INVESTIGATION OF SELECTED POTENTIAL
ENVIRONMENTAL CONTAMINANTS:
EPICHLOROHYDRIN AND EPIBROMOHYDRIN
Joseph Santodonato
Sheldon S. Lande
Philip H. Howard
Denise Orzel
Dennis Bogyo
March 1980
FINAL REPORT
Contract No. 68-01-3920
SRC No. L1342-05
Project Officers - Frank J. Letkiewicz
Carol E. Glasgow
Prepared for:
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
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TECHNICAL REPORT DATA
{Phase rrad faur.icnuns yi the rci'ersc before compleitng/
^E30RT SO.
EPA-560/11-80-006
'3. a€Ci?iENT's access;o**no
PR 80 19758 5
J TL: A\0 SU8TiTLc
Investigation of Selected Potential Environmental
Contaminants: Epichlorohydrin and Epibromo'nydrin
|S. REPOHT DATE
| March 1980
16. PERFORMING ORGAN'-/,'
I /£¦'
CODE
7 iUfHORISI
'8. PERFORMING ORGANIZATION RE°OR~ MO
Joseph Santodonato, Sheldon S. Lande, Philip H. Howard]
Denise Orzel, Dennis Bogyo i TR 80-543
9 PERFORMING ORGANIZATION NAME AND A 0 DRESS
Center for Chemical Hazard Assessment
Syracuse Research Corporation
Merrill Lane
Syracuse, New York 13210
I 10. program element no
|11. CONTRACT/GRANT NO.
I EPA 68-01-3920
12. SPONSORING AGENCY NAME ANQ.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 ASENC" CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report reviews the potential environmental and health hazards associated
with the commercial use of epichlorohydrin and epibromohydrin. Epichlorohydrin
is used primarily as a chemical intermediate in the production of glycerin and
epoxy resins, with small amounts exported or used for elastomers or other products.
Epibromohydrin was last produced on a commercial scale in 1975; the only current
use of epibromohydrin appears to be as a laboratory research reagent. Information
on physical and chemical properties, production methods ana quantities,
commercial uses and factors affecting environmental contamination, as well as
information related to health and biological effects, are reviewed and evaluated.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS.'OPEN ENDED TERMS c. COSATI HcM-'C
13. 'J1STHISUTICN STATEMENT i 19. SECURITY CLASS (This Reportf
Document is available to the public through]
the National Technical Information Service, (20. security class tThiipag<-t
Springfield, VA 22151 i
"l'Uroup
21. NO OF PACcS
22. PRICE
EPA Form 2220-1 (9-73)
/
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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
Epichlorohydrin (ECH) is produced in about 400 million lbs per year. It
is produced by two companies (Dow and Shell) at three sites. ECH is primarily
used as a chemical intermediate in the production of glycerin and epoxy
resins, with small amounts exported or used for elastomers or other products.
Epibromohydrin (EBH) was last produced on a commercial scale in 1975 when a
batch of 20,000 lbs was manufactured. Substantial amounts of ECH and other
chlorinated organics are released in air effluents or have to be disposed of
during production of ECH. One estimate suggests that approximately 600,000
lbs/per year of ECH are released in atmospheric venting. A recent derailment
and rupture of a tank car of ECH resulted in the release of 20,000 gallons of
ECH, evacuation of 400 people, and the closing of a public water supply
plant.
Almost no U.S. effluent monitoring data and no ambient monitoring data
on ECH are available, although Russian studies have detected ECH in air
samples near factories and in structures where epoxy resins and plastics were
used. ECH hydrolysis occurs in water with a half-life of 4-8 days. Under
smog conditions, its half-life in the atmosphere is 16 hrs but its reactivity
under less polluted conditions is unknown.
Investigations of the biological effects produced by contact with ECH
were begun several decades ago. Animal studies and case reports from occu-
pational exposures have clearly shown that ECH is irritating to the eyes,
skin, and respiratory tract.
Systematic studies of ECH-exposed worker populations have recently re-
vealed the presence of chromosome abnormalities in certain blood cells. The
iii
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significance of these changes is not known, but they may indicate a potential
increase in carcinogenic and/or mutagenic risk from ECH absorption. One
epidemiologic investigation of 864 active and retired workers exposed to ECH
has shown an excess incidence of death due to cancer of respiratory organs.
Deficiencies in the available data base prevent the formulation of definitive
conclusions, but nevertheless the results were interpreted to indicate a
possible carcinogenic threat by ECH in occupational situations. There are no
confirming data in human populations, however, regarding ECH as a carcinogen.
Preliminary results from animal bioassays with ECH are now available
which demonstrate a carcinogenic effect from inhalation exposures to rats.
Using various concentrations and treatment schedules, ECH induced squamous
cell carcinomas of the nasal cavity in certain animals. This type of tumor
is very rare in rats, and thus clearly appeared to be treatment-related. The
potential carcinogenicity of ECH is further supported by the results of muta-
genicity assays with bacteria.
It is not clear whether current levels of ECH in the environment pose a
threat to public health. Likewise, there is at present an insufficient data
base to predict any ecological effects due to ECH contamination. However,
extrapolations from animal bioassay data and studies in worker populations
lead to the conclusion that ECH may pose a carcinogenic threat to man. The
magnitude of any potential threat is presently unquantified.
iv
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TABLE OF CONTENTS
Page
EXECUTIVE SUMMARY iii
LIST OF TABLES viii
LIST OF FIGURES x
I. Physical and Chemical Data 1
A. Structure and Properties 1
1. Chemical Structure and Nomenclature 1
2. Physical Properties of the Pure Material 1
3. Properties of Commercial Material 4
4. Principal Contaminants of the Commercial Product 5
B. Chemical Reactions in the Environment 6
Hydrolysis and Related Reactions 6
2. Oxidation 17
3. Photolysis 20
II. Environmental Exposure Factors 21
A. Production and Consumption 21
1. Quantity Produced 21
2. Producers, Distributors, Production Sites
and Capacities 24
3. Production Methods and Processes 26
4. Market Prices 32
5. Market Trends 32
B. Use of Epihalohydrins 33
1. Major Uses and Their Chemistry 33
a. Synthetic Glycerin 33
b. Epoxy Resins 34
2. Minor Uses of Epichlorohydrin 37
a. Epichlorohydrin Elastomers 37
b. Other Uses 40
3. Discontinued Uses 40
4. Proposed Uses 41
5. Alternatives to Uses 42
v
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TABLE OF CONTENTS (Continued)
Page
C. Environmental Contamination Potential 42
1. General 42
2. From Production 43
3. From Transport and Storage 46
4. From Use 50
5. From Disposal 50
6. Potential Inadvertent Production in
Industrial Processes 53
7. Potential Inadvertent Production in the Environment 56
D. Analytical Methods 62
E. Monitoring 66
III. Health and Environmental Effects 70
A. Environmental Effects 70
1. Persistence 70
a. Biological Degradation Organisms and Products 70
b. Chemical Degradation in the Environment 73
2. Environmental Transport 75
3. 3ioaccumulation and Biomagnification 77
B. Biological Effects 78
1. Toxicity and Clinical Studies in Man 78
a. Occupational Studies 78
b. Poisoning Incidents and Case Histories 84
c. Epidemiology 86
2. Effects on Non-Human Mammals 38
a. Absorption, Distribution, and Excretion 88
b. Pharmacology and Metabolism 89
c. Acute Toxicity 90
(1) Acute Inhalation Exposures 90
(2) Acute Oral Exposures 95
(3) Acute Dermal and Eye Contact 95
(4) Acute Parenteral Administration 97
d. Subchronic Toxicity 98
e. Sensitization 106
f. Reproductive Effects and Teratogenic Effects 106
vi
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TABLE OF CONTENTS (Continued)
Page
g. Mutagenicity 108
(1) Epichlorohydrin 108
(2) Epibromonydrin 114
h. Carcinogenicity 114
3. Effects on Other Vertebrates 117
4. Effects on Invertebrates 117
5. Effects on Plants 117
6. Effect on Microorganisms 118
IV. Regulations and Standards 119
A. Current Regulations 119
1. NFPA Hazard Identification Code 119
B. Food Tolerances 120
1. Food 120
2. Pesticides 120
3. Standard for Human Exposure 121
C. Current Handling Practices 121
1. Special Handling in Use 121
2. Storage and Transport 122
3. Accident Procedures 123
a. First Aid 123
b. Spill or Leak Procedures 123
V. Exposure and Effects Potential 124
A. Human Exposure 124
B. Environmental Effects 125
VI. Iechnical Summary 127
REFERENCES 132
CONCLUSIONS AND RECOMMENDATIONS 144
vii
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LIST OF TABLES
Table Page
1. Structure and Nomenclature of Epichlorohydrin and
Epibromohydrin 2
2. Physical Properties of Epichlorohydrin and Epibromohydrin 3
3. Rate Constants for Hydrolysis of Epichlorohydrin 11
4. Rate Constants for Epichlorohydrin Reaction with Various Anions 12
5. Activation Parameters for Epichlorohydrin Hydrolysis Reactions 13
6. Values for Calculating Epichlorohydrin Reaction Rates with
Various Nucleophiles Using the Scott-Swain Relationship 16
7. U.S. Production and Sales of Refined Epichlorohydrin
(Millions of pounds) 22
8. Estimated U.S. Consumption and Exports of Epichlorohydrin - 1973
(Millions of Pounds) 23
9. Plant Capacity and Site for Epichlorohydrin Manufacture 25
10. U.S. Imports of Epichlorohydrin, 1974 27
11. Estimated U.S. Consumption of Refined Epichlorohydrin for
Unmodified Epoxy Resins, 1973 38
12. Producers and Sites of Unmodified Epoxy Resins 39
13. Expected 1977 Pollutant Generation from Epichlorohydrin
Manufacture (Based upon Figure 1) 45
14. Atmospheric Emissions from Glycerin (Glycerol) Plants using
Epicholorohydrin and/or Allyl Chloride as Feedstocks 47
15. Major Components of the Liquid Heavy Ends (Still Bottoms) from
Epichlorohydrin Manufacture 52
16. Potential Precursors for the Inadvertent Production of
Epihalohydrins 54
17. Observations of Potential Epihalohydrin Precursors in Water 57
18. Kinetic Data for Epoxide Formation from Halohydrins in Water 60
19. Summary of Analytical Methods for Epihalohydrins 67
viii
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LIST OF TABLES (Continued)
Table Page
20. Atmospheric Monitoring of Epichlorohydrin in the Soviet Union 69
21. Products from Enzymatic Conversion of Epihalohydrins and
Raloalcohols 71
22. Mutagenic Effect of Epichlorohydrin and TEPA in Different
Concentrations (Lymphocytes exposed to epichlorohydrin (ECH)
and TEPA during last 24 hours of cultivation) 81
23. Chromosomal Analysis of Workers Occupationally Exposed to
Epichlorohydrin 82
24. Acute Toxicity of Epichlorohydrin (ECH) 91
25. Effect of Epichlorohydrin on Fertility in Male Rats 107
26. Reverse Mutations Induced by Epichlorohydrin Without Metabolic
Activation 109
27. ECH Induced Changes in Mouse Bone Marrow by Intraperitoneal
Application 112
28. ECH Induced Changes in Mouse 3one Marrow by Peroral Application 113
ix
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LIST OF FIGURES
Figures Page
1. Epichlorohydri.il Manufacture 28
2. Glycerin (Glycerol) Manufacture 31
x
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I. Physical and Chemical Data
A. Structure and Properties
1. Chemical Structure and Nomenclature
Epihalohydrins are y-halogenated derivatives of ct,6-propylene
oxide:
In this review, X is either chloride or bromide; they are commonly known as
epichlorohydrin and epibromohydrin, respectively. The IUPAC system names them
as derivatives of oxirane (which is commonly known as ethylene oxide):
Thus, epichlorohydrin and epibromohydrin are listed as chloromet'nyloxirane
and bromomethyloxirane, respectively, by the IUPAC system. Table 1 lists
other common names and the CAS Registry Numbers. Throughout this report, the
names "epichlorohydrin" and "epibromohydrin," or abbreviations "ECH" and "EBH,"
respectively, will be used.
2. Physical Properties of the Pure Material
Table 2 summarizes the major physical properties of ECH and EBH.
Both are colorless liquids at room temperature with irritating chloroformlike
odors. ECH is slightly volatile and water soluble. EBH is denser, higher
boiling, and less water soluble (Weast, 1975). Both form azeotropes with water
and also with organic liquids (Prager and Jacobson, 1933). The ECH water
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Table 1. Structure and Nomenclature of Epichlorohydrin and Epibromohydrin
Molecular
Structure
CAS Number
IUPAC Name
Common Names
0
/ \
H C - CHCH Br
3132-64-7
bromometliyloxirane
epibromohydrin
l-bromo-2,3-epoxypropane
1-chloro-2,3-epoxypropane
3-chloro-l,2-cpoxypropane
(chloromethyl)ethylene oxide
2-(chloromethyl) oxirane
chloropropylene oxide
y-chloropropylene oxide
3-chloro-l,2-propylene oxide
a-epiclilorohydrin
(DL)-a-epichlorohydrin
1.2-epoxy-3-chloropropane
2.3-epoxypropyl chloride
0
/ \
h2c - chch2ci
106-89-8
chloromethyloxirane
epichlorohydrin
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Table 2. Physical Propcrti
es of Epichlorohydrin and Epibromohydrin^"
-6
Epichlorohydrin
Epibromohydrin
Molecular weight
92.53
136.98
Color
none
none
State at STP
liquid
liquid
Boiling point
116. 2°C (760 nun) ;
47.4-48.4°C (70 nun)
138-140°C (760 nun);
63-64.4°C (60 nun)
Melting point
-57.2°C4
-40°C
Density
20 25
d. 1.1812; d. 1.1750
4 4
d^l-663
Refractive index
25
n^ 1.4359
n^3l.4780
Vapor pressure
79.8 torr (55.2°C)
Viscosity
0.9116 g/cra-sec (29°C)
0.92 centistokes (25°C)
Solubility
Water (weight percent)
Ethanol
Diethyl ether
Acetone
Chlorinated aliphatic hydrocarbons
PenLroleum hydrocarbons
Benzene
6.52 (10°C); 6.58 (20°C)
soluble
soluble
soluble
soluble
soluble
soluble
insoluble
soluble (hot)
soluble
soluble
soluble
iIARC, 1976 3NIOSH, 1976
^Prager and Jacobsen, 1933
2Weast, 1975 4Shell, 1969
^Great Lakes Chemical Corp., 1975
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azeotrope distills at 86° and contains 75% epichlorohydrin by weight
(Licntenwalter and Riesser, 1964).
No ultraviolet spectra were available for the two compounds.
Based upon the epihalohydrin structure (which combines alkyl halide and alkyl
epoxide), it is reasonable to infer that absorption maxima will be below
300 nin, which is the cutoff for sunlight. The tail of the EBH absorption
peak might extend above the 300 nm region (Calvert and Pitts, 1966).
Electron diffraction studies on EBH by Igarachi (1961) showed
that the bromine atom favors trans orientation to the oxirane ring. Thus, it
appears that the epihalohydrins favor the rotameric structure:
X
X0
The 5-carbon of the halohydrins is asymmetric and the enantiome
18
have been isolated. Optical activity has been reported as [o.]^ = -25.6° for
18
the levorotatory enantiomer of ECH and [ci]^ = +23.1° for dextrorotatory.
Enantiomers of both halohydrins are racemized by distillation at atmospheric
pressure (Prager and Jacobson, 1933).
3. Properties of Commercial Material
Commercial refined grade epichlorohydrin is a high-purity
material (ca. 99%) with properties as described previously for the pure mate-
rial. The sales specifications for refined epichlorohydrin are as follows
(Shell, 1970):
-------
Purity, % weight, min.
Specific Gravity, 20/20°C
Water, % weight, max.
Color, APHA, max.
Distillation Range
99.0
1.181-1.184
0.10
15
Distillation Range, max.
Initial BP, min.
113 aC
118 °C
Specific sales specifications for crude ECH are not available
because practically all of it is used captively either to make glycerin or
refined ECH for epoxy resins. The properties of the crude no doubt differ from
the specifications above in relation to the impurities present in the particu-
lar batch.
Commercial specifications for EBH are not available from the
Great Lakes Chemical Corporation, the sole U.S. manufacturer, which claims it
is produced only occasionally in small batches on special order.
4. Principal Contaminants of the Commercial Product
Epichlorohyarin is prepared commercially by a sequence of
reactions: propene and chlorine are reacted to form allyl chloride; allyl
chloride is reacted with hypochlorous acid to form dichlorohydrins; and the
dichlorohydrins are reacted with sodium hydroxide or calcium hydroxide to form
ECH (Oosterhof, 1975). The reactions are described in Section II-A-3.
The major by-products are:
cis- and trans- 1,3-dichloropropene
1,2-dichloropropene
1,2,3-trichloropropane
Dichloropropanols
Chlorinated ethers
Chlorinated, saturated, and unsaturated short-chained
aliphatic hydrocarbons
All of these chemicals are potential contaminants of the final product. They
are rated as moderately toxic (Gruber, 1976).
The dichloropropenes are commercially useful as nematocides.
Dow Chemical and Shell Chemical recover them and they are marketed under the
:>
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tradenames "Telone" and "D-D," respectively. The active ingredient is 1,3-
dichloropropene, which accounts for approximately 50-60% (by weight) of the
commercial nematocide (Oosterhof, 1975).
The refined, commercial epichlorohydrin is specified as 99% pure
(see Section I-A-3) which can include as much as 0.1% water. The composition
of the organic contaminant was not available.
No information was available concerning the principal contaminants
of commercial epibromohydrin.
B. Chemical Reactions in the Environment
While available literature provides a good description of hydrolysis
and related reactions of the epichlorohydrins, little information was available
on their photochemistry or oxidation in environmentally significant conditions.
The epihalohydrins are not persistent and appear to hydrolyze in several weeks'
time. No field studies on the epihalohydrins were found in the literature.
1. Hydrolysis and Related Reactions
The epihalohydrins hydrolyze by a complex scheme. Although most
of the studies have investigated only ECH, based upon limited available litera-
ture EBH does appear to hydrolyze by the same scheme and probably at slightly
faster rates. Virtually all the published information has attempted to deline-
ate mechanisms and rates of epoxide hydrolysis. Although none of the studies
have investigated hydrolysis at environmental conditions, the large quantity of
excellent data permits insight into expected hydrolysis rates and products in
the ambient environment.
The literature concensus is that ECH hydrolyzes as expected of a
derivative of 1,2-propene oxide. The chlorine atom does not react or directly
participate in initial hydrolysis, but it does affect the initial hydrolysis
6
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race by its inductive and electronic effects (Ross, 1950, 1962; Pritchard and
Long, 1956; Pritchard and Siddiqui, 1973; Kwart and Goodman, 1960).
ECH, as well as other 1,2-propene oxides, hydrolyzes by four
pathways (Bronsted et_ aJL. , 1929; Ross, 1950):
/°\ k!
C1CH2CH - CH2 + H O —ClCH2CH(OH)CH2OH Reaction 1
/°\ + k2 +
CICH^CH - CH,, + H30 —C1CH7CH(0H)CH20H + H Reaction 2
0 i,
/ \ 3
A + ClCH^CH - CH0 + H^O —=L-> CICH^CH(OH)CH0A + OH Reaction 3
+ k4
A + C1CH CH - CH,, + HO —C1CH,CH(0H)CH,A + H?0 Reaction 4
The reaction mechanisms are similar for the uncatalyzed (Reactions 1 and 3) and
acid-catalyzed (Reactions 2 and 4) hydrolyses. In uncatalyzed reactions,
either water or anion opens the epoxide by attack at C-l in Che rate deter-
mining step (Bronsted e_t al. , 1929; Kwart and Goodman, 1960; Long and
Pritchard, 1956; Addy and Parker, 1965):
/A
C1CH? CH - CH2 + A
0
X \
C1CH0CH - CH2
h2o
OH
i
ClCH.CHCH^A +
OH
/
-------
The acid catalysed reactions have been identified as an A-2 mechanism. ECH is
protonated reversibly, then the protonated ECH reacts with water or anion.
Ring opening again occurs at C-l in the rate determining step (Bronsted et_ al.,
1929; Long and Pritchard, 1956; le Noble and Duffy, 1964):
H .
K
0
/ \
C1CH_,CH - CHn + H_0 -
I I J t
/0\
-h2o
^ C1CH2CH - CH, + A
v/
C1CH.CH - CH
i 2
I
A
J
OH
I
C1CH CHCH2A
Rate for Reaction 1 = k, C„„T
1 r.Cn
Rate for Reaction 2 = k0 C +
2 ECH rl^O
Rate for Reaction 3 = k C C
.J DL
-------
discussion. The reaction between ECH and water, which yields 3-chloro-l,2-pro-
panediol (CPP), has the rate expression:
rpp
- = (k, + k„ C„ rt+)C__, Equation 5
at 1 2 H30 ECH
The reaction between ECH and each anion, A^, will yield l-substituted-3-chloro-
2-propanol (SCPi). For example, ECH reacts with chloride, yielding 1,3-di-
chloro-2-propanol at a rate given by:
dCcrPi
-dT" " 'S/a, +k4.CA.W>CECH Equation 6
i i 1 i 3
The ratio of each substitution product to CPP (initial production, prior to all
subsequent product degradation reactions) can be calculated as:
CSCP, k3 CA. + k4.CA.CH.0+
i - —i—i i—i—-— Equation 7
CCPP k3 + k2CH30+
The overall degradation rate is the sum of water hydrolysis and all reactions
with anions:
d C
ECH
d C
d C
CPP
dt
dt
SCP,
dt
kl + k2CH30+ +
I(k
1
3. + k4.CH,0+)CA( iCECH
i x 3 ij
Equation 8
9
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The initially formed products can react further. The two most
common reactions of the initial products are their subsequent hydrolysis to
yield 3-chloro-l,2-propanediol or ring closure to yield a new epoxide. An
example of the former is the apparent reaction between carbonate or bicarbonate
with ECH. Shvets and Aleksanyan (1973) deduced that carbonate (and bicarbonate)
directly reacts with ECH from observed reaction kinetics, but a carbonate (or
bicarbonate) ester could not be isolated. They concluded that the carbonate
(and bicarbonate) esters are hydrolyzed. The epoxide formation is a general
base assisted reaction; 3-chloro-l,2-propanediol reacts with hydroxide to yield
glycidol (Shell, 1969):
OH + CLCH2CHCH2OH CH, - CHC^OK + CI
Epoxide formation is discussed further in Section III-A-1-2 (Chemical Degrada-
tion in the Environment).
Most of the information necessary for the product and half-life
calculations for environmental hydrolysis of ECH either has been experimentally
measured or a reasonable value can be estimated from available data. Table 3
summarizes the ECH hydrolysis rate constants, k^ and k2> Table 4 lists the
experimentally derived rate constants, k2 and k^, for anion reactions with ECH.
Rate constants can be calculated at any temperature with the
activation energy, E^, by the Arrenhius equation:
ln W ¦ r Equation 9
where R is the gas constant and T is the absolute temperature. Activation
energies only were available for a few of the ECH hydrolysis reactions (Table 5),
10
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Table 3. Rate Constants for Hydrolysis of Epichlorohydrin
6 5
temperature 10 k. 10 k?
