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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 33





    EPICHLOROHYDRIN







    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 Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1984


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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR EPICHLOROHYDRIN

PREFACE

1. SUMMARY

2. PROPERTIES AND ANALYTICAL METHODS

    2.1. Chemical and physical properties
    2.2. Analytical methods

3. SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT
    AND DISTRIBUTION

    3.1. Industrial production, uses, disposal of wastes
         3.1.1. Industrial production
         3.1.2. Uses
         3.1.3. Disposal of wastes
    3.2. Environmental transport and distribution

4. ENVIRONMENTAL LEVELS AND EXPOSURES

    4.1. Occurrence
    4.2. Occupational exposure
    4.3. General population exposure

5. CHEMOBIOKINETICS AND METABOLISM

    5.1. Absorption
    5.2. Distribution
    5.3. Metabolic transformation and excretion

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7. EFFECTS ON ANIMALS

    7.1. Short-term exposures
         7.1.1. Oral exposure
         7.1.2. Subcutaneous exposure
         7.1.3. Inhalation exposure
         7.1.4. Effects on the eyes and skin
    7.2. Carcinogenicity
         7.2.1. Short-term studies
                 7.2.1.1  Oral exposure
         7.2.2. Long-term studies
                 7.2.2.1  Oral exposure
                 7.2.2.2  Inhalation exposure
                 7.2.2.3  Subcutaneous exposure
                 7.2.2.4  Intraperitoneal exposure
                 7.2.2.5  Dermal exposure
    7.3. Mutagenicity
    7.4. Effects on reproduction
    7.5. Teratogenicity

8. EFFECTS ON MAN

    8.1. Controlled studies
    8.2. Accidental exposures
    8.3. Epidemiological studies
         8.3.1. Sensitization
         8.3.2. Carcinogenic effects
         8.3.3. Mutagenic effects
         8.3.4. Effects on reproduction

9. EVALUATION OF HEALTH RISKS FOR MAN

10. SOME CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

    10.1. Occupational exposure
    10.2. Ambient air levels
    10.3. Surface water levels
    10.4. Levels in food
    10.5. Labelling and packaging
    10.6. Storage and transport

REFERENCES

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. Tassignon, 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 M. Mercier, Manager, International Programme on Chemical
   Safety, World Health Organization, Geneva, Switzerland

Dr F. Valic, 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 
Epichlorohydrin 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. Mercier, 
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 epichlorohydrin. 

    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. 


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. 


1.  SUMMARY

    Epichlorohydrin 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/m3 
in air and 40 µg/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 
epichlorohydrin in occupational and ambient air, and in water and 
food.  Occupational air levels generally seem to remain below 18.9 
mg/m3.  Epichlorohydrin 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, gastro-
intestinal 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 epichlorohydrin 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.  Epichloro-
hydrin 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 epichlorohydrin occur first in the epithelia of the nose and 
stomach where 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. 

    Epichlorohydrin is mutagenic in most short-term assays. 
Conflicting results were obtained when the lymphocytes of workers, 
occupationally exposed to concentrations below 18.9 mg/m3, 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 embryotoxic, 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. 

2.  PROPERTIES AND ANALYTICAL METHODS

2.1.  Chemical and Physical Properties

    Epichlorohydrin (C3H5Cl0) 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, 
epichlorohydrin attacks steel. 

Chemical structure:       0
                         / \
                        /   \
                       CH2---CH---CH2Cl

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), (chloromethyl) ethyl-
                       ene oxide, chlormethyl oxirane, 2-
                       (chloro-methyl) oxirane, 1-chloro-
                       propene oxide, 3-chloropropene oxide,
                       3-chloro-1,2-propylene oxide, (DL)-
                       alpha-epichlorohydrin, ECH, ECHH, EPI,
                       1-epichlorohydrin, 1,2-epoxy-3-chloro-
                       propane, 2,3-epoxypropyl chloride,
                       gamma-chloropropylene oxide, glycerol
                       epichlorohydrin, glycidyl chloride

Trade names:           SKEKHG

Some physical and chemical data on epichlorohydrin

physical state                                liquid                     
colour                                        colourless                 
odour                                         chloroform-like,           
                                              threshold                  
                                              38-95 mg/m3 air            
relative molecular mass                       92.53                      
melting point                                 -26 °C                     
boiling point                                 115 °C                     
water solubility                              66 g/litre, 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/m3

2.2.  Analytical Methods

    A summary of methods for the sampling and determination of 
epichlorohydrin in air, water, and food is presented in Table 1. 


