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

    World Health Orgnization
    Geneva, 1985

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     2.1. Identity
     2.2. Chemical and physical properties of ethylene oxide
     2.3. Analytical methods


     3.1. Production, uses, disposal of wastes
          3.1.1. Production levels and processes
          3.1.2. Uses
          3.1.3. Disposal of wastes
     3.2. Transport and fate in the environment


     4.1. Occurrence in the environment
     4.2. General population exposure
          4.2.1. Exposure via food and tobacco
          4.2.2. Exposure via medical equipment
     4.3. Occupational exposure


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



     7.1. Acute exposures
          7.1.1. Oral, intravenous, and inhalation studies
          7.1.2. Acute effects on eyes and skin
     7.2. Short-term studies
          7.2.1. Inhalation exposure
          7.2.2. Oral exposure
     7.3. Long-term inhalation studies
     7.4. Carcinogenicity
          7.4.1. Inhalation exposure
          7.4.2. Oral exposure
          7.4.3. Subcutaneous exposure
          7.4.4. Dermal exposure
     7.5. Mutagenicity and related end-points
     7.6. Effects on reproduction
     7.7. Teratogenicity


     8.1. Exposure of the skin and eyes
     8.2. Sensitization
     8.3. Accidental inhalation exposure
     8.4. Other accidental exposures
     8.5. Occupational inhalation exposure
     8.6. Mortality studies
     8.7. Mutagenicity and related end-points
     8.8. Effects on reproduction







Dr R. Bruce, Environmental and Criteria Assessment Office, US
   Environmental Protection Agency, Research Triangle Park,
   North Carolina, USA  (Rapporteur)

Mr T.P. Bwititi, Hazardous Substances and Articles Department,
   Ministry of Health, Harare, Zimbabwe

Dr B. Gilbert, CODETEC, University City, Campinas, Brazil

Prof P. Grasso, Robens Institute, University of Surrey,
   Guildford, Surrey, United Kingdom

Prof M. Ikeda, Department of Environmental Health, Tohoku
   University School of Medicine, Sendai, Japan  (Chairman)

Dr T. Lewis, US National Institute for Occupational Safety and
   Health, Cincinnati, Ohio, USA

Dr B. Malek, Prague Hygiene Station, Department of Industrial
   Hygiene, Prague, Czechoslovakia

Prof N.C. Nayak, Department of Pathology, All-India Institute
   of Medical Sciences, New Delhi, India

Prof M. Noweir, Occupational Health Research Centre, High
   Institute of Public Health, Alexandria, Egypt  (Vice-

Dr G.J. Van Esch, Bilthoven, The Netherlands

 Members of Other Organizations

Dr A. Berlin, Health and Safety Directorate, Commission of the
   European Communities, Luxembourg

Dr R. Steger, International Commission on Occupational Health,
   Geneva, Switzerland

Mme M.Th. Van der Venne, Health and Safety Directorate,
   Commission of the European Communities, Luxembourg


Dr E. Longstaff (European Chemical Industry Ecology and
   Toxicology Centre), ICI Central Toxicology Laboratory,
   Genetic Toxicology Section, Macclesfield, United Kingdom

Dr M. Martens, Institute of Hygiene and Epidemiology, Division
   of Toxicology, Brussels, Belgium

 Observers  (contd.) 

Dr W. Moens, Institute of Hygiene and Epidemiology, Division
   of Toxicology, Brussels, Belgium

Dr M. Wooder (European Chemical Industry Ecology and
   Toxicology Centre), Shell International Petroleum Company,
   Health, Safety and Environment Division, London, United


Prof F. Valic, Andrija Stampar School of Public Health,
   University of Zagreb, Zagreb, Yugoslavia  (Secretary)a

Dr T. Vermeire, National Institute of Public Health and
   Environmental Hygiene, Bilthoven, The Netherlands  (Temporary 

Mr J. Wilbourn, International Agency for Research on Cancer,
   Lyons, France

a  IPCS Consultant.


    Although only key references essential for the evaluation of 
the risks for human health and the environment are cited, this 
document is based on a comprehensive search of the available, 
original scientific literature, while valuable information has also 
been obtained from various reviews. 

    A detailed data profile on ethylene oxide can be obtained from 
the International Register of Potentially Toxic Chemicals 
(UNEP/IRPTC, Palais des Nations, CH-1211 Geneva 10, Switzerland, 
telephone number 988400 - 985850). 

    The document focuses on describing and evaluating the risks of 
ethylene oxide for human health and the environment. 

    Every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors, which may have occurred, 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. 


    The WHO Task Group for the Environmental Health Criteria for 
Ethylene Oxide met at the Institute of Hygiene and Epidemiology, in 
Brussels, Belgium, on 21 - 26 October 1985.  Dr G. Thiers, who 
opened the meeting, welcomed the participants on behalf of the host 
government, and Dr F. Valic welcomed them 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 ethylene 

    The efforts of DR T. VERMEIRE, of the NATIONAL INSTITUTE OF 
Netherlands, who was 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. 


    Ethylene oxide is a colourless, highly reactive, and flammable 
gas at room temperature and ambient pressure.  The current world 
production is greater than 5.5 million tonnes.  Its major use is as 
an intermediate in the production of various chemicals.  Since 
ethylene oxide is a reactive epoxide and potent biocide, a small 
quantity (less than 1%) is used for the fumigation and 
sterilization of foodstuffs and medical equipment.  Because of its 
high odour threshold (900 - 1260 mg/m3), sensory recognition does 
not offer adequate warning of a health hazard. 

    Detection limits of 0.024 mg/m3, 2 mg/litre, and 0.15 mg/kg 
have been reported for gas chromatographic determinations in air, 
water, and food, respectively.  A total loss to the atmosphere of 
1 - 2% of production occurs during its manufacture and use.  Its 
removal from the atmosphere and neutral water is slow, but it is 
more rapid under acidic or basic catalysis.  Aerobic biodegradation 
is slow. 

    Human exposure mainly occurs through inhalation in 
sterilization facilities and in production plants.  In 
sterilization facilities, 8-h time-weighted average levels have 
usually been below 36 mg/m3, with short-term exposures of about 
100 mg/m3, and peak levels of up to 1800 mg/m3.  In production 
plants, the time-weighted average has usually been below 4 mg/m3.  
Ambient levels at a distance from point sources of emission have 
been estimated to be below the limit of detection. 

    Exposure to residues of ethylene oxide or its reaction 
products, halohydrins and ethylene glycol, also occurs from 
fumigated foods, pharmaceutical products, and sterilized medical 
equipment.  2-Chloroethanol levels as high as several g/kg have 
been measured in food and levels of several hundred mg/kg in 
medical equipment. 

    Ethylene oxide is not expected to bioaccumulate in the 
environment.  Fish are the most susceptible aquatic organisms.  An 
LC50 of 90 mg/litre was observed for goldfish exposed for 24 h.  
2-Chloroethanol, a degradation product in saline water, is equally 
toxic but, 1,2-ethanediol, a major degradation product, is much 
less toxic. 

    When inhaled, ethylene oxide is readily absorbed, distributed 
throughout the body, and rapidly metabolized.  Accordingly, most 
organs receive equivalent doses of the chemical and its 
metabolites.  The degree of alkylation of proteins and DNA varies 
slightly between the different organs and blood.  In man and 
rodents, the half-life of the compound in tissues has been 
estimated to be 9 - 10 min.  Two metabolic pathways have been 
identified including hydrolysis to 1,2-ethanediol and conjugation 
with glutathione.  Excretion is primarily via the urine. 

    Ethylene oxide is moderately toxic for mammals (the LD50 for 
the rat is 280 - 365 mg/kg body weight; the 4-h LC50 is 2630 
mg/m3).  Both experimental animal and human data show that aqueous 
solutions of ethylene oxide are irritating for the skin and eyes; 
the irritant effects of ethylene oxide vapour or residues in 
medical equipment on the eyes and the respiratory tract have also 
been observed.  These effects are often delayed.  Severe skin 
irritation is characterized by the formation of vesicles.  A 
concentration of 10 mg/litre produced mild irritation of the human 
skin; a concentration of 500 g/litre was most injurious to the 
human skin.  Allergic contact dermatitis has been reported; 
systemic immunologically mediated allergy is considered rare.  
Respiratory tract irritation increases with inhaled vapour 
concentration and may result in severe life-threatening pulmonary 
disease.  Repeated exposure (2 - 8 weeks) to ethylene oxide vapour 
at or above 900 mg/m3 produced sensory and motor neurological 
impairment and may result in a peripheral neuropathy.  In animals, 
the latter was often accompanied by muscular atrophy.  Lesions in 
the medulla oblongata of monkeys, following 2 years of intermittent 
exposure (7 h/day, 5 days/week) to 90 and 180 mg/m3 indicated 
neuropathy in the brain, which may be related to the neuropathies 
observed in man and other animal species.  Cardiovascular collapse 
and renal failure have been attributed to residues of ethylene 
oxide in medical equipment. 

    Ethylene oxide alkylates DNA and is mutagenic for plants, 
microorganisms, insects, and mammals.  Cytogenetic studies on man 
have shown dose-related increased frequencies of both sister 
chromatid exchanges (SCEs) and chromosomal aberrations; in one 
study, SCEs developed following daily exposure for less than 5 min 
per day. 

    The evidence that ethylene oxide is a reproductive toxin is 
less conclusive.  Where fetal developmental effects have occurred, 
the doses of ethylene oxide approached or equalled those producing 
maternal toxicity.  To date, impaired male reproductive function in 
animals has been demonstrated only at concentrations of 90 mg/m3 or 
more in long-term intermittent exposures or at higher air 
concentrations for brief exposures.  In pregnant women, the results 
of one study suggest that occupational exposure estimated to be an 
8-h time-weighted average of 0.18 - 0.90 mg/m3, with peak 
concentrations up to 450 mg/m3, was associated with spontaneous 
abortions.  However, limited exposure data prevents the 
establishment of a relationship between abortion rates and exposure 

    Ethylene oxide is carcinogenic for animals when administered by 
the intragastric, subcutaneous injection, and inhalation routes of 
exposure.  In man, 2 studies have shown an association between 
ethylene oxide exposure and an excess risk of cancer, but both 
studies have limitations.  Airborne concentrations of ethylene 
oxide in the 2 studies were reported to be time-weighted averages 
of 36 ± 18 mg/m3 and 10 - 50 mg/m3, with occasional brief exposures 
in excess of the odour threshold (900 - 1260 mg/m3). 

    Taking into account available data concerning the alkylating 
nature of ethylene oxide, the demonstration of DNA adducts, and the 
overwhelmingly positive  in vivo responses in mutagenic and 
clastogenic assays, the reproducible positive carcinogenic findings 
in animals, and the epidemiological findings suggesting an increase 
in the incidence of human cancer, ethylene oxide should be 
considered as a probable human carcinogen, and its levels in the 
environment should be kept as low as feasible. 


2.1.  Identity

Structural formula:                         O
                                           / \
                                          /   \
                                         /     \
                                        |       |
                                        |       |
                                        H       H

Molecular formula:            C2H4O

Abbreviation:                 EO, ETO

Common synonyms:              dihydrooxirene; dimethylene oxide;
                              1,2-epoxyethane; ethene oxide; 
                              oxane; alpha, beta-oxidoethane; 
                              oxirane (CAS and IUPAC name)

Common trade names:           Anprolene; Melgas; Merpal; Sterigas
                              P (pure products); Carboxide;
                              Cartox; Etox; Oxyfume 20; Oxyfume
                              30; Sterigas 90/10; Steroxide 20;
                              T-gas (formulations with carbon
                              dioxide); Oxyfume 12; Sterigas
                              12/88; Steroxide 12/88 (formulations
                              with fluorocarbons); Etoxiat

CAS registry number:          75-21-8

RTECS registry number:        KX 2450000

2.2.  Chemical and Physical Properties of Ethylene Oxide

    Ethylene oxide is a gas at room temperature and normal 
atmospheric pressure.  It condenses to a liquid at 10 °C.  The 
vapour is highly flammable and subject to explosive decomposition.  
The liquid is stable to common detonating agents, but may 
polymerize violently after initiation by acids, bases, or heat.  
Polymerization is catalysed by metal chlorides and oxides.  
Ethylene oxide is very reactive in both the liquid and vapour 
phase.  Ring opening readily occurs with release of energy, 
particularly in reactions with nucleophiles such as water, 
alcohols, halides, amines, and sulfhydryl compounds. 

    Some physical and chemical data on ethylene oxide are given in 
Table 1. 

Table 1.  Some physical and chemical data on ethylene oxide
Physical state                  gas

Colour                          colourless

Odour                           ethereal

Odour threshold                 470 mg/m3 for perception and
                                900 - 1260 mg/m3 for recognitiona

Relative molecular mass         44.05

Melting point                   -111 °C

Boiling point                   10.4 °C

Water solubility                infinitely soluble

log  n-Octanol-water partition   -0.30

Density                         0.87 g/ml, 20 °C

Relative vapour density         1.5

Vapour pressure                 146 kPa (1095 mm Hg), 20 °C

Flash point                     < -18 °C (open-cup)

Flammable limits                3 - 100% by volume
a From:  Jacobson et al. (1956) and Hellman & Small (1974).

     Conversion factor

    ethylene oxide      1 ppm = 1.80 mg/m3 air at 25 °C
                                and 101.3 kPa (760 mm Hg)

2.3.  Analytical Methods

    Methods for the sampling and determination of ethylene oxide in 
air, water, food, plastic materials, blood, and urine are 
summarized in Table 2.  Some methods are also suitable for 
measuring important reaction products such as 2-chloroethanol 
(ethylene chlorohydrin) and 1,2-ethanediol (monoethylene glycol). 

