This report contains the collective views of an

international group of experts and does not

necessarily represent the decisions or the stated
policy of the United Nations Environment Pro-
grainme, the International Labour Organisa-
tion, or the World Health Organization

Environmental Health Criteria 33

EPICHLOROHYDRIN

Published under the joint sponsorship of

the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization

0
1'---
World Health Organization
Geneva, 1984
' 61PVV
 The International Programme on Chemical Safety (IPCS) is a joint
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tional Labour Organisation, and the World Health Organization. The main
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field of toxicology. Other activities carried out by IPCS include the devel-
opment of know-how for coping with chemical accidents, coordination of
laboratory testing and epidemiological studies, and promotion of research
on the mechanisms of the biological action of chemicals.

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 -3-

CONTENTS

Page

ENVIRONMENTAL HEALTH CRITERIA FOR EPICHLOROHYDRIN

PREFACE .........................7

1. SUMMARY ........................

2. PROPERTIES AND ANALYTICAL METHODS .......... 11

2.1 Chemical and physical properties ........ 11

2.2 Analytical methods ............... 12

3. SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT

AND DISTRIBUTION ................... 14

3.1 industrial production, uses, disposal of wastes 14

3.1.1 Industrial production .......... 14
3.1.2 Uses ................... 14
3.1.3 Disposal of wastes ............ 14
3.2 Environmental transport and distribution .. . . 15

4. ENVIRONMENTAL LEVELS AND EXPOSURES .......... 16

4.1 Occurrence ................... 16

4.2 Occupational exposure .............. 16
4.3 General population exposure ........... 16

5. CHEMOBIOKINETICS AND METABOLISM ............ 17

5.1 Absorption ................... 17

5.2 Distribution .................. 17
5.3 Metabolic transformation and excretion ..... 17

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT ....... 19

7. EFFECTS ON ANIMALS .................. 22

7.1 Short—term exposures .............. 22

7.1.1 Oral exposure .............. 22
7.1.2 Subcutaneous exposure .......... 23
7.1.3 Inhalation exposure ........... 23
7.1.4 Effects on the eyes and skin ....... 25
7.2 Carcinogenicity ................. 25
7.2.1 Short—term studies ............ 25
7.2.1.1 Oral exposure .......... 25
 -4-

Page

7.2.2 Long-term studies 25

7.2.2.1 Oral exposure .......... 25
7.2.2.2 Inhalation exposure ....... 26
7.2.2.3 Subcutaneous exposure ...... 27
7.2.2.4 Intraperitoneal exposure . . . 27
7.2.2.5 Derinal exposure ......... 27
7.3 Mutagenicity .................. 28
7.4 Effects on reproduction ............. 28
7.5 Teratogenicity ................. 31

8. EFFECTS ON MAN ....................32

8.1 Controlled studies ............... 32

8.2 Accidental exposures .............. 32
8.3 Epidemiological studies ............. 32
8.3.1 Sensitization .............. 32
8.3.2 Carcinogenic effects ........... 33
8.3.3 Mutagenic effects ............ 34
8.3.4 Effects on reproduction ......... 35

9. EVALUATION OF HEALTH RISKS FOR MAN .......... 36

10. SOME CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . 38

10.1 Occupational exposure ..............38

10.2 Ambient air levels ...............38
10.3 Surface water levels ..............38
10.4 Levels in food .................38
10.5 Labelling and packaging .............38
10.6 Storage and transport ..............39

REFERENCES........................40
 -5-

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR

EPICHLOROHYDRIN

Members

Dr C.M. Bishop, Health and Safety Executive, London, England

Dr V. Hristeva-Mirtcheva, Institute of Hygiene and
Occupational Health, Sofia, Bulgaria
Dr R. Lonngren, National Products Control Board, Solna, Sweden
(Chairman)
Dr M. Martens, Institute of Hygiene and Epidemiology,
Brussels, Belgium
Dr W.O. Phoon, Department of Social Medicine & Public Health,
Faculty of Medicine, University of Singapore, National
Republic of Singapore
Dr L. Rosenstein, Assessment Division, Office of Toxic
Substances, US Environmental Protection Agency, Washington
DC, USA
Mr C. Satkunananthan, Consultant, Colombo, Sri Lanka
(Rapporteur)
Dr G.O. Sofoluwe, Oyo State Institute of Occupational Health,
Ibadan, Nigeria
Dr A. Takanaka, Division of Pharmacology, Biological Safety
Research Center, National Institute of Hygienic Sciences,
Tokyo, Japan
Dr R.G. Tardiff, Life Systems, Inc., Arlington, VA, USA

Representatives of Other Organizations

Dr J.P. Tassigrion, European Chemical Industry Ecology and

Toxicology Centre, Brussels, Belgium

Observers

Dr M. Nakadate, Division of Information on Chemical Safety,

National Institute of Hygienic Sciences, Tokyo, Japan
Dr R. McGaughy, Carcinogen Assessment Division, US
Environmental Protection Agency, Washington, DC, USA

Secretariat

Dr M. Gilbert, International Register of Potentially Toxic

Chemicals, United Nations Environment Programme, Geneva,
Switzerland
Dr K.W. Jager, Scientist, International Programme on Chemical
Safety, World Health Organization, Geneva, Switzerland
Dr H. Mercier, Manager, International Programme on Chemical
Safety, World Health Organization, Geneva, Switzerland
 -6-

Secretariat (contd).

Dr F. Va3ic, Scientist, International Programme on Chemical

Safety, World Health Organization, Geneva, Switzerland
(Secretary)
Dr G.J. Van Esch, National Institute for Public Health,
Bilthoven, Netherlands (Temporary Adviser)
Dr T. Vermeire, National Institute for Public Health,
Bilthoven, Netherlands, (Temporary Adviser)

The WHO Task Group for the Environmental Health Criteria

for Epichiorohydrin met in Brussels from 19 to 22 September,
1983. Professor A. Lafontaine opened the meeting and welcomed
the participants on behalf of the host government, and Dr M.
Nercier, Manager, IPCS, on behalf of the heads of the three
IPCS co-sponsoring organizations (ILO/WHO/UNEP). The Group
reviewed and revised the second draft criteria document and
made an evaluation of the health risks of exposure to
epich lorohydrin.
The efforts of Dr G.J. Van Esch and Dr T. Vermeire, who
were responsible for the preparation of the draft, and of all
who helped in the preparation and the finalization of the
document are gratefully acknowledged.