Table 1.  Sampling, preparation, analysis
---------------------------------------------------------------------------------------------------
Medium    Sampling method  Analytical method  Detection  Comments                 Reference            
                                              limit
---------------------------------------------------------------------------------------------------
air       sampling on      desorption with    1 µg (2 -  recommended for the      NIOSH (1984)       
(occupa-  charcoal         carbon disulfide,  30 litre   range 2 - 60 mg/m3                        
tional)                    gas chromato-      sample)    (20 litre sample)                         
                           graphy with flame                                                            
                           ionization                                                            
                           detection                                                         

air       sampling in 40%  colorimetry        0.5 mg/m3  interference from for-   Jaraczewska &   
(occupa-  sulfuric acid                                  maldehyde and compounds  Kaszper (1967) or    
tional)   with oxidation                                 with vicinal terminal    Daniel & Gage        
          to formaldehyde                                hydroxyl groups          (1956)               
                                                                                                   
air       sampling on      desorption by                                          Brown & Purnell  
          Tenax porous     by heating                                             (1979)           
          polymer          gas chromato-                                                           
                           graphy with                                                             
                           flame ionization                                                            
                           detection

water                      extraction with    3 mg/      no interference from     Adamek & Peterka     
                           carbon tetra-      litre      glycerine, glycidol      (1971)         
                           chloride                      and monochlorohydrin                           
                           infra-red                                                         
                           spectroscopy 

water                      potentiometric                reaction with sodium     Swan (1954)          
                           titration                     sulfite and titration                     
                                                         of the liberated sodium                   
                                                         hydroxide; aldehydes                      
                                                         interfere                                 
                                                                                                   
water                      gas chromato-      40 µg/     headspace analysis       Piringer (1980)      
                           graphy and mass    litre      signal - noise ratio                      
                           spectrometry                  is 5:1 at detection                       
                                                         limit                                     

food      extraction by    gas chromato-                 determination of epi-    Daniels et al.       
          closed-system    graphy                        chlorohydrin in corn     (1981)               
          vacuum                                         starch down to 30 mg/kg                   
          distillation
---------------------------------------------------------------------------------------------------

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., 1980) 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 hypochlorous acid to yield a mixture of isomeric 
glycerol chlorohydrins.  After dehydrochlorination 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, dichloropropanols, 1,2-
dichloropropene, cis- and trans-1,3 dichloropropene, glycidol, 
alpha- and beta-mono-chlorohydrin, and 1,2,3-trichloropropene.  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 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 epichlorohydrin mainly occurs 
via air ducts and waste disposal of heavy ends in industries that 
produce or use epichlorohydrin.  Assuming an industrial production 
of 181 kilotonnes in the USA, it was estimated that these 2 
pathways accounted for the transport of 273 and 193 tonnes, 
respectively, into the environment in 1977.  Other contaminants 
associated with these industrial processes are allyl chloride, 
trichloropropanes, chloroethers, and dichlorohydrins.  Epichloro-
hydrin can also be lost to the environment via industrial water, 
during transport and storage, by volatilization during use, and by 
inadvertant industrial production (Santodonato et al., 1980). 

    The half-life for the reaction of epichlorohydrin with water, 
at room temperature, to form 3-chloro-1,2-propanediol (alpha-
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). 

4.  ENVIRONMENTAL LEVELS AND EXPOSURES

4.1.  Occurrence

    No data are available that indicate that epichlorohydrin occurs 
naturally in ambient air, water, soil, or biota. 

