EPA 560/11-80-005
INVESTIGATION OF SELECTED
POTENTIAL ENVIRONMENTAL CONTAMINANTS:
EPOXIDES
March 1980
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
SYRACUSE RESEARCH CORPORATION
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EPA-560/11-80-005 TR 80-535
INVESTIGATION OF SELECTED POTENTIAL
ENVIRONMENTAL CONTAMINANTS:
EPOXIDES
Dennis A. Bogyo
Sheldon S. Lande
William M. Meylan
Philip H. Howard
Joseph Santodonato
March 1980
FINAL REPORT
Contract No. 68-01-3920
SRC No. L1342-05
Project Officer - Frank J. Letkiewicz
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
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NOTICE
This 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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EXECUTIVE SUMMARY
Information has been reviewed on ethylene oxide, propylene oxide, butylene
oxide, and diepoxybutane. Annual production for 1978 was estimated at 5,012
million pounds, 2,047 million pounds, 5-7 million pounds, and <1,000 pounds,
respectively. Ethylene oxide is primarily consumed as feedstock for ethylene
glycol, glycol ethers, polyols and polyol ethers, and ethanolamines. The propylene
oxide consumption pattern is similar; it is feedstock for polyols used for poly-
urethane polymers, propylene glycol, non-urethane polyols, and polyol and
glycol ethers. Butylene oxide is primarily consumed as a stabilizer for
chlorinated solvents. Small amounts (<0.1 million pounds) of ethylene oxide
and of propylene oxide are applied as sterilants or pesticides to commodities,
Pharmaceuticals, medical devices, tobacco, and other items. Although this use
is only a small fraction of the total epoxide consumption, it represents a
considerable potential for human exposure.
The epoxides are prepared by oxidation of the corresponding olefins.
Ethylene oxide manufacture utilizes catalytic oxidation of ethylene, while
propylene oxide currently utilizes chlorohydrination or peroxidation.
No quantitative information was available on environmental release of the
manufactured epoxides. Release factors are definitely low, but since annual
epoxide manufacturing volume is so large, release of even a small fraction of
the total could result in several hundred thousand pounds of emissions.
Release could arise through fugitive emissions, venting losses, losses during
handling, and release with waste streams. Application of epoxide as a sterilant
or a pesticide places the user of the treated product at risk of exposure.
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Epoxides are inadvertent products of combustion. They have been observed
in emissions from fuel burning, in automotive exhaust, and in cigarette smoke.
Also, alkanes can react by several atmospheric routes to yield epoxides.
The epoxides are mobile in the environment, but degrade by chemical and
biochemical routes. In water they are subject to hydrolysis and reactions
with anions such as chloride and bromide. At ambient temperature (25°C),
maximum half-life is about two weeks. They degrade in soil by pathways
similar to those in water. Epoxides will oxidize in the atmosphere. They
appear about as reactive as acyclic and other cyclic ethers, which places them
among the most reactive compounds. The epoxides applied as sterilants or
pesticides are lost from the treated object by a combination of volatilization
and degradation (with reaction pathways similar to those described for water).
Although the epoxides are mobile (high vapor pressure and water solubility), the
information on hand did not characterize transport between water and the
atmosphere. The epoxides will not bioaccumulate.
The epoxides have produced varied toxic effects in man following acute
inhalation or dermal exposure. These effects have involved the central nervous
system, gastrointestinal tract, lungs, skin, and bone marrow. Dermal exposure
to ethylene oxide has resulted in formation of large blisters. Clinical
reports of reactions following intravenous use of ethylene oxide-sterilized
medical devices show that hemolysis, anaphylactic reactions, and sensitization
to the compound may be produced if sterilized plastic.devices have been
poorly aerated before use. Conjunctivitis and corneal burns have been seen
following exposure to high levels of ethylene oxide and propylene oxide vapor.
Diepoxybutane is the most acutely toxic agent of the group, showing lethal
toxicity (i.p.) in experimental animals at levels of 16 mg/kg; ethylene oxide
produces similar effects at levels approximately tenfold higher.
iv
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Metabolism of the epoxides is rapid, with most of the administered compound
being removed by urinary excretion. Distribution throughout the body is widespread,
although localization in certain tissues occurs.
Long-term exposure to the epoxides in worker populations has produced
effects on the bone marrow, reproductive system, central nervous system, and
peripheral blood. Lower limb neuropathy seen in three ethylene oxide steri-
lizer operators was shown to be reversible. Leukemia and anisocytosis have
been reported in workers at ethylene oxide facilities, but this represents a
small number of cases (4) in two reports. A Russian report has indicated
increased miscarriages and toxicosis in pregnant ethylene oxide workers;
levels of exposure and quantitation were not available to assess the relevance
of this study.
Animal studies on prolonged exposure to epoxides show similar types of
toxic effects, including bone marrow effects, anemia, neurotoxicity, and
reproductive effects. There is therefore a good possibility that epidemi-
ological studies now underway will confirm the preliminary reports made on
some of these long-term human effects.
The epoxides have demonstrated mutagenic activity in a wide variety of
systems. These include the Ames test, mutation of several plant species,
various microbial system mutations, Drosophila lethal mutations, and mammalian
genetic damage. This last system involves an increased production of chromosome
breaks in mice and rats exposed to ethylene oxide or diepoxybutane. Diepoxy-
butane is the most effective mutagen of the group, due to its bifunctional
reactive character, and acts as a direct mutagen. Ethylene oxide, propylene
v
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oxide, and butylene oxide also act directly in decreasing order of reactivity.
However, ethylene oxide, unlike diepoxybutane, shows increased activity in the
Ames test after microsomal enzyme activation, indicating that a more mutagenic
product may be produced by this process.
Teratogenic effects have been observed following intravenous injection of
pregnant rats with relatively large doses of ethylene oxide. Chloroethanol, a
potential reaction product of ethylene oxide, has produced teratogenic effects
in the chick embryo, but not in the CD-I mouse.
Studies on the carcinogenic potential of the epoxides have produced
varied results. Diepoxybutane has been studied most extensively and has been
shown to induce tumors following skin painting and injection. This compound
has also acted as a tumor initiating agent when applied to mouse skin before
administration of a promoting agent. One report concerning germ-free mice
raised on ethylene oxide-sterilized bedding showed numerous tumors in these
animals. However, this was a retrospective observation and the causative
agent was not characterized. Other studies with ethylene oxide administered
by skin painting or injection have failed to show increased tumor production.
Propylene oxide injected into rats has reportedly produced tumors; this is an
early study which has not been confirmed. Skin painting with butylene oxide
has shown no tumorigenic effects.
The long-term effects of these epoxides in human populations have not
been extensively investigated. Based on the results of animal studies and
preliminary reports from human studies, the epoxides produce effects involving
the central nervous system, bone marrow, peripheral blood, and reproductive
system. The incidence and reversibility of these effects are unknown at present.
In addition, the carcinogenic and teratogenic activity of all of these compounds,
although suspect, awaits confirmation.
VI
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Table of Contents
EXECUTIVE SUMMARY iij
I. PHYSICAL AND CHEMICAL DATA 1
A. Structure and Properties 1
1. Chemical Structure and Nomenclature 1
2. Physical Properties of the Pure Material 2
3. Description of Grades of Material Available Commercially 6
4. Physical Properties of Commercial Material 11
5. Description of Other Products of Which Epoxides
May be a Contaminant 11
II. ENVIRONMENTAL EXPOSURE FACTORS 13
A. Production Aspects 13
1. Quantity Produced and Imported 13
a) Butylene Oxide 13
b) Ethylene Oxide 13
c) Propylene Oxide 15
d) 1,2,3,4-Diepoxybutane 15
2. Producers, Production Sites, Production Capacity, and
Distributors, and Importers 15
a) Butylene Oxide 15
b) Ethylene Oxide 16
c) Propylene Oxide 16
d) 1,2,3,4-Diepoxybutane 19
3. Production Methods and Processes 19
a) Butylene Oxide 19
b) Ethylene Oxide 19
c) Propylene Oxide 26
d) Diepoxybutane 33
4. Market Price and Influencing Factors 35
5. Market Trends and Influencing Factors 35
a) Butylene Oxide 35
b) Ethylene Oxide 37
c) Propylene Oxide 37
vii
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Table of Contents (Cont'd)
Page
B. Use Aspects 40
1. Consumption by Major and Minor Use, Manufacturers
and Use Sites 40
a) Butylene Oxide 40
b) Ethylene Oxide 40
c) Propylene Oxide 45
d) Diepoxybutane 50
2. Chemistry Involved in Use 50
3. Discontinued Uses of Epoxides 56
4. Projected or Proposed Uses 57
5. Alternatives to Uses for Epoxides 58
a) Butylene Oxide 58
b) Ethylene Oxide 59
c) Propylene Oxide 60
C. Entry Into the Environment 60
1. Points of Entry 60
a) Production 60
i. Ethylene Oxide 60
ii. Propylene Oxide 61
iii. Butylene Oxide 62
b) Handling, Transport, and Storage 62
c) From Use 63
i. Ethylene Oxide 63
ii. Propylene Oxide 64
iii. Butylene Oxide 64
•d) From Disposal 64
2. Disposal Methods, Emission Controls, and Effluent Controls 64
3. Potential Production in the Environment 67
D. Environmental Pathways and Fate 69
1. Transport Within and Between Media 70
2. Chemical and Biological Degradation 73
viii
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Table of Contents (Cont'd)
a) Degradation in Water 73
b) Degradation in Soil 84
c) Degradation in Commodities and Manufactured Products 85
d) Atmospheric Degradation 90
3. Persistence, Bioaccumulation and Food-Chain Accumulation 96
E. Detection in Environmental and Biological Samples 96
1. Monitoring 96
2. Analytics 97
III. HEALTH AND ENVIRONMENTAL EFFECTS 105
A. Humans 105
1. Occupational Exposure Studies and Poisoning Incidents 105
2. Controlled Human Studies 107
3. Epidemiology 107
B. Reported Effects on Non-Human Animals from Industrial
Release, Spills, and Accidents 109
C. Experimental Studies on Animals 110
1. Toxicity and Effects on Mammals 110
a) Metabolism 110
b) Acute Toxicity 111
c) Subacute Toxicity 119
d) Chronic Toxicity 122
e) Mutagenicity 123
f) Teratogenicity and Reproductive Effects 131
g) Carcinogenicity 133
h) Neurotoxicity 142
2. Toxicity and Effects on Other Vertebrates 143
3. Toxicity and Effects on Invertebrates 143
D. Toxicity and Effects on Plants 144
E. Toxicity and Effects on Microorganisms 145
F. jn Vitro and Biochemical Studies 146
G. Effects on Foods 147
H. Effects of the Compounds on Environmental Quality 147
I. Effects on Inanimate Objects 148
ix
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Table of Contents (Cont'd)
Page
IV. CURRENT REGULATIONS 149
A. Federal, State, and Local Standards 149
1. Food, Drug, and Pesticide Authorities 149
2. Other EPA Authority 151
3. OSHA 151
4. DOT, ICC, CG - Transport Regulations 151
B. Concensus and Similar Standards • 151
1. TLV 151
2. TWA 152
C. Current Handling Practices 152
1. Special Handling in Use 152
2. Storage and Transport Practices 152
3. Accident Procedure 153
V. EXPOSURE AND EFFECTS POTENTIAL 155
VI. TECHNICAL SUMMARY 160
REFERENCES 170
CONCLUSIONS AND RECOMMENDATIONS 200
x
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List of Tables
Table No. Page
1 Epoxide Structure and Nomenclature 3
2 Physical Properties of Epoxides 4
3 Manufacturers' Specifications for Ethylene Oxide 7
4 Manufacturers' Specifications for Propylene Oxide 8
5 Manufacturers' Specifications for Butylene Oxide 9
6 Production Volumes of Ethylene Oxide and Propylene Oxide
1970-1978 14
7 Plant Capacity, Sites, and Manufacturers of Ethylene Oxide 17
8 Plant Capacity, Sites, and Manufacturers of Propylene Oxide 18
9 Reactants and Products of the Ethylene Oxide Chlorohydrin
Process 27
10 Domestic Prices for Various Epoxides 36
11 Users and Use Sites of Ethylene Oxide 42
12 Users and Use Sites of Propylene Oxide 47
13 Estimated Vaporization Rate for Ethylene Oxide from Commodities 71
14 Hydrolysis Kinetics of Selected Epoxides 75
15 Specific Rate Constants for Alkaline-Catalyzed Hydrolysis
of Diepoxybutane 77
16 Specific Rate Constants for Acid-Catalyzed Hydrolysis of
Diepoxybutane 78
17 Specific Rates of Reaction of Anions and Lewis Bases with
Selected Epoxides 80
18 Product Distribution from Unsymmetrical Epoxide Reaction
with Chloride 82
19 Changes in Concentration of Ethylene Oxide During the
Fumigation Period of Dates 88
20 Summary of Ethylene Oxide and Chlorohydrin Determinations
on a Variety of Surgical Equipment 98
xi
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List of Tables (Cont'd)
Table No. Page
21 Breakthrough Volume for Propylene Oxide with Several Sorbents 100
22 Acute Toxicity of Ethylene Oxide 112
23 Acute Toxicity of Propylene Oxide 115
24 Acute Toxicity of Butylene Oxide 117
25 Acute Toxicity of Diepoxybutane 118
26 Ames Mutagenicity Assay for Ethylene Oxide 124
27 Ames Mutagenicity Assay for Epoxides and Reaction Products 127
28 Carcinogenesis Bioassay of Ethylene Oxide 134
29 Carcinogenesis Bioassay of Propylene Oxide 136
30 Carcinogenesis Bioassay of Butylene Oxide 138
31 Carcinogenesis Bioassay of Diepoxybutane 139
xii
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List of Figures
Number Page
1 Direct-oxidation process for manufacturing ethylene oxide. 22
2 Chlorohydrin process for manufacturing ethylene oxide. 25
3 Diagram of a typical chlorohydrin propylene oxide plant. 29
4 Preparation of propylene oxide by peroxidation of propylene. 31
5 Chlorohydrin-propylene oxide production modified by
electrolytic regeneration of chlorine. 32
6 Market trends for ethylene oxide. 38
7 Dissipation of ethylene oxide following gas treatment
of polystyrene creamer cups. 72
8 Changes in levels of the toxic residues in dates fumigated
for 20 hrs with 16 ml ethylene oxide per kg fruit, and kept
under room conditions in open jars. 89
xiii
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I. PHYSICAL AND CHEMICAL DATA
A. Structure and Properties
1. Chemical Structure and Nomenclature
Epoxides contain the three-membered cyclic ether structure
depicted:
0
/ \
I I
Nomenclature in Chemical Abstracts (CA) (or the International Union of Pure
and Applied Chemists system) is based upon the simplest epoxide, oxirane, as
a unique ring:
0
\
CA and IUPAC name all epoxides as derivatives of oxirane and apply the system-
atic nomenclature to ring substitution. Epoxides have several common nomen-
clature systems and they are usually discussed in the literature by common
system names rather than by the IUPAC system names. The simple epoxides are
most commonly named as olefin oxides (e.g., ethylene oxide) or as epoxyalkanes
(e.g., epoxyethane) .
This report reviews four epoxides and uses the names which are
most generally applied to the selected epoxides: ethylene oxide; propylene
oxide; butylene oxide; and diepoxybutane.
Three of the selected epoxides have asymmetric carbon atoms.
Two of these, propylene oxide and butylene oxide, have a single asymmetric
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carbon:
0
/ \
H - C GIL
I*
R
This asymmetry results in optical activity, but does not otherwise affect
physical or most chemical behavior (March, 1977; Lapkin, 1965). Since
diepoxybutane has two asymmetric carbons, it exists as two distinct stereo-
isomers: an optically active form (the d^,^ pair):
0 H H
/ \ I I
C — C*-*' —/ - H
H H 0
and an optically inactive, meso form:
0 0
/ \ / \
H_ p _____ r* ^_«_ f* -,. _ /^
L/ L* L —— v,
I I I I
H H H H
The physical and chemical properties of the two forms of diepoxybutane (d^,!^
pair and meso form) are different.
Table 1 lists the structure, IUPAC names, common names and
CAS Numbers of the selected epoxides.
2. Physical Properties of the Pure Material
Table 2 summarizes physical properties of the four epoxides
selected for study. The epoxides are a class of ethers. The physical pro-
perties of the ethers have been associated with the net dipole moment of the
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Table 1. Epoxide Structure and Nomenclature
u>
Compound CAS Number
^ 0 75-21-8
cn2 cu2
0 75-56-9
cn3 cn cn2
0 106-88-7
CTI PIT PIT
9*1|- Lll ' " "" \jllr\
0 0 1464-53-5
HP P11 Pll - PIT
«U L.11 v»ll 1*11,1
2 2
0 H 298-180
X X 1
HP P P - . PTT
«L. LV'L. Ullrt
H V 30419-67-1
30031-64-2
0 0 564-00-1
/ \ / \
-C C.-C t,ll«
II
H H
IUPAC Name
Oxirane
Methyloxirane
Ethyloxirane
2,2'-Bioxirane
(R*,R*)-(+ -)-2,2'-
Bioxirane
[R-(R*,R*)]-2,2'-
Bioxirane
[S-(R*,R*)]-2,2-
Bioxirane
(R*,S*)-2,2'-
Bioxirane
Common Names
£L b C
Ethylene oxide ' ' ; dihydrooxirene, dimethylene
oxide; 1,2-epoxye thane; oxacyclopropane; ETO;
oxane; oxidoethane; a,3-oxidoethane
"h f* 3.
Propylene oxide ' ; 1,2-epoxypropane ; methyl
ethylene oxide; methyl oxirane; propene oxide
Q
Butylene oxide; 1,2-epoxybutane ; butene oxide;
ethyl ethylene oxide
Diepoxybutane ; 1,2,3,4-diepoxybutane; butadiene
diepoxide; butadiene dioxide; 2,4-diepoxybutane;
dioxybutadiene; erythritol anhydride
D,L-diepoxybutane; 1,2,3,4-dianhydro-DL-threitol
^-diepoxybutane; 1, 2,3,4-dianhydro-D-threitol;
(2R, 3R) -diepoxybutane
I^-diepoxybutane ; 1,2,3, 4-dianhydro-L-threitol ;
(2S , 3S) -diepoxybutane
Meso-diepoxybutane ; 1,2,3, 4-dianhydroery thritol ;
(R* , S*) -diepoxybutane
aName listed in Registry of Toxic Substances (Fairchild et al., 1977)
^Narne listed in IARC (1976)
'DOT name
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Table 2. Physical Properties of Epoxides. Adapted from BASF, 1972; Celanese Chemical Co., undated;
Dow Chemical Co., 1977; Jefferson Chemical Co., undated a and b; Oxirane, undated; Union
Carbide Corp., 1977; Weast eit al^., 1975; Gallant, 1967; Schultze, 1965; Gait, 1973; Lapkin, 1965.
Molecular Weight
Index of refraction, n_
Freezing point, °C
Boiling point, °C at 760 torr
Vapor pressure, torr at 25°C
Vapor density (air = 1.0)
Specific gravity
Viscosity, cp
Specific heat, cal/°C-g)
Heat of vaporization (1 atm) ,
cal/g
1 8
Dipole moment, 10 esu
Flash point
Autoignition temperature in
air, °F at 1 atm
Flammability limits, Vol. %
Critical Properties
Temperature
Pressure
Density
Solubility, g/lOOg solvent
Inorganic solvents
(acetone, benzene,
carbon tetrachloride,
ether, methanol)
Epoxide in water
Water -in epoxide
Ethylene Oxide
44.053
1.3614 (4°C)
-112.44
10.5
1305
149
0.8711*J
0.31 (4°C)
0.44 (20°C)
136.1
1.9
<0°C
804
3-100
195. 8°C
1043 psia
0.315 g/ml*
complete
complete
Propylene Oxide
58.080
1.3632 (25°C)
-104; -112
34.2
538
0.830^
0.28 (25°C)
0.51 (20°C)
89
1.88
<-35°C
869
1.8-36
209. 1°C
48.6 atm
0.312 g/ml
complete
59; 66
15
Butylene Oxide Diepoxybutane
d,l pair meso
72.107 86.09 86.09
1.381 (25°C) 1.4330 (20°C) 1.4330 (20°C)
-129.28 -16 4
63.4 138 (767 torr) 144
176
0.826^ 1.11572° 1.132°
0.40 (25°C)
822
1.9-19
243°C*
630 psia*
0.290 g/ml*
complete
9.5 miscible soluble
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of the ether linkage (Morrison and Boyd, 1973). The normal ether linkage
has a C-O-C bond angle, a, of approximately 110°. The three-membered epoxide
ring severely contracts this angle; a is 61° 24' in propylene oxide (Lapkin,
1965). The effect of the smaller angle of a on the physical properties of
the epoxides appears consistent with an increase in polarity of the molecule.
Epoxides exhibit higher melting points, boiling points, and water solubilities
than ethers of similar chemical structure (Weast et_ a_l^ , 1975; Morrison
and Boyd, 1973):
Molecule
Dipole
Moment, Molecular Melting Boiling
1018 esu Wei§ht Point, °C Point, °C Solubility
CH3OCH3 1.3
CII2 CII2 1.9
PTJ CM~*TJ PU 1 O*3
L*n«u^n.nV-*n.^ j..^o
Lill~ L«£lUilA X.OO
2 3
46
44
60
58
-140 -24
-111 11
7
-112 34
3700 cc/lOOg
complete
8 g/lOOg
59 g/lOOg
At ambient temperature ethylene oxide is a colorless gas with an
ether-like odor. It condenses to a colorless liquid at 10°C. It is completely
miscible with water and organic solvents. Ethylene oxide, like other epoxides,
is hazardous to handle because of its high reactivity; the reactivity will be
-------
described in the section on chemical properties. It is extremely flammable from
3 to 100% by volume in air, explosive, and undergoes an exothermic, self-polymerization
reaction (Dow Chemical Co., 1977; Jefferson Chemical Co., undated).
Properties of propylene oxide and butylene oxide are similar
to ethylene oxide properties. All are members of the same homologous series
and differ only by the number of methylene groups. Increasing the molecular
weight in the series raises boiling and melting point, reduces water solubility,
and reduces the flammability and explosion hazard.
Diepoxybutane does not belong to the same homologous series as
the other three epoxides. As described in Section I.I, diepoxybutane occurs in
two isomeric forms: meso, and the
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Table 3. Manufacturers' Specifications for Ethylene Oxide*
Purity, wt. % min.
Water, wt. % max.
Aldehydes, as acetaldehyde, wt. % max.
Acidity as acetic acid, wt. % max.
C0?, wt. % max.
Total Cl as Cl , wt. % max.
Nonvolatile residue, gm/100 ml, max.
Color, APHA, max.
Residual Odor
Appearance
Acetylene, max.
BASF
99.95
0.005
0.005
0.002
0.005
0.005
0.010
10
Celanese
99.95
0.02
0.01
0.002
0.01
10
none
clear
Dow
0.03
0.005
0.002 .
0.002
0.005
**
0.01
5
0.0005
Jefferson
0.03
0.025
0.005
nil
0.01
none
clear
nil
Shell Wyandotte
0.03
0.010 0.003
0.0020 0.002
0.005
0.0005
0.010 0.01
10 10
none mild
clear
This information was obtained from the respective manufacturers product data sheets, available from
each manufacturer on request.
&
Presently 0.005 gm/100 ml in Dow ethylene oxide - Kurginski, Dow Chemical Co.
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Table 4. Manufacturers' Specifications for Propylene Oxide*
Specific Gravity
Acidity as acetic acid,
max.
Water, max.
Chloride ion, max.
Color, APHA, max.
Aldehydes, total, max.
Appearance
Dow
0.825-0.827
@25/25°C
20 ppm
500 ppm
40 ppm
5
100 ppm
Jefferson
0.829-0.831
@20/20°C
0.005 wt. %
0.050 wt. %
10
0.040 wt. %
clear
Oxirane
0.829-0.831
@20/20°C
0.005 wt. %
0.050 wt. %
0.010 wt. %
10
0.040 wt. %
clear
This information was obtained from product data sheets supplied by the
manufacturers.
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Table 5. Manufacturer's Specifications for Butylene Oxide
(Dow Chemical Co., 1977)
Assay, (IR), min. 99.0%
Chloride ion, max. 0.05%
Aldehydes as butyraldehyde, max. 0.05%
Acidity as butyric acid, max. 0.01%
Water, max. 0.10%
Isobutylene oxide (IR), max. 0.30%
Color, APHA, max. 10
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(see Section II.A.3). Chlorinated products from intermediate ethylene chloro-
hydrin can potentially remain as residues in refined ethylene oxide; the prin-
ciple chlorinated organic products are 1,2-dichloroethane and bis(2-chloro-
ethyl) ether (Schultze, 1965). Other potential by-products from the chloro-
hydrin process include inorganic chlorides, oxidation products (aldehydes,
acids, etc.), hydrolysis products (glycol), and polymerized ethylene oxide.
The most probable contaminants in ethylene oxide prepared by direct oxidation
include oxidation products, hydrolysis products, ethylene oxide polymerization
products, solvents, and traces of inorganic catalyst.
Propylene oxide is also manufactured via direct oxidation and
chlorohydrin route (see Section II.A.3). The side reactions and by-products
are expected to parallel those described for ethylene oxide (Lapkin, 1965;
Gait, 1973).
Butylene oxide is prepared commercially by chlorohydrin technology
(see Section II.A.3). The manufacturers' specifications describe the commercial
product as 99.0% butylene oxide. The major contaminant is isobutylene oxide
(0.3%), which is produced from isobutylene in the feedstock. Other contaminants
are water, acid components (specified as butyric acid), aldehyde (specified as
butyraldehyde), and chloride ion.
10
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Diepoxybutane is manufactured in small quantities. No infor-
mation was available on either the product specifications or potential con-
taminants in the product. Several routes are available for its preparation
(see Section II.A.3) and the potential contaminants will depend, in part,
upon the method used. Its preparation via l,4-dichloro-2,3-dihydroxybutane
will yield potential contaminants analogous to those in ethylene oxide prepared
from ethylene chlorohydrin; potential contaminants would include chlorinated
butanes, chlorinated butyl ethers, acids, aldehydes and ketones, chloride
ion, water, alcohols, and products of self-condensation. Its preparation by
the oxidation of butadiene with peroxides can be expected to yield similar
by-products except for the chlorinated organics. Additional impurities could
result from the feedstock, but lack of information about the latter precludes
specific identification.
4. Physical Properties of Commercial Material
Since commercial grade ethylene oxide, propylene oxide, and
butylene oxide are virtually pure materials, their physical properties are
the same as those previously described for pure materials. No information was
available on the physical properties of commercial diepoxybutane.
5. Description of Other Products of Which Epoxides May be a
Contaminant
There was sparse information available in the literature on
inadvertent epoxide production in other chemical processes. Inadvertent
production is possible as the result of cyclization of glycols, olefin halo-
hydrins, and similar products, which are usually either prepared from epoxides
(see Section II.B.I) or epoxide precursors (Lande et^ a_l. , 1979). The epoxides
could also inadvertently form during alkane oxidation. Hayes (1963) mentions
11
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epoxides as trace by-products of saturated alkane oxidation in acetaldehyde
manufacture. Schneider (1974) has a patented process for isoprene production
from isobutane which yielded propylene oxide as a commercially important by-
product. The process consisted of catalytic oxidation of isobutane with
hydroperoxides. Although epoxides are potential by-products of alkane oxida-
tion, no specific information was available on any commercial product contam-
ination by any of the selected epoxides. Lowenheim and Moran (1975) described
the butane oxidation process for acetaldehyde and did not include epoxides
among the by-products. Pervier and coworkers (1974) have investigated some
other processes which conceivably could yield epoxides, among which were
ethylene oxidation to acetaldehyde; acetic acid production by butane oxidation;
and ethyl acetate from oxidation of an acetic acid-ethylene mixture. While
epoxides are likely products of side reactions, they are also likely to react.
For example, glycols are observed by-products of alkane oxidation (Lowenheim
and Moran, 1975), and from ethyl acetate manufacture (Pervier et^ al., 1974),
and possibly are products of epoxide hydrolysis. In conclusion, epoxides are
unlikely inadvertent contaminants of other manufactured products.
12
-------
II. ENVIRONMENTAL EXPOSURE FACTORS
A. Production Aspects
1. Quantity Produced and Imported
a) Butylene Oxide
Commercial quantities of butylene oxide are produced by
only one manufacturer in the United States; therefore, production quantities
are not listed by the U.S. International Trade Commission. However, Cosslett
and Gerry (1976) estimated that approximately 7 million Ibs of n-butene were
used in the synthesis of butylene oxide in 1974; this would correspond to a
butylene oxide production of roughly 9 million pounds. Likewise, in 1977 an
estimated 6.2 million pounds of butene were used to make butylene oxide (Hoff
et al., 1978), which would correspond to an approximate production of 8 million
pounds. Kurginski (1979) indicated that Dow Chemical believed that the U.S.
production of butylene oxide in 1977 was 5.7 million pounds. According to these
estimates, butylene oxide accounts for less than 0.1% of all epoxides produced
domestically. Butylene oxide imports are considered negligible to nonexistent.
b) Ethylene Oxide
The quantities of ethylene oxide produced in the United
States over the period 1970-1978 are summarized in Table 6. Ethylene oxide
accounts for about 70% of the total annual epoxide production volume in the
United States.
Imports of ethylene oxide, in million of Ibs, are listed
below (Blackford, 1976a):
1975 4.00
1974 1.51
1973 2.86
1972 7.21
1971 0.06
In 1978, 76 million pounds of ethylene oxide were exported (Anon., 1979a).
13
-------
Table 6. Production Volumes of Ethylene Oxide and
Propylene Oxide 1970-1978 (USITC, Annual) >
Year
1978
1977
1976
1975
1974
1973
1972
1971
1970
Quantities
Ethylene Oxide
5,012
4,364
4,184
4,467
*
4,200
4,167
3,962
3,598
3,865
(Millions of Pounds)
Propylene Oxide
2,047
1,866
1,823
1,524
1,756
1,753
1,520
1,194
1,179
revised figure
14
-------
c) Propylene Oxide
The quantities of propylene oxide produced in the United
States over the period 1970-1978 are indicated in Table 6. Propylene oxide
accounts for about 30% of the total annual epoxide production volume in the
United States.
Recent imports of propylene oxide, in millions of Ibs,
are listed below (Blackford, 1976b):
1975 20.99
1974 32.30
1976 33.07
1972 30.33
1971 33.34
Most imports of propylene oxide come from Canada; they
amount to only 1-2% of the U.S. production. In 1978, 75 million Ibs of propylene
oxide were exported (Anon., 1979a). For 1979, export of propylene oxide was
expected to rise above 100 million Ibs with imports in the neighborhood of
100 million Ibs (Anon., 1979b).
d) 1,2,3,4-Diepoxybutane
There is no evidence in the literature which indicates
that 1,2,3,4-diepoxybutane is produced in commercial quantities. Therefore,
it may be assumed that less than 1000 Ibs per year are produced. Production
appears limited to laboratory reagent supplies.