(°C) , -17 n
(s > (1 no 1 s )
20.0 .
0.97
25.0
,3
35
5.9
37
5"3d
45
13.8^
50
20.4d
75
129d
85
246d
3 Pritchard and Siadiqui, 1973
^ 3ronsted, Kilpatrick, and Kilpatrick, 1929
c
le Noble and Duffy, 1964
^ Shvets and Aleksanvan, 1973
6 Ross, 1962
11
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Table 4. Rate Constants for Spichlorohydrin Reaction with Various Anions
105k, 102U
Temperature, 3 , 7
Anion °C (I mol s ) (1^ mol
Chloride, Cl" 20 1.15a, 0.99C 0.45a
40 6.3b 6.8
Bromide, Br 20 6.2a, 6.3° 2. 2a
Iodide, 1~ 20 10.0a
Thiosulfate, §20^ 20 6.3a
Fooiate, HC0? 20 0.47a
Benzoate, C,H.C0^ 20 0.52a
b j I
Acetate, CH C0? 20 C.62a
37 3.33°
Nitrate, NO ~ 20 0.022d
Bicarbonate, HC0. 65 0.176
75 0.30e
80 0.52e
85 0.68e
Carbonate, CO. 35 0.42e
3 45 0.336
50 1.426
60 2.5e
3 Brcinsted, Kilpatrick, and Kilpatrick, 1929
k Adciy and Parker, 1965
C Ross, 1950
Petty and Nichols, 1954
6 Shvets and Aleksenyan, 1973
12
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Table 5. Activation Parameters for Epichlorohydrin Hydrolysis Reactions
Reference
Reaction
AS
Shvets and Aleksanyan, 1973
ECH + HC03 v
ECH + C03" >•
18.A + 0.8 -21.7 + 0.9
17.7 + 0.7 -16.8 + 0.7
Pritchard and Siddiqui, 1973
Addy and Parker, J 9 6 5
ECH + HO ~
0
+
CH CHCH + H O ~
J L 3
0
/1 +
(CH3)2CIICH2 + H30 >
0
/ \
CH CHCH + CI >-
0
/\ - +
CH CHCH CI + HO
19.86 + 0.91 -8.1 + 3.2
19.01 + 0.23 -5.1 + 0.8
19.34 + 0.23 +7.9 + 0.8
18.8 + 0.9
-22.2 + 2.7
18.3+0.9 -3.A + 2.7
-------
but this limited group includes the most significant environmental reactions:
hydrolysis and the reactions with chloride, carbonate, and bicarbonate. The
activation energies are in the narrow range of approximately 17.5 to 20 kcal/mole.
An E of ca. 19 kcal/mole is suggested as an estimate £or other anion reactions.
Bronsted ana coworkers (1929) noted a proportionality between
the rate constants for catalyzed and uncatalyzed reactions:
ko = K
T k~ ^ 450
1 3
Their data was limited to the hydrolysis (reaction with water) and the re-
actions with chloride and bromide at 20°. Petty and Nichols (1954) reported k^
and k^ with approximately this ratio for ECH reaction with nitrate at 20°,
also. If this ratio does extend to all anions, then for prevalent environ-
mental conditions the acid catalyzed reactions will not significantly con-
tribute to the hydrolysis rates. For this approximate ratio, Equation 6 yields
the following rates for pH 7 and pH 4, respectively (see below):
^ ^SCP f -7 \
- ' k„ C. + 450 x 10 k„ C. \ ~ k_ C. C,
dt \ 3 A 3 A ECP ~ 3 k ECP
ii|CP - (k3 CA + A50 X 10"4 k3 CA) CEcp« 1.05 k3 C4 C£cp
The Swain-Scott relationship provides an excellent estimate for
k^ values (Ross, 1964; Petty and Nichols, 1954):
log ka/ko = sn
where ka and ko (= k^/55.56) are rate constants for anion reaction and hydroly-
sis, respectively, and s and n are the substrate (0.93 for ECH) and nucleophile
14
-------
constants, respectively. It could be used to estimate the rate for anions for
which no experimental values are listed. Table 6 summarizes values for n.
Although very little information was available for EBH, a study
by Pritchard and Long (1956) on hydrolysis rates at 0° for both ECH and EBH,
as well .as other epoxides, demonstrated that the two epihalohydrins have almost
identical rates and undoubtedly have similar mechanisms. The rate constants
(as log k^) were linear as functions of Hq, but not when graphed as functions
of C„+. At H = 0, the rate constants for ECH and ECB, respectively, were
II o
3.8 x 10 ^ s ^ and 4.8 x 10 ^ s ^ and had slopes (log k^ vs. -H ) of 0.86 and
0.87, respectively.
Equation 7 was used to calculate ECH half-lives for hydrolysis
in distilled water (pH 7) and sea-water (?H 7, 3% NaCl) at 20°. Hydrolysis
**6 —1 —4
rate constants applied to the calculations are k^ ¦ 1 x 10 s ; k9 =» 4.3 x 10
1 mol"1 s"1; k3 = 1 x 10~5 1 nol"1 s"1;. and k4= 0.5 x 10"2 l2 nol"2 s_i.
Degradation half-times were 8.0 days in distilled water and 5.3 days in 3%
NaCl. The product ratio of l,3-dichloro-2-propanol:3-chloro-l,2-propanediol
was calculated by Equation 8 as 2:1.
In conclusion, ECH and ECB will hydrolyze in the environment.
The half-life and products will vary with the ionic content of the water. The
maximum half-life for ECH at 20° is about 8 days. ECH is expected to hydrolyze
faster if the water contains high chloride or high carbonate-bicarbonate content.
While the hydrolysis product is 3-chloro-l,2-propanedioI, significant concen-
trations of other products can be formed from reaction with aqueous anions.
These products include 1,3-dichloro-2-propanol from reaction with aqueous
chloride. The initial products can react further (see Section III-A-l-b).
15
-------
Table 6. Values for Calculating Epichlorohydrin Reaction Rates with Various
Nucleophiles Using the Scott-Swain Relationship3, (adapted from Ross,
1962)
Nucleophile n
H2°
0
SO, ~
4
2.5
ch3co7-
2.72
Cl"
3.04
W
3.6
OH"
4.2
SCN"
4.77
I"
5.04
MS-
5.1
S2°3=
6.36
a log ka/ko = 0.93n
16
-------
EBH will react in analogous pathways and, most probably, at a slightly faster
rate.
2. Oxidation
Shell Chemical Company (1969) lists several oxidation 3nd
reduction reactions of ECH:
HNO ?,
CH. - CHCK.Cl C1CHoC0H
N: / ^
x 0
ITT
CH„ - CHCH CI v C1CH-CH.CH,
"V ' 2 ^ 3
Na (Hg)
CH„ - CHCH0Cl —-— CH. » CHCH-OH + other products
>v2 / 2 net ether 2 2
0
None of these reactions are important in the environment.
The epihalohydrins can be oxidized by free radical processes in
liquid phase (Dobbs ^t_ al_., 1976; Beckwit'n, 1972) or gas phase (Dilling et al.,
1976). These reactions probably occur in epihalohydrin oxidation in p'noto-
chetnically initiated atmospheric reactions (Gay and Bufalini, 1971; 3ufalini,
1971). The liquid phase free-radical oxidations which are discussed herein are
probably not important in environmental waters, but they are possible mechanisms
by which the epihalohydrins are oxidized with atmospheric free-radical initia-
tors .
Available literature only evaluated the mechanisms of liquid
phase reactions with a few free radical initiators. The epihalohydrins yield
free-radicals which, in part, depend upon the radical initiator. Dobbs and
coworkers (1976) suggested that _t-butoxyl radical, (CH^^CO*, preferentially
17
-------
abstracts an alicyclic hydrogen atom, while hydroxyl radical, HO-, prefer-
entially reacts with acyclic alkyl groups. Their experimental work on the
epihalohydrins was limited to the identification of species formed fay reactions
with hydroxyl radicals produced by the titanium (III) ion-hydrogen peroxide
system. ECH yielded two radicals which they identified by electron spin reso-
nance (esr) as:
and CHCl CH CH(OH)
Also, they trapped the initially formed radicals with nitromethane and identi-
fied the only new adduct by means of esr as:
They interpreted the results as evidence for two pathways of hydrogen abstrac-
tion. Dobbs and coworkers suggested that the propenediol radical formed by the
sequence:
CH2 C
-------
The tertiary radical initially generated would also yield the nitromethylene
adduct observed by esr. A second radical would explain the chloropropenol
radical:
ClCH. - CH - CH. '°H v clCH - CH - CH. ~ ClCH CH CHOH
2 \ / 2 \ / 2
x0 x0
Another type of radical abstraction reaction has been identified
with EBH (Dobbs et_al., 1976; Beckwith, 1972). The system of titanium (III) -
hydrogen peroxide - phosphorous acid or "nypophosphorous acid will yield various
2-
phosphorus-containing radicals: ; -HPO^ ; ! etc. These phos-
phorous radicals will abstract bromine atoms, rather than hydrogen atoms, from
organics activated by resonance. However, the phosphorous radicals will not
abstract chlorine atoms from analogous structures (Beckwith, 1972). EBH will
react to yield an allylic alcohol radical:
HPO ~
BrCH. - CH - CH. —>- -CH. - CH - CH. <- CH. CH CH(OH)
2 \
-------
other than gas phase radical reactions initiated by species expected in the
photochemical smog cycle.
3. Photolysis
No ultraviolet absorption data were available for the epihalo-
hydrins. Neither the alkyl halides nor epoxides have strong absorption in the
sunlight region (wavelengths above 300 nm) (Calvert and Pitts, 1966). The
epihalohydrin absorption maxima are probably below 250 nm and, at most, will
have the tail ends of their absorption peak above 300 nm. No significant
environmental photochemistry is expected.
20
-------
II. Environmental Exposure Factors
A. Production and. Consumption
1. Quantity Produced
The total U.S. production of ECH for 1973 was estimated to be
approximately 345 million lbs. (Oosterhof, 1975). This included roughly
160 million lbs. of ECH as a feedstock for the manufacture of glycerin and
180 million lbs. of refined ECH, most of which went into production of epoxy
resins. Current production of ECH is judged to be higher than the 1973 esti-
mate. Industry expanded production capacity from 450 million lbs. in 1975 to
640 million lbs. annually by the end of 1978 (SRI, 1977). Market trends
discussed in Section 1I-A-5 can be used to estimate the 1977 production level
of ECH as roughly 400 million lbs. Table 7 lists data for the production and
sales of refined ECH from 1958 through .1973, with an estimated breakdown of
sales for 1973. Note from Table 7 that the quantity sold represents but a
fraction of the manufactured totals, much of which was (and still is) used
captively for producing glycerin, epoxy resins, and other products (Table 8).
The sole U.S. manufacturer of EBH, Great Lakes Chemical
Corporation (1978), has indicated that as of January, 1978, they last produced
a batch of EBH in 1975. The batch amounted to roughly 20,000 lbs. While they
have retained the ability to manufacture more in the future, they will do so
only on the demand of a customer, as the chemical is no longer an intermediate
for any other Great Lakes product. It therefore appears that EBH is only
marginally a commercial product, marketed by small companies such as Aldrich
Chemical, for sale as a research material.
21
-------
Table 7. U.S. Production and Sales of Refined Epichlorohydrin
(Millions of pounds) (Oosterhof, 1975)
Year
£
Production
C 1 b
Sales
1958
12.7
1959
25.2
1960
29.3
1961
20.1
1962
68.8
19.3
1963
A
1964
(85)
32.0
1965
1966
1967
1968
75.0
1969
(130)
1970
1971
1972
1973
(180)
(95)C
a _
Data
include production for
captive use in the manufacture of epoxy resins
and
other
products. Data exclude production of crude epichlorohyd
rin used
in the manufacture of synthetic glycerin.
b „
Data
include exports.
c
Sales of
refined epichlorohydrin in 1973 by the two U.S. producers
have been
estimated
to be as follows
(Oosterhof, 1975):
Millions
Estimated
Sales—1973
of
Pounds
For
epoxy
resins (estimated
at about 35%
of
the
total consumption
for epoxy
resins
of 130 million pounds)
45
For
epichlorohydrin elastomers
6
For
other
products
31
For
export
13
Estimated total sales
95
d
Figures in parenthesis are
estimated.
22
-------
Table 8. Estimated U.S. Consumption and Exports of Epichlorohydrin - 1973
(Millions of Pounds) (Qosterhof, 1975)
Crude Refined
Epichlorohydrin Epichlorohydrin
Synthetic Glycerin
160a'b
Epoxv Resins
134
130
Epichlorohydrin Elastomers
6
6
Other Products
32
31
Exports
13
13
Total Consumption
345
180
Crude epichlorohydrin used in the manufacture of synthetic glycerin is not
included in the production and sales data for refined epichlorohydrin
published by the U.S. International Trade Commission.
Chenical Marketing Reporter (1978) indicates that the demand for epichloro-
hydrin in the synthetic glycerin market has shrunk from 134 million pounds
in 1973 co about 65 million in 1977.
23
-------
2. Producers, Distributors, Production Sites, and Capacities
ECH is produced by Shell Chemical Company and Dow Chemical USA.
Plant sites and capacities are listed in Table 9. In addition, Ciba-Geigy
Corporation (Toms River, New Jersey) and Union Carbide Corporation (Institute,
West Virginia) have capacities for 35 million lbs. and 25 million lbs., re-
spectively, of refined ECH, although neither have recently produced it.
EBH is listed by Great Lakes Chemical Corporation as a current
product, but according to a spokesman for the company they ceased using it
captively six or seven years ago when a flame retardant for which it was an
intermediate was dropped from their product line. They do, however, retain
the capacity to produce EBH as customers require it. The last batch of about
20,000 lbs. was manufactured at El Dorado, Arkansas, in 1975. The actual
capacity of the El Dorado plant to manufacture this chemical is not available.
A number of relatively small chemical companies specializing in
rare and research grade chemicals offer ECH and EBH in their catalogs. Two
examples are Pfaltz and Bauer of Stamford, Connecticut, and Aldrich Chemical
of Milwaukee, Wisconsin. It is likely they purchase refined ECH from one of
the two manufacturers mentioned above, and they further purify it, if neces-
sary, before selling it. In the case of EBH, they may find it just as eco-
nomical to synthesize their own in small batches as to purchase it from Great
Lakes.
There is no indication that EBH is imported, but more than
500,000 lbs. of ECH were imported in 1974 (Oosterhof, 1975). This is less
24
-------
Table 9. Plane Capacity and Sice for Zpichlorohydrin Manufacture (SRI, 1979)
Annual Capacity
(millions of pounds)
Dow Chemical USA Freeport, Texas 260*
Shell Chemical Co. Deer Park, Texas 110
Norco, Louisiana 110
Total 480
*
To be expanded to 440 million lb/yr.; completing date third quarter 1980.
25
-------
Chan 0.5% of the domestic production. Table 10 lists the countries of origin
and the quantities involved for that year. An estimated 13 million lbs. were
exported in 1973 (Tables 7 ana 8).
3. Production Methods and Processes
The "allyl chloride" route is the only economically competitive
method for the synthesis of ECH and it is therefore the only one used by Dow
and Shell in the United States (Oosterhof, 1975). The raw materials required
are propene, chlorine, hypochlorous acid, and an alkali, either sodium or
calcium hydroxide. Figure 1 depicts the overall manufacturing sequence.
The first step in the process is the reaction of propene with
chlorine under free-radical conditions which favor substitution of a methyl
hydrogen with a chlorine atom rather than addition of chlorine to the double
bond. Such conditions include the presence of ultraviolet light and/or a
catalyst appropriate to encourage chlorine radical formation which initiates a
chain reaction:
Cl2 2C1-
•ci + h9c = CHCH3 ~ H2C - CHCH2 + HC1
H0C = CHCH2 + Cl2 >• H2C = CHCH2C1 + ci-
No natter how the reaction conditions may be adjusted to maximize the produc-
tion of the desired 3-chloropropene product as shown above, a mixture of by-
products is also produced consisting principally of 1,2-dichloropropane and
cis- and trans-1,3-dichloropropene. These by-products are isolated and sold
in nematocide products (see Section I-A-4).
26
-------
Table 10. U.S. Imports of Epichlorohydrin, 1974
(Oosterhof, 1975)
£
Country of Origin Pounds
Japan 246,917
The Netherlands 165,403
Italy 66,264
United Kingdom 39,154
Canda 15,800
Germany, Federal Republic of 3,596
Total 537,134
£
Some of the countries mentioned in the table do not produce
epichlorohydrin.
27
-------
BASIS: 1 KG EPICHLOROHYDRIN
H,0
VENT |
/
TAIL GAS
/•-JiSUnilUf
ci2
o!"9025
LIME SLURRY 1.009
CHLORIDE 0.977
REACTOR
,— *"
SOLVENT
(THI CHLOfiOPROPANE)
iCI'ARAT OK
o
TAIL GAS AOSOROER VENT-GAS
CHLORINE 0.0000005
HYDROGEN CHLORIDE 0.0000005
ALLYL CHLORIDE 0.002
ro AIR
©
VENT
REACTOR
SEPARATOR
Q
WATER
CaC 1.
©
REACTOR VENT-CAS
allyl CHLORIDE 0.002
CHLORINE 0.000DD05
TRICHLOROPROPANF 0.0005
HYDROGEN CHLORIDE 0.00000C5
EPICHLOROHYDRIN 0.0015
I
TO AIR
F
R
A
C
T
I
0
II
A
T
0
R
EPICJILOROHYORIN 1.0
SOLVENT TO RECYCLE
©
HEAVY ENDS
® ©
WATER • HEAVY ENDS 0.053 ©
„ „ , , CIILORGETHERS .0074
DICHLOROHYDRI.'I 0.01 EPICHI ORQMYDP.IN .00106 CaC32 0.590
i DICIILOKOIIYDRIN .00:,7 ,
T„ TRlCliLOROPCOPANE .03/1 »
TO WATER ^ TO WAT E R
TO LAND
Figure 1. Epiehlorohydrin Manufacture (Gruber, 1976)
-------
The second step in the commercial production of ECH is the re-
action of the 3-chloropropene (allyl chloride) with hypochlorous acid to yield
a mixture of dichlorohydrins (2,3-dichloro-l-propanol and 1,3-dichloro-2-
propanol):
h2c = chch2ci + hoci ~ cich2chcich2oh + cich2chohch?ci
In the third step, the dichlorohydrins are reacted with hydroxide
ion (from sodium or calcium hydroxide) to form the epoxide ring:
cich2cichch,oh
cich2ohch^ci
0
/ \
> + OH H?C - CHCH2C1 + HOH + CI
The resulting crude product is satisfactory for use in glycerin manufacture.
It is refined by distillation when destined for use in the manufacture of
epoxy resins and other applications requiring pure ECH.
Figure 1 illustrates the process flow for the production of ECH
from allyl chloride; the diagram also indicates process by-products ana re-
leases. Allyl chloride is fed continuously to a stirred tank where it reacts
at atmospheric pressure at 30-40°C in the liquid phase with a solution of
hypochlorous acid. The hypochlorous acid is produced in a packed tower by
dissolving chlorine in water. The reaction tank effluent is fed to a separator;
the upper layer (aqueous phase) is recycled to the hypochlorous acid tower.
The underflow, chiefly dichlorohydrins, is fed to the second agitated reactor,
where virtually quantitative conversion to epichlorohydrin by reaction with
lime slurry takes place. Trichloropropane is used as a solvent for the ECH.
The effluent from the second reactor is steam stripped, removing ECH as the
29
-------
water azeotrope. The undercut (calcium chloride solution, and the excess
line, in suspension) is sent to by-product recovery, or discharged through an
industrial outfall. The distillate's water and organic phases are separated,
with the undercut fed to a fractionating tower for recovery of ECH and sol-
vent. Ihe purified ECH cut is sent to storage. The recovered solvent is
recycled (Gruber, 1976).
Dow (1979) and Shell (1979) Chemical Companies have made the
following comments regarding Figure 1:
Vent No. 1: Does not exist in shell facilities.
Undergoes further processing at Dow - after processing,
atmospheric emissions are essentially negligible with
respect to chlorinated hydrocarbons.
Vent No. 2: Shell data show an emissions rate of 0.000005 pound ECH
emitted per pound produced.
Dow - same as Vent No. 1.
Stream No. 3: Is recovered by both Dow and Shell processes.
Stream No. 4: Recovered at Shell facilities, no discharge.
Undergoes further chemical processing for recovery or
thermal degradation of waste products (none subjected
to land disposal).
Stream No. 5: Subjected to biooxidation post treatment at Dow.
Notes: (1) The Shell facility has an additional vent not shown on
Figure 1; it is atop ECH finishing column and emits
0.0004 pound ECH per pound production.
(2) Shell estimates ECH waste from Shell facility to amount
to 0.00045 pound total per pound production.
(3) Dow estimates emission from process vents and storage
tanks to be less than 0.00003/lb.
A large fraction of ECH production is used to make glycerin.
In this process, the ECH is not purified or isolated from the system, but
rather, is used in a continuous flow operation. This entire operation is
shown in Figure 2.
30
-------
!
3
tornoci&s
SO* NaOM
SOllltllM
locnuoifo* »tn is
(IIIHAtl
chum i > iimciiiuRurAiifAw insniRACI tnm
*VV(NDSI««IIMNAM< (*• ii n'ium rftpu«Asn
ni lIMM^ in |N lllOMmi>OA|M|IOI| (villi* I
0-
f ^
1
f,
I
p
«
t
I
£
CIVClHOI
rnoouci
• OSIOBAf.l
Figure 2. Glycerin (Glycerol) Manufacture (Pervier et al., 1974)
i
-------
EBH could be made by a similar route, although the tendency to
form products other than. 3-bromopropene in the first step would be rather
high. This would tend to raise the cost of EBH even if it were made on as
large a scale as ECH. Blicke and Anderson (1954) report that EBH can be
prepared in 85-90% yields from y,g-dibromohydrin, which is made from
CH2:CHCH2OH and Br2-
Many chemical plants are capable of producing ECH from purchased 3-
chloropropene by running the last two steps of the sequence shown above.
Ciba-Geigy and Union Carbide used to make ECH this way (Oosterhof, 1975).
However, the economics of this route have been very unfavorable in recent
years and will probably remain so in the foreseeable future.
4. Market Prices
Prices for commercial quantities of EBH are not available since
this product is not presently marketed. In research quantities, it is availa-
ble from Aldrich Chemical Company for $5 per 100 grams, or S15 per 500 grams
(Aldrich, 1977). Other specialty chemical vendors are selling it for about
the same price.
The price of ECH in 1954 was 37c/lb. (tank cars, f.o.b. works).
It declined over the next decade to 27c/lb. (tank cars, delivered) in 1964.
Then, after a decade of stability, the price rose to 35-38c/lb. in 1975
(Oosterhof, 1975) and is currently about 48c/lb. (tank cars, delivered)
(Chemical Marketing Reporter, 1978a).
5. Market Trends
According to Oosterhof (1975), the total amount of ECH used for
the manufacture of glycerin will remain constant over the next few years, even
though the total quantity of glycerin produced will increase at a race of
about 2-3% per year; the balance will be manufactured by other means. Demand
32
-------
for ECH for other purposes is expected to grow at about 6-7% annually due to a
10% growth rate anticipated for its main use, epoxy resins. The total U.S.
capacity for ECH production is expanding to meet this increased demand and is
estimated to reach approximately 640 million pounds by the end of 1978 (see
Section 1I-A-2).