Partial financial support for the publication of this

criteria document was kindly provided by the United States
Department of Health and Human Services, through a contract
from the National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina, USA - a WHO
Collaborating Centre for Environmental Health Effects.
 -7-

PREFACE

A partly new approach to develop more concise

Environmental Health Criteria documents has been adopted with
this issue. While the document is based on a comprehensive
search of the available, original, scientific literature, only
key references have been cited. A detailed data profile and a
legal file on epichlorohydrin can be obtained from the
International Register of Potentially Toxic Chemicals, Palais
des Nations, 1211 Geneva 10, Switzerland (Telephone No. 988400
or 985850).
The document focuses on describing and evaluating the
risks of epichlorohydrin for human health and the environment.
While every effort has been made to present information in
the criteria documents as accurately as possible without
unduly delaying their publication, mistakes might have
occurred and are likely to occur in the future. In the
interest of all users of the environmental health criteria
documents, readers are kindly requested to communicate any
errors found to the Manager, International Programme on
Chemical Safety, World Health Organization, Geneva,
Switzerland, in order that they may be included in corrigenda,
which will appear in subsequent volumes.
 -9-

1. SUMMARY

Epichiorohydrin is a highly reactive and flammable

chemical. It is used as an intermediate in the production of
numerous substances, notably glycerol and epoxy resins. It
can be detected using gas chromatography at concentrations as
low as 0.25 mg/in 3 in air and 40 pg/litre in water.
Human exposure mainly occurs at the place of work through
inhalation and skin contact.
Limited data are available concerning the occurrence of
epichiorohydrin in occupational and ambient air, and in water
and food. Occupational air levels generally seem to remain
below 18.9 nig/m 3 . Epichiorohydrin is released to the
environment as a result of its manufacture, use, and
disposal. Migration into food and drinking-water of
epichlorohydrin used as a cross-linking agent in packaging
materials and epoxy resins is possible,but is expected to be
low.
In the troposphere, epichlorohydrin is probably
photodegraded. The rate of disappearance from water or
aqueous media is expected to be rapid through hydrolysis or
evaporation. The compound has been shown to be
biodegradable. Bioaccumulation seems unlikely and the acute
toxicity for aquatic organisms is moderate to low.
Epichlorohydrin is absorbed rapidly via the skin,
gastrointestinal tract, and, in vapour form, via the lungs.
It is distributed widely throughout the body. In rodents,
retention in tissues mainly occurs at the portal of entry,
i.e., the nasal epithelium during inhalation and the stomach
after oral exposure. The extent of alkylation of
macromolecules by the epoxide is unknown. In rats, most
absorbed epichiorohydrin is metabolized rapidly, partly to
carbon dioxide, which is excreted via the lungs, and partly to
urinary metabolites, mainly conjugates. Hydrolysis is the
most probable first reaction in the metabolic pathway of
epichlorohydrin, resulting in the formation of
3-chloro-1,2-propanediol, which is much less toxic.
The few human studies available and also animal studies
show effects on the central nervous system, respiratory tract,
liver, blood, eyes, and skin. The degenerative effects on the
kidney tubuli with cortex necrosis, which are very conspicuous
in studies on rodents, have not been found in human beings, so
far. Epichiorohydrin vapour is strongly irritating to the
eyes and respiratory tract and local contact will result in
protracted skin burns, though the effects may not appear until
some time after exposure. Epichlorohydrin can sensitize the
skin. In rats, the toxic effects of epichiorohydrin occur
first in the epithelia of the nose and stomach where
 - 10 -

inflammation and degenerative changes develop, with

hyperplasia and squamous cell metaplasia. Ultimately, after a
long latent period, papillomas and squamous cell carcinomas
are induced. In mice, epichlorohydrin induces local skin
carcinomas following subcutaneous injection and can act as a
weak initiator, when applied to the skin. Epidemiological
studies to date have not provided evidence of malignant
neoplasms in human beings due to exposure to epichlorohydrin.
However, the epidemiological data do not have a sufficient
number of recorded deaths to detect a weak carcinogenic
response. Therefore, a longer observation time will be needed
before a final assessment can be made.
Epichiorohydrin is rnutagenic in most short-term assays.
Conflicting results were obtained when the lymphocytes of
workers, occupationally exposed to concentrations below 18.9
mg/rn 3 , were examined for chromosomal aberrations.
The compound has caused sterility in male rats and mice.
However, a fertility study in male workers did not reveal any
effects on the reproductive system. No evidence has been
obtained of any embryoloxic, fetotoxic, or teratogenic effects.
On the basis of the above data, it can be assumed that
epichlorohydrin is mutagenic and carcinogenic for animals.
Therefore, exposure of human beings should be avoided due to
its possible carcinogenicity to human beings as was also
assessed by IARC (1982). In dealing with this chemical,
impervious protective clothing and breathing protection should
be worn. Rubber and leather are unsuitable materials, in this
respect. Contaminated clothing should be removed and the skin
should be washed carefully.
 - 11 -

2. PROPERTIES AND ANALYTICAL METHODS

2.1 Chemical and Physical Properties

Epichiorohydrin (C3H5C1O) is a colourless liquid the

vapour of which forms explosive mixtures with air. Phosgene,
hydrogen chloride, and carbon monoxide are liberated during
burning. Acids, caustic solutions, and halide salts initiate
polymerization reactions. The compound is very reactive with
metals such as zinc and aluminium, anhydrous metal halides,
strong acids and bases, and alcohol-containing materials. In
the presence of moisture, epichiorohydrin attacks steel.

Chemical structure:

/O\
Cl2 IIC _ CH 2C1

CAS registry number: 106-89-8

RTECS registry number: TX4900000

Common synonyms: alpha-epichlorohydrin, CEP, 1-chloro-

2, 3-epoxypropane, 3-chloro-1 , 2-epoxy-
propane (IUPAC), (chioromethyl) ethyl-
ene oxide, chlormethyl oxirane, 2-
(chloro-methyl) oxirane, 1-chioro-
propene oxide, 3-chioropropene oxide,
3-chloro-1, 2-propylene oxide, (DL)-
alpha-epichlorohydrin, ECH, ECHH, EPI,
l-epichlorohydrin, 1,2-epoxy-3-chloro-
propane, 2, 3-epoxypropyl chloride,
gamma-chioropropylene oxide, glycerol
epichiorohydrin, glycidyl chloride

Trade names: SKEKHG

Some physical and chemical data on epichiorohydrin

physical state liquid

colour colourless
odour chloroform-like, threshold
38-95 mg/rn 3 air
relative molecular mass 92.53
melting point -26 'C
boiling point 115 'C
 - 12 -

water solubility 66 gilitre, 20 C

log n-octanol-water partition
coefficient 0.30
density 1.18 g/ml, 20 ° C
relative vapour density 3.21
vapour pressure 1.7 kPa (12.5 mm Hg), 20 ° C
flash point (open-cup) 34 ° C
flammable limits 0.15-0.82 g/litre

Conversion factor for epichlorohydrin

epichlorohydrin 1 ppm = 3.78 mg/rn 3

2.2 Analytical Methods

A summary of methods for the sampling and determination of

epichiorohydrin in air, water, and food is presented in
Table 1.
 - 13 -

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 - 14 -

3. SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT

AND DiSTRIBUTION

3.1 Industrial Production, Uses, Disposal of Wastes

3.1.1 Industrial production

Figures concerning the total world production are not

available. In the USA, production increased from 156
kilotonnes in 1973 (Santodonato et al., 1930) to 250
kilotonnes in 1975 (NIOSH, 1976) and 213 kilotonnes in 1978
(Rose & Lane, 1979).
Epichlorohydrin is also produced in Czechoslovakia,
France, the Federal Republic of Germany, the Netherlands, and
the USSR (Fishbein, 1976).
The compound is usually prepared from propene, which is
chlorinated to allyl chloride. The allyl chloride is
chlorinated in water by hypochiorous acid to yield a mixture
of isorseric glycerol chiorohydrins. After dehydrochloririation
with alkali, epichlorohydrin can be Separated by steam
distillation. Possible impurities associated with this
process are; chlorinated ethers, chlorinated, saturated, and
unsaturated short-chain aliphatic hydrocarbons, 1,4-dichloro-
hexane, dichioropropanols, 1,2-dichloropropene, cia- and
trans-1,3 dichioropropene, glycidol, alpha- and beta-mono-
chlorohydrin, and 1,2,3-trichioropropene. The commercial
product is more than 98% pure (WHO, 1978; Santodonato et al.,
1980).