2. Producers, Production Sites, Production Capacity, Distributors,
and Importers
a) Butylene Oxide
The only commercial producer of butylene oxide in the
United States is Dow Chemical U.S.A. in Midland, Michigan. Production capa-
15
-------
city was not available. The following companies can supply laboratory amounts
of 2,3-butylene oxide (OPD Chemical Buyers Directory, 1977; Chemical Week, 1977):
Farchan Div., Chemical Samples Co.
Willoughby, Ohio
Research Organic/Inorganic Chemical Corp.
Sun Valley, Calif.
b) Ethylene Oxide
Table 7 lists the manufacturers who produce ethylene oxide and
the plant locations. With a few exceptions, production is concentrated
in the major industrial chemical centers of Texas and Louisiana. The total
capacity of the United States to produce ethylene oxide is 5,931 million Ibs
annually (Chemical Profiles, 1978).
The manufacturers of ethylene oxide are the major users
and distributors of the compound. Additional distributors of ethylene oxide
include the following (OPD Chemical Buyers Directory, 1977; Chemical Week, 1977):
Air Products and Chems. Allentown, Pa.
Arc Chem. Corp. Slate Hill, N.Y.
Devon Chem. Inc. Princetown, N.J.
MG Scientific Gases Somerville, N.J.
Nippon Soda Co. Ltd. Tokyo, Jap.
Scientific Gases Plainfield, N.J.
Warren Chemical Co. Seabrook, Md.
c) Propylene Oxide
Manufacturers producing propylene oxide and plant sites are
listed in Table 8. As with ethylene oxide, a large percentage of the production
capacity is located in the Texas and Louisiana area. The total capacity
of the United States to produce propylene oxide is 2,944 million Ibs annually
(Chemical Profiles, 1979). By 1980, capacity may be up to 3,315 million Ibs
(Blackford, 1976b).
16
-------
Table 7. Plant Capacity, Sites, and Manufacturers
of Ethylene Oxide (Chemical Profiles, 1978; SRI, 1979;
Kurginski, 1979)
Ethylene oxide (Dihydro-oxirene)
(Dimethylene oxide) (1,2-Epoxy- Annual Capacity
ethane) (ETO) (Oxirane) (Millions of Pounds)
BASF Wyandotte Corp. Geismar, La. 316
*
Calcasieu Chem. Corp. Lake Charles, La. 225
Celanese Corp. Clear Lake, Tex. 475
Dow Chem., U.S.A. Freeport, Tex. 260
Plaquemine, La. 450
Eastman Kodak Co. Longview, Tex. 195
Northern Petrochemical Morris, 111. 230
Olin Corp. Brandenburg, Ky. 110
PPG Industries, Inc. Beaumont, Tex. 155
Guayanilla, P.R. 300
Shell Chem. Co. Geismar, La. 670
SunOlin Chem. Co. Claymont, Del. 100
Texaco Inc.
Jefferson Chem. Co. Inc.,
subsid. Port Neches, Tex. 675
Union Carbide Corp. Seadrift, Tex. 850
Taft, La. 1,100
Penuelas, P.R. 550
TOTAL 6,661
Note: Oxirane Chemical Co. which produces ethylene glycol directly from
ethylene is given an oxide equivalent of 575 million pounds.
Closed by fire and explosion, scheduled to reopen in 1980.
17
-------
Table 8. Plant Capacity, Sites, and Manufacturers
of Propylene Oxide (Chemical -Profiles, 1979;
SRI, 1979)
Propylene Oxide
(1,2-Epoxypropane)
Annual Capacity
(Millions of Pounds)
BASF Wyandotte Corp.
Dow Chem. U.S.A.
Olin Corp.
Oxirane Corp.
Wyandotte, Mich.
Freeport, Tex.
Plaquemine, La.
Brandenburg, Ky.
Bayport, Tex.
Channelview, Tex.
TOTAL
194
1100
440
130
920
400
3,184
Dow Chemical Co. has the capability to switch some 200 million to 300 million
pounds per year of propylene oxide capacity to ethylene oxide.
Jefferson Chemical Co., Inc., a subsidiary of Texaco, stopped producing propylene
oxide December 1, 1978, but remains a merchant marketer of propylene oxide and
derivatives through a tolling agreement with Oxirane Corp.
18
-------
The manufacturers of propylene oxide are the major
distributors of the compound. Additional distributors of propylene
oxide include the following (Chemical Week, 1977):
Ashland Chemical Co. Columbus, Ohio
McKesson Chemical Co. San Francisco, Calif.
d) 1,2,3,4-Diepoxybutane
There are no known commercial producers of 1,2,3,4-
diepoxybutane. Laboratory reagent quantities of the compound can be supplied
by:
Pfaltz & Bauer Stamford, Conn.
Matheson Coleman & Bell Norwood, Ohio
Koppers Co. Pittsburgh, Pa.
3. Production Methods and Processes
a) Butylene Oxide
Butylene oxide is commercially prepared from 1-butene
(Cosslett and Gerry, 1976). It is manufactured by Dow by utilizing
chlorohydrin technology (Huff et al, 1978). The chlorohydrin process is
described in the following ethylene oxide section.
b) Ethylene Oxide
Two major processes have been used to manufacture ethylene
oxide in large, commercial quantities: the direct oxidation of ethylene and
the chlorohydrination of ethylene.
19
-------
In 1975, about 99% of all ethylene oxide was produced by
the direct oxidation method (Blackford, 1976a). In this method, ethylene is
oxidized in the vapor phase using either air or oxygen and a silver catalyst.
9
Approximately 65% of industry capacity is based upon air and the remainder
uses oxygen. There is a trend toward oxygen to increase yields
(Blackford, 1976a).
The overall reaction may be represented as follows:
CH2 = CH2 + 1/2 02 —^S-> CH2 - CH2
\ /
0
s
One of the by-products of ethylene oxidation is ethylene glycol (Blackford,
1976a). This compound is often not considered a serious impurity because
many of the ethylene oxide manufacturers use the oxide to produce this glycol.
Some carbon dioxide and water are also formed by complete oxidation of
ethylene (Lowenheim and Moran, 1975).
Figure 1 diagrams the process flow for production of
ethylene oxide via oxidation. Ethylene (95-98% purity) and air are
mixed in a volume ratio of 1:8 and passed over a catalyst of silver
oxide deposited on an inert carrier. The catalyst is usually replaced
every 18 months. Generally, an anticatalyst such as ethylene dichloride
is added to the ethylene feed to suppress C02 formation. With process
conditions consisting of atmospheric pressure and a temperature of 270-
290°C, a reactor contact time of one second converts about 60% of the
ethylene to the oxide. The effluent gases from the reactor are washed
20
-------
m
s
Main
reactor
Main
absorber
Purge
reactor
Purge
absorber
Desorber
Stripper Refiner
Steam
Coolant
Ethylene
.•-Heat
exchanger
Compressor
Waste Condenser
gas
Coolant
— Air
,-~ Heat
exchanger
Purge
Compressor
Recycle water
Ethylene oxide solution |_|egt
exchanger I
Ethylene
oxide
Figure 1. Direct-oxidation process for manufacturing ethylene oxide (Schultze, 1965) .
-------
with water under pressure in an absorber. The aqueous ethylene oxide
solution is sent to a vacuum stripping column where ethylene oxide is
liberated from solution and passed overhead to a fractionating column
for final purification (Lowenheim and Moran, 1975).
Reactor design and process operations are not
standardized throughout the ethylene oxide oxidation industry, so
variations of the described process are in use (Lowenheim and Moran,
1975). The average industry yield of ethylene oxide from ethylene is
about 64% of theoretical (Blackford, 1976a).
The chlorohydrin process was the main method of
ethylene oxide manufacture until 1957. In 1972, the Dow Chemical Company
converted the remaining chlorohydrin capacity to the production of propylene
oxide, and the process was not used again for ethylene oxide production
until 1975. The Dow Chemical Company has built-in flexibility for using
the chlorohydrin process to produce either propylene oxide or ethylene
oxide. Since 1975, part of this capacity has been used for ethylene oxide.
During 1975, the Dow Chemical Company made between 25 to 50 million Ibs
of ethylene oxide via the chlorohydrin process (Blackford, 1976a), representing
about 1% of the total U.S. production. The chlorohydrin process is
attractive commercially only when a good supply of captive low-cost chlorine
and lime or caustic soda is available. Also, satisfactory markets or
disposal facilities are needed for the by-products produced (Schultze, 1965).
22
-------
The chlorohydrin process starts by converting ethylene
to ethylene chlorohydrin with hypochlorous acid. The chlorohydrin is con-
verted to ethylene oxide by dehydrochlorination with slaked lime. The hypo-
chlorous acid can be formed to two ways: (1) by mixing a slurry of hydrated
lime with a stream of chlorine gas to yield the unstable calcium oxychloride
which decomposes to give calcium chloride and hypochlorous acid, or (2) by
dissolving chlorine gas in water. The hypochlorous acid then is reacted with
ethylene to yield a 35% to 40% solution of ethylene chlorohydrin. However, two
major by-products, 1,2-dichloroethane and bis(2-chloroethyl)ether, are formed
during the chlorohydrin formation as shown:
C12 + H20 * HO~C£+
-OH, CH2OH
PH "^ CHo .1. ^^^ ^
CH2 CiT2 \CT
i 2
CH2C£
HOCH2CH2CX. CH2CH2C&
A+ . : „ Q'
XCH2CH2C&
From the equations above, it can be seen that the amount of 1,2-dichloroethane
formed is dependent upon the ethylene and chlorine gas concentrations and that
the amount of ether formed is dependent upon the ethylene chlorohydrin concen-
tration. In most chlorohydrin processes, ether formation is minimized by avoid-
ing high chlorohydrin concentrations (Lichtenwalter and Riesser, 1964).
23
-------
The formation of ethylene oxide from ethylene chlorohydrin
can be represented by the following equation:
2 HOCH2CH2C1 + Ca(OH)2 > 2 CH2CH2 + CaCl2 + 2H20
0
A simplified diagram of a typical chlorohydrin process
ethylene oxide plant is depicted in Figure 2. The reactor is usually a
corrosion-resistant tower measuring 4 ft in diameter and 50 ft high. Its
lower section contains spargers and porous plates for the effective dispersion
of chlorine into water and for injecting ethylene into the hypochlorous acid
medium. Ethylene chlorohydrin formation proceeds rapidly in the lower section
of the tower. Gases are separated from the dilute chlorohydrin solution in
the top section and the vent gases from the condensing apparatus pass in series
to acidproof water and caustic scrubbers, where residual chlorine and HC1 gas
are removed before recycling the unreacted ethylene. The aqueous chlorohydrin
solution is mixed with a 10% solution of milk of lime at the inlet to the
hydrolyzer (Schultze, 1965).
The crude ethylene oxide product from the hydrolyzer con-
tains about 77.5% ethylene oxide, 10% water, 12% chlorinated organic compounds
(principally 1,2-dichloroethane and bis(2-chloroethyl)ether), and 0.5% acetal-
dehyde together with small amounts of hydrocarbon gases. This crude ethylene
oxide is refined in two columns; the first column removes chlorinated hydro-
carbons and the second removes acetaldehyde. Table 9 describes the quanti-
ties of reactants consumed and the products formed in the manufacture of
1000 Ibs of ethylene oxide (80% yield).
24
-------
I
8
«t
N3
Water and
caustic soda
scrubbers
Chlorohydrin
reactor and
condenser
Hydrolyzer
Ethylene oxide
distillation
system
Ethylene
Chlorine
Water
Water +
calcium
chloride
and some
ethylene
dichloride
^
1
J
TCV
_SL
HM-
(
I LC\
3 N
n
J
V_
f
^
1
L
_<^
i
ICV
*1
i
_^ r
,
^
Nhl
FCV
Chlorinated
hydrocarbon
by—products
to recovery
unit
Lr1
3
at
c
~0
o
O
Refined
ethylene
oxide to
storage
Figure 2. Chlorohydrin process for manufacturing ethylene oxide (Schultze, 1965).
-------
c) Propylene Oxide
Two major processes are used to manufacture propylene
oxide from propylene in large quantities: peroxidation and chlorohydrination.
In 1978, about 41% of the total nameplate capacity for propylene oxide will be
based on the peroxidation of propylene and the remainder on chlorohydrination
(Blackford, 1976b).
The chlorohydrination processes for propylene oxide and
ethylene oxide are related. The propylene oxide process yields a more complex
mixture of by-products.
While propylene chlorohydrin, like ethylene chlorohydrins,
is formed by reaction with hypochlorous acid, unlike the ethylene chlorohydrin
process, two chlorohydrins are possible with propylene chlorohydrin and as a
result three chloroethe.rs may be formed:
HO~C£+
CH3CH=CH2
cv
< \ H20
— CH.2
CA
CH3dH-CH2
CH3-CH-CH2
II
OH ca
CH3-CH-CH2
+ I '!
CA OH
a-chlorohydrin 8-chlorohydrin
CH3CHCH2
CH3CHCH2
one a
VCH3CHCH2
C20H
CH3-CH-0-CH-CH3
j* CH2C£CH2C£
^•v^ CH3-CH-CH2OCHCH3
C£ CH2CJi
CH3-CH-CH2OCH2CHCH3
C£ CH
major ether
26
-------
Table 9. Reactants and Products of the Ethylene Oxide
Chlorohydrin Process (Schultze, 1965)
Reactants
Compound
Ethylene
Chlorine
Lime (as CaO)
Quantity (Ibs)
800
2000
1600
Products
Compound Quantity (Ibs)
Ethylene oxide 1000
Calcium chloride 3200
1,2-dichloroethane 100-150
Bis(2-chloroethyl)ether 70-90
Acetaldehyde 5-10
27
-------
Although the a-chlorohydrin is the major product, because of the stability
of the secondary carbon atom, some g-chlorohydrin forms, and the a-chlorohydrin:
3-chlorohydrin isomer ratio varies from 3:1 to 9:1 depending on reaction conditions
(Lapkin, 1965). The major by-product ether is bis(2-chloroisopropyl)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
propylene chlorohydrin plant produces, for every 100 kg of propylene oxide, about
9 kg of propylene dichloride, 2 kg of dichloropropyl ethers, and 215 kg of calcium
chloride brine (Lowenheim and Moran, 1975).
The overall reaction of the chlorohydrin process for
production of propylene oxide can be represented by the following sequence:
CH,
! 3
CH0 = CHCH- + HOC1 >• C1CH0CH
Z J /!
OH
CHQ
I 3
2 C1CH0CH + Ca(OH)- f 2 CH-CHCH., + CaCl0 + 2H00
2. | I . L, 3 22
OH \0/
A diagram of a typical chlorohydrin propylene oxide plant
is depicted in Figure 3. Operation is similar to that of a chlorohydrin
ethylene oxide plant. While yield varies from plant to plant, the industry
average is estimated as 77% of theoretical propylene oxide from propylene
(Blackford, 1976b).
The peroxidation of propylene to propylene oxide can be
represented by the following reactions:
28
-------
D
I
N>
V0
Chlorohydrin
tower
propylene dichloride
Aqueous
Crude
propylene
dichloride ^Sr^
Figure 3. Diagram of a typical chlorohydrin propylene oxide plant (Fyvie, 1964)
-------
3/2 02 *• (CH3)3COOH
(CH3)3COOH > C
0
Propylene oxide is produced by a two-step process. Isobutane is air-oxidized
in the liquid phase to tert-butyl hydroperoxide, which is used to oxidize
propylene to the oxide. The diagram of this process is shown in Figure 4.
The yield of propylene oxide is about 93% of theoretical using the peroxida-
tion method; approximately 2.2 kg of tert-butyl alcohol are formed per kilo-
gram of propylene oxide produced (Lowenheim and Moran, 1975). Feeds other
than isobutane can be used. For example, in 1977, Oxirane Corporation brought
on-stream a 400 million Ib-per-year propylene oxide plant in Texas which uses
ethylbenzene feed instead of isobutane. In this process, ethylbenzene hydro-
peroxide is formed and reacted with propylene to make propylene oxide and
methyl phenyl carbinol; the carbinol is used to make styrene (Soder, 1977).
Because of the large amounts of coproducts formed, the economics of the per-
oxidation methods depend as much on the coproducts as on the propylene oxide
market.
Several patents on propylene oxide production have been
reported in the literature. These are new technologies which could impact
on future production practices, but are not in use at the present time.
A new technology has been described for the chlorohydrin
approach (Anon., 1978b,c). The technical advancement will alter the process
by recycling the brine waste (Figure 5). This waste will be purified and sent
to a chlorine-caustic cell. Chlorine will be reacted with _t-butyl alcohol to
yield _t-butyl hypochlorite, which will be the chlorinating agent.
30
-------
3
r»
tM
m
Isobutane
Oxygen
Oxidation Zone
Reactor
Separator
Propylene oxide
Propylene
tert — Butyl alcohol
Distillation column
Dehydrogenator
Dehydrator
Figure 4. Preparation of propylene oxide by peroxidation of propylene (Lowenhiera and Moran, 1975).
-------
w
Brine
1
ater Hydrogen
1
^""^* uiapnragm
__ ^. <•>!!
Brine
Propylene
Chlorine tert - Butvl hvpochlorite *
Cell Liquor
( NaOH + NaCI )
Chlorination
tert — Butanol Chlorohydrina
Propylene chlorohvdrin | •
Saponification
tion
I Water
Propylene oxide
Figure 5. Chlorohydrin-propylene oxide production modified by electrolytic
regeneration of chlorine (Anon., 1978b).
-------
Adaptations of the peroxidation method would utilize
new methods for peroxide generation and modify the reaction sequence (Anon.,
1977c, 1978a,c,d; Rozenzweig, 1977). One approach employs as feed a mixture
of propylene, oxygen, and acetic acid. The reaction sequence initiates with
peracetic acid formation. The sequence continues with olefin epoxidation
and conversion of the epoxide to propylene glycol monoacetate. Propylene
oxide subsequently is prepared by cracking the glycol acetate. Another
procedure utilizes a feed of propylene with an acetaldehyde-ethyl acetate
mixture for peracetic acid preparation. The process, which also produces
acetic acid, will require an acetic acid market. Other advancements in the
hydroperoxide technology utilize transition metal (Mo, V, Cr, or W) or arsenic
compounds as catalyst.
Perhaps the most important new technology would produce
propylene oxide by direct, catalytic oxidation (Anon., 1977c). The patented
procedure utilizes as catalyst an arsenical compound which contains polycyano-
ethylene ligands. Reaction conditions are 150°C and 850 psi with two-hour contact
time. The procedure produces propylene oxide with 48% conversion and 52% efficiency.
d) Diepoxybutane
Domestic production of diepoxybutane appears limited to
relatively small amounts for laboratory use or as a specialty chemical. The
two diepoxybutane isomers (see Section I.A.I) have been prepared by a variety
of synthesis schemes, which all involve alkaline-assisted cyclization of
butanediol or butanetetraol derivatives.
Most of the synthetic schemes employ the Si (internal
nucleophilic substitution) cyclization of l,4-dihalo-2,3-butanediols
33
-------
(Wallace, 1965; IARC, 1976). The dichloro- and dibromobutanediols have been
utilized as precursors:
OHOH 0 OH 00
1 I Base X X I Base ' \ / \
XCH0CHCHCH0X „"? CH0 - CH - CHCH.X ^—•*• CH0 - CH - CH - CH0
z z — HA z z —HA. z /
The Si reaction is stereospecific; while threo-2,3-butanediol yields the ji,_l
isomer, the erythro-2,3-butanediol is precursor for the meso-isomer. A method
for preparing the isomeric epoxybutanes from l,4-dichloro-2-butene has been
developed (Starcher et^ al^., 1958; Benerito et^ al_., 1964). Preparation of the
individual isomers is possible, since the isomeric diepoxybutanes can be
individually prepared. While trans-1,4-dichloro-2-butene is a precursor for
meso-diepoxybutane, cis-1,4-dichloro-2-butene is a precursor for • CH0 - CHCH - CH0
^|2 Z|2 2 \/2
OH OH 0
0
/ \
roi CH ci " CH c
H H
? '"I** XH
CH- C - C
\ / 2 — H | 0
H+
:i H ,
aqueous
dioxane
OH~
ether
HO
1
cicnr-/
z^i
H
C1H2C
un r1
rlU •" L»
i
H
^-CH
1^
OH
H
1
- C - OH
CH2C1
34
-------
4. Market Price and Influencing Factors
Current selling prices for bulk commercial quantities of the
epoxides are listed in Table 10. Ethylene oxide, propylene oxide, and butylene
oxide are bulk chemicals. Diepoxybutane is sold only in small quantities for
laboratory and research purposes for a price ranging from $1.20-$1.95 per gram.
In the early 1970*s, ethylene oxide was being sold for roughly
seven cents per pound. However, ethylene oxide supplies became severly limited
and the price for ethylene feedstock rose rapidly causing producers to succes-
sively raise prices to 26-28.5 cents per pound by April 1975 (Blackford, 1976a).
Similar factors, demand for propylene oxide and rising costs of
propylene feedstock caused prices for propylene oxide to rise from 8.5 cents
per pound in 1971 to 23-25 cents per pound in 1975 (Blackford, 1976b).
5. Market Trends and Influencing Factors
a) Butylene Oxide
Domestic production of butylene oxide in the near term
is expected to decline; Cosslett and Gerry (1976) have estimated that the 1980
production of butylene oxide will total only 15% of the 1974 production. The main
use of butylene oxide is to stabilize chlorinated solvents such as trichloro-
ethylene and 1,1,1-trichloroethane. A projected decline in use of these
chlorinated solvents appears to be part of the reason for the predicted decline
in domestic butylene oxide production. Another reason for predicting a decline
in domestic production is that the Dow Chemical Company's patents on butylene
oxide production expire in 1979 making it feasible for the Showa Denko Chemical
Company of Japan to build a butylene oxide facility with a 4.4 million Ib/yr
capacity (Anon., 1978d,f). Output from this competing facility could effectively
reduce the Dow Chemical Company's overseas markets for butylene oxide.
35
-------
*
Table 10. Domestic Prices for Various Epoxides
Epoxide Price Reference
Butylene Oxide $1.65/lb (bulk) Dow Chem. Sales Off., Buffalo, NY
Ethylene Oxide $0.36/lb (bulk) Chem. Mktg. Rptr., Jan. 21. 1980
Propylene Oxide $0.25/lb (bulk) Chem. Mktg. Rptr., Jan. 21, 1980.
1,2,3,4-Diepoxy-
butane $19.50/10 grams Pfaltz & Bauer Catalog
*Note that prices of petrochemicals can change rapidly due to the energy crisis.
36
-------
b) Ethylene Oxide
Figure 6 shows plant capacity and production data for
ethylene oxide from 1950 to 1977. The growth in the consumption of ethylene
oxide has largely depended upon its use as an intermediate for ethylene
glycol production (Blackford, 1976a; Chemical Profiles, 1975a). Although future
growth of ethylene glycol for use in polyesters is expected to be considerably
less dramatic than it was during the recent past, ethylene glycol is estimated
to grow in the range of 7% to 8% per year in the near future (Anon., 1977a).
If all of the announced expansions for ethylene oxide come
on stream as scheduled, United States ethylene oxide capacity will increase to
6,400 million Ibs annually in 1979 (Chemical Profiles, 1978). Provided there is
sufficient ethylene feedstock available, consumption of ethylene oxide is
expected to increase at an average rate of approximately 4.7% to 5.2% per year until
1980 (Blackford, 1976a). Chemical Profiles (1978) has projected a 5% annual
growth rate for ethylene oxide until 1982. Ethylene feedstock is not expected
to be in short supply through 1980, if all announced new plants and expansions
come on stream as planned.
c) Propylene Oxide
Although propylene oxide production was down in recession-
ary 1975, its production rebounded strongly in 1976 and 1977. Future growth
of the propylene oxide market depends upon its two major uses: propylene
glycol and polypropylene glycol, and polyether polyols for urethanes. Various
sectors of the urethane market are expected to grow from 8 to more than 10%
annually; the overall growth rate of the propylene oxide market is expected
37
-------
10000
9000
8000
7000
Total Production
Oxidation Process
1950
1955
1960
1965
1970
1975
1980
1985
1990
1995
2000
Figure 6. Market trends for ethylene oxide
(Blackford, 1976b; SRI, 1977;
USITC, Annual).
38
-------
to increase about 5.5% to -6.0% per year through 1983 (Chemical Profiles, 1979).
No significant new uses of propylene oxide are forecasted.
United States propylene oxide capacity is estimated at
2,944 million Ibs per year for 1979/1980 (Chemical Profiles, 1979). The estimated
demand for propylene oxide in 1983 is 2,691 million Ibs (Chemical Profiles, 1979).
Most industry estimates on propylene feedstock forecast a comfortable situa-
tion for users over the next few years (Anon., 1977b). Therefore, raw material
supply should not be a limiting factor in the near future.
39
-------
B. Use Aspects
1. Consumption by Major and Minor Use, Manufacturers and
Use Sites
a) Butylene Oxide
Currently, more than 95% of the butylene oxide produced
annually is used as a stabilizer in chlorinated solvents, such as 1,1,1-trichloroethane
(methyl chloroform) and trichloroethylene (Taylor, 1978). Depending upon the
solvent's use, up to 8% butylene oxide may be added to the chlorinated solvent but
is usually closer to 0.7 wt %.
There are several minor uses of butylene oxide. For
example, it is used to reduce corrosion in oil and gas well casings (Dow Chemical
Co., 1977). Other current commercial applications include use in production of
Pharmaceuticals, surfactants, and agrachemicals (Anon., 1978d).
Exports of butylene oxide are not listed separately by the
Department of Commerce (Bureau of the Census). However, it has been suggested
that the Dow Chemical Company is currently enjoying a virtual world monopoly on
1,2-butylene oxide production due to patent restrictions which are due to expire
in 1979 (Anon., 1978d). Under these circumstances, it seems likely that a sizeable
portion of the Company's production is currently exported.
b) Ethylene Oxide
A description of the various uses of ethylene oxide is given
below:
Lawler, 1977 Chemical Profiles, 1978
Ethylene glycol 63% 60%
Nonionic surface-active agents 11% 11%
Glycol ethers 6%
Diethylene glycol 5%
Ethanolamines 5% 7%
Triethylene glycol 2%
Polyethylene glycol 2% Glycolethers 7%
Exports 2%
Miscellaneous applications 4% Other 16%
40
-------
The major users and use sites for ethylene oxide are listed in Table 11; as
can be seen from this table, a very large percentage of production is captively
consumed by the primary manufacturers. A general description of the various
uses of ethylene oxide is presented below.
Ethylene Glycol; By far, the largest single use of
ethylene oxide is as an intermediate in the synthesis of ethylene glycol,
which is currently produced by hydration of ethylene oxide. Current industry
capacity to produce ethylene glycol is 5,155 million Ibs annually (SRI, 1977).
The growth in consumption of ethylene oxide has largely depended on its use
as an intermediate for ethylene glycol production (Blackford, 1976a). Ethyl-
ene glycol is mainly used for polyester production and antifreeze formulations
(Anon., 1977a; IARC, 1976).
Nonionic Surface-Active Agents; Approximately 25% of the
nonionic surface-active agents synthesized from ethylene oxide are of the
cyclic variety while 75% are of the acyclic variety. In the cyclic group,
ethylene oxide is used to make ethoxylate alkyl phenols and alkylphenol-
formaldehyde condensates. Production of ethoxylated nonylphenol is probably
the largest volume product of the cyclic group; another large-volume product
is ethoxylated dodecylphenol. Industry estimates of ethylene oxide consump-
tion growth rates for cyclic surface-active agents range from -2% to +4% per
year through 1980 (Blackford, 1976a). These surface-active agents are pri-
marily used in detergents.
The acyclic surface-active category includes ethylene
oxide used in the synthesis of surface-active polyethylene glycol esters,
41
-------
Table 11. Users and Use Sites of Ethylene Oxide (SRI, 1977)
BASF Wyandotte Corp.
Calcasieu Chem.
Celanese Chem.
Dow Chem.
Eastman Kodak
Northern Petrochem.
Olin Corp.
PPG Ind.
Shell Chem.
Texaco Jefferson Chem.
Union Carbide
Ashland Chem.
Uoadag Chem.
Geismar, La.
Wyandotte, Mich.
Lake Charles, La.
Clear Lake, Tex.
Freeport, Tex.
Plaquemine, La.
Midland, Mich.
Long view, Tex.
Morris, 111.
Brandenburg, Ky.
Beaumont, Tex.
Guayanilla, PR
Geismar, La.
Port Necnes, Tex.
Seadrift, Tex.
Taft, La.
Penuelas, PR
Texas City, Tex.
Institute & S. Charleston, W. Va.
Janesville, Wise.
Skokie, 111.
Ethylene
Clycol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
•J)
o
0
o
X
X
X
X
X
X
X
X
X
Dletllylene
01 y col
X
X
X
X
X
X
X
X
x
X
X
X
X
X
X
KClianolamlnea
X
X
X
X
X
Trlethylene
Clycol
X
X
X
X
Y
x
X
X
X
*
X
X
X
Polyethylene
Clycol
X
X
X
X
x !
X
X
42
-------
ethoxylated alcohols, polyether polyols, ethoxylated fats and oils, and
miscellaneous ethoxylated products, such as mercaptans, glycols, and polyols
(Blackford, 1976a). Industry estimates that ethylene oxide consumption for
acyclic surface-active agents is expected to increase at an annual rate of
8% to 9% through 1980. The manufacture of ethoxylated linear alcohols, used in
heavy-duty liquid detergents, will account for most of this growth (Blackford,
1976a).
Pi-, Tri-, and Polyethylene Glycols: Ethylene oxide and
ethylene glycol react to form diethylene glycol, triethylene glycol, and
polyethylene glycol. Diethylene and triethylene glycols are obtained mainly
as by-products of ethylene glycol manufacture. Diethylene glycol is used to
produce polyester resins, as a textile lubricant, and in solvent extraction.
Triethylene glycol is used as a humectant and in natural gas dehydration,
vinyl plasticizers, and polyesters. Industry capacity to make diethylene
glycol is 472 million Ibs per year; capacity to make triethylene glycol is
about 145 million Ibs per year (SRI, 1977).