The Chemical Marketing Reporter (1978b) has indicated that
Shell expects a growth rate of 0 to 1% for ECH over the next 5 years; in con-
trast Dow indicated that the glycerin decline has been offset by a 8% increase
in the epoxy resin market resulting in a 3% per year increase since 1976.
3. Use of Epihalohydrins
1. Major Uses and Their Chemistry
ECH is primarily consumed as a chemical intermediate in the
production of epoxy resins and glycerin. The uses of ECH in 1973 are outlined
in Table 7 (see Section II-A-1). On a percentage basis, they were as follows:
glycerin, 46%; epoxy resins, 39%; exports, 4%; elastomers, 2%; and other
products, 9%. Current uses are judged to be generally the same, with a slight
rise in percentage going for epoxy resin production.
The only current use of EBH at the present time appears to be
as a laboratory research reagent. The remainder of this section is therefore
devoted exclusively to the major uses of ECH. Minor uses of SCH are described
in Section II-B-2.
a. Synthetic Glycerin
Approximately 37% of the total industry capacity to produce
glycerin (both synthetic and natural) is based upon synthesis from ECH (Oosterhof,
1976); about 65.5% of the synthetic capacity is based upon synthesis from ECH.
The chemical reaction for this synthesis can be represented as follows (Oosterhof,
1976):
33
-------
CH2CHCH:> +¦ H2O CH2CH CH2
\/ I III
O Cl OK OH Cl
epichloro'nydrin a-monochlorohvdrir.
CH-,CH CH2 +• NaCH ¦ CH2CH CH2 + NaCl
ri i mi
OH OH Cl (or CaC03) OH OH CH (or CaCl2)
ct-monochlorohydrin glycerin
The manufacturers who produce glycerin from ECH (Dow Chemical in Freeport,
Texas, and Shell Chemical in Deer Park, Texas) produce it in a continuous
operation, as depicted in Figure 2 (Section III-A-3). In actuality, the ECH
in this process is only an intermediate which is not isolated from the system.
ECH. is fed into aqueous caustic in a stirred reaction maintained at 150"C.
Reaction time is 30 minutes. A solution of 5% glycerin content is produced
along with salts (sodium or calcium chloride). The crude glycerin is concen-
trated to 80% with multiple-effect evaporators. Salt is removed by centrifuge
and the glycerin is again concentrated and desalted to yield 98% glycerol.
After colored impurities are removed by solvent extraction, the glycerol is
purified by stean distillation (Lowenhein and Moran, 1975; Kern, 1966).
Glycerin is used in drug and chemical manufacture, food
products, tobacco products, and cellophane, as well as other uses. No informa-
tion described the specific uses of glycerin produced from ECH. Also, no
information was available describing residual ECH in the glycerin. Based upon
the expected hydrolysis behavior (see Section I-B-l) and manufacturing proc-
esses, no significant ECH should remain in the final product,
b. Epoxy Resins
Epoxy resins are commercially used in protective coatings,
bondings and adhesives, and reinforced plastics. According to Weschler (1965),
consumption for 1963 had the following pattern:
34
-------
bonding and adhesives 16%
protective coatings 43%
reinforced plastics 14%
other uses 27%
The term "epoxy resin" is assigned to polymeric materials containing epoxide
groups. Weschler has noted the epoxy resins are actually intermediates; a
curing or hardening agent is required to convert the epoxide resin to a thermo-
set material. The thermoset materials are noted for toughness, adhesion,
chemical and abrasion resistance, and electrical insulation. Although the
epoxies are more expensive than any other thermosetting plastics, their high
consumption results from their unique combination of the above properties.
Almost all (90% - Chemical Marketing Reporter, 1978b) commercially
produced epoxy resins are made by the reaction between ECH and 2,2—di(4-hydroxy-
phenyl)propane (also known as 4,4'-isopropylidenediphenol or bisphenol A) (EPA,
1974). The two reagents are dissolved in methanol and placed in a reactor. Sodium
hydroxide is added and the mixture refluxed at 171°F (Monsanto Research Corp.,
1976). The following reaction sequence takes place (EPA, 1974). First, the ECH
and 2,2-di(4-hydroxyphenyl)-propane react to form a chlorohydrin (I):
0
2 h2c - chch2ci - H0-<^o)-C(CH3)?-^O^-0H ~
CH2C1CH0HCH20 -<^^-c(CH3)f(|O^OCH2CHOHCH0Cl
I
Alkali converts the chlorohydrin intermediate to an ether with terminal epoxy
groups (II)
I + NaOH
-(oV0CH2CH "^CH2 + 2NaCl + H20
h2c - chch2o-^o>c(ch )
II
35
-------
II can now react with additional 2,2-di(4-hydroxyphenyl)propane by the same
sequence to yield a long chain compound with terminal epoxy rings (III):
0+1^x1^1 H0-<^Oyc(CH3)2
A
H,C - CHCH2-
—\
0 -0^Oj>-0\O/C(CH3)2^O/0CH2CH - ch2
•n
III
Any excess ECH in the product is removed by vacuum (Monsanto Research Corp., 1976)
The chain length, n, of III determines the properties of
the product. Chain length is controlled by reactant concentrations, catalysts,
and other reaction parameters. The epoxy resins are mixtures of various molecu-
lar weight polymers. Low molecular weight liquid products have a relatively
low concentration of III and a high concentration of II (i.e., n < 1 and ranges
between 0.1 to 0.6). High molecular weight solid epoxies have n in the range
1.8 to 16 (EPA., 1974). Also, polymers containing undesirable branched chains
CH
—OCK-CH - CH
CH_ — CHCH
Formation of branched chain products are minimized by reactant concentrations,
catalysis, other reaction parameters, and equipment design.
When the hardening agent is added to the epoxy, very
extensive cross-linking occurs, resulting in the desired final properties of
the cured material. Curing agents are selected from a variety of chemicals
capable of reacting with either the epoxy or hydroxy groups in the resin. An
agent is selected on the basis of the final properties desired. Suitable
hardeners include Lewis acids, polyamides, amines, acids, acid anhydrides, and
urea or melamine formaldehyde resins, as well as other resins (EPA, 1974).
36
-------
The estimated, consumption of refined ECH for unmodified
epoxy resins in 1973 is listed in Table 11. Table 12 lists the major producers
of unmodified epoxy resins along with product tradenames and capacities. It
may be possible that the resin product contains a small amount of unreacted ECH
as a contaminant.
2. Minor Uses of Epichlorohydrin
a. Epichlorohydrin Elastomers
Epichlorohydrin elastomers were developed and patented by
Hercules, Inc. In 1964, Hercules granted an exclusive license to B.F. Goodrich
Chemical Co. to produce and distribute certain types of epichlorohydrin elasto-
<£D
ners. Production of Hydrin lOCrH a homopolymer of epichlorohydrin, and Hydrin
an equimolar copolymer of epichlorohydrin and ethylene oxide, was started
by Goodrich Chemical in 1965 in semicommercial facilities- at Avon Lake, Ohio.
The production capacity of the Avon Lake plant was expanded to 8 million lbs.
per year in 1969 (Oosterhof, 1975).
Hercules started production of Herclor ¦f® a homopolymer of
epichlorohydrin, and Herclor <®, a copolymer of epichlorohydrin and ethylene
oxide, at Hattiesburg, Mississippi, in May, 1970. The plant has a capacity of
10 million lbs. per year (Oosterhof, 1975).
Both types of epichlorohydrin rubber have outstanding
resistance to ozone, oil, chemicals, and solvents, and have excellent impermea-
bility to gases. The copolymer has higher resilience and better flexibility at
low temperatures. Applications include automotive and aircraft parts, seals
and gaskets, wire and cable jackets, hose and belting, adhesives, packing
applications, and rubber-coated fabrics. It is estimated that the U.S. produc-
tion of these elastomers amounted to about 7 million lbs. in 1973, and that the
37
-------
Table 11. Estimated U.S. Consumption of Refined Epichlorohydrin for Unmodified Epoxy Resins, 1973
(Oosterhof, 1975)
Type of Kpoxy Resin
Conventional DCEBA Resins
Liquid types (65%)
Solid types (35%)
Epoxy Novolac Resins
Phenoxy Resins
Subtotal
Unmodified Epoxy
Resin Production
Percent of
Production
58.5
31.5
90%
4
2
Produc tion
(millions
of pounds)
130.3
70.2
200. 5
8.9
4.5
Ep ichlorohydr in
Consumption
Pounds per
Pound of Resin
96%
213.9
0.68
0.47
0.73
0.40
0.61
Millions
of Pounds
88.6
33.0
121.6
6.5
1.8
129.9
Cycloaliphatic and
Other Resins 4 8.9 0
100% 222.8 0.59 129.9
a Diglycidyl elhcr of bisphenol A resins, based on cpichlorohydrin and bisplienol A.
-------
Table 12. Producers and Sites of Unmodified Epoxy Resins (SRI, 1977)
Annual Capacity
(millions of pounds)
Celanese Corp.
Celanese Coatings and Specialty
Clients. Co., subsid.
Celanese Resins Div.
Ciba-Celgy Corp. "
Plastics and Additives Div.
Resins Dept.
Dow Client. U.S.A.
Haven Tndust., inc.
Haven Chem. Div.
Polychrome Corp.
Cellomer Corp., subsid.
Pratt & Lambert, fnc.
Rcichhold Chcms., Ind.
Resyn Corp.
Seton Co.
Wilmington Chem. Corp., div.
Shell Chem. Co.
Union Carbide Corp.
Chems. and Plastics, div.
Louisville, Ky.
Toms River, N.J.
Freeport, Tex.
Philadelphia, Pa.
Newark, N..J.
Buffalo, N.Y.
Andover, Mass.
Azusa, Calif.
Detroit, Mich.
Houston, Tex.
Linden, N.J.
Wilmington, Del.
Deer Park, Tex.
Taft, La.
(Epi-Rei^)
(Araldite^)
®
(I).E.R. )
EpipheiY
(Epotu
to
(Resypox®)
(Epon
i®)
25
60
75
<1
n. a.
n. a.
32
40
4
100
Total
<343
-------
consumption of ECH in manufacturing the elastomers was about 6 million lbs.
(Oosterhof, 1975). It is again possible that the final elastomer product may
contain a small amount of ECH as contaminant.
b. Other Uses
A variety of other products are produced from ECH, most of
them in relatively small volumes. Among then are glycidyl ethers, some types
of modified epoxy resins, wet-strength resins for the paper industry, water
treatment resins, surfactants, and ion-exchange resins. The available break-
down, by use, for the 1973 consumption of ECH in these uses is listed below
(Oosterhof, 1975):
Glycidyl ethers and modified epoxy resins 6 million lbs.
Wet-strength resins 6 million lbs.
Water treated resins 5 million lbs.
Surfactants 4 million lbs.
Miscellaneous applications 10 million lbs.
Total 31 million lbs.
Some of the miscellaneous applications of ECH include
intermediates for plasticizers, dyestuffs, pharmaceuticals, oil emulsifiers,
and lubricants (Lichtenwalter and Riesser, 1964). It is also used as a stabi-
lizer in chlorine containing materials such as chlorinated rubber and chlorina-
ted insecticides (Shell, 1969; Sayed et al., 1974). ECH is also registered as
an inactive ingredient in numerous pesticide formulations and is added as a
stabilizer to dibromochloropropane (DBCP) (Von Sumpter, 1978).
3. Discontinued Uses
EBH was used formerly as an intermediate in the manufacture of a
nematocide by Great Lakes Chemical Corporation. The product was discontinued
some years ago and EBH has not had commercial significance since.
40
-------
4. Proposed Uses
ECH has been recommended as a good solvent for cellulose acetate
and rosin and ester gums (Shell, 1969), although its toxicity may preclude such
use. It has been proposed as a solvent for chlorosilanes for treating cotton
fabrics to improve their dimensional stability (Dorset, 1969). It has also
been suggested as a soil fuiaigant for the control of wireworms (Shell, 1969).
ECH has been documented as a suppressor of male fertility
for a number of species, including rats, guinea pigs, sheep, pigs, and
hamsters. Kalla and Bansal (1977) have suggested that the effect is due
to the alkylation of testicular cysteine, removing the protective effect
of cysteine in seminal physiology. The authors suggest that administering
ECH and copper ions simultaneously might inhibit the cysteine and allow
the copper ions to act as an effective spermicide. Although the authors
feel that an alkylating agent will not necessarily induce tumors, the
safety of ECH as a contraceptive agent would have to be demonstrated
before this proposed use could be considered seriously.
Another suggested use for ECH is the treatment of rice in
the canning process (Rutledge and Islam, 1973). Rice is seldom found in
canned food because the grains do not hold up well under the canning
process; clumping, matting, and disintegration of the grains render the
product unpalatable. Treating the rice with ECH cross-links the starch
granules and produces a stable rice which could retain favorable organoleptic
properties after canning. The authors did not discuss the possibility
of ECH residues in the canned product.
41
-------
5. Alternatives to Uses
Glycerin is being manufactured by at least three
processes other than ECH hydrolysis. None require chlorinated hydrocarbons
as intermediates (Kern, 1966; Oosterhof, 1975). Since they are already
competitive economically with ECH., their replacement of it would be a
function of production capacity rather than economics or technology. In
fact, the ECH share of the total glycerin production has recently diminished
(Oosterhof, 1975). The acrolein-allyl alcohol route for manufacturing
glycerin utilizes propene, 2-butanol, and hydrogen peroxide as starting
materials. Methyl ethyl ketone is the major by-product. The allyl
alcohol-peracetic-glycidol route requires propylene oxide and peracetic
acid as starting materials. Acetic acid is the major by-product. The
saponification and the high temperature hydrolysis of fats and oils
produce large quantities of glycerin which are recoverable from the
aqueous layer.
The unique properties of epoxy resins and ECH elastomers (see
Sections II-B-1 and 2) are difficult to replace, especially if the use of
closely related chemicals such as EBH or halogenated 1,2-epoxybutanes were also
prohibited. Other compounds containing an epoxy ring could be used to make
epoxy resins, but the properties of the resins, as well as manufacturing
costs, might be adversely affected by substituting for ECH.
C. Environmental Contamination Potential
1. General
Sources of ECH entry to the environment have been identified.
Information has been developed which quantifies discharges from ECH production,
from glycerol production, and from industrial waste disposal. A transportation
42
-------
accident was responsible for a massive ECH release. While ECH could be
inadvertently produced, the potential hazard from this entry appears
negligible.
Mo information was available to describe E3H entry to the
environment. The only potential sources identified were inadvertent production
within industrial processes or from environmental transformations of anthropo-
genic substances. No quantitative data was available concerning EBH formation
or if it has ever been found in the environment (see Section II-E).
2. From Production
ECH is manufactured on a large scale. While most of the material
is purified and subsequentially used for epoxy resin or elastomer production, a
sizeable proportion is converted to glycerin with only partial purification
(see Section II-A-l-a). Pollutant generation and discharge to the environment
have been evaluated for ECH and for glycerin production (Gruber, 1976; Pervier
et al., 1977). Since the information generated on discharges from glycerin
production is directly applicable, it will also be discussed in this section
rather than with use (see Section III-C-4).
Gruber (1976) has assessed wastes generated during ECH production.
The report also presented some information on pollutants emitted to the atmos-
phere with waste vent gases. The salient details are depicted in Figure 1 (see Sec-
tion II-A-3); it describes the manufacturing process, atmospheric emissions
from various manufacturing stages, and other wastes generated (discussed in Sec-
tion II-C-5). In addition to ECH, the process discharges cnloroethers, di-
chlorohydrin, trichloropropane, and allyl chloride, which are also hazardous.
43
-------
Table 13 summarizes the expected annual emissions from ECH manufacture based
upon the emissions described in Figure 1 and upon the assumption that roughly
181 thousand metric tons (400 million pounds) of ECH are produced by the same
methods industry wide on an annual basis.
Dow (1979) and Shell (1979) have indicated that the Gruber (1976)
emission estimates are much too high and do not reflect current technology.
Shell (1979) estimates that, on a basis of 400 million pounds per year production,
ECH losses would be 18 thousand pounds total which is significantly less than
the estimates in Table 13.
Pervier and coworkers (1974) assessed potential discharges to
the environment from glycerin manufacture through caustic hydrolysis of ECH.
They sent survey letters to ECH manufacturers and received two responses. The
manufacturers reported that ECH and other potential hazardous pollutants were
formed and were potentially lost to the environment as atmospheric emissions or
through liquid or solid wastes. While this section limits discussion to
emissions from the manufacturing process, other sections of this report discuss
potential losses from storage (see Section II-C-6) and waste disposal (see
Section II-C-5) based upon their report.
Environmental losses during the manufacturing process consist of
three types of atmospheric emission: continuous air emissions; intermittent
air emissions; and fugitive emissions. Fugitive emissions could result from
leaks, sampling, gauge glass blowdowns, and equipment purges. Pervier et_ al.
did not specify all sources of intermittent emissions, but did account for two:
process start-up and emergency venting.
Vent streams do emit significant concentrations of chlorinated
and non-chlorinated hydrocarbons to the atmosphere. Identified constituents of
vent gases are:
44
-------
Table 13. Expected 197/ Pollutant Generation from Epichlorohvdrin Manufacture
(Based upon Figure 1) (Gruber, 1976)
Metric Tons
(thousands of pounds)
Reactor Vent Emitted to the Atnosphere
Epichlorohydrin 273 (600)
Allyl chloride 364 (800)
Trichloropropane 91 (200)
Chlorine 0.1 (0.2)
Hydrogen chloride 0.1 (0.2)
Water from Separator
Dichlorohydrin 1818 (^000)
Heavy Ends from Fractionator Requiring Disposal
Epichlorohydrin 193 (424)
Chloroethers 1345 (2960)
Dichlorohydrin 1036 (2280)
Trichloropropane 6745 (14,840)
Assuming an industry wide annual production of 181 thousand metric tons
(400 million pounds)
45
-------
ECH
1,2,3-trichloropropane
propyl chlorides
dichloropropenes
acrolein
acetone
The two responding manufacturers have supplied descriptive and quantitative
data on emissions and emissions controls. Figure 2 (see Section II-A-3) de-
scribes the process sequence and specifies vents emitting gases to the atmos-
phere. Table 14 summarizes salient quantitative and other information for the
two plants. One plant has listed ECH emission from only one vent; ECH emission
was reported as 0.001539 ton per ton glycerin or 73 tons (66.5 metric tons)
annually. The second plant had replied that five vents emitted ECH; total
emission was 0.0002036 ton per ton glycerin or 11.2 tons (10.2 metric tons)
annually.
The reports by Gruber (1976) and Pervier et_ al. (1974) estimated
ECH emissions within an order of magnitude of each other. Approximately
300 tons (273 metric tons) would be a reasonable estimate for total annual ECH
emissions from manufacture using these sources. Dow (1979) has indicated that
the information in Table 14 and the Pervier _et al. (1974) data are outdated.
3. From Transport and Storage
Transport and storage can release ECH to the environment through
continuous or intermittent emissions, or discharges as the result of accidents.
No information was available by which to quantify such releases to the environ-
ment •
Continuous emissions result from tank venting. Pervier and
coworkers (1974) reported that atmospheric storage tanks which are used for ECH
are unpadded and without vapor conservation devices. They did not estimate
emissions from venting. Shell (1979) has estimated storage losses at 0,0005
pound of ECH per pound of production.
46
-------
Table 14. Atmospheric Emissions from Glycerin (Glycerol) Plants using Epichlorohydrin and/or
Allyl Chloride as Feedstocks (adapted from Pervier et al., 1974)
PLANT 1
Capacity In Short Tons
47,500
Description Diagram
(Figure 2) Stream Designation
A
B
C tl
E
F
C
i-'mlssion
(10^ tons/ton glycerol)
Ally! chloridf
—
Included villi propyl chloride
—
Included with propyl chloride
...
IsopropyI alcohol
—
—
1.665
0.4283
...
1 so- and n-propyl chloride
—
26.31
—
0.1681
1,2,3-Tr ichlotopi opane
—
3.269
—
2,j-Dichloropropene
—
...
...
Acrolein
—
Act Cone
—
5.151
...
I .840
Hydiucaibon, unshoe 1 f led
(e.%.t oethmp, ethane)
—
8.238
—
—
...
...
2, 3- Dichioi ohytJr in
—
...
—
...
Epichlorohydrln
—
...
1.519
...
—
Kmls^lon control device
—
Scrubber
Scrubber
Scrubber
-------
Table 14. Atmospheric Emissions from Glycerin (Glycerol) Plants using Epichlorohydrin and/or
Allyl Chloride as Feedstocks (adapted from Pervier et_ al^., 1974) (Cont'd)
Capacity In Short Tons
^.000
Drsrr Ipt Ion DI.iRr.im
( K i Rure 2 ) Si re.im Di»ii I ftiui
I)
K
K
llypochlur In.ii Ion
Vent
llydrol y/iT EPI
Vriit 111'.I 'n. V. >U
Glycerol
KPI Finishing Glycerol Evaporation
Oisl'n V«*nl Kr.utor Vent
C
CI yi.crol
1)1 sr 'n.
VetU
Glycerol Light
Di :»t ' n . Vent
¦P-
00
I'm I ss Ion
(11)1 Ctin-./1 on g 1 ycerol)
Allyl chloride
I bopt upy 1 a I colto I
l:;o- and n-pro|»yl chloride
1,2, 1-Tr tchloiopt opjno
2, J-Dichloropropene
Ac rnIe In
At. ..•tunc
II yd rot,i r bon, uaspoc i f led
(e.g., raeth.ine, ethane)
? , l-l)lch lorohyd r in
bp it h I oi 1111y>1t in
Km lesion control devie*
0.1717
o.oh..'/ o.o.'oi'.
le ( l-'uin«* S< I'lildn* I
0.1056
0.IH'M
O.UlW/i! 0.002HH'
0.04 2H'. —- Tr.»(»
o.ni i r.' o n r.
-------
Fervier and coworkers (1974) estimaced the ECH emissions from
tank filling. Their estimate assumed that the vapor pressure and partial
pressure are the same for atmospheric pressure storage. They suggested emis-
sions as high as 50 lbs./hour with a vent concentration of 14% ECH in air.
Accidents can release hazardous levels to the environment.
Information on a transportation related accident near Point Pleasant, West
Virginia, was the only incident that has been described. No information was
available on storage tank accidents discharging ECH.
The Point Pleasant accident occurred on January 23, 1978, when a
tank car derailed, ruptured, and spilled 20,000 gallons (^197,000 lbs) of
ECH. Because of immediate health and safety hazards, 400 persons were evacuated
and the city's water plant was shut down (Anon., 1978a). The major concern
was ground water contamination. The public water supply was drawn from wells
at 25 feet depth, and the wells became heavily contaminated by the spilled
ECH. Specific information is not yet available on the ECH concentration, the
time required for self-cleaning (see Section III-A-1), or other salient
details (Rosencrance, 1978).
The known details of the Point Pleasant spill demonstrate that
transport accidents can occasionally result in a local hazard. No information
was available upon which to predict the frequency of transport-related acci-
dents.