3.1.2 Uses

Epichlorohydrin is mainly used for the manufacture of

glycerine and unmodified epoxy resins. It is also used in the
manufacture of elastomers, glycidil ethers, cross-linked food
starch, wet strength resins for the paper industry,
water-treatment resins, surfactants, ion-exchange resins,
plasticizers, dyestuffs, pharmaceutical products, oil
emulsifiers, lubricants, and adhesives. It may also be used
as a solvent for resins, gums, cellulose, esters, paints, and
lacquers, and as a stabilizer in chlorine-containing
substances such as rubber, pesticide formulations, and
solvents (Santodonato et al., 1980).

3.1.3 Disposal of wastes

Aqueous, epichlorohydrin-containing wastes are saponified

by caustic solutions and the resulting glycerol is biodegraded
in sewage-treatment plants (Anon, 1971). Concentrated wastes
 - 15 -

are destroyed in special incinerators with flue-gas washing to

avoid the formation and emission of phosgene (Ottinger et al.,
1973).

3.2 Environmental Transport and Distribution

Environmental contamination by epichiorohydrin mainly

occurs via air ducts and waste disposal of heavy ends in
industries that produce or use epichiorohydrin. Assuming an
industrial production of 181 kilotonnes in the USA, it was
estimated that these 2 pathways accounted for the transport of
213 and 193 tonnes, respectively, into the environment in
1977. Other contaminants associated with these industrial
processes are allyl chloride, trichioropropanes, chloroethers,
and dichlorohydrins. Epichiorohydrin can also be lost to the
environment via industrial water, during transport and
storage, by volatiliration during use, and by inadvertant
industrial production (Santodonato et al., 1980).
The half-life for the reaction of epichiorohydrin with
water, at room temperature, to form 3-chloro-1,2-propanediol
(aipha-chlorohydrin) was found to be 148, 79, and 62 h,
respectively, in neutral, acidic, and alkaline solutions
containing 9 mg of the compound per litre, initially. The
rate of hydrolysis increased 7-fold, when the temperature was
raised to 40 C. The presence of nucleophilic ions also
increased the rate of hydrolysis (Piringer, 1980). Once in
the troposphere, photodegradation takes place (Dilling et al.,
1976).
Epichlorohydrin was biodegraded slowly by aerobic bacteria
from the effluent of a biological waste--treatment plant, after
adaptation. Five days after seeding, the biological oxygen
demand amounted to 14% of the theoretical oxygen demand
(Bridie, 1979b). When a solution containing epichlorohydrin
at 169 mg/litre was incubated with activated sludge
micro-organisms, 89% of the compound had disappeared within
24 h (measured by the chemical oxygen demand removal
efficiency). Controls revealed that 73% of this loss could be
accounted for by evaporation (Matsui et al., 1975).
 - 16 -

4. ENVIRONMENTAL LEVELS AND EXPOSURES

4.1 Occurrence

No data are available that indicate that epichiorohydrin

occurs naturally in ambient air, water, soil, or biota.
On the basis of use patterns and the physical and chemical
properties of epichiorohydrin, it can be derived that human
exposure is mainly occupational, through vapour inhalation,
sometimes accompanied by direct skin contact. Slight exposure
may occur via food.

4.2 Occupational Exposure

Data from 7 plants in the USA, engaged in the production

of epichlorohydrin, glycerol, or epoxy resins, from 1973
onwards, showed that 7-h or 8-h time-weighted-average
exposures to epichiorohydrin ranged from less than
0.04 mg/rn 3 air to 57 mg/rn 3 . The median was below
8 mg/rn 3 air (NIOSH, 1976; Oser, 1980). In 2 other epoxy
resin plants, the time-weighted-average exposures for 1973-76
were generally below 3.8 mg/rn' air, except for those of
laboratory personnel in one of the plants, which varied
between 3.8 and 18.9 mg/rn' (Shellenberger et al., 1979). A
survey of epichiorohydrin exposure in European manufacturing
plants in 1977-78 indicated that personal exposures were at,
or below, 3.8 mg/rn 3 air (TWA) (Tassignon et al., 1983). In
glycerol-manufacturing plants in the USSR, the concentrations
ranged from 12 to 21 mg/rn 3 air. It was not reported whether
these values were time-weighted-averages over a working day
(Petko et al., 1966).

4.3 General Population Exposure

At a distance of 100-200 rn from a factory discharging

epichlorohydrin into the atrnosphere, in the USSR, the airborne
epichiorohydrin concentration ranged from 0.5 to 1.2 mg/rn 3
air. At 400 m, 5 Out of 29 samples revealed levels exceeding
0.2 mg/rn 3 , while no epichiorohydrin was detected at 600
(Fomin, 1966). Two reports were available concerning the
migration of epichiorohydrin from various epoxy resin-coated
materials into water or food. In one case, no epichlorohydrin
could be detected in the water. The detection limit was
reported to be 3 pg/litre water (Lierop, 1978). In the
other case, foods, preserved in cans coated with epoxyphenolic
lacquers, were found to contain epichlorohydrin, phenol, and
formaldehyde (Pestova, 1979).
 - 17 -

5. CHEMOBIOKINETICS AND METABOLISM

5.1 Absorption

When the tails of mice were immersed in undiluted

epichlorohydrin for 15-60 mm, most mice died, showing severe
systemic poisoning (Kremneva & Tolgskaja, 1961; Pallade et
al., 1967). Within 7 days, 50% of rabbits died after the
application of epichiorohydrin at 0.75 g/kg body weight on an
occluded patch of shaved skin for 24 h (Lawrence et al., 1972).
Eight hours after oral administration of epichiorohydrin
to rats, less than 10% of the dose was recovered in the
gastrointestinal tract; peak tissue levels occurred
approximately 2 h after dosing in males and 4 h in females
(Weigel et al., 1978). Almost all orally ingested
epichiorohydrin was absorbed from the gastrointestinal tract
of rats. The plasma concentration of epichiorohydrin or its
nietabolites in rats was 36.1 mg/litre, 3 h after oral
administration of 100 mg/kg body weight and 18.3 mg/litre
directly after inhalation at a level of 378 mg/rn 3 (Smith et
al., 1979). In mice, peak concentrations in blood of only 0.5
mg/litre were reached within the first 5 min following oral
administration of 200 mg epichlorohydrin/kg body weight (Rossi
at al., 1983b).
It can be concluded that epichiorohydrin is absorbed well
by all routes in all species tested.