Glycol Ethers: Ethylene oxide is combined with alcohols
to manufacture glycol monoethers, which include ethylene glycol monomethyl,
monoethyl and monobutyl ethers, diethylene and triethylene monoethyl, mono-
methyl, and monobutyl ethers. Ethylene oxide consumption for these ethers
is expected to increase at an average rate of 6% per year to 1980 (Blackford,
1976a). Solvent applications dominate the many uses of glycol ethers. Indus-
try capacity to make glycol ethers is 865 million Ibs annually (SRI, 1977).
Ethanolamines; Ethylene oxide reacts with ammonia to
form a mixture of mono-, di-, and triethanolamines. The proportion of the
43
-------
three ethanolamines is dependent upon the ratio of reactants used. Ethylene
oxide consumption for ethanolamines is expected to increase at a rate of 8% to 12.8%
annually to 1980 (Blackford, 1976a). About 25% to 30% of all ethanolamines are
used for soaps and detergents, 5% to 20% for gas conditioning, 10% by the metal
industry, 8% for textiles, 5% to 15% for toilet goods, and the remainder in varied
applications (Blackford, 1976a). Industry capacity to make ethanolamines in
415 million Ibs annually (SRI, 1977).
Miscellaneous Applications; Ethylene oxide is consumed
in the synthesis of numerous commercial chemicals. The largest amount in the
miscellaneous group goes into production of polyether polyols for flexible
polyurethane foams. In 1975, about 75 million Ibs of ethylene oxide were
consumed in these polyols (Blackford, 1976a).
Approximately 13 to 18 million Ibs of ethylene oxide are
annually used to make the medicinals, choline and choline chloride (Blackford,
1976a).
As much as 20 million Ibs of ethylene oxide were consumed
in the production of ethylene chlorohydrin in 1974 by the Union Carbide Corporation
for use as an intermediate in chemical synthesis (Blackford, 1976a). However, the
Union Carbide Corporation is not currently making ethylene chlorohydrin.
Approximately 10 million Ibs annually of ethylene oxide
are used in the manufacture of hydroxyethyl starch which is a semi-synthetic
gum used in textile sizing and adhesives (Blackford, 1976a). Hydroxyethyl
cellulose is produced by reacting cellulose with ethylene oxide. In 1975,
20 million Ibs of ethylene oxide were used to make these adhesive additives
(Blackford, 1976a).
44
-------
Arylethanolamines are made by reacting ethylene oxide
with either aniline or aniline derivatives. It is estimated that 3 million
Ibs of ethylene oxide were used for arylethanolamines in 1974 (Blackford,
1976a). They are used as intermediates for monoazo dyestuffs.
Acetal copolymer resins are produced by catalytically
copolymerizing 1,3,5-trioxane with a cyclic ether having at least two adjacent
carbon atoms (e.g., ethylene oxide). Ethylene oxide consumption for these resins
is believed to have amounted to about 2 to 3 million Ibs per year from 1972 to 1975.
Acetal copolymer resins are made by Celanese Plastics at Bishop, Texas under the
trade name Celcoir^ (Blackford, 1976a).
Like nonionic surface-active agents, ethylene oxide is
used to produce ethoxylated cationic surface-active agents. Several million
Ibs of ethylene oxide are annually used to produce these cationic agents such
as ethoxylated (coconut oil alkyl) amine, ethoxylated (tallow alkyl) amine,
and various ethoxylated fatty acid amino amides (Blackford, 1976a).
Small amounts of ethylene oxide are also consumed as a
fumigant, as a food and cosmetic sterilant, and in hospital sterilization
(Gilmour, 1978). In 1975, an estimated 0.1 million Ibs of ethylene oxide
were used for fumigant purposes (Landels, 1976). However, 1979 Dow Chemical
(Kurginski, 1979) has estimated that 0.2% of production (M.O million Ibs/yr)
of ethylene oxide is used as a fumigant.
c) Propylene Oxide
An analysis of the various uses of propylene oxide is given
below • (Lawler, 1977; Blackford, 1976b; SRC Estimates):
Polyurethane polyols 54.5%
Propylene glycol 19.5%
Non-urethane polyether polyols 6 %
Exports 6-7 %
Surface-active agents 4 %
Dipropylene glycol 2.5%
Glycerine 2 %
Glycol ethers 2 %
Miscellaneous 2.5-3.5%
45
-------
The major users and use sites are described in Table 12.
A general description of the various uses of propylene oxide is given below.
Polypropylene Polyols; Propylene ether polyols are con-
sumed primarily for polyurethane polyols and in a minor amount for non-poly-
urethane applications. The polyols for polyurethane application are utilized
in the production of flexible and rigid foam, which are used in furniture,
automobile seating, insulation and packaging. Growth rate for propylene oxide
in polyurethane polyols is forecast at 15% annually to 1980 (Blackford, 1976b).
The majority of the propylene oxide consumed as polyether
polyols for non-urethane uses went into the production of random and block
copolymers of polypropylene glycol and polyethylene glycol; the remainder was
consumed in the production of polypropylene glycol for industrial purposes.
Non-urethane markets for these compounds include surface-active agents, func-
tional fluids, lubricants, and heat transfer fluids (Blackford, 1976b).
Propylene Glycol; While propylene glycol has many uses,
production of polyester resins is the most important. Annual growth rate of
propylene glycol is expected to average 7% to 8% per year to 1981 (Chemical Profiles,
1977a). Propylene glycol is made by companies producing propylene oxide.
Industry capacity is 695 million Ibs annually (SRI, 1977).
Surface-Active Agents; Propylene oxide is used in pro-
duction of a wide variety of surface-active agents, among which are amphoteric
surface-active agents, anionic agents, cationic agents, and nonionic agents.
Most of these surface-active agents are some form of propoxylated compound.
Mixed linear propoxylated alcohols have the largest production volumes. The
largest market for the block copolymers surface-active agents is in crude-oil
demulsifiers used in breaking water-in-oil emulsions (Blackford, 1976b).
46
-------
Table 12. Users and Use Site of Propylene Oxide (SRI, '1977)
Ashland Oil, Inc.
BASF Wyandotte Corp.
Baychem Corp.
E.R. Carpenter Co.
Dow Chemical
ICI America
Jefferson Chemical
Co.
Olin Corp.
Owens -Corning
Fiberglass
Pelron Corp.
PPG Indust.
Union Carbide Corp.
The Upjohn Corp.
Witco Chem. Corp.
Hoadag Chem. Corp.
Nalco Chem. Corp.
Emery Indust.
Magna Corp.
Petrolite Corp.
Celanese Corp.
Oxirane
Janesville, Wise.
Geismar, La.
Washington, NJ
Wyandotte, Mich.
New Martinsville , W.Va.
Bayport, Tex.
Midland, Mich.
Freeport, Tex.
Plaquemine, Tex.
New Cascle, Del.
Austin, Tex.
Conroe, Tex.
Port Neches, Tex.
Lake Charles, La.
Brandenburg, Ky.
Newark, S.J.
Lyons, 111.
Circleville, Oh.
Institute & South
Charleston, W.Va.
Seadrift, Tex.
LaPorte, Tex.
Clearing, 111.
Los Angeles, Ca.
Perth Amboy, S.J.
Skokie, 111.
Sugar land, Tex.
SantaFeSprings, Ca.
Houston, Tex.
Brea, Ca.
St. Louis, Mo.
Bishop, Tex.
Bayport, Tex.
Polypropylene
Polyols for
Uretliane
Application
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Polypropylene
Polyols for
Non-uretliane
Application
X
X
X
X
X
X
1
X
X
X
X
X
X
j
Polypropylene
Clycol
X
X
X
X
X
X
X
Surface Active
Agents
X
X
X
X
X
a
a
p-4 1^
>, a
a.
-------
Table 12. Users and Use Sice of Propyler.e Oxide (SRI, 1977)
SCM
Chicago, 111.
co i
* en o 03
cu <-l u u
O O - -rl
W >, I 1-1
x a o S
-i cu z <
o
o
u £
*^ CO
••a
a
. . o
2. a
o >
=. u
5
Akzona, lac.
McCook, 111.
The C.P. Hall Co.
Chicago, 111.
PVO Int'l.
Boonton, N.J.
Dupont
Niagara Falls, H.Y.
Minn. Mining & Mfg.
Decaucer, Ala.
Scher Bros. , Inc.
Clifton, S.J.
E.F. Hougton & Co.
Carrolton, Ga.
Philadelphia, Pa.
Diamond Shamrock
Charlotte, N.C.
Glyco Chems, lac.
Williamsport, Pa.
Andrew Jergens Co.
Cincinnati, Oh.
Wilson Pharm. &
Chemica Corp.
Philadelphia, Pa.
48
-------
Dipropylene glycol is primarily used to make polyester resins and plasticizers;
growth rate is expected to average 8% per year to 1979 (Chemical Profiles, 1975b).
Dipropylene glycol is produced by the producers of propylene oxide.
Glycerine; In 1975, FMC Corporation in Bayport, Texas,
consumed roughly 26 million Ibs of propylene oxide in the production of glycerine
(Blackford, 1976b). Glycerine is mainly used as an ingredient in drugs and
cosmetics, and in alkyd resins.
Glycol Ethers; Propylene oxide is combined with alcohols
(methanol, ethanol, and isobutylalcohol) to manufacture glycol monoethers. The
most important group of compounds is made from methanol. The reaction does not
stop at the monoglycol ether, since some propylene oxide reacts with residual
hydroxyl groups to form monoethers of di- and tripropylene oxide.
Propylene oxide consumption for glycol ethers is expected
to increase annually about 8% to 1980 (Blackford, 1976b). Glycol ethers are
useful as solvents in the coating industry and as lubricants and coupling
agents.
Miscellaneous; Propylene oxide and ammonia react to form
mono-, di-, and triethanolamines in a manner similar to the reaction of ethylene
oxide and ammonia to form ethanolamines. These chemicals, isopropanolamines, are
produced by the Dow Chemical Company in Midland, Michigan. It was estimated that
in 1975, from 10 to 15 million Ibs of propylene oxide were consumed in production
of isopropanolamines (Blackford, 1976b). The latter are used to make isopropanol-
amides and isopropanolamine soaps.
Approximately 1 to 2 million Ibs per year of propylene oxide
are used to make propylene carbonate for solvent extractions, plasticizers,
syntheses, and natural gas purification (Blackford, 1976b).
49
-------
Propylene oxide has other minor applications in the production
of hydroxypropyl cellulose, starch, and many miscellaneous chemicals. Hercules
Incorporated makes a sulfur-vulcanizable elastomer from propylene oxide and
allyl glycidyl ether called Parel^% which is used in automotive engine mounts.
Propylene oxide is also used as a low-boiling solvent for nitro cellulose
adhesives, as a fumigant, and as a food preservative (Blackford 1976b).
d) Diepoxybutane
No information was available on domestic use of diepoxy-
butane. IARC (1976) reports use of the compound in some countries for polymer
curing, crosslinking textile fibers, and as an antimicrobial agent to prevent
spoilage.
2. Chemistry Involved in Use
Most epoxides are consumed as chemical intermediates in syn-
thesis of a variety of products, some of which are finished products while
others are further processed before marketing. The parent epoxides are used
directly in only a few applications, the largest of which is the approximately
4 million Ibs of butylene oxide added to chlorinated solvents as a stabilizer.
The chemistry important in epoxide use primarily involves ionic reactions
which open the epoxide ring. The chemistry discussed herein is centered upon
ethylene oxide and propylene oxide, since they are the most important commercially.
Reactivities of propylene and butylene oxide are virtually identical.
The epoxides are a class of ethers and their reactions with
ionic substrates conform to the general behavior of other ethers. The typical ionic
reaction cleaves one of the carbon-oxygen bonds of the oxirane ring and forms
a new bond between the carbon and a nucleophile. Reaction pH is critical
50
-------
since it affects reaction mechanism and kinetics (discussed in more detail for
hydrolysis in Section II.C.3). The pH can affect product distribution from
ambident epoxides (March, 1977; Lapkin, 1965), which are those epoxides con-
taining nonequivalent carbon-oxygen bonds. Since propylene oxide and butylene
oxide are ambident epoxides, nucleophiles can react with them at either the
primary (1°) or secondary (2°) carbon atom:
OH
I
1° RCHCH2N
N
2° I
>- RCHCH2OH
Ethylene oxide is non-ambident, so only one structural isomer is possible.
The pH affects reaction rate and products in part by altering mechanisms. In
neutral or alkaline conditions the epoxide is cleaved by an S 2 mechanism
(bimolecular nucleophilic substitution); alkaline conditions can affect reaction
rates by increasing nucleophilicity of substrates that can ionize. In substrates
such as alcohols, the alkoxide ion (RO ) reacts faster than the parent alcohol
(ROH). In either neutral or alkaline conditions the epoxide is cleaved only
at the primary position, where steric hindrance is least:
0 OH
/ \ I
ROH + CH2 CHCH3 >• ROCH2CHCH3
/°\ H2° °H
RO + CH_ CHCH. 1- ROCH CHCH
Z J -OH~ Z J
Epoxide reactions in acidic solutions follow more complex pathways, which are
interpreted mechanistically as intermediate between A-l and A-2 (see the discussion
51
-------
on hydrolysis in Section II.C.3) (Long and Pritchard, 1956). The reaction
is consistent with the following:
0 0
CH HC CH2 + H+
H
CH HC CH2
0
/ \
ROH + CH-HC CH~
k_.n,,m, L.
V ~ J
H
1
0
x \
**»». r^TT TT^l ^TTT
•^ CH-HC - Cn_
— 3 2- "^
1°
2
4
H
1
x\
Un_nL. \siin
J ^
OH
ru urrn nr? -i- w
OR
CH HCCH2OH + H+
In summary, ionic reaction rates are controlled by the carbon-
oxygen bond cleavage. The reactions are acid catalyzed and with nucleophiles
that yield anions, the reactions are alkaline catalyzed; also, only one product
(1° substitution) is expected with reaction in neutral or alkaline systems but
two products (1° or 2° substitution) can occur with acid catalysis.
Most of the commercial processes using epoxides as synthesis
intermediates involve their reactions with water or hydroxyl-containing organic
substrates, which include alcohols, phenols, and carboxylic acids. The reac-
tions are all accelerated by general acid or base catalyses. Glycol preparation
requires epoxide hydrolysis in a dilute aqueous solution:
x°\
CH CH
OH
I
CH3CHCH2OH
Di-, tri-, and polyglycols are prepared by increasing the concentration of the
epoxide. or altering the nature of the catalyst and/or solvent systems. Alkaline
52
-------
catalysts generate oligimers and polymers with head-to-tail structure (Lapkin, 1965)
0 ' OH CH
' \ alkaline ' '
CH.CH CH0+H 0 r% - ' CH-CHCH. - OCHCH0OH
3 ^ 2 catalyst j 2 L
0 CH ,
/ \ alkaline / ' \
nCH-CH CH_ + H00 —„ . ' H - 0 f- CHCH-0 f H
3 22 catalyst y 2 J
These polymers have a largely isotactic structure (head-to-tail polymerization)
but selectivity is not 100%. Since the alkaline hydrolysis of epoxides pro-
ceeds with a high retention of configuration at the asymmetric carbon atom
(see Section I.A.I), optically active propylene oxide can be polymerized to
produce an optically active polymer. According to Lapkin (1965) acid catalysis
of the propylene oxide polymerization yields polymers indistinguishable from
those prepared by alkaline catalysis. Copolymers of ethylene oxide and propylene
oxide have been prepared with each other and with other epoxides (e.g., 4-
vinylcyclohexene dioxide) or olefins (e.g., ethylene or vinylidene chloride).
The polymerization initiators and conditions are chosen for selective polymer
characteristics. Catalysts utilized have included Bronsted acids (H ), Lewis
acids (iron salts, BF_, etc.), organometallics, and metallic hydroxides (in
homogeneous solution, as emulsion, and as solid).
Epoxides are reacted with alcohols to yield monoethers. The
reactions of methanol with propylene oxide illustrates ether formation
(Jefferson Chemical Co., undated b):
OH
alkaline. ™CH™OCIL
CH3HC
catalyst
/ \ m _ _ ,
OH OCH,
acid
catalyst
CH^CHCH^OCH^ + CH_CHCH0OH
Polyether glycols are prepared by reacting polyols (e.g.,
glycerine or sorbitol) with solutions containing high epoxide concentrations
53
-------
(Blackford, 1976b): CH
I 3
CH2OH CH20 i CH2CHO > H
I °x | OH
X ^ base I
CHOH + n CH-HC CH9 °*, f i CHO i CH.CHO > H
3 2 catalyst 2 y
I I CH3
CH OH CH,0 { CH0CHO > H
* ^ z z
(n = x + y + z)
In urethane preparations the polypropylene and polyethylene glycols are
reacted with isocyanate:
rv Lewis rw n
Lrl_ . , Ln_ U
| 3 acid | 3 „
- CH.O i CH.CHO > H 4- RNCO ——-: -> - CH00 •( CH0CHO > CNHR
A. £- H C3.u3.XyS t Z ^.
Glycol esters of carboxylic acids and phenols and ethers of
cellulose, starch, and other polyols are also prepared as described above.
For example, reaction of ethylene oxide and nonylphenol yields nonylphenoxy-
polyethoxyethanol, a non-ionic, surface-active agent (Blackford, 1976b):
OH 0-f CH0CBLO > H
/ z n
C9H19 C9H19
The epoxides react with amines by pathways similar to reactions
with hydroxyl compounds. Reaction of ethylene oxide and ammonia yields the
commercially important ethanolamines :
n
where n is typically 1 to 4.
54
-------
Choline is prepared by reacting trimethylamine with ethylene oxide (Jukes,
1964) :
0
(CH3)3N + CH2 - CH2 - >• (CH3)3N + CH2CH2OH
Other ionic reactions of the epoxides include the following
(Lapkin, 1965; Jefferson, undated a and b; March, 1977; Schultze, 1965):
0
/ \
RSH + CH2 - CH2 - >
0
/ \
0
' \
ROCH2C1 + CH2 - C
0 4.
' \ Et M Br~
RR'CO + CH. - CH0 V RR'C
L L >•
o
:)
0
0
/ \ ^ JIW
RMgX + CH0 - CH0 > "^"vnu^"""" ' RCH2CH2OH
0
\
- CH - >• Si
0
/ \
OPC13 + CH2 - CH2 - f OP(OCH2CH2C1)3
X°\ R,N+Br- / ° - CHCH3
CO + CH-CH - CH, — - - »• 0=C |
£ J ^ ^
0 - CH2
0 Lewis
/ \ acid
ArCH.CH^H
X + CH? - CH? - -J= - >• HOCH2CH-X
OH"
where X is inorganic ions such as Cl , CN , CNS , etc.
55
-------
Butylene oxide is added to chlorinated solvents to scavenge
HC1 liberated by solvent degradation. The scavenging reaction is
Q OH Cl
/ \ I I
CH CH - CH + HC1 - >• CH
Propylene oxide is isomerized by thermal or by catalytic acti-
vity. Catalytic isomerization is used in the commercial manufacture of allyl
alcohol (Oosterhof, 1976). The conversion is almost quantitative with Li_PO,:
/°\ Li3p°4
CH3CH - CH2 — - — - - >- CH2 = CHCH2OH
Isomerization of propylene oxide over Al_0. or pumice at 500° C yields a mixture of
propionaldehyde and acetone (Jefferson, undated b; Horsley, 1968) :
0
3. Discontinued Uses of Epoxides
Until 1953 (when acetylene was first used) , all acrylonitrile
was produced by the catalytic dehydration of ethylene cyanohydrin that was
prepared from ethylene oxide and hydrogen cyanide. The reaction may be repre-
sented as follows:
CH0 - CH0 + HCN - >• HOCH0CH9CN - > CH0 = CHCN + H00
/ / Z L L L L
V
In 1956, American Cyanimid Company closed down its 35 million Ibs per year
plant at Warners, New Jersey, which was based on this process. From then to 1966
when it was discontinued this process was used only by Union Carbide at Institute,
W. Virginia (Blackford, 1974),
56
-------
In 1965, Union Carbide consumed 90 million Ibs of ethylene oxide to make acryloni-
trile. No other significant discontinued uses of the epoxides under consideration
are known.
4. Projected or Proposed Uses
Wood treatment is a potentially important market for epoxides
(Anon. , 1977d) . The USDA Forest Product Laboratory has reported that treating
southern yellow pine with epoxides (including ethylene oxide, propylene oxide,
and butylene oxide) improves its durability. The treatment adds 20% to 30% (by
weight) of the epoxide to the wood. A mild alkaline catalyst (typically
trimethyl or triethyl amine) catalyzes the initial reaction of the epoxide
with cellulose hydroxyl groups and the polymerization reactions of the epoxide
(Rowell and Gutzmer, 1975; Rowell et^ a^. , 1976):
0 R
\
Cellulose -OH + n RCH - CH_ — -—, - -> Cellulose - 0 { CH CHO > H
^ Cci L3.J_y s c ^ n
The treatment is facile at 120°C and 150 psi with triethylamine catalysis.
Required treatment time , increased with molecular weight for the above three
epoxides; butylene oxide required 4 hours for a 25% weight addition, while
under the same conditions propylene oxide yielded a 32.5% weight addition
after one hour. The treated wood had improved dimensional stability (shrink-
age and swelling as the result of weathering effects were less) and was
resistant to degradation by fungi or by termites. This treatment did not
yield any reaction by-products and residual epoxide and catalyst were easily
removed. The bonding of the polyethers to the treated wood was stable.
57
-------
Other projected and proposed uses have minor potential market
impact in comparison to the proposed use for wood treatment. Most represent
expansions of existing markets rather than new applications. Extentions of
current uses include new applications of propylene oxide and ethylene oxide
for disinfecting dried foods, packaging materials, surgical equipment and
other materials requiring disinfection (Hart and Brown, 1974; Tompkin and
Stozek, 1974; Alguire, 1973). Commercial literature from epoxide manufacturers
suggest some reactions of epoxides which could be applied to new products, and
new applications of existing products. Butylene oxide has been suggested as
an intermediate for nonionic emulsifiers and detergents, petroleum demulsifiers,
oil additives, lubricants, textile chemicals, and similar products (Lapkin,
1965). Additionally, butylene oxide could have some use in production of
polyether polyols (Lawler, 1977).
5. Alternatives to Uses for Epoxides
a) Butylene Oxide
More than 95% of butylene oxide annually produced is used
as a stabilizer in chlorinated solvent such as 1,1,1-trichloroethane and tri-
chloroethylene. Other chemical compounds, which have been patented for use as
stabilizers in these chlorinated solvents, include glycol diesters, ketones,
nitriles, dialkyl sulfoxides, imines, dialkyl sulfides, dialkyl sulfites, tetra-
ethyl lead, morpholine, nitroaliphatic hydrocarbons, 2-methyl-3-butyn-2-ol,
tertiary-butyl alcohol, tetrahydrofuran, 1,4-dioxan, sec-butyl alcohol, and
monohydric acetylenic alcohols (Whetstone, 1964). Butylene oxide is apparently
used because it is the best available commercial compound for these applications
in terms of usefulness and economics, but industry could find a suitable re-
placement stabilizer if butylene oxide was no longer available.
58
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b) Ethylene Oxide
More than 99% of the U.S. production of ethylene oxide is
used as a chemical intermediate in chemical syntheses of glycols and other compounds.
Alternatives would require production routes from raw materials other than ethylene
oxide.
Roughly 63% of the ethylene oxide production is hydrolyzed
to ethylene glycol. A new process for making ethylene glycol directly from
ethylene has been developed by Halcon, Inc. (Klapproth, 1976). Ethylene is
reacted with acetic acid in the presence of a catalyst to form mono- and
diacetates, which are then hydrolyzed to ethylene glycol. Oxirane Corp. has
constructed an 800 million Ib per year plant based upon this technology in
Channelview, Texas. This capacity represents roughly 25% of the total industry
ethylene glycol capacity.
In the past, there have been other commercial routes to
ethylene glycol. In 1968, the DuPont Chemical Company shut-down a plant that used
a methanol-to-formaldehyde-to-glycolic acid-to-ethylene glycol route. At one
time, ICI United States Inc. manufactured ethylene glycol by the hydrogenation and
hydrolysis of carbohydrate feedstock (e.g., molasses); the plant is now on
standby. Prior to 1973, Celanese Corp. obtained small quantities from the
vapor-phase oxidation of propane (Klapproth, 1976).
As far as the other compounds synthesized from ethylene
oxide are concerned, no information was available on syntheses from other raw
materials.
Relatively small quantities of ethylene oxide, roughly
0.1 million Ibs annually (Dow Chemical estimates that the volume of ethylene oxide
used as a fumigant is less than 0.2% of total production which in 1978 would
equal 10 million Ibs - Kurginski, 1979), are used for fumigant purposes. Since
there are many commercial fumigants available, it seems likely that many of
its fumigant uses could be replaced by an alternative fumigant.
-------
c) Propylene Oxide
Since nearly all propylene oxide is consumed in chemical
synthesis, alternatives require different compounds as raw materials for pro-
duction. Currently, there are no commercially viable alternative routes for
the formation of the derivatives normally made with propylene oxide.
Until 1970 the Chemicals Division of Atlas Chemical Ind.
(now ICI United States) produced propylene glycol by the hydrogenation and
hydrogenolysis of molasses at it's 5 million Ibs per year plant in Atlas,
Delaware (Blackford, 1976b). This plant is no longer producing propylene
glycol.
There is no information available in the literature on
propylene glycol production from propylene and acetic acid in a manner similar
to the direct production of ethylene glycol from ethylene as discussed above.
The small amounts of propylene oxide used as fumigant
could likely be replaced by some other commercial fumigant.
C. Entry Into the Environment
Sparse information was available on entry of the subject epoxides
into the environment. The potential for entry was assessed from the engin-
eering aspects of the manufacture, handling and transport, use and disposal,
and from the properties of the selected epoxides.
1. Points of Entry
a) Production
i. Ethylene Oxide
Ethylene oxide is mainly made by direct oxidation of
ethylene (see Section II.A.3). The process consists of vapor phase oxidation
60
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of the ethylene, followed by adsorption and wash of the effluent gases in
water, and then by vacuum stripping and fractionation of the ethylene oxide.
Ethylene oxide can be lost from the vapor phase as fugitive emissions or with
vented gases. No information was available on its possible loss with waste
waters or with any solid wastes. Since ethylene oxide vapor pressure is high,
atmospheric emissions appear a more likely environmental entry than waste dis-
posal.
Pervier and coworkers (1974) surveyed air emissions
from ethylene oxide production plants and estimated a total annual emission of
air pollutants of 120 million Ibs by 1980. The emissions had the following
composition:
hydrocarbons 118.6 million Ibs
nitrogen oxides 0.45 million Ibs
sulfur oxide 0.14 million Ibs
Most of the emissions are released by vents on process equipment. They reported
no details on the contribution of ethylene oxide to this total. Most of the
emission appears to be ethylene gas. Dow Chemical (Kurginski, 1979) indicates
that these emissions appear to be out of date and are at least 20 times too high.
They estimated that less than 5 million Ibs of ethylene oxide is released
annually during production and processing.
Potential contaminant releases from chlorohydrination
procedure is discussed below. This route provides only a small amount of the
ethylene oxide manufactured each year (see Section II.A.2).
ii. Propylene Oxide
The chlorohydrination route is currently the principal
method for propylene oxide manufacture. The propylene oxide is produced in
aqueous solution and is separated by distillation (see Section II.A.3). The
61
-------
most probable release is into the atmosphere through fugitive emissions and
with vented gases. The process generates about 45 to 50 tons of waste water per ton
of propylene oxide produced (Kurginski, 1979; Anon., 1978b). Its treatment is
discussed below (see Section III.C.3).
Propylene oxide is also manufactured by a peroxida-
tion procedure. The process has a similar potential for emission of propylene
oxide as via chlorohydrination during its separation from the liquid phase but
waste water and by-product generation is significantly less.
iii. Butylene Oxide
The production of butylene oxide and its potential
release to the environment will be similar to propylene oxide (see Section II.A.3).
b) Handling, Transport, and Storage
The selected epoxides could be emitted to the atmosphere
as the result of fugitive emissions or venting during their handling, transport,
or storage. No specific information was available to describe these losses.
Information on current practices, procedures or environmental controls was
sparse and no monitoring information was available. The following paragraphs
discuss potential releases of epoxides without making any attempt to establish
relative importance.
Bulk shipments of ethylene, propylene, and butylene oxide
are commonly made by railroad freight tanker; the sizes of the tankers are
commonly 10,000 and 20,000 gallons. Shipments of these oxides are also made
in special 55-gallon drums and by highway truck tankers. The epoxides are
stored in bulk containers as well as in smaller quantities in 55-gallon drums.
No information was available on the usual emission controls
used on storage and transport containers. "Padded" containers, if used, would
conserve vapors which would otherwise be vented to the atmosphere. Emissions
could also occur during equipment purging in routine maintenance, gauge glass
blowdown or leaks.
62
-------
Release is possible during transfer of the selected
epoxides. In normal practice railway tankers are loaded and unloaded directly
from or into storage tanks. The transfer utilizes nitrogen pressurization to
approximately 50 psi or pumping. Faulty equipment or over-pressurization can
cause epoxide emissions. Small amounts spilled during handling could also
release small amounts of epoxides.
A major concern is release from a storage container or
transport-related accident. This could vary in scope from a relatively minor
incident, such as release through pressure safety valve or rupture disc, to a
major accident in which an entire storage container or tanker would rupture.
No information was available to predict how often the minor release accidents
do, in fact, occur or on the amount of epoxides they annually release. Al-
though none of the selected epoxides appear directly involved with previous,
major accidents, the potential is present.
c) From Use
i. Ethylene Oxide
Most ethylene oxide is used in chemical syntheses of
various compounds. The potential for environmental exposure of ethylene oxide
during syntheses use is, perhaps, equivalent to the potential for release
during production as discussed above.
Small amounts of ethylene oxide are consumed as a
fumigant, as a food and cosmetic sterilant, and in hospital sterilization. In
1975, an estimated 0.1 million Ibs of ethylene oxide were used for these fumi-
gant purposes (Landels, 1976) while it would appear to be 10 million Ibs according
to Dow Chemical Co., (Kurginski, 1979). All of the ethylene oxide used as a
fumigant enters the environment (soil, food products, and air) and also presents
a potentially serious hazard to the applicators.
63
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ii. Propylene Oxide
Like ethylene oxide, most propylene oxide is used in
chemical syntheses and potential for environmental exposure is perhaps the
same as for production. Propylene oxide is also used as a fumigant like
ethylene oxide. Therefore, similar exposure potentials exist.
iii. Butylene Oxide
Most butylene oxide is used as a stabilizer in chlor-
inated solvents, such as trichloroethylene and methyl chloroform. These
chlorinated solvents are, in turn, primarily used for metal cleaning and
vapor degreasing of metal parts. Under these circumstances, direct environ-
ment escape during use is a real possibility.
d) From Disposal
About 99% of the epoxides produced in this country are used
to make other chemicals, so only a small fraction of the total production could
possibly be released to the environment from disposal. Excess or unwanted
ethylene and propylene oxide which were to be used as fumigants and the butylene
oxide which may be disposed in chlorinated solvents are possible exceptions. ,
The potential emissions of process wastes generated from
manufacture or from use as an intermediate of the selected epoxides is dis-
cussed below.