Monitoring information on this spill is not yet available
(Rosencrance, 1978). When it is released, the data will provide an estimate on
hazards. Significant information is expected on the risk period to potable
water as the result of a single, massive contamination of a water supply.
49
-------
4. From Use
The discharge of ECH to the environment during use is most
likely to occur as a result of volatilization. The emissions of ECH during
glycerin manufacture were discussed in Section II-C-2, since the process uses
crude ECH as an intermediate without isolating it. Emissions from glycerin
manufacture were the only quantitative data. The remaining information on
discharges from use are taken from monitoring reports (see Section II-E).
ECH has been monitored near factories in Russia. Fomin (1966)
detected ECH in the atmosphere up to 200 meters from a factory, but did not
specify whether it resulted from manufacturing operations or use. Lipina and
Belyakov (1975) monitored ECH at a glycerin manufacturing plant, but infor-
mation was not available on whether the feedstock was ECH or allyl chloride.
When epoxy resins were used for waterproofing the walls of
pumping stations in an irrigation project at Uzbekistan, USSR, the air became
contaminated with ECH (Danilov and Muratova, 1972). Pinchuk et al. (1969)
found that the air inside a new five-story dwelling (in or near Moscow, USSR)
constructed extensively of plastic materials was contaminated with ECH. The
largest amounts of volatiles were given off by materials made from, among
other things, epoxy cements. Lawrence and Autian (1972) suggested that epoxy
resin volatiles (which may include ECH) are present in the atmosphere of
small dental laboratories, where epoxy cements are used extensively. They
also stated that these volatiles may alter the biological activity
of medications the workers may be taking.
5. From Disposal
The generation and disposal of wastes from the manufacture of
ECH and by glycerin production through ECH has been discussed and partially
50
-------
quantified (Gruber, 1976; Pervier et al., 1974). Although the studies have
described waste stream composition and disposal methods, no information was
presented on environmental discharge.
Gruber (1976) delineated the origin and composition of wastes
generated by ECH production from allyl chloride. The overall process and its
associated wastes are illustrated in the discussion on production nethods (see
Section II-A-3). The liquid heavy ends from a fractionating column at a 75,000
metric tons per year plant yield approximately 3,975 metric tons of organic
waste which are described in Table 15. According to Gruber, these are
not landfilled or encapsulated. The wastes are stored in large steel
tanks in on-site facilities for eventual thermal destruction using
controlled incineration. In addition, aqueous wastes from the separator
contain dichloropropanol (0.01 ton per ton glycerol produced), but
treatment of the aqueous waste was not described.
Pervier _et_ al. (1974) described wastes from glycol manufacture.
Two manufacturers (see Section II-C-2) described their waste generation and
treatment. According to Pervier and coworkers, no discrete solid wastes form.
Liquid wastes of 1200 and 1500 gallons per minute were generated in the
two plants. No qualitative or quantitative information was available on
ECH or other organic components of the waste. Waste water from glycerin
production does not appear hazardous. Spencer (1971) reported a "very
high" toxic threshold for aquatic organisms for the effluent from glycerin
~anufacturing plants.
Shackelford and Keith (1976) listed frequency for chemicals
observed in water; ECH was listed three times. Twice it was reported in
t
effluent from an unspecified chemical plant in Louisville, Kentucky. Also, ECH
was contained in one of several industrial waste filled drums which were dumped
at sea near the coast of Holland (Grieve, 1971).
51
-------
Table 15. Major Components of Che Liquid Heavy Ends (Still Bottoms) from
Epichlorohydrin Manufacture at a 75,000 Metric Ton per Year Plant
(Gruber, 1976)
Component
Quality
(metric tons per year)
1,2,3-Irichloropropane
Tetrachloropropyl ethers
Dichloropropanol
Chlorinated aliphatics and alcohols
Epichlorohydrin
Water and unidentified products
2783
557
425
130
80
100
52
-------
6. Potential Inadvertent Production in Industrial Processes
Although no information was available on inadvertent production
of epihalohydrins during industrial processes, numerous possible pathways were
speculated based upon known reaction mechanisms (Gould, 1959). The flow chart
delineates simple pathways by which precursors might be converted into epihalo
hydrins:
Precursor
I
CH2 = CHCH?X
[0]
/°\
CH2— CH2CH2X
Base
catalyzed
HOCH-CHYCH-X YCH_CH0HCHoX
L L Z 4
T
Precursor
H^O/H-1" Precursor
YCH=CHCH2X
or
YCH2CH=CHX
The epihalohydrins would most likely form from allylic halides or substituted
propyl halohydrins. These could form in turn from other precursors. The in-
dustrial chemicals in Table 16 which would potentially be converted to the
epihalohydrins were gathered from the Directory of Chemical Producers (SRI,
197?). Although reaction pathways could be devised for other propane deriva-
tives, these are judged the most likely precursors for inadvertent epihalohydr
-------
Table 16. Potential Precursors for the Inadvertent
Production of Epihalohydrins
Allyl chloride (3-chloropropene)
Allyl bromide (3-bromopropene)
2,3-Dichloropropene-l
1,3-Dichloro-2-propanol
1,3-Dichloropropene
2,3-Dibrociopropanol
Tris(dichloropropyl) phosphate
Iris(dibromopropyl) phosphate
DBCP (dibromochloropropane)
Propylene glycol
Glycerin
54
-------
production. These generalized pathways also describe inadvertent production in
the environment (see Section II-A-7).
Allylic rial ides can be epoxidized by oxygen transfer agents such
as peroxides (e.g., benzoyl peroxide) or metal oxides (e.g., copper or silver
oxide). Catalytic oxidation of propane or propenes in the presence of halides
could also yield epihalohydrins. The epihalohydrins could form from 1,2- or
1,3-dihalopropanols or other halopropanols by S^i (internal nucleophilic sub-
stitution) reactions (Gould, 1959). These halogenated propanols could either
be commercial chemicals, such as 2,3-dibromopropanol, or produced from commer-
cial chemicals. Examples of the latter would include hydration of 1,3-dichloro-
propene or hypochlorite addition to the allyl halides. Hypochlorite addition
could be important if an industrial waste containing the allyl halide were
chlorinated; this chlorination route will be discussed as a potential inadvert-
ent production in the environment (see Section II-C-7).
The production and use of tris(halopropyl) phosphates, especially
tris(dibromopropyl) phosphate and its precursor, 2,3-dibromo-l-propanol, are
considered likely precursors for inadvertent epihalohydrin formation. 2,3-
Dibromo-l-propanol is commercially manufactured by allyl alcohol bromination in
aqueous lithium bromide (demons and Overbeek, 1966; Thomas and Levek, 1971).
Although no information was available on the inadvertent production of EBH or
its contamination of the commercial dibromopropanol, Great Lakes Chemical Corp.
(1972) cautions that dehydrobromination to yield EBH could contaminate the
product. Tris(dibromopropyl) phosphate is a fire retardant commercially pro-
duced by reacting dibromopropanol with phosphorous oxychloride in the presence
of a tertiary amine base (Lande et_ a_l. , 1976). Although epibromohydrin has not
55
-------
been reported as a by-product, base could conceivably catalyze the S..I
N
epoxidation. The use of tris(dibromopropyl) phosphate or tris(aichloro-
propyl) phosphate as a fire retardant for fabrics could also inadvertently
produce epihalohydrin. However, the rate of production of these compounds
has decreased considerably in recent years because of the mutagenicity of
these fire retardants. The initial washing leaches these chemicals from the
fabric; any hydrolysis within the alkaline wash waters will likely yield
epihalohydrin. Since this is also a possible route for inadvertent pro-
duction of epihalohydrins in the environment, further discussion is presented
below (see Section II-A-7).
7. Potential Inadvertent Production in the Environment
Epihalohydrins could inadvertently form from biological or
chemical transformations of halogenated propenes and propanols. The con-
ceivable precursors are synthetic organic chemicals; however, no available
evidence suggests that epihalohydrins form from naturally occurring organic
chemicals. Some potential precursors listed above (Table 14) have been
observed in water (Table 17) (Shackelford and Keith, 1976).
Epihalohydrins have been identified as intermediates in
dibromopropanol metabolism (Bartnicki and Castro, 1969; Castro and Bartnicki,
1968). The conversion is an equilibrium process:
OH 0
I / \
BrCHoCH - CH„Br >¦ CH„ CHCH„Br + Br
If chloride ion is present, ECH is also produced. Since the equilibria in-
volved in epihalohydrin formation are closely related to transformations in
their metabolic degradation, the subject is discussed in greater detail in the
56
-------
Table 17. Observations of Potential Epihalo'nydrin Precursors in Water
(Shackelford and Keith, 1976)
Compound
Source
Propanol, dichloro-
Propanol, l,3-dichloro-2-
Propanol, 2,3-dibrorao-l-
Propylene, dibromo
Propylene, 1-chloro (allyl chloride)
Propylene, 1,3-dichloro
Seawater
Effluent from chemical plant
Effluent from chenical plants; effluent
from landfills; well water
Effluent from chemical plant
Finished drinking water
Finished drinking water
57
-------
section on Biological Degradation, Organisms, and Products (see Section III-A-
1-a).
Although no kinetic information was available which described
chemical transformation of the precursor dihalopropanols to E3H or ECH in the
environment, several studies on kinetics and mechanisms by which short-chained,
aliphatic halohydrins cyclize to yield epoxides contain some useful data on the
expected rates of epihalohydrin formation in water (Winstein and Lucas, 1939;
Nilsson and Smith, 1933; McCabe and Warner, 1948; Winstrom and Warner, 1939;
Stevens et_ _al. , 1948) . These studies were primarily concerned with the mecha-
nisms of reaction between halohydrins and base. The concensus is that the
chlorohydrins and bromohydrins almost exclusively react with aqueous base to
yield epoxide; direct hydrolysis of the halide to yield glycol does not com-
pete. The reaction pathway has been described as the sequence:
X °H X 0- 0
I I - on I 1 K3 / \
- CH - CH - 4- OH —N - CH - CH ~ CH — CH —
The kinetics have been well delineated. The alcohol-alkoxide equilibrium is
fast and the rate determining step is ascribed to the S^i reaction of the
halohydrin anion (k.) . The epoxide formation rate, dx/dt, is given by:
= k C C -
dt OH HH OH
where k. = k k., and CTTTT and CL,y - are the concentrations of halohydrin and
OH eq 3 HH OH }
hydroxide, respectively.
58
-------
Nilsson and Smith (1933) published data that suggest a second
path. In this alternative path, neutral halohydrin directly cyclizes to
yield an epoxide:
OH X
k
0
CH - CH
+ K+ + X'
The overall rate, k0ks> must then contain contributions from both paths:
k , m k ~
obs neut. OH OH
Although no rate data were available for the dihalopropanols,
data have been published for epoxide formation from ethylene halohydrins, propyl-
ene chlorohydrins, and various derivatives of *,6-propylene chlorohydrins
(Table 18). The rate constant increases observed with the addition of methyl
groups have been ascribed to the relief of steric crowding as the bond angles
open up during the epoxide formation (Gould, 1959). If this interpretation is
correct, the minimum second order reaction rate (k „-) must be about 2 1 mole ^
utt
mim * at 18° for the chloropropyl alcohol cyclization to epihalohydrin, and at
least an order of magnitude faster (> 20 1 mole ^ min "*") for epihalohydrin for
formation from the bromopropylalcohols (McCabe and Warner, 1948; Nilsson and
Smith, 1933). Estimation of k is more tenuous. The effect of the addi-
neut.
tional halide is assumed to affect epoxide formation rate mainly through steric
effects. The relatively high rate for 2-chloro-2-methyl-l-propanol cyclization
to the epoxide (0.00393 min "S at 18°) is taken as a reasonable estimate of the
59
-------
Table 15. Kinetic Data for Epoxide Formation from Halohydrins in Water
Halohydrin
Temperature
(°C)
koh
(luiole ^ nin ^")
?
10"k
neut.
(min
CH?0HCHoCl
18
0
15
25
35
0.31 (estimate)3
0.0167b
0.153b
0.600
2.17 b
CH'20HCH23r
0
5.0
10.0
0.987b
2.03b
3.95b
CH CHOHCH^Cl
18
6.5a
CH„CHC1CH„0H
j 2
18
1.7 (estimate)3
(CH3)2C0HCH?C1
18
7 8a
(CH-)_CC1CH,0H
J J-
18
-,-a
/ /
0.3933
(CH3)2CC1CH(0H)CH3
18
633a
0.2063
(CH3)2C(0H)CC1(CH3)2
18
3600 (estimate)3
0.3593
(c h ) c(oh)ch?ci
18
1793
(C,H ) CC1CH70H
18
353a
2.67a
f Nilssor. and Smith, 1933
McCabe and Warner, 1948
60
-------
upper limit for chloropropyl alcohol cyclization. The rate of cyclization of
2-chloro-l-propanol is assumed to be the lower limit. If for k„,, and k
OH neut.
the relative ratios of 2-chloro-2-methyl-l-propanol:2-chloro-l-propanol are the
same, then the lower rate limit is within a factor of 50, or 8 x 10 ^ min
The observed rate for epihalohydrin formation from the cyclization of chloro-
halopropanol will then be given by:
-5 -1 -1 -1
k »8 x 10 min + 2 lmol min CAU-
OH
Half-lives for epihalohydrin formation were estimated assuming constant pH. At
neutral pH, epihalohydrins would form from chlorohydrin cyclization with an
estimated 6.0 days at 18° in water. At pH 9, t^9 would decrease to
4.8 days. Since ethylene oxide formation from ethylenebromohydrin reaction
with caustic is more than an order of magnitude faster than from ethylene
chlorohydrin (McCabe and Warner, 1948), then it is expected that precursor
bromohydrins will yield epihalohydrins with less than one day in
water.
The precursor dihalopropanols can enter water directly or from
other propane derivatives:
Hon
CH0=CHCH„X —C1CH„CH0HCH„X
jl L L
-------
Hydrolysis of haloalkylphosphates is a potential source of
epihalohydrin formation. These have been used as fire-retardants for clothing
and other consumer items (see Section II-A-7). They are known to leach from
fabric during laundering and night nydrolyze under alkaline conditions of
washing (Lande ex_ al., 1976). A potential sequence for epihalohydrin formation
is:
QU-
(CH BrCHBrCHo0) PO nnn„ > CH.BrCHBrCH.O"
2 2 '3 -(CHoBrCHBrCHn0)oP00H -Br"
0
/ \
BrCH.CK - CH„
L /
fClCH2)2CH°~^ P° - [(C1CH ) CHOt^-POOH * (C1CH2*2~CH0 _C1-
or:
0
/ \
C1CH2 — ch —CH?
Although metabolic oxidation can convert olefins to epoxides
(Williams, 1959), it is unlikely to produce epihalohydrins from allylic halides.
Castro and Belser (1968) reported that allylic halides are hydrolyzed to allyl
alcohol in soil by metabolic and chemical pathways.
D. Analytical Methods
The two general approaches that have been developed for determining
epoxy compounds are wet chemical and instrumental methods, including chroma-
tography. Interest in devising analytical methods for epoxy compounds devel-
oped in the late forties and has been primarily concerned with qualitative and
quantitative methods suitable for quality control rather than for environmental
monitoring.
62
-------
The most common wet chemical method for the determination of compounds
containing an epoxy ring involves ring opening by halogen acids to yield a
halo'nydrin. While quantitative consumption of the hydrogen halide and forma-
tion of the halohydrin is the basis of the determination, there are many varia-
tions. One variation, which uses methyl ethyl ketone as the solvent and HC1 as
the acid, is claimed to provide good results for ECH (Dobinson et al., 1969).
Daniel and Gage (1959) determined ECH in prepared air samples with a
colorimetric method involving oxidation of ECH with periodic acid followed by
the reaction of the formaldehyde produced with ammonia and acetylacetone to
give a yellow color. Levels of ECH down to about 6 ppm could be determined
with an error of about 2%. Similar procedures have been reported by Gronsberg
(1961, 1966), Pimenova and Khamaza (1962), Jaraczewski and Kaszper (1967),
Krynska (1968, 1973), Fomin (1976), and Stanislav (1976). These latter papers
were published in Russian or Polish. Gronsberg (1961) reports a sensitivity
for his method of about 6 ppm.
Ring opening methods "by sulfur-containing nucleophilic reagents such
as sodium thiosulfate or sodium sulfite are particularly useful with ECH, which
is generally more reactive with those reagents than other epoxides. The pres-
ence of the electron withdrawing group C1CH9- is responsible for the greater
reactivity of ECH. An extensive collection of halogen acid and sulfur nucleo-
phile ring opening methods has been summarized by Dobinson et_ al. (1969).
Unfortunately, sensitivity data were not provided.
Misnash and Meloan (1972) described an indirect spectrophotometry
method for all types of oxiranes which involves hydrolysis to glycols, followed
by cleavage with excess periodate. The technique is said to be sensitive to
the nanomole range, but data for ECH and EBH are not given.
63
-------
The use of infrared spectroscopy as an analytical tool for epoxides
was first explored by Geddu and Delker (1958). The sharp absorbances exhibited
by terminal epoxides at 1.65 and 2.2 mu can be used to determine these compounds
down to about 10 ppm of terminal epoxy ring with an accuracy and precision on
the order of +2%. The major advantage of IR over chemical methods is that it
is very fast. Terminal olefins, which absorb in the same regions, can inter-
fere.
In recent years more advanced techniques have been applied to the
determination of epihalohydrins, although the emphasis has been on qualitative
methods rather than the quantitative techniques essential for good monitoring
studies. For example, photoelectron spectroscopy can be used to distinguish
qualitatively EBH, ECH, epifluorohydrin, and other halo-oxygen compounds (Baker
et al., 1971). Photoelectron spectroscopy is not suitable for quantitative
studies.
Muganlinskii and coworkers (1974) worked on analytical procedures by
gas chromatography primarily to identify and quantify impurities contained in
technical ECH. Their optimum analytical procedure used a 3 ra by 4 mm diameter
column packed with 20% polyethylene glycol 1540 on diatomaceous brick (0.25-
0.5 mm). Operating conditions included: injector port temperature of 200°;
carrier gas (hydrogen) flow rate of 80 ml/min; column temperature was linear
programmed between 50 and 130°C at 7°/min. Ten 4I samples were used with
thermal conductivity detection. The retention times for ECH and components of
the technical material which could potentially interfere with the ECH'peak are
as follows: chloroform (2.2); 1,2-dichloropropane (2.47); 2,3-dichloropropene
(2.67); ECH (3.04); and trichloropropane (5.10). They did not publish any
useful data on sampling.
64
-------
The National Institute for Occupational Safety and Health (NIOSH)
method (NIOSH, 1976; White et_ al., 1970) describes sampling and gas chromato-
graphic (GC) analysis for measuring ambient atmospheric concentration of ECH.
The method requires sampling with standard commercial charcoal tubes. The
tubes are glass and have the dimensions 7 cm long by 6 mm OD and 4 mm ID. They
are packed with 150 g of 20/40 mesh activated charcoal separated by 2 mm of
polyethylene foam into two sections: 100 cm in front and 50 cm in the rear.
The NIQSH method will allow samples as large as 20 1 collected at 200 ml/min.
The sample tubes are then capped (plastic) until analysis. The organics are
desorbed from each charcoal section with 1.0 ml of carbon disulfide for 30 min-
utes; the front and rear sections are to be separately analyzed. Samples of
5.0 ul of the carbon disulfide solution are analyzed by GC using a 10 foot by
1/8 inch stainless steel column packed with 10% FFAP on acid washed DMCS chromo-
sorb W (80/100). Conditions are 200° injector port, 230° detector (flame-
ionization), 135° column, and carrier gas (helium) at 20 ml/min. The overall
method will reportedly operate over the concentration range 11.7 - 43.1 mg/cu m
of ECH. At an ECH concentration of 5 ppm (18.9 mg/cu m), the relative error
was 0.7%. NIOSH (1976) reported that the method can be used down to 0.25 ug/1.
No specific lower detection limit or sensitivity was reported for the GC
analysis of the charcoal desorption. The estimated efficiency of the charcoal
desorption step was 82.7% after 14 day tube storage. Over 90% efficiency was
achieved for the upper end of the working range for sample desorption if the
tubes were desorbed soon after samples were collected.
The West Virginia Health Department Laboratory has developed a
method which uses GC for quantitative analysis of aqueous ECH (Rosencrance,
65
-------
1978). The method was developed to monitor ECH contaminated waters as the
result of the transportation related spill at Point Pleasant, West Virginia
(see Section II-C-3). Experimental details are not yet available.
The analytical methods described above are summarized in Table 19.
Lower detection limit and analytical error are estimated.
E. Monitoring
Pervier and coworkers (1974) have published some information gathered
from manufacturers on atmospheric emissions of ECH and other chemicals from
glycerol manufacturing plants (see Section II-C-2). Although it is not known
how the manufacturers derived the information, monitoring was one likely source.
No quantitative monitoring information was available on ambient ECH
or E3H concentrations in the environment. The only monitoring information
available for the U.S. was its observation in effluent from an unspecified
chemical plant in Louisville, Kentucky (Schackelford and Keith, 1976).
The remaining monitoring data available for ECH is based on work done
in the Soviet Union, where it has been monitored in the atmosphere in the
vicinity of factories which manufacture epoxy resins and glycerin, as well as
in plants producing ECH.
In a study of the ECH manufacturing industry in Russia, Pet'ko et_ al.
(1966) found ECH in atmospheric samples taken from the working area. Of 206
samples, the ECH concentration was below the permissible level (0.05 ppm) "in
only a very few of the tests, and in some instances exceeded the maximum per-
missible limit by a factor of 2-14 times." Hydrogen chloride was also found in
high concentrations. Although it isn't possible to extrapolate these findings
to manufacturing conditions in the U.S., this study does establish the potential
66
-------
Table 19. Summary of Analytical Methods for P.p ihalohydr ins
Technique
Compound
Colorimetrie
Colorimetric
Infrared
Gas-Liquid
Chromatography
Misc ellaneous
Chemical Methods
ECH
ECH
ECH
ECH
Approximate Lower
Detection Limit
¦^6 ppm
8 ppm
VLO ppm
(50 ppb in 20 1
atmospheric
samples)
Error
Source
^2%
+ 2%
Daniel and Gage, 1959
Gronsberg, 1961
Geddu and Delker, 1958
0.7% for 5 ppm NIOSH, 1976
in 20 1 atmos-
pheric samples
Dobinson et al., 1969
-------
atmospheric contamination near ECH plants in the U.S. It was reported that
tank filling and transferring operations were particularly liable to give rise
to contamination in the immediately surrounding air (see Section II-C-3).
In a pollution study of a factory which discharged ECH to the
atmosphere, 0.1-3 ppm of the chemical was monitored within 100-200 meters of
the factory (Fomin, 1966). At 400 meters, five of 29 samples exceeded the
author's recommended maximum permissible level of 0.05 ppm.
Pinchuk et al. (1969) detected ECH in the atmosphere of a building
whose construction employed extensive use of plastic materials. Epoxy cements
were reported to be the main source. Danilov and Muratova (1972) found that
when epoxy resins were used for waterproofing the walls of a pumping station,
the air became polluted with ECH.