    On the basis of use patterns and the physical and chemical 
properties of epichlorohydrin, 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 
epichlorohydrin ranged from less than 0.04 mg/m3 air to 57 mg/m3.  
The median was below 8 mg/m3 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/m3 air, except for those of 
laboratory personnel in one of the plants, which varied between 3.8 
and 18.9 mg/m3 (Shellenberger et al., 1979).  A survey of 
epichlorohydrin exposure in European manufacturing plants in 1977-
78 indicated that personal exposures were at, or below, 3.8 mg/m3 
air (TWA) (Tassignon et al., 1983).  In glycerol-manufacturing 
plants in the USSR, the concentrations ranged from 12 to 21 mg/m3 
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 m from a factory discharging 
epichlorohydrin into the atmosphere, in the USSR, the airborne 
epichlorohydrin concentration ranged from 0.5 to 1.2 mg/m3 air.  
At 400 m, 5 out of 29 samples revealed levels exceeding 0.2 mg/m3, 
while no epichlorohydrin was detected at 600 m (Fomin, 1966).  Two 
reports were available concerning the migration of epichlorohydrin 
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 µg/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). 

5.  CHEMOBIOKINETICS AND METABOLISM

5.1.  Absorption

    When the tails of mice were immersed in undiluted 
epichlorohydrin for 15-60 min, 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 
epichlorohydrin 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 epichlorohydrin to 
rats, less than 10% of the dose was recovered in the gastro-
intestinal 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 epichlorohydrin was absorbed from the 
gastrointestinal tract of rats.  The plasma concentration of 
epichlorohydrin or its metabolites 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/m3 (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 et 
al., 1983b). 

    It can be concluded that epichlorohydrin 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 epichlorohydrin 
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 epichlorohydrin per kg body weight or a 6-h exposure at 
levels of 3.78 or 378 mg/m3 air, approximately 90% of absorbed 
epichlorohydrin 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% of the absorbed dose).  No unchanged 
epichlorohydrin was excreted via these routes.  The results were 
not affected by the position of the 13C-label, indicating that, 
if any 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 epichlorohydrin
was hydrolysed into 3-chloro-1,2-propanediol by the microsomal 
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-propanediol 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 epichlorohydrin 
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).  

6.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    A summary of the acute toxicity of epichlorohydrin for aquatic 
organisms and plants is presented in Table 2.  The subject of 
biodegradation has already been discussed in section 3.3.2. 


Table 2.  Acute aquatic toxicity
------------------------------------------------------------------------------------------------------
Organism   Description          T    pH   Hardness  Flow  Parameter   Concentration Reference
                                (°C)      (mgCaCO3/ or                (mg/litre)
                                          litre)    stat1
------------------------------------------------------------------------------------------------------
algae      blue algae           27   7.0            stat  8-day MIC2  6.0           Bringmann (1975)3
            (Microcystis 
            aeruginosa)

algae      green algae          27   7.0            stat  8-day MIC   5.4           Bringmann & Kühn
            (Scenedesmus                                                             (1977a)3 
            quadricauda)
                       
bacteria    Pseudomonas putida   25   7.0            stat  16-h MIC    55            Bringmann & Kühn
                                                                                    (1977a)3

protozoa    Entosiphon sulcatum  25   6.9            stat  72-h MIC    35            Bringmann
                                                                                    (1978)4,7

protozoa    Chilomonas           25   7.0            stat  72-h MIC    29            Bringmann & Kühn
            paramecium                                                               (1981)5,7

protozoa    Uronema parduczi     25   7.0            stat  72-h MIC    57            Bringmann & Kühn
                                                                                    (1981)6,7

crustacea  water flea           20-  7.6-           stat  24-h LC50   30            Bringmann & Kühn
            (Daphnia magna)      22   7.7                                           (1977b)8,14
------------------------------------------------------------------------------------------------------