5.2 Distribution

After absorption by rats, epichlorohydrin was distributed

widely throughout many tissues. Concentrations of epichloro-
hydrin found in blood, 2-4 h after oral ingestion, were
subsequently exceeded by a factor of 2 or more in the stomach
and intestines, the kidneys, the prostate and lacrimal glands,
and the liver. Directly after inhalation, such levels
occurred mainly in the epithelium of the nasal turbinates, the
lacrimal glands, kidneys, liver, and large intestines (Weigel
et al., 1978; Smith et al., 1979).

5.3 Metabolic Transformation and Excretion

After a single oral administration to rats of 1 or 100 mg

of labelled epichiorohydrin per kg body weight or a 6-h
exposure at levels of 3.78 or 378 mg/rn3 air, approximately
90% of absorbed epichiorohydrin was excreted within 72 h,
regardless of the level or the route of exposure. It was
excreted as carbon dioxide via the lungs (25 - 42% of the
absorbed dose) or as other metabolites via the urine (46 - 54%
 - 18 -

of the absorbed dose). No unchanged epichlorohydrin was

excreted via these routes. The results were not affected by
the position of the ' C-label, indicating that, if any
3

carbon-to-carbon bond is broken, the entire molecule is

metabolized to carbon dioxide. Urinary excretion was a
biphasic process, the slow phase starting 24 h after exposure
(Smith et al., 1979).
The following metabolites have so far been identified in
the urine of rats: 2,3-dihydroxypropyl-S-cysteine and its
mercapturic acid, beta-chlorolactic acid, oxalic acid, and
1,3-(bis-mercaptyl)propanol-2-ol. The first 2 compounds were
also found in the urine of rats given 3-chloro-1,2-propanediol
(alpha-chlorohydrin) (Jones et al., 1969; Fakhouri & Jones,
1979). In in vitro studies, it was shown that epichiorohydrin
was hydrolysed into 3-chloro-1,2-propane-diol by the
microsoinal epoxide hydrolase(s) (EC 3.3.2.3) of mouse liver in
the absence of NADPH, the roles of protein or glutathione in
this detoxification being insignificant (Rossi et al.,
1983a). Within 20 min of the oral or intraperitoneal
administration of epichlorohydrin in mice, the compound was no
longer detectable in the blood by gas chromatography with mass
spectrometric detection, while the level of 3-chloro-1,2-
propane-diol reached a peak. The latter was measurable up to
5 h after exposure (Rossi et al., 1983b). It was proposed
that the biodegradation of the epichlorohydrin molecule was
initiated by enzymatic or non-enzymatic hydrolysis, possibly
also yielding 1-hydroxy-2, 3 epoxypropane (glycidol), after
which conjugation with glutathione took place via glutathione
transferases (EC 2.5.1.18). Direct conjugation of epichioro-
hydrin with glutathione was also proposed. A minor reaction
could be oxidation via 3-chloro-1,2-propanediol and
beta-chlorolactic acid to oxalic acid (Shram et al., 1981a;
Fakhouri & Jones, 1979).
Epichlorohydrin is an alkylating agent and has been found
to react with the nucleic-acid bases deoxyguanosine and
deoxyadenosine in vitro (Hemminki et al., 1980).
 - 19 -

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

A summary of the acute toxicity of epichiorohydrin for

aquatic organisms and plants is presented in Table 2. The
subject of biodegradation has already been discussed in
section 3.3.2.
 — 20 —

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 - 22 -

7. EFFECTS ON ANIMALS

7.1 Short-Term Exposures

After acute intoxication through oral, inhalation, or skin

exposure, death was generally due to respiratory failure
(Freuder & Leake, 1941). At lethal doses, histopathological
changes were found in the lungs, liver, kidneys, adrenals, and
thyroid of mice and rats (Grigorowa et al., 1974). Acute
respiratory irritation with haemorrhages and severe oedema
occurred in rats after inhalation or oral application
(Kremneva & Tolgskaja, 1961; Laskin et al., 1980).
In general, rats were more sensitive to epichiorohydrin
than mice, especially with regard to kidney toxicity (Quast et
al., 1979a,b).
Relevant acute mortality data are shown in Table 3.

Table 3. Acute mortality after oral intake or

inhalation of epichiorohydrin

Species Route Vehicle Parameter Value Reference

studied

rat oral none LI) 5 0 260 Lawrence et al.

(mg/kg body (1972)
weight)

rat inhalation - 6-h LC50 1360 Laskin et al.

(mg/rn') (1980)

rat inhalation - 4-h LC50 2400 Grigorowa et al.

(mg/rn') (1974)

mouse oral none LI)50 236 Lawrence et al.

(mg/kg body (1972)
weight)

mouse inhalation - 2-h L050 3000 Grigornwa et al.

(mg/rn') (1974)

rabbit dermal none 24-h LC50 754 Lawrence et al.

(mg/kg body (1972)
weight)

7.1.1 Oral exposure

Rats received 11 - 80 mg of epichiorohydrin per kg body

weight, orally or intraperitoneally, 3 - 7 times a week for
 - 23 -

2 - 12 weeks. Reduced body weight gain, an increase in the

relative weight of the kidneys, heart, and liver, and
haematological changes were observed. Degeneration of kidney
tubuli was found at exposure levels of 40 and 80 mg/kg body
weight. Two rats died (I at 40 mg/kg and I at 80 mg/kg). The
most frequently observed haematological changes were a
decreased haemoglobin concentration and haematocrit and
changes in (differential) white cell counts (Lawrence et al.,
1972; Van Esch, 1981). A decreased cytochrome P-450 content
was reported in the liver, kidneys, and testes of rats after
an oral dose of 80 mg/kg body weight (Moody et al., 1982).
Kidney damage together with vacuolization and fatty
degeneration of the liver were found in rats and mice after
oral administration of epichiorohydrin at 325 or 500 mg/kg
body weight. Foci of necrosis were also observed in the
gastrointestinal tract (Kremneva & Tolgskaja, 1961).

7.1.2 Subcutaneous exposure

The kidneys were the main target organ, also at non-lethal

doses. Rats injected once, subcutaneously, with approximate
LI)50 doses of 150 or 180 mg epichlorohydrin per kg body
weight showed nephrotoxic degeneration of the epithelium of
the proximal tubules with ischemic cortex necrosis, in the
first days after exposure (Pallade et al., 1967). This phase
was accompanied by anuria or oliguria and death at a dose
level of 100 - 125 mg/kg body weight (Pallade et al., 1967,
1968; Fakhouri & Jones, 1979). Renal insufficiency was
illustrated further at a dose of 125 mg/kg body weight by
functional disturbances such as proteinuria, an increased
sodium-ion concentration in the urine, and an increased
potassium-ion concentration in serum (Pallade et al., 1968).
The activity of the enzymes cytochrome-c-oxidase (EC 1.9.3.1),
catalase (EC 1.11.1.6), glutamic pyruvic transaminase (EC
2.6.1.2) and, to a lesser extent, alkaline phosphatase (EC
3.1.3.1) and glutamic oxaloacetic transaminase (EC 2.6.1.1)
was inhibited in renal tissue, while catalase activity was
increased in urine (Pallade et al., 1970). Regeneration of
the kidneys in surviving rats started 5 days after exposure
(Pallade et al., 1967).
Doses of 50 and 75 mg/kg body weight administered to rats
resulted in polyuria and the excretion of large quantities of
glucose. Many crystals of calcium oxalate were found in the
diuretic urine (Fakhouri & Jones, 1979).