Lipina and Belyakov (1975) found ECH in the air of a glycerin
manufacturing plant, along with allyl alcohol and allyl chloride. Specific
data as to the ECH concentrations measured were not given in the translated
abstracts examined.
Although no specific mention is made concerning monitoring water, a
paper by Fedyanina (1968) on the effect of ECH in water on rats, rabbits, and
guinea pigs, as well as the inclusion of human taste and irritation data, made
statements which suggest that ECH has been monitored in tap water in Russia.
Fedyanina found that 30% of the initial amount of ECH placed in water samples
remained after seven days (see Sections I-B-2 and III-A-l-b). Whether the tap
water was quiescent and/or in contact with air is not indicated.
A summary of the monitoring of ECH in the Soviet Union is listed in
Table 20.
68
-------
Table 20. Atmospheric Monitoring of Zpichlorohvdrin in the Soviet Union
Source Reference
Epichiorohydrin manufacturing plant Pet'ko et_ £l., 1956
Factory (type not specified) Fomin, 1966
Newly constructed housing Pinchuk al_., 1969
Clycerin manufacturing plant Lipina and Belvakov, 197 5
69
-------
III. Health and Environmental Effects
A. Environmental Effects
1. Persistence
a. Biological Degradation Organisms and Products
The epihalohydrins have been identified as intermediates
in the enzyme catalyzed hydrolysis of 2,3-dibromo-l-propanol (Section II-C-7).
This was the only work available on microbial degradation (Castro and Bartnicki,
1968; Bartnicki and Castro, 1969). The salient information was limited to
product and qualitative reaction rate studies with enzyme extracts of gram-
negative Flavobacterium sp.
The Flavobacterium sp. was collected from an alfalfa field
-3
soil and grown in an aqueous broth containing 5 x 10 M dibromopropanol. The
enzyme was extracted from the cells by a combination of centrifugation and
sonication. The enzyme activity in the extracted solution was equivalent to
activity of the bacterium cell suspension. The crude enzyme extract was
partially purified, precipitated, and part of the protein fraction was placed
onto Sepnadex G-200.
Dibromopropanol, the epihalohydrins, and epi'nalohydrin
hydrolysis products were metabolized with the crude enzyme extract and the
partially purified enzyme at pH 7. If the enzyme solution was boiled, its
hydrolysis activity was lost. The earlier study (Castro and Bartnicki, 1968)
demonstrated that 2,3-dibromo-l-propanol is initially converted to epibromo-
hydrin. The subsequent reactions depend, in part, upon the added salt (KC1 or
KBr). Table 21 summarizes products and rates for reactions of the epihalo-
hydrins and their degradation products; these data were derived from incuba-
_3
tion of 10 M substrate in 10 ml of a 0.01 M phosphate buffer (pH 7.0) and
70
-------
Table 21. Products from Enzymatic Conversion of Epihalohydrins and Haloalcohols (Bartnicki .and CasLro, 1969)
Substrate
Added Salt
(0.1 M)
Time
(min)
%
Conversion
Products (% yield)'
Epibromohydrin
Epichlorohydrin
l-Bromo-3-c.hloro-2-hydroxy propane
l-3-Dibromo-2-hydroxypropane
1,3-Dichloro-2-hydroxypropane
KC1
KC1
KBr
KBr
None
None
KC1
KC1
KBr
KBr
None
None
None
None
None
None
1
60
1
60
1
60
1
60
1
60
1
60
5
120
10
30
7.4
100
2.0
95
1.7
81
1.6
100
1.2
60
0.4
31
30
100
10
50
69
l-Bromo-3-chloro-2-hydroxypropane
1,3-Dichloro-2-hydroxypropane, 1-
chloro-2,3-dihydroxypropane, 1-bromo-
2,3-dihydroxypropane
1,3-Dibromo-2-hydroxypropane
l-Bromo-2,3-dihydroxypropane, glycidol
(trace)
l-Bromo-2,3-dihydroxypropane
l-Bromo-2,3-dihydroxypropane, glycidol
(trace)
1,3-Dichloro-2-hydroxypropane
1,3-Dichloro-2-hydroxypropane, 1-chloro-
2,3-dihydroxypropane
l-Bromo-3-chloro-2-hydroxypropane
l-Chloro-2,3-dihydroxypropane, 1-bromo-
2,3-dihydroxypropane, epibromohydrin
l-Chloro-2,3-dihydroxypropane
l-Chloro-2,3-dihydroxypropane
Epichlorohydrin (85), epibromohydrin (15)
l-Chloro-2,3-dihydroxypropane (86),
l-bromo-2,3-dihydroxypropane (14)
Epibromohydrin
Epichlorohydrin
l-Chloro-2,3-dihydroxypropane, epi-
chlorohydrin
Where yields are not given, products are listed in a decreasing order of significance,
product/inoles of .substrate converted) 100.
Yields of all single products are. 100%.
Yield = (moles of
-------
0.25 mg of protein theraostated at 24°C. The hydrolysis of 2,3-dibromo-l-
propanol followed the reaction sequence:
BrCH2CHBrCH2OH
0
/ \
3rC.H2CH - CH2 + H?0
OK /\ - +
BrCH2CHCH2OH »• CH, - CHCH^OH + Br + H
/\ OK
CH2 - CHCH20H + H20 - hoch2chch2oh
Bromide ion can open the epoxide to yield 1,3-dibromo-
propanol (see Section I-B-l):
y°\ ?H
H O + Br + BrCH CH - CH7 * BrCH.CHCH.3r + 0H~
i. i ^ 2 2
Incubation with the addition of 0.1 M KCl establishes the following equilibrium:
+ - /°\ 0H
H + CI + BrCH-CH - CH„ * BrCH„CHCH„Cl
I I I I
011 „ -A + +
BrCH.CCH.Cl * CH„ - CHCH.C1 + 3r + H
z z ^ z z
+ - /°\ 0H
H 4- CI + CH. - CHCH.C1 =* C1CH„CHCH_C1
Z Z k: Z Z
/°\ OH
Ho0 + C1CH.CH - CH. =* C1CH_CHCH.0H
Z Z v z z
OH /°\ - +
C1CH,CHCH20H -—=* CH, - CHCH2OH + CI + H
/ \ +
BrCH2CH - CH? + Br + H
OH
BrCH,CHCH2OH
72
-------
In summary, the epihalohydrins appear susceptible to
metabolic hydrolysis in soil. Products vary as the result of the ionic content
of the media and the metabolic transformations parallel chemical reactions (see
Section I-B-10). Metabolic reaction rates in soil were not available,
b. Chemical Degradation in the Environment
The epihalohydrins will chemically degrade in the environ-
ment. The initial chemical reactions are discussed in Section I-B.
The hydrolysis and related reaction rates and products
depend upon the ionic content of the water. Reaction with water to yield 1-
halo-2,3-propanediols will compete with anion reactions to open the epoxide and
yield the corresponding l-substituted-3-chloro-2-propanols. While some anions
(such as chloride) yield products which are stable enough to isolate, others
(such as bicarbonate or nitrate) yield transient products. For example, the
bicarbonate adduct, which is the monocarbonate ester of 3-chloro-l,2-propane-
diol, rapidly hydrolyzes (Shvets and Aleksanyan, 1973) :
So, bicarbonate and other anions which yield transient intermediates are
catalyses for hydrolysis to halopropanediols. As Section I-B-l described,
the maximum hydrolysis half-life for ECH at 20°C is 8.0 days in C02~free» dis-
tilled water. A change in pH down to pH 4 is expected to alter the hydrolysis
rate only slightly (an increase less than 5%), but not to affect products. The
ECH half-life in C02~free water containing 3% NaCl (approximation for sea
H CO ' + H0CHoCHCHoCl
H0C0CH„CHCH„C1
CHCH.C1
73
-------
water) was calculated as 5.3 days, and the resulting ratio of l-chloro-2,3-
propanediol:l,3-dichloro-2-propanol was calculated as 2.0. Dissolved
carbonate is expected to reduce the ECH half-life and increase the proportion
of l-chloro-2,3-propanediol as the result of bicarbonate and carbonate
catalyzed hydrolysis.
further at first to yield a new epoxide. The most important reaction will
be formation of glycidol.
Products formed by anion attack on this epoxide can yield a new halohydrin
(Section II-C-7, "Potential Inadvertant Production in the Environment"):
Because chloride is probably the most common anion, the most likely reaction
of this type is the back attack of chloride in the equilibrium reaction.
The most significant reaction of glycidol is its hydrolysis to yield terminal
product glycerin:
The initial hydrolysis products are expected to react
OH OH
OH 0
. 1 / \ +
^ CH CH — CH + CI + H
CH_CHCH„Cl
HOCH.CH
HOCH CHCH,A
H0CH_CHCH-,0H
CHCH.OH + H.O
74
-------
The races for glycidoi formation from the chloro- and b.romapropanediols are
expected to be similar to rates of EBH and ECH formation from Che dihalopro-
panols (see Section II-C-7). So, it is reasonable to expect half-lives of
about 6 days and less than 1 day for chloropropanediol and bromopropanediol,
respectively, in water at 18'.
The epihalohydrins are expected to degrade rapidly in air
by free-radical reactions of the photochemical smog cycle (Dilling et al.,
1976). ECH appears to degrade very rapidly, and it is expected that EBH will
also rapidly be degraded. Products are unknown (see Section I-B-3).
2. Environmental Transport
Although no direct information was available on the environmental
transport of the epihalohydrins, transport characteristics can be estimated
from physical properties (Table 2). Sufficient information is available to
delineate the transport of ECH, but insufficient data on solubility and vapor
pressure are available for reasonable approximation on EBH.
ECH is water soluble (about 66 g/l) and volatile (about
80 torr at 55.2°C). These values indicate that ECH can be transported as a
vapor in the atmosphere and in solution in water.
The evaporation half-life was estimated by the method of
Dilling (1977). The evaporation half-life, is calculated as:
= 0.6931d
Cl/2 Kl
75
-------
where d is water depth in cm. Calculation of the exchange constant, K, re-
quires the Henry's law constant, H, and molecular weight, M:
K, = 221'1
1 1 04? 1/?
( . + 100.0)M ~
The vapor pressure at ambient temperature must be known for calculation of H.
Since vapor pressure data for ECH at ambient temperature was not available,
vapor pressure was assumed as 15 torr at 20°. This assumption is probably
within a factor of 2 of the actual value and will provide a reasonable, quali-
tative estimate. Henry's law constant, H, was calculated by the equation:
„ 16.04 MP
H " IS
where M is the molecular weight (92.53 g), P is the pressure (15 torr), T is
3
the absolute temperature (293°X), and S is the solubility 65.2 x 10 ppm).
-4
These values yielded H = 11.8 x 10 . The exchange constant, X^, was calcu-
lated as 0.023 min ^ and t-j./2 as ^ = cm). For a 1 i depth of
water, evaporation half-life is about 2.1 days at 20°C.
No information was available concerning epihalohydrin sorption
with aquatic sediment or soil, nor were any data found concerning soil trans-
port processes.
76
-------
3. Bioaccumulation and Biomagnification
Laboratory or field studies on the bioaccumulation and
biomagnification are not available. While ECH solubility data pemit its
assessment, the lack of data precludes any such attempt for EBH.
The bioconcentration factor (BF) was calculated by the method of
Neely et_ al_. (1974) :
log BF = 0.542 log K + 0-124
where K is the n-octanol:water partition coefficient. BF is a measure of the
expected concentration of an organic chemical in tissue based upon its solu-
bility in fat. A partition coefficient of about 10 for ECH was extrapolated
from a graphed relationship between K and water solubility (Freed and coworkers,
1977). The calculated SF was approximately 4.6 (log BF = 0.666). This is a
relatively low value, which indicates that bioaccumulation in the environment
is not likely.
77
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3. Biological Effects
1. Toxicity and Clinical Studies in Man
a. Occupational Studies
In the industrial setting, ECH is well-known for its
ability to irritate the eyes, skin, and respiratory tract upon contact with
vapor or liquid (NIOSH, 1976, 1977; ACGIH, 1977). In addition, systemic
absorption may occur by passage of ECH across the respiratory epitheliun or
the skin to result in gastrointestinal disturbances, pain in the region of
the liver, labored breathing, cough, cyanosis, and chemical pneumonitis.
ECH has been implicated in the allergic contact dermatitis associated
with the handling of epoxy resins (Hamilton and Hardy, 1974), although
its role as a causative agent has been discounted (NIOSH, 1976; Nater
and Gooskens, 1976; Askarova and Muryseva, 1976). No cases of death in
humans have been reported to result from direct contact with ECH.
There has been little evidence in the past to suggest that
worker populations as a whole may be adversely affected by exposure to ECH.
Pet'ko and coworkers (1966) examined the health of 82 persons (49 men and 33
women, primarily in the 20-35 age range) engaged in the production of ECH from
dichlorohydrin glycerin. Although average exposure levels were not reported,
isolated exposures sometimes reached 19-21 mg/m (approximately 4.9-5.5 ppn) ,
and emergency conditions resulted in levels of 210-211 mg/m (approximately
54.6-54.9 ppm). Several parameters of health were examined such as: days lost
due to illness; condition of the ocular mucous membranes, skin, respiratory
organs, cardiovascular system, and nervous system; peripheral blood morphology;
reticulocyte count; bilirubin and cholesterol levels; blood protein fractions;
78
-------
respiratory function; and general urinalysis. It was concluded that no
deviations from the normal could be identified, with the possible exception
of two cases of occupational dermatitis.
NIOSH (1976) has summarized the results of a morbidity study
involving 48 persons, presumably employed by the Dow Chemical Company, having
at least one occupational exposure to ECH. Blood chemistry determinations,
hematocrit index, and total and differential leukocyte counts were made. In
39 of the 48 workers, most determinations of percent polymorphonuclear leuko-
cytes were below normal; determinations of percent of monocytes were mostly
above normal for 35 of the employees. Both the leukocyte and monocyte changes
were common to 32 of the 48 employees, and might thus have been related.
Other abnormalities found included: majority of determinations of percent
eosinophilic leukocytes above normal in 16 employees; total leukocyte counts
and hemoglobin concentrations increased in 15 employees; decreased total
leukocytes and hemoglobin levels in five and eight employees, respectively;
and decreased blood SGOT activity in 13 employees. Most of these deviations
from normal were no longer detectable after a few months removal from exposure.
In a related morbidity study conducted in Russia, workers
3
(number unspecified) exposed to ECH at levels of 0.23-3.1 mg/m (approximately
0.06-0.8 ppm) were examined for adverse health effects (Kovalenko and Bokav,
1975). The authors reported that an increased phagocytic activity of the
leukocytes was observed, which apparently resulted as an adaptive effect.
The potential importance of ECH as an occupational health
hazard has been greatly underscored by recent cytogenetic studies conducted on
workers exposed to ECH. A series of reports from investigators in Czechoslovakia
79
-------
arid Russia (Kucerova, 1975, 1976; Kucerova et al_., 1976, 1977) established that
chromosome changes occur in human lymphocytes exposed to ECH either in vitro or
in vivo. Initial studies with cultured human lymphocytes exposed to ECH for
-4 -1
24 hours at concentrations ranging from 10 to 10 M established that dose-
dependent chromosome damage could occur (Kucerova et al^. , 1976) . Chromatid
breaks and chromosome breaks were the most common aberration; chromatid ex-
changes and chromosomal exchanges were rare (Table 22). The distribution of
ECH-induced breaks was nonrandom, and suggested that certain segments of the
chromosomes were more sensitive to damage than others (Kucerova and Polivkova,
1976). The potency of ECH was considerably less than that of the strong muta-
gen, tris(l-aziridinyl)-phosphine oxide (TEPA).
In a subsequent study, 35 workers (23 to 54 years of age)
occupationally exposed to ECH were examined for chromosomal aberrations in
their lymphocytes (Kucerova et al., 1977). Blood samples were taken from the
workers both before and after they had been exposed to ECH on the job.
Lymphocytes were cultured for 56 to 58 hours prior to analysis. ECH exposure
3
in these workers ranged from 0.5 to 5.0 mg/m (approximately 0.13 to 1.3 ppm).
Cytogenetic analyses revealed that the percentage of aberrant cells collected
before the start of ECH exposure did not differ from that in other normal
human populations. However, blood samples taken after one and two years
of exposure showed increasing numbers of cells with chromosome defects
(Table 23). In accordance with the results of earlier in vitro tests,
chromatid and chromosomal breaks were the most frequent aberration observed.
Although the authors indicated that the workers had not been concurrently
exposed to radiation or other known mutagens, it is not known to what extent
80
-------
a
Table 22. Mutagenic Effect of Epichlorohydrin and TEPA in Different Concentrations
(Lymphocytes exposed to epichlorohydrin (ECH) and TEPA during last 24 hours
of cultivation.)
Type of aberration
Number
of eel1s
scored
(¦ells with
ahcrr.i r ions
number
(X)
Number of
clirouut U
breaks
Number of
chromuI Id
exchanges
Number of Number of
chromosomal chromosomal
breaks cxchanp.es
Number of
dberratlonu
pec 100 eel la
Number of
breaks
per 100 cells
Number
of gaps
KCIl 10 M
360
28
/.a
16
I
13
2
8.9
9.7
8
ECH 10 ,M
300
9
3.0
8
0
2
0
3.3
3.3
5
KCIl 10 M
100
8
2. /
5
0
4
0
3.0
3.0
5
ECU 10 ®M
300
<•
1.3
0
3
1
0
1.3
2.3
2
ECU 10~ M
300
3
1.0
I
1
1
0
1 .0
1.3
3
KCH 10-IOh
300
5
1.7
3
1
0
1
1.7
2.3
0
ECU 10"!
300
2
0. 7
1
0
1
0
0.7
0. 7
1
TEl'A 10~ cM
200
103
1)1.5
1 18
12
48
0
89.0
95.0
103
TEPA 10 ?M
200
75
37.5
44
4
47
2
48.5
51.5
15
TEPA 10 ?M
300
42
14.0
16
1
25
0
14.0
14.3
15
TKPA 10 M
260
10
3.8
J
0
6
1
3.8
4.2
3
TEPA 10 H
100
3.0
5
0
6
I
4.0
4.3
4
tf.pa io m
J00
5
1.7
3
0
2
0
1. 7
1.7
1
TEl'A 10-I0M
100
2.0
5
0
2
0
2.3
2.3
2
TKPA 10"''m
too
7
2. 3
2
1
5
1
3.0
3.7
3
Cunr ro 1
;o"
5
0. 7
3
0
1
0.7
0.9
7
Com i ol with
200
2
1.0
2
0
,)
0
1 .0
1.0
0
OMSO
a
Krom Knci-rova
el a 1.
l')7f>
-------
Table 23. Chromosomal Analysis of Workers Occupatlonally Exposed to Epichlorohydrin3
(summarized results from Prague and Moscow)
Number of
persons
Number
of I I n
scored
Cells with
aberrations
Number
Types of nberrntlon
Number of Number of Number of
chromatid chromatid chromosome
breaks exchanges breaks
(per 100 cells) (per 100 rolls) (per 100 cells)
Number of
chromosome Number of Number of Number of
exchanges aberrations breaks gaps
(per 100 cells) (per 100 col In) (per 100 cells) (per 100 cells)
35 5054
1st collect.
(conL ro 1)
69 1.37
49
(0.97)
3
(0.06)
14
(0.2ft)
6
(0.12)
72
(1.42)
81
(1.60)
19
(0.3H)
oo
K>
33 5445
2nd collect.
31 6175
3rd collect.
104 1.91
16ft 2.69
57
(1.05)
100
(1-62)
6
(0.11)
6b
(0.10)
33
(0.61)
64
(1.04)
From Kucerova el al., 1977
One chromatid exchange wan kIster-unIont therefore. It wan calculated as only one break.
.2
Difference between 1st and 2nd collections:
Difference helween 2nd and 3rd collections:
Difference between 1st and 3rd collections:
8
(0.15)
13
(0.21)
5.0, P - 0.025; significant difference.
X' - 8.0, P - 0.005; significant difference.
X =» 24.0, P •' 0.0001; lilpjtly significant difference.
104
(1.91)
188
(2.96)
118
(2.17)
201
(3.26)
49
(0.90)
64
(1.04)
-------
simultaneous exposure to other chemicals in the workplace may have affected
the results.
In the United States, a recent report has also linked
occupational ECH exposure to chromosome damage among workers (Picciano, 1979).
In a group of 93 epoxy resin workers exposed to ECH at levels below 5 ppm an
excess of chromosome abnormalities was found in their peripheral lymphocytes
when compared to 75 controls. The incidence of abnormalities was approximately
double that found in control workers having no ECH exposure. The possibility
of simultaneous exposure to chemicals other than ECH must be considered, however,
in evaluating these results. In addition, it was noted that the production of
chromosome abnormalities may be a reversible effect, and thus its ultimate health
impact is unclear.
These data on ECH-exposed workers in the United States were
expanded and further analyzed by Barna-Lloyd et al. (1979) at Dow Chemical.
They presented cytogenetic data on a group of 76 epoxy resins workers compared
with 26 controls and on a group of 115 glycerine workers compared with 37 con-
trols. It is not known to what extent this study overlaps with that reported
by Picciano (1979). Levels of chromosome aberrations were apparently elevated
in the epoxy resins workers but not among the glycerine workers when compared
to the control group. The eleveated levels of damage in the epoxy resins group
were reduced when retested eight months later.
Both the Picciano et_ al_. (1979) study and the Barna-Lloyd
et al. (1979) study suffer from a similar methodologic drawback in that reliance
was plased on external control groups for comparison rather than upon the pre-
ferable method of using pre-exposure determinations in the same individuals.
It should be noted that the Kucerova et al. (1977) study summarized above, pre-
exposure determinations were employed.
-------
The significance of cytogenetic analysis of human chromo-
somes is claimed to be for the indication of increased cancer risk and possible
transmission of birth defects and mutations from one generation to the next.
On the other hand, it is often stated that there is no a priori reason why
neoplastic transformation or mutagenesis should involve any kind of visible
chromosome damage (Kucerova, 1976). One can argue that the induction of point
mutations, a process which is consistent with chemical carcinogenesis, occurs
without gross chromosome damage. Moreover, the use of somatic cells to predict
a mutagenic effect that might occur in germinal cells may have limited validity.
Nevertheless, numerous examples of the positive correlation between a chemical's
ability to produce chromosome aberrations in somatic cells and its carcinogenic/
mutagenic activity indicate that cytogenetic data should be carefully evaluated.
The most recent study concerning health impairment among
ECH workers at Dow Chemical examined potential effects on male fertility (Venable
and McClimans, 1978). Sperm counts taken from 128 volunteers showed no variation
from that of a control group, although a lower percentage of motile sperm was
found in the ECH-exposed group. Similarly, measurements of hormone levels in
these workers did not differ significantly from controls (method for selection
of controls not specified). Sperm counts did not correlate either to the dura-
tion or intensity of exposure to ECH. However, ECH is suspect as a reproductive
hazard on the basis of animal data which indicate an antifertility effect in
males (see Section III.B.2.f).
b. Poisoning Incidents and Case Histories
Cases of acute intoxication by ECH have only infrequently
been reported in the scientific literature. In Germany, Schultz (1964) pub-
lished a case report concerning a 39 year old worker exposed to a single gust
84
-------
of ECH. The immediate reaction to exposure was eye and throat irritation,
followed by facial swelling, nausea, vomiting, headache, and dyspnea. Subse-
quent clinical examinations revealed an enlarged liver accompanied by jaundice.