Table 2.  (contd.)
------------------------------------------------------------------------------------------------------
Organism   Description          T    pH   Hardness  Flow  Parameter   Concentration Reference
                                (°C)      (mgCaCO3/ or                (mg/litre)
                                          litre     stat1
------------------------------------------------------------------------------------------------------
fish       goldfish             20   6-8            stat  24-h LC50   23            Bridié et al.
            (Carassius auratus)                                                      (1979a)9

fish       golden orfe               7.5            stat  48-h LC50   24            Juhnke & Lüdemann
            (Leuciscus idus)                                                         (1978)10,14

fish       zebra fish                7.5            stat  96-h LC50   30.5          Wellens
            (Brachydanio rero)                                                       (1982)11,14

fish       bluegill sunfish     23   7.6  55        stat  96-h LC50   35            Dawson et al.
            (Lepomis                                                                 (1977)12,14
            marcochirus)

fish       harlequin fish       20   7.2  20        flow  48-h LC50   36            Alabaster
            (Rasbora                                                                 (1969)14
            heteromorpha)

fish       tidewater silver-    20   7.9  55        stat  96-h LC50   18            Dawson et al.
           sides  (Menidia                                                           (1977)13,14
            beryllina)
------------------------------------------------------------------------------------------------------
Notes

  1 Flow through or static method.
  2 MIC = Minimum inhibitory concentration for cell multiplication.
  3 Growth was measured turbidimetrically, no analysis for epichlorohydrin was reported.
  4 Bactivorous, beta-mesosaprobic, flagellate.
  5 Saprozoic, flagellate.
  6 Bactivorous, holozoic, ciliate.
  7 Growth was measured by an electronic cell counter, no analysis for epichlorohydrin was reported. 
  8 Test water was oxygen saturated, hardness was 16° (German), LC0 was 20 mg/litre, LC100 was 
    44 mg/litre.
  9 6 fish per concentration, no aeration, analysis for epichlorohydrin by gas chromatography or by 
    total organic carbon analysis.
 10 Aeration, LC0 was 12 mg/litre, LC100 was 35 mg/litre.
 11 No aeration, LC0 was 26 mg/litre, LC100 was 31 mg/litre.
 12 Discontinuous aeration.
 13 Salt water species, continuous aeration, specific gravity of salt water was 1.018.
 14 No analysis for epichlorohydrin was reported.

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 epichlorohydrin 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 
epichlorohydrin
-------------------------------------------------------------------------
Species  Route       Vehicle  Parameter    Value        Reference
                              studied     
-------------------------------------------------------------------------
rat      oral        none     LD50         260          Lawrence et al.
                                           (mg/kg body  (1972)
                                           weight)

rat      inhalation  -        6-h LC50     1360         Laskin et al.
                                           (mg/m3)      (1980)

rat      inhalation  -        4-h LC50     2400         Grigorowa et al.
                                           (mg/m3)      (1974)

mouse    oral        none     LD50         236          Lawrence et al.
                                           (mg/kg body  (1972)
                                           weight)

mouse    inhalation  -        2-h LC50     3000         Grigorowa et al.
                                           (mg/m3)      (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 epichlorohydrin per kg body weight, 
orally or intraperitoneally, 3 - 7 times a week for 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 (1 at 40 
mg/kg and 1 at 80 mg/kg).  The most frequently observed haematollogical 
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 epichlorohydrin 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 LD50 
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 range.  
At 1280 mg/m3, the observed mortality rate was 5% compared with 
75% at 1395 mg/m3 (Laskin et al., 1980). 

    Twenty-four hours after a single 4-h inhalation exposure of 
rats to epichlorohydrin levels of 7 - 350 mg/m3, 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 (Szumskaja, 1971). 

    Slight histopathological liver changes were also found in mice 
after a 2-h inhalation exposure to a concentration of 1680 mg/m3 
(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 
epichlorohydrin concentration of 30 mg/m3 also produced signs of 
kidney and liver toxicity (Grigorowa et al., 1977).  When rats were 
exposed continuously to 0.2 mg/m3 for 98 days, no effects were 
observed.  At 2 mg/m3, an increase in the number of altered 
leukocytes was reported, while at 20 mg/m3, slight histopatho-
logical 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/m3, 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/m3.  The most pronounced effect was 
inflammation and degeneration of the epithelium in the nasal 
turbinates, with hyperplasia and squamous cell metaplasia at 377 
mg/m3.  At concentrations of 211 mg/m3 or more, body weight 
gain was reduced.  At a concentration of 377 mg/m3, the kidney 
tubuli were dilated and the tubular epithelial cells were swollen, 
proteinuria was also found.  Other changes at 377 mg/m3 were:  
leukocytosis, liver congestion, oedema, 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 epichlorohydrin concentrations in air of 19, 94, or 189 mg/m3.  
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/m3, body weight gain was reduced and 
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 epichlorohydrin 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 epichloro-
hydrin in cottonseed oil (Lawrence et al., 1972). 