7.1.3 Inhalation exposure

The 14-day mortality response of rats, after a single

inhalation exposure, increased over a narrow concentration
 - 24 -

range. At 1280 mg/n 3 , the observed mortality rate was 5%

compared with 7'/ at 1395 mg/rn 3 (Laskin et al., 1980).
Twenty-four hours after a single 4-h inhalation exposure
of rats to epichiorohydrin levels of 7 - 350 mg/rn 3 , polyuria
was accompanied by increases in kidney weight and in the
specific gravity, and the protein and chloride contents of the
urine. In this study, bromosulphthalein retention decreased
and the liver weight increased (Szumskaa, 1971).
Slight histopathological liver changes were also found in
mice after a 2-h inhalation exposure to a concentration of
1680 mg/rn 3 (Grigorowa et al., 1974). Other signs of liver
toxicity were an increased pentobarbital sleeping time in mice
(Lawrence et al., 1972) and a dose-related decrease in
histaminase (EC 1.4.3.6) activity in rats (Soloimskaja, 1967).
Daily 4-h inhalation exposures of rats during 4 weeks to
an epichiorohydrin concentration of 30 mg/rn 3 also produced
signs of kidney and liver toxicity (Grigorowa et al., 1977).
When rats were exposed continuously to 0.2 mg/rn 3 for 98
days, no effects were observed. At 2 mg/rn 3 , an increase in
the number of altered leukocytes was reported, while at
20 mg/rn 3 , slight histopathological changes were seen in the
lungs, kidneys, heart, and neurons, together with a reduction
in body weight gain (Fomin, 1966).
When rats were exposed to epichlorohydrin concentrations
in air of up to 377 mg/rn 3 , 9 - 18 times, for 4 - 7 h/day,
during 1.5 - 4 weeks, there were no deaths. Mild nasal
irritation occurred at a concentration of 102 mg/rn 3 . The
most pronounced effect was inflammation and degeneration of
the epithelium in the nasal turbinates, with hyperplasia and
squamous cell metaplasia at 3]] mg/rn 3 . At concentrations of
211 mg/rn3 or more, body weight gain was reduced. At a
concentration of 377 mg/rn 3 , the kidney tubuli were dilated
and the tubular epithelial cells were swollen, proteinuria was
also found. Other changes at 377 mg/rn 3 were: leukocytosis,
liver congestion, oederna, consolidation, congestion and
inflammation of the lungs, and changes in the increased
relative weight of the adrenals, slight epithelial
desquamation and oedema of the thyroid, and atrophy of the
thymus (Gage, 1959; Grigorowa et al., 1974; Quast et al.,
1979b).
In a 90-day study, rats were exposed 6 h/day, for 5 days a
week to epi.chlorohydrin concentrations in air of 19, 94, or
189 mg/rn 3 . Of the rats that survived, some were killed
after 30 days, and some at the end of the study. No effects
were found on haematology, urinalysis, and biochemistry. At
the two highest concentrations, the epithelium of the nasal
turbinates showed dose-related changes, similar to those
described above and the relative kidney weights were
increased. At 189 mg/rn 3 , body weight gain was reduced and
 - 25 -

focal tubular nephrosis with dilated tubules was observed in

the kidneys. Minimal changes were observed in the adrenals,
the contents of the epididimydes, and in the liver (Quast et
al., 1979a). In a similar study the changes in the nose and
the kidneys appeared to be reversible (John et al., 1983b).

7.1.4 Effects on the eyes and skin

Application of an 80% solution of epichiorohydrin in

cottonseed oil caused corneal damage in the rabbit eye. A 20%
solution induced definitive conjunctival and palpebral
irritation with oedema.
Severe skin irritation was seen in a 24-h occluded patch
test on the shaved back of rabbits using a 5% solution of
epichiorohydrin in cottonseed oil (Lawrence et al., 1972).
When 15 guinea-pigs were treated dermally with a 5%
solution of epichiorohydrin in ethanol, sensitization was
observed in 9 animals after a challenge dose, 2 weeks later,
with a 1% solution during 24 h (Thorgeirsson & Fregert,
1977). A negative result was obtained in a skin maximization
test using a 0.01% solution of epichiorohydrin in cottonseed
oil (Lawrence et al., 1972).

7.2 Carcinogenicity

7.2.1 Short-term studies

7.2.1.1 Oral exposure

Groups of 20 male Wistar rats received 0, 20, 40, or 80 mg

of epichlorohydrin per kg body weight in distilled water, by
stomach tube, 5 times per week for 12 weeks. The animals were
killed after 1, 2, 4, or 12 weeks. At the highest dose, 2
rats died and a reduced body weight gain was noted. From the
first week onwards, a time- and dose-related increase was
observed in the changes in the basal cell layer of the
forestomach such as thickening of the stomach wall,
haemorrhaging, hyperplasia, and an increased number of mitotic
figures and nuclei. After 12 weeks at 80 mg/kg body weight, 2
out of 5 rats had papillomas and squamous cell carcinomas (Van
Esch & Wester, 1982b).

7.2.2 Long-term studies

7.2.2.1 Oral exposure

Groups of 18 male Wistar rats received epichiorohydrin in

the drinking-water at concentrations of 0, 375, 750, and
1500 mg/litre over a period of 81 weeks. At intervals, the
 - 26 -

exposure was stopped for some days because of the poor

condition of the rats. The average total intakes were,
respectively, 0, 8.8, 15.7, and 26.6 ing per rat, per day. All
surviving rats were examined at 81 weeks. The survival rates
were, respectively, 55, 50, 55, and 67%. Body weights were
reduced in a dose-related manner.
The incidence of hyperplasia of the forestomach epithelium
at 0, 375, 750, and 1500 mg/litre was 0, 78, 90, and 100%,
respectively. The incidence of papillomas was 0, 0, 10, and
58%, respectively, and the incidence of carcinomas, 0, 0, 10,
and 17%, respectively. The number of tumours of the
forestomach per rat rose from 5.6 at the lowest dose level to
32.8 at the highest. Two Out of the 12 surviving rats
receiving 1500 mg/litre had squamous cell carcinomas in the
oral cavity (Konishi et al., 1980).
Groups of 50 male and 50 female Wistar rats received 0, 2,
and 10 mg of epichiorohydrin per kg body weight in distilled
water, by stomach tube, 5 times per week for 104 weeks. Gross
and histopathological studies were carried out on all animals;
haematological studies were carried out at week 55 on 10 rats
per sex and per dose.
In males, the body weight gain was significantly and
dose-dependently reduced. An elevated mortality rate was
noted, reaching a maximum of 60%. A high mortality rate,
especially in females, between weeks 20 and 50 was due to
obstruction by hair balls in the intestines, caused by the
composition of the diet. A dose-related decrease was found in
the number of leukocytes in the females. The incidence of
hyperplasia of the forestomach epitheliurn at 0, 2, and
10 mg/kg body weight for female and male rats was 6 and 10%,
24 and 48%, and 14 and 12%, respectively. The incidence of
papillomas at this site was 4 and 2%, 4 and 12%, and 0 and 4%,
respectively, and the incidence of carcinomas, 0%, 4 and 12%,
and 48 and 70%. Females were less affected than males. The
first carcinomas appeared after 20 months of exposure (Van
Esch & Wester, 1982a).