Table 2.  Sampling, preparation, analysis
Medium    Sampling method   Analytical method      Detection limit  Comments                   Reference
Air       sampling on       gas chromatography     0.024 mg/m3      sample size 1 litre;       US Department of
          charcoal;         with electron capture                   suitable for personal      Labor (1984)
          desorption with   detection after der-                    and area monitoring
          carbon disulfide  ivatization with
                            hydrogen bromide

Air       sampling on       gas chromatography     0.27 mg/m3       sample size < 10           Quazi & Ketcham
          charcoal;         with flame ionization                   litre; suitable for        (1977)
          desorption with   detection                               personal and area
          carbon disulfide                                          monitoring

Air       trapping in       gas chromatography     1.8 mg/m3        sample size 12 - 99        Romano & Renner
          dilute sulfuric   with flame ionization  (99-litre        litre; suitable for        (1979)
          acid using        detection              sample)          personal and area
          a microimpinger                                           monitoring

Air                         infrared spectro-      1.8 mg/m3        direct analysis; suitable  Korpela et al.
                            scopy                                   for instantaneous and      (1983)
                                                                    continuous area monitor-
                                                                    ing; limited specificity

Air                         colorimetric direct    18 mg/m3         simple, cheap method       Mouilleseaux et
                            reading indicator                       giving a good correlation  al. (1983)
                            tubes                                   with gas chromatographic
                                                                    analysis; suitable for
                                                                    short-term area measure-
                                                                    ments; limited specificity

Water                       gas chromatography     2 mg/litre       direct analysis; also      Hartman & Bowman
                            with flame ionization                   suitable for measuring     (1977)
                            detection                               main reaction products;
                                                                    drugs and formulations
                                                                    can be analysed after
                                                                    extraction with water

Table 2.  (contd.)
Medium    Sampling method   Analytical method      Detection limit  Comments                   Reference
Food      extraction by     gas chromatography     0.15 mg/kg       sample size 5 - 30 g;      Scudamore &
          5:1 acetone-      with flame ionization  wet weight       also suitable for meas-    Heuser (1971)
          water (by vol-    detection                               uring reaction products
          ume) for 24 h
Food      thermal           colorimetry using      0.7 mg/kg        simple, cheap method;      Rajendran &
          desorption in an  paper strips with      wet weight       headspace analysis;        Muthu (1981)
          airtight bottle   sodium sulfite and                      sample size 75 g; other
          at 40 °C for      thymol blue-phenol-                     alkene oxides and alde-
          30 min            phthalein indicator                     hydes may interfere

Plastic   thermal desorp-   gas chromatography     0.1 mg/kg        headspace analysis         Romano et al.
material  tion in an air-   with flame ionization                                              (1973)
          tight vial at     detection
          100°C for 15 min

Blood,                      gas chromatography                      direct analysis after      Martis et al.
Urine                       with flame ionization                   centrifugation in air-     (1982)
                            detection                               tight vials; also suit-
                                                                    able for measuring
    Instantaneous gas chromatographic measurements of ethylene 
oxide in air can be performed after taking grab samples 
(Mouilleseaux et al., 1983).  The rather complex gas 
chromatographic procedure of Scudamore & Heuser (1971) for the 
determination of ethylene oxide and reaction products in food could 
be replaced by a simpler procedure, using temperature programming 
(Pfeilsticker et al., 1975).  Titrimetric or colorimetric methods 
are available, but these methods are not specific, are often 
subject to systematic errors, and are not applicable for continuous 

    In studies on mice and rats, the degree of alkylation of amino 
acids, particulary of histidine, in haemoglobin can be used for 
monitoring the tissue doses of ethylene oxide.  Assuming even 
distribution, tissue dose is defined as the integral of the 
calculated concentration of free ethylene oxide in the tissues over 
a specified period of time (Ehrenberg et al., 1974; Osterman-Golkar 
et al., 1983; Segerbäck, 1983).  A sensitive method, based on 
derivatization with heptafluorobutyric anhydride followed by gas 
chromatography and mass spectrometry was developed to measure the 
amount of N3-(2-hydroxyethyl)histidine in haemoglobin (Calleman et 
al., 1978).  This method has a detection limit of 0.004 µg/g 
haemoglobin.  It was used in industrial workers by Calleman et al. 
(1978) and van Sittert (1985).  Human haemoglobin has a life span 
of about 4 months and, therefore, may integrate the dose of 
ethylene oxide over a long period (Osterman-Golkar et al., 1976).  
The resolving power of detection of haemoglobin alkylation due to 
exposure to ethylene oxide appears to be limited by the occurrence 
of background alkylations.  It was estimated that exposures of less 
than 9 mg/m3 could be masked by these background alkylations 
(Osterman-Golkar, 1983).  More validation work in human beings is 
still needed. 


3.1.  Production, Uses, Disposal of Wastes

3.1.1.  Production levels and processes

    In 1978, world production of ethylene oxide was estimated to be 
4540 kilotonnes (Clayton & Clayton, 1981).  The USA production, 
which roughly accounted for half of this figure, rose from 1750 
kilotonnes in 1970 to 2400 kilotonnes in 1980 (USITC, 1971, 1981).  
For 1983, USA production was estimated to be 2540 kilotonnes 
(Webber, 1984).  In western Europe, 865 kilotonnes were produced in 
1972 (Glaser, 1979), while for 1981, production was estimated to be 
1370 kilotonnes (IARC, 1985).  In Japan, 470 kilotonnes were 
produced in 1982 (IARC, 1985).  Ethylene oxide is also produced in 
Australia, Brazil, Bulgaria, Canada, China, Czechoslovakia, the 
German Democratic Republic, India, the Republic of Korea, Mexico, 
Poland, Romania, and the USSR (IARC, 1985).  From the above data, 
it can be derived that the current world production will be far 
above 5500 kilotonnes per year. 

    Ethylene oxide is chiefly produced by the oxidation of ethene 
with air or oxygen in the presence of a silver oxide catalyst.  
This process has virtually replaced the chlorohydrin process in 
which 2-chloroethanol (ethylene chlorohydrin) reacts with potassium 
hydroxide or calcium oxide.  Common impurities in the oxidation 
process are water, acetic acid, acetaldehyde, and organic and 
inorganic chlorides (WHO, 1978).  Common impurities in the 
chlorohydrin process are vinyl chloride, 1,2-dichloroethane, 
chloroethane, and ethylene chlorohydrin. 

3.1.2.  Uses

    Virtually all the ethylene oxide produced is used as an 
intermediate in the production of various chemicals.  In order of 
importance in the USA, the principal chemicals are:  the antifreeze 
1,2-ethanediol; polyethylene terephthalate polyester for fibres, 
films, and bottles; non-ionic surface active agents; glycol ethers; 
ethanolamines; and choline.  A small fraction of the total 
consumption (about 1% in the USA in 1976) was used as an 
antimicrobial sterilant or as an insecticidal fumigant (WHO, 1978; 
Glaser, 1979).  Less than 0.02% of this production (500 000 kg) was 
used for sterilization in hospitals (Glaser, 1979).  In Belgium, an 
estimated 0.07% of the total consumption of ethylene oxide (120 000 
kg) was used in the health care and medical products industries in 
1980 (Wolfs et al., 1983). 

3.1.3.  Disposal of wastes

    Escape through air vents during production and sterilization 
appears to be the most important source of release of ethylene 
oxide into the environment.  The waste gas can be removed from the 
air by scrubbing.  Emission control of liquid wastes mainly occurs 
by incineration in liquid-burning hazardous waste incinerators.  
Process waters for the manufacture and use of ethylene oxide are a 
minor problem with respect to waste management.  Conventional 
effluent water treatment including biological treatment is reported 
to be sufficient.  No specific solid wastes are associated with the 
manufacture of ethylene oxide (Bogyo et al., 1980). 

3.2.  Transport and Fate in the Environment

    The main pathway of entry of ethylene oxide into the 
environment is through its escape into the atmosphere due to 
evaporation and with vented gases during production, handling, 
storage, transport, and use.  Most of the ethylene oxide applied as 
a sterilant or fumigant will enter the atmosphere (Bogyo et al., 
1980).  In the USA, production losses were estimated at 13 kg per 
tonne of ethylene oxide produced by catalytic oxidation.  
Sterilization and fumigation processes were estimated to account 
for a loss of 9 kg per tonne of ethylene oxide produced or 
approximately 1% of the total consumption (WHO, 1978).  In 1980, 
this would have meant a combined loss of 53 kilotonnes of ethylene 
oxide into the atmosphere in the USA, which is approximately 2% of 
the total production in the USA. 

    At ambient levels, ethylene oxide will be removed from the 
atmosphere via oxidation by hydroxyl radicals.  On the basis of a 
theoretical rate constant for this reaction, the atmospheric 
residence time of ethylene oxide was estimated to be 5.8 days 
(Cupitt, 1980).  However, experimental data have shown the 
residence time to be 100 - 215 days, depending on the hydroxyl 
radical concentration and the ambient temperature (US EPA, 1985).  
Because of its high water solubility, ethylene oxide levels in air 
will also be reduced through washout by rain (Conway et al., 1983).  
The photochemical reactivity of ethylene oxide, in terms of its 
ozone-forming ability, is low (Joshi et al., 1982).  Evaporation 
from water is a significant removal process.  Under specific 
conditions, Conway et al. (1983) found a half-life of 1 h for the 
evaporation of ethylene oxide from water.  In the environment, 
chemical degradation in water through ionic reactions appears to be 
comparatively slow.  In neutral, fresh water at 25 °C, ethylene 
oxide is broken down to form 1,2-ethanediol with a half-life of 
14 days (Conway et al., 1983).  At 0 °C, the half-life is 309 days.  
The reaction is acid- and base-catalysed (Virtanen, 1963).  In the 
presence of halide ions, 2-haloethanol will also be formed.  In 
neutral water of 3% salinity, at 25 °C, 77% of ethylene oxide was 
found to react to form 1,2-ethanediol and 23%, to form 2-
chloroethanol with a half-life of 9 days (Conway et al., 1983). 

    Ethylene oxide and its possible metabolites can be biodegraded 
slowly by aerobic microorganisms.  Biological oxygen demands of 3 - 
5% and 52% of the theoretical oxygen demand were determined for 
ethylene oxide after 5 and 20 days, respectively, using a domestic 
sewage seed (Bridié et al., 1979b; Conway et al., 1983). 


4.1.  Occurrence in the Environment

    No data are available concerning levels of ethylene oxide in 
air, water, or soil, following emission from production plants, and 
there are no data indicating that ethylene oxide occurs as a 
natural product.  Most of the ethylene oxide used for fumigation or 
sterilization finally enters the environment, mainly the air.  
Uncontrolled emission of ethylene oxide from a hospital 
sterilization chamber led to high levels of the sterilant in the 
immediate surroundings.  Concentrations of between 7700 and 12 000 
mg/m3 were measured, 2 - 3 m from an exhaust pipe on the outside 
wall (Dunkelberg & Hartmetz, 1977). 

4.2.  General Population Exposure

4.2.1.  Exposure via food and tobacco

    Residue levels, after fumigation or sterilization using 
ethylene oxide, depend on a number of factors, such as the 
concentration of ethylene oxide, the composition of the gas, 
temperature, aeration, and storage conditions after treatment, 
the type of commodity and its moisture and lipid content, pH, 
permeability, particle size, and packaging.  Absorbed ethylene 
oxide disappears rapidly.  In a variety of commodities, 
concentrations between 32 and 7000 mg/kg wet weight, found 1 h 
after treatment, dropped to below 1 mg/kg within 14 days of 
storage, at ambient conditions.  However, sealed storage or storage 
at low temperatures will impede desorption considerably (Scudamore 
& Heuser, 1971).  In spices, ethylene oxide at concentrations of 
53 - 116 mg/kg wet weight, measured 2 days after fumigation, fell 
to less than 25 mg/kg within another 24 days (Gerhardt & Ladd 
Effio, 1983). 

    Ethylene oxide will react with chloride and bromide ions in 
commodities to form 2-chloroethanol and 2-bromoethanol, 
respectively.  This reaction can continue after treatment.  Levels 
of 2-chloroethanol of up to several thousands of mg/kg wet weight 
have been measured, depending on, among other factors, the chloride 
content and pH of the commodity, and the concentration of ethylene 
oxide (Wesley et al., 1965; Ragelis et al., 1968; Buquet & Manchon, 
1970; Scudamore & Heuser, 1971; Gerhardt & Ladd Effio, 1983).  
Under unfavourable (e.g., air-tight) conditions, 2-chloroethanol 
can persist much longer than residues of ethylene oxide, even 
longer than one year after treatment.  2-Chloroethanol will 
disappear rapidly from freely-aerated and finely-divided 
commodities.  However, 2-bromoethanol decomposes slowly (Scudamore 
& Heuser, 1971; Stijve et al., 1976). 

    The formation of 1,2-ethanediol (monoethylene glycol) and 
2,2'oxybisethanol (diethylene glycol) from water and ethylene oxide 
are competitive reactions (Gordon & Thornburg, 1959; Buquet & 
Manchon, 1970; Scudamore & Heuser, 1971).  Levels in food up to 
2420 mg/kg wet weight have been reported for 1,2-ethanediol and up 

to 65 mg/kg wet weight for 2,2'-oxybisethanol, 6 - 12 months after 
sterilization (Scudamore & Heuser, 1971).  Food constituents can 
also be alkylated.  Hydroxyethylated derivatives of amino acids, 
vitamins, alkaloids, and sugars have been identified that might 
affect the nutritive value of food.  A change in organoleptic 
properties has been reported for a variety of foodstuffs (Oser & 
Hall, 1956; Gordon & Thornburg, 1959; Windmueller et al., 1959; 
Kröller, 1966; Pfeilsticker & Siddiqui, 1976). 

    2-Chloroethanol was detected in cigarette smoke at levels of 
350 and 82 mg/m3 trapped smoke, 1 and 49 days, respectively, after 
fumigation of the tobacco (Chaigneau & Muraz, 1981). 

4.2.2.  Exposure via medical equipment

    Ethylene oxide may also be absorbed by medical equipment during 
sterilization and may remain in the materials for some time, as the 
unchanged compound or as its reaction products.  Factors affecting 
residue levels are similar to those mentioned in section 4.2.1 for 
food.  Aeration and storage conditions are very important, 
particularly with respect to possible worker exposure. 

    Other conditions being equal, the removal of ethylene oxide 
residues by aeration takes longer in plastics such as polyvinyl 
chloride, polyether-polyurethane, polyglycolic acid, and glassy 
polymers.  Desorption periods for ethylene oxide in polyethylene 
and rubber materials and textiles are shorter (McGunnigle et al., 
1975; Gillespie et al., 1979; Gilding et al., 1980; Star, 
1980b,c,d; Dauvois et al., 1982).  Star (1980b) sterilized 
polyvinyl chloride and rubber tubes and found that initial residues 
of ethylene oxide in polyvinyl chloride tubes of between 3510 and 
7300 mg/kg dropped to between 3 and 443 mg/kg after 7 days of 
aeration at room temperature.  In rubber tubes, ethylene oxide 
residues dropped from 291 and 858 mg/kg after sterilization to 
levels of between 2 and 24 mg/kg, after 24 h of aeration at room 
temperature.  Using the same sterilization method, similar levels 
in polyvinyl chloride and rubber tubes were reached after 24 and 
4 h of aeration, at 62 °C, respectively (Star, 1980c).  Ethylene 
oxide residues in sterilized cotton wool, adhesive dressings, and 
compresses dropped from between 270 and 3600 mg/kg to 2 mg/kg or 
less, in 7 - 8 days of storage.  In sanitary pads, the latter 
residue level was only reached after 14 - 32 days of storage 
(Dauvois et al., 1982).  In sterilized pharmaceutical products, 
ethylene oxide levels ranging from the detection limit up to 16 300 
mg/kg wet weight were measured after 2 - 8 h of vacuum treatment; 
1,2-ethanediol was also identified (Adler, 1965).  Ethylene oxide 
levels in water eluates from hollow-fibre dialysers corresponded to 
a theoretical residue of 1 mg of ethylene oxide per dialyser (50 
mg/kg) after an aeration period of 60 days.  During 6 h of elution, 
the concentration of ethylene oxide in the hourly water eluates did 
not change substantially (Henne et al., 1984). 