Five months after the incident, liver damage and abnormal liver function were
found along with bronchitic alterations in the right lung and elevated blood
pressure. Even after two years, liver function remained abnormal and chronic
asthmalike bronchitis was present.
NIOSH (1976b) reported the case of a 53-year-old worker
exposed to ECH fumes for about 30 minutes whose symptoms resembled those in
the case presented above. However, recovery from the exposure was rapid and
complete, with the exception of recurrent infections of the upper respiratory
tract. Since the intensity of ECH exposure was not known, it is not possible
to relate specific effects to the amount of ECH absorbed.
The adverse effects of ECH resulting from contact with the
skin and the respiratory and conjunctival mucosae have been well documented.
NIOSH (1976b) summarized data indicating that a concentration of 20 ppa ECH
causes a transient burning of the eyes and nasal mucosa. At a concentration
of 40 ppm, ECH produces eye and throat irritation which persists for 48 hours.
Concentrations of ECH in excess of 100 ppm are considered intolerable, even
for brief periods. In addition it was stated that lung edema and kidney
lesions may result with concentrations of ECH at 100 ppm in air.
Several detailed accounts of workers receiving skin burns
as a result of contact with ECH were published by Ippen and Mathis (1970) in
Germany. A common observation among the five cases studied was that the
appearance of symptoms (redness, swelling, itching, burning) was usually
delayed. In one case, two days passed before symptoms were noted. The inten-
sity of skin reaction to ECH varied, although it was not possible to relate the
85
-------
degree of exposure to the effect produced. In. the mildest cases, severe red-
ness, swelling, itching, and red papules appeared on the hands or legs, which
required treatment lasting up to several weeks. In more severe cases, ECH
caused blisters and severe skin erosion accompanied by lymph node enlargement,
c. Epidemiology
Detailed epidemiologic studies on ECH have not been reported
in the scientific literature. However, two studies conducted on ECH workers
have recently been summarized. In the first, a retrospective examination of
morbidity among 507 Dow Chemical Company employees was conducted (Hine, 1976).
Most of the workers were exposed to ECH for five years or less, although
exact numbers and quantitative exposure data were not given. In addition, there
was no defined sampling scheme reported either for initial selection of indivi-
duals or for subsequent measurements. A medical examination of the workers
revealed no apparent abnormalities in blood chemistry or liver and kidney
function. However, episodes of illness due to respiratory problems were judged
to occur more often when ECH workers were compared in exposure and non-exposure
situations. In addition, employees having the greatest exposure to ECH also
showed slight elevations in the white blood cell count and wide fluctuations
in the monocyte cell count. The lack of a control group prevented a critical
comparison of clinical and laboratory findings in ECH workers to those of a
normal population. The more appropriate units of comparison would have been
an individual's hematologic values upon entry into employment and the same
individual's values after exposure to ECH. Furthermore, this study has little
value in the assessment of many chronic diseases, including cancer; insufficient
time had elapsed for such effects to be expressed, and workers who dropped out
of the study due to illness, retirement, or death were not considered.
86
-------
A mortality study was conducted on 364 active and retired
Shell Chemical Company workers exposed to ECH for at least six months during
the period from 1948 to 1965 (Enterline and Henderson, 1978; Enterline et_
al., 1979). Mortality information was gathered on the entire cohort through
1977. This report is the first to suggest a possible carcinogenic risk for
workers exposed to ECH. Out of a total of 52 deaths in this cohort, nine
(17.3%) were due to respiratory cancer. This is a statistically significant
number (P<.05) when compared to the expected respiratory cancer death rate
of 6 to 7% for men in this age group. Although these results x^ere considered
as "highly suggestive of a carcinogenic risk of ECH," it was also recognized
that unresolved difficulties complicated the analysis of results. These
problems included the lack of accurate pathological diagnoses in most cases,
the absence of quantitative monitoring and exposure data, and the absence
of tobacco smoking and alcohol consumption histories. Nevertheless, in con-
junction with the results of animal bioassays with ECH (see Section III.B.2.h),
this substance must be viewed with increased suspicion.
Dow Chemical (Shellenberger .et al.•, 1979) has reported
that among ECH-exposed workers in their Glycerine Department and Epoxy Resins
Department, Texas Division, "no association was found between an increased
risk of mortality and exposure to epichlorohydrin." However, this conclusion
cannot be accepted without reservation, since the cohort described was probably
too young (62% under age 40) and too recently exposed (63% with less than 10
years elapsed since onset of exposure) to fully exhibit the effect of chronic
ECH exposure on mortality.
87
-------
2. Effects on Non-Human Mammals
a. Absorption, Distribution, and Excretion
The pharmacokinetics of ECH in mammalian systems has only
recently been explored in detail. Weigel and coworkers (1978) have examined
14
the tissue distribution and excretion of C-ECH following an oral dose of
10 ag/kg given to male and female Charles River CD rats. Various body tissues
were examined at 2, 8, 12, 24, 48, and 72 hours post administration in an
attempt to: (1) determine major routes of excretion; (2) observe any sex-
related differences in distribution and excretion; and (3) correlate the known
target organ effects of ECH with the tissue distribution of the compound. In a
14
separate study, the respiratory excretion of orally administered C-ECH was
14 14
determined by the measurement of CO^ and unchanged C-ECH in expired air at
various intervals following exposure.
Interpretation of their results is complicated by the fact
that recovery of administered radioactivity was low. Nevertheless, it was
14
apparent that absorption of C-ECH was rapid, with peak tissue concentrations
being reached at 2 hours in males and 4 hours in females. In general, the
tissue with the highest level of radioactivity was the kidney, followed in
decreasing order by the liver, pancreas, adrenals, and spleen.
14
The major route of excretion for C-ECH-derived radio-
activity was in the urine, accounting for 30-40% of the administered dose
14
within 72 hours. Excretion of CO2 in expired air accounted for 18-21% of the
administered radioactivity (24 hours), whereas fecal excretion accounted for
less than 4% of the dose over a 72 hour period. The rapid appearance of large
14
amounts of in expired air suggested a rapid and extensive metabolism of
14C-ECH by the rat.
88
-------
The pharmacokinetics of radiolabelled epichlorohydrin administered
to rats by gavage or inhalation have been studied by Dow Chemical (Snith et
14
al-, 1979). Rats were administered epichloronydrin-l,3- C at levels of
100 or 1 ppm by the two routes indicated. Inhalation studies were conducted
for 6 hrs. of exposure. Within 72 hours, 90% of the administered radio-
activity had been recovered from the urine (46-54%) and expired air (25-42%).
Orally exposed rats showed 9 urinary metabolite peaks, but only eight peaks
were observed following inhalation exposure. None of the excreted radio-
activity represented unchanged compound. Tissue distribution studies showed
similar patterns following either route of exposure, except that nasal turbinates
and the stomach showed high levels after inhalation and oral exposure,
respectively. Quantitation of relative tissue levels of compound cannot be
relied upon, since extensive breakdown of labelled compound to one carbon units
occurs, following which redistribution and incorporation can take place,
b. Pharmacology and Metabolism
Only limited data are available concerning the mammalian
metabolism of ECH. Nevertheless, it was demonstrated in studies with rats
that ECH may be hydrolyzed in vivo to yield a-chlorohydrin (Jones et al.,
1969). This pathway of metabolism is supported by data indicating that
common urinary metabolites are obtained after treatment of rats with either
ECH or ct-chlorohydrin. The urinary metabolites produced are apparently
substituted cysteine derivatives.
89
-------
Further data to suggest the role of a-chlorohydrin as an
intermediate during ECH metabolism are available from studies showing that
both compounds produce antifertility effects in male rats (Cooper et al.,
1974; see Section III.B.2.f.).
Additional possibilities for intermediates in ECH metabolism
were suggested by Van Duuren (1977). The following pathway was postulated:
A /°\ /°\ /°\
CH2 - CHCH2CL * CH2 - CHCH20H CH2 - CHCHO »¦ CE2 - CHC02H
ECH Glycidol Clycidaldehyde Epoxypropionic
acid
It is noteworthy that both ECH and glycidaldehyde are suspect as carcinogens
(Van Duuren, 1977).
c. Acute Toxicity
Studies with various animal species have established that
ECH is highly irritating upon contact and moderately toxic by systemic absorp-
tion. The major target organs adversely affected by ECH are the central nervous
system, spleen, liver, respiratory tract, and the kidneys (Lawrence et al., 1972).
A summary of ECH dose-response information for acute lethality by various routes
of administration and in several species is presented in Table 24. Further
experimental data are summarized in the following sections of this report.
(1) Acute Inhalation Exposures
In one of the earliest reports on ECH toxicity, white
mice were exposed to ECH vapors at 2370, 8300, and 16,600 ppm for 30 or 60
minutes (Freuder and Leake, 1941). A dose-related irritation of the nose and
eyes was observed; all of the mice exposed to ECH at 8300 and 16,600 ppm died.
90
-------
Table 24. Acute Toxicity of Epichlorohydrin (ECH)
Speci cs
Mouse
Route
Dose
Results
Reference
oral
oral
oral
ihl
i hi
ihl
ihl
ihl
ihl
scu
scu
ip
skin
238 mg/kg LD
0.5 ml/kg
0.23 ml/kg
7,400 ppm x 30 min
2,370 ppm x 1 hr
8,300 ppm x 30 min LC
16,600 ppm x 30 min I.C
793 ppm x 2 hr
250 mg/kg
500, 375 mg/kg
155 mg/kg
tail dipped in
undiluted ECH x 1 hr
tail dipped in
undiluted ECH x 20-30
min, 203X
50
LD100
Not lethal
lclo
Not lethal
100
100
71.89 mg/1 x 9.13 min LT
50
LC50
7/10 died
LD
100
LD50
6/10 died
LD
100
NIOSH, 1976a
Freuder and
Leake, 1941
Freuder and
Leake, 1941
NIOSH, 1976a
Freuder and
Leake, 1941
Freuder and
Leake, 1941
Freuder and
Leake, 1941
Lawrence et^
al. , 1972
Grigorowa et_
al., 1974
Pallade et^
al., 1967
Pallade et^
al., 1967
NIOSH, 1976a
Pal lade <2t
al., 1967
Pallade e^
al., 1967
-------
Table 24. Acute Toxicity of Epichlorohydrin (ECH)
(Cont inued)
Species
Route
Dose
Results
Reference
Rat
tsJ
Rats and mice
oral
oral
oral
ihl
ihl
ihl
ihl
scu
skin
skin
skin
ihl
ihl
LC
90 mg/kg LD
260 mg/kg 1,1)
0.21 ml/kg LD
360 ppm x 6 hr
250 ppm x 4 hr
635 ppm x 4 hr
250 ppm x 8 hr
150 mg/kg LD
125 mg/kg
50
50
50
LC
LC,
50
L0
50
4/6 died
50
2 ml/kg x 1 hr
1 ml/kg x 1 hr
0.5 ml/kg x 1 hr
6-7 mg/1
3 mg/1
6% polyuric
79% oliguric
15% normal
death rate = 13.4%
18/20 died
2/10 died
0/10 died
LC
LC
100
50
NIOSH, 1976a
Lawrence et
al., 1972
Weil ct al.,
1964
Snyder, 1978
NIOSH, 1976a
Grigorowa et^
al., 1974
Weil et^ al_. ,
1964
Pallade ej^
al., 1967
Pallade £jt_
al., 1968
Freuder and
Leake, 1941
Freuder and
Leake, 1941
Freuder and
l.eake, 1941
Kremneva, 1960
Kremneva, 1960
-------
Table 24. Acute Toxicity of Epichlorohydrin (ECU)
(Continued)
Species
Route
Dose
Results
Reference
Rabbit
Guinea pig
Cats, dogs
Mice, rats,
rabbits, guinea
pigs
skin
skin
skin
skin
unk (oral?)
iv
IP
1300 mg/kg
0.64 ml/kg
1.3 ml/kg
0.76 g/kg
280 mg/kg
0.08 ml/kg
0.10-0.14 ml/kg
LD
l.D
50
50
LD
50
LD
50
LD50
minimum
lethal dose
LD
50
NIOSH, 1976a
Lawrence et
al., 1972
Wei 1 e£ al.,
1964
Lawrence et_
al., 1972
Fedyanina,
1968
Krimneva and
Tolgskaya, 1
Lawrence tit_
al., 1972
'^Abbreviations: ihl, inhalation; scu, subcutaneous injection; ip, intraperitoneal injection; skin,
dermal application; iv, intravenous injection
1>1 ml ECH = 1.18g
-------
Among 10 mice exposed to 2370 ppm ECH for 60 minutes each dayj two animals died
on day 3, two on day 6, one on day 7, two on day 8, on day 9, and the last two
on day 16. Symptoms leading to death included gradual cyanosis, muscular par-
alysis, and depressed respiration which preceded cardiac arrest.
The acute symptoms of ECH vapor intoxication in rats
and mice were further described by Kremneva (1960). She reported central nervous
system impairment, characterized initially by locomotor excitability, and followed
by nervous depression and breathing difficulty. In addition, a reddening of the
skin and subcutaneous hemorrhage were noted.
A more recent report on systemic damage produced by
inhalation of ECH was published by Shumskaya and coworkers (1971) in Russia.
Rats receiving single four hour exposures to ECH at 1.8 to 91 pun experienced
functional alterations in the kidneys, liver, lungs, and central nervous system.
Kidney dysfunction was evidenced by polyuria, proteinuria, reduced urinary
chloride levels, and increased urinary excretion of nitrogen-containing sub-
stances. Liver and kidney weights were increased, while spleen and lung weights
were decreased. Impairment of liver function was indicated by a decreased
ability to remove bromosulfophthalein from the blood. Oxygen consumption and
body temperature were also reduced by the ECH treatment.
The results of another recent study have shown that
the acute six-hour for ECH in male Sprague-Dawley rats is approximately
360 ppm (Snyder, 1978). The range of lethal concentrations was apparently very
narrow, suggesting that a critical ceiling may exist for acute inhalation ex-
posures. Pathologic findings on gross autopsy included hemorrhage and edema
which presumably resulted from respiratory irritation. In animals still sur-
viving four weeks after the ECH exposure, signs of recovery were evident.
94
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(2) Acute Oral Exposures
Freuder and Leake (1941) firsc reported the toxic
effects of ECH by ingestion. A single dose of 0.5 ml/kg ECH in gum arabic
given by stomach tube was lethal to all of a group of 15 animals. No deaths
resulted from administration of ECH at 0.23 ml/kg. However, four doses of
0.23 ml/kg each given at daily intervals were lethal to all mice treated. The
symptoms of intoxication were the same as previously described for inhalation
exposures; death resulted from effects on the central nervous system, primarily
the respiratory center.
Kremneva and Tolgskaya (1961) observed the effects of
acute oral doses of ECH administered to both rats and mice. At the lowest dose
tested, 250 mg/kg, no obvious signs of toxicity were noted during a 14 day
observation period. All animals given doses of 325 and 500 mg/kg, however, died
within two days. The symptoms observed in both species included decreased
locomotor activity, body tremors, muscular incoordination, breathing difficulty,
abdominal distention, skin hyperemia, and subcutaneous hemorrhage. Histopatho-
logic examination revealed hepatic vacuolization and fatty degeneration, pul-
monary edema and hemorrhage, renal necrosis with epithelial degeneration of the
convoluted tubules, and necrotic areas in the gastrointestinal mucosa.
(3) Acute Dermal and Eye Contact
Several investigators established that ECH can produce
systemic poisoning from skin absorption. In 1941, Freuder and Leake applied
ECH to the bare skin of guinea pigs and rats. On the shaven abdominal area,
2
about 1 cm gauze saturated with ECH was placed and then covered with plastic
for one hour. Following the appearance of local discoloration and irritation,
95
-------
symptoms of systemic intoxication occurred. At the 2 ml/kg dose, 18 out of 20
rats died; at 1 ml/kg, 2 out of 10 rats died, while all 10 rats survived the
0.5 ml/kg dose.
A more recent study (Pallade et al., 1967) examined
the results of immersing the tails of 20 mice in pure ECH. A one hour expo-
sure was lethal within 3 days to 6 out of 10 mice. Repeated immersions lasting
20-30 minutes each were lethal to all 10 mice by the second or third treatment.
Necropsy revealed widespread congestion and edema in addition to brain hemorr-
hage , as well as severe damage to the epithelium of the renal convoluted tubules.
They also found that 15-20 minute immersions of 10 mice's tails in undiluted ECH
resulted in the death of seven mice and local damage in survivors leading to the
loss of the ends of the tails. Another experiment by Pallade and coworkers (1967)
studied the local effects of 0.5 ml of ECH applied for 24 hours to the skin of
rabbits. The resulting lesion was described as having a region of necrosis
bounded by edema of the superficial skin layers. Peripheral to this area of
exposure, erythema and focal points of hemorrhage were observed. A scab cover-
ing the area of irritation formed in 2-3 days and lasted as long as 30 days.
All rabbits recovered from the treatment. Lesions of lesser severity were
observed for applications of 0.1-0.2 ml of ECH.
Several researchers have studied the effects of ECH on
the eyes and conjunctivae of test animals. In 1961, Kremneva and Tolgskaya
placed a drop of ECH on the conjunctival sac of a rabbit's eye, which resulted
in lacrimation, edema and hyperemia of the lid and mucous membrane, corneal
clouding, blepharospasm, constriction of the pupil, and reduced eye slit. In
1969, Golubev reported that 0.25 M ECH solution instilled in rabbit's eyes caused
96
-------
no damage to either the cornea or conjunctiva; however, constriction of the
pupils occurred on the order of 1-16% of the pretreatment pupil diameter.
Lawrence and coworkers (1972) dropped 0.1 ml of ECE dissolved in cottonseed oil
into the right eyes of rabbits, leaving the untreated eyes to serve as controls.
Corneal injury resulted in 80% of the treated eyes while the remainder suffered
irritation to a lesser extent. From these studies, it was concluded that ECH
is a strong ocular irritant.
(4) Acute Parenteral Administration
Subcutaneous injection of ECH produces nephrotoxic
action in test animals. In 1968, Pallade and coworkers found that single
injections of ECH (125 mg/kg) caused polyuria in 6% of the 67 rats treated, and
oliguria or anuria in 79%; the remaining 15% exhibited normal urine flow. Seven
rats which initially produced little or no urine became polyuric in 2-3 days.
Deaths occurred at a rate of 13.4% but was restricted to anuric or oliguric
rats. Urinary protein and potassium levels were high immediately after treat-
ment, but returned to normal in 8 days. Sodium concentrations, however, were
still low after 8 days (Pallade et_ al., 1968).
In 1966, Rotaru and Pallade reported that single sub-
cutaneous injections of ECH in rats (150 or 180 mg/kg) caused severe injury to
the kidneys, especially to nephrons. Regeneration of the structural components
of the kidneys was seen on days 5 and 10 following treatment, but no positive
determination could be made from the data available regarding the restoration
of function. Injury to the other internal organs was also evident as pulmonary
congestion and edema, bronchial catarrh, hemorrhage and congestion of the
spleen, congestion and edema of the gastrointestinal tract, and congestion in
97
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the brain and adrenals. Changes in the liver and heart were insignificant.
Severity of injury appeared to be dose-dependent. Criteria for determining
these changes were not available for evaluation.
Two dogs and three cats anesthetized with pentobarbi-
tal were injected intravenously with single 0.008 mg/kg doses of ECH. The
only effect observed was a temporary drop in blood pressure. The minimum
intravenous lethal dose, determined by the same investigators to be 0.08 ml/kg,
caused.death in 2 hours (Kremneva and Tolgskaya, 1961).
d. Subchronic Toxicity
Repeated oral administration of ECH to both rats and mice
has been conducted by various investigators. Four treatments of ECH were
sufficient to cause death at a dose level of 0.23 ml/kg (Freuder and Leake,
1941). Feayanina (1968) found administration of 0.1 mg/1 ECH in the water of
rats for six months had adverse effects on conditioned reflexes and liver
function.
In early studies, Freuder and Leake (1941) severely exposed
10 white mice to 2370 ppm/60 min/day until all had died. All animals exhibited
the same sequence of symptoms. Initially eye and nose irritation occurred
followed by gradual cyanosis, relaxing of the muscles of the extremities,
stiffening of the tail and a slight body tremor. Several hours before death,
respiration decreased and ceased before cardiac arrest. In some animals ter-
minal clonic convulsions were observed. Two deaths occurred on the third day,
two on the sixth day, one on the seventh day, two on the eighth day, one on the
ninth day, and the two final deaths occurred on the sixteenth day.
98
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Gage (1959) exposed groups of Wistar rats by inhalation
to varying concentrations of ECH for 6 hours/day, 5 days/week and observed
dose-related toxic effects. Rats receiving 11 exposures to ECH at 120 ppm in
air began to have difficulty in breathing after the first three hours; this
condition persisted throughout the entire series of treatments. The poor
condition of the rats became progressively worse and between exposures the
rats exhibited symptoms of lethargy. After the fourth exposure the rats had
profuse nasal discharge along with considerable reductions in weight. Blood
analysis revealed marked leucocytosis due to an increase in polymorphs and
monocytes. Urinary protein excretion had more than doubled at the termination
of the treatment period. The death of one rat occurred after the eleventh
exposure. Necropsy revealed patches of discoloration in the lungs of all
rats, two livers exhibited uneven coloration, the kidney cortices of two rats
were unusually pale, and intestines were found to contain bile in addition to
being distended with gas. Further examinations showed congestion of the
lungs, edema, consolidation, and areas of inflammation with possible abscessing.
Leucocytic reaction was evident in the kidneys of all rats and in four rats
there was atrophy of the peripheral cortical tubules. The degree of functional
impairment which accompanied these lesions and their possible reversibility
was not determined in this study.
Another group of rats received 18 six-hour exposures to
56 ppm ECH (Gage, 1959). Lethargy and respiratory difficulties were again
noted but not until the tenth, exposure. A nasal discharge appeared later.
Weight losses were recorded during the exposure period but some recovery was
made on weekends. Neither urine and blood analysis nor necropsy and histo-
99
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pathological examination revealed any abnormalities. A group of rats re-
ceiving 18 exposures at 27 ppm suffered minor nasal irritation but body
weights remained constant. Hemorrhage and consolidation was only seen in the
lung of one rat. Nineteen exposures to 17 ppm produced no definitive altera-
tions yet the condition of the treated rats did appear to be inferior to
normal controls. A final group of rats was exposed 18 times to 9 ppm ECH.
No ill effects were noted although two rats suffered pulmonary infections.
Further inhalation studies by Gage (1959) were conducted
using New Zealand white rabbits weighing 1.8-2.0 kg. Twenty daily exposures to
35 ppm caused nasal irritation but no alterations in normal weight gain. Two
rabbits exposed to 16 ppm (2 exposures) experienced nasal irritation, whereupon
the concentration of ECH was then decreased to 9 ppm for 20 days. This treatment
produced no adverse effects on the rats, nor were any abnormalities observed in
post-mortem examinations.