2. Disposal Methods, Emission Controls, and Effluent Controls
Atmospheric emissions of the epoxides through process vents
appear the most important source of their release to the environment. Incin-
eration appears the method applied for emissions control. Moore and Frisch
(1971) reported that catalytic combustion is applied to ethylene oxide tail
gas from scrubbing operations. No information was available concerning other
64
-------
emission controls for epoxides from manufacturing or use. Catalytic oxidation
does appear to be another choice for emission control (Moore and Frisch, 1971;
Spencer, 1971).
Storage, transport, and handling methods have been extensively
described in literature supplied by manufacturers (BASF Wyandolte Corp, 1972;
Dow Chemical Company, 1977; Jefferson Chemical Company, undated a, undated b;
Oxirane Chemical Company, undated) and safety information sources (NFPA, 1975;
MCA, 1971). This literature chiefly concerns safety of humans and property.
Tank cars for ethylene oxide and propylene oxide are specified as ICC-105A100W
and 105A100. These are equipped with pressure relief valves which vent excessive
pressure into the atmosphere. The epoxides should preferrably be stored in an
area detached from the plant site and storage tanks should be diked. Ethylene
oxide should be equipped with cooling pipes. Tanks must be equipped with
pressure relief valves, but specific instructions on emission control of excess
pressure was not included. Vapor recompression systems could be applied to
prevent emissions (Spencer, 1971).
Process waters for ethylene oxide manufacture and use appear to
be minor problems with respect to waste treatment. The process water is re-
cycled in its manufacture and its primary use as an intermediate in ethylene
glycol manufacture (Sittig, 1962, 1965). No information was available on how
much of the process water eventually is treated and no specific details were
provided on treatment methods. The waste water will contain high BOD, but
inorganic composition and refractory organics appear minimal problems with
ethylene oxide manufacture or ethylene glycol production from ethylene oxide
(Sittig, 1962, 1965; Spencer, 1971). Conventional water treatment (including
filtration and flocculation) with a biological treatment appears sufficient
(Spencer, 1971; Shenderova ^t al., 1972). Patents (Kadoi and Kataoki, 1968;
65
-------
Ishishi and Kobayashi, 1973) describe physical-chemical treatments with
saponification, neutralization, and active carbon filtration for epoxide
waste water treatment.
The environmental problem from propylene oxide manufacture via
chlorohydrination is caused by the large amounts of by-products formed. The
process generates about 60 tons of calcium chloride-containing waste water per
ton of propylene oxide (Anon., 1978b). In addition, various chlorinated
organic by-products are formed. Little, if any, residual propylene oxide is
in the waste water. The waste water effluent is unsuitable for disposal directly
into natural drainage and will not be accepted in municipal sewage systems
without expensive pretreatment (Hancock, 1973). There is only a limited market
for the organic chlorinated by-products, and disposal of them may sometimes be
a problem. One of the major producers of propylene oxide via the chlorohydrin
route reportedly collects and burns most of the by-product bis(2-chloro-l-
methylethyl)ether (SRI, 1977).
There is currently a proposed solution to the calcium chloride-
waste water effluent disposal problem (Anon., 1978b). The C-E Lummus Company
has demonstrated on a laboratory scale that the calcium chloride (or sodium
chloride) brine solution can be fed to an electrolytic diaphram cell to regen-
erate chlorine gas and caustic, which is used in the propylene oxide manufac-
ture process. Currently, this proposed solution to the propylene oxide waste
water problem appears to be feasible, but full-scale commercial trials have not
been made.
No specific solid wastes are associated with manufacture of the
selected epoxides. Ethylene oxide manufacture does utilize a solid catalyst,
which must be periodically replaced. Because the silver catalyst is expensive,
66
-------
it is regenerated rather than disposed. Information was not available on
solid waste generation from all uses of the selected epoxides. The major
uses, as chemical intermediates, will sometimes have heavy ends from distilla-
tion pots which require disposal. Incineration appears the method of choice
(Spencer, 1971) but no information was available on actual practices.
The recommended methods for disposal of unwanted epoxide is
either dilution with large amounts of water (to prevent fire hazard) or con-
trolled incineration (BASF, 1972; MCA, 1971; Spencer, 1971). Disposal with
water could allow entry of the corresponding glycol into the environment.
3. Potential Production in the Environment
The major source of potential inadvertent production in the
environment of the considered epoxides is probably the combustion of hydro-
carbon fuels. Hughes et_ al. (1959) utilized gas-liquid partition chromato-
graphy to separate and identify oxygenated derivatives of hydrocarbons which
were found in the combustion products of hydrocarbon fuels. Among the oxygen-
ated combustion products identified were ethylene oxide and propylene oxide.
Barnard and Lee (1972) identified these compounds in the oxygenated combustion
products from n-pentane combustion. It is conceivable that quantities of
ethylene oxide and propylene oxide, which may approach millions of Ibs, are
annually emitted in automobile exhaust. Stationary sources of hydrocarbon
combustion may also emit large quantities of these compounds into the environ-
ment.
Ethylene oxide has been identified in tobacco smoke (Binder
and Lindner, 1972; Binder, 1974). It is not uncommon for tobacco to be treated
with ethylene oxide by cigarette manufacturers for its fumigant properties.
67
-------
Binder and Lindner (1972) determined that the ethylene oxide concentration of
unfumigated tobacco was 0.02 yg/ml, while fumigated tobacco had a concentra-
tion of 0.05 yg/ml and extensively fumigated tobacco had a concentration of
0.30 yg/ml. Binder (1974) determined the ethylene oxide content of smoke from
unfumigated tobacco as 1 yg/g.
DeBont and Albers (1976) have concluded that ethylene oxide is
a product of ethylene catabolism by the ethylene-oxidizing strain E20 bacterium.
Sato and Cvetanovic (1958) have reported that butylene oxide is
formed by the photooxidation of 1-butene by nitrogen dioxide. Both of the
compounds, 1-butene and nitrogen dioxide, are emitted in substantial amounts
by automobile exhaust. There may be a very slim chance that two compounds
could react by photooxidation in the atmosphere to produce butylene oxide.
The epoxides are formed in the photochemical smog cycle. Olefins
can be converted to the corresponding epoxides by reaction with an organic
peroxide (Altshuller and Buffalini, 1965).
0
/ \
CH3CH = CH2 + ROOH - »- CH3CH - CH2 + ROH
Alkyl peroxides can decompose to yield an epoxide and oxy radical (NAS, 1976).
CH.CH - CH0 - *• CH-CH - CH0 + CH_0
3( X2 3 / 2 3
CH3 V 0
•0
CH.CH - CH0 CH-CH - CH-
3 2 3 \2
H
CH CH - CH2 + HO-
68
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Water disinfection has the potential to convert olefins to
epoxides. Olefin conversion during chlorination would proceed by the same
route as for chlorohydrination production of the epoxide. The olefin would
first be converted to the chlorohydrin (Morris, 1975; Carlson and Caple,
1977). The subject epoxides would only form by alkaline-catalyzed cycli-
zation. Cyclization would not occur in neutral solution for the precursors of
the subject epoxides; instead, those chlorohydrins would hydrolyze directly to
yield glycols (Frost and Pearson, 1961). Epoxides could form during ozona-
tion, also (Carlson and Caple, 1977). The epoxidation is a secondary reaction
in which aqueous organics are first converted by ozone to peroxides and result-
ant peroxide epoxidizes the olefin.
Although water treatment can convert olefins to epoxides, this
route is probably not important with respect to the selected epoxides. This
conclusion is based upon the low solubilities and high vapor pressures of the
precursor olefins. Also, the hydrochlorination route for epoxide formation is
unlikely unless it is performed at an unusually high pH. These factors limit
ambient concentrations of the olefins in environmental waters.
D. Environmental Pathways and Fate
The epoxides are not persistent in the environment. Available infor-
mation on their chemical and biological properties characterize them as highly
reactive. The available information on transport was not sufficient to develop
a definite description of transport characteristics. Interphase transport from
water to air seems a slow process, but evaporation of ethylene oxide applied as
a sterilant or a fumigant appears to be an important process. High water solu-
bility and high vapor pressure.result in significant mobility of the epoxides
within water or air.
69
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1. Transport Within and Between Media
No specific information on environmental transport was avail-
able for any of the selected epoxides. Chemodynamic relationships applied to
known physical properties (see Table 2) permit some insight into the transport
behavior (Freed et ail., 1977).
Ethylene oxide, propylene oxide, and butylene oxide possess
high solubilities in water and high vapor pressure (ethylene oxide is a gas
at ambient temperature). No information was available on adsorption character-
istics with soil, sediments or particulates. Because of their physical pro-
perties, these epoxides will undoubtedly move freely within water systems and
in the atmosphere and they are likely to migrate rapidly in soil.
A description of intermedia transport is made difficult by the
lack of any direct measurements. The only information available consisted of
studies of ethylene oxide loss from fumigated materials (see Section II.D.2).
Scudamore and Heuser (1971) examined the fate of ethylene oxide in various,
treated commodities. They determined that ethylene oxide dissipation was an
apparent first order kinetics process. The dissipation rates were measured
for some samples stored both in sealed containers and in trays (Table 13).
Dissipation rate in open trays will include both vaporization and degradation
processes, while sealed containers would measure only degradation. So, vapor-
ization rates can be estimated by differences between the two storage methods:
K = K - K ^ .
vapor trays containers
The estimated vaporization rates suggested vaporization half-lives in the range
of approximately four hours to 17.5 days. Their data also indicated more rapid
vaporization at 25°C than at 10°C, which is expected.
70
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Table 13. Estimated Vaporization Rate for Ethylene Oxide from
Commodities (Adapted from Scudamore and Heuser, 1971)
Rate of Ethylene Oxide Loss,
Commodity
Semolina
Wheat I
Wheat II
Wheat II
Sultanas
Sultanas
Cocoa beans
Ground nuts
Ground nuts
Experimental Conditions
M.C.
13.6
14.5
15
15
12.5
17
5
7
7
c.t.
825
500
1000
1000
600
600
600
500
500
25
25
25
25
10
25
10
25
25
25
25
25
10
10
25
10
10
25
K (days"1)
In sealed
containers
(A)
0.74
0.62
0.45
0.09
0.28
1.2
0.24
0.22
0.78
Spread on
open trays
(B)
>5
0.66
0.62
0.18
0.61
1.8
1.5
0.43
1.72
B-A
>4
0.04
0.17
0.09
0.33
0.6
1.26
0.21
0.94
MC = moisture content (%)
c.t. = EO concentration-time product (mg h/£)
ti = Gas treatment temperature (°C)
t£ = Storage temperature (°C)
71
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A study by Alguire (1973) on dissipation of ethylene oxide
from treated packaging materials demonstrated rapid vaporization. The salient
study concerned ethylene oxide dissipation from polystyrene creamer cups,
Figure 7. The vaporization half-life was less than one day. No other direct
information on ethylene oxide evaporation was available (see Section II.D.2.c).
10 —
g __
8 —
7 —
S 5 —
I 4.
3 —
2 —
1 —
0 —
Ethylem oxide
days
Figure 7. Dissipation of ethylene oxide following gas
treatment of polystyrene creamer cups (from
Alquire, 1973).
The rate for epoxide evaporation from water cannot be adequately
estimated from the information available. This rate can be derived from the
Henry's Law Constant, H, but only for substrates of low water solubility
(Mackay and Leinonen, 1975; Billing, 1977). Since the epoxides are very
soluble, calculation of evaporation rate and half-life by the Billing approach
is suspect. Henry's Law Constant could not be calculated for ethylene oxide
because it is completely miscible with water, but was calculated as 2.8 x 10
-4
and 7.6 x 10 at 25°C for propylene oxide and butylene oxide, respectively,
-4
72
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from the data of Table 2. Based upon the Henry's Law Constants, a low rate
of epoxide evaporation is speculated. Epoxide hydrolysis rates (see Section
II.D.2.1) seem competitive with evaporation rates.
2. Chemical and Biological Degradation
Epoxide degradation has been fairly well characterized. The
selected epoxides are reactive in all media. Available information on their
ionic reactions indicate that chemical and biological degradation follow
parallel pathways with respect to products. Their degradation in. water, soil,
commodities, and manufactured products proceed through ionic reactions. Their
degradation in the atmosphere has not been well characterized with respect to
products. Available information indicates that they are very reactive in
photochemical smog cycle reactions. No information was available on whether
ionic reactions (e.g., with water vapor or water within aerosols) significantly
contributed to their degradation in the atmosphere. The information on epoxide
degradation is discussed in four sections: a) degradation in water; b) degrada-
tion in soil; c) degradation in commodities and manufactured products; and d)
atmospheric degradation.
a) Degradation in Water
The epoxides degrade in water by hydrolysis and related
ionic reactions. The chemistry involves cleaving a carbon-oxygen bond of the
cyclic ether. This reaction has been studied in great detail by organic
chemists and extensive descriptions have been published which are primarily
concerned with the mechanism by which the epoxide ring is opened. Since a
complete description of all the work is beyond the scope of this present work,
the evaluation of the mechanistic papers, herein, is limited to their descrip-
tion of degradation kinetics and products.
73
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BrBnsted and coworkers (1929) first noted the pathways
for ethylene oxide hydrolysis in aqueous hydrochloric acid some 50 years ago.
They described hydrolysis as a combination of a noncatalytic reaction (herein
referred to as the spontaneous hydrolysis) and an acid-catalyzed hydrolysis.
Reaction with chloride paralleled hydrolysis; chloride and epoxide reacted
without catalysis and with acid catalysis.
Later work has extended and refined the description of
BrBnsted and coworkers. Long and Pritchard (1956) demonstrated that epoxide
hydrolysis was base catalyzed also. For any epoxide the degradation pathways
are as follows for the spontaneous (I), acid-catalyzed (II), and alkali catal-
yzed hydrolyses (III):
(I) RCH-^- k. RCHOH
l/° + H 0 -±-* I
CH^ 2U CH2OH
Rate = m
at 1 epox
(II) RCH k RCHOH
I > + H2° -+-* I
CH/ H CH2OH
HP
Rate = epox = k0 C Cu+
——c— 2 epox H
(III) RCHX k
I ^0 + H0 -^—*• k, C „ ,
CH2 2 QH- 3 epox CR+
_ j f*
Rate = epox = k_ C €_„-
——r— 3 epox OH
Table 14 summarizes hydrolysis data for the epoxides. The chemical hydrolysis
in the environment is expected to proceed primarily by the spontaneous hydrolysis
74
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Table 14. Hydrolysis Kinetics of Selected Epoxides
Ep oxide
Temperature
°C
Ethylene oxide 1.0
10.1
30.0
40.0
20
25
60
70
Propylene oxide 1.0
10.1
30
40
25
37
60
Specific Rate Constant
63 4
sec £/mol-sec Jl/mol-sec
0.579d
8.46d
16. 9d
43.6d
a a
0.36 5.33a
0.556°, 9° 1.0f, 1.1°
0.58e
19.2°
43.9°
2.79d
8.46d
74. 5d
199d
0.69e 0.87f
2.22b 124b 2.75b
21. le
Diepoxybutane
37
2.1-1.4b 1.94
* k. , k?, and k_, are described in the text.
(a) Bronsted _e_t _al., 1929.
(b) Ross, 1950
(c) Long and Pritchard, 1956
(d) Long et _al., 1957-
(e) Koskikallio and Whalley, 1959
(f) Pritchard and Siddigui , 1972
75
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pathways. At ambient temperature (25°C) the half-lives for propylene oxide
and ethylene oxide were 3.6 days and 13.8 days, respectively, for spontan-
eously hydrolysis.
Diepoxybutane exists as two isomers (d_, 1_ and meso) . The
separate epoxide groups of each hydrolyze at different rates. Ross (1950)
observed a large variation in hydrolysis rates for diepoxybutane; initial
hydrolysis rate (15% to 28% epoxide reacting) was 1.9 x 10~ sec while the rate
later (68% epoxide reacting) was 1.22 x 10 sec. This difference probably
arises as the result of the variation in hydrolysis rates of the two epoxide
functions. A group at the Southern Regional Research Laboratory, USDA
(Benerito £t al., 1964, 1969; Ziifle et al^., 1965) has investigated diepoxybutane
hydrolysis in acid and alkaline systems. Table 15 summarizes alkaline hydrol-
ysis rates for _d_,l_ and meso-diepoxybutane. These rates were measured with a
heterogenous system composed of aqueous sodium hydroxide and carbon tetra-
chloride, which measured the partition of the diepoxybutanes between the two
phases and the hydrolysis rate in the aqueous phase. Some difference in
specific rate constants might occur with a simple aqueous hydrolysis. At
-4
ambient temperature the specific rates were measured as 0.9-4.7 x 10
Jl/mole-sec and 3.0-5.7 x 10 £/mole-sec, respectively, which are values in
the same range as those measured for alkaline hydrolyses of propylene oxide
and ethylene oxide. Benerito et al. (1964) did not distinguish between
hydrolysis rates for the first or second epoxide ring. Acid-catalyzed
hydrolysis kinetic measurements showed no difference for specific rate con-
stants of meso or cl,l_-diepoxybutane, but the two epoxide rings hydrolyze with
different specific rates; Table 16 summarizes pseudo-first order rate constants
from pH 1.65 to 3.62.
76
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Table 15. Specific Rate Constants for Alkaline-Catalyzed
Hydrolysis of Diepoxybutane (Adapted from
Benerito et al., 1964)
Specific Rate Constant at 25°C
Isomeric Diepoxybutane NaOH, _
JL 10 k (£/mole-min)
Meso 0.504 2.82
1.008 2.81
1.453 2.81
2.769 2.03
4.335 1.60
9.113 0.53
_i,l. 2.868 1.81
4.599 3.40
77
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Table 16. Specific Rate Constants for Acid-Catalyzed Hydrolysis of Diepoxybutane
(Adapted from Ziifle et^ al_. , 1965, Benerito_e_t al. . 1969)
-1 *
Specific Rate Constant (Pseudo first-order in min )
00
Acid
PH
Temperature,
25
40
60
75
90
°C 10
0
3
19
50
320
HC1
3.25
'Me! 10^2 k2
.46
.49
.70
.08
.63
0.
0.
2.
21.
371.
11
35
97
49
16
0
0
0
0
1
3.62
/kj lO^k! 10ttk2
.24 —
.10 3.61 1.3
.15 18.7 6.4
.43 58.7 26.0
.16 —
HBFU
2.65 1.65
k2/ki 10l*k2 lO^kj k2/k! lO^ki 10l*k2 k2/ki
7.5 10.8 1.44 64.8 96.0 1.43
*
0.7 36.0 58.0 1.61 368 560 1.52
0.34 170 360 2.12 —
0.44
— — — «. — — — — — — __
,CH,
*CH CH,
CH,
H20
HOCH.
1
HOCH
k2
H20
HOCH2
HOCH-CH OH
CH2OH
-------
Epoxides can also react with nucleophiles (anions or
Lewis bases) by pathways which parallel hydrolysis (reaction with water or
hydroxide). The chemistry, although similar to hydrolysis, is more complex.
The epoxide ring can be cleaved by spontaneous reaction or by acid-catalyzed
reaction:
I I
k -COH
+ X- + H0 - > + OH-
I
~COH
Table 17 summarizes specific rate constants for reactions of the selected
epoxides with various anions. BrSnsted and coworkers (1929) noted a proportion-
ality between the rate constants for catalyzed and uncatalyzed reactions:
kl ~k3
Their data was limited to hydrolysis and anion reactions with chloride and
bromide at 20°.
Anions can react with the unsymmetrical epoxides to yield
two products. With terminal epoxides, the products result from anion attack
at the primary carbon atom or at the secondary carbon atom:
uncatalyzed - „ RCHQH
R TH + °r
| ^0 + *- + H90 H Catalyzed
CH
RCHX
79
-------
Table 17. Specific Rates of Reaction of Anions and Lewis Bases
with Selected Epoxides
Epoxide
Ethylene oxide
Propylene oxide
Butylene oxide
Diepoxybutate
Lewis base
or Temperature
Anion °C
Cl~ 20
25
27
Br~ 20
25
Pyridine 22
Cl~ 0
20.0
30.1
40.0
27
N03~ 20.0
OAc~ 37
Pyridine 22
Pyrazine 22
Cl~ 40
OAc~ 37
105k3
(£/mole - sec)
20 (water)2
517 (THF)d
0.259 (9:1 water-
dioxane) c
0.728 (9:1 water-
dioxane) c
2.14 (9:1 water-
dioxane) c
0.139 (water)b
16 (water)2
0.29 (water)2
1.45 (9:1 water-
dioxane)6
1.33 (water)b
()l2/mole2- sec)
2.17 (water)3
3.67 (water)3
8.23 (50% Aqueous
ethanol)^
8.67 (water)3
14.5 (water)3
10.64 (9:1 water-
dioxane) c
30.1 (9:1 water-
dioxane)0
81.5 (9:1 water-
dioxane) c
21.17 b
0.410 (water)6
56.6 (9:1 water-
dioxane)6
(a) Bronsted et_al_., 1929
(b) Ross, 1950
(c) Addy and Parker, 1963
(d) Addy. and Parker, .1965
(e) Petty and Nichols, 1954
(f) Lamaty et_ al.. , 1975
(g) Pritchard and Siddiqui, 1972
80
-------
The product distribution has primarily been studied in research attempts to
distinguish mechanisms of epoxide ring opening. The consensus agrees that
the spontaneous reaction is S 2 but disagreement exists whether acid catalyzed
epoxide ring opening is Al-like or A2-like (Long et al., 1957; Lamaty et al.,
1975; Pritchard and Long, 1956b; Pritchard and Siddiqui, 1973; Virtanen and
Kuokkanen, 1973). A discussion of the mechanism is beyond the scope of this
review. Salient information on product distribution for propylene oxide and
butylene oxide reaction with chloride is summarized in Table 18. Reaction at
neutral (or alkaline) pH yields mainly the secondary alcohol, but it is not
quantitative. The production of primary alcohol increases to approximately
35% at pH 3.6 to 3.8.
Some products of epoxide reaction with Lewis bases or with
anions are not stable. For example, tertiary amines, such as pyridine, are
capable of catalyzing epoxide hydrolysis to glycol:
J rate fast . RCHOH
R-CH ^ determznzng RCHOR -5-5 I
step | // Vv 2 CH-OH
+C,HCN CH--N +
j j f- \
Aqueous chemical degradation in the environment can be
estimated from the contributions of hydrolysis (Equation 1) and anion reac-
tions (Equation 2):
(1)
(2)
81
-------
Table 18. Product Distribution from Unsymmetrical Epoxide
Reaction with Chloride* (Adapted from Addy and
Parker, 1963, 1965)
Temperature
Epoxide °C pH
Propylene oxide 20.0 7.0
4.5
3.8
3.6
30.1 7.0
4.5
3.8
3.6
40.0 7.0
4.5
3.8
3.6
Butylene oxide 40.0 7.0
4.5
3.8
3.6
Percentage
RCHOHCH2X
91
75
68
66
88
73
66
65
86
72
64
64
84
77
69
68
Product
RCHXCH2OH
9
25
32
34
12
27
34
35
14
28
36
36
16
23
31
32
* In 9:1 (v/v) water dioxane.
82
-------
where C. . , k, . , and k, . refer to the concentration and specific rate constants
for each anion or Lewis base. The overall degradation rate is the sum of all
contributions; as given in Equation 3
dC
(3)
The initial ratio of an anion substitution product (both
possible isomers of an unsymmetrical epoxide) to glycol product can be calcu-
lated by Equation 4.
Ratio (substitution product: glycol) = k_ + k, C +
-31 41 H3U _ (4)
kl + k2CH30+ + k3COH-
The relative importance of chemical hydrolysis and reaction
with chloride was assessed for ethylene oxide and propylene oxide. Degradation
half-lives and product distributions (chlorohydrin to glycol ratios) were esti-
mated for fresh water and marine water (NaCl concentration of 3% or 0.57M).
Specific rates for 25°C were either taken directly or estimated from Tables 14
and 17. The following specific rate constants were utilized:
Ethylene Oxide Propylene Oxide
0.57 x 10~6 s"1 0.69 x 10~6 s'1
k3
9
1
0
, 3
x
x
.24
.67
io-3
io-4
x 10
x 10
-1 -1
0\f g
-1 -1
&M S
~5 Uf1 S'1
-2 -2 -2
&M s
52
0.
0.
20
x
87
52
x
10
x
X
10
-3
10
10
-2
£1
-4
-5
W
1 X s
m"1
£M-1
r2 s
-i
s
s
-2
Estimates were calculated for pH 5, 7, and 9, which is approximately the pH
range of natural waters. Half -lives for chemical degradation and the chloro-
hydrin/glycol ratios (for sea water reactions) are summarized below:
83
-------
Ethylene Oxide Propylene Oxide
pH 5 7 9 579
Half-life -(hrs)
Fresh water 292 338 338 159 279 279
Marine water 55.6 99 99 36.3 99 99
Ratio of chlorohydrin 4.2 2.4 2.4 3.4 4.3 4.3
glycol
While calculated degradation half -lives (and product ratios) were the same in
waters of pH 7 and pH 9, half-lives were shorter at pH 5. Acid catalysis
differed in effect on relative rates for chlorohydrin formation and glycol
formation. So, the chlorohydrin/ glycol ratio with acid catalysis was increased
with ethylene oxide but was decreased with propylene oxide. The metabolic
degradation reactions are not included in the above evaluation.
b) Degradation in Soil
There was no information available which directly evaluated
reactions of the selected epoxides in soil. Epoxide degradation has been
examined in cell-free extracts of a Flavobacterium sp. isolated from an alfalfa
field soil (Castro and Bartinicki, 1968; Bartinicki and Castro, 1969). These
studies indicated that enzymes of the Flavobacterium sp. catalyzed reaction
sequences analogous to behavior described for epoxide hydrolysis.
With the cell-free Flavobacterium sp. extract, the epoxide-
halohydrin reaction was reversible:
0 OH X
/ \ I I
CH - CH + X + H0 ^ CHCH + OH
where X is bromide or chloride. The epoxide reacts with water and yields glycol:
0 OH OH
\ II
These reactions required the enzyme (cell-free extract) . Relative reaction
rates for enzyme catalyzed reactions of the epoxide decreased in the order
Cl >Br >H20 or OH .
84
-------
c) Degradation in Commodities and Manufactured Products
Many food commodities and manufactured products are fumi-
gated with ethylene oxide or propylene oxide (see Section II.B.I). The fate
of these epoxides and their residues is especially important in those mater-
ials, commodities, and products coming into close contact with humans, such
as surgical equipment, Pharmaceuticals, and food service and packaging materials
(Wesley et al., 1965; Alguire, 1973; Holmgren et^ al., 1969; Gilmour, 1978).
Delineation of epoxide fate in these materials has estab-
lished that they will degrade to glycol and halohydrin or evaporate. The
degradation could result from chemical or enzymatic activity or from some com-
bination of the two. The halohydrin formation requires epoxide reaction with
inorganic halide. The halide could be naturally present, be added, or be
derived from organic halides. Bromide ion often comes from degraded methyl
bromide, which is also a fumigant (Rowlands, 1971; Lindgren et_ ail., 1968).
Scudamore and Heuser (1971) evaluated ethylene oxide fate
for a variety of treated commodities. They examined degradation and apparent
vaporization of ethylene oxide and its residues:
HO
CH
I SH
^ y-i TT x-v-fTTr "rtU
X=Br or Cl
i
Vaporization Vaporization
85
-------
The losses of the ethylene oxide, ethylene chlorohydrin, and ethylene bromo-
hydrin were measured over a one-year period. Apparent first order specific
rate constants, k, were calculated for epoxide dissipation. The rate constant
k combined losses from the degradation (chemical and metabolic pathways), k^,
and vaporization, k:
The glycols (ethylene and diethylene) were only determined once at either
six months or a year after treatment. Table 13 (Section II. D.I) summarizes
salient data for ethylene oxide residues on a variety of products. Effects
considered included ethylene oxide treatment (dose and temperature during
application), moisture content of the commodity, storage temperature, and
storage in closed containers or in open trays. Ethylene oxide residues rapidly
dissipated. While its estimated half -life was longest at 10°C in sealed
containers, it never exceeded two weeks. Increasing the ethylene oxide dose
had a varied effect on its loss rate. While small dose increases generally
slightly decreased the loss rate, very large increases caused larger decreases
in the rate of loss and sometimes caused non-linear correlations. The effect
of moisture content appeared varied and relatively small. Scudamore and
Heuser also monitored some commercially treated products (see Section II. E.I)
and found ethylene halohydrin residues but no ethylene oxide residues. They
concluded that ethylene oxide will normally dissipate from treated commodities
but under some circumstances, small quantities could persist for several
months .
Stijve and coworkers (1976) discussed the fate of ethylene
oxide applied as a fumigant to commodities. They suggested that ethylene oxide
86
-------
could be retained by physical adsorption but that it would persist not more than
a few weeks before volatilization or reaction.with natural constituents of the
commodity.
Ben-Yehoshua and coworkers (1971) examined ethylene oxide
residues during the treatment of dates. Table 19 describes the ethylene oxide
concentration for treatment of the fruit in a 20-liter, closed—glass container.
The small ethylene oxide loss in the empty container was ascribed to apparent
adsorption to container walls. The larger losses experienced with 2.1 kg of
dates in the container resulted from ethylene oxide uptake by the fruit.
Figure 8 describes the ethylene oxide loss in treated dates, which were left
in open containers. It apparently summed losses from degradation to the
chlorohydrin and glycol combined with volatilization.
The available information on fate of ethylene oxide applied
to manufactured goods was not as extensive as that on its fate in commodities.
All available information suggested that its behavior in manufactured products
corresponds to the pathways of degradation and volatilization described above.
Alguire (1973) described losses of ethylene oxide from
polystyrene creamer cups and cream cheese wrappers at ambient temperature and
open to the environment. The ethylene oxide did not degrade on the polystyrene
cups, and was lost solely through vaporization. More than 90% vaporized in
the first day and no residual ethylene oxide remained after five days (Figure 7,
Section II.D.I). Ethylene oxide loss from cream cheese wrappers primarily
consisted of its conversion to ethylene glycol; no ethylene chlorohydrin was
detected at any time. Ethylene oxide was completely gone by the tenth day.