    Maximum residues of 2-chloroethanol in polyvinyl chloride 
tubes, ranging between 20 and 40 mg/kg, dropped to below the 
detection limit, within 4 days (Star, 1980d; Jordy, 1983).  In 

rubber, however, the 2-chloroethanol level rose from 300 mg/kg, 
directly after sterilization, to a maximum of 800 mg/kg, 3 h later; 
desorption was slow (Jordy, 1983).  Gamma-irradiaton before 
sterilization of polyvinyl chloride by ethylene oxide can increase 
the 2-chloroethanol residues considerably (Star, 1980d).  For the 
toxicology of 2-chloroethanol, see Vettorazzi (1979). 

4.3.  Occupational Exposure

    In a total of 8 production plants, the levels of worker 
exposure to ethylene oxide, in recent years, were reported 
generally to be below 18 mg/m3 (Hogstedt et al., 1979b; Morgan et 
al., 1981; Thiess et al., 1981b).  In a modern production plant in 
western Europe, the geometric mean of 0.5 hour-samples, taken in 
1974, was less than 0.02 mg/m3.  The geometric mean of 8-h samples 
was less than 0.02 mg/m3 in 1978 and 1980, and 0.22 mg/m3 in 1981.  
In 89% of the total of 273 samples, the concentration of ethylene 
oxide was less than 0.2 mg/m3.  In the remaining samples, 
concentrations of up to 11.6 mg/m3 were found (van Sittert et al., 
1985).  In a plant in the USA, typical average daily exposures were 
reported to be 0.3 - 4.0 mg/m3 in 1979 (Flores, 1983).  
Occasionally, higher values can occur.  Thiess et al. (1981a) 
reported a maximum of 3420 mg/m3, during a plant breakdown.  Flores 
(1983) reported worst-case peak exposures of up to 17 000 mg/m3.  
In the past, exposure levels were higher (Joyner, 1964; Hogstedt et 
al., 1979b). 

    Although the volume of ethylene oxide used for sterilization is 
relatively small, many workers are involved. In the USA, 
approximately 75 000 health-care workers were estimated to be 
potentially exposed in 1977 (Glaser, 1979).  Peak concentrations of 
up to 1800 mg/m3 have been measured and occurred mainly when the 
sterilization chambers were opened.  Exposure levels very much 
depend on the scale and techniques of the process used. 

    In 4 hospital sterilization units in France, in 1980, 
concentrations of between 0.9 and 410 mg/m3 were measured, after 
sampling for several minutes.  During the loading of the 
sterilizers, the average levels per unit ranged from 3 to 45 mg/m3.  
During unloading, averages of 8 - 97 mg/m3 were measured.  In a 
desorption room, 1- or 2-h time-weighted average levels of between 
18 and 173 mg/m3 were measured; at other sites, time-weighted 
averages were less than 17 mg/m3 (Mouilleseaux et al., 1983).  
Exposures, after the opening of sterilizers, ranging from less than 
0.2 to 111 mg/m3 were found by personal sampling over several 
minutes in 16 hospitals, in Belgium, in 1981 - 83.  In one other 
hospital, an average of 477 mg/m3 was measured by personal 
sampling.  In the desorption rooms of a total of 19 hospitals in 
Belgium, the time-weighted average concentrations, over 30 min, 
ranged from less than 0.02 mg/m3 up to 120.6 mg/m3.  In nearby 
rooms of several hospitals, average 30-min exposure levels of up to 
15 mg/m3 were measured (Lahaye et al., 1984).  In 6 hospital 
sterilization units in Italy, using pure ethylene oxide, the 8-h 
time-weighted average concentrations were 6.7 - 36 mg/m3 with an 
average of 19.3 mg/m3.  Continuous sampling during the 5-min 

interval following the opening of sterilizers revealed time-
weighted average concentrations of 18 - 288 mg/m3 (average 112.5 
mg/m3).  In 2 other hospitals in Italy, using 11% ethylene oxide in 
freon, the 8-h time-weighted average levels were 0.36 - 0.90 mg/m3 
with an average of 0.63 mg/m3, and the 5-min exposure levels were 
9 - 47 mg/m3 (average 15.5 mg/m3) (Sarto et al., 1984).  Time-
weighted average exposures of Swedish personnel involved in 
sterilizing medical equipment in 1975 were 14 mg/m3, when the 
sterilizer door was open, and 2.3 mg/m3, when the door was closed.  
Before working routines were changed, these levels had been 52 and 
16 mg/m3, respectively.  Instantaneous peak levels had reached 
94 mg/m3.  In another Swedish factory, in 1978, the time-weighted 
average personal exposure, during a total shift, was 4.3 mg/m3
(Högstedt et al., 1983).  Pero et al. (1981) reported 1-h time-
weighted average personal exposures of up to 18 mg/m3 for a 
sterilization facility in Sweden. 

    Data from the USA agree with the data from Europe.  For workers 
in 5 sterilization rooms of a hospital in the USA, 15-min exposures 
of up to 86 mg/m3 were found with 8-h time-weighted averages 
ranging from less than 0.13 to 7.7 mg/m3 and instantaneous peaks of 
up to 1430 mg/m3 (Hansen et al., 1984).  At 3 work-sites in the 
sterilization facilities of a plant manufacturing health-care 
products, 8-h time-weighted averages of 0.9, 9 - 18, and 9 - 
36 mg/m3 were measured prior to 1980, but from that year onwards, 
the 8-h time-weighted averages were below 1.8 mg/m3 (Stolley et 
al., 1984). 


5.1.  Absorption

    Ethylene oxide is very soluble in blood.  Therefore, pulmonary 
uptake is expected to be fast and to depend only on the alveolar 
ventilation rate and the concentration of ethylene oxide in the 
inspired air.  Ehrenberg et al. (1974) came to such a conclusion 
after inhalation studies on mice.  The rate of uptake of ethylene 
oxide was 1.1 µg/kg body weight, per min, at an exposure level of 
1 mg/m3.  This corresponds to nearly 100% absorption of ethylene 
oxide from 1.1 litre of air per min and per kg body weight, which 
is the reported rate of alveolar ventilation in resting mice 
(Altman & Dittmer, 1974).  No specific information pertaining to 
skin absorption is available, but accidental exposure of the skin 
of 3 industrial workers to 1% aqueous solution of ethylene oxide 
was reported to have resulted in marked nausea and profuse vomiting 
(Sexton & Henson, 1949). 

5.2.  Distribution

    Ethylene oxide is rapidly distributed throughout the body.  In 
mice, body autoradiography, 2 min after intravenous injection, 
showed that concentrations of ethylene oxide in the liver, kidneys, 
and pancreas were 3 - 4 times those in the blood.  Between 20 min 
and 4 h after exposure, radioactivity was distributed throughout 
the body (Appelgren et al., 1977).  Directly after inhalation by 
mice, the highest concentrations of labelled ethylene oxide or its 
metabolites were found in the liver, kidney, and lung.  The 
radioactivity in the liver and kidney dropped exponentially and 
approached the levels in the lung, testes, spleen, and brain within 
4 h, indicating rapid metabolism and excretion (Ehrenberg et al., 
1974).  On the basis of tissue alkylation data (Ehrenberg et al., 
1974) or haemoglobin alkylation data (Osterman-Golkar et al., 1976, 
1983), a half-life of approximately 10 min was estimated for the 
first-order clearance of ethylene oxide from mouse or rat tissues.  
A similar value for man was estimated on the basis of haemoglobin 
alkylation data (Calleman et al., 1978).  In dogs, intravenously-
administered ethylene oxide cleared from plasma with a mean half-
life of 33 min, which was independent of the dose levels of 25 and 
75 mg/kg body weight.  Clearance of the confirmed metabolite 1,2-
ethanediol from plasma, following intravenous administration, was 
slower with a half-life of between 3 and 4.4 h (Martis et al., 

    When the degree of protein and DNA alkylation was investigated 
in mice and rats, only small variations were observed between the 
different tissues in the species.  Apparently, most organs receive 
a more or less equal dose of ethylene oxide after distribution 
throughout the body.  The extent of protein alkylation was 
approximately equal in the lung, liver, kidney, and spleen of mice, 
120 min after inhalation of 2 mg ethylene oxide/m3 air, for 75 min, 
but in the testes, it was about 50% lower.  When the vapour 
concentration was increased (up to 59 mg/m3), the degree of protein 
alkylation in the liver increased relative to that in the other 

tissues.  In all the tissues investigated, protein alkylation 
increased linearly with the dose up to an exposure level of 
59 mg/m3, and was relatively constant for at least 3.5 h following 
exposure (Ehrenberg et al., 1974).  Haemoglobin alkylation was 
previously discussed in section 2.3. 

    When 0.4 mg ethylene oxide/kg body weight was administered 
intraperitoneally to mice, DNA alkylation in the testes and spleen 
was, respectively, 50 and 40% of that in the liver, 5 h after 
exposure.  The approximate half-lives of the alkylation products 
were 24 h in the spleen, 10 h in the testes, and 12 h in the liver.  
For the spleen, this half-life was found to be shorter  in vivo 
than  in vitro, indicating active removal (Segerbäck, 1983).  In a 
similar study on rats receiving 0.1 or 0.9 mg ethylene oxide/kg 
body weight, DNA alkylation in the testes was about one-third of 
that in the liver (Osterman-Golkar et al., 1983).  So far,  N7-(2-
hydroxyethyl)guanine is the only DNA alkylation product that has 
been found  in vivo (Ehrenberg et al., 1974; Segerbäck, 1983).  This 
reaction product has also been identified  in vitro (Brookes & 
Lawley, 1961).  In addition, adenosine also reacted  in vitro with 
ethylene oxide to form  N1-(2-hydroxyethyl)-adenosine (Windmueller 
& Kaplan, 1961).  When ethylene oxide reacted  in vitro with 
uridine,  N3-(2-hydroxyethyl)uridine was the only product found, 
but in the reaction with uridine-5-phosphate, phosphodiester 
formation was observed (Ukita et al., 1963). 

5.3.  Metabolic Transformation and Excretion

    Available animal data indicate 2 possible pathways for the 
metabolism of ethylene oxide, i.e., hydrolysis and glutathione 
conjugation (Fig. 1). 

    In dogs, peak levels of 13 and 33 mg 1,2-ethanediol/litre 
blood-plasma were measured between 1 and 3 h after intravenous 
administration of 25 or 75 mg ethylene oxide in water/kg body 
weight, respectively.  As the half-life for hydrolysis is about 
60 h at 40 °C in neutral fresh water (Virtanen, 1963), the 
involvement of an epoxide hydrolase (EC has been 
suggested, but this has not yet been confirmed.  The peak 
concentration of 1,2-ethanediol at 25 mg ethylene oxide/kg body 
weight represented approximately 25% of the dose of ethylene oxide.  
Within 24 h, 7 - 24% of the dose was excreted in the urine as 1,2-
ethanediol.  No other compound-related metabolites were identified 
(Martis et al., 1982).  In the serum of 18 workers occupationally 
exposed to ethylene oxide (range 0.54 - 27 mg/m3; average 7.56 
mg/m3), for an average of 5.3 years, the blood concentration of 
1,2-ethanediol was found to be elevated compared with that in 
unexposed controls (Wolfs et al., 1983). 

    The results of studies on rats, rabbits, and monkeys have shown 
that some 1,2-ethanediol is metabolized but that most of it is 
excreted unchanged in the urine (Gessner et al., 1961; McChessney 
et al., 1971). 


    When a single dose of 2 mg labelled ethylene oxide in 
propanediol/kg body weight was applied intraperitoneally to rats, 
43% of the administered radioactivity was excreted in the urine 
within 50 h (41% within 24 h) of exposure, 9% as  S-(2-
hydroxyethyl)cysteine and 33% as  N-acetyl- S-(2-hydroxyethyl)
cysteine, both products of glutathione conjugation.  Via the lungs, 
1.5% was excreted as carbon dioxide and 1% as unmetabolized 
ethylene oxide (Jones & Wells, 1981).  The involvement of 
glutathione-epoxide- S-transferase (EC has not been 
investigated further.   In vitro glutathione conjugation of the 
homologue propylene oxide was shown to proceed only in the presence 
of an enzyme (Fjellstedt et al., 1973).  In rabbits, no effect was 
found on liver- and blood-glutathione levels, after 12 weeks of 
exposure to concentrations of ethylene oxide at 18, 90, or 450 
mg/m3, for 5 days per week, 6 h per day (Yager & Benz, 1982). 

    As ethylene oxide can react with chloride ions, and this 
reaction is acid catalysed, 2-chloroethanol might be expected to be 
a metabolite, especially after oral administration.  However, 
neither 2-chloroethanol, nor its metabolites (Johnson, 1967; Grunow 
& Altman, 1982) have been found in the plasma, tissues, or urine of 
species exposed to ethylene oxide. 

    Ehrenberg et al. (1974) found that an average of 74% of 
labelled ethylene oxide, inhaled by mice, was excreted in the urine 
within 24 h in the form of unidentified metabolites, and only 4% 
within the next 24 h.  Thus, on the basis of this and previously-
presented excretion data, excretion of metabolites of ethylene 
oxide mainly takes place via the urine, within 24 h following 


    A summary of the acute toxicity of ethylene oxide for aquatic 
organisms is presented in Table 3.  Data on the most likely 
reaction products, 1,2-ethanediol and 2-chloroethanol, are 

    LC50s of ethylene oxide for aquatic species have been reported 
to range from 90 mg/litre (goldfish, 24-h exposure) to 745 mg/litre 
(brine shrimp, 48-h exposure).  Microorganisms in activated sludge 
showed 50% inhibition at concentrations between 10 and 100 
mg/litre.  Hydrolysis to 1,2-ethanediol results in detoxification.  
The toxicity of 2-chloroethanol for aquatic organisms resembles 
that of ethylene oxide, though 2-chloroethanol seems to be more 
toxic for  Daphnia magna.  Nevertheless, under environmental 
conditions, the conversion of ethylene oxide to 2-chloroethanol or 
1,2-ethanediol will be slow. 