A comprehensive ECH inhalation study was conducted by Fomin
(1966). Male albino rats were exposed in groups of 15 to ECH vapor for 24
hours per day for 98 days at the following dose levels:
3
a. 20 + 0.026 mg/m (5.2 ppm + 0.01); total ECH inhaled = 1722 mg/kg
3
b. 2 + 0.007 mg/m (0.5 ppm + 0.002 ppm); total ECH inhaled = 172 mg/kg
c. 0.2 + 0.001 mg/m3 (0.05 ppm + 0.0003 ppm); total ECH inhaled » 17 mg/kg
Rats exposed to 5.2 ppm ECH vapor exhibited a decrease in total nucleic acid
content of the blood to 90.73 mg% (versus 127.07 mg% in the controls) and
increase in urinary coproporphyrin to 2.68 yg (versus 1.07 yg in the controls).
The health-related significance of these results was not shown. Reduced
weight gain and prolonged latent periods in a motor defense reaction test
were additional symptoms of ECH exposure cited in this abstract. Necropsy
100
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revealed abnormalities of the lungs including emphysema (diagnostic criteria
not specified), bronchopneumonia, edematous areas and loosening and swelling
of the adventitia of blood vessels. Examination of the kidney found cloudy
swellings of the epithelium of the convoluted tubules. Interstitial hemor-
rhage and venous congestion were noted in the heart. The brain contained
severe lesions of neurons in the medulla oblongata, Amnion's harm and the
cerebellum. The degree of functional impairment or the reversibility of
these lesions was not examined. The groups exposed to 0.5 and 0.05 ppm ECH
revealed no morphological abnormalities upon analysis. The low dose (0.05 ppm)
group exhibited no blood changes. Analysis of this data is not possible until
the full report is available.
A group of ten rats was exposed three hours daily to 0.02-
0.06 mg/I (5.2-15.6 ppm) of ECH for 6.5 months. Kremneva and Tolgskaya
(1961) recorded no deaths or signs of intoxication attributable to the treat-
ment. Reduced weight gains were found in the treated rats in addition to an
increase in the threshold of excitability of the nervous system during months
2-5. 31ood pressure was normal in the treated rats and although oxygen
consumption increased during the first two months of exposure it decreased
during the fifth and sixth months. No abnormalities were found upon analysis
of peripheral blood. Examination of the liver and kidney revealed no sig-
nificant effects. Occasional slight thickening of the alveolar walls and the
presence of bronchitis led the authors to conclude that this dose level of ECH
was the threshold for production of tissue damage in rats.
Snyder (1978) exposed rats to 100 ppm ECH for 30 days.
Although the treated animals had a reduced rate of survival, their rate of
weight gain was greater than for controls. Rhinitis and squamous cell meta-
101
-------
plasia were evident upon examination of the nasal mucosa. Chronic exposure
to 30 ppm ECH for more than 734 days or 10 ppm ECH for more than 670 days
resulted in increased survival of treated groups versus controls. Those rats
exposed to 30 ppm exhibited significant weight losses, however. Further
details of this study are reported in Section III. B. 2. h.
A Dow Chemical Study on the subchranic toxicity resulting
from ECH inhalation in rats and mice has been carried out by Quast et al.
(1979). Two species of rats and one of mice (both sexes) were exposed to
ECH vapor at concentrations of 5-50 ppm for 6 hours/day, 5 days/week for a
total of 65 exposures. Pathological changes were noted primarily at the
two highest exposure levels, 25 and 50 ppm. All species and sexes showed
inflammatory and degenerative changes in the nasal turbinates; male Sprague-
Dawley rats showed the most severe changes. These included rhinitis, focal
erosions, hyperplasia, and metaplasia with a squamous appearance. Moderate
and severe focal tubular nephrosis was observed in the high dose rats.
Gross pathological changes in the livers of high exposure male rats were
seen in half the animals. This included pale discoloration and accent ratios
of the lobular pattern. However, histopathology did not reveal significant
microscopic changes. Several male rats from the 50 ppm group showed altered
epididymal contents which included amorphous eosinophilic staining material
and increased numbers of nucleated cells. The sperm count in these animals
was normal. Weight loss in the 50 ppm exposure groups was slight. The
role of secondary effects produced by stress at the highest ECU exposure is
difficult to evaluate, but is probably not a major factor.
A follow-up on this study by the same investigators
(Quast £t_ al., 1979) utilized continuous 7 hour exposures to higher ECH vapor
102
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levels for 12 consecutive days. At the exposure level of 100 ppm, rats and
mice showed symptoms of decreased body weight, nasal irritation, and in-
creased kidney weights (rats). The changes in the nasal turbinates observed
were similar to those noted in the previous study except that they were more
severe. Slight degenerative changes were noted in the kidneys of the rats,
and slight non-degenerative changes were seen in the rats and mice. Changes
in epididymal contents were the same as those observed after the longer
50 ppm exposure. No evidence of cystic or degenerative changes in the
epididymides was noted in this study.
Grigorowa and coworkers (1974) studied the effect of
environmental stress on the response of 60 male albino rats exposed by in-
halation to 0.6 or 0.06 mg/liter (15.8-158 ppm) ECH for four hours per day
over an eight-day period. One half of each exposure group was subjected to a
temperature of 35°C and relative humidity of 35-50% for 45 minutes after each
exposure to ECH. Exposure to the higher dose of ECH reduced body weight by
9%; exposure to ECH and stress had the same effect. Examination of rats
throughout the study revealed a modification of the toxic effects of ECH by
the addition of heat stress. Those rats subjected to heat stress suffered
less severe variations in liver and thyroid follicles but the effects on the
adrenal medulla were increased. Leukocyte accumulation around blood vessels
was noted in the thyroids of five rats. Compared to controls, the treated
animals exhibited increased relative weights of lungs, liver, kidneys and
adrenals. Urinalysis revealed a decrease in volume and protein concen-
tration. Serum lactate dehydrogenase activities increased while serum
sodium, potassium and leucine aminopeptidase showed variable changes. The
103
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authors found an increase in blood catalase activity to be the main effect of
heat stress and noted that these effects were less severe at the lower dose
of ECH.
Rats exposed to 32 ppm ECH for a period of 91 days, 7 hours
per day, 5 days per week suffered reduced weight gains. Exposure to 16 ppm on
the same schedule produced an increase in kidney size and small amounts of
coproporphyria in the urine (ACGIH, 1974).
3
Fomin (1968) in a later study exposed mice to 20 mg/tn
(5.3 ppm) of ECH producing weight loss, deterioration of conditioned reflexes
and unspecified morphological changes of some organs and the central nervous
3
system. A smaller dose, 2 mg/m (0.5 ppm), increased the white blood cell
counts in mice.
Lawrence and coworkers (1972) undertook a comprehensive
study of the cumulative and subchronic parenteral toxicity of ECH in rats.
Groups of 12 male Sprague-Dawley rats were employed. The controls received
daily injections of cottonseed oil for 30 consecutive days while another group
received 0.00955 ml/kg (0.1 acute LD,^) of epichlorohydrin daily, and a final
group 0.01910 ml/kg ECH (0.2 acute LD^^). No deaths occurred during the 30
treatment days in any group. However, weight gains in the treated rats were
significantly less than those recorded for the controls. These differences
were significant after 15, 20, and 30 days at the high dose and after 20 days
for the low dose. ECH had no apparent effect on hepatic function as evidenced
by the sodium sulfobromophthalein disappearance test. There was a signifi-
cant increase in hemoglobin in those rats exposed to the low dose of ECH, but
a decrease at the high dose. There was a significant increase in neutrophilic
104
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metamyelocytes (metas) at the high dose as well. The organ co body weight
ratios did not differ from the controls except for a statistically signifi-
cant dose-related increase in the kidney to body weight ratio. Lesions of
the lungs including bronchitis, peribronchitis, interstitial pneumonia, and
emphysema were observed in all groups but their severity and incidence were
slightly greater in the ECH-treated rats.
Another subchronic study (Lawrence et al., 1972) was
conducted using 4 groups of male Sprague-Dawley rats. Each group received
intraperitoneal injections of ECH 3 days/week for 12 weeks. The control
group was given cottonseed oil and each of the other groups received in-
jections of 0.0095 ml/kg, 0.0190 ml/kg, 0.04774 ml/kg of ECH corresponding to
0.1, 0.2, and 0.5 of the acute LD^q As a result of the treatment, animals
in the two higher dose groups consumed less food when expressed on a per body
weight basis (significant only for the first week at the highest dose and the
twelfth week at the middle dose). Throughout the study, the highest dose
group exhibited significantly reduced weight gain, but by the end of the 12-
week study none of the three groups differed significantly from the controls.
Hematologic parameters showed a significant dose-related decrease in hemo-
globin in addition to lower hematocrit values and erythrocyte counts in all
treated groups (significant for the middle dose only), and 72% higher mean
corpuscular volume at the low dose. Other suggested trends, although not
statistically significant, were a general increase in platelets; an altered
total leukocyte count, the low dose being less than the controls and the high
dose greater; a dose-related increase in percent of neutrophils (significant
at the high dose); increase in percent of eosinophils in all treated groups
105
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(significant for the high and low doses only); and a decrease in percent of
lymphocytes (significant for the two highest doses). The organ to body
weight ratios differed significantly from the controls at the high doses
only. The brain to body weight ratio was 27% less, but the organ to body
weight ratio for the heart, kidneys, liver and spleen were 29.1 to 38.1%
greater than controls, thus ruling out simple growth retardation as a cause.
e. Sensitization
Two studies have evaluated the sensitization of guinea pigs
with epichlorohydrin (Weil et al., 1963; Lawrence et al-, 1972). Lawrence et
al- (1972) found no sensitization after application of 0.01% epichlorohydrin in
cottonseed oil by the method of Magnnsson and Klingman. This test involved only
five animals. Weil et al. (1963) injected 18 guinea pigs eight times with 0.1 ml
of diluted material (concentration not specified) and challenged these animals
3 weeks later. No positive reactions were observed.
f. Reproductive and Teratogenic Effects
Dow Chemical has in progress a study of the teratogenic
and embryotoxic effects in rats and rabbits of ECH inhalation (John et al.,
1979). The animals were exposed to 2.5 or 25 ppm ECH for 7 hrs/day during days
6-15 or days 6-18 of gestation for rats and rabbits, respectively. Rats exposed
to 25 ppm ECH showed maternal weight loss and an increased resorption rate.
This increase was not significant when compared to the historical rate of
resorptions in these animals. Similarly, rabbits exposed to 2.5 ppm ECH showed
an increased resorption rate which was not significant compared to
historical controls. Examinations of external and soft tissue alterations
in both groups showed no teratogenic effects. Examination of fetal
heads in rats and fetal skeletal alterations in both groups has not
been completed.
106
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The antifertility properties of ECH have been investigated
by several researchers. Hahn (1970) administered 15 mg/kg day of ECH orally
to male Sprague-Dawley rats (240-260 g) for 12 days. The fertility of the
males was determined by placing two pre-estrous females in the cage of each
male overnight. After seven days, the number of uterine implantations was
counted as an index of fertility. One week of treatment"left all males
sterile. Within one week after treatment, however, the sterility was reversed.
A histopathological examination on the twelfth day showed no abnormalities of
the testis, epididymis, or prostate or seminal vesicles. Neither libido nor
ejaculation were adversely affected.
Further studies were conducted by Cooper and coworkers
(1974). ECH was administered orally to adult male Wistar rats (280-320 g) in
a suspension of arachis oil at several dose levels. The average weekly
litter size in females mated to the ECH-treated males was recorded and the
data are presented in Table 25.
£
Table 25. Effect of Epichlorohydrin on Fertility in Male Rats
Average
weekly
litter
size
in mated
[ females
Dose Level
Weeks: 1
2
3
4
5
6
7
8 9
10
5 x 20 mg/kg
0
0
9
11
11
5 x 50 mg/kg
0
0
0
0
0
0
0
0 0
0
1 x 100 mg/kg
0
4
3
4
4
2
n
4 2
3
aCooper et al., 1974.
A single dose, 1 x 100 mg/kg, did not reader the males infertile as did
several small doses, 5 x 50 mg/kg. The effect of several smaller doses (5 x
50 mg/kg) of ECH was found to be similar to a single larger dose (1 x 100 mg/kg)
107
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of a-chlorohydrin, a presumed ECH metabolite. The single larger dose of
ECH reduced fertility but did not cause any serious histological aberrations
after eight weeks of observation, except for small spermatocoeles in the
ductuli efferentes; this is in contrast to a single 100 mg/kg dose of ct-
chlorohydrin, which did induce sterility. Large retention cysts were present
in the ductuli efferentes ana the proximal caput became sterile 12 weeks after
exposure in four of the five test animals.
The suggested mode of antifertility action for ECH is the
in vivo hydrolysis of the epoxide ring to yield a-chlorohydrin (Hahn, 1970;
Cooper et al., 1974; Jones, et al., 1969). Jones et al. (1969) conducted in
vitro experiments with a-chlorohydrin and found it to be an effective antifer-
tility agent. Further experiments in which ECH or a-chlorohydrin were ad-
ministered to Wistar rats, showed that both caused sterility and 2,3-
dihydroxypropyl-S-cysteine was excreted in the urine of all animals. The
presence of a common urinary metabolite indicates that ECH may be hydrolyzed
in vivo to a-chlorohydrin and then further metabolized to an intermediate
which affects spermatogenesis (see Section III.B.2.b.). Mashford and Jones
(1978) have suggested that the final metabolite, 3-chloro-l,2-propanediol
phosphate, is responsible for this effect on spermatogenesis,
g. Mutagenicity
(1) Epichlorohydrin
Without prior metabolism (i.e., metabolic activation)
3CH has been shown to cause reverse mutations in several microorganisms (Table
26). Salmonella typhimurium has been the organism most commonly used in
these studies (i.e., .Ames assay) and information on the dose-response of ECH
108
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Table 26. Reverse Mutations Induced by Epicnlorohydrin
Without Metabolic Activation
Species Concentration Response Reference
Escherichia coli
0.017 M
Increase of 30 mutations/
mole/minute over background.
Strauss ant^
Okubo, 1960
1.27 M
A 20-fold increase in
nutations over control.
Mukai and
Hawryluk,
1973*
Klebsiella
pneumoniae
0.00637 M
A 45.4-fold increase in
mutations over control.
Voogd, 197 3
Neurospora
crassa
0.15 M
Increase of 20 mutations/
mole/minute over background
at optional conditions.
Kc/lmark
and Giles,
1955
Salmonella
typhimurium
1.27 M
A 20-fold increase in
revertants over control.
Mukai and
Havryluk,
1973
0.001 M
An unspecified increase
in the number of mutations
over control values.
Voogd, 1973
0.00030-0.005 M
A significant dose-related
increase in the number of
revertant colonies per
plate.
Elmore et
al., 1976
0.001-0.108 M
A increase up to 5.3 x 10^
relative mutation frequency
over control values (see
text).
Sram et
al., 1976
a and b
109
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exposure to mutagenesis has been provided by Elmore and coworkers (1976) and
Sram and coworkers (1976a,b). In Salmonella typhimurium strain TA100 — used
to detect base-pair substitutions — ECH caused a dose-related increase in the
number of revertant colonies per plate after a 48 hour incubation period.
Plotted on log-log paper, this increase was linear over a concentration range
of about 30 micromolar (which resulted in about 20 revertant colonies per
plate) to about 500 micromolar (which resulted in about 800 revertant colonies
per plate). In the same study, ECH did not inhibit the growth of a repair
deficient strain of Bacillus subtilis (Elmore _et_ al., 1976). Sram and coworkers
(1976a&b) used two strains of Salmonella typhimurium, TA100 and G-46, and
measured the dose-response relationship after 60 minute exposure periods to
various concentrations of ECH. The index of mutagenicity was taken as the
number of revertants in the experimental group divided by the number of
revertants in untreated controls. In strain G-46, ECH concentrations of
0.108 M and 0.054 M caused 5.3 x 10^ and 280-fold increase, respectively, in the
mutation index as well as marked decreases in cell survival. In strain TA100,
0.054 M ECH caused a 220-fold increase in the mutation index. Similarly, in a
host-mediated assay using ICR female mice given single intramuscular or
subcutaneous injections of 50 mg/kg or 100 mg/kg, increased reverse mutation
frequencies (up to 5-fold) were seen in Salmonella typhimurium strains G46,
TA100, and TA1950.
In the dominant lethal assay, ECH has yielded negative
results. This assay system, however, is not highly sensitive to mutagens.
Epstein and coworkers (1972) administered ECH i.p. to male ICR/Ha Swiss mice as a
single dose of 150 mg/kg. Over an eight week mating period, early fetal
110
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deaths and preimplantation losses were within control limits- Similarly, Sram
and coworkers (1976a) administered the following doses of ECH to male ICR
mice:
Over an eight week mating period, early fetal deaths were not noted.
Although negative in the dominant lethal assay, ECH
has been shown to induce genetic damage in higher organisms. Rapoport (1948)
reported that unspecified levels of ECH caused 4 mutations in a total of 526
chromosomes in Drosophila melanogaster. No mutations were seen in 887 chromosomes
from a control group. More recently, Sram and coworkers (1976a) have found
chromosomal abnormalities — primarily chromosome breaks — in the bone
marrow of ECH-treated mice. These results are summarized in Tables 27 and 28.
These data are difficult to interpret since the authors
do not indicate what the distribution of breaks within the test population is,
or the size of this test population.
effects of ECH treatment in rats (Dabney et_ al., 1979). Test animals were
exposed to ECH at levels of 5-50 ppm for 6 hours/day, 5 days/week for a total
of 20 exposures. Bone marrow cells, scored for chromosome breaks, showed a
trend toward increased chromosomal aberrations at the 25 and 50 ppm exposure
levels. However, when the frequency of breaks was analyzed, less than one
abnormal cell per animal was found. The investigators have recommended a
repeat of this study scoring more cells per bone marrow sample and using a
single i.p. injections:
single oral doses:
multiple i.p. injections:
multiple oral doses:
5, 10, and 20 mg/kg
20 and 40 mg/kg
1 mg/kg x 5, 4 mg/kg x 5
4 mg/kg x 5, 16 mg/kg x 5
Dow Chemical has conducted a study on the cytogenetic
111
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Table 27. iCH Induced Changes in i^.ouse Bone Marrow by
Intraperitoneal Application (Sram et al., 1976a)
Dose rag/kg h Total Abnormal Breaks B/C Gaps G/C
number cells (%) % cells % cells
of cells
Single application
1
24
250
5.2
2.8
0.003
3.2
0.040
3
24
250
8.4
6.0
0.084
3.2
0.040
5
24
250
10.8
10.0
0.112
3.2
0.032
10
24
250
21.6
16.0
0.360
7.2
0.095
20
24
250
28.4
27.2
0.488
3.2
0.040
50
. 24
250
27.6
20.4
0.360
9.2
0.124
50
6
250
32.8
30.0
0.560
12.8
0. 204
50
48
250
22.0
23.6
0.392
6.4
0.088
Repeated
doses
(interval
between doses
24 h)
5 x 10
6
250
35.2
20.8
0.350
12.8
0.170
Repeated
doses
(5 doses
per 7 days)
5x5
6
250
38.0
37.2
0.692
7.2
0.072
5 x 10
6
250
36.0
33.6
0.600
9.2
0.124
5 x 20
6
250
30.4
78.8
2.176
5.2
0.080
Control
DMSO
500
4.0
C. 6
0.006
3.8
0.038
B/C, G/C - Breaks, gaps per cell
112
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Table 2S. ECH Induced Changes in Mouse Bone Marrow by
Peroral Application (Sran et al., 1976a)
Dose
mg/kg
h
Total
number
of cells
Abnormal
cells (%)
3reaks
% cells
B/C
Caps
% cells
G/C
Single application
5
24
250
6.0
4. S
0.064
2.0
0.020
20
24
250
24.0
23.2
0.372
3.2
0.036
40
24
250
22.4
17.6
0.288
9.2
0.132
100
24
250
29.5
25.2
0.372
12.4
0.176
100
6
250
30.0
23.2
0.350
12.8
0.175
100
48
250
34.0
32.0
0.648
4.4
0.052
Repeated
doses (interval
between doses
24 h)
5 x 20
6
250
30.4
26.0
0.648
12.8
0.185
Repeated
doses (5 doses
per 7 days)
5 x 20
6
250
36.0
29. 2
0.460
12.8
0.184
Control DMSO
500
4.0
0.6
0.006
3.8
0.038
3/C, G/C - Breaks, gaps per cell
113
-------
higher range of ECE exposure. According to their calculations, this regimen
could have achieved total ECH exposure levels comparable to those used by
Sram et al. (1976a); however, their results indicate a lower frequency of
aberrations than this earlier study reported.
(2) Epibromohydrin
Kjilmark and Giles (1955) evaluated the mutagenicity
of both ECH and EBH to Neurospora crassa. Under optimal conditions i.e., the
combinations of concentration and exposure period yielding the highest mutation
incidence — EBH induced only 3 mutations/mole/minute of exposure. Thus, in
this test system, EBH is markedly less mutagenic than ECH, which induced 20
mutations/mole/minute (see Table 26).
h. Carcinogenicity
While ECH appears to have only limited tumorigenic poten-
tial when applied dermally, positive carcinogenic effects have been observed
when the compound is administered by injection or inhalation exposures.
Dermal applications of ECH, in the absence of a promoting
agent, have resulted in no evidence of tumor development in mice. Weil and
coworkers (1964) painted the clipped backs of 90-day old C3H mice (sex not
specified) with a "brushful" of undiluted ECH three times weekly for 25-months.
All mice were observed until death. Of the 40 mice in the experimental group,
only one survived after 24 months of exposure. No skin tumors were noted in
any of the exposed animals. No apparent attempt was made to identify tumors
in other tissues. In a similar study, Van Duuren and coworkers (1974) applied
2.0 ng of ECH in 0.1 ml of acetone to the shaved backs, of 6-8 weeks old female
ICR/Ha Swiss mice thrice weekly for 83 weeks. All animals were completely
114
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autopsied, except for the cranial region. Papillomas were defined as skin
3
lesions which reached 1 aim in size and persisted for 30 days or more. Of the
50 mice exposed to ECH in acetone, none developed papillomas or carcinomas.
Van Duuren and coworkers (1974) also conducted a comparison
study to evaluate the ability of ECH to initiate the tumorigenic process. In
this study, a single application of 2.0 rag ECH was made to shaved backs of 30
mice (same age, sex, and strain as above). Two weeks after this application,
2.5 micrograms phorbol myristate acetate (PMA) was applied thrice weekly for
53 weeks to the same site. In this group, 9 mice developed papillomas, the
first tumor appearing 92 days after the initiation of PMA treatment, and one
organism developed a carcinoma. Three papillomas developed in 30 mice exposed
to PMA alone and no tumors developed in 30 mice exposed to acetone alone or in
100 untreated control organisms. Based on these results, Van Duuren and co-
workers concluded that ECH is not a mouse-skin whole carcinogen but does have
a low order tumor initiation activity.
Injections of ECH have been shown to cause an increased
incidence of malignant tumors in mice. As part of the same study cited above,
Van Duuren and coworkers (1974) administered 1.0 mg of ECH in 0.05 ml tricaprylin
by subcutaneous injection in the left flank of 50 mice. The material was injec-
ted once weekly for 83 weeks. Six of the exposed animals developed sarcomas
and one developed an adenocarcinoma at the injection site. This tumor incidence
was significantly (p<0.05) greater than that seen in vehicle and untreated
control organisms. On the same dose schedule, 30 mice given intraperitoneal
injections of ECH in tricaprylin for 64 weeks developed no local sarcomas but
11 mice did develop papillary lung tumors. However, the incidence of papillary
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lung tumors was similar to that seen in vehicle controls (10/30) and untreated
controls (29/100).