Some studies have identified ethylene chlorohydrin residues
in manufactured goods sterilized with ethylene oxide. These studies did not
seek any information on volatilization losses. Brown (1970) identified
87
-------
Table 19. Changes in Concentration of Ethylene Oxide during
the Fumigation Period of Dates (From Ben-Yehoshua,
et al., 1971)
Ethylene
Oxide
Dose (ml)
0.4
0.6
0.4
0.2
Expected
Concentration
9.3
14.0
9.3
4.6
Kg Fruit
per
Container
0
2.1
2.1
2.1
Actual Concentration (%)
after
2 h 22 h
of Fumigation
8.2
7.1
5.1
2.4
7.8
2.1
1.4
0.8
88
-------
r*.
3
9000
8000
7000
H -5
1000
I
234
Days After Fumigation
Ethylene glycol
Ethylene chlorohydrin
• Ethylene oxide
Figure 8. Changes in levels of the toxic residues in dates
fumigated for 20 hrs with 16 ml ethylene oxide
per kg fruit, and kept under room conditions in
open jars (from Ben-Yehos hua et al., 1971).
89
-------
ethylene oxide and its derivatives on treated equipment made of rubber, dacron
and polyvinylchloride, but did not detect chlorohydrin on polyethylene equip-
ment. Holmgren et_ ai^. (1969) measured 0 to 1500 ppm chlorohydrin on 21
ethylene oxide treated drugs.
Although propylene oxide is also applied as a fumigant or
sterilant, its fate has not been described in the same detail as ethylene oxide.
Propylene chlorohydrins and propylene glycol have been identified as degrada-
tion products (Lindgren et^ al_., 1968; Rosenkranz &t_ al., 1975; Wesley et al.,
1965). However, no information was available concerning propylene oxide dissi-
pation.
d) Atmospheric Degradation
Epoxide degradation in the atmosphere can be suggested
from information derived from their oxidation by free-radical pathways. No
direct information on epoxide behavior in the environment was available.
Atmospheric reactivity of hydrocarbons has been character-
ized by their relative reaction rates with hydroxyl radicals in the gas phase
(Darnall et al., 1976). Ethers as a class (epoxides are a type of ether) have
been classified among the most reactive hydrocarbons. Specific information on
free-radical chemistry of the epoxides was found only for liquid phase studies.
Kulevsky and coworkers (1969) examined photooxidation of
ethers (including propylene oxide) in the liquid phase. They irradiated oxygen-
ated ethers (neat solution) with a Hanovia mercury vapor lamp and measured
the uptake of oxygen after one hour of irradiation. Oxygen uptake for propylene
oxide was slower than uptake by other ethers by about an order of magnitude:
Ether 02 uptake after 1 hr. (mol.)
Diethyl ether 2.0 x 10~^
Tetrahydrofuran 2.2 x 10~
Tetrahydropyrene 1.2 x 10_.,
Propylene oxide 0.1 x 10
90
-------
They investigated the products and assigned a mechanism based upon behavior
of two ethers; diethyl ether and tetrahydrofuran. The initial reaction of
the photochemical oxidation was assigned to hydroperoxide formation from an
oxygen-ether, charge-transfer complex
02H
_, , . .. hv -COR
Ether >• CL complex >•
The difference in oxygen uptake of the ethers was assigned to the basicities
of the ether and its control of the equilibrium on charge-transfer complex
formation. Since epoxides are less basic than analogous acyclic ethers,
corresponding photolytic degradation of propylene oxide is slower. The etheral
hydroperoxide subsequently cleaves and the ether further degrades by free-radical
reactions.
0-OH 0-
-COR ~^>- -COR + OH- >• Products
or heat
Some free-radical chain propagation was postulated in the formation of hydro-
peroxide:
0-0-
-COR + 02 >• -COR
0-0* H 0-OH
-COR + -COR >• -COR + -COR
Results of this study do not directly apply to atmospheric reactions of
epoxides, since the reactions utilized high energy ultraviolet light (253.7 nm)
and oxygen uptake was measured as a combination of ether-oxygen charge-transfer
complex formation, of photodegradation of the complex, and of the possible
radical chain propagation. However, the results do suggest that epoxides will
exhibit atmospheric reactivities similar to other ethers.
91
-------
Gritter and Sabatino (1964) examined ultraviolet photolysis
of propylene oxide (also at 253.7 nm) in the liquid phase but in the absence
of oxygen. The initial degradation was assigned to carbon-oxygen bond break-
ing:
0 0- O
/ \ .1 I
PIT PTJ PU -r--r; -_*_ PTJ PTJ PTJ -L PtJ PTI_PII •
v-»n_ v>n v^ii,-. ~ i^xin v^n v^iin ~ v^n^un v^n/*
•j £ -j £ j <-
The significant observation of this study concerned reaction of these initial
radicals with propylene oxide:
O
I
0 CH3CH2CH2 Q
or + CH3CH - CH2 >• or + CH-^C - CH2
0- 0*
CH CHCH CH LcH
The study concluded that radical reactions with propylene oxide abstract the
hydrogen at the alkyl substituted epoxide.
Sabatino and Gritter (1963) examined the reaction of propylene
oxide and butylene oxide with ^-butyl peroxide. They reacted each epoxide with
J^-butyl peroxide at 150°C in a deaerated glass bomb. The initial reaction in
this system was peroxide decomposition to _t-butoxy radicals:
BuOOBu heat> 2BuO-
The _t-butoxy radicals then abstracted hydrogen from the epoxides. Sabatino and
Gritter delineated the site of hydrogen abstraction and the subsequent reaarrange-
ment of the intermediate free-radicals by product analysis. Propylene oxide
y ieLded only the oxiranyl radical (a-hydrogen abstraction). Allyl alcohol was
92
-------
the only product:
0 0
\ / \
BuO- + CH3CH - CH2 »• CH3C - CH2 + BuOH
Butylene oxide yielded a mixture of 2-butanone, crotyl alcohol, and croton-
aldehyde. Sabatino and Gritter assigned the first product to a-hydrogen
abstraction and the latter two products to 3-hydrogen abstraction:
0
a-abstraction „ ' y,
Q / -BuOHtH3LH2C - LH2
\ -BuOH - CH.W-V
B-abstraction
T
Dobbs and coworkers (1976) examined free-radicals of epoxide
reactions with hydroxyl radicals by electron-spin resonance spectrometry (esr) .
The hydroxy radicals were generated from the titanium (III) -hydrogen peroxide
system in aqueous solution. Radicals were examined with nitromethane as a
radical trap and without any radical trap. The esr for hydroxide radical-
propylene oxide system in the absence of nitromethane indicated that only prod-
ucts of 3-hydrogen atom abstraction were generated. They concluded that the
propylene oxide yielded 1-hydroxyallyl radical, which was present as two
geometric isomers:
H H
-OH .
CH3-CH - CH2 > CH^ C + CH2" "C-OH
OH H
In the presence of nitromethane they observed evidence for the formation of
the propylene oxide a-radical as well as the g-radical:
93
-------
/°x CH2N°2 /°\
n g-abstraction . CH.-CH - CH0 >• CH.C - CH
U / ' J * £- J I £
/ \ -OH / I -
CH CH - CH -H"_/ /ON CH N(V
\e-abstraction_ -OCH - CH »•
H
I
^CH(OH) c
Dobbs and coworkers (1976) only examined the esr of radicals gen-
erated from butylene oxide in the absence of the radical trap. Butylene oxide
yielded radicals from apparent abstraction of 3-nydrogen and y~hydrogen:
0
Q Y-abstraction
/ \ OH-
0
g-abstraction , CH CHC/_\H
I
I Rearrangement
•
CHCH ILJ1 CH ^^ CH(OH)
They identified the 3-hydroxy-l-methylallyl radical, which is an apparent re-
arrangement product of the ^-radical and the unrearranged y~ra(iical.
Although no direct information was available on the atmos-
pheric reactions of ethylene oxide, a description of its probable degradation
pathway can be constructed from studies on its photochemistry and on its reac-
tion with oxide radicals. Dobbs and coworkers (1971) examined the latter.
They generated oxiranyl radical using hydroxyl radicals (generated from Ti(III)
ion-hydrogen peroxide) or _t-butoxyl radicals (from di-_t-butyl peroxide) in
94
-------
aqueous solution. The oxide radicals abstracted hydrogen and yielded oxiranyl
radical:
fH
• 2\
^O + «OH
This oxiranyl radical was also generated by photochemical reaction (Corner and
Noyes, 1950; Cvetanovic, 1955). Ethylene oxide yielded primarily CO, H~ and
CH, when it was irradiated in the gas phase with mercury added as a photo-
sensitizer. The primary irradiation process assigned was:
CH,,
\ >i
I 0 > -CH3 + HCO (or H« + C02>
CH,
The ethylene oxide was subsequently degraded by a chain mechanism:
CH3-
0 » CH + CH
CH/ I /°
On0 r»u^
£• \>n.n
•CH
I 0 >• CH3 + CO
In conclusion, the epoxides evidently are degraded in the
atmosphere by free-radical processes. Their reactivity with hydroxyl radical
has not been documented, but the evidence at hand indicates that the epoxides
have a similar reactivity to other ethers. They are expected to degrade rapidly
in the environment.
95
-------
3. Persistence, Bioaccumulation and Food-Chain Accumulation
Epoxides will not persist in the environment nor will they
accumulate in the food chain. The epoxides degrade through chemical and meta-
bolic pathways. Bioaccumulation potential has been correlated with water
solubility (Freed et^ a.1., 1977). The high water solubilities of the selected
epoxides characterize them as incapable of bioaccumulating.
E. Detection in Environmental and Biological Samples
1. Monitoring
Ambient monitoring has portrayed the selected epoxides as minor
contaminants of environmental or biological samples. The epoxides produced
and consumed in the greatest amounts are ethylene oxide and propylene oxide.
Although these two epoxides appear seldom identified in monitoring studies,
their principal degradation products (glycols and halohydrins) have been iden-
tified (see Section II.D).
No monitoring data was available for epoxides in biological
tissues except for some tissue distribution studies (see Section III C.I.a).
Since the epoxides are reactive alkylating agents, it is reasonable to expect
such results (Anderson, 1971).
Shackelford and Keith (1976) listed one monitoring observation
for propylene oxide in water. It was observed in the effluent from a chemical
plant in Bandenburg, Kentucky. No other epoxide observation was reported.
Shackelford and Keith also noted observations of ethylene and propylene halo-
hydrins, but they might be industrial wastes rather than residues from the
epoxides.
Several studies have examined the residues of ethylene oxide
and propylene oxide applied to commodities and manufactured goods as fumigants
and disinfectants. The information on residues in commercial products is dis-
96
-------
cussed here. Another portion of this report (Section II.D) describes inves-
tigations on the fate of these same epoxides. The present section differs in
that the information concerns residues in actual commercial products.
Scudamore and Heuser (1971) evaluated ethylene oxide and its
metabolites in commercially treated products, and also did some fate studies
(discussed in Section II.D). While they never detected ethylene oxide in
commercial products, they did find ethylene chlorohydrin residues ranging
from 10 to 70 ppm.
Lindgren et al. (1968) reviewed studies on residues from
ethylene oxide and propylene oxide treatment; most of which were fate studies
rather than ambient monitoring studies. Their review suggested that residual
epoxide could be present in commercial products.
Ethylene oxide is a common sterilant for surgical equipment
(see Section II.B.I). Its fate in plastic and rubber surgical equipment
parallels its behavior in commodities. Brown (1970) monitored residues on
various hospital equipment sterilized with ethylene oxide. Table 20 summarizes
results of the study. Brown did observe ethylene oxide in three samples, one
of which had received treatment about 80 days previously.
No information was available on selected epoxide monitoring in
the ambient atmosphere.
2. Analytics
Gas chromatography (GC) is currently the best available method
for epoxide analysis. The GC contains an analytical column to separate compo-
nents of the sample and a detector to quantify each component as it leaves the
97
-------
Table 20. Summary of Ethylene Oxide and Chlorohydrin Determinations
on a Variety of Surgical Equipment (From Brown, 1970)
vo
00
Sample
Heart catheters (Gensini)
Heart catheters (Gensini)
Heart catheters (Cournand)
Heart catheters (Gensini)
Tubing
Suction catheters
Tubing
Tubing
IV catheter unit
Sterile gloves
Transfusion unit
Transfusion unit
Foley catheter
Surgeons ' gloves
Surgeons ' gloves
Surgeons' gloves
Surgeons' gloves
Penrose tubing
Surgeons ' gloves
Surgeons' gloves
Surgeons1 gloves
Material
Woven Dacron
Woven Dacron
Woven Dacron
Woven Dacron
Polyethylene
Polyethylene
Polyethylene
Polyethylene
Teflon
Plastic
PVC
PVC
Rubber
Rubber
Rubber
Rubber
Rubber
Rubber
Rubber
Rubber
Rubber
Time from
Sterilization to
Extraction, Days
Unknown
Unknown
Unknown
1
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
ca 50
ca 80
Unknown
Unknown
Unknown
1
1
1
2
8
35
Extraction
Time
3 days
3 days
3 days
3 days
2 days
2.5 days
3 days
2 days
19 hr
2.5 days
1 hr
1 hr
20 hr
28 hr
28 hr
3 days
3 days
1 day
1 hr
1 hr
1 day
Ethylene
Oxide,
ppm
NDa
ND
ND
ND
ND
ND
ND
ND
ND
ND
-
1.8
ND
ND
ND
2.4
3.1
None
-
-
-
Ethylene
Chloro-
hydrin,
ppm
2.0
3.0
ND
27
ND
ND
ND
ND
ND
ND
1.5
ND
ND
ND
ND
1.9
1.9
7.1
13
11
3.3
None detected.
Same lot number.
-------
column. The analysis requires that the sample is injected into the column in
a suitable solvent or as a gas. The sample preparation is critical to analysis.
The state-of-the-art in air sampling utilizes solid sorbents.
Samples can subsequently desorb by solvent or by thermal means. Critical
factors in the method are the sorbent's capacity to retain the epoxide during
the collection and the complete desorption of epoxide.
Pellizzari and coworkers (1976) evaluated Tenax GC and other
sorbents for sampling atmospheric propylene oxide. Table 21 compares the
breakthrough volumes for several sorbents. The effect of humidity on the
breakthrough volume was tested for Tenax GC. Breakthrough volume increased
from 4.0 to 4.5 liters/g when humidity was increased from 41% to 92%.
Pellizzari and coworkers (1976) also examined the effect of storage time on
the recovery of diepoxybutane (300 ng) loaded onto Tenax GC cartridges. They
desorbed thermally and analyzed by GC. When analysis was immediate, recovery
was 100%. After the loaded cartridge was stored one week, the recovery
dropped to 76%. Combined transport (six days) and storage yielded recoveries
of 75% and 64% after one and two weeks, respectively.
The National Institute for Occupational Safety and Health
(NIOSH) has published standard procedures for ethylene oxide and propylene
oxide collection in air (NIOSH, 1976). Their procedure calls for the sampling
of 5 liters of air through glass tubes packed with activated coconut shell
charcoal. For ethylene oxide two tubes mounted in series are used; the front
and back-up tubes contain 400 mg and 200 mg, respectively, of charcoal. For
propylene oxide NIOSH recommends a commercially available 150 mg tube which
contains 100 mg charcoal in the front section and 50 mg in the back-up section.
99
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Table 21. Breakthrough Volume for Propylene Oxide
with Several Sorbents. (From Pellizzari
et al., 1976)
Sorbent Breakthrough Volume (£/g)
PEL Carbon
PCB Carbon
SAL9190
MI 80 8
Tenax GC (35/60)3
Porapak Q (100/120)
Chromosorb 101 (60/80)
Chromosorb 102 (60/80)
Chromosorb 104 (60/80)
36
40
40
24
4
4
4
8
>36
size.
100
-------
The front and back-up sections are individually measured for epoxide. If the
back-up portion contains more than 25% of the epoxide, the analysis is not
considered valid. The method suggests desorbing the epoxide with carbon di-
sulfide. The required solvent amounts are 2.0 and 0.5 ml for ethylene oxide
and propylene oxide, respectively. Aliquots of the desorbed solutions are
then analyzed by GC with flame ionization detection. NIOSH conducted tests
on the analytical parameters. Ethylene oxide was examined at concentrations
from 41 to 176 mg/cu m (0.23 - 0.98 ppm); precision (CVT) was 0.103 (or standard
deviation of 9.3 mg/cu m) and accuracy was 0.9% lower than the "true" value.
NIOSH recommended sample concentrations of 20 to 270 mg/cu m for this method.
Propylene oxide samples were evaluated at concentrations from 121 to 482 mg/cu m
(50 to 200 ppm); precision (CV ) was 0.085 (or standard deviation of 20 mg/cu m)
and accuracy was 5.6% below "true" value. NIOSH recommended sample concentrations
of 25 to 720 mg/cu m with this method.
Romano and Renner (1975) described the results of a six labora-
tory intercomparison of three methods for sampling ethylene oxide in surgical
equipment, the study was administered through the Z79 Subcommittee on Ethylene
Oxide Sterilization of the Association for Advancement of Medical Instrumenta-
tion. The three sampling methods were vacuum extraction with sample freeze-
out; headspace analysis; and acetone extraction. The vacuum-freezeout technique
required distillation of volatiles from the sample and freezing them in a cold
trap. The sample was then vaporized and an aliquot removed with a vacuum
syringe for GC analysis. Romano and Renner reported that the method requires
greater time and equipment than the other techniques and is subject to errors
from equipment leaks. Its advantages are that it is the most sensitive, and
since the sample injected into the GC is a vapor, column life is long. Acetone
extraction consists of partitioning the epoxide between the sample and the
acetone solvent. Its advantage is its simplicity. Its disadvantages include
101
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its inability to quantitatively extract epoxide, problems from impurities in
the solvent and extraction of other compounds from the plastics, the reduced
lifetime of columns because of these impurities, and low sensitivity. In headspace
analysis the sample is placed into a vial which is equipped with a septum for
gas withdrawl by syringe. The epoxide partitions between the sample and head-
space gases. The advantages of this technique include its ease of performance,
speed, sensitivity and relatively long column life. Its disadvantage is that
leaks in septa, vial caps, etc., can yield low measurements.
Romano and coworkers (1973) reported that the headspace tech-
nique has a lower limit of 0.1 ppm and that the technique can be automated.
Romano and Renner (1975) evaluated results for the three methods at six labor-
atories by analysis of variance. Among overall methods there were no signifi-
cant differences. However, slight differences between laboratories were
detected.
Ben-Yehoshua and coworkers (1971) extracted fruit pulp by
blending it with 50 ml of analytical grade acetone for 30 seconds, filtering
the homogenate to clarity. The samples were then stored at -10°C in bottles with
self-sealing stoppers. Measurements (by GC) of added ethylene oxide and its
residues were accurate to +5%.
Scudamore and Heuser (1971) extracted wheat flour and other
commodities including coconut, sultanas, lentils, and ground nuts with 5:1
(v/v) analytical grade acetone-water. The extraction used as little as 3 ml
solvent/g sample. A contact time of 24 hours was sufficient to yield ethylene
oxide recoveries (by GC) of 95% or better.
102
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Pfeilsticker and coworkers (1975) extracted 10 g grain (not
comminuted) with 5 ml of methanol using continuous agitation for 24 hours.
Recovery of ethylene oxide (25 ppm) was 73% and standard deviation (with GC
analysis) was 1.70 ppm.
Brown (1970) sampled and analyzed surgical materials (plastic
and rubber) for ethylene oxide residues by means of a three column chromatography
system. Brown could separate ethylene oxide and its degradation product, ethylene
chlorohydrin. Samples were extracted with _p_-xylene (3 days contact) or co-sweep
distillation. The three column system consisted of: I. Fluorosil, II. acid-celite,
and III. Fluorosil. The ja-xylene solution was passed through Column I; ethylene
chlorohydrin remained fixed in the column and ethylene oxide passed through. The
ethylene oxide solution was passed through the acid-celite column which converted
it to ethylene chlorohydrin. Column III retained the ethylene chlorohydrin which
was subsequently eluted with petroleum ether. The sample was concentrated with
a Kuderna-Danish apparatus, then analyzed by GC. Brown (1970) reported values
as low as 1.8 ppm, but accuracy, precision, and minimum detection limit were not
described.
Thus far, GC for the epoxides has only used flame-ionization
or thermal conductivity detection. Neither detection system is selective so the
epoxides must be separated from all interferences and the choice of analytical
Q
column depends on potential interferences. Columns for epoxide analysis have
included uncoated Poropak Q, QS and R, and Chromosorb 102 (Taylor, 1977a,b;
Ben-Yehoshua and Krinsky, 1968; Steinberg, 1977) and a variety of coated columns.
The most common liquid phases appear to be SE-30, Carbowax 20M, and polypropylene
glycol (Ben-Yehoshua and Krinsky, 1968; Casteignau and Halary, 1972; Steinberg,
1977; Hughes eit al. , 1959). The GC methods in current use appear capable of
epoxide analysis at the ppm level.
103
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Complex mixtures of hydrocarbons and other organic substrate
could interfere with epoxide elution through a single GC column. When Hughes
and coworkers (1959) examined products from gasoline combustion in automobile
engines, they utilized a three-stage GC system to overcome the lack of suffi-
cient separation capacity of any single column. The three stages were: (1)
glycerol on firebrick, (2) PEG400 on firebrick, and (3) DC550 silicone oil and
stearic acid on firebrick. Analysis for ethylene oxide and propylene oxide
required sample elution through all three to separate them from interferences;
for example, propionaldehyde interference with propylene oxide and acetalde-
hyde interference with ethylene oxide.
Other analytical methods include alternative forms of chromato-
graphy and various wet chemical techniques. The other chromatographic methods
such as thin-layer, gel permeation, and paper, are only qualitative. Epoxides
can be analyzed by ring opening with specific reagents and subsequent analysis
for the reagent or one of its products (Dobinson et al., 1969). Mishmash and
Meloan (1972) reported perhaps the most recent use of this approach. Butylene
oxide was hydrolyzed to its glycol, then the glycol was oxidized with periodic
acid. Residual oxidant was analyzed by adding Cdl_-starch and then measuring
the starch-I_ complex concentration at 590 nm. They claimed a detection limit
in the nmole range.
104
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III. HEALTH AND ENVIRONMENTAL EFFECTS
A. Humans
1. Occupational Exposure Studies and Poisoning Incidents
Ethylene oxide toxicity following acute vapor exposure has been
reviewed in a number of sources (Hollingsworth _e_t al., 1956; Curme and Johnston,
1952). Three cases of systemic poisoning were cited by von Oettingen (1939) in
which headache, vomiting, dyspnea, diarrhea, and lymphocytosis were observed.
Sexton and Henson (1949) describe symptoms in three chemical plant workers
drenched with 1% aqueous ethylene oxide solution. All three workers developed
marked nausea and profuse vomiting after a delay of several hours. Exposed
skin areas developed large vesiculated blisters without significant erythema.
The two workers who had complete blood counts taken following exposure showed
a transient elevation of the total leukocyte count (12,000-16,000/cubic millimeter)
In a case of illness observed in six workers exposed to carboxide (ethylene
oxide/carbon dioxide) gas while working in a ship compartment, Blackwood and
Erskine (1938) reported symptoms of headache, nausea, vomiting, and respira-
tory irritation. Similar effects were reported in 10 women workers overcome
by ethylene oxide in a California food plant (Anon., 1947). Thiess (1963)
reported that high concentrations of ethylene oxide for brief periods produced
bronchitis, pulmonary edema, and emphysema in industrial accidents.
The dermatological effects of ethylene oxide contact were reviewed
by Taylor (1977c). Pure ethylene oxide evaporates rapidly from the skin and
produces a freezing effect. Burns ranging from first degree through third degree
severity have been seen after ethylene oxide exposure. Phillips and Kaye (1949)
reported foot burns from rubber boots sterilized with ethylene oxide. Royce
and Moore (1955) recorded burns after use of rubber gloves exposed to ethylene
oxide. Biro and coworkers (1974) described a hospital incident in which 19 women
105
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suffered from burns received from surgical gowns and drapes sterilized with ethylene
oxide. Joyner (1964) reported burns experienced by workers in an ethylene oxide
plant in a two-year retrospective study of medical records.
In a study of chemical burns of the human cornea, Mclaughlin
(1946) reported an acute case induced by ethylene oxide and three cases resul-
ting from propylene oxide exposure. All of the workers showed rapid healing
in the 48 hours following a corneal denudement procedure. Thiess (1963)
described two cases of accidental eye injury with ethylene oxide. A nurse
was exposed to a direct blast of ethylene oxide from a sterilizer cartridge,
and developed an epithelial keratitis of the cornea within three hours.
Within 24 hours the eye was entirely normal. The second case involved a
patient who received a squirt of liquid ethylene oxide (concentration not
stated) in the eye. After extensive washing, irritation of the conjunctivae
followed and persisted for about one day.
Clinical reports of hemolysis following usage of ethylene
oxide sterilized plastic tubings have been made by Hirose and coworkers (1953)
and Clarke and coworkers (1966). Ethylene oxide, rather than a chemical
reaction product, was implicated since this type of effect can be prevented by
extensive aeration of ethylene oxide sterilized plastic devices.
Anaphylactic reactions have been observed in patients using
ethylene oxide sterilized plastic tubing for hemodialysis (Poothullil et al.,
1975) or cardiac catheterization (Pessayre and Trevoux, 1978). These symptoms
included uticaria, breathlessness, and hypotension. In a followup study on
a patient apparently sensitized to contact with hemodialysis tubing, Dolovich
and Bell (1978) illustrated that this patient showed a positive skin test
106
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response to ethylene oxide-serum albumin conjugate and produced in vitro
histamine release to this antigen. This response indicates that a specific
IgE antibody to ethylene oxide had been induced in this patient.
Propylene oxide shares many of the toxic properties of ethylene
oxide with injury to the eyes and skin having been reported (Mine and Rowe,
1973). Based on animal studies, Jacobsen and coworkers (1956) have estimated
that propylene oxide is approximately two to three times less toxic than
ethylene oxide.
2. Controlled Human Studies
In an investigation of the effects of ethylene oxide on human
volunteers, Greaves-Walker and Greeson (1932) observed that ethylene oxide at
approximately 2200 ppm was slightly irritating to four subjects. At a five-
fold higher concentration the compound had a definite irritating effect on
nasal mucosa within about 10 seconds. Liquid ethylene oxide applied to the
skin boiled off rapidly without producing irritation or erythema. Similarly,
ethylene oxide vapor in a test tube held inverted on the skin of volunteers
for 15 minutes produced no visible effects.
Sexton and Henson (1950) tested human subjects for dermal
reactions to aqueous ethylene oxide solutions. The most severe development
of characteristic bullae (blisters) was with a 50% ethylene oxide solution.
Three of eight volunteers showed signs of delayed skin sensitization.
3. Epidemiology
An investigation of health incidents in Veterans Administration
hospitals (162 hospitals and 7 outpatient clinics) using ethylene oxide steriliza-
tion equipment indicated that, in an 8-year period, several employees suffered
watering eyes, nausea, and skin irritation (NIOSH, 1977). A followup study is in
107
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progress to determine possible sequelae to these incidents. Jensen (1977,
unpublished) reported that three workers using ethylene oxide sterilizers were
hospitalized for neuropathy of the lower limbs. Followup indicated these
effects were reversible. Gross et al. (1979) also reported finding peripheral
neuropathy in three workers and acute encepholopathy in an additional operator
of a leaking ethylene oxide sterilizer. One worker removed from exposure showed
evidence of recovery.
Joyner (1964) conducted a retrospective morbidity study of
37 male employees at an ethylene oxide production plant. These 29-to-56-year
old male workers were exposed to 5 to 10 ppm for a period of 5 to 16 years.
Controls consisted of operators assigned to other production units, with no
indication of types of chemical exposure in these units. Three ethylene oxide
operators refused to participate in the study, but their previous medical records
were used in the overall evaluation. Workers exposed to ethylene oxide who had
left the plant were not included. No significant increase in health problems
relative to controls was found. This evaluation should identify major toxic
effects of ethylene oxide, but the size of the group studied, the exposure
duration, and the duration of observation preclude any evaluation of more subtle
toxic or carcinogenic responses.
Hematological and chromosomal studies were performed on all
factory workers (male) in a Swedish ethylene oxide production factory during
1960 and 1961 (Ehrenberg and Hallstrom, 1967). Workers were classified in one of
the following five groups: 66 persons not in contact with ethylene oxide, 86
persons in intermittent contact, 54 persons with some extended contact, 37
persons in permanent contact, and 8 persons exposed to high accidental concen-
trations of ethylene oxide. The comparison of exposed and control groups
indicated certain differences. Certain cellular abnormalities, such as three
108
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cases of anisocytosis and one case of leukemia, were observed in the exposed
group. Lower hemoglobin values were found in the exposed group. The high
ethylene oxide (accident) exposure group showed higher numbers of chromosomal
aberrations. Statistical evaluation of these findings was not available for
examination. A followup of this study is planned.
Recently, a study of 230 Swedish factory workers exposed to
20 + 10 ppm (TWA) ethylene oxide over a nine year period was reported
(Hogsted jeit aJL., 1979). Three cases of leukemia were found in the 236
workers compared with an expected 0.2 case incidence in this population. The
gas used for sterilization of hospital products was an equal mixture of
ethylene oxide and methyl formate. Leakage from gas-sterilized storage boxes
located in a working-hall area could have produced local levels of 150 ppm.
Monitoring of ethylene oxide levels was done only recently, and correlation
with levels several years previously may be very poor. Methyl formate may
have contributed to the effects seen, but it is less volatile than ethylene
oxide and less reactive chemically. Latency time for the three leukemia
cases was four years, six years, and eight years, respectively.
Yakubova and coworkers (1976) reported that pregnant workers in
ethylene oxide production facilities were prone to miscarriages and toxicosis
in the second half of pregnancy. Levels of exposure and quantitation of effects
were not available for analysis.
B. Reported Effects on Nonhuman Animals from Industrial Release,
Spills, and Accidents
No data are available concerning these types of effects from the
epoxides under consideration.
109
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C. Experimental Studies on Animals
1. Toxicity and Effects on Mammals
a) Metabolism
3
Inhalation studies with radioactively labelled [1,2 H]
ethylene oxide were carried out by Ehrenberg et al. (1974). Following expo-
sure of mice to 1.1 ppm labelled ethylene oxide for 75 minutes, high levels
of radioactivity were measured in the lungs, kidney, liver, testis, and
moderate levels in the brain and spleen. Approximately 80% of the radio-
activity absorbed was excreted in the urine within 48 hours indicating rapid
urinary elimination. The only urinary metabolite characterized was
1-hydroxyethyl guanine which comprised a minor amount (.007%) of the total
urinary radioactivity. Tissue proteins isolated from lung, liver, kidney,
spleen, and testis were alkylated in vivo by ethylene oxide, as was a nucleic
acid fraction of the kidneys. Thus, ethylene oxide distributes and reacts
extensively throughout the body. A biological half-life for ethylene oxide
following i.p. injection was determined as nine minutes.