    In a study on the albino guppy,  Poecilia reticulata, desorption 
of ethylene oxide or its reaction products from non-aerated plastic 
materials into water can lead to behavioural disturbances in the 
fish almost immediately, and to death within about one h.  No such 
toxicity was found when the materials were aerated for 24 h 
(O'Leary et al., 1969). 

    Ethylene oxide is very soluble in aqueous media and evaporates 
from water to a significant degree.  The log  n-octanol water-
partition coefficient was reported to be -0.30 (Radding et al., 
1977).  Thus, ethylene oxide will not bioaccumulate. 

Table 3.  Acute aquatic toxicitya
Organism    Description     T     pH   Dissolved  Parameter   Test             Concentration  Reference
                            (°C)       oxygen                 substance        (mg/litre)
Micro-     activated        22                    50% growth  ethylene oxide   10 - 100       Conway et al.
organisms  sludge                                 inhibition  1,2-ethanediol   > 10 000       (1983)b

Crustacea  water flea       17    7.0  minimal    48-h LC50   ethylene oxide   212            Conway et al.
            (Daphnia magna)             aeration               1,2-ethanediol   > 10 000       (1983)c
                                                              2-chloroethanol  100

Fish       fathead minnow   22    7.0  no         96-h LC50   ethylene oxide   84             Conway et al.
            (Pimephales                 aeration               1,2-ethanediol   > 10 000       (1983)c
            promelas)                                          2-chloroethanol  90

Fish       goldfish         20    6-8  no         24-h LC50   ethylene oxide   90             Bridié et al.
            (Carassius                  aeration               1,2-ethanediol   > 5000         (1979a)d
            auratus)                    (> 4

Fish       brine shrimp     24    7.0  minimal    48-h LC50   ethylene oxide   745            Conway et al.
            (Artemia                    aeration               1,2-ethanediol   > 20 000       (1983)e
            salina)                                            2-chloroethanol  680
a All tests were static.  Water analysis for the substance under test was reported by all authors.
b Incubation on a shaker for 16 h.
c Medium was fresh water, reconstituted using dechlorinated, carbon-treated tap water; 10 fish per 
d Medium was local tap water; 6 fish per concentration.
e Medium was sea water, reconstituted using dechlorinated, carbon-treated tap water, 30 - 50 shrimps per 

7.1.  Acute Exposures

7.1.1.  Oral, intravenous, and inhalation studies

    The LD50s for ethylene oxide, administered orally and dissolved 
in water, were 330 mg/kg body weight for male rats and 280 and 
365 mg/kg body weight for female and male mice, respectively (Smyth 
et al., 1941; Woodard & Woodard, 1971). After inhalation, the 4-h 
LC50s were 1500 and 1730 mg/m3 for mouse and dog, respectively, and 
2630 mg/m3 for rat (Jacobson et al., 1956).  1,2-Ethanediol, a 
metabolite, is less toxic:  LD50s for rat were above 10 000 mg/kg
body weight, after oral administration, and 5210 mg/kg body weight, 
after intravenous administration (Woodard & Woodard, 1971). 

    The slope of the dose-response curve in relation to the 
mortality rate for ethylene oxide was steep.  After oral 
administration to rats, the difference between 0.1% mortality 
(325 mg/kg) and 99.9% mortality (975 mg/kg) was approximately 
650 mg/kg body weight (Smyth et al., 1941).  After inhalation for 
4 h, this difference was approximately 3000 mg/m3, in mice, and 
approximately 5000 mg/m3 in rats.  No deaths occurred in dogs at 
1280 mg/m3 (Jacobson et al., 1956).  While no guinea-pigs died 
after inhalation of 450 mg ethylene oxide/m3 air for 8 h, the 
majority did so at 2400 mg/m3 (Waite et al., 1930).  In the above 
mortality studies, the lungs and nervous system were the main 
targets in rodents and dogs.  In dynamic inhalation exposure 
studies on guinea-pigs (Waite et al., 1930), rats, mice, and dogs 
(Jacobson et al., 1956), nasal irritation was the first clinical 
effect, as evidenced by scratching the nose, nasal discharge, 
lachrymation, and salivation.  Respiratory problems occurred 
ranging from gasping to laboured breathing.  Dogs exhibited 
laboured breathing, vomited, and suffered convulsions.  Guinea-
pigs, exposed to a concentration of 13 000 mg ethylene oxide/m3, 
for 2.5 h, were found lying on their sides, unable to stand, and 
quiet.  Gross pathological changes in animals that did not survive 
included moderate congestion in the lungs of dogs, minor patchy 
oedema in the lungs of rats, and congestion with oedema in the 
lungs of guinea-pigs.  In rats, moderate congestion with petecchial 
haemorrhage of the trachea was also observed.  Lobular pneumonia 
and hyperaemia of the liver and kidneys were observed in guinea-
pigs.  Parenchymatous changes in the kidney of guinea-pigs were 
seen at 2300 mg/m3. 

    Ataxia, prostration, laboured breathing, and occasional tonic 
convulsions were effects shown by rats and mice at lethal oral or 
intravenous doses of ethylene oxide (Woodard & Woodard, 1971).  
Vomiting was the only effect shown by dogs that had received 25 or 
75 mg ethylene oxide/kg body weight intravenously (Martis et al., 

    In order to investigate the effects of residues of ethylene 
oxide or reaction products in sterilized medical equipment, rabbits 
were exposed for 2 h via polyvinyl chloride endotracheal tubes 
containing 0, 80, or 600 mg ethylene oxide/kg material.  There were 
no deaths, but rabbits receiving the tubes with the highest 
residues showed increased incidences of hyperaemia, oedema, 
leukocyte infiltration, and epithelial erosion of the larynx and 
trachea (Star et al., 1980).  Two groups of nine dogs each were 
exposed through extracorporeal perfusion for 40 min via a polyvinyl 
chloride oxygenator containing 12 g ethylene oxide/kg material.  
Nine dogs with an interrupted pulmonary circulation died from shock 
and pulmonary oedema.  Six out of 9 dogs with a preserved pulmonary 
circulation died from pulmonary distress.  A group of 9 control 
dogs was treated in the same manner using a steam-sterilized 
oxygenator.  Only 1 control dog died (Stanley et al., 1971). 

7.1.2.  Acute effects on eyes and skin

    As noted above, ethylene oxide is an irritating agent for 
several different species.  A maximum non-damaging concentration of 
0.1% ethylene oxide in balanced physiological salt solution 
(prepared daily and kept at 0 °C) was established after 
instillation of 0.05 ml solution, every 10 min for 6 h, into the 
conjunctival sac of rabbits.  The concentrations above 1% caused 
reversible changes in conjunctiva such as hyperaemia and swelling, 
and irreversible opacity, both in the cornea and in the lens.  
Possible reaction products, 2-chloroethanol and 1,2-ethanediol, 
were less irritating to the eye (McDonald et al., 1973).  The 
results of  in vitro tests with isolated rabbit cornea were in 
agreement with the results of these studies.  In the  in vitro 
tests, the endothelia were perfused for 1 - 3 h with a balanced 
salt solution containing 250 mg ethylene oxide, 2250 mg 
2-chloroethanol, or 5000 mg 1,2-ethanediol/litre.  No effects were 
observed on corneal thickness and cellular ultrastructure 
(Edelhauser et al., 1983). 

    Skin irritation with hyperaemia, oedema, and scar formation was 
observed from 6 min after application of pads of cotton, moistened 
with solutions of 100 or 500 g ethylene oxide/litre water, on the 
shaved skin of rabbits, under a plastic cover.  The intensity of 
the response was reported to be roughly proportional to the length 
of exposure time (1 - 60 min) and the concentration (Hollingsworth 
et al., 1956). 

    According to Hine & Rowe (1981), liquid ethylene oxide is 
apparently without adverse effects on rabbit and human skin, on 
single mild exposures, if the material evaporates rapidly.  If 
large amounts of material are involved, evaporation may cause 
sufficient cooling to cause a lesion similar to frost-bite. 

7.2.  Short-Term Studies

7.2.1.  Inhalation exposure

    Groups of 10 - 20 Wistar rats per sex, 8 guinea-pigs per sex, 
1 - 2 rabbits per sex, and 1 - 2 female rhesus monkeys were each 
exposed to concentrations of ethylene oxide at levels of 0, 90, 
200, 370, 640, or 1510 mg/m3, for 7 h per day, and 5 days per week.  
The female monkeys were not tested at 90 mg/m3, and an additional 3 
male monkeys were tested at 640 mg/m3.  The test period varied with 
the species tested, and the severity of exposure, i.e., 
approximately 26 weeks at 90 mg/m3, 25 - 32 weeks at 200 and 
370 mg/m3, 7 - 25 weeks at 640 mg/m3, and 10 days at 1510 mg/m3.  
Guinea-pigs, rabbits, and monkeys tolerated 90 and 200 mg/m3, and 
rats tolerated exposure to 90 mg/m3 without adverse effects on 
general appearance, behaviour, mortality rate, growth, body and 
organ weight, gross- and histopathology.  Rats showed elevated 
mortality rates from 370 mg/m3, rabbits from 640 mg/m3, and all 
exposed animals died at 1510 mg/m3.  Secondary respiratory 
infection caused the deaths of an appreciable number of rats and 
mice in these studies. 

    Surviving rats showed increased relative lung weights after 
26 - 27 weeks at 200 and 370 mg/m3.  At 370 mg/m3, haemorrhages, 
hyperaemia, emphysema, and local alveolar collapse were observed in 
these lungs.  Lungs of male rabbits also showed hyperaemia and 
slight oedema at 370 mg/m3.  Even more severe lung injury was seen 
in rats at 640 mg/m3 and the higher exposure.  Gross respiratory 
tract irritation was apparent in all species at 1510 mg/m3. 

    Delayed reversible effects were observed on the peripheral 
nervous system.  Monkeys and rabbits exhibited paralysis of the 
hind legs at 370 mg/m3 and, together with rats, at 640 mg/m3.  This 
was accompanied by atrophy of the muscles of the hind legs, except 
in rabbits at 370 mg/m3.  The effects on the peripheral nervous 
system were investigated further in monkeys, and loss of both 
sensory and motor function was noted at levels of 370 and 
640 mg/m3. 

    Significant increases in body weight were also observed in 
rats, at levels of 200 mg/m3 or more.  Rats showed slight but 
significant increases in the relative weights of kidney and liver 
at 370 mg/m3 (Hollingsworth et al. 1956). 

    The findings of Jacobson et al. (1956) are in agreement with 
these results.  Groups, comprising 20 male rats and 30 female mice 
each, were exposed to concentrations of ethylene oxide at levels of 
0, 180, or 730 mg/m3, for 6 h/day, and 5 days per week.  The 
exposures lasted 26 weeks at 180 mg/m3 and 6 weeks at 730 mg/m3.  
Additional groups of 15 rats and mice at the higher, and 60 rats 
and mice at the lower, exposure level were used for interim gross 
pathology.  No clear toxic effects were reported at 180 mg/m3.  No 
pathological changes were observed except for marked haemosiderosis 
in the spleen of a few rats at 730 mg/m3.  The highest exposure 
(730 mg/m3) resulted in death for both species without clinical 

signs in mice.  Effects on the respiratory and nervous system were 
shown by rats as laboured breathing, reddish nasal discharge, 
diarrhoea, tendency towards a side position, and dragging of the 
hind-quarters.  Rats also lost weight, which was regained by 

    More recently, groups of 30 B6C3F1 mice of each sex were 
exposed to concentrations of ethylene oxide (purity 99.9%) at 0, 
18, 86, 187, or 425 mg/m3, for 6 h/day, and 5 days per week.  The 
exposures lasted for 10 weeks for males and 11 weeks for females.  
No effects were observed in relation to survival, body weight, 
clinical signs, white blood cell count, serum clinical chemistry, 
urinalysis, and histopathology.  At the highest exposure level, 
changes at terminal sacrifice included an increased relative liver 
weight in female mice, and a decreased testicular weight in males.  
A decreased relative spleen weight was observed at 187 and 
425 mg/m3 in both sexes.  In addition, the red blood cell count, 
the packed cell volume, and the haemoglobin concentrations were 
decreased at 425 mg/m3.  Screening of neuromuscular function in 
groups of 5 female mice, in week 6, and 5 mice of both sexes, in 
week 10 or 11, revealed altered reflex responses at 425 mg/m3 and a 
dose-related trend in alterations of locomotor function from 
86 mg/m3 upwards (Snellings et al., 1984a). 

    Groups of 3 male beagle dogs each were exposed to 
concentrations of ethylene oxide (purity 99.7%) of 180 and 
530 mg/m3, for 1 - 3 days.  No effects were observed on mortality 
rate, body weight, electrocardiogram, blood-calcium and -urea, 
icteric index, and rectal temperature.  Anaemia was noted at both 
exposure levels.  Effects on the respiratory and nervous systems 
were shown at 530 mg/m3, such as hyperaemia and local alveolar 
collapse in lungs, vomiting, and occasional slight tremors and 
transient weakness in the hind legs.  Muscular atrophy was also 
observed (Jacobson et al., 1956).  No haematological changes were 
noted when groups each comprising 3 male New Zealand rabbits were 
exposed repeatedly for 12 weeks to 0, 18, 90, or 450 mg/m3 (Yager & 
Benz, 1982).  The white cell count was depressed in Fischer rats 
exposed in groups of 3 or 4, for 3 days, 6 h per day, to 90, 270, 
or 810 mg/m3.  There was a poor correlation with exposure level 
(Kligerman et al., 1983). 

    The possible neurotoxic effects of ethylene oxide noted in the 
above studies were investigated further in groups each comprising 
12 male cynomolgus monkeys.  These animals were exposed to 0, 90, 
or 180 mg ethylene oxide/m3 (purity 99.7%), for 7 h per day, 5 days 
per week, for 2 years.  In 2 monkeys per group, brain, ulnar and 
sciatic nerves, and spinal cord were examined histologically after 
exposure.  No clinical signs were reported.  The only treatment-
related lesions found were in the medulla oblongata of the brain.  
Axonal dystrophy was found in the nucleus gracilis, primarily in 
the exposed groups.  Demyelination of the terminal axons of the 
fasciculus gracilis occurred in one monkey at each exposure level, 
but not in the controls (Sprinz et al., 1982).  Paralysis of the 
hind limbs was observed in monkeys repeatedly exposed for up to 
32 weeks to 370 mg/m3, for 7 h per day, 5 days per week 
(Hollingsworth et al., 1956). 

7.2.2.  Oral exposure

    Groups of 5 Wistar rats each received, by gavage, 22 doses of 
3, 10, or 30 mg ethylene oxide/kg body weight in 30 days and 15 
doses of 100 mg/kg in 21 days.  The vehicle was olive oil.  There 
were 10 vehicle controls. 

