydrin route (1973 capacity -
1,227 million Ibs).
Bis(2-chloroethyl)ether and bis(2-chloroisopropyl)ether are both more
stable to chemical hydrolysis than the a-chloroethers (t. = 12.8 days for
bis(2-chloroethyl)ether in a water-dioxane solution compared to 18 minutes
for CMME. The preliminary studies on biodegradability reported in the literature
are difficult to interpret, but monitoring data in the Ohio River would
suggest that bis(2-chloroisopropyl)ether does not degrade rapidly. Acetals,
such as bis(2-chloroethoxy)methane, are much less stable to chemical hydrolysis,
especially under acid conditions.
Contamination of raw and drinking water by bis(2-chloroethyl)ether
and bis(2-chloroisopropyl)ether is well documented by monitoring. In
fact, bis(2-chloroethyl)ether was noted as a water contaminant as early
as 1963. These compounds have been detected in the Kanawha, Mississippi,
Ohio, and Delaware Rivers. One study showed that a glycol plant having
a propylene oxide plant capacity of 130 million Ibs/year had a daily effluent
of approximately 150 Ibs. If similar losses take place from other propylene
oxide chlorohydrin plants, the quantity released in 1973 would be approximately
153
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600,000 Ibs of bia(2-chloroisopropyl)ether. This sdme study showed that
conventional drinking water treatment processes only removed 60% of the
bis(2-chloroisopropyl)ether. On the other hand, Dow Chemical, a major
producer of propylene chlorohydrin, states that they burn all their by-
product bis(2-chloroisopropyl)ether, although they do emit 20 Ibs/day of
the ether in their air effluent. Since ethylene oxide is no longer being
made from ethylene chlorohydrin, bis(2-chloroethy1)ether contamination
must be a product of some other source. Recently, bis(2-chloroethyl)ether
has been detected in the effluent from a Rohm and Haas plant in Philadelphia.
The compound was being used as a chemical intermediate in the production
of detergents. Bis(2-chloroethyoxy)methane has been reported in the
treated effluent from a synthetic rubber plant but has not been detected
in raw or drinking water.
The well-documented chloroether contamination resulting from the
propylene chlorohydrin process suggests that other chlorohydrin processes
might be sources of chloroether contamination. The chlorohydrin synthesis
of epichlorohydrin from alkyl chloride is such a process (capacity in
1975 - 495 million Ibs). Bis(2,2'-dichloroisopropyl)ether would be the
major ether formed, and it should be stable to chemical hydrolysis since it
is not an a-chloroether. No environmental detection of this compound has
been reported.
The potential dangers of such widespread exposure to the g-chloroethers
is difficult to assess. Unlike the a-chloroethers, these compounds are not
extremely corrosive. Available information from standard toxicity tests
154
-------
indicates that these compounds have little effect at concentrations below
100 ppm. Bis(2~chloroethyl)ether is a respiratory irritant and can be
fatal if inhaled at concentrations above 100 ppm. Bis(2-chloroisopropyl)
ether is fatal at slightly greater concentrations 0 300 ppm) and may cause
liver as well as lung damage. By far, the greatest concern, however, is
the apparent oral carcinogenicity of bis(2-chloroethyl)ether. This com-
pound has been shown to induce hepatomas in young mice at concentrations
of lOOmg/kg/day x 7 days (incubation) followed by 300mg/kg/day x 21 days
(in diet). By all other routes of administration - inhalation, dermal,
subcutaneous - this and other 3-chloroethers show no marked carcinogenic
activity.
The findings of this single study raise serious questions about the
4
potential danger of g-chloroether contamination in fresh water. If bis(2-
chloroethyl)ether is an oral carcinogen, then bis(2-chloroisopropyl)ether
is also suspected. Further tests on both of these compounds are clearly
indicated to determine not only a dose-response effect, but also the
proximal carcinogen(s). Bis(2-chloroisopropyl)ether is currently being
evaluated for carcinogenicity by the National Cancer Institute (1975).
The results of this investigation should be carefully reviewed. If the
oral route is not employed, oral carcinogenicity tests should be begun
as soon as possible.
Information on the sources of these two compounds needs to be more
exact than is presently available. It appears that the chlorohydrin
synthesis of propylene chlorohydrin is the major source of bis(2-chloro-
isopropyl) ether. However, much better effluent and ambient monitoring
data is necessary. Information on the quantities of the ethers that are
155
-------
produced and a more detailed breakdown of their uses is required. Better
information on the biodegradability of these compounds is also needed. The
possibility of contamination from epichlorohydrin production should also be
considered.
Thus, since the g-chloroethers are (1) produced or may be formed as
by-products in large quantities, (2) are released to and appear to persist
in the environment, (3) can pass through drinking water treatment plants,
and (4) may be carcinogenic, it is suggested that intensive research and
study of these compounds be undertaken.
The potent carcinogenicity of the a-chloroethers, particularly BCME,
requires that effort be continued to understand the parameters involved in
their information and that efforts be undertaken to assure that these
materials are not released to the environment.
156
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