Appelgren and coworkers (1977) carried out whole body
14
autoradiography on mice that were injected i.v. with radioactive [ C]
ethylene oxide (label position unspecified). Preliminary inhalation studies
with labelled ethylene oxide showed a similar tissue distribution of the com-
pound as that seen following i.v. injection, except for a high initial
labelling of respiratory mucosa (data not shown). Concentrations of radio-
activity two to three times those seen in the blood were observed after two
minutes in the liver, kidney, and pancreas. Tissue labelling after 20 minutes
to four hours showed high levels in the liver, kidney, lung, intestinal mucosa,
epididymis, cerebellum, and testes. Twenty-four hours after injection,
110
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radioactivity was still found in the liver, intestinal mucosa, epididymis,
cerebellum, bronchi, and bone marrow. Since these observations were made
on autoradiographs quantitative results were not reported.
b) Acute Toxicity
Ethylene Oxide - The acute toxicity of ethylene oxide is
summarized in Table 22. Exposure to concentrated ethylene oxide produces
systemic poisoning with symptoms of salivation, nausea, vomiting, diarrhea,
delayed paralysis of the hind quarters, convulsion, and death (Mine and Rowe,
1973). Sexton and Henson (1949) have noted symptoms of respiratory irritation,
nausea, vomiting, incoordination, and cardiac arrhythmia. Studies on rabbits
administered lethal doses of ethylene oxide intravenously indicated that death
followed convulsive seizures. Pathology revealed congestion of all organs
(Greaves-Walker and Greeson, 1932). Inhalation studies at a lethal concentra-
tion (vLl,100 ppm) in mice, rats, and guinea pigs showed pathological conges-
tion of the lungs and, in some cases, an acute pneumonic condition. Guinea
pigs exposed to lethal inhalation levels (3,000 to 50,000 ppm) showed acute con-
gestion of the lungs, hyperemia of the liver and kidneys, and gray discolora-
tion of the liver (Waite et al., 1930). Animals that showed delayed deaths
had developed lobar and lobular pneumonia. Hollingsworth and coworkers (1956)
detailed symptoms seen after lethal inhalation exposure to ethylene oxide
(250 to 4,000 ppm) in mice, rats, dogs, guinea pigs, and rabbits. Animals sur-
viving initial exposures showed subsequent bronchitis and loss of appetite.
Delayed effects of apathy, dyspnea, vomiting, hind leg paralysis, severe
respiratory distress, periodic convulsions, and death were observed. Path-
ology showed emphysema of the lungs, congestion and fatty degeneration of the
liver, cloudy swelling of kidney tubules, and congestion of the spleen and
111
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Table 22. Acute Toxicity of Ethylene Oxide
Route
Oral
Oral
Ihl.
Ihl.
Ihl.
Ihl.
I.v.
I. p.
I. p.
I.v.
S.c.
Oral
I.v.
I. p.
Ho
**LC-,
Species
rat
guinea pig
rat
guinea pig
mouse
dog
dog
mouse
rabbit
rabbit
rabbit
rabbit
rat
rat
Sex
M
M,F
M,F
F
M
M,F
M,F
M,F
M,F
M,F
M
M,F
Strain LDsn
Wistar 330 mg/kg
270 mg/kg
Sherman 4000 ppm/4 hrs.*
7000 ppm/2 1/2 hrs.**
835 ppm/4 hrs.*
960 ppm/4 hrs.*
125 mg/kg
178 mg/kg
251 mg/kg
178 mg/kg
200 mg/kg
631 mg/kg
355 mg/kg
178 mg/kg
Reference
Smyth et al. (1941)
Smyth et al. (1941)
Carpenter et^ al. (1949)
Waite et al. (1930)
Jacobsen et al. (1956)
Jacobsen et al. (1956)
Patty (1973)
Bruch (1973)
Woodward and Woodward (1971)
Woodward and Woodward (1971)
Woodward and Woodward (1971)
Woodward and Woodward (1971)
Bruch (1973)
Bruch (1973)
-------
brain. In general, rats, guinea pigs, rabbits, cats, and dogs showed no
deaths following up to 8 hours of exposure to 250-280 ppm ethylene oxide
(Hine and Rowe, 1973).
Ethylene oxide in 10% and 50% aqueous solutions produced
hyperemia and edema in shaved rabbit skin when applied through cotton pads for
one to sixty minutes (Hollingsworth et al., 1956). Bruch (1973) studied the
dermal irritation properties of 2% to 10% aqueous ethylene oxide solutions in
guinea pigs and rabbits. Subcutaneous injection in the guinea pig resulted in
ecchymoses and skin thickening, while intradermal injection and topical appli-
cation in the rabbit resulted in mild irritation.
McDonald and coworkers (1977) studied the ocular effects
of varied concentrations of ethylene oxide in saline applied repeatedly over a
six-hour period to the eyes of rabbits. They observed a dose-dependent increase
in congestion, swelling, discharge, iritis, and corneal cloudiness indicating
the irritating effect of ethylene oxide on mucous membranes and corneal epi-
thelium. The maximum nondamaging concentration for this time period was 0.1%
ethylene oxide. In another study of ocular irritation in rabbit eyes, Woodward
and Woodward (1971) found slight irritation following a single application of
10% aqueous ethylene oxide (duration of exposure unknown). A no-effect concen-
tration of 2.1% ethylene oxide was determined. The higher values determined
in this study are probably the results of a different mode of application and,
thus, different duration of exposure.
Zamlauski and Cohen (1976) have reported that infusion of
ethylene oxide in the rat at blood levels of 0.45 to 4.5 mg/ml produced a
significant decrease (^30%) in glomerular filtration rate, indicating ethylene
oxide effects on kidney function.
113
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Propylene Oxide - Acute toxicity resulting from exposure
to propylene oxide is shown in Table 23. Rowe and coworkers (1956) determined
that oral feeding (intubation) of 1000 mg/kg aqueous propylene oxide killed
all rats tested, while a single oral dose of 300 mg/kg allowed the survival of
all animals fed. Rats and guinea pigs exposed to high vapor concentrations of
propylene oxide (4,000 to 16,000 ppm) developed persistent lung irritation.
Secondary respiratory infections in these animals often led to death. Propy-
lene oxide was shown to have a relatively weak anesthetic effect. Rats were
able to tolerate exposure to concentrations of 4000 ppm for one half hour or
2000 ppm for two hours without organic damage. Application of undiluted or
strong aqueous (10% to 20%) propylene oxide solutions to the skin of rabbits for
six minutes or longer produced hyperemia and edema. Undiluted propylene oxide
produced severe burns when applied directly to the eyes of rabbits (Carpenter
and Smyth, 1946).
Inhalation studies with propylene oxide vapor conducted by
Weil and coworkers (1963) showed that exposure of rats to concentrated vapor
caused the death of all animals in five minutes. A concentration of 4000 ppm
propylene oxide killed four of six rats exposed for a period of four hours.
Jacobsen and coworkers (1956) conducted inhalation studies
comparing the toxicity of ethylene oxide and propylene oxide. Symptoms pro-
duced in rats, mice, and dogs following acute exposure to propylene oxide
vapor for four hours paralleled those seen following ethylene oxide adminis-
tration - lacrimation, salivation, nasal discharge, gasping, convulsions,
vomiting (in the dogs), and death. Pathologic examination of the dogs showed
damage to respiratory epithelium, vascular congestion, and edema of the lungs.
Based on the relative LC_n values calculated for these species, the authors
114
-------
Table 23. Acute Toxicity of Propylene Oxide
Route
Oral
Oral
Dermal
Ihl.
Ihl.
Ihl.
Ihl.
Ihl.
*LC50
*LCn
Species
rat
guinea pig
rabbit
rat
rat
mouse
guinea pig
dog
Sex Strain
M Wistar
M,F
Sherman
M
F
F
M Beagle
LD50
1140 mg/kg
690 mg/kg
VL730 mg/kg
*
<4000 ppm/4 hrs.
*
4000 ppm/4 hrs.
*
1740 ppm/4 hrs.
**
4000 ppm/4 hrs.
**
2000 ppm/4 hrs.
Reference
Smyth e± al. (1941)
Smyth et_ al. (1941)
Smyth and Carpenter (1948)
Smyth and Carpenter (1948)
Jacobsen et^ al. (1956)
Jacobsen et_ al. (1956)
Rowe e^ al. (1956)
Jacobsen et^ al. (1956)
-------
concluded that propylene oxide was one-half to one-third as toxic as ethylene
oxide.
Butylene Oxide - Acute toxicity data for butylene oxide
are summarized in Table 24. In a series of toxicological studies Smyth and
coworkers (1962) determined that the LDrn value for oral administration of
butylene oxide to rats was similar to the value determined for propylene oxide
in the same animals (M.100 mg/kg). Dermal application to shaved rabbit skin
also showed.the comparable toxicity of butylene oxide and propylene oxide.
Exposure of rats to 4000 ppm concentration of butylene oxide vapor for four
hours by inhalation resulted in the death of one of six test animals. Dermal
irritation to shaved rabbit skin using a one-day uncovered application was
found to be insignificant. However, it is not clear if concentrations other
than pure material were tested. Corneal injury produced in rabbit eyes was
slightly less than that produced by propylene oxide in the same animals,
indicating that concentrated butylene oxide solutions could induce corneal
burns with sufficient duration of exposure. Exposure to concentrated butylene
oxide vapor caused the death of all rats in 12 minutes; animals exposed six
minutes showed some deaths from secondary pneumonia (Hine and Rowe, 1973).
Diepoxybutane - The acute toxicity produced by diepoxy-
butane is summarized in Table 25. Determination of the oral LD level in
rats by Weil and coworkers (1963) indicates that diepoxybutane is more toxic
by this route than -ethylene oxide. The concentrated compound is well absorbed
when applied to the shaved skin of rabbits, showing an LD,-0 value of 39 mg/kg.
Exposure of rats to a concentrated diepoxybutane vapor resulted in the death
of all test animals in 15 minutes. Diepoxybutane vapor at 125 ppm killed one
out of five rats in a four-hour period. The compound is quite irritating to
rabbit skin and produces pronounced corneal injury to the eyes of rabbits
116
-------
LC
low
Table 24. Acute Toxicity of Butylene Oxide
Route
Species
Sex
Strain
LD
50
Reference
Oral
Ihl.
Dermal
rat
rat
rabbit
M Wistar
M,F Wistar
M New Zealand
LDlow 1170 mg/kg
4000 ppm/4 hrs.
1740 mg/kg
Smyth et al. (1962)
Smyth £t al. (1962)
Smyth et^ al. (1962)
-------
Table 25. Acute Toxicity of Diepoxybutane
Form
1.1
I.I
1.1
1
1.1
1,1
1.1
Route
oral
dermal
i.p.
i.p.
ihl.
oral
dermal
Species Sex
rat M,F
rabbit M
mouse
mouse
rat
rat
rabbit
Strain
Wistar
New Zealand
A/J
LD50
780 mg/kg
970 mg/kg
25 mg/kg
16 mg/kg
125 ppm/4 hrs.
97 mg/kg
39 mg/kg
Reference
Smyth et^ al. (1954)
Smyth et al. (1954)
Merck (1968)
Shimkin et^ al. (1966)
Weil £t al. (1963)
Weil et al. (1963)
Weil et^ al. (1963)
oo
LC
low
-------
(severe burns from 0.5 ml of a 1% solution). Intracutaneous injection of
diepoxybutane produced delayed hypersensitivity in all eighteen guinea pigs
tested.
c) Subacute Toxicity
Ethylene Oxide - Woodward and Woodward (1971) noted anemia
in dogs injected subcutaneously with ethylene oxide saline solutions of 6 to
36 mg/kg daily for 30 days. The severity of this effect was dose related.
Pathology showed hyperplastic bone marrow and ectopic hematopoiesis. Balazs
(1976) was unable to repeat these effects in beagle dogs with ethylene oxide-
glucose solutions injected intravenously over the same concentration range
in a 21-day study. Apparently, differences in metabolism caused by the two
routes of administration may be important.
Inhalation studies using several animal species exposed
repeatedly to ethylene oxide vapor were conducted by Hollingsworth and coworkers
(1956). All animals (rats, guinea pigs, mice, rabbits, and monkeys) died when
exposed to ethylene oxide for eight periods of seven hours each at 841 ppm.
Pathologic examination showed the same changes in the lungs, liver, and kidneys
as observed after acute lethal exposures to ethylene oxide. In a second
experiment rats and mice were exposed to 357 ppm ethylene oxide. Death in
most animals was observed after 33 to 38 exposures (7 hrs) and was attributed to
secondary respiratory infections. Impairment of sensory and motor function of
the nervous system at the sacral and lumbar region level was observed in the
latter period of this study, resulting in paralysis and atrophy of the
hind leg muscles. Surviving animals showed reversal of the paralytic symptoms
in the next 100 to 132 days. Guinea pigs survived 123 exposures to this concen-
tration of ethylene oxide (357 ppm). Growth depression was seen, as well as
119
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degeneration of the testicular tubules in males and slight fatty degeneration
of the adrenal cortex in females. No nervous system effects were seen in the
guinea pigs. Four monkeys exposed to this level of ethylene oxide for 38 to 94
times did show the paralysis and muscular atrophy of the hind limbs previously
described. Rats subjected to repeated (127 to 133) seven-hour exposures of
204 ppm ethylene oxide showed weight loss, some deaths, and effects on the
lungs, kidneys, and testes. These included congestion of the lungs, slight
cloudy swelling of some of the convoluted tubules, and slight degeneration of
a few testicular tubules.
In an inhalation study with ethylene oxide, Jacobsen and
coworkers (1956) exposed several species of animals for six hours per day,
five days a week. Dogs given six weeks of exposure to 292 ppm ethylene oxide
showed significant hematological changes. These included a decrease in red
blood cells, hemoglobin, and hematocrit. Two dogs showed symptoms of anemia
following six months' exposure to 100 ppm ethylene oxide.
An oral feeding study using 10% ethylene oxide in olive
oil was performed on rats (Hollingsworth et al., 1956). Rats fed 100 mg/kg
ethylene oxide in 15 doses over 21 days showed marked weight loss, gastric
irritation, and slight liver damage. Feeding of 30 mg/kg in 22 doses produced
no observable adverse effects.
Rats injected subcutaneously with ethylene oxide at a dose
level of 54 mg/kg daily for 30 days showed weight loss and injection site
hemorrhage and inflammation. Ethylene oxide administered at 18 mg/kg for the
same schedule produced no observed toxicity (Hollingsworth et al., 1956).
120
-------
Propylene Oxide - Rowe and coworkers (1956) performed
experiments on repeated inhalation exposure to propylene oxide vapor. Guinea
pigs, rabbits, and one monkey survived 79 to 154 seven-hour exposures to 457 ppm
propylene oxide. Rats showed increased mortality due to the development of
pneumonia. Pathology done on these animals revealed slight alveolar hemorr-
hage and edema, congestion of the lungs, and slight fatty degeneration of the
liver (guinea pigs). At the level of 195 ppm, propylene oxide administered
for 128 to 154 seven-hour exposures did not induce observable toxic effects.
Feeding studies with 10% propylene oxide in olive oil were
conducted by this same group. Following 18 doses of 300 mg/kg propylene
oxide, rats showed slight weight loss, gastric irritation, and slight liver
damage. Comparable studies at 200 mg/kg did not produce observable toxicity.
Subacute vapor inhalation studies with propylene oxide
were conducted by Midwest Research Institute (1976) for Tracer Jitco Inc.
Mice were exposed for six hours per day for 63 days to propylene oxide vapor.
At the highest level tested, 500 ppm, there were no deaths. A significant
(p<0.01) weight loss was observed in these animals, but no histopathologic
changes could be seen upon tissue examination. Rats treated under the same
schedule also showed total weight loss at the highest level of propylene oxide
vapor tested (500 ppm).
Butylene Oxide - Hine and Rowe (1973) reported that rats,
guinea pigs, and rabbits can tolerate repeated seven-hour exposures to butylene
oxide at a concentration of 400 ppm. These vapor studies indicate that butylene
oxide is less toxic than ethylene oxide after inhalation, and possibly less toxic
than propylene oxide.
121
-------
Diepoxybutane - Skin painting of mice with ^40 mg/kg
^,_l-diepoxybutane or meso-diepoxybutane three times per week produced notice-
able toxicity. Median survival times were 78 and 154 days, respectively
(Van Duuren e± al. , 1963, see Section III.G.l.g).
Hendry and coworkers (1951) injected rats intraperito-
neally twice weekly for 6 to 7 weeks with 20 mg/kg d^3.-diepoxybutane, and then
twice weekly for another six weeks with 10 mg/kg. All test animals were dead
within 18 months after the start of treatment. Loss of spermatogenesis was
observed in the testes of one mouse.
Diepoxybutane (mixed isomers) was painted on mouse skin
daily for nine applications in two weeks (Weil et a^., 1963). Concentrations
of 5% and 10% diepoxybutane in acetone significantly suppressed the number of
sebaceous glands. Intense hyperkeratosis and hyperplasia have been noted
after skin painting with diepoxybutane as well as the development of sarcomas
(see Section Ill.C.l.g).
Hine and Rowe (1973) reported that rats injected i.m. with
25 mg/kg of diepoxybutane showed leukopenia and lymphopenia following six treatments.
d) Chronic Toxicity
Diepoxybutane (mixed isomers) was administered intra-
gastrically in tricaprylin to rats once weekly for a year (Van Duuren et al.,
1966). At the level used, ^10 mg/kg, no decrease in median survival time was
observed in the rats tested. Since this study was undertaken to study the
carcinogenic activity of diepoxybutane, the determination of complete toxic
effects was not made.
122
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e) Mutagenicity
Ethylene Oxide - The mutagenic effects of ethylene oxide
in the Ames Salmonella assay are summarized in Table 26. Rannug and coworkers
(1976) investigated the mutagenicity of ethylene oxide dissolved in cold
ethanol using the Ames assay (Salmonella typhimurium). Ethylene oxide
(9.55 mM) produced reverse mutations in tester strain TA 1535, indicating
effects on base-pair substitution. Higher concentrations produced a dose-
dependent increase in the number of mutations. No S-9 microsomal activation
mix was required to produce this effect, indicating that ethylene oxide is
a direct-acting mutagen.
Taylor (1979) tested the mutagenic activity of ethylene
oxide gas in several Ames assay tester strains. At concentrations between
10 ppm and 100 ppm, ethylene oxide increased the number of mutants in tester
strains TA 1535 and TA 100 in a dose-dependent relationship, without S-9
activation. Addition of S-9 mix increased the number of mutations observed.
Ethylene oxide was thus effective in producing mutations both with and without
metabolic activation. Experiments (unpublished) by Kauhanen (1977) at the
Stanford Research Institute also indicate that ethylene oxide gives positive
results in the Ames mutagenesis assay in a dose-dependent manner in tester
strains TA 1535 and TA 100. Ethylene oxide concentrations from 0.01% to 0.1%
produced mutations without S-9 mix. Preliminary results reported by Embree
and Hine (1975) indicated that ethylene oxide produced base-pair substitution
type mutations in the Ames system in tester strain TA 1535 without activation.
Ethylene oxide has been shown to produce mutations in a
wide variety of other test systems. Sulovska and coworkers (1969) have shown
a ten-fold mutation increase in pollen grains of barley plants exposed for
24 hours to 100 ppm ethylene oxide. Moutschen and coworkers (1968) showed a
123
-------
Table 2 d Ames Mutagenicity Assay for Ethylene Oxide
Number of Revertants Per Plate
to
JS
Application Tester Type of
Compound Route Strain Activation
Ethylene oxide vapor TA 1535 Aroclor
1 ppm
5 ppm
10 ppm
50 ppm
100 ppm
vapor TA 100 Aroclor
1 ppm
5 ppm
10 ppm
50 ppm
100 ppm
growth
medium TA 1535
.96 mM
4.77 mM
9.55 mM
47.70 mM
95.50 mM
S-9 Source,
Concentration
Rat liver
20 vH
16
35
93
520
72000
Rat liver
20 p£
183
249
531
968
1928
—
Minus S-9 Pre- Controls
Activation incubation +S-9 -S-9 Reference
Taylor (1979)
21 7 12
28
80
371
592
Taylor (1979)
190 187 215
251
442
396
1640
yes — 6.8 Rannug et al.
(1976)
7.4
13.4
17.4
42.8
106.2
-------
dose-related increase in anaphase and metaphase chromosome aberrations in
barley seeds exposed for 10 hours to 2.5 mM to 25 mM ethylene oxide. Back mutations
(^1000) were induced at the adenine loucus of Neurospora crassa by a 15 minute
exposure of the mold to 0.025 M ethylene oxide (Kolmark and Westergaard, 1953).
Blixt and coworkers (1958) produced a high rate of mutation (26.7%) in field
peas exposed for five hours to ^30 mM ethylene oxide.
Studies with Drosophila melanogaster (Fahmy and Fahmy,
1970) have shown that ethylene oxide (114 mM) microinjected into adults pro-
duces point mutations, chromosome deletions, and chromosome breaks. Ethylene
oxide (0.8%) injected into Drosophila was also shown to increase the number
of lethal mutations observed (Bird, 1952).
Lambda bacteriophage has been induced in Escherichia coli
after a 30 minute exposure of E_. coli containing this prophage to 15 mM
ethylene oxide (Hussain and Ehrenberg, 1975). Loveless and Wheatley (1966)
were unable to show mutations induced in the r II region of T, bacteriophage
after treatment with 0.1 M ethylene oxide for 10 minutes.
The mutagenicity of ethylene oxide has been evaluated by
Embree and Hine (1975) in several mammalian assay systems. Rats exposed to
ethylene oxide inhalation for four hours at 1000 ppm showed mutagenic effects
in the dominant lethal assay. Ethylene oxide produced an increase in the
ratio of dead implants to total implants but did not increase preimplantation
losses. Rats exposed to 250 ppm ethylene oxide by inhalation seven hours per
day for three days showed mutagenic effects in bone marrow samples. Twenty-
four hours after exposure these bone marrow samples showed increased chromatid and
isochromatid gaps, increased breaks, rearrangements and exchanges, and increased
chromatid rings. Total aberrations were increased from 6% to 84% in metaphases
125
-------
examined. Examination of erythrocytes indicated that ethylene oxide induced
an increase in red blood cells with micronuclei following a single four-hour
exposure to concentrations of 50 to 1000 ppm. Experiments conducted by Appelgren and
coworkers (1978) using this micronucleus test indicated ethylene oxide-induced
mutations in both mice and rats. Ethylene oxide (aqueous) administered intra-
venously twice (30 hrs and 6 hrs before sacrifice) at a dose of 100 mg/kg
increased (p<0.05) the proportion of polychromatic erythrocytes showing micro-
nuclei in the test animals. This effect was shown to be dose dependent in
mice. Severe bone marrow depression in rats prevented testing of ethylene
oxide over an extended concentration range.
Strekalova (1971) reported that oral administration of
9 mg/kg of aqueous ethylene oxide produced increased chromosomal fragments and
bridges in rat femur bone marrow at 24 and 48 hours following exposure.
In chronic inhalation studies, Strekalova and coworkers (1975)
continuously exposed male rats to 2 ppm and 62 ppm ethylene oxide for 66 days.
Both levels produced an increase in fetal deaths in untreated pregnant rats.
Propylene Oxide - Loveless and Wheatley (1966), citing the
early studies of Rappaport, reported that propylene oxide, like ethylene oxide,
will induce sex-linked lethal mutations in Drosophilia. Brief immersion
of flies into a 10% propylene oxide solution increased the mutation rate ten-
fold. Back mutations at the adenine locus of Neurospora crassa were produced
after treatment with 0.5 M propylene oxide (aqueous) for 15 minutes (Kolmark
and Giles, 1955).
Wade and coworkers (1978) investigated the mutagenicity of
propylene oxide in the Ames assay (see Table 27). The compound, dissolved in
dimethyl sulfoxide, was incorporated into the top agar layer. At concentrations
126
-------
Table 27. Ames Mutagenicity Assay for Epoxides and Reaction Products
Number of Revertants Per Plate, Ames Mutagenicity Assay
to
Compound
Chloropropanol
(mixed isomer)
1.1 mg
2.2 mg
5.5 mg
11.0 mg
16.5 mg
22 mg
Butylene oxide
14 mg
16 mg
4.2 mg
• 8 mg
Diepoxybutane
25 yg
50 yg
22 yg
66 yg
110 yg
Propylene oxide
1.5 mg
1 mg
Application Tester Type of S-9 Source,
Route Strain Activation Concentration
Agar
Overlay TA 1530
Agar
Overlay TA 100
Agar TA 1530
Overlay
Agar TA 1535
Overlay
Agar TA 1535 — Rat liver,
Overlay 400 yg/plate
164
Agar TA 1535
Overlay
Agar TA 1535
Overlay
Paper TA 1535 — Rat liver,
Disc 400 yg/plate
66
134
218
Agar TA 100
Overlay
Agar TA 1535
Overlay
Minus S-9 Pre-
Activation incubation
32
37
89
182
224
305
430
506
333
428
M.20
91
140
488
914
346
42
Controls
+S-9 -S-9 Reference
Rosenkranz
22 et al. (1975)
Speck and
72 Rosenkranz (197i
10 Chen et al.
(1975)
20 McCann et al.
(1975)
Rosenkranz and
Poirer (1979)
12 9
^40 Simmon (1979a)
20 McCann et al.
(1975)
18 21 Rosenkranz and
Poirer (1979)
180 Wade et al.
(1978)
20 Wade et al.
(1978)
-------
of 1 to 1.5 mg propylene oxide per plate, both tester strains TA 100 and TA 1535
showed increased revertants over controls without activation. No dose
response data were presented, but values reported were taken from the mid-
point of the linear portion of a dose-response curve generated with the
compound. Mutagenicity in TA 100 was 166 revertants/1500 yg compound. The
reaction product of propylene oxide, chloropropanol, has been shown to increase
mutations in tester strain TA 1530 by Rosenkranz and coworkers (1975) (see
Table 27).
Butylene Oxide - The mutagenic effects of butylene oxide
in the Ames assay are summarized in Table 27.
Investigation of the mutagenicity of butylene oxide in the
Ames assay was performed by Speck and Rosenkranz (1976). Butylene oxide (14 yg)
incorporated into the agar overlay without S-9 activation produced approximately
350 more revertants than the control when tester strain TA 100 was used. Other
work from this laboratory inciated that comparable levels of mutations are
produced by butylene oxide applied to tester strains TA 1530 (Chen et al.,
1975) and the nitrofurazone-resistant tester strain TA 100-FRI (Rosenkranz and
Speck, 1975). In a recent report Rosenkranz and Poirer (1979) showed a
dose-dependent increase in mutations produced by butylene oxide applied to the
agar overlay with tester strain TA 1535. Addition of S-9 activation mix
prepared from the livers of uninduced rats produced a decrease in mutants seen
with all concentrations of butylene oxide. Metabolic conversion by microsomal
enzymes therefore seems to inactivate the butylene oxide in this test system.
Simmon (1979a) was unable to show mutagenic activity after
application of butylene oxide to any of the Salmonella test strains used
128
-------
(TA 1535, 1538, 1537, 1536, 98, and 100) either with or without activation.
The compound was tested at concentrations up to 500 yg/plate. However, in
another study Simmon (1979b) did show increased mutation in Saccharomyces
cerevisiae D3 after treatment with butylene oxide. Applications of 0.6%
butylene oxide to Saccharomyces produced 1500 recombinants at the adenine 2
locus; inclusion of S-9 activation mix prepared from livers of Aroclor-pretreated
rats reduced the number of mutations observed.
Butylene oxide has been tested for its ability to modify
DNA in _E. coli DNA polymerase deficient strains (Rosenkranz and Poirer, 1979).
Comparison of the zones of inhibition produced by application of butylene oxide
(50 yg/ml) to JE. coli strains with or without normal production of this DNA
repair enzyme indicates that the compound does damage DNA. This assay correl-
ates well with the mutagenic activity determined by the Ames Salmonella assay.
Diepoxybutane - Diepoxybutane was found to produce lethal
mutations in barley seeds (Ehrenberg and Gustaffson, 1957) after application
of a 0.003% aqueous solution for two hours. Comparison of effects on germina-
tion relative to those produced by ethylene oxide indicates that diepoxybutane
is approximately 200 times more effective in mutation induction in this assay.
Bianchi and Contin (1962) studied the mutagenic effects of diepoxybutane on
pollen from maize following treatment with 0.15 to 0.25 percent solutions of the
compound. Endosperm mutation frequencies indicated that the racemic diepoxy-
butane was the most effective mutagen, followed in relative order by the L-
isomer, the d-isomer, and the meso-isomer.
Administration of diepoxybutane to Drosophilia by feeding
or injection into the hemocoel produced varied mutations (Bird and Fahmy, 1953).
These included lethal mutations, semi-lethal mutations, visible mutations, trans-
locations, and "minute" type chromosome breaks.
129
-------
Hendry and coworkers (1951) reported that diepoxybutane-
treated (0.25 percent aqueous solution) spores of Penicillium mold showed an
increase in the percentage of mutant colonies. Diepoxybutane-induced muta-
tions at the adenine locus of Neurospora were seen after treatment of the
conidia with 0.2 M compound for 15 minutes (Kolmark and Westergaard, 1953).
Heinemann and Howard (1964) activated lambda bacteriophage
in Escherichia coli following one hour treatment of cultures with diepoxy-
butane at a concentration of 7.5 ug/ml. Mutations in Saccharomyces cerevisiae
have been reported following five hours of treatment with 0.005 M diepoxybutane
solution (Zimmermann, 1971).
Diepoxybutane has been shown to increase the number of
histidine revertants in the Ames assay (McCann et al., 1975) (see Table 27).
Fifty micrograms of compound per plate produced mutations in tester
strain TA 1535 without S-9 activation. Rosenkranz and Poirer (1979) found
a dose-dependent increase in mutations produced in tester strains TA 1535
and 1538; addition of S-9 activation mix lowered the number of mutants seen.
Simmon (1979) reported that addition of 25 yg of diepoxybutane per plate
increased histidine revertants in tester strain TA 1535; this level of compound
produced a very weak level of activity in tester strain TA 100.
Simmon and coworkers (1979) investigated the activity of
diepoxybutane in the host mediated assay. Diepoxybutane injected intramuscu-
larly into mice at a concentration of 444 mg/kg produced an increase in the mutation
frequency of Salmonella strain TA 1530 that was injected intraperitoneally
into the same animals. At a lower treatment level (56 mg/kg) no increase in
mutations was seen in tester strain TA 1535. Saccharomyces cerevisiae D3
injected into the peritonum of treated mice did show an increase in mutation
frequency at this level of exposure.