    No effects on mortality rate, growth, haematology, blood urea-
nitrogen, organ weights, gross- and histopathology were reported at 
the 3 lower dose levels.  At 100 mg/kg, there was marked loss in 
body weight, gastric irritation, and slight (not further specified) 
liver damage (Hollingsworth et al., 1956). 

7.3.  Long-Term Inhalation Studies

    In a combined toxicity-carcinogenicity study, groups of 120 
male and 120 female Fischer 344 rats were exposed to actual 
concentrations of ethylene oxide of 18 mg/m3 (10 ppm), 58 mg/m3 
(32 ppm), and 173 mg/m3 (96 ppm), for 6 h per day, 5 days per week, 
over 25 months.  Two control groups each comprising 120 male and 
120 female rats were used.  There was an exposure-free period of 2 
weeks in month 15, because of infection with sialoacryoadenitis 
virus.  Interim sacrfices occurred at 6, 12, and 18 months. 

    The mortality rates of male and female rats increased 
significantly from the 22nd or 23rd month, at the highest exposure, 
with a trend towards an increase at a level of 58 mg/m3.  Body 
weights in both sexes were depressed at 173 mg/m3, from the end of 
the first week onwards, until the end of the study.  At 58 mg/m3, 
the body weights of female rats were decreased between week 10 and 
80.  In females, the relative liver weights were increased in the 
18th month at 173 mg/m3.  This effect on the liver could not be 
related to increases in the activities of serum alkaline 
phosphatase (EC, aspartate aminotransferase (EC, 
or alanine aminotransferase (EC, found mainly at the 2 
highest exposures during interim sacrifices.  Relative spleen 
weights were increased in rats that developed leukaemia (section 
7.4.1).  Haematological changes were found in rats at all doses, 
but mainly at the end of the study in animals exposed to 173 mg/m3; 
these included an elevated leukocyte count in both sexes, and a 
depressed red blood cell count and haemoglobin value in females.  
Some of these rats had leukaemia. 

    Non-neoplastic histopathological changes observed included an 
elevated frequency of focal fatty metamorphosis of the adrenal 
cortices in both sexes and bone marrow hyperplasia in females at 
173 mg/m3.  Although no effect was observed on the hind-quarter 
lift reflex, examined monthly, mild skeletal muscular atrophy was 
observed, after 2 years of exposure to 173 mg/m3.  Observations on 
general health and ophthalmology did not reveal anything abnormal.  
Neoplastic changes are reported in section 7.4.1 (Snellings et al., 
1981, 1984b). 

    In another toxicity-carcinogenicity study (Lynch et al., 
1984a), groups of 80 male Fischer 344 rats were exposed to actual 
concentrations of ethylene oxide of 92 mg/m3 (51 ppm) and 182 mg/m3 
(101 ppm), for 7 h per day, 5 days per week, over 2 years.  The 
control group also comprised 80 rats.  There was an exposure-free 
period of 2 weeks in month 16 because of a pulmonary infection, 
which contributed to the mortality rate. 

    The mortality rate increased at both exposure levels, the 
increase being significant at 182 mg/m3.  Only 19% of the rats 
survived 2 years of exposure at 182 mg/m3 compared with 49% in the 
unexposed group.  Body weights were reduced from the 3rd or 4th 
month onwards.  The relative weights of adrenals and brain were 
increased at both exposure levels.  The relative weights of lung 
and kidney were increased at 92 mg/m3.  Serum aspartate 
aminotransferase activity was increased in rats exposed to 92 and 
182 mg/m3 (section 7.4.1).  No other changes were found in 
haematology or clinical chemistry. 

    Non-neoplastic histopathological changes included an elevated 
incidence of vacuolization and hyperplasia or hypertrophy in the 
adrenals at both exposure levels, and of atrophy and degeneration 
of skeletal muscle fibres at 182 mg/m3.  There were also increased 
incidences of inflammatory lesions of the lungs, nasal cavities, 
trachea, and internal ear at both exposure levels.  Eye cataracts 
developed in 9 out of 78 rats at 182 mg/m3, 3 out of 79 in the 
92 mg/m3 group, and 2 out of 77 in the controls. 

7.4.  Carcinogenicity

7.4.1.  Inhalation exposure

    In the studies by Snellings et al. (1981, 1984b) (section 7.3) 
(Table 4), several neoplasms were induced by ethylene oxide.  A 
dose-related increased incidence of mononuclear cell leukaemia was 
found in both sexes, significant at the 2 highest exposures in 
females, from the 18th or 19th month onwards.  Trend test revealed 
a treatment-related response in both sexes.  In males, an increased 
incidence of peritoneal mesotheliomas originating from the 
testicular mesothelium, occurred at 58 and 173 mg/m3 from the 23rd 
month onwards, and an increased incidence of subcutaneous fibroma 
was seen in male rats exposed to 173 mg/m3 that had survived for 24 
months.  Trend analysis showed that there was a treatment-related 
increase in peritoneal mesothelioma.  There was no increased 
incidence of pituitary tumours, but they appeared earlier in the 
173 mg/m3 group. 

    Following the report by Lynch et al. (1984a) of an increased 
incidence of brain tumours in Fischer 344 rats exposed to ethylene 
oxide (see below), the brain tissue from this study was re-examined 
both macro- and microscopically, and a dose-related incidence of 
primary brain tumours was observed at 58 and 173 mg/m3 that 
appeared to be treatment related in the trend test, but was not 
statistically significant.  The tumours were mainly diagnosed as 
gliomas and malignant reticular tumours.  The percentage of rats 

with multiple neoplasms was greater than in controls at all 
exposure levels in females and at 173 mg/m3 in males.  At 58 and 
173 mg/m3, the percentage of female rats with at least one 
malignancy was increased.  The authors considered that a 
contribution of the viral outbreak to the toxicity of ethylene 
oxide was unlikely (Snellings et al., 1981, 1984b). 

    Lynch et al. (1984a) (section 7.3, Table 4) also found an 
increased incidence of mononuclear cell leukaemia, which was 
significant at the lower exposure level.  The absence of a dose-
relationship was attributed to the increased mortality rate at 182 
mg/m3.  Dose-related increased incidences of peritoneal 
mesotheliomas, originating from the testicular mesothelium, and of 
mixed-cell gliomas in the brain, were found.  The increases in both 
tumours were significant at 182 mg/m3 (Lynch et al., 1984a). 
Table 4.  Tumours induced by ethylene oxide in Fischer 344 rats
Concen-  Leukaemia          Meso-     Pituitary  Subcutaneous     Braina
tration  (mononuclear)      thelioma  adenoma    fibromaa
         M         F        M         M          F        M       M      F

                        Snellings et al. (1981, 1984b)

173      26(119)b  28(113)  22(119)   27(117)    32(117)  11(30)  3(30)  2(26)
58       25(81)    24(79)   7(91)     16(79)     38(90)   1(39)   1(39)  2(48)
18       21(79)    14(77)   3(89)     27(80)     39(90)   3(51)   0(51)  0
0        20(116)   9(118)   2(114)    28(117)    38(119)  1(48)   1(48)  0
0        18(118)   13(117)  2(116)    22(117)    38(116)  2(49)   0(49)  0

                           Lynch et al. (1984a)c

182      30(76)    NA       21(79)    21(67)     NA       NR      5(79)  NA
92       38(79)    NA       9(79)     20(66)     NA       NR      2(77)  NA
0        24(77)    NA       3(78)     48(73)     NA       NR      0(76)  NA
a Only animals that survived for 24 months were included, because these
  tumours appeared after the 18-month interim sacrifice.
b Numbers in brackets refer to the number of rats examined.  They include 
  interim and final kills.
c Only male rats were used.
NA = Not applicable.
NR = Not reported.
7.4.2.  Oral exposure

    Groups of 50 female Sprague Dawley rats received, in salad oil, 
7.5 or 30.0 mg ethylene oxide/kg body weight, by gavage, in the 
empty stomach, twice a week, for 110 weeks.  There were 50 vehicle 
controls, 50 untreated controls, and 50 positive controls.  The 
rats were observed for their life span.  No statistical analysis 
was reported.  The mean survival period was over 100 weeks for all 

groups.  The mortality rate increased at 30.0 mg/kg body weight, 
from week 100 onward.  Elevated incidences of tumours were only 
observed in the forestomach, the first tumour appearing in week 79.  
The incidences of squamous cell carcinomas were 0/50, 8/50, and 
29/50 at 0, 7.5, and 30 mg/kg body weight, respectively.  At 
30 mg/kg body weight, invasive growth and metastases were observed 
in 10 rats.  At 30 mg/kg body weight, 2 fibrosarcomas were also 
noted.  At both doses, the incidences of hyperplasia, 
hyperkeratosis, papillomas, and/or carcinomas were increased in the 
forestomach (Dunkelberg, 1982). 

7.4.3.  Subcutaneous exposure

    Groups of 100 female NMRI mice were injected once a week with a 
tricaprylin solution containing 0.1, 0.3, or 1.0 mg ethylene oxide 
per animal, for 106 weeks.  There were 200 vehicle controls and 200 
untreated controls.  From week 35 to week 85, the mortality rate 
increased by a maximum of 10% at a dose of 1.0 mg per mouse.  The 
mean length of survival in this group was 75 weeks.  An elevated 
incidence of tumours was only observed at the injection site, the 
first tumour appearing in week 79.  There was a dose-related 
increased incidence of sarcomas, mainly fibrosarcomas, which was 
significant at 0.3 and 1.0 mg per mouse.  The tumour incidence was 
11% at the highest dose compared with 2% in vehicle controls 
(Dunkelberg, 1981). 

7.4.4.  Dermal exposure

    Each of a group of 30 female Swiss Millerton mice received, for 
their lifetime, approximately 100 mg of a 10% solution of ethylene 
oxide (purity 99.7%) in acetone, brushed on the clipped dorsal 
uncovered skin, 3 times a week.  A group of 60 mice did not receive 
any treatment, and a group of 60 mice received the vehicle only.  
No skin tumours were found, nor was there any sign of skin 
irritation.  The median length of survival was 493 days for treated 
mice and 445 days for controls (Van Duuren et al., 1965).  It is 
assumed that ethylene oxide, applied in this manner, evaporated 
rapidly from the skin. 

7.5.  Mutagenicity and Related End-Points

    Almost all the reports available demonstrate the mutagenic 
action of ethylene oxide.  A summary of mutagenicity tests with 
positive results is presented in Table 5. 
    Ethylene oxide is an alkylating agent (section 5.2).  It has 
induced gene mutations in all plants, bacteria, fungi, insects, and 
mammalian cells investigated  in vitro, with and without metabolic 
activation.  Chromosome damage and sister chromatid exchanges were 
observed in plants, insects, and mammalian somatic cells exposed  in 
 vivo and  in vitro. Fomenko & Strekalova (1973) and Strekalova et 
al. (1975) reported an increased incidence of chromosomal 
aberrations in the bone-marrow cells of rats exposed by inhalation 
to concentrations of ethylene oxide vapour at 3.6 and 112 mg/m3. 
Unscheduled DNA synthesis, induced by the  N-acetoxy-2-acetylamino-
fluorene, was inhibited by ethylene oxide in human lymphocytes  in 

 vitro (Pero et al., 1981).  The positive results in the 
micronucleus tests are in agreement with those from a distribution 
study showing that ethylene oxide, or its metabolites, was retained 
in the bone marrow of mice (Appelgren et al., 1977).  An increased 
incidence of micronuclei was observed after one intraperitoneal 
dose of 100 mg/kg body weight in mice (Lyarskii et al., 1983) and 
after 4 h of vapour exposure of rats to a concentration of 90 mg/m3 
(Embree & Hine, 1975). 
Table 5.  Mutagenic tests for ethylene oxide with positive resultsa 
Test description          System description                 Reference 
                     Organism      Strain/cell type
Gene mutations

 Forward mutations   plant         barley                    Ehrenberg et al. (1956,
 Forward mutations                 barley                    Shulovsk et al. (1969)
 Forward mutations                 rice                      Jana & Roy (1975)
 Forward mutations                 pea                       Blixt et al. (1963)
 Reverse mutations   bacterium      Escherichia coli          Hussain & Osterman-Golkar
                                   SD-4                      (1984)
 Reverse mutations                  Salmonella typhimurium    Rannug et al. (1976);
 (base-pair                        TA1535, TA100             Kauhanen (1978)b;
  substitutions)                                             Pfeiffer & Dunkelberg
 Reverse mutations                  Bacillus subtilis         Tanooka (1979)
                                   (spores) HA101, TKJ5211,
 Reverse mutations   fungus         Neurospora crassa         Kolmark & Westergaard
                                   (macroconidia)            (1953); Kolmark & Kilby
 Forward mutations                  Aspergillus nidulans      Morpurgo (1963)
 Forward mutations                  Schizosaccharomyces       Migliore et al. (1982)c
                                    pombe Pl

 Sex-linked          insect         Drosophila melanogaster   Bird (1952); Nakao &
  recessive lethals                                          Auerbach (1961)
 Forward mutations   mammal        Chinese hamster           Tan et al. (1981)b;
  on specific locus  ( in vitro)    ovary cells               Zamora et al. (1983)

Chromosome damage

 breaks, erosions,   plant          Tradescantia paludosa     Smith & Lofty (1954)
 contractions                      (pollen)
 translocations                    barley                    Ehrenberg et al. (1956,
 breaks                            barley                    Moutschen-Dahmen et al.
 breaks                            wheat (hexaploid)         MacKey (1968)
 translocations      insect         Drosophila melanogaster   Nakao & Auerbach (1961)
 small deletions     insect         Drosophila melanogaster   Fahmy & Fahmy (1970)

Table 5.  (contd.)
Test description          System description                 Reference 
                     Organism      Strain/cell type
Chromosome damage (contd.)

 breaks,             human         anion cells               Poirier & Papadopoulo
 gaps, exchanges,    ( in vitro)                              (1982)
 sister chromatide   human         lymphocytes               Star (1980a);
 exchanges           ( in vitro)    fibroblasts               Garry et al. (1982)
                     rat           lymphocytes               Kligerman et al. (1983)
                     rabbit        lymphocytes               Yager & Benz (1982)
 sister chromatide   monkey        lymphocytes               Lynch et al. (1984b)d
 exchanges,          (inhalation)
 breaks, acentric 

 chromosomal         rat           bone marrow cells         Strekalova et al. (1975)
 aberrations         (inhalation)

 breaks, gaps,       rat           bone marrow cells         Embree & Hine (1975)
 rearrangement,     (inhalation)
 ring formations

 micronuclei         mouse (ip)    polychromatic             Conan et al. (1979);
                                   erythrocytes              Jenssen & Ramel (1980);
                                                             Lyarskii et al. (1983)

 micronuclei         mouse (iv)    polychromatic             Appelgren et al. (1978)

 heritable           mouse (ip)    germ cells                Generoso et al. (1980)

 dominant lethals    mouse         germ cells                Cumming & Michaud (1979)
                     mouse (ip)                              Generoso et al. (1980);
                                                             Lyarskii et al. (1983);

                     mouse                                   Generoso et al. (1983)