7.2.2.2 Inhalation exposure

Groups of 100 male Sprague-Dawley rats were exposed for

their lifetime (16 - 136 weeks), for 6 h per day and 5 days
per week, to epichlorohydrin vapour at concentrations of 38
and 113 mg/rn 3 air. The contro's comprised 100 air-treated
and 50 untreated rats. Survival was poor in both exposed and
unexposed rats. A mortality rate of 45% was reached in week
45 at 38 mg/rn3 air and in week 60 at 113 mg/rn3 air. After
week 40, a reduced body weight gain was seen at 113 mg/rn 3
air. In all cases, severe lung congestion, bronchiolectasis,
and pneumonia were observed. At the highest concentration, 1
 - 27 -

papilloma was detected in the nasal cavity after 57 weeks and

1 squamous cell carcinoma after 107 weeks. At 38 mg/rn 3 , 1
pituitary adenorna was found compared with two at 113 mg/rn 3
air. No tumours were detected in the controls. The kidney
tubules were dilated and degenerated in 24% of air-treated
rats, in 37% of the rats exposed to epichiorohydrin at
38 mg/rn 3 , and in 65% of the rats exposed to 113 mg/rn 3
(Laskin et al., 1980).
A group of 140 male Sprague-Dawley rats was exposed for 30
days, 6 h per day, to epichlorohydrin vapour at a concentra-
tion of 378 mg/rn 3 and observed for the lifetime. The
controls comprised 100 air-treated and 50 untreated rats.
Almost all animals showed inflammation of the mucous membranes
of the turbinates, larynx, and trachea. Dilatation of the
renal cortical and medullary tubules, which were filled with
hyaline casts, was seen more frequently in exposed rats than
in controls. Between 330 and 933 days from the start of expo-
sure, 17 exposed rats showed 15 squamous cell carcinomas and 2
papillomas of the nasal epithelium. One bronchial papillorns
was observed at day 583 after the start of exposure. Four
exposed rats had pituitary adenomas and one rat had a squamous
cell carcinoma of the forestomach. None of these tumour types
was found in the controls (Laskin et al., 1980).

7.2.2.3 Subcutaneous exposure

Each of a group of 50 female ICR/BA Swiss mice received a

dose of 1.0 mg of epichlorohydrin in tricaprylin,
subcutaneously, once a week, for up to 580 days. A group of
100 mice did not receive any treatment and a group of 50 mice
received the vehicle only. Local skin sarcomas were found in
6 treated mice and 1 vehicle-treated mice. A local
adenocarcinoma was found in one treated rat. The median
survival time was 486 days (Van Duuren et al., 1974).

7.2.2.4 Intraperitoneal exposure

Each of a group of 30 female ICR/HA Swiss mice received an

intraperitoneal dose of 1.0 mg of epichlorohydrin in
tricaprylin, once a week, for up to 450 days. A group of 100
mice did not receive any treatment and a group of 50 mice
received the vehicle only. Papillary tumours were observed in
the lungs of 11 exposed and 10 vehicle control mice (Van
Duuren et al., 1974).

7.2.2.5 Dermal exposure

A group of 40 C31-I mice was painted three times a week with

"one brushful" of undiluted epichiorohydrin on the clipped
 - 28 -

midline of the back for up to 25 months. At month 17, 30 mice

were still alive and, at month 24, only 1. No tumours were
found (Weil et al., 1963).
Each of a group of 50 female ICR/HA Swiss mice received
2.0 mg epichlorohydrin in acetone applied to the shaven skin,
three times a week, for up to 580 days. A group of 100 mice
did not receive any treatment and a group of 50 mice received
the vehicle only. No tumours were found. The median survival
time was 506 days (Van Duuren et al., 1974).
In an initiation-promotion study, each of 30 female 1CR/HA
Swiss mice received a single dose of 2.0 mg of epichiorohydrin
in acetone applied to the skin, followed 2 weeks later by
applications of 2.5 ig of phorbol myristate acetate in
acetone three times a week for up to 385 days. Several
control groups were used. After 106 weeks, 9 exposed mice had
developed skin papillomas compared with none of the vehicle
controls, and 3 out of a group of 30 that had received the
promotor only. One exposed mouse developed a skin carcinoma
compared with none of the controls. The median survival time
was over 385 days (Van Duuren, 1974).

7.3 Mutagenicity

A summary of mutagenicity tests with positive results is

given in Table 4. The direct alkylating agent epichiorohydrin
(Hemminki et al., 1980) induced gene mutations in all cellular
systems and chromosome damage, including sister chromatid
exchanges, in eukaryotes. Negative results were obtained in
dominant lethal assays with mice (Epstein et al., 1972; Shram
et al., 1976) and in tests for chromosomal aberrations in rat
bone marrow cells after in vivo exposure (Dabney et al., 1979;
Shram et al., 1981a). In contrast with other tests, one test
with mouse bone marrow cells did not show chromosome
aberrations (Rossi et al., 1983b). One DNA-repair test with
rat hepatocytes also failed to show a positive mutagenic
effect (Probst et al., 1981).

7.4 Effects on Reproduction

Epichiorohydrin induced antifertility effects in male rats

resembling those induced by aipha-chiorohydrin after a single
oral or intraperitoneal dose of 50 mg/kg body weight (Jones et
al., 1969). Male fertility was also reduced after daily oral
doses of 10 mg/kg body weight, 5 days per week, for 3 months,
while doses of 2 mg/kg body weight were without effect (van
Esch, 1981). After 7 daily oral doses of 15 mg/kg body
weight, this effect was reversible in rats within one week
(Hahn, 1970). While 5 oral doses of 20 mg/kg body weight
caused reversible sterility in male rats, 5 daily doses of
 - 29 -

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 - 31 -

50 mg/kg body weight or one single dose of 100 mg/kg body

weight caused permanent sterility. In permanently sterile
male rats, large retention cysts were found in the ductuli
efferentes and proximal caput of the reproductive organs
(Cooper et al., 1974). When male rabbits and male and female
rats were exposed for 6 h daily, 5 days per week, to
epichiorohydrin vapour at concentrations of 0, 19.7, 93.4, and
189.0 mg/m 3 air for 10 weeks, a dose-related transient
infertility was induced at the 2 higher levels in male rats,
but not in female rats or male rabbits. Microscopic
examination did not reveal any abnormalities in the
reproductive organs. The sperm of rabbits was investigated,
but no adverse effects were found (John et al., 1983b). The
sperm of rats that had received 25 or 50 mg epichlorohydrin/kg
body weight orally, showed an increased percentage of abnormal
sperm heads at the higher dose and a reduced number of sperm
heads at the lower dose, while no changes were observed in the
weight and microscopic picture of the testes (Cassidy et al.,
1983).