130
-------
Rosenkranz and Poirer (1979) reported increased inhibition
of DNA polymerase deficient I£. coli strains after application of diepoxybutane,
indicating modification of the DNA of these strains. Simmon (1979b) observed
increased numbers of recombinants in ^. cerevesiae D3, with or without S-9
activation, after treatment with a 0.04% solution of diepoxybutane.
Mammalian systems also show increased genetic damage following
exposure to diepoxybutane. Moutschen (1961) evaluated the effects of diepoxybutane
on murine sperm chromosomes. Mice injected intraperitoneally with 5 mg/kg
diepoxybutane showed chromosome effects in 24 hours. This included increased
chromosome breaks and anaphase bridges. At 20 days following administration of
diepoxybutane these changes were no longer significant relative to controls,
indicating an efficient repair of this type of chromosome lesion.
The dominant lethal assay in the mouse has been used to
evaluate the mutagenicity of diepoxybutane (Epstein et_ a.1., 1972). Injection
of male mice with 17 mg/kg (intraperitoneal) diepoxybutane produced an increase
in the percentage of impregnated females with early deaths; however, early
fetal deaths and preimplantation losses were within the variance range of
controls.
f) Teratogenicity and Reproductive Effects
Ethylene Oxide - In a study of teratogenic effects induced
by inhalation of ethylene oxide, Snellings and coworkers (1979) exposed rats
from day 6 to day 15 of gestation to 10 to 100 ppm ethylene oxide (6 hrs/day).
Evaluation of day 20 fetuses showed no developmental effects other than a
reduced body weight in the 100 ppm group. The reproductive effects were studied
following exposure of male and female weanling rats to 10 to 100 ppm ethylene
131
-------
oxide six hours per day, five days per week, for 12 weeks. Animals were
mated and ethylene oxide exposure was continued through day 19 of gestation.
Female rats exposed to 100 ppm ethylene oxide had a longer gestation period,
reduced fertility index, and significantly fewer pups per litter. No differ-
ences were found for gestation survival or postpartum survival. The effects
seen are probably the result of the nonspecific toxicity produced by this
level of ethylene oxide inhalation.
Kimmel and Laborde (1979) studied the effects of ethylene
oxide when injected intravenously into the tail veins of female mice. Doses
of 75 mg/kg and 150 mg/kg ethylene oxide in saline were injected daily for
three days at four periods during gestation: days 4-6, 6-8, 8-10, and 10-12.
Mice receiving 150 mg/kg showed toxic symptoms (unspecified) during treatment
but recovered and showed no ultimate change in maternal weight gain during
pregnancy. Litters were examined at day 17 of gestation. Animals treated
during the first and last gestation periods with ethylene oxide showed an
increase in the percentage of resorptions. Significant increases in malforma-
tions were seen in animals treated on days 6-10 of gestation at the high
(150 mg/kg) ethylene oxide level. Malformations noted included fused vertebral
arches, fused and branched ribs, scrambled sternabrae, and some exencephaly.
Embryotoxicity and teratogenicity are thus indicated by this route of exposure
to ethylene oxide.
Chloroethanol, a potential reaction product of ethylene
oxide, has produced teratogenic effects when injected into the air sack of
chick embryos (Versett, 1974) at levels of 5 to 50 mg per egg.
Hollingsworth and coworkers (1956) observed effects of
ethylene oxide on the testes of guinea pigs. Animals inhaling 357 ppm
132
-------
ethylene oxide during 123 seven-hour exposures showed tubular degeneration and
fibrosis of the testes. Rats exposed to 204 ppm ethylene oxide for 122 to 157
seven-hour periods showed decreased size of testes and some tubular degener-
ation. Whole body autoradiographs of mice injected with radioactive ethylene
oxide indicate that this compound accumulates in the epididymis and testes
(Appelgren jit al., 1977).
Diepoxybutane - Epstein and coworkers (1972) investigated
the effects of diepoxybutane in the dominant lethal assay. Male mice were
injected intraperitoneally with 17 mg/kg of diepoxybutane and then mated for
several weeks with virgin females. Pregnant females showed an increased rate
of early fetal deaths in this study. Effects on implantation were not seen.
Prolonged exposure of rats to high levels of diepoxybutane (10 to 20 mg/kg,
26 doses) produced loss of spermatogenesis in one test animal (Hendry et al.,
1951).
g) Carcinogenicity
Ethylene Oxide - The carcinogenic effects of ethylene
oxide are summarized in Table 28.
In a study of the carcinogenicity of ethylene oxide
dissolved in arachis oil, Walpole (1958) injected rats subcutaneously with a
maximum total dose of 1 gm/kg of ethylene oxide over 94 days (dosing schedule not
specified) and found no tumors induced. Rats were observed for their lifetime
following treatment. Since the amount administered and the frequency of in-
jection was not specified, it is difficult to evaluate these negative results.
Tumors were induced by the same technique with propylene oxide, but duration
of treatment was much longer.
Lifetime skin painting studies with 10% ethylene oxide
in acetone (3 times weekly) were performed on female mice by Van Duuren et al.
133
-------
Table 28. Carcinogenesis Bioassay of Ethylene Oxide
Route
S.c.
Dermal
Species,
Sex
Rat,
M,F
Mouse,
F
Dosage
1000 mg
total (oil)
10 rag /animal
Duration Duration
of of
Treatment Observation
94 Lifetime
3 time/wk Lifetime
life (493 days)
Premature
Deaths Controls Tumors Reference
No Pos. ? Sarcoma - 0 Walpole (1958)
Neg. ?
No Pos. yes Papilloma-0 Van Duuren et al.
Neg. yes Carcinoma-0 . (1965)
-------
(1965). Application of 0.1 ml of ethylene oxide solution to the clipped dorsal
skin produced no tumors. Median survival time for the mice was 493 days. The
investigators indicated that rapid evaporation of the compound from the skin
could have been responsible for the negative results observed.
Reyniers and coworkers (1964) conducted a retrospective
study on female germ-free mice that developed tumors after being exposed to
ethylene oxide-treated ground-corncob bedding for 150 days. Ovarian, lymphoid,
and pulmonary tumors developed in these animals after being moved to untreated
bedding. Colony mates maintained on nontreated bedding did not develop
tumors. All the males exposed to ethylene oxide-treated bedding died, with
necropsy showing massive hemorrhage. The causative agent was not identified
since chemical analysis of the bedding was not done. High toxicity is indi-
cated by these findings in the male mice. Because germ-free mice are T-
lymphocyte deficient, they may be more susceptible to tumor development than
normal animals.
A long-term carcinogenicity bioassay to study the effects
of inhalation exposure to ethylene oxide is currently underway at Carnegie-
Mellon Institute. Carcinogenicity studies on the effects of skin painting
with ethylene oxide are scheduled to begin for the National Cancer Institute.
Propylene Oxide - Carcinogenic effects of propylene oxide
are summarized in Table 29.
Injection of propylene oxide subcutaneously into rats was
shown to produce local (injection site) sarcomas (Walpole, 1958). Propylene oxide
dissolved in arachis oil or water was injected over 325 days for a total maximum
dosage of 1.5 gm/kg (schedule not specified). Eight of the animals administered
propylene oxide in oil developed tumors in 507 to 739 days. Three of the animals
135
-------
Table 29. Carcinogenesis Bioassay of Propylene Oxide
Duration
Route
S.c.
S.c.
Species,
Sex
Rat,
M,F
Rat,
M,F
Dosage
1500 mg
total (H20)
1500 mg
total (oil)
of
Treatment
325
325
days
days
Duration
of
Observation
739
737
days
days
Premature
Deaths
No
No
Controls Tumors
Pos.
Neg.
Pos.
Neg.
? Sarcoma-3
?
? Sarcoma-8
?
Reference
Walpole
Walpole
(1958)
(1958)
U)
-------
receiving the aqueous solution of the compound developed sarcomas, one in 158 days
and the other two after 737 days. These tumors (except one at 158 days) were quite
late in developing. Since the schedule of administration is not known and
control data were not reported, evaluation of these data is not possible.
Butylene Oxide - The careinogenieity of butylene oxide was
studied by Van Duuren and coworkers (1967) following extended skin painting of
mice (see Table 30). Approximately 100 mg of butylene oxide (10% in acetone)
was applied three times weekly to clipped mouse skin for 540 days. This
schedule of application did not produce toxicity in the test animals, and skin
tumors were not seen during the time period indicated. The late development
of injection site tumors observed by Walpole (1958) after subcutaneous injection
of propylene oxide suggests that a similar extended latency period for tumors may
follow butylene oxide treatment. These may be missed if the experimental protocol
is not optimized for long term observation of test animals.
Diepoxybutane - Carcinogenic effects of diepoxybutane are
summarized in Table 31.
McCammon and coworkers (1957) reported that skin painting
of mice with _d,_l-diepoxybutane produced tumors. The compound was applied
three times weekly by intrascapular painting. Total dose and duration of
treatment were not reported, nor was the incidence of tumors. Subcutaneous
injection of diepoxybutane into rats was also reported to increase tumor
incidence.
Lifetime mouse skin painting studies with d_,l;-diepoxybutane
were performed by Weil and coworkers (1963). Mice received three applications
per week of 10% diepoxybutane in acetone. Two papillomas and one carcinoma were
produced by this method, with a median latent period of 18.5 months. This regime
137
-------
Table 30. Carcinogenesis Bioassay of Butylene Oxide
Duration Duration
Species, of of Premature
Route Sex Dosage Treatment Observation Deaths Controls Tumors Reference
Dermal Mouse, 10 mg/animal 3 times/wk Lifetime No Pos. yes Papilloma-0 Van Duuren et al.
F life (540 days) Neg. yes Carcinoma-0 (1967)
OJ
00
-------
Table 31. Carcinogenesis Bioassay of Dlepoxybutane
u>
VO
Route
Dermal
I. p.
I. p.
Dermal
Dermal
Dermal
Dermal
Dermal
Dermal
S.c.
S.c.
S.c.
Dermal
Dermal
Species,
Sex
mouse,
M,F
rat,
M,F
mouse,
M,F
mouse,
M
mouse,
M
mouse,
F
mouse,
F
mouse,
F
mouse,
F
mouse,
F
mouse,
F
rat,
F
mouse,
F
mouse,
F
Dosage
10% in
acetone
20 mg/kg,
10 mg/kg
16 mg/kg
(L form)
10 mg/animal
(meso form)
10 mg/animal
10 mg/animal
3 mg/animal
10 mg/animal
(meso form)
3 mg/animal
(meso form)
1.1 mg/
animal
0.1 mg/
animal
1 mg/animal
1 mg/animal
1 mg/animal
(meso form)
Duration Duration
of of
Treatment Observation
3 times/wk,
20 months
13 doses high
12 doses low
3 times/wk
4 weeks
3 times/wk
life
3 times/wk
life
3 times/wk
life
3 times/wk
life
3 times/wk
life
3 times/wk
life
1 time/wk
life
1 time/wk
life
1 time/wk
life
Lifetime
18 months
39 weeks
Lifetime
(154 days)
Lifetime
(78 days)
Lifetime
(165 days)
Lifetime
(475 days)
Lifetime
(357 days)
Lifetime
(491 days)
Lifetime
(328 days)
Lifetime
(456 days)
Lifetime
(470 days)
single + Lifetime
phorbol ester
3 times/wk, life
single +
phorbol ester
Lifetime
Premature
Deaths
Yes 22/25
Yes 14/14
Yes 3/30
Yes 30/30
Yes 30/30
Yes 30/30
No
No
No
No
No
No
No
ft
No
Controls
Neg.
Pos.
Neg.
Pos.
yes
\
Neg. 32%
tumors
Pos. yes
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
Neg.
Pos.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
Tumors
Papilloma-2
Carcinoma-1
Sarcoma-1
lung tumors
78%
Papilloma-6
Carcinoma-4
Papilloma-2
Carcinoma-1
Papilloma-1
Carcinoma-0
Papilloma-10
Carcinoma-6
Papilloma-5
Carcinoma-4
Papilloma-1
Carcinoma-0
Papilloma-0
Sarcoma-5
Papilloma-0
Sarcoma-5
Carcinoma-1
Sarcoma-9
Papilloma-7
Carcinoma-2
Papilloma-4
Carcinoma-0
Reference
Weil et al.
(1963)
Hendry et al. (1951)
Shimkin et
Van Duuren
(1963)
Van Duuren
(1963)
Van Duuren
(1965)
Van Duuren
(1965)
Van Duuren
(1965)
Van Duuren
(1965)
Van Duuren
(1966)
Van Duuren
(1966)
Van Duuren
(1966)
Van Duuren
Van Duuren
al. (1966)
et al.
et al.
et al.
et al.
et al.
et al.
et_ al.
.ejt. al.
et al.
(1969)
(1969)
3 times/wk, life
-------
was quite toxic since only three mice were still alive at 18 months. Negative
control data for these animals were not reported.
Van Duuren and coworkers (1963) tested both the mixed d.,.1-
isomer of diepoxybutane and the meso isomer of the compound for carcinogenicity
by skin painting. Acetone solutions of both the mixed isomer and the meso form
were applied (10 mg per animal) to the clipped dorsal skin of male mice, three times
weekly for life. Following application of d^-diepoxy butane, two mice developed
skin tumors; one of these was a squamous cell carcinoma. Squamous cell carcinomas
were also seen in 4/6 mice which developed tumors after application of meso-
diepoxybutane. The dose schedule used in these studies produced toxicity,
since the median survival times of treated animals were markedly shorter than
those seen for controls (78 days lifespan for the mixed isomer and 154 clays for
the meso isomer group). Late developing tumors would be missed under these
conditions.
These studies were therefore repeated using lower levels
of the d_,l_ and meso isomers of diepoxybutane applied by skin painting to
female mice by the same schedule (Van Duuren et al., 1965). At a dose of
10 mg per animal, one of thirty mice treated with d^l-diepoxybutane developed a
skin papilloma. Median survival time (165 days) was shortened at this level
of treatment, again indicating a significant toxic effect that confuses inter-
pretation of the dose-response relationship. Mice given d_,I/-diepoxybutane at
the level of 3 mg per animal developed tumors (16/30); of•these 16, six showed
squamous cell carcinomas. Median survival time was 475 days for this group.
Meso-diepoxybutane tested at the same dosages produced five incidences of skin
papilloma and four of squamous cell carcinoma at the 10 mg per animal level. The
low-dose application of meso-diepoxybutane produced one incidence of a skin
papilloma. Median survival times for the groups treated with the meso compound
140
-------
were comparable to control values. Skin irritation was severe after admin-
istration of the mixed isomer diepoxybutane and moderate following application
of the meso compound.
Intraperitoneal injection of the mixed isomer diepoxybutane
into rats reportedly produced one case of sarcoma development (Hendry et al.,
1951). Ten male and four female rats were injected with 20 mg/kg of diepoxybutane
in arachis oil twice weekly for 13 doses, and then with 10 mg/kg twice weekly
for another 12 doses. All animals were dead at 18 months from the start of
treatment. Necropsy in one animal that died at 13 months showed large masses
of a mixed cell sarcoma.
Bird and Fahmy (1953) injected rats subcutaneously with
mixed isomer diepoxybutane in arachis oil at the level of 2 mg per animal, once
weekly for 16 weeks. Positive results in the production of sarcomas were
reported, but no experimental details were published.
Diepoxybutane was tested for carcinogenicity in mice and
rats by subcutaneous injection (Van Duuren et^ ajL., 1966). Female mice were
injected with ji,JL-diepoxybutane in tricaprylin at 0.1 or 1.1 mg per animal once
weekly for over one year. Tumor latency was eight to 12 months. At the lower
dose level, five of 30 animals developed fibrosarcomas and two of 30 animals
developed adenocarcinomas. Five of 30 animals developed fibrosarcomas at the
higher dose level. Survival time was comparable to controls. In the study
with rats, animals were injected subcutaneously with 1 mg, once weekly for over
one year. Out of a test group of 50 animals, ten animals developed tumors,
including nine with fibrosarcomas and one with an adenocarcinoma. Median
cumulative dose of jd,JL-diepoxybutane in this study was 67 mg of compound.
Gastric feeding studies were performed with each rat receiving 5 mg of d_,^-
diepoxybutane in tricaprylin once weekly for life. Median survival time of treated
141
-------
animals was 342 days compared to 525 days for controls. No tumors were
detected by this feeding study.
Shimkin and coworkers (1966) studied the effects of
1-diepoxybutane on the development of pulmonary tumors in strain A mice. The
^-isomer of diepoxybutane .was dissolved in either water or tricaprylin and
injected three times weekly (i.p.) into mice for 12 weeks. Total doses in
water were 1.7, 6.7, 27, 108, and 192 mg/kg, with resulting tumor incidences
of 21, 40, 55, 64, and 78%, respectively, at 39 weeks after treatment. Total
doses in tricaprylin were 3, 12, 48, and 192 mg/kg, which produced tumor inci-
dences of 40, 43, 46, and 50%. Controls showed a spontaneous rate of lung
tumor development of 35%. Significant tumor increases were seen at the three
highest dose levels in water. This test evaluates the acceleration of lung
tumor development rather than the actual induction of tumors, and has been
designed as a short term in vivo carcinogenieity screening assay.
The mixed ji,_l-isomer of diepoxybutane and the meso-isomer
have both been tested for tumor initiating activity by Van Duuren (1969).
Following an initial application of 1 mg of compound in 0.1 ml of acetone to
mouse skin, phorbol ester was applied three times weekly for life, beginning
two weeks after initiation. Twenty mice that received c[,l-diepoxybutane
showed seven cases of papilloma and two cases of carcinoma. Following admin-
istration of the meso compound four mice developed papillomas. The incidence
of tumors after initiation with either
-------
and atrophy of the muscles of the hind limbs. These effects were reversible
after discontinuation of exposure for 100 to 132 days. Special studies on
monkeys were carried out with repeated (38 to 94) exposures to this level of
ethylene oxide. Knee jerk reflexes became very weak, pain perception in the
hind quarters decreased, the cremasteric reflex was elicited, and the extensor
reflex of the palms of the hind feet was abolished. Impairment of both sen-
sory and motor functions at the lumbar and sacral level of the spinal cord was
indicated. Exposure of monkeys to a lower level of ethylene oxide (2.4 ppm
for 176 to 226 days) produced partial paralysis and some muscular atrophy of the
hind legs with moderate suppression of the leg reflexes. The Babinski reflex
was present after this lower level exposure to ethylene oxide.
Balazs (1976) reported that dogs given the ethylene oxide
reaction product 2-chloroethanol orally developed an abnormal posture of the
hind legs in a subacute test. Chloroethanol given to cats subcutaneously at
10 mg/kg on three consecutive days produced decreased performance in a conditioned
reflex test.
2. Toxicity and Effects on Other Vertebrates
The effects of these epoxides on other vertebrates have not
been characterized.
3. Toxicity and Effects on Invertebrates
Ethylene oxide has been utilized as a fumigant for foods and
spices and shows major insecticidal activity (Lindgren and Vincent, 1966).
Susceptible insects common to stored products include the flour beetle, rice
weevil, and grain weevil (Lindgren et_ al_., 1954). Ethylene oxide will kill
one-half the stored product insect population at a concentration range of
6 to 18 mg/liter, while propylene oxide is effective at 25 to 32 rag/liter (Ong, 1948)
143
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Lindgren and Vincent (1966) reported a major reduction in available tissue
glutathione content of Calliphora larvae exposed to ethylene oxide. Decrease in
tissue glutathione via depletion of reduced-SH groups may be the mechanism of
toxicity. The insect toxicity of ethylene oxide has been ranked by Lindgren as
intermediate between that of ethylene dibromide and ethylene dichloride. A
bibliography of ethylene oxide insecticidal properties citing 185 references
has been published (Young and Busbey, 1935).
Bird (1952) reported on the toxicity of ethylene oxide and
diepoxybutane to Drosophila. Ethylene oxide injected into adult males at the
level of 0.8% solution (arachis oil) killed half the population, while injection
of a 0.1% solution of diepoxybutane killed approximately one half of the flies
tested. Based on this comparison these investigators estimate that diepoxybutane
is at least tenfold more toxic than ethylene oxide.
D. Toxicity and Effects on Plants
The epoxides are agents capable of producing mutations in plants by
interaction with chromosomal materials (see Section Ill.l.g). Ehrenberg and
coworkers (1959) found that treatment of barley seeds with 0.1 to 0.3% ethylene
oxide solution produces increased mutations; some of these mutations are lethal
and others induce sterility in the subsequent plants. Comparison of the effects
of diepoxybutane and ethylene oxide solutions on barley seeds by Ehrenberg and
Gustaffson (1957) indicated that 0.15% aqueous ethylene oxide exposure for two
hours kills half the resting seeds treated, while 0.001% diepoxybutane treatment
produces the same effect. Ark (1947) has reported that treatment of club wheat
seeds with propylene oxide gas at the concentration of 35,000 ppm under vacuum
for six hours produces a 50% loss in germination. The level of propylene oxide
gas producing germination loss is generally higher than the level needed to kill
associated pathogenic bacteria or fungi.
144
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E. Toxicity and Effects on Microorganisms
Ethylene oxide and propylene oxide have been used to kill a wide
variety of bacteria and fungi in foods and spices. Sykes (1964) reported that
exposures to gaseous ethylene oxide at concentrations of 1 to 10% will kill
Bacillus globigii, Staphylococcus aureus, IS. coli, Chromobacterium prodigiosum,
and Mycobacterium phlei within a few hours. Roberts and coworkers (1943)
found that 10% gaseous ethylene oxide will kill Bacillus anthracoides in
eight hours. A 5% gaseous concentration of ethylene oxide produced 90%
kill of airborne 15. globigii spores in less than two hours.
Skeehan (1959) indicated that herpes simplex, vaccinia, and
bovine respiratory viruses are susceptible to saturated ethylene oxide vapor
treatment.
Treatment of agar slants containing yeasts and fungi with 8% gaseous
ethylene oxide for three hours was lethal to these microorganisms (Whelton
et al., 1946).
Ark (1947) reported that exposure of several types of pathogenic
bacteria and fungi to 10% to 18% gaseous propylene oxide for one hour resulted in
their inactivation.
Both propylene oxide and ethylene oxide produce significant spori-
cidal activity against dry bacterial spores (Bruch and Koesterer, 1961).
Exposure of Bacillus subtilis spores to 1% to 2% vapor concentrations of ethylene
oxide and propylene oxide killed 95% or more of the spores within four hours.
Ethylene oxide produced a greater reduction in spore survival than did propylene
oxide over short time periods.
Himmelfarb and coworkers (1962) tested the bactericidal activity of
propylene oxide vapor on 16 strains. All strains tested were killed by
145
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varying the time of exposure (4 to 356 minutes) to 0.1% gaseous propylene oxide
at a given relative humidity. Spores showed a greater resistance than vegetative
forms to this treatment.
Exposure of bacteriophage !„ to 2 M ethylene oxide solutions for
four minutes has been shown to produce a 50% reduction in infectivity
(Loveless and Wheatley, 1966).
F. In Vitro and Biochemical Studies
Ethylene oxide and propylene oxide have been shown to react with
RNA isolated from tobacco mosaic virus (Fraenkel-Conrat, 1961). The site
of alkylation has been proposed as the N-7 guanine position. Alkylation was
increased in the presence of magnesium ion which induced a hypochromic state
in the RNA structure.
Treatment of protein with ethylene oxide and propylene oxide has
also led to chemical modifications (Fraenkel-Conrat, 1944). Egg albumin
treated with 4.8% ethylene oxide or propylene oxide showed decreased amounts
of reactive carboxyl, amino, phenol, and sulfhydryl groups. The majority of
the reaction products formed after treatment with the epoxides were stable
to both acid and alkali treatment.
Dent and Schnell (1979) studied the interaction of ethylene, propylene,
and butylene oxides with epoxide hydratase. All three compounds produced
inhibition of enzyme activity in vitro. The order of inhibition indicated that
ethylene oxide was the most effective compound, but that it had a low order of
affinity for the enzyme and thus was a weak competitive inhibitor.
Investigation of hemolysis produced by ethylene oxide (Jones, 1979)
indicated that 2 mg/ml aqueous concentrations of the compound (2000 ppm) will
146
-------
lyse human red cells in vitro. Cultured mouse fibroblast cells showed toxi-
city when exposed to tubing containing residual ethylene oxide at the level of
2 mg/gm of tubing.
G. Effects on Foods
Windmueller and coworkers (1956) noted that rats fed diets fumigated
with ethylene oxide suffered nutritional deficiencies. Examination of the
casein from this treated chow showed destruction of major amounts of the amino
acids, histidine and methionine, after 24 hours of ethylene oxide fumigation
(concentration not indicated).
Investigation of the effect of saturated ethylene oxide vapor on dog
meal indicated a significant loss of thiamine content (Bakerman et^ al_., 1956).
Further examination of mixtures of vitamins and cornstarch exposed to satur-
ated ethylene oxide in a dessicator for 18 hours indicated that thiamine,
niacin, pyridoxine, riboflavin, and folic acid were all destroyed by this
treatment. Hawk and Mickelsen (1955) also reported that rat chow exposed 12 to 24
hours to saturated ethylene oxide vapor treatment suffers from major loss of
thiamine content. Growth defects in rats fed this treated diet can be reversed
by the addition of thiamine.
H. Effects of the Compounds on Environmental Quality
The selected epoxides are potential hazards to soil microbial com-
munities. Propylene oxide and ethylene oxide have been examined as soil ster-
ilants (Skipper and Westingmann, 1973). Addition of 1 to 2 ml of propylene
oxide was sufficient to sterilize 25 g soil samples. They also reported that
the epoxide increased soil pH by 0.5.to 1.1 units. Propylene oxide apparently
sterilizes soils by alkylation of functional groups in proteins of the micro-
organisms. Also, propylene oxide residues remain in the soil and hinder subsequent
plant growth.
147
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No adverse environmental effects, other than the hazard to microbial
systems and possibly to plants, are anticipated.
I. Effects on Inanimate Objects
No information was available on effects of the selected epoxides to
inanimate objects. It is anticipated that the epoxides could react with func-
tional groups, for example, with cellulosic hydroxyl groups. Such reactions,
which are known in the laboratory, could alter properties of some inanimate
objects. Since effects have neither been documented nor been suggested else-
where, this possibility is only hypothetical.
148
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IV. CURRENT REGULATIONS
A. Federal, State, and Local Standards
1. Food, Drug, and Pesticide Authorities
Ethylene oxide and propylene oxide are applied as fumigants
or sanitizers to a variety of products and thus are subject to appropriate
regulations. Ethylene oxide is currently on the RPAR list. Both epoxides
are applied as fumigants to bulk foods (including grains, cereals, nuts, and
spices). Ethylene oxide is a sterilant which is applied to cosmetics, drugs,
medical devices, single service food service items, and other products. The
application limitations and tolerances established for their residues are
described below. Tolerances in drugs and medical devices for ethylene oxide
and its metabolites (ethylene chlorohydrin and ethylene glycol) are as follows
(Federal Register, 1978):
(Parts per million)
Ethylene Ethylene Ethylene
Drug product oxide chloro- glycol
hydrin
Ophthalmics (for topical
use) 10 20 60
Injectables (including
veterinary intra-
mammary infusions) 10 10 20
Intrauterine device
(containing a drug) 5 10 10
Surgical scrub sponges
(containing a drug) 25 250 500
Hard gelatin capsule
shells 35 10 35
149
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(Parts per million)
Ethylene
Medical device oxide
Implant:
Small (<10 grams)
Medium (10-100 grams)
Large (>100 grams)
Intrauterine device
Intraocular lenses
Devices contacting mucosa
Devices contacting blood
(ex vivo)
Devices contacting skin
Surgical scrub sponges
250
100
25
5
25
250
25
250
25
Ethylene
chlorohydrin
250
100
25
10
25
250
25
250
' 250
Ethylene
glycol
5,000
2,000
500
10
100
5,000
250
5,000
500
Ethylene oxide use with commodities and food service materials
are subject to the following regulations:
21CFR178.3520 limits ethylene oxide to less than 3 pet of
reacted ethylene oxide in finished industrial starch.
21CFR193.200 describes allowed application of ethylene oxide
as fumigant for natural spices and establishes its tolerance
at 50 ppm.
40CFR180.152 describes allowed application of ethylene oxide
as a fumigant for black walnut meats, copra, whole spices,
etc. and establishes its tolerance at 50 ppm.
Propylene oxide is subject to the following regulations:
21CFR193.380 describes its application as a package fumigant
with dried prunes and glace fruit, and as fumigant for bulk
cocoa, gums, spices, nutmeats (except peanuts), and starch.
It also establishes a propylene oxide tolerance of 300 ppm.
21CFR172.890 describes its application to food starch modified
in combination with epichlorohydrin (propylene oxide not to exceed 10%)
and alone (not to exceed 25%).
The use of butylene oxide as an adjuvant substance for slime
control in paperboard is described in 21CFR176.300.
150
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2. Other EPA Authority
The selected epoxides are not specifically regulated by other
EPA authorities. RCRA (43FR58946) classed waste pesticides (Group 2-A) as a
source of toxic substance release in case of fire or explosion. This applies
to the small amounts of ethylene oxide and propylene oxide formulated as
pesticides.
3. OSHA
OSHA has set the TLV1s for ethylene oxide and propylene oxide
at 50 ppm (90 mg/cu m) and 100 ppm (240 mg/cu m), respectively.
4. DOT, ICC, CG - Transport Regulations
Ethylene oxide and propylene oxide are both classed as flammable
liquids. Both require labels ("Flammable Liquid") and placarding as "Flammable."
Ethylene oxide must be transported according to the DOT regulations for flammable
liquids and packing specifications are described in 49CFR173.124 (ethylene oxide).
Propylene oxide may be transported as flammable liquids with the exemption of
49CFR173.118. Its packing regulations are described in 49CFR173.119.
B. Concensus and Similar Standards
1. TLV
The American Conference of Governmental Industrial Hygenists
(ACGIH, 1977) has set TLVs for ethylene oxide and propylene oxide at 50 ppm
and 100 ppm, respectively and recently has recommended values of 10 and 20 ppm,
respectively (Kurginski, 1979). The earlier values are the same as OSHA standards.
In 1965 the Dow Chemical Company provided some estimates for
ethylene oxide and propylene oxide limits (Kereluk, 1971).
Exposure Ethylene Oxide Propylene Oxide
Daily, up to 8 hrs. 50 100
Single, for several hrs. 150 400
Single, for 1 hr. 500 1000
151
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2. TWA
No TWAs have been established for the selected epoxides.