Table 5.  (contd.)
Test description          System description                 Reference 
                     Organism      Strain/cell type
 dominant lethals    rat                                     Embree et al. (1977)
 (contd.)            (inhalation)

DNA repair

 unscheduled         mouse         germ cells                Cumming & Michaud (1979)
  DNA synthesis      (inhalation)
 unscheduled         human         lymphocytes               Pero et al. (1981)
  DNA synthesis      ( in vitro)    
a For details of these studies, see text and data profile (IRPTC, 1984).
b A similar effect after metabolic activation by rat liver microsomal fraction.
c A slight reduction in mutagenicity after metabolic activation by mouse liver 
  microsomal fraction.
d 2-year exposure groups of 12 male monkeys to 0, 90, and 180 mg/m3 for 7 h per day and 
  5 days per week.
    Dose-related damage to germ cells was established in the mid 
and late spermatid stages in the dominant lethal assay.  One oral 
dose of 100 mg/kg body weight in mice generated inconsistent 
results (Appelgren et al., 1977), but 150 mg/kg proved positive 
(Generoso et al., 1980).  After short-term repeated exposures, 
dominant lethals were induced in mice at intraperitoneal doses from 
40 mg/kg body weight, given over a period of 3 months, 5 times per 
week (Lyarskii et al., 1983) and at vapour exposures from 
460 mg/m3, for 6 h/day, 5 days per week, over 11 weeks (Generoso et 
al., 1983).  Heritable translocations were induced in the germ 
cells of mice after repeated intraperitoneal exposure, at doses of 
30 mg/kg body weight or more, for 5 days/week, over a 5-week period 
(Generoso et al., 1980).  Recent studies have investigated the 
dose-response of inhaled ethylene oxide and have compared effects 
of different dose rates (contributions of different concentrations 
and durations of exposure, maintaining total exposure (C x t) 
constant) on the dominant-lethal response in male mice.  In the 
dose-reponse study, male mice were exposed by inhalation to 
ethylene oxide at concentrations of 540, 720, or 900 mg/m3 (300, 
400, or 500 ppm), respectively.  Exposures were for 6 h/day, for 4 
consecutive days.  A dose-related increase in dominant-lethal 
mutations was observed; however, the dose-response curve was 
nonlinear, i.e., increasing embryonic mortality occurred with 
increasing mg/m3 x h.  In the dose-rate study, mice had a total 
exposure of 3240 mg/m3 (1800 ppm) x h/day for 4 consecutive days, 
delivered either at 540 mg/m3 (300 ppm) in 6 h, 1080 mg/m3 in 3 h, 
or 2160 mg/m3 (1200 ppm) in 1.5 h.  The highest airborne 
concentration resulted in the greatest embryonic mortality, 64%, 
versus 32 and 11% for the intermediate and lowest airborne 
concentrations, respectively (Generoso et al., 1985).  According to 
an abstract, DNA repair was induced in the germ cells of mice 

exposed to 540 mg/m3, for 8 h.  The repair seemed inhibited at 
higher exposures (Cumming & Michaud, 1979).  No details were 

    Negative results were observed on a few occasions only.  In one 
study, with vapour-exposed rats, chromosome aberrations or slowing 
of mitotic activity and cell cycle kinetics were not observed in 
lymphocytes at levels at which sister chromatid exchanges occurred 
(Kligerman et al., 1983).  In a dominant-lethal assay with mice, 
relatively high intravenous doses of ethylene oxide (up to 
100 mg/kg body weight) did not cause any treatment-related effects 
(Appelgren et al., 1977).  An intraperitoneal dose of 10 mg/kg body 
weight to mice was reported to give a slight increase in the number 
of polychromatic erythrocytes with micronuclei, but the statistical 
analysis was not adequate (Conan et al., 1979). 

7.6.  Effects on Reproduction

    Rats and guinea-pigs were exposed to vapour concentrations of 
370 and 640 mg ethylene oxide/m3, for 7 h per day, 5 days per week, 
for up to 32 weeks.  Among other effects (section 7.2.1), 
degeneration of testes tubules was observed at the higher exposure 
level in guinea-pigs, while at 370 mg/m3, there was a decrease in 
the relative weights of testes in rats and guinea-pigs, which was 
not statistically significant (Hollingsworth et al., 1956).  
Significantly-decreased absolute testicular weights were observed 
in mice exposed to ethylene oxide at a concentration of 425 mg/m3, 
for 6 h/day, 5 days per week, over 10 - 11 weeks (Snellings et al., 
1984a).  However, the testicular effects may have been secondary to 
toxic effects (e.g., growth inhibition).  Male and female Fischer 
344 rats exposed repeatedly to concentrations of ethylene oxide of 
up to 182 mg/m3, for 6 h/day, 5 days per week, over 25 months, did 
not show any histopathological effects on the reproductive tissues 
(Snellings et al., 1981). 

    When groups of 12 male Cynomolgus monkeys were exposed to 
concentrations of ethylene oxide at 90 or 180 mg/m3, for 7 h/day, 
5 days per week, over 2 years, spermatogenic functions were found 
to differ from those of controls.  At both exposure levels, sperm 
motility and sperm count were decreased and the sperm drive range 
was increased, but there was no increase in effect with increase in 
dose.  The incidence of abnormal sperm heads did not change (Lynch 
et al., 1984c). 

    Groups, each comprising 30 male and 30 female Fischer 344 rats, 
were exposed to concentrations of ethylene oxide (purity 99.9%) of 
18, 58, or 173 mg/m3, for 6 h/day, 5 days per week, over 12 weeks.  
Two control groups of 30 rats per sex each were exposed to air 
only.  After mating, females were further exposed for 7 days/week, 
up to 3 weeks after delivery, with the exception of the first 5 
days of lactation.  Effects on the reproductive performance were 
detected.  The number of pups per litter was decreased at 173 
mg/m3, as well as the number of implantation sites per female, and 
the number of fetuses born per implantation site.  The number of 
females with a gestation period longer than 22 days was also 

increased at this concentration, but no effects were noted on the 
average length of the gestation period.  Neither parents nor pups 
showed signs of toxicity from ethylene oxide.  The percentages of 
pregnant females and fertile males were not affected (Snellings et 
al., 1982a). 

7.7.  Teratogenicity

    Groups of 22 female Fischer 344 rats were exposed to 
concentrations of ethylene oxide of 18, 58, or 173 mg/m3, for 
6 h/day, on days 6 - 15 of gestation.  Two control groups 
comprising 22 rats each were exposed to air only.  The numbers of 
pregnant dams ranged from 17 to 22.  Maternal behaviour was normal, 
and there were no deaths.  The only effect on the fetuses was a 5 - 
8% decrease in weight at 180 mg/m3 (Snellings et al., 1982b). 

    Groups of 32 - 45 female Sprague Dawley rats were exposed to 
concentrations of ethylene oxide (purity 99.7%) of 0 or 270 mg/m3, 
for 7 h/day, on days 7 - 16 of gestation (Group 1) or on days 1 - 
16 of gestation (Group 2) or during 3 weeks before mating (5 days 
per week), and on days 1 - 16 of gestation (Group 3).  No dams 
died, but body weights were decreased in Group 3.  In all exposed 
groups, the relative and absolute weights of kidney and spleen were 
increased.  The results of histopathological examination did not 
show any abnormalities.  There was a significant increase in 
resorptions per litter and per implantation site in Group 3, with 
no significant effects on the number of implants, live fetuses, and 
pregnancies.  In all exposed groups, weights and lengths of the 
fetuses were decreased.  Reduced ossification of sternebrae and 
primary skull was observed (Hackett et al., 1982). 

    New Zealand rabbits were similarly exposed to a concentration 
of ethylene oxide of 270 mg/m3 from days 1 - 19 or from days 7 - 19 
of gestation.  There was no evidence of toxicity in the mothers, 
embryos, or fetuses, or of developmental defects (Hackett et al., 

    Groups of 24 - 37 female CD-1 mice each received, 
intraveneously, doses of 0, 75, or 150 mg ethylene oxide (purity 
not stated)/kg body weight in an aqueous dextrose solution on days 
4 - 6, 6 - 8, 8 - 10, or 10 - 12 of pregnancy.  Dams exposed on 
days 6 - 8 of pregnancy did not show toxic signs.  In the other 
groups, at the highest dose, toxic signs such as weakness, laboured 
respiration, and tremor were observed with a mortality rate of 19 - 
48%.  In the group without signs of maternal toxicity, fetotoxicity 
was observed at 150 mg/kg, as shown by a 20% decrease in mean fetal 
weight.  Fetal malformations were shown in 19.3% of fetuses in 
exposed litters compared with 2% in control groups.  These 
malformations were mainly fused cervical arches.  In addition, 
fused thoracic arches, scrambled and fused sternebrae, and fused, 
branched, or missing thoracic ribs were observed (Laborde & Kimmel, 


8.1.  Exposure of the Skin and Eyes

    Undiluted ethylene oxide, applied to the skin of volunteers, 
evaporated rapidly without leaving any mark or irritation.  A 
15-min exposure to cotton wool soaked in undiluted ethylene oxide 
also did not produce any effects (Greaves Walker & Greeson, 1932).  
However, with exposure to larger quantities, there may be 
sufficient cooling to produce a lesion similar to frost-bite (Hine 
& Rowe, 1981).  Skin injury following exposure to aqueous solutions 
of ethylene oxide is characterized by the appearance of oedema and 
erythema, 1 - 5 h after exposure, followed by the formation of 
vesicles.  On healing, incrustation, often with itching and 
desquamation, is observed.  The magnitude of the skin injury seems 
to depend on the length of contact and the concentration, a 50% 
aqueous solution (500 g/litre) being most hazardous.  More 
concentrated solutions were less harmful.  The lowest concentration 
tested, a 1% solution, produced a mild reaction after a 50-min 
exposure.  Such effects have been observed in a number of accidents 
(Sexton & Henson, 1949, 1950; Joyner, 1964; Ippen & Mathies, 1970).  
Vapour exposure was found to produce the above dermal effects, 
mainly on the humid parts of the skin (Ippen & Mathies, 1970).  The 
effects were also found, to different extents, after exposure via 
ethylene oxide-sterilized materials such as face masks, gloves, and 
surgical gowns (Royce & Moor, 1955; Marx et al., 1969; Hanifin, 
1971; Biro et al., 1974; Lamy et al., 1974).  Patch tests on 
volunteers with various sterilized materials containing residues of 
ethylene oxide and its reaction products, showed erythema, without 
oedema, after 4 - 8 h of contact, from a residue level of 890 mg 
ethylene oxide/kg up to 2890 mg/kg of a polyvinyl chloride block.  
Most skin types tolerated residues of ethylene oxide of up to 
2270 mg/kg polyvinyl chloride film, 2800 mg/kg brown-milled rubber, 
and 5100 mg/kg non-woven fabric (Shupack et al., 1981). 

    Accidental skin exposure to a 1% aqueous solution, from the 
waist down, was also reported to result in effects on the nervous 
system, such as nausea and repeated vomiting (Sexton & Henson, 

    Accidental exposure of the eyes to the vapour of ethylene oxide 
can lead to conjunctivitis (Thiess, 1963; Joyner, 1964).  Exposure 
of 12 men via a leaking sterilizer resulted in neurological 
disorders (section 8.3) in 4 of the men, 3 of whom had eye 
cataracts; one of the latter also showed an increase in corneal 
thickness.  Two additional men showed only an increase in corneal 
thickness (Gross et al., 1979; Jay et al., 1982).  In one case of 
accidental exposure of the eyes to pure ethylene oxide, only slight 
irritation of the conjunctiva was seen (Thiess, 1963). 

    The implantation of artificial lenses, sterilized with ethylene 
oxide, in 103 eyes was compared with the implantation of lenses, 
sterilized with sodium hydroxide (200 control eyes), in a 
retrospective study.  The follow-up period was 10 months for the 
exposed patients.  Post-operative inflammatory complications 

occurred in 30% of the eyes exposed to residues of ethylene oxide 
or its reaction products compared with 9% of the control eyes.  
Cystoid macular oedema with reduction in visual acuity developed in 
16% of the exposed eyes and in 7% of the control eyes (Stark et 
al., 1980). 

8.2.  Sensitization

    No dermal sensitization was observed in a total of 47 workers 
frequently exposed to ethylene oxide (Royce & Moor, 1955; Thiess, 
1963).  In another study using patch tests, one of 12 volunteers 
showed a recurrent reaction, 3 weeks after the trial.  When 
challenged afterwards with a 2 mm-thick patch of polyvinyl chloride 
containing 100 mg ethylene oxide/kg, a mild reaction was observed, 
which reappeared after 3 weeks (Shupack et al., 1981) (section 
8.1).  When the skin of 8 workers was exposed repeatedly to aqueous 
solutions of ethylene oxide, all sites of previous contact, with 
and without a primary reaction, flared up in 3 of them showing 
pruritus, erythema, and slight oedema, 5 - 9 days after the last 
exposure (Sexton & Henson, 1950).  Another case of an apparently 
allergic reaction was reported.  The patient concerned was exposed 
to ethylene oxide via a sterilized face mask (Alomar et al., 1981). 

    A case of anaphylaxis has been reported in a patient receiving 
haemodialysis treatment with equipment that had been sterilized 
with ethylene oxide (Poothullil et al., 1975).  A cause-effect 
relationship with ethylene oxide exposure was demonstrated by 
haptan specificity (Dolovich & Bell, 1978). 

8.3.  Accidental Inhalation Exposure

    Respiratory tract irritation was reported as hoarseness 
(Thiess, 1963) and cough (Metz, 1939) in 5 cases of acute 
accidental exposure to ethylene oxide vapour. 

    Acute effects on the nervous system in nearly all inhalation 
cases were marked by nausea, recurrent vomiting, and headache.  
Less frequently reported effects included decreased consciousness 
(one case of coma), excitement, sleeplessness, muscular weakness, 
diarrhoea, and abdominal discomfort (Blackwood & Erskine, 1938; 
Metz, 1939; Thiess, 1963; Capellini & Ghezzi, 1965). 