Kotin and Falk (1963) administered single 5 micromole —
about 0.5 mg — doses of ECH by subcutaneous injection to 30 C3H strain mice.
Over a two year observation period, the following tumors were noted: four
malignant lymphomas, two lung adenomas, one hepatoma, and one skin papilloma.
The incidence of hepatomas and lung adenomas was comparable to that seen in
control organisms. However, the incidence of malignant lymphomas was twice
that seen in control organisms, and no skin papillomas were seen in control
organisms.
Inhalation studies on the carcinogenicity of ECH are
currently being conducted at the New York University Medical Center, Institute
of Environmental Medicine. A summary of these studies have been forwarded to
the EPA, OSHA, NIOSH, and other interested parties by Dr. Norton Kelson
(Nelson, 1977) and a more recent update has appeared (Nelson, 1978). In two
parallel studies, groups of 40 and 100 Sprague-Dawley rats were exposed to
3
100 ppm (^380 mg/o ECH for 6 hours per day for 30 days. Out of the 140
exposed rats, 13 have died with squamous cell carcinomas of the nasal cavity.
In addition, rhinitis and squamous metaplasia have been noted in the living
epithelium of the nasal cavity. No such effects were seen in control organisms.
Nelson (1977) has commented on the rarity of squamous cell carcinomas of the
nose in rats. This is the same type of tumor caused by bis(chloromethyl)ether
(Leong et al., 1975). In further studies conducted by the same investigators,
Sprague-Dawley rats are receiving chronic lifetime exposures to ECH vapors at
a level of 30 ppm, 6 hours per day, 5 days per week. Out of 100 animals, 2
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have thus far ("- 2 yrs.) developed tumors. One has developed a nasal squamous
cell carcinoma and the other showed a papilloma of the larynx. None of the
animals exposed to 10 ppm epichlorohydrin has shown this type of tumor develop-
ment to date. The results have led the investigators to conclude that, "our
findings strongly suggest a potential risk to workers from exposure to ECH"
(Nelson, 1978).
3. Effects on Other Vertebrates
No data are available.
4. Effects on Invertebrates
ECH is an effective organic fumigant against larval wireworms.
The LD^q for Limonius canus and Limonius californicus was determined in the
laboratory in a silt loam soil and was found to be 67.2 ppm (Lehman, 1942).
5. Effects on Plants
The cytogenetic effects of ECH were studied by Akhund-Zade and
Kasumova (1974). Pea and chick-pea seeds were exposed to ECH at a concentration
of 0.028 - .01% for 6 hours. Delayed disruption of chromosomal neiosis and
accelerated aging of both the pea and chick-pea plants wefce noted.
ECH is known to greatly accelerate abscission and increase the
percentage abscission in seedlings. Hall and Liverman (1956) treated the
distal ends of the petioles of Gossypium hirsutum with a 1% lanolin paste of
epichlorohydrin. Following the chemical treatment, the seedlings were exposed
to various light regimes. Those seedlings exposed to far-red light showed
greater increases in abscission than those maintained in darkness, room-light,
or red light.
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6. Effect on Microorganisms
Bringmarm (1975) conducted a study to determine the effect of
ECH on the proliferation of Microcystis aeurginosa. Varying concentrations of
ECH (period dilution) were added to test cultures to find the lowest concen-
tration at which inhibition of cell numbers occurred. The cell number was
measured by turbidity and the resulting degree of transmission of monochromatic
light (mercury light-5780nm). If the mean transmission of light after the
test was 1% greater than the mean value using non-toxic material, the substance
is considered to be damaging. The concentration at which the first signs of
inhibition were noted for ECH was found to be 6 ppm (ion concentration).
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IV. Regulations and Standards
A. Current Regulations
Epichlorohydrin has been designated as a Class 1C flammable liquid
and Class B poison; necessary labeling is specified in 49CFR. The following
label has been proposed by NIOSH 1976b):
EPICHLOROHYDRIN
POISON! FLAMMABLE!
SKIN CONTACT CAUSES DELAYED BURNS
Avoid contact with eyes, skin, and clothing.
Avoid breathing vapor.
Use only with adequate ventilation.
Keep away from heat and open flame.
Keep container closed.
Do not take internally.
First Aid: In case of skin contact, immediately remove all contam-
inated clothing, including footwear, wash skin with plenty of water
for at least 15 minutes and call a physician. In case of eye con-
tact, flush eyes with water for 15 minutes and call a physician.
The following sign should be posted where there is danger of occupa-
EPICHLOROHYDRIN
POISON! FLAMMABLE!
SKIN CONTACT CAUSES DELAYED BURNS
VAPOR IRRITATING TO EYES
HARMFUL IF SWALLOWED OR INHALED
1. NFPA Hazard Identification Code
The hazard identification system recommended in the National
Fire Protection Guide provides basic emergency information on health, flamma-
bility and reactivity. The NFPA (1975) symbol includes color and numerical
tional exposure (NIOSH, 1976b):
codes as follows:
HEALTH
yellow
FLAMKABILITY
REACTIVITY
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Each diamond is assigned a number from 0 (no special hazard) to 4
(severe hazard or danger). The NFPA symbol for ECH is:
B. Food Tolerances
1. Food
The use of ECH as a direct and indirect food additive is re-
stricted according to the Code of Federal Regulations. ECH crosslinked
with ammonia may be safely used as an ion-exchange resin in the treatment of
food and potable water (21 CFR 173.25). ECH may also be employed as a cross-
link in molecular sieve resins used in processing foods (21 CFR 173.40). Food
starch may be etherified by treatment with ECH (not to exceed 0.3%) alone or
in conjunction with propylene oxide, acetic anhydride or succinic anhydride
(21 CFR 172.892).
Various resins of ECH can be used in the manufacture of paper
and paperboard which will be in contact with dry aqueous and fatty foods.
Restrictions pertaining to this use are set forth in paragraphs 176.170 and
176.180 of 21 CFR. 4,41-Isopropylidenediphenol-epichlorohydrin resins (minimum
molecular weight 10,000) and 4,4'-isopropylidenediphenol-epichlorohydrin
thermosetting epoxy resins nay be used as articles or components of articles
intended for food related uses (21 CFR 177.1440, 177.2280).
2. Pesticides
ECH is exempt from tolerance levels when used with good agri-
cultural practice as an inert ingredient (stabilizer) in pesticide formulations.
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It must not comprise more than 27. of the pesticide formulation and must be
applied before the crop emerges from the soil or in the case of soil fumigants
before and after the crop emerges.
3. Standard for Human Exposure
The American Conference of Governmental Industrial Eygienists
(1974, 1977) has established a threshold limit value of 5 ppm for ECH in air.
This criterion is intended to prevent irritation as well as acute and chronic
systemic toxicity, but is probably not low enough to prevent flareups when a
previous high sensitizing exposure has occurred.
A time-weighted air concentration of 0.5 ppm for a 10 hour
workday, 40 hour week, with a ceiling concentration of 5 ppm has been recommended
by the National Institute for Occupational Safety and Health (NIOSH, 1976b).
This exposure level was designed to prevent the acute and chronic effects of
ECH exposure, skin irritation, and is measurable as well as attainable by
techniques available to industry and government agencies. The OSHA standard
for ECH is presently 5 ppm. The maximum percaissable concentration for the
U.S.S.R. (1967) is 0.25 ppm (ACGIH, 1974).
C.. Current Handling Practices
1. Special Handling in Use
Protective clothing and equipment must be used to prevent
exposure of workers to ECH. The type of respiratory protection required is
dependent upon the maximum exposure concentration CNIOSH, 1976b). For con-
centrations of 25 ppm or less, a gas mask with an organic vapor canister is
sufficient, or a type C supplied-air respirator may he used. During emergency
conditions, self-contained breathing apparatus with a full facepiece or an
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air-supplied respirator with an auxiliary air supply must be worn. For
further information on respirator types at various concentrations consult the
NIOSH Criteria Document on Epichlorohydrin.
NIOSH-approved splash proof goggles as well as gloves and
other protective body coverings should be worn as needed to prevent contact
with eyes and skin (Shell, 1976). ECH is capable of penetrating neoprene,
rubber, and leather. Their use in protective clothing is unsuitable; instead
polyethylene, polypropylene, polyvinyl chloride, and other low permeability
materials should be used (NIOSH, 1976b). Both local and general mechanical
ventilation are highly recommended for work areas (Shell, 1976).
Decomposition of ECH results in the production of hydrogen
chloride, phosgene, and carbon monoxide. Conditions to avoid include tempera-
tures greater than 600°F and contact with acids; bases; amines; NH^; Na, Zn,
Al, Mg and their alloys; and Fe, A1 and Zn halides. Contact with these sub-
stances may cause hazardous polymerization (Shell, 1976).
2. Storage and Transport
ECH should be stored in tightly closed containers in a cool,
well ventilated area away from the incompatible materials listed above (Shell,
1976). Discoloration and turbidity have resulted when stored in contact with
copper and lead (Shell, 1969).
Electrical equipment in surrounding areas should be compatible
with Article 501 of the National Electrical Code for Class I hazardous loca-
tions (NFPA, 1975).
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3. Accident Procedures
a. First Aid
Medical attention should be sought immediately upon acci-
dental exposure to ECH. The victim should be removed to fresh air and if
necessary artificial respiration should be administered.
Clothing and shoes which have been contaminated must be
removed and later destroyed. If contact with the skin or eyes has occurred,
wash with water for at least 15 minutes. If accidentally ingested, induce
vomiting except when victim is unconscious (Shell, 1976).
b. Spill or Leak Procedures
In case of a spill or leak, all ignition sources and
unprotected personnel should be removed. A small spill can be absorbed with
an inert material whereas large quantities should be collected into containers
or vacuum trucks. Label ECH POISON, KEEP OUT OF ALL PUBLIC WATER SUPPLIES AND
SEWERS. The proper authorities should be notified if exposure to the general
public or environment may occur as a result of a spill or leak (Shell, 1976).
ECH may be disposed of by controlled burning in equipment
capable of handling hydrogen chloride fumes and under approved EPA conditions.
The Environmental Protection Agency has proposed the addi-
tion of ECH and 27 other chemicals to the 271 chemicals already designated as
hazardous and governed by EPA's hazardous spill rules (Anon. 1978a).
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V. Exposure and Effects Potential
A. Human Exposure
Because it has not been produced in significant quantities, there
does not appear to be any potential for human exposure to EBH. Human exposure
to ECH can occur to worker populations, general populations near manufacturing
and use plants, and possibly to consumer populations who use epoxy resin
preparations. Because of ECH's reactivity in water (half-life of 4 to 8 days)
and air (exact rates unknown), it appears unlikely that ECH will be a wide-
spread environmental contaminant. Exposure to worker populations should be
below the OSHA standard of 5 ppm and it is likely that general populations
near plants or consumer populations will be exposed to concentrations which
are considerably less, except where spills or accidents occur. Such a spill
has occurred at Point Pleasant, W. V., where significant amounts of ECH were
subsequently found in water (Rosencrance, 1978). The general lack of monitoring
information in the United States precludes more exact estimates of exposure
to human populations. A group of 93 epoxy resin workers (Anon. 1978a) were
apparently exposed to concentrations of less than 5 ppm. Several Russian
studies have reported worker populations exposed to concentrations of approxi-
mately 5 ppm (Kucerova et_ al., 1977 - 0.13 to 1.3 ppm; Pet'ko et al., 1966 -
4.9 to 5.5 ppm; and Kovalenko and Bokav, 1975 - 0.06 to 0.8 ppm). In another
Russian study, Fomin (1966) detected 0.1 to 3 ppm ECH in the air within 100 to
200 meters of a factory; also 5 of 29 air samples at 400 meters from the
factory exceeded 0.05 ppm. Pinchuk et al. (1969) detected ECH in the atmos-
phere of a building whose construction employed extensive use of plastic water-
rails. Whether this is representative of the situation in the U.S. is un-
known. However, based on air emission estimates of Gruber (1976), we have
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estimated an annual release of 600,000 lbs of ECH from the three known manu-
facturing plants. Amounts of ECH in water effluents appear to be very small
based upon reviews by Gruber (1976) and Pervier et_ al. (1974) but little
monitoring data is available.
The effects on humans from chronic inhalation of ppm quantities or less
of ECH is not conclusively known. However, the possible carcinogenic threat
to man by ECH must be considered in deriving public health risk assessments.
Current exposure standards (i.e. OSHA) do not take into consideration the
recent data implicating ECH as a carcinogen/mutagen in humans and experimental
mammals¦
The absence of quantitative exposure data in the single epidemio-
logic study which associates ECH exposure with excess cancers prevents the
formulation of dose-response relationships. Nevertheless, many cancer assess-
ment models are based on a non-threshold strategy, and thus predict that a
real risk occurs at all dose levels. Therefore extrapolation from presently
available animal bioassay data may indicate a carcinogenic threat to man
from ECH at any concentration in the environment.
B. Environmental Effects
No ambient monitoring data on ECH or ecological effects information
is available from which reasonable conclusions can be reached on the potential
for exposure to and effects on the ecosystem. Most emissions appear to be
atmospheric and the stability of ECH in air is unknown. No major water
effluents are suggested except for the spill in Point Pleasant, W. V. However,
if there are major water releases, ECH is stable enough (half-life 4 to 8 days)
to travel significant distances. Surface water (to a 1 meter depth) containing
125
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ECH could show evaporative losses; the half life of ECH at 20° and this
depth is ^2 days (p. 76). No significant effects on fish, invertebrates,
plants, etc., have ever been studied.
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VI. Technical Summary
In 1977 the annual production of epichlorohydrin (ECH) was roughly 400
million lbs. and production capacity was 640 million lbs. (SRI, 1977). The
chemical is manufactured by two companies (Dow and Shell) at three locations
(Freeport and Deer Park, Texas, and Norco, Louisiana). ECH is primarily
consumed as a chemical intermediate in the production of glycerin and epoxy
resins. On a percentage basis, the consumption of ECH in 1973 was as follows:
glycerin, 46% (produced from crude, unrefined ECH); epoxy resin, 39%; exports,
4%; elastomers, 2%; and other products, 9% (Oosterhof, 1975). Since then the
quantity used for glycerin has remained approximately the same while the
epoxy resin market has increased substantially (Chemical Marketing Reporter,
1978b). Epibromohydrin (EBH) was used as an intermediate in the manufacture
of a nematocide some years ago by the Great Lakes Chemical Corporation. The
last batch (roughly 20,000 lbs.) was made in 1975 arid, therefore, EBH is no
longer a significant commercial chemical, although Great Lakes has retained
the ability to manufacture more in the future.
ECH is produced by the "allyl chloride" route which consists of (1)
reaction of propane with free-radical chlorine to form allyl chloride, (2)
reaction of allyl chloride with hypochlorous acid to yield a mixture of di-
chlorohydrins, and (3) reaction of the aichlorohydrins with calcium on sodium
hydroxide to form the epoxide ring and yield ECH.
Two detailed studies of effluents from an ECH production plant and from
a glycerin plant using ECH as a feedstock have been conducted. Based upon a
study of an ECH plant by Gruber (1976), the following annual amounts of pollu-
tants from total ECH production are estimated (thousands of pounds): Atmos-
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pheric venting-ECH - 600, allyl chloride - 800; trichloropropane - 200, chlorine -
0.2, hydrogen chloride - 0.2; Water from separation - dichlorohydrin - 4000;
Heavy ends from fractionator requiring disposal - ECH-424, chloroethers - 2960;
dichlorohydrin - 2280; and trichloropropane - 14,840- Gruber (1976) reported
that the heavy ends from the fractionator are stored for eventual thermal
destruction by incineration. The study by Pervier et al. (1974) only examined
atmospheric emissions and their estimates were in basic agreement with the work
of Gruber (1976).
Dow (1979) and Shell (1979) have commented that the estimates of Gruber (1976)
and Pervier et al. (1974) are much too high as they do not reflect current technology.
Shell (1979) estimates that the Gruber (1976) data is on the order of 300 times
too high with respect to ECH emissions.
On January 23, 1978, a major spill of ECH occurred in Point Pleasant, West
Virginia, when a tank car derailed, ruptured, and spilled 20,000 gallons (about
197,000 lbs.) of ECH. The spill necessitated the evacuation of 400 people and
the closing of the city's water plant (Anon., 1978a). The public water supply
was from wells 25 feet deep but specific information on ECH concentrations,
time for self-cleaning, or other details are not yet available (Rosencrance,
1978).
Other data on ECH release to the environment are much less quantitative.
ECH has been detected in the following areas: air near a Russian factory
(Fomin, 1966); air at a Russian glycerin plant (Lipina and Belyakov, 1975); air
in a Russian pumping station where epoxy resins were used for waterproofing
(Danilov and Muratova, 1972); and air in a Russian five-story dwelling which
had used plastic materials for construction (Pinchuk et al_., 1969).
Because of the reactivity of the epoxide ring, ECH released to the environment
does not appear to be stable enough to be a widespread contaminant. Considerable
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information is available on the hydrolysis rates under varying conditions of pH
and ion strength (Pritchard and Siddiqui, 1973; Bronstead et al., 1929; Le
Noble and Duffy, 1964; Shvets and Aleksanyon, 1973; and Ross, 1962). Under
environmental conditions, the half-life is likely to be between 4 and 8 days
depending upon conditions. These hydrolysis studies also suggest that ECH or
EBH may be formed from a number of precursors under basic conditions in water.
Dilling and coworkers (1976) determined the decomposition rate of 10 ppm ECH in
air containing 5 ppm nitric oxide and irradiated with sunlamps of intensity 2.6
times the intensity of Texas sunlight at noon in summer. The half-life was
16.0 hours. These reaction conditions simulate photochemical smog conditions,
so the rates of decomposition under other conditions could be substantially
longer.
No ambient monitoring studies that have been conducted so far have de-
tected ECH or EBH in air, water, or soil samples. However, this may be due to
the fact that no ambient monitoring work has been directed at detecting ZCH or
EBH.
The irritating properties of ECH to the eyes, skin, and respiratory tract
of man have been recognized for many years (NIOSH, 1976b, 1977). Systematic
absorption of ECH in man is known to occur, and has led to episodes of acute
intoxication. Occupational exposure criteria have been developed by several
agencies which are based primarily upon the irritating properties of ECH.
Recent studies have revealed, however, that 2CH may produce adverse
biological effects after chronic exposures in occupational situations. Cyto-
genetic damage, detected as chromosome abnormalities in peripheral lymphocytes,
has been found in ECH-exposed workers in Czechoslovakia (Kucerova, 1977) and
the United States (Anon. 1978a). These abnormalities may be taken as presumptive
evidence of a carcinogenic/mutagenic threat to man, although their real significance
and possible reversibility are not understood. Additional occupational
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morbidity studies (Pet'ko et_al., 1966; NIOSH, 1976; Anon. 1978b) have failed
to reveal alterations in a number of health parameters measured in ECH-exposed
worker groups.
A recent examination of mortality among 864 active and retired workers
exposed to ECH has revealed a statistically significant (P<.05) excess of
deaths due to respiratory cancer (Snterline and Henderson, 1978). This report
is the first to suggest that ECH may represent a carcinogenic threat to man.
However, the lack of important data concerning exposure levels, pathology,
and medical history prevents a definitive cancer risk assessment at this time.
The biological effects produced by ECH have been studied in numerous
animal model systems. These investigations have provided not only important
information which confirms observed effects in humans but also new data re-
garding mechanisms of toxic action. ECH is rapidly absorbed, widely distri-
buted, and extensively metabolized in a manner which is consistent with other
structurally-related chlorinated hydrocarbons (Weigel et^ al., 1978). One of
the major metabolites of ECH in the rat is a-chlorohydrin; a compound known
to have antifertility effects in the male (Jones et al., 1969; Cooper et al.,
1974).
Studies with various animal species have established that ECH is highly
irritating upon contact and moderately toxic by acute systemic absorption.
The major organs adversely affected by acute exposures to ECH are the central
nervous system, spleen, liver, respiratory tract, and the kidneys (Lawrence
at al., 1972). The acute LD^q for ECK in the rat by oral administration is
about 90-260 mg/kg (NIOSH, 1976b; Lawrence et_ al. , 1972), and the (4-6 hour)
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for inhalation exposures is about 360-635 ppm (Synder, 1978; Grigorowa et_
al., 1974). The toxic effects produced and major target organs affected hy
repeated administration of ECH are similar to those for acute exposures
(Fomin, 1966; Gage, 1959; Oser et a^., 1975; Lawrence et al., 1972). How-
ever, several investigators reported hematologic disturbances with chronic
exposures. In addition, the repeated oral administration of ECH to male
rats produced a reversible sterility (Hahn, 1970; Cooper et al., 1974).
In several bacterial test systems, most notably the Ames assay, ECH was
shown to be a direct-acting (i.e., without metabolic activation) mutagen
(Elmore et al_., 1976; Sram et al., 1976a,b). These positive results indi-
cate that ECH may directly interact with DNA, and implicates ECH as a poten-
tial carcinogen/mutagen in higher organisms.
The potential carcinogenicity of ECH has been confirmed in animal bio-
assays. Among 140 rats inhaling ECH at 100 ppm (6 hours/day for 30 days),
13 died with squamous cell carcinomas of the nasal cavity (Nelson, 1978).
Similar cancers were also produced in rats receiving lifetime exposures to
ECH at a level of 30 ppm. It was concluded that, at least in occupational
situations, ECH may present a potential risk to man.
There is very little information available regarding the effects of ECH
on lower animals, plants, or microorganisms. Likewise, almost nothing is
known concerning the biological activity of EBH.
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CONCLUSIONS AND RECOMMENDATIONS
From the preceding literature review and evaluation the following
conclusions and recommendations seem justified.
1. Epichlorohydrin (ECH) is produced and used in large
quantities (^400 million lbs/year) and has considerable
potential for environmental release.
2. Epibromohydrin (EBH) is insignificant commercially and
should receive little if any attention.
3. Atmospheric release of ECH could amount to 600,000 lbs/year.
Air monitoring data near production and use (glycerin and
epoxy resin) plants are needed as well as in areas where
substantial amounts of epoxy resins are used.
4. Substantial amounts of by-product waste (chloroethers,
dichlorohydrins, and trichloropropanes) are generated
during ECH production. The way in which this material
is disposed of should be carefully examined.
5. ECH should be regarded as a potential carcinogenic threat
to man in occupational situations. Further epidemiologic
research is needed to confirm the existence of this hazard
to man, and to evaluate the impact of ECH in community
settings.
6. Additional experimental studies are required to more fully
understand the potential hazards of ECH at low levels in the
environment. Important data are lacking in the following
areas: (a) pharmacokinetics and metabolism; (b) dose-response
for toxicity and carcinogenicity; (c) in vitro bioassays for
mutagenicity/carcinogenicity in mammalian cells; (d) effects
on fertility; (e) reversibility of cytogenetic damage and
ECH-induced sterility; and (f) effects on fish, invertebrates,
wildlife, plants, and microorganisms.
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