    When 15 guinea-pigs were treated dermally with a 5% solution of 
epichlorohydrin 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 epichloro-
hydrin 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 epichlorohydrin in the 
drinking-water at concentrations of 0, 375, 750, and 1500 mg/litre 
over a period of 81 weeks.  At intervals, the 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 mg 
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 epichlorohydrin per kg body weight in distilled water, by 
stomach tube, 5 times per week for 104 weeks.  Gross and histo-
pathological studies were carried out on all animals; haemotological
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 epithelium 
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/m3 air.  
The controls 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/m3 air and in week 60 
at 113 mg/m3 air.  After week 40, a reduced body weight gain was 
seen at 113 mg/m3 air.  In all cases, severe lung congestion, 
bronchiolectasis, and pneumonia were observed.  At the highest 
concentration, 1 papilloma was detected in the nasal cavity after 
57 weeks and 1 squamous cell carcinoma after 107 weeks.  At 38 mg/m3, 
1 pituitary adenoma was found compared with two at 113 mg/m3 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 epichlorohydrin at 38 mg/m3, and in 65% of the 
rats exposed to 113 mg/m3 (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 concentration of 
378 mg/m3 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 exposure, 17 exposed rats showed 15 squamous cell 
carcinomas and 2 papillomas of the nasal epithelium.  One bronchial 
papilloma 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/HA 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 C3H mice was painted three times a week with "one 
brushful" of undiluted epichlorohydrin on the clipped 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 ICR/HA 
Swiss mice received a single dose of 2.0 mg of epichlorohydrin in 
acetone applied to the skin, followed 2 weeks later by applications 
of 2.5 mg 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 epichlorohydrin (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

    Epichlorohydrin induced antifertility effects in male rats 
resembling those induced by alpha-chlorohydrin 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
sible 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 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 epichlorohydrin vapour 
at concentrations of 0, 19.7, 93.4, and 189.0 mg/m3 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). 


Table 4.  Mutagenic tests with positive resultsa
-------------------------------------------------------------------------------------------------
     Test description        System description                      Reference
                        Species              Strain                                              
-------------------------------------------------------------------------------------------------
  G  eceriferum         plants               barley                  Lundqvist et al. (1968)
     mutants
  E
     reverse            bacteria              Escherichia coli        Kline et al. (1982)
  N  mutations                               WP2 uvrA
  
  E  reverse muta-                            Salmonella typhimurium  Shram et al. (1976)
     tions (base-pair                        TA1535, TA100, GA46     Laumbach et al. (1977)
     substitution,                                                   Bridges (1978)
     frame-shifts)                                                   Andersen et al. (1978)b
                                                                     Stolzenberg & Hine (1979)b 
                                                                     Voogd et al. (1981)b
  M                                                                                              
     reverse mutations  bacteria in mice      Salmonella typhimurium  Shram et al. (1976)
  U  in host-           (intraperitoneal,    TA1535, TA100, G46,     Kilian et al. (1978)
     mediated assay     urine) and men       TA1950
  T                     (urine)         
     forward mutations  bacteria              Klebsiella pneumoniae   Knaap et al. (1982)     
  A  reverse mutations  fungi                 Neurospora crassa       Kolmark & Giles (1955)  
                                                                                                 