    Because of a leaking sterilizer, 4 young men were exposed 
intermittently, for 2 - 8 weeks, to ethylene oxide at levels of 
approximately 1000 mg/m3.  Three of the men developed a reversible 
peripheral neuropathy showing abnormal nerve conduction and, in 2 
cases, headache, weakness and decreased reflexes in the 
extremities, incoordination, and a wide-based gait.  The fourth man 
developed a reversible acute encephalopathy with headache, nausea, 
vomiting, lethargy, recurrent motor seizures, agitation, and a 
diffusely slow electroencephalogram (Gross et al., 1979).  
Following this, 6 more cases were reported concerning sterilizer 
operators, suffering from reversible peripheral neuropathy 
following ethylene oxide exposure for 0.5 - 1.5 years.  Finelli et 
al. (1983) described 3 persons showing subacute polyneuropathy with 

bilateral foot-drop, slowing of nerve conduction velocity, and 
denervation potential on electromyography as the main findings.  
All 3 persons had noticed the smell of ethylene oxide regularly at 
work, while 2 persons experienced eye irritation.  Polyneuropathy 
was also reported in 3 sterilizer operators by Kuzuhara et al. 
(1983).  Two of these cases were described in detail.  Sural nerve 
biopsies revealed axonal degeneration with mild changes in the 
myeline sheath.  Unmyelinated fibres were also involved.  Muscle 
biopsies showed typical denervation atrophy. 

8.4.  Other Accidental Exposures

    Severe respiratory problems due to inflammatory reactions in 
the trachea and larynx were reported in 17 hospital patients who 
had received endotracheal intubation.  The tubes had been 
sterilized with ethylene oxide (Marx et al., 1969; Holley & Gildea, 
1971; Lipton et al., 1971; Mantz et al., 1972). 

    Reversible vocal paralysis was reported to be associated with 
ethylene oxide exposure in 5 cases:  one woman had been exposed to 
vapour (Troisi, 1965), and the other 4 patients were exposed via 
sterilized endotracheal tubes (Holley & Gildea, 1971).  The vocal 
cords showed no or only slight damage.  In one of these patients, 
who died from a cause unrelated to the intubation, myelin 
degeneration of parts of the nervus vagus was noted at autopsy.  It 
was suggested, therefore, that the paralysis was of neural origin. 

    Four cases of shock, 1 - 10 h after endovascular examination, 
were associated with the catheters used, which contained residues 
of ethylene oxide.  The presence of bacterial toxins was considered 
unlikely.  One patient died as a result of renal insufficiency 
(Lebrec et al., 1977).  Cases of cardiovascular collapse in 
children, 3 of which were fatal, were considered by the authors to 
be the result of residues of ethylene oxide in a heart-lung machine 
on the basis of subsequent studies on dogs (Stanley et al., 1971) 
(section 7.1.1).  Among others, Hirose et al. (1963) and Clarke et 
al. (1966) measured haemolysis due to residues in ethylene oxide-
sterilized plastic tubes  in vitro. 

8.5.  Occupational Inhalation Exposure

    The health status of 37 male operators from an ethylene oxide-
producing plant in the USA during the period 1953 - 62 was compared 
with that of age-matched operators from other production units.  
The average employment period was 11 years for exposed workers and 
12 years for controls.  The usual average exposure level was 
between 9 and 18 mg/m3, with occasional peaks up to 230 mg/m3 for 
one particular job (collecting a sample of the product).  According 
to the medical records, the health of the exposed workers was 
somewhat better than that of the controls.  A physical examination 
and extensive clinical tests did not reveal any exposure-related 
effects with the exception of a slightly increased white blood cell 
count (Joyner, 1964). 

    Chromosomal damage was found in a group of 12 workers from a 
hospital sterilization facility in the USA (section 8.6).  The 
maximum exposure concentration measured during sterilization was 
65 mg/m3.  Another group of 12 persons, who worked in the adjacent 
operating room area, volunteered as representatives of an unexposed 
or accidentally exposed group.  To insure adequate control 
throughout the study, unexposed laboratory staff members served as 
a third group.  Frequently-reported subjective complaints indicated 
irritation of the mouth, throat, and eyes, and effects on the 
nervous system, such as headache, nausea, speech difficulty, memory 
loss, dizziness, and incoordination (Garry et al., 1979). 

    In Belgium, a group of 18 workers, using or distributing the 
sterilant ethylene oxide, was compared with a well-matched control 
group by means of a questionnaire, and by analyses for urinary 
retinol-binding protein and albumin, beta-microglobulin, and 
chromosomal damage in lymphocytes.  The overall mean exposure level 
was 7.6 mg/m3, and the time-weighted average exposure, over a 
working day, ranged between 0.2 and 95 mg/m3.  A significant 
increase in the incidence of sleeplessness and leg cramps was 
recorded, but not irritation or allergy.  These studies did not 
reveal any abnormalities with the exception of an increase in 
sister chromatid exchanges in lymphocytes (Wolfs et al., 1983; 
Laurent et al., 1984; section 8.7). 

    In a plant in Bulgaria, 196 workers engaged in the production 
of ethene and ethylene oxide were examined.  About 73% of all 
concentrations of ethylene oxide measured were 1 mg/m3 or less, 
while 27% were between 1 mg/m3 and 3.5 mg/m3.  Significant 
increases were found in deviations of the autonomous nervous system 
and in neurosis-like manifestations, especially in female workers 
(Spasovski et al., 1980).  Because of a mixed exposure, it is 
difficult to evaluate the findings. 

    Haematological changes were reported in a group of 27 workers 
in an ethylene oxide manufacturing and processing plant, in Sweden, 
in 1967.  The exposure period varied from 2 to 20 years, the 
average length being 15 years.  Controls worked with ethylene oxide 
in other departments, where no leakages were possible.  No exposure 
data were reported.  When 2 cases of anaemia were excluded, there 
was still a significantly-decreased haemoglobin value in exposed 
workers.   There was a 30% increase in the number of lymphocytes, 
and one case of chronic lymphatic leukaemia was noted (Ehrenberg & 
Hällström, 1967). 

    In the Federal Republic of Germany, 279 employees from 8 plants 
in which alkene oxides were produced or processed, were examined 
for morbidity during 1978.  They were employed for an average of 
10.8 years.  Of these workers, 21 had been involved in accidents 
with ethylene oxide.  Taking into account age and length of 
exposure, they were compared with groups of industrial and clerical 
workers within the same company.  The exposure concentrations were 
not reported.  The workers were also exposed to many other 
chemicals, some of which may be carcinogenic for man. 

    No abnormalities were found that could be related to exposure 
to ethylene oxide or propylene oxide.  The investigators related 
increases in haemoglobin and mean erythrocyte volume to smoking 
habits.  Slight lymphocytosis was found to be unrelated to exposure 
time, though there was a distinct age influence (Stocker & Thiess, 

8.6.  Mortality Studies

    Two studies were conducted in Sweden to investigate the 
possible neoplastic effects from occupational exposure to ethylene 
oxide (Hogstedt et al., 1979a,b, 1984).  The first study originally 
included 58 male and 172 female workers in a small factory, 
sterilizing hospital equipment with a 1:1 mixture of ethylene oxide 
and methyl formate, over a period from 1968 to 1977 (Hogstedt et 
al., 1979a). 

    Two cases of leukaemia (one was diagnosed as chronic myeloid 
leukaemia and the other as acute myelogenous leukaemia) occurred 
among 68 women who were exposed to vapours from sterilized boxes 
stored for weekly periods in a factory storage hall where about 30 
persons were exposed at any one time.  A third case was the local 
male manager who developed primary macroglobulinaemia (Morbus 
Waldenström; this case was later diagnosed as a non-Hodgkin 
lymphoma), 9 years after the installation of the sterilization 
equipment; his exposure was estimated to be about 3 h per week in 
the storage hall.  He is also reported to have had some exposure to 
benzene in the past.  The concentration of ethylene oxide in the 
hall was in the range of 3.6 - 128 mg/m3, and the 8-h time-weighted 
average in the breathing zone was calculated to be between 36 ± 
18 mg/m3.  The other workers had occasional exposure to ethylene 
oxide, and 7 operators had relatively high exposure (amount 
unspecified) during the sterilization process. 

    In a follow-up study (Hogstedt et al., 1984), a further case of 
leukaemia was found in a woman who had been exposed to ethylene 
oxide in the storage hall between 1969 - 72.  In this study, the 
cohort consisted of 203 workers who had been employed for more than 
one year at the plant. 

    Altogether, 4 deaths from malignancies of the lymphoreticular 
system were reported from this factory.  The expected number was 

    A second study to investigate the carcinogenic effects of 
ethylene oxide was conducted on 241 Swedish male workers in an 
ethylene oxide-producing plant (Hogstedt et al., 1979b).  These 
men were examined medically in 1960.  Twenty-three deaths 
occurred during the 16-year observation period dating from 
1961 - 77 (13.5 expected).  The excess mortality was due to cancer 
and cardiovascular disease.  Three cases of stomach cancer (0.4 
expected) and 2 cases of leukaemia (one chronic myeloid and once 
acute myeloid leukaemia) (0.14 expected) accounted for the excess 
mortality from cancer.  No increase in mortality was observed among 
86 maintenance workers exposed intermittently to ethylene oxide 

among 66 unexposed controls. Average exposure levels during 
1941 - 47 were estimated to be below 25 mg/m3 and, during the 1950s 
up to 1963, these levels were 10 - 50 mg/m3, but peak exposures 
above the odour threshold (about 1000 mg/m3) were known to occur. 

    The ethylene oxide was manufactured by the chlorohydrin process 
so that significant exposure to other chemicals such as 1,2-
dichloroethane, ethylene, ethylene-chlorohydrin, and bis(2-
chloroethyl)ether might have occurred. 

    This investigation was followed up by a study that extended the 
period of observation up to 1982.  Seven more deaths had occurred 
among the workers exposed to ethylene oxide for the whole of the 
working day against 6.6 expected.  Three of these were due to 
cancer (1.6 expected).  Two of these 3 cases were cancer of the 
stomach (0.2 expected) and one an oesophageal cancer (0.04 
expected).  In the period from 1961 - 82, 6 deaths due to stomach 
or oesophageal cancer had occurred in workers exposed to ethylene 
oxide for the whole of the working day (0.7 expected).  Alimentary 
tract cancer was observed in 2 maintenance workers (0.8 expected) 
and in 1 unexposed worker (0.8 expected).  One new case of chronic 
myeloid leukaemia was reported during this follow-up period.  
During the 20-year period of observation, a total of 17 cases of 
cancer were notified to the Cancer Registry against 7.9 expected 
(Hogstedt et al., 1984). 

    The Task Group evaluated these data and concluded that the 
evidence was adequate to consider the mixtures of compounds to 
which these workers were exposed as carcinogenic for human beings, 
but inadequate to label ethylene oxide as a proved human 
carcinogen.  This conclusion was in agreement with that arrived at 
by an International Agency for Research on Cancer Working Group 
(IARC, 1985). 

    A similar study in the USA concerned 767 male workers at an 
ethylene oxide producing plant.  They were employed for at least 
5 years between January 1955 and December 1977 and "potentially 
exposed".  Concentrations of ethylene oxide were reported to be 
below 18 mg/m3, but no further details concerning exposure levels 
were reported.  Exposure to other chemicals was not reported.  
Control data came from national statistics and was adjusted for 
sex, age, and calendar time.  There were 46 deaths against an 
expected 80; there were 11 malignant neoplasms against 15.2 
expected.  No statistically-significant excess deaths could be 
found due to any cause.  There were no deaths due to leukaemia, 3 
deaths from pancreatic cancer (0.8 expected), 1 death from bladder 
cancer (0.3 expected), 2 deaths from brain cancer (0.7 expected), 
and 2 deaths from Hodgkin's disease (0.4 expected) (Morgan et al., 

    In the Federal Republic of Germany, 602 workers were 
investigated for mortality experience during the period 1928 - 80.  
The workers had been employed for at least 6 months in 8 plants 
producing or processing ethylene oxide and propylene oxide.  A 
subcohort of 351 workers was observed for more than 10 years.  

Control data came from a styrene plant and from national 
statistics.  Since 1978, exposure to ethylene oxide had normally 
remained below 9 mg/m3.  In the past, occasional excursions above 
90 mg/m3 (50 ppm) had been reported.  On one occasion during plant 
breakdown, 3420 mg/m3 (1900 ppm) was measured.  No statements were 
offered concerning human exposure or the use of personal protective 
equipment.  The workers were also exposed to many other chemicals, 
some of which might be carcinogenic for human beings.  There were 
56 deaths compared with 76.6 expected.  There were 14 deaths from 
cancer compared with 16.6 expected.  No statistically-significant 
excess deaths could be found due to any cause in the cohort.  In 
the subcohort of 351 workers, there was a significant increase in 
mortality rate due to kidney disease (3 against 0.4 expected).  
There was 1 death from gall bladder cancer, 1 death from urinary 
bladder cancer, 1 death from brain cancer, and 1 death from myeloid 
leukaemia.  Two stomach tumours were observed compared with 1.8 
expected (Thiess et al., 1981a,b). 

8.7.  Mutagenicity and Related End-Points

    An increase in chromosomal aberrations was found in the 
lymphocytes of 3 groups of workers sterilizing medical equipment in 
hospitals or factories (Abrahams, 1980; Pero et al., 1981; Högstedt 
et al., 1983).  A 50% increase in aberration rate was found in 28 
workers exposed to 8-h time-weighted average concentrations of 
ethylene oxide below 1.8 mg/m3 in the 2.5 years before the study.  
Before this period, higher exposures were reported to have 
occurred.  The workers had been exposed for 0.5 - 8 years.  The 
mean number of micronuclei in the bone marrow cells of 18 of these 
workers was 3 times higher than in the controls (Högstedt et al., 
1983).  Pero et al. (1981) found that, while workers exposed to 
concentrations of ethylene oxide between 0.9 and 1.8 mg/m3, for 
40 h per week, did not show an increased aberration rate; others, 
exposed to bursts of ethylene oxide at concentrations between 9 and 
18 mg/m3, for 8 h per week, did.  The Task Group noted that the 
sterilization procedure involved the use of a 50:50 mixture of 
ethylene oxide and methyl formate.  At the same time, DNA repair, 
induced  in vitro by the mutagen  N-acetoxy-2-acetylamino-fluorene, 
was reversibly inhibited in the low exposure group compared with an 
unexposed control group, but not affected in the other group.  DNA 
repair inhibition was positively correlated with duration of 
exposure (Pero et al., 1981).  In 43 male workers from the cohort 
of 602 workers (section 8.5) (Thiess et al., 1981b), an increase in 
chromosomal aberration rate was found that was significant for the 
workers exposed for more than 20 years, but not for those 
accidentally exposed or exposed for average periods of 12 and 
17 years (Thiess et al., 1981a). 