7.5 Teratogenicity

Female rats received orally 0, 40, 80, or 160 mg and

female mice 0, 80, 120, or 160 mg of epichiorohydrin per kg
body weight per day in cottonseed oil, between the 6th and the
15th day of pregnancy. Although the higher dose levels were
toxic to the dams, no embryotoxic, fetotoxic, or teratogenic
effects were observed (Marks et al., 1982). Similar negative
results were obtained, when female rats and rabbits inhaled
vapours of epichlorohydrin at concentrations of 0, 9.4, or
94.5 mg/m 3 air for 7 h/day, between the 6th and the 15th or
18th day of pregnancy (John et al., 1983a).
 - 32 -

8. EFFECTS ON MAN

8.1 Controlled Studies

In the USSR, 5 human volunteers showed significant

electroencephalogram changes in the voltage of spikes of the
alpha rhythm, when they were exposed to epichlorohydrin vapour
at a concentration of 0.3 mg/rn 3 air for up to 18 mm (Fomin,
1966).
Burning of the eyes and nasal mucosa was reported to occur
at an epichiorohydrin vapour concentration of 76 mg/rn 3 air,
while throat irritation, which lasted for 48 h, was
experienced at 151 mg/rn 3 (Wexler, 1971).
The sensitization capacity of epichiorohydrin was tested
on 1 volunteer. After an occluded patch test of 2 days with
0.1 - 1.0% solutions of epichiorohydrin in ethanol, a late
reaction developed after 8 - 11 days. After a challenge
exposure of 2 days, erytherna was seen immediately after using
a 0.01% solution; a "positive reaction" was seen, using a 0.1%
solution (Fregert & Gruvberger, 1970).

8.2 Accidental Exposures

Seven cases of epichlorohydrin spills on the hands,

thighs, or feet have been extensively described. In 2 of the
cases, epichlorohydrin had been mixed with methanol. All
spills resulted in protracted chemical burns with a latent
period of between 10 min and several hours before the first
symptoms and redness appeared. Doctors were consulted after
periods ranging from 2 h to 5 days. The most frequent signs
were redness, swelling, oedema, erosion, and ulceration. Two
of the exposed persons were re-exposed within 8 days and 20
months, respectively. No sensitization was noted.
Epichlorohydrin was found to penetrate rubber gloves and
leather shoes (von Ippen & Mathies, 1970).
One case was reported of a 39-year-old man who inhaled a
few deep breaths of epichlorohydrin vapour. Initially, only
slight irritation of the eyes and throat was experienced with
headache, nausea, and vomiting; later, chronic asthmatic
bronchitis developed. Several biopsies over a 2-year period
showed fatty degeneration together with functional
disturbances of the liver (Schultz, 1964).

8.3 Epidemiological Studies

8.3.1 Sensitization

In a group of 34 workers with hypersensitivity towards

epoxy resins, 6 were found to be hypersensitive to 1%
 - 33 -

epichiorohydrin (Jiràsek & Kalensky, 1962). One case of

allergic contact dermatitis in relation to epichlorohydrin in
a solvent cement was also reported (Beck & King, 1983).

8.3.2 Carcinogenic effects

A retrospective cohort study for mortality experience

during the period 1966-77 was conducted in the USA on 864 male
workers, exposed during the manufacture of epichlorohydrin for
more than 3 months, before 1966. There were no exposure
data. The reference population consisted of white males from
Louisiana and Texas. A total of 52 deaths was recorded. The
observed number of deaths in the entire cohort was less than
the expected number for all causes, except for primary lung
cancer (9 cases) and leukaemia (2 cases). When only the 31
deaths were considered from a fairly young cohort of 715 men
with more than 15 years of exposure, the incidences of death
due to all cancers (13), primary lung cancer (8), leukaernia
(2), and suicide were higher than expected, but none of the
increases was significant. Four of the lung cancer cases had
also been exposed to isopropyl alcohol (Enterline, 1977;
Enterline & Henderson, 1978). In a further update of the
study through 1979, 13 more deaths were identified including 1
due to lung cancer. It was reported that one case, originally
diagnosed as primary lung cancer, later appeared to be a
reticulum cell sarcoma, and that a second case was found to be
an adenocarcinoma with unknown primary site. The increased
incidence of lung cancer was still not significant. All but I
of 7 confirmed lung cancer cases were smokers. Four of the 6
lung cancer cases in one plant had also been previously
engaged in an isopropy] alcohol manufacturing plant. Here,
the excess in lung cancer was only among workers previously
employed at the isopropyl alcohol manufacturing unit.
However, a slight excess in lung cancer cases was also
observed (4 against 3.09 expected) in the other plant
(Enterline & Hartley, 1981).
Another retrospective cohort study for mortality
experience during the period 1957-76 was carried out on 553
white employees with a potential for epichiorohydrin exposure
in a plant manufacturing epoxy resins and glycerol. The
time—weighted average exposures to epichiorohydrin ranged from
below 3.8 mg/rn 3 air to 18.9 mg/m 3 . The exposure period
was between 1 month and 15 years. Workers could also have
been exposed to allyl chloride and solvents. The reference
population comprised white males from Texas. A total of 12
deaths was recorded. The observed number of deaths was lower
than, or equal to, the expected number for all causes except
accidents (Shellenberger et al., 1979).

3
 -. 34 -

A study was also undertaken on the mortality rate up to

1978 in 606 male workers whose average age was 42 years and
who had at least one year of exposure prior to 1968, at 4
European sites engaged in the production of epichiorohydrin,
epoxy resins, glycerine, and other chemicals derived from
epichiorohydrin. Personal exposures in 1977-78 were at, or
below, a time-weighted-average of 3.78 mg/rn 3 . Earlier
exposures occasionally reached levels high enough to be
irritating (38 - 95 mg/rn'). The mean duration of the
exposure to epichiorohydrin was 9.3 years. Of the cohort, 45%
had more than 10 years of exposure. The death statistics of
the countries in which the plants were situated served as a
reference. A total of 10 deaths were recorded. No excess
mortality for cancer (4 deaths) was observed in the entire
cohort, in a subgroup. with more than 10 years of exposure, or
in a subgroup with 10 or fewer years of exposure (Tassignon at
al., 1983).