  T  Reverse mutations,                       Saccharomyces cere-     Vashihat et al. (1980)   
     gene conversion,                         visiae  D7                                      
  I  miotic crossing over                                                                               
     forward mutations                        Schizosaccharomyces                             
  O                                           pombe  Pl               Migliore et al. (1982)b  
     sex-linked         insects               Drosophila melano-      Rossi et al. (1983a,b) 
  N  recessive                                gaster                  Knaap et al. (1982)     
     lethals                                                                                  
  S  forward mutations  mammalian cells      mouse lymphoma cells    Knaap et al. (1982)     
     exposure  in utero  mammalian cells      Syrian hamster          Shram et al. (1981b)     
     forward mutations                       embryonic cells                                 
-------------------------------------------------------------------------------------------------

Table 4.  (contd.)                                
---------------------------------------------------------------------------------------------------------
     Test description                 System description                        Reference
                                Species                 Strain                                              
---------------------------------------------------------------------------------------------------------
  C
  H  chromosome aberrations     plants                   Vicia faba  root tip    Loveless (1951)
  R  chromosome breaks          mammalian cells         Chinese hamster cells   Sasaki et al. (1980)
  O  chromatid and chromosome                           human lymphocytes       Kucherova et al. (1976)
  M  breaks
  O  chromatid and chromosome                           human lymphocytes       Norppa et al. (1981)
  S  breaks and sister
  O  chromatid exchanges
  M  sister chromatid exchanges                         human lymphocytes       White (1980)b
  E  sister chromatid exchanges                         human lymphocytes       Carbone et al. (1981)b
     chromosome aberrations     mammalian cells,        mouse bone marrow cells Shram et al. (1976)
  D                              in vivo intraperitoneal and rat lymphocytes     Shram et al. (1981a)
  A                             or inhalation exposure
  M  aberrations and             in vivo inhalation      mouse spermatogonia     Shram et al. (1981a)
  A  morphological anomalies    exposure                and sperm
  G
  E
---------------------------------------------------------------------------------------------------------
D R  Rec-assay                  bacteria                 Bacillus subtilis       Kada (1981)**
  E  Pol-assay                                           Escherichia coli        Rosenkranz (1981)
N P
  A
A I
  R
---------------------------------------------------------------------------------------------------------
a  Epichlorohydrin was also tested in the International Collaborative Program on short-term test for
   carcinogenicity (De Serres & Ashby, 1980).  The consensus data were, that epichlorohydrin:  (a) was
   positive in all bacterial mutagenicity assays, in all microbial DNA damage repair assays, and in all
   yeast assays with only two exceptions, i.e., it was questionable in one  Salmonella assay and
   negative in one Rec assay; (b) increased unscheduled DNA synthesis (two out of three assays) and
   sister chromatid exchange, and induced point mutations in mammalian cells  in vitro; (c) was
   generally negative  in vivo , except in the sister chromatid exchange test.
b  Metabolic activation abolished or decreased the mutagenic activity and increased the rate
   of survival.

7.5.  Teratogenicity

    Female rats received orally 0, 40, 80, or 160 mg and female 
mice 0, 80, 120, or 160 mg of epichlorohydrin 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/m3 air for 7 h/day, between 
the 6th and the 15th or 18th day of pregnancy (John et al., 1983a). 

8.  EFFECTS ON MAN

8.1.  Controlled Studies

    In the USSR, 5 human volunteers showed significant electro-
encephalogram changes in the voltage of spikes of the alpha rhythm, 
when they were exposed to epichlorohydrin vapour at a concentration 
of 0.3 mg/m3 air for up to 18 min (Fomin, 1966). 

    Burning of the eyes and nasal mucosa was reported to occur at 
an epichlorohydrin vapour concentration of 76 mg/m3 air, while 
throat irritation, which lasted for 48 h, was experienced at 151 
mg/m3 (Wexler, 1971). 

    The sensitization capacity of epichlorohydrin was tested on 1 
volunteer.  After an occluded patch test of 2 days with 0.1 - 1.0% 
solutions of epichlorohydrin in ethanol, a late reaction developed 
after 8 - 11 days.  After a challenge exposure of 2 days, erythema 
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, epichloro-
hydrin 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% epichlorohydrin 
(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), leukaemia 
(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 1 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 isopropyl 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 epichlorohydrin exposure in a plant manufacturing 
epoxy resins and glycerol.  The time-weighted average exposures to 
epichlorohydrin ranged from below 3.8 mg/m3 air to 18.9 mg/m3.  
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). 