C. Current Handling Practices
1. Special Handling In Use
Ethylene oxide requires special handling in use because it is
a gas at ambient temperature. Batch reactions should be carried out in a
special kettle. The kettle should be fitted with pressurized feed lines from
the ethylene oxide storage and it should be capable of maintaining the gas
pressure generated during the process. Cooling and heating lines are required
to initiate and maintain reaction (Jefferson Chemical, undated a).
Technical information on propylene oxide does not specify any
special equipment for its handling (Jefferson Chemical Company, undated b; Oxirane
Corporation, undated). Since propylene oxide is a liquid at ambient temperature,
pressurization of reactors and feed lines from storage are not as critical as
required for ethylene oxide. Batch reactors should be equipped with heating and
cooling lines as described for ethylene oxide reactors.
Work areas, where ethylene oxide or propylene oxide are used,
should be ventilated. Workers should wear appropriate protective clothing and
respirators.
2. Storage and Transport Practices
Epoxide transport must follow DOT regulations. Propylene oxide
should be shipped in unlined I.C.C.-17C drums (55 gal), or I.C.C.-105A and I.C.C.-lllA
100-W-3 tank cars. Tank cars should contain all connections, a gauging device,
thermometer, and a safety release valve within the car's dome. Ethylene oxide
should be shipped in I.C.C. spec. 5P drums, I.C.C.-4B-400 cylinders (l.or 5 gal. size),
or I.C.C.-105-AW tank cars. The tank car construction described for propylene
152
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oxide is suitable. The drum is a double walled insulated steel construction of
approximately 260 pounds capacity. Its working pressure is 50 psig and it has a
pressure relief valve set at 70 psig (Jefferson Chemical Co., undated a,b;
Oxirane, undated).
Ethylene oxide and propylene oxide should be stored in areas
that are well ventilated and protected from heat. Both are volatile, flammable
and reactive. Ordinary carbon steel tanks are adequate. Some polymerization
can occur during storage, which could subsequently foul valves and other
equipment. Thus, storage facilities should have access for cleaning (Jefferson
Chemical Co., undated a,b). As for other organic chemicals, the epoxides should
be kept, if possible, in outside storage and away from combustible materials.
3. Accident Procedure
The potential hazards of spilled ethylene oxide or propylene
oxide primarily stems from its fire or explosion potential. The primary
response action should eliminate these hazards. Health hazards include possible
inhalation toxicity, pollution of water supplies and in case of fire, the pro-
duction of more toxic gases (DOT, 1974; ChemTrec, 1971). The recommended
response to spills first addresses the fire hazard of these solvents: eliminate
all sources of fire; stop leak if it is without risk; and reduce vapors with
water spray. Large spills should be diked and small spills can be adsorbed with
a noncombustible sorbent. The runoff should be kept from entering a sewer to avoid
possible fire or explosion hazards.
Fires of liquid ethylene oxide are difficult to extinguish; it
requires diluting the liquid 22:1 with water.
Vapor fires can be controlled with dry powders, vaporizing liquids,
carbon dioxide, special alcohol-type air foam (not protein foam), and water fog.
153
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Since ethylene oxide fires can lead to explosions, it is recommended that
fires be isolated from other combustibles. Massive fires in cargo areas
should be fought with unmanned hose holder or monitor nozzles. Storage equip-
ment should be cooled with water spray.
154
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V. EXPOSURE AND EFFECTS POTENTIAL
Since insufficient quantitative information was available on the selected
epoxides in the environment, the exposure risk assessment is based upon quali-
tative information and upon hypothetical arguments. The exposure risk con-
siders epoxide from manufacturing and from inadvertent sources. The evidence
at hand suggests the bulk of manufactured epoxide does not create exposure
risk. The majority of the epoxides are consumed in intermediate use in
synthesis and relatively minor amounts are released. The risk of direct human
exposure appears greatest with (1) medical devices, foodstuffs, and other
products treated with ethylene or propylene oxide; (2) chlorinated solvents
containing butylene oxide as a stabilizer; and (3) epoxides from inadvertent,
nonmanufactured sources, in particular, from fuel combustion and cigarette
smoke.
There is no evidence that epoxide exposure through water is significant.
Epoxides have been identified in some industrial effluents (see Section II.E)
but are not common constituents of effluents (Shackelford and Keith, 1976) and
the epoxides degrade fairly fast (two weeks or less) (see Section II.D).
Sparse data exists on atmospheric emissions of the epoxides. The hypothe-
sized possibilities discussed herein are based primarily on the processes for
manufacture, handling, and use of the selected epoxides. None of the epoxides
have been reported in analysis of plant effluents. Since at ambient tempera-
ture ethylene oxide is a gas and propylene oxide is a volatile liquid, fugitive
emissions from industrial processing equipment, equipment cleaning, gauges,
etc. are expected within the plant. Transfer of the materials would release
only small amounts, if adequate precautions were adopted. If poor handling
practices were applied during routines such as transfer from a transport tank
to a storage tank, an epoxide emission of large size might result. Such an
155
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emission would create an occupational exposure risk. Risk to populations near
a plant which manufacture or use an epoxide in synthesis is not clear. Little
evidence is available on the atmospheric emissions of the epoxides or their
exposure to nearby populations.
An accident, spill, or problem in transport, storage, or processing
could, of course, release hazardous quantities. Available information on
epoxide properties (physical, chemical, and biological reactivity) suggest
that atmospheric degradation is relatively fast, which limits the geographic
range and time of human exposure hazard.
The application of ethylene oxide and propylene oxide as fumigants or
sterilants are the only uses which have been clearly associated with a signi-
ficant human exposure. Less than 0.1 million pounds of ethylene oxide and
even less of propylene oxide are applied for these purposes. The hazard from
exposure through commodities are considered minimal. The epoxides are rapidly
dissipated by volatilization and degradation. Although an unusual set of cir-
cumstances could create an incident of exposure by this route, all available
information suggests that no problem exists under typical application and use
conditions. Exposure to ethylene oxide through treated medical devices appears
a more hazardous route. Health effects have been associated with devices
implanted into humans (see below), but it is not certain if the toxic effect
resulted from ethylene oxide or its metabolite ethylene chlorohydrin. Levels
of ethylene oxide and its metabolites in medical products are regulated (see
Section IV.A.I).
Butylene oxide's chief use is in chlorinated solvents as a stabilizer.
Exposure to this epoxide is associated with use of these solvents. If pre-
cautions are utilized in the use and handling of chlorinated solvents,, then
exposure to butylene oxide is also minimized.
156
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The epoxides are also inadvertently produced during combustion. They
enter the environment through burning of fuel in stationary sources and from
automobile exhaust. The amounts produced have not been quantified, but it was
estimated that several million pounds of ethylene oxide and propylene oxide
could be emitted through these combustion sources (see Section II.C.3). The
general population would be at risk of exposure and exposure risk would be
greatest near areas of high traffic or stationary emission sources.
Ethylene oxide has been identified as a component of cigarette smoke
(see Section II.C.3). Tobacco fumigated with ethylene oxide appears to
generate greater concentrations of ethylene oxide in the smoke; untreated,
fumigated, and extensively fumigated tobacco yielded 0.02, 0.05, and 0.5 yg
ethylene oxide per ml, respectively. Filtered cigarettes produced less
ethylene oxide. The population at risk includes those exposed to side-stream
smoke as well as the smoker.
The epoxides show potential health effects through their ubiquitous
reactivity with functional groups of DNA, RNA, and proteins. Diepoxybutane,
based on acute toxicity studies in animals, shows the highest reactivity of
the compounds studied. This is further confirmed in mutagenicity studies
carried out in animals, plants, and microorganisms, and carcinogenic activity
noted in bioassays.
Most of the available published work regarding health effects of these
epoxides deals with ethylene oxide. Occupational studies and clinical reports
indicate that clothing articles (rubber shoes, rubber gloves, surgical gowns)
sterilized with ethylene oxide can produce skin burns and blisters (Royce and
More, 1955; Biro et^ al_., 1974). These effects could be prevented by adequate
ventilation of sterilized materials before use (Taylor, 1977c).
157
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Hemolysis and anaphylactic reactions have been reported after the use
of plastic medical devices sterilized with ethylene oxide (Hirose et al.,
1953; Poothullil ^t al., 1975). Balazs (1976) estimated that ethylene
oxide-sterilized plastic devices in prolonged contact or multiple use situa-
tions could release levels of compound well in excess of a theoretical no-
effect level of 2.1 mg/day. This level is based on calculations of a 3 mg/kg
(subcutaneous) no-effect level for ethylene oxide administered for 30 days to
dogs. Use of a factor of 100 then leads to a derived safe level of 0.03 mg/kg
or 2.1 mg for a 70 kg man. Further data concerning levels of release of
ethylene oxide from sterilized plastic devices in vivo needs to be evaluated
in order to assess the magnitude of this type of exposure. 2-Chloroethanol, a
more persistant residue in these devices, may be formed after ethylene oxide
sterilization; this compound has demonstrated mutagenicity in microbial
systems (Rosenkranz et al., 1974).
Health effects in workers exposed to ethylene oxide vapor (ethylene oxide
production plants, ethylene oxide sterilizer equipment) indicate neurological
effects (Jensen, 1977), reproductive effects (Yakubova et_ ail., 1976), chromo-
somal effects (Ehrenberg and Hallstrom, 1967), and an increased incidence of
leukemia (Hogstedt et al., 1979). Animal studies with ethylene oxide confirm
these classes of human effects: positive dominant lethal assay in mice,
testicular atrophy in guinea pigs, teratogenicity in mice, chromosomal breaks
in rats, and mutagenicity in a variety of microbial and plant systems.
Ehrenberg and coworkers (1974) calculated that workers exposed to daily
levels of 5 to 10 ppm ethylene oxide gas recieve the mutagenic equivalent of 4 to 8
rads gonadal dose of radiation weekly. If this estimate is correct, then
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long-term effects in workers exposed to ethylene oxide gas should be evaluated,
particularly in women of child bearing age. The Veterans Administration and
NIOSH are currently initiating separate studies covering large worker popula-
tions exposed to ethylene oxide gas.
Exposure to ethylene oxide residues in foods and spices sterilized with
this compound involves levels considerably lower than those from sterilized
medical devices. Based on the mutagenicity and possible carcinogenicity of
ethylene oxide, further evaluation of the effects of extremely low levels of
ethylene oxide exposure following ingestion seems appropriate.
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VI. TECHNICAL SUMMARY
Four epoxides were studied: ethylene oxide; propylene oxide; butylene
oxide; and diepoxybutane. Chemically, the epoxides are ethers which are
characterized by the three membered oxygen-containing ring. They are slightly
lower boiling and more reactive with acids and nucleophiles than are the
analogous acyclic ethers. Ethylene oxide is a gas at ambient temperature and
propylene oxide is a low boiling liquid (boiling point 34°C). The other
epoxides are liquids (see Section I).
Ethylene oxide is among the leading chemicals in current production. For
1977 its production was estimated at 4,423 million pounds. It was primarily
consumed in ethylene glycol manufacture (63%) and manufacture of polyols,
polyol and glycol ethers, and ethanolamines (20 to 25%). Propylene oxide produc-
tion in 1977 was estimated at 1,897 million pounds. It is mainly consumed in
manufacture of polyurethane polymers (55%). It is also a feedstock for
propylene glycol (20%), and various polyols (non-urethane), polyol ethers and
glycol ethers (13%). Relatively small amounts of propylene oxide and ethylene
oxide (less than 0.1 million pounds of each) are consumed as sterilants or pesticides
for a variety of commodities, medical devices, cosmetics, and Pharmaceuticals.
Butylene oxide production has been decreasing from 9.5 million pounds in 1974
to an estimated 1.5 million pounds in 1980. It is primarily used as a stabil-
izer for chlorinated solvents. Diepoxybutane is a specialty chemical with an
assumed annual production of less than 1000 pounds (see Section II.A and
II.B).
Ethylene oxide is manufactured by catalytic oxidation of ethylene although
a small amount is still manufactured by the older chlorohydrin route. Currently,
propylene oxide is prepared by chlorohydrination or peroxidation of propylene,
160
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but new methods of catalytic oxidation, which have recently been developed,
appear competitive. Butylene oxide is prepared by peroxidation or catalytic
vapor phase oxidation of butylene. Diepoxybutane is synthesized from buta-
diene by chlorohydrination or an analogous method (see Section II.A.3).
Information was sparse on atmospheric release of manufactured epoxides.
The available information indicates that only a small percentage of manu-
factured ethylene oxide and propylene oxide enters the environment. Because
annual epoxide production is so large, even a small fraction of the total
could result in several hundred thousand pounds of emissions. Pervier and
coworkers (1974) surveyed ethylene oxide manufacturing plants and estimated
that 118.6 million pounds of hydrocarbons were annually discharged; discharge
was primarily vent loss. They noted that the discharge primarily consisted
of ethylene; ethylene oxide release was not mentioned. Some losses are
expected from fugitive emissions, ventings (especially during distillation),
transfer and handling, spills, etc., but amounts are not known. Dow Chemical
(Kurginski 1979) has indicated that the hydrocarbon loss figure is at least
20 times too high and ethylene oxide annual loss from production and processing
is less than 5 million Ibs. A report of ethylene oxide in chemical plant effluent
(Shackelford and Keith, 1976) was the only monitoring data concerning waste-related
epoxide release. No information on propylene oxide release to the environment
was available. Butylene oxide, which is added to chlorinated solvents, will share
the fate of the solvent; losses to the atmosphere are expected.
The application of ethylene oxide and propylene oxide to consumer
commodities and other items as sterilant or pesticide creates the possibility of
human exposure. The epoxide and its residues (halohydrins and glycols) have
been identified in treated products including food (Wesley et_ a^., 1965),
drugs (Holmgren et_ ad. , 1969), and medical devices (Brown, 1970). In fact, human
health effects were traced to surgically implanted devices that were treated
-------
with ethylene oxide (see below). The extent of this exposure is unknown
because of the limited monitoring data that is available.
The monoepoxides (ethylene, propylene, and butylene oxide) can be inad-
vertently produced through a variety of sources. They are known products of
atmospheric oxidations (Sato and Cvetanovic, 1958; Altshueller and Buffalini,
1965). They have also been observed as products of partial combustion of
fuels (Hughes et^ aJL., 1959) and in automotive exhaust (Barnard and Lee, 1972);
epoxides emitted from these sources may approach millions of pounds annually.
Ethylene oxide has been measured in cigarette smoke, the amount depending in
part upon fumigation of the tobacco with ethylene oxide (Binder, 1974). While
unfumigated tobacco yielded smoke with an ethylene oxide concentration of
0.02 yg/ml, in extensively fumigated tobacco its concentration was 0.3 ug/ml
(see Section II.C.7).
The epoxides degrade in the environment. In water they react by chemical
hydrolysis and with anions such as chloride and carbonate (Bronsted et al.,
1929; Ross, 1950). Although intermediates form (such as chlorohydrins from
epoxide reaction with chloride), glycols are the terminal products. Half-
lives were calculated for aqueous degradation in ambient conditions (pH 7 and
25°C) in fresh water and in sea water (0.57 M chloride) as follows: ethylene
oxide - 2 weeks in fresh water and 4 days in sea water and propylene oxide -
12 days in fresh water and 4 days in sea water. These half-lives do not account
for biodegradation routes. The only information available on epoxide degrada-
tion in soil described metabolic transformations, which parallel chemical
hydrolysis and reaction with anions. Rate factors for the metabolic processes
were not available (Castro and Bartnicki, 1968; Bartnicki and Castro, 1969).
Atmospheric degradations of the epoxides have not been directly studied.
162
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Since the information available on their free-radical reactions describe their
reactivity as similar to acyclic ethers and to other cyclic ethers, the
epoxides probably degrade very rapidly (Darnall et al., 1976). Epoxides
applied as sterilants or'pesticides for commodities and other items dissipate
through a combination of volatilization and degradation (Scudamore and Heuser,
1971; Stijve^al. , 1976). Storage in closed containers will stop the vola-
tilization loss. The epoxide degradation pathways parallel the chemical
degradation described above. If inorganic halide (chloride or bromide) is
present, then halohydrins form. Reaction of epoxide or halohydrins with water
yields glycol (see Section II.C).
Physical properties of the epoxides suggest that they are very mobile and
do not bioaccumulate. Their high water solubility precludes any capacity to
bioconcentrate. Solubility factors also suggest potential for transport with
surface or ground water. 'Since ethylene oxide and propylene oxide possess
high vapor pressures, they will volatilize readily (Alguire, 1973). There was
no information available concerning transport between air and water. It is
not certain which media is most important in the fate of the epoxides.
The toxic effects of human exposure to ethylene oxide and propylene oxide
appear to be quite similar (Hine and Rowe, 1973). Based on animal toxicity
studies, propylene oxide is one-half to one-third as acutely toxic as ethylene
oxide (Jacobsen et al., 1956). Systemic poisoning following accidental expo-
sure to high ethylene oxide concentrations has produced symptoms of headache,
vomiting, dyspnea, diarrhea, and lymphocytosis (Sexton and Henson, 1949).
Thiess (1963) reported that accidental brief exposure to high concentrations
of ethylene oxide vapor has produced bronchitis, pulmonary edema, and emphysema
in workers. Dermatitis has resulted from contact with ethylene oxide,
163
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producing large characteristic blisters (Taylor, 1977). Sensitization to
ethylene oxide has been described by Dolovich _et a.1^. (1978), and anaphylactic
reactions to ethylene oxide residues in medical devices has also been reported
(Pessayre and Trevoux, 1978; Poothullil e£ a.L., 1975). Clinical reports of hemol-
ysis following usage of ethylene oxide sterilized plastic tubing have also
been published (Hirose et_ al., 1953). Conjunctivitis and corneal burns have
been produced by exposure to high levels of ethylene oxide and propylene oxide
(Mclaughlin, 1946); these effects may be reversible within a few days.
Three incidences of lower limb neuropathy in workers using ethylene oxide
sterilizers were reported by Jensen (1977); a followup indicated that these
effects were reversible.
Epidemiological studies on ethylene oxide exposure have produced varied
findings. Joyner (1964) was unable to show significant adverse health effects
in an investigation of workers exposed for five to sixteen years in an ethylene
oxide production plant. A preliminary study of health records of employees in
162 Veterans Administration hospitals and seven clinics using ethylene oxide
sterilizers failed to show any effects other than watering eyes, nausea, and
skin irritation (NIOSH, 1977). A followup of this survey is planned. A study
by Ehrenberg and Hallstrom (1967) of 251 Swedish workers in an ethylene oxide
production facility found three cases of blood cell anisocytosis and one case
of leukemia. Workers exposed to high (accident) ethylene oxide concentrations
showed greater numbers of chromosomal aberrations. A follow up of this study
is also planned.
Recently, a study of 230 Swedish workers exposed to a mixture of ethylene
oxide and methyl formate gas in a storage hall containing gas-sterilized boxes has
shown the development of three cases of leukemia with latencies of 4 years,
164
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6 years, and 8 years, respectively (Hogstedt eit_ ai_, 1979). This is con-
siderably higher than the projected incidence rate of 0.2 cases for this
population. Workers were exposed to an assumed concentration of 20 + 10 ppm
ethylene oxide over a nine-year period, but concentrations in the storage
hall could have reached levels of approximately 150 ppm or higher.
Yakubova and coworkers (1976) reported that pregnant workers in ethylene
oxide production facilities were prone to miscarriages and toxicosis in the
second half of pregnancy. Levels of exposure and quantitation of effects were
not available for analysis. Neither the study by Joyner nor the study conducted
by Ehrenberg and Hallstrom involved any female participants.
The acute toxicity of epoxides in animal studies indicates that diepoxybutane
shows high acute toxicity (LD in the mouse after i.p. injection, 16 mg/kg;
Weil, 1963), followed in decreasing order by ethylene oxide, propylene oxide, and
butylene oxide. Comparative acute toxicity of ethylene oxide administered by
inhalation demonstrates that mice and dogs seem most susceptible while rats and
guinea pigs appear less sensitive.
Animal studies with radioactively labelled ethylene oxide have indicated
that after injection this compound may be found in tissues throughout the body
including the liver, kidneys, lungs, pancreas, epididymis, testes, and cere-
bellum (Appelgren _e_t _al., 1977). The major portion of absorbed ethylene oxide
is metabolized rapidly and excreted. Eighty percent of the labelled compound in
animals exposed by inhalation was found in the urine within 48 hours (Ehrenberg
esit al. , 1974). Tissue components alkylated in vivo by ethylene oxide may
represent the remainder of compound absorbed.
Ethylene oxide inhalation has produced bone marrow effects in several
species of animals. Jacobsen and coworkers (1956) noted a decrease in red
165
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blood cell count, hemoglobin, and hematocrit in dogs exposed for 6 hrs/day
to 292 ppm ethylene oxide for six weeks. Woodward and Woodward (1971) deter-
mined that dogs injected s.c. for 30 days with 6 to 36 mg/kg ethylene oxide de-
veloped anemia and showed bone marrow hyperplasia. Increased chromosomal
aberrations (breaks, rings, gaps, bridges) have been observed in rats treated
with ethylene oxide (Embree and Hine, 1975; Strekalova, 1971). Appelgren and
coworkers (1978) noted bone marrow depression and increased red blood cells
with micronuclei in rats injected twice i.v. with ethylene oxide at the level
of 100 mg/kg.
Diepoxybutane showed effects on mouse sperm chromosomes 24 hours after
i.p. injection at 5 mg/kg (Moutschen, 1961). This exposure included increased
chromosome breaks and anaphase bridges.
Reproductive effects have been seen in animals, including degeneration of
the testicular tubules of guinea pigs following inhalation of ethylene oxide
(Hollingsworth et al., 1956) and a positive dominant lethal assay in rats
(Embree and Hine, 1977). Epstein and coworkers (1972) reported that i.p. injection
of 17 mg/kg of diepoxybutane into mice produced an increase of early fetal deaths
in the dominant lethal assay.
Neurotoxic effects were observed in mice, rats, and monkeys exposed
repeatedly (33 to 94 times) to 357 ppm ethylene oxide inhalation (Hollingsworth
£t: a^. , 1956). Paralysis and atrophy of the hind-limb muscles developed, and
impairment of sensory and motor function at the sacral and lumbar regions of
the spinal chord was inferred. Reversal of paralytic symptoms in rats and
mice was seen in 100 to 132 days after exposure was stopped.
The epoxides have been shown to produce mutagenic effects in a wide variety
of plant and microbial systems. Positive results in the Ames mutagenicity assay
166
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have been seen with ethylene oxide (Rannug et^ al^. , 1976; Taylor, 1979; Embree
and Hine, 1975; Kauhanen, 1977) without the addition of microsomal activation
mix. Taylor (1979) showed that addition of microsomal activation enzymes
(S-9 mix) increases the number of mutants produced in tester strains TA1535
and TA100 at ethylene oxide vapor concentrations from 10 ppm to 100 ppm.
Propylene oxide increases mutations in tester strains TA100 and TA1535 at the
level of 1 to 1.5 mg/plate without activation (Wade et^ al_., 1978).
Diepoxybutane exhibited mutagenic activity in the Ames assay without
activation (McCann £t al., 1975; Rosenkranz and Poirer, 1979; Simmon, 1979).
Rosenkranz and Poirer (1979) showed that the increase in mutations induced by diepoxy-
butane in tester strains TA1535 and TA1538 is partially eliminated if micro-
somal activation mix is added.
Butylene oxide also showed positive activity in the Ames assay. Speck and
Rosenkranz (1976) reported increased mutants in tester strains TA 100 without
activation following application of 14 yg of compound. Positive Ames assay
results have also been reported by others (Chen et_ al_., 1975; Rosenkranz and
Speck, 1975; Rosenkranz and Poirer, 1979).
Diepoxybutane and ethylene oxide have both induced mutations at the
adenine locus of Neurospora (Kolmark and Westergaard, 1953) and to increase
several types of mutations in barley seeds (Ehrenberg and Gustaffson, 1957).
Ehrenberg has estimated that diepoxybutane is 200 times more active than
ethylene oxide in producing this effect in barley. Both ethylene oxide and
diepoxybutane increase the incidence of lethal mutations after injection in
Drosophila (Bird and Fahmy, 1953).
167
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Simmon (1979b) showed increased mutations in Saccharomyces following
exposure to 0.6% butylene oxide; inclusion of microsomal activation mix
reduced the number of mutations observed.
Teratogenic effects have been observed following injection of ethylene
oxide into rats during gestation (Kimmel and Laborde, 1979). Doses of 150 mg/kg of
ethylene oxide injected daily for three days at different times during gestation
increased fetal malformations when injected at days 6 to 10 of gestation. Chloro-
ethanol, a potential reaction product of ethylene oxide, produced fetal malforma-
tions after injection into the air sack of chick embryos (Versett, 1974).
Carcinogenic effects were reported after exposure of test animals to
ethylene oxide, propylene oxide, and diepoxybutane. Reyniers and coworkers
(1964) noted ovarian, lymphoid, and pulmonary tumors in female germ-free mice
exposed to ethylene oxide-treated corncob bedding. No chemical analysis of
the bedding was carried out, so the implication of ethylene oxide involvement
is circumstantial. Colony mates raised on nontreated bedding did not develop
tumors. Both Van Duuren et al. (1965) in skin painting studies on mice, and
Walpole (1958) in injection studies on rats, were unable to demonstrate in-
creased tumors from ethylene oxide exposure. Walpole (1958) reported that
eight rats injected subcutaneously with a total dose of 1.5 mg/kg of propylene
oxide over 325 days developed tumors in 507 to 739 days (schedule not indicated).
Diepoxybutane has been shown to produce tumors following skin painting
(McCammon jit al., 1957; Weil ^t al., 1963; Van Duuren et^ al., 1966; Shimkin
e£ 3..L. , 1966), and to act as a tumor initiating agent in mouse skin (Van Duuren,
1969). Butylene oxide applied for 540 days (3 times weekly) at the level of
100 mg to mouse skin did not produce tumors (Van Duuren et al., 1967).
168
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The epoxides have produced neurotoxic effects, reproductive effects,
and bone marrow effects, and have demonstrated mutagenicity, teratogenicity,
and carcinogenicity. Exposure of humans to these compounds should therefore
warrant caution. Long-term effects from low-level exposure of these compounds
have not been well characterized; this type of exposure and consequent effects
appear to be very pertinent to human exposure and risk. Industry is sponsoring
inhalation studies on ethylene oxide (complete by summer 1980) and propylene oxide
(complete by summer 1982) (Kurginski, 1979).
169
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CONCLUSIONS AND RECOMMENDATIONS
From the preceeding literature review and evaluation the following
conclusions and recommendations seem justified.
1. Ethylene oxide (EO) and propylene oxide (PO) are produced and
consumed in very large quantities (estimated at 4,423 million
pounds and 1,897 million pounds, respectively, in 1977). They
are primarily consumed as synthetic intermediates and in
polymer production.
2. Butylene oxide is produced and used in a moderate amount
(ca. 9.5 million pounds in 1974) but the current trends indi-
cate that commercial production and use will fall to 1.5 million
pounds in 1980. It is primarily consumed as a scavanger in
chlorinated solvents.
3. Diepoxybutane is produced in insignificant quantities.
4. At ambient temperature EO is a gas and PO is a volatile liquid,
so potential exists for their release to the environment.
5. Insufficient information currently exists on the atmospheric
release of EO and PO during manufacture and use for chemical
synthesis and in polymer manufacture. Specific evaluation of
all modes of environmental release of EO and PO should be per-
formed.
6. Relatively small amounts of EO and PO are applied as a fumigant or
sterilant to a wide variety of consumer items (less than 0.1
million pounds per year for EO and even less for PO), which
include food commodities, medical devices, Pharmaceuticals,
and cosmetics. This use of EO and PO created the only documented
human exposure from the manufactured product other than accidental
occupational exposure. The extent of this exposure needs to be
documented.
7. EO and PO are products of partial combustion and have been
identified in automotive exhaust, roasted foods, and tobacco
smoke (inhaled and side stream). EO appeared in smoke from
tobacco which was not fumigated with EO, but if tobacco was
so fumigated, the EO concentration of the smoke increased.
8. The epoxides show a wide range of mutagenic effects. Mammalian
mutagenic effects need to be confirmed in experiments involving
administration of the compounds by routes relevant to human
exposure - i.e., dermal, oral, and inhalation routes. Diepoxy-
butane and other reactive epoxides have been shown to have
tumorigenic activity.
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9. The carcinogenic activity of ethylene oxide, propylene oxide,
and butylene oxide should be further evaluated, as well as
the teratogenic activity of these same compounds.
10. Long term effects of neurotoxicity, chromosome aberrations,
reproductive effects, and leukemia in workers exposed to
ethylene oxide have been reported. The incidence and
reversibility of these effects in human populations needs
to be defined. Similarly, long term effects from indwell-
ing or repeated usage of plastic medical devices sterilized
with ethylene oxide needs evaluation. Effects of human
exposure to butylene oxide and diepoxybutane have not been
reported.
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TECHNICAL REPORT DATA
(Please read lauructitim on the reverse before completing)
1. REPORT NO.
EPA-560/11-80-005
3. RECIPIENT'S ACCESSION-NO.
4. TITLE AND SUBTITLE
Investigation of Selected Potential
Environmental Contaminants: Epoxides
S. REPORT DATE
March 1980
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Dennis A. Bogyo, Sheldon S. Lande, William M. Meylan,
Philip H. Howard, Joseph Santodonato
8. PERFORMING ORGANIZATION R'EPORT NO
TR 80-535
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Center for Chemical Hazard Assessment
Syracuse Research Corporation
Merrill Lane
Syracuse, New York 13210
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
EPA 68-01-3920
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Final Technical Report
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report reviews the potential environmental and health hazards associated with
the commercial use of selected epoxide compounds. Four commercial compounds are
discussed in the report: ethylene oxide - primarily used as a chemical intermediate;
propylene oxide - primarly used as a chemical intermediate; butylene oxide-primarily
used as a stabilizer for chlorinated solvents; and diepoxybutane - primarily used
as a specialty chemical. Data on physical-chemical properties, production methods
and quantities, commercial uses and factors affecting environmental contamination,
as well as information related to human health and biological effects, are reviewed
and evaluated.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
ethylene oxide
propylene oxide
butylene oxide
diepoxybutane
b.lOENTIFIERS/OPEN ENDED TERMS
epoxides
toxicity
production
commercial use
chemistry
environmental fate
c. COSATI I'icld/Group
18. DISTRIBUTION STATEMENT
Document is available to the public through
the National Technical Information Service
Springfield. VA 22151
19. SECURITY CLASS (This Report)
21. NO. OF PAGtS
20. SECURITY CLASS (This page)
22. PRICE
EPA Form 2220-1 (9-73)
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