8.3.3 Mutagenic effects

Cytogenetic analyses of peripheral lymphocytes were

reported for 3 groups of workers. In a group of 35 workers in
an epichiorohydrin-producing plant in Czechoslovakia, who were
exposed for 2 years to concentrations between 0.5 and
5.0 mg/rn 3 air, an increase in chromatid and chromosome
breaks and in aberrant cells was found, which was related to
the length of exposure. Pre-exposure values were used as
control data (Kucherova et al., 1977). When the same group
was re-examined after another 2 years, using matched controls
and with an average exposure level below 1 mg/m' air, the
number of breaks per cell was unchanged and only a slight
increase was found in the number of aberrant cells (Shram,
1981). Four years later, when the average exposure level was
down to 0.4 mg/rn 3 air, significant clastogenic effects were
no longer found. The clastogenic effect of epichiorohydrin on
human lymphocytes therefore seems to be related to the extent
of the more recent exposures (Shram et al., 1983). Another
group of 93 workers in the USA, probably exposed to average
concentrations below 18.9 mg/rn 3 air, showed increases in
aberration rates compared with 75 pre-employrnent individuals.
Significant differences were found in the distribution of
individuals with chromatid and chromosome breaks, aberrant
cells, and severely damaged cells (Picciano, 1979). In the
lymphocytes of 191 workers, probably exposed to average
concentrations below 18.9 mg/m' air, no significant
increases in aberrations were found compared with a control
group of 63 pre-employment individuals (BarnaLloyd et al.,
1979).
 - 35 -

8.3.4 Effects on reproduction

The fertility status of 64 glycerol workers, in the USA,

exposed to epichlorohydrin, allyl chloride, and 1.3-dichioro-
propene was compared with that of a control group of 63
workers who had not been engaged in handling chlorinated
hydrocarbons for more than 5 years. No association was found
between exposure levels, exposure duration, or exposure
intensity and sperm characteristics or hormone levels. The
volunteer rate was 64% (Venable et a1., 1980). A similar
negative result for the sperm count and hormone leve1s was
obtained for a group of 128 workers from 2 plants compared
with external chemical plant workers, who had not been exposed
to any chemical known to be toxic to the testes. In one of
these plants, most of the employees were exposed to
epichlorohydrin concentrations below 3.8 mg/m 3 air. The
rate of non-participating employees was high in both plants
and amounted to a total of 172 workers (Milby et al., 1981).
 - 36 -

9. EVALUATION OF HEALTH RISKS FOR MAN

On the basis of observations following short-term

exposures to epichiorohydrin, human beings are likely to begin
to experience eye and upper respiratory tract irritation at
concentrations of approximately 76 mg/rn 3 (Wexler, 1971).
If man were equally as sensitive to epichlorohydrin as
animals, lethal inhalation doses for human beings, calculated
on the results of animal studies (Lawrence et al., 1972;
Grigorowa et al., 1974; Laskin et al., 1980), would be likely
to range from 1360 to 3000 mg/n 3 , with exposure lasting a
few hours. At such doses, it is expected that the target
organs would be the lungs, kidneys, and liver. However, such
concentrations could be obtained only in the event of massive
accidental spills.
Epichiorohydrin can sensitize the skin of human beings
(Jirasek & Kalénsky, 1962; Von lppen & Mathies, 1970; Fregert
1. Gruvberger, 1970; Beck & King, 1983).
Observations on laboratory animals have indicated that
short-term exposures to epichiorohydrin for periods of from
weeks to months are likely to induce kidney damage (Gage,
1959; Lawrence et al., 1972; Grigorowa et al., 1974; Quast et
al., 1979b; Van Esch, 1981). Kidney damage has not been
reported in man so far.
In male rodents, exposure to epichiorohydrin induced
sterility (Jones, 1969; Hahn, 1970; Van Esch, 1981; John et
al., 1983b). If human beings were as sensitive to
epichlorohydrin as rodents, reversible decreased male
fertility would occur with exposures to about 90 mg1rn 3 air
for a few months. Such exposures are not likely to be
tolerated by man for extended periods because of the
irritation of the eyes and respiratory tract that occur below
this level. Much higher doses are required to induce
permanent sterility or sperm head abnormalities (Cooper et
al., 1974; Cassidy et al., 1983). Limited epidemiological
studies did not reveal effects on the fertility status of male
workers exposed to epichlorohydrin (Venable et al., 1980;
Milby et al., 1981).
In animals, epichlorohydrin is carcinogenic when
administered by inhalation, orally, or by subcutaneous
injection. The site of tumour induction has been localized to
the site of administration, i.e., the nasal epithelium after
inhalation, stomach epithelium after gavage and drinking-water
administration, and the site of injection after injection
(Konishi et al., 1980; Laskin et al., 1980; Van Esch & Wester,
1982a,b). On the basis of this evidence, together with the
inutagenic effects observed in several short-term test systems,
it can be concluded that epichiorohydrin could be carcinogenic
 - 37 -

for human beings. Epidemiological studies to date have not

provided evidence of malignant neoplasms in human beings, due
to exposure to epichiorohydrin. However, the epidemiological
data do not have a sufficient number of recorded deaths to
detect a weak carcinogenic response. A longer observation
time is needed before a final assessment can be made
(Enterline & Henderson, 1978; Shellenberger et al., 1979;
Enterline & Hartley, 1981; Tassignon et al., 1983).
 - 38 -

10. SOME CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

10.1 Occupational Exposure

Legal maximum allowable cconcentrations2 range from

1 mg/rn 3 (0.25 ppm, ceiling value) in the USSR and 2 mg/rn'
(0.5 ppm, TWA) in Sweden to 4 mg/rn 3 (I ppm, TWA) and a peak
value of 19 mg/rn 3 (5 ppm) in the Netherlands and 8 mg/rn'
(2 ppm, TWA) in the United Kingdom. In the USA, the American
Conference of Governmental Industrial Hygienists recommends
10 mg/rn 3 (2 ppm, TWA). Short-term exposure limits are
20 mg/rn 3 (5 ppm) in the United Kingdom and 4 mg/rn' (1 ppm)
in Sweden. In most regulations and guidelines, warnings are
given concerning the carcinogenic nature of, and the
possibility of skin penetration by, epichiorohydrin (IRPTC,
1984).

10.2 Ambient Air Levels

In the USSR, the maximum allowable concentration is an

average of 0.2 mg/rn 3 per day (IRPTC, 1984).

10.3 Surface Water Levels

In the USSR, the maximum allowable concentration is

0.01 mg/litre (IRPTC, 1984).

10.4 Levels in Food

In the USA, the substance is exempted from tolerance

requirements in plant products, when used according to good
agricultural practice as an inert (or occasionally active)
ingredient of pesticides applied to growing crops for some
specified purposes (IRPTC, 1984).

10.5 Labelling and Packaging

The European Economic Commission regulations require that

the label should state that epichiorohydrin is flammable and
toxic by inhalation, in contact with skin, and if swallowed;
that a container must be kept tightly closed in a well-
ventilated place; that contact with the eyes should be
avoided; and that medical advice should be sought, when a
person is feeling unwell (IRPTC, 1984).

Values quoted in national lists.

 - 39 -

10.6 Storage and Transport

The United Nations Committee of Experts on the Transport

of Dangerous Goods (1984) qualifies epichiorohydrin as a toxic
substance (Class 6.1) with medium danger for packing purposes
(Packing Group II). Packing methods and a label are
recommended. The label is; -

The Inter-Governmental Maritime Consultative Organ-

ization.. (1981) also qualifies epichiorohydrin as a toxic
substance and recommends packing, stowage, and labelling
method for maritime transport. The recommended labels are:

Background: red

! Now the International Maritime Organization.

 - 40 -

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