    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 epichlorohydrin, epoxy resins, 
glycerine, and other chemicals derived from epichlorohydrin.  
Personal exposures in 1977-78 were at, or below, a time-weighted-
average of 3.78 mg/m3.  Earlier exposures occasionally reached 
levels high enough to be irritating (38 - 95 mg/m3).  The mean 
duration of the exposure to epichlorohydrin 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 et 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 
epichlorohydrin-producing plant in Czechoslovakia, who were exposed 
for 2 years to concentrations between 0.5 and 5.0 mg/m3 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/m3 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/m3 air, significant clastogenic effects were no longer found.  
The clastogenic effect of epichlorohydrin 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/m3 
air, showed increases in aberration rates compared with 75 pre-
employment 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/m3 air, no significant increases in 
aberrations were found compared with a control group of 63 pre-
employment individuals (Barna-Lloyd et al., 1979). 

8.3.4.  Effects on reproduction

    The fertility status of 64 glycerol-workers, in the USA, 
exposed to epichlorohydrin, allyl chloride, and 1.3-dichloro-
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 al., 
1980).  A similar negative result for the sperm count and hormone 
levels 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/m3 air.  The rate of non-participating 
employees was high in both plants and amounted to a total of 172 
workers (Milby et al., 1981). 

9.  EVALUATION OF HEALTH RISKS FOR MAN

    On the basis of observations following short-term exposures to 
epichlorohydrin, human beings are likely to begin to experience eye 
and upper respiratory tract irritation at concentrations of 
approximately 76 mg/m3 (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/m3, 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. 

    Epichlorohydrin can sensitize the skin of human beings (Jirasek 
& Kalénsky, 1962; Von Ippen & Mathies, 1970; Fregert & Gruvberger, 
1970; Beck & King, 1983). 

    Observations on laboratory animals have indicated that short-
term exposures to epichlorohydrin 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 epichlorohydrin 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 mg/m3 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 mutagenic effects observed in several short-term 
test systems, it can be concluded that epichlorohydrin could be 
carcinogenic for human beings.  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.  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). 

10.  SOME CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

10.1.  Occupational Exposure

    Legal maximum allowable concentrationsa range from 1 mg/m3 
(0.25 ppm, ceiling value) in the USSR and 2 mg/m3 (0.5 ppm, TWA) 
in Sweden to 4 mg/m3 (1 ppm, TWA) and a peak value of 19 mg/m3 
(5 ppm) in the Netherlands and 8 mg/m3 (2 ppm, TWA) in the United 
Kingdom.  In the USA, the American Conference of Governmental 
Industrial Hygienists recommends 10 mg/m3 (2 ppm, TWA).  Short-term 
exposure limits are 20 mg/m3 (5 ppm) in the United Kingdom and 
4 mg/m3 (1 ppm) in Sweden.  In most regulations and guidelines, 
warnings are given concerning the carcinogenic nature of, and the 
possibility of skin penetration by, epichlorohydrin (IRPTC, 1984). 

10.2.  Ambient Air Levels

    In the USSR, the maximum allowable concentration is an average 
of 0.2 mg/m3 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 epichlorohydrin 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). 




---------------------------------------------------------------------------
a  Values quoted in national lists.

10.6.  Storage and Transport

    The United Nations Committee of Experts on the Transport of 
Dangerous Goods (1984) qualifies epichlorohydrin 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: 

FIGURE 1

    The Inter-Governmental Maritime Consultative Organizationa 
(1981) also qualifies epichlorohydrin as a toxic substance and 
recommends packing, stowage, and labelling method for maritime 
transport.  The recommended labels are: 

FIGURE 2

-------------------------------------------------------------------------
a  Now the International Maritime Organization.

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    See Also:
       Toxicological Abbreviations
       Epichlorohydrin (HSG 8, 1987)
       Epichlorohydrin (ICSC)
       Epichlorohydrin (IARC Summary & Evaluation, Volume 71, 1999)