    In another ethylene oxide manufacturing plant, no chromosomal 
aberrations were detected in the lymphocytes of 36 male workers.  
These men had been exposed for 1 - 14 years to average 
concentrations of up to 0.28 mg/m3 (van Sittert et al., 1985). 

    The sister chromatid exchange rate in lymphocytes was not 
increased in groups of 28 and 14 sterilization workers exposed to 
8-h time-weighted averages, below 1.8 mg/m3 for 2.5 years before 
the study (Högstedt et al., 1983) and below 8 mg/m3 (Hansen et al., 
1984), respectively.  In the second study, peaks up to 1430 mg/m3 
were also measured.  Increases in sister chromatid exchange rate 
were found in 4 other studies on sterilization workers (Garry et 
al., 1979; Abrahams, 1980; Yager et al., 1983; Laurent et al., 
1984).  In one of these studies, in which 75 workers were exposed 
to levels generally below an 8-h time-weighted average of 90 mg/m3, 
this increase was found in cells together with quadriradial 
aberrations (Abrahams, 1980).  In the other studies, groups were 
small, exposure conditions often unclear, and the number of 
metaphases scored, in some cases, limited.  Yager et al. (1983) 
only found an increased sister chromatid exchange rate at 
relatively high calculated integrated doses of more than 100 mg per 
person.  The length of exposure to ethylene oxide averaged 3.6 min 
per day; these tasks were performed between 6 and 120 times during 
the 6-month study period.  Laurent et al. (1984), studied sister 
chromatid exchange rates in 2 groups of ethylene oxide-exposed 
workers (estimated ethylene oxide dose in past 2 years, 530 - 
715 mg and 1185 - 5800 mg, respectively) as well as unexposed 
controls.  Although the sister chromatid exchange rates in the 
high-exposure group did not differ significantly from the rates in 
the low-exposure groups (not adjusted for smoking), the difference 
among non-smokers between the exposed (n = 20) and the controls 
(n = 15) was significant. 

    In a study on 41 sterilization workers in 8 hospitals in Italy, 
increases in both sister chromatid exchanges and in chromosomal 
aberrations were detected in lymphocytes; these effects persisted 
for months after exposure was reduced or interrupted.  The workers 
were exposed to average 8-h time-weighted averages of either 
0.63 mg/m3 or 19.3 mg/m3 (section 4.3).  A statistically-
significant correlation was found between sister chromatid exchange 
frequency and the level of ethylene oxide, as well as a multiple 
correlation between sister chromatid exchange frequency and 
ethylene oxide exposure, smoking, and age (Sarto et al., 1984).  
Similarly, in the USA, the sister chromatid exchange frequencies in 
the lymphocytes of 61 sterilization workers involved in sterilizing 
health-care products, were monitored over a period of 2 years and 
compared with those of 82 unexposed controls.  During the study 
period, 8-h time-weighted-average exposures were reported to be 
less than 1.8 mg/m3.  Prior to the start of the study, 8-h time-
weighted averages between 0.9 and 36 mg/m3 were measured.  Results 
were adjusted for smoking habits, sex, and age.  Workers exposed to 
low levels of ethylene oxide such as those at a worksite with 8-h 
time-weighted-average ethylene oxide levels below 1.8 mg/m3 prior 
to and during the study, did not show increased frequencies of 
sister chromatid exchange.  Workers who had been exposed to levels 
of 5 - 36 mg/m3, prior to the study, showed an increased frequency 
of sister chromatid exchange that persisted for at least 24 months 
after cessation of exposure (Stolley et al., 1984). 

8.8.  Effects on Reproduction

    In a study from the USSR (Yakubova et al., 1976), the course of 
pregnancy and birth was followed in 57 operators, 38 laboratory 
workers, and 65 adminstrative staff in an ethylene oxide-producing 
plant, the majority of the women being between 20 and 29 years of 
age.  A group of 50 pregnant women working outside the plant served 
as additional controls.  It was estimated that the operators were 
exposed to ethylene oxide concentrations of 0.2 - 0.3 mg/m3 for 80% 
of the working time and 1.0 mg/m3 for the remaining 20%, while the 
laboratory workers were exposed only to the lower concentrations. 

    Pregnancy toxaemia in the latter half of pregnancy and other 
complications were higher in the operators (14.7%) and laboratory 
workers (9.9%) than in the administrative staff (4.6%) and outside 
controls (8%).  On the other hand, the primiparae among the 
operators lost less blood perinatally than those among the other 
groups.  Spontaneous abortion occurred in 6 out of 57 (10.5%) 
operators, 3 out of 38 (7.9%) laboratory workers, and in 5 out of 
65 (7.7%) administrative staff.  The operators were subjected to 
the additional stress of high levels of noise and vibration and 
wide variations in atmospheric temperatures. 

    Findings in this study do not indicate any unequivocal adverse 
effect of ethylene oxide exposure at these concentrations on the 
outcome of pregnancy. 

    An increase in spontaneous abortions was also found in a study 
on Finnish hospital sterilizing staff in 1980, using questionnaires 
and hospital discharge records.  The sterilizing agents were 
ethylene oxide, glutaraldehyde, and formaldehyde.  Controls were 
nursing auxiliaries, from various hospitals, who did not work in 
sterilization, anaesthetization, or X-ray recording departments.  
Results were adjusted for age, parity, decade of the reported 
pregnancy, coffee and alcohol consumption, and smoking habits. 

    The rate of spontaneous abortions in the sterilization staff 
members as a whole (9.7% in 1443 pregnancies) was similar to the 
rate in the controls (10.5% in 1179 pregnancies).  A significant 
increase, however, was observed when the adjusted spontaneous 
abortion rate in the sterilization staff who were exposed during 
pregnancy (15.1% in 545 pregnancies) was compared with the rate in 
the staff members who were not exposed during pregnancy (4.6% in 
605 pregnancies).  On the basis of a separate study, the time-
weighted average exposure concentration was estimated to be in the 
range of 0.18 - 0.90 mg/m3 (0.1 - 0.5 ppm), with peak concentrations 
up to 450 mg/m3 (250 ppm).  It was considered by the authors that 
exposure to ethylene oxide accounted for most of the excess 
spontaneous abortions (Hemminki et al., 1982). 

    In a new analysis of the data, controls were chosen from the 
same hospitals, and only pregnancies that started during hospital 
employment were analysed in all groups.  The spontaneous abortion 
rate was still highest for the pregnancies during which exposure to 
ethylene oxide took place (20.4%), and the difference compared with 

controls (11.3%) was significant.  The abortion rate of the group 
exposed to glutaraldehyde alone (16.6%) was also significantly 
elevated (Hemminki et al., 1983). 

    Despite any methodological shortcomings of this reproductive 
study, such as (a) the statement by Hemminki in 1983 that there was 
limited exposure data, which prevented a comparison between 
abortion rates and defined exposure levels; and (b) the fact that 
the ethylene oxide-exposed and unexposed cohorts were not balanced 
with regard to the incidence of prior abortions, there is a 
suggestion of an association between ethylene oxide exposure and 
adverse pregnancy outcome. 


    Human exposure is mainly through inhalation of the vapour.  
Residues in medical equipment that has been sterilized with 
ethylene oxide and not sufficiently aerated can migrate into 
tissues and blood, producing primarily local effects (section 8.4).  
Oral ingestion of ethylene oxide residues in most fumigated or 
sterilized foodstuffs is unlikely, as they disappear rapidly 
through evaporation or reaction with food constituents.  A major 
conversion product in foodstuffs is 2-chloroethanol, which is more 
persistent than ethylene oxide (section 4.2.1). 

    Most ethylene oxide is used in the chemical plant in which it 
is produced.  Because of the explosion hazard, ethylene oxide is 
stored and handled in chemical process plants in closed, automated 
systems.  This equipment is often located outdoors, and, except 
during maintenance, workers have a minimal chance of exposure.  Air 
samples collected in processing areas of chemical production plants 
have shown that ethylene oxide vapour concentrations are generally 
less than 4 mg/m3 with occasional high peak exposures (section 
4.3).  Occupational exposure to ethylene oxide tends to be much 
higher in health instrument manufacture and in hospitals than in 
the chemical processing industries.  Ethylene oxide concentrations 
near malfunctioning or improperly designed equipment may reach 
hundreds of mg/m3 of air for brief periods.  However, 8-h time-
weighted average breathing-zone air concentrations in hospitals are 
generally less than 36 mg/m3.  It should be emphasized that the 
exposure of hospital workers to ethylene oxide tends to be of a 
short-term and intermittent nature with the likelihood of exposure 
to short-term (5 - 120 min) concentrations of about 100 mg/m3 and 
to peak concentrations of up to 1800 mg/m3 following the opening of 
sterilization chambers (section 4.3). 

    Ethylene oxide has a high solubility in water but will 
evaporate to a great extent.  Degradation of ethylene oxide in 
neutral water is slow, even in the presence of aerobic 
microorganisms.  Because of the low log  n-octanol water-partition 
coefficient, it is unlikely that ethylene oxide and its conversion 
products (such as 1,2-ethanediol) will bioaccumulate.  The toxicity 
of ethylene oxide for aquatic organisms is low (all available LC50s 
are above approximately 90 mg/litre) (Table 3).  The probable 
effects of ethylene oxide on the aquatic environment are, 
therefore, considered negligible (sections 3.2, 6).  There are no 
data concerning the toxicity of ethylene oxide for terrestrial 

    No ambient air monitoring data are available from which the 
effects of ethylene oxide on the health of man and the environment 
can be assessed.  However, the risk for health from exposure to 
ethylene oxide in the ambient air, apart from point source 
emissions and accidental spillage, is likely to be negligible. 

    Inhaled ethylene oxide is readily absorbed into the blood, 
distributed throughout the body, and rapidly metabolized.  The 
half-life in the tissues of man and rodents is approximately 
10 min; clearance from the blood of dogs occurred with a half-
life of 33 min (section 5.2).  Marked nausea and profuse vomiting 
following dermal exposure of man to aqueous solutions of ethylene 
oxide suggest that absorption can occur through the skin (section 

    Case reports indicate that headache, nausea, vomiting, 
dyspnoea, and respiratory tract irritation are common effects of 
acute inhalation exposure to ethylene oxide (section 8.3).  Case 
reports and the results of animal studies indicate that 
sensorimotor neuropathies may follow repeated exposure to 
concentrations of ethylene oxide recognizable by its odour 
(approximately 900 mg/m3 or more) (sections 2.2, 7.2.1, 8.3). 

    Dermatological effects in man following skin contact with 
ethylene oxide include erythema, oedema, and vesiculation, in that 
order.  The severity of the skin injury is related to concentration 
(a 50% (500 g/litre) solution being most hazardous) and duration of 
contact.  Liquid ethylene oxide, as it vaporizes, can result in a 
freeze burn.  On repeated exposure, ethylene oxide may cause 
delayed allergic contact dermatitis (sections 8.1, 8.2).  Ethylene 
oxide and its conversion products are irritating to the eyes and 
can produce corneal injury.  Cataracts have occurred following 
repeated exposure to concentrations of the vapour recognizable by 
its odour (approximately 900 mg/m3 or more) (Table 1, sections 8.1, 

    Ethylene oxide directly alkylates proteins and DNA and is 
mutagenic in microorganisms, plants, insects, mammalian cells  in 
 vitro, and mammals  in vivo, including both gene mutations and 
chromosomal abnormalities (section 7.5).  In man, ethylene oxide 
induces chromosomal aberrations and sister chromatid exchanges in 
lymphocytes at air concentrations found at the workplace (section 
8.7).  Tissue distribution studies provide evidence that ethylene 
oxide reaches the gonads, supporting the findings of heritable 
mutations in insects and rodents (sections 5.2, 7.5).  Ethylene 
oxide may, therefore, be considered a potential human mutagen for 
both somatic and germ cells. 

    The potential of ethylene oxide to cause teratogenic or adverse 
reproductive effects has been examined in 4 animal species (mouse, 
rat, rabbit, and monkey) by 2 routes of administration.  Results 
from these studies showed that ethylene oxide is toxic to 
reproductive function in both males (reduced sperm number and sperm 
motility, and an increased time to traverse a linear path) and 
females (depression of fetal weight gain, fetal death, and fetal 
malformation).  The levels needed to produce these fetal effects 
approach or equal the dose needed to produce maternal toxicity 
(section 7.6).  The results of animal studies suggest possible 
reproductive impairment in human males but are inadequate for 
assessing the fetal risk.  Data on reproductive effects in human 
beings are insufficient; one study, however, suggests an increase 

in spontaneous abortion rate in women occupationally exposed to 
ethylene oxide (section 8.8).  However, the reported time-weighted 
average air concentrations may not reflect the exposure levels that 
induced the effect. 

    It has been clearly demonstrated in experimental animal studies 
that ethylene oxide is carcinogenic via different routes of 
exposure (intragastric, subcutaneous injection, and inhalation).  
In 2 inhalation studies, confirmatory data demonstrated dose-
related increases in the incidences of leukaemia, peritoneal 
mesothelioma, and cerebral glioma (section 7.4).  Although the 
evidence for the carcinogenicity of ethylene oxide in man is 
inadequate, epidemiological studies indicate that exposure to 
ethylene oxide (in mixtures with other chemicals) increases the 
risk of malignancies (section 8.6). 

    Taking into account available data concerning the alkylating 
nature of ethylene oxide, the demonstration of DNA adducts, the 
overwhelming positive  in vivo responses in mutagenic and 
clastogenic assays, the reproducible positive carcinogenic findings 
in animals, and the epidemiological findings suggesting an increase 
in the incidence of human cancer, ethylene oxide should be 
considered as a probable human carcinogen, and its levels in the 
environment should be kept as low as feasible. 


    1.  The study indicating that exposure to ethylene oxide may be 
        associated with spontaneous abortion needs to be 
        corroborated and the implication explored further.

    2.  The possible effects of ethylene oxide on the reproductive 
        function of man should be studied.

    3.  The epidemiological studies indicating an increased risk of 
        cancer in workers exposed to ethylene oxide in combination 
        with other chemicals strongly suggest that additional 
        epidemiological studies should be carried out on 
        populations whose exposure has been primarily to ethylene 
        oxide, including adequate quantification of past exposure.

    4.  The temporal relationships of air concentrations of 
        ethylene oxide and duration of exposure must be examined to 
        determine which of these two factors has the greater impact 
        on health.

    5.  Development of methods and research should be conducted to 
        assess the endogenous occurrence of hydroxyethylation and 
        the exogenous (environmental) contribution of ethylene 
        oxide and its precursors to the formation of macromolecular 
        adducts as markers of internal dose.


    An International Agency for Research on Cancer Working Group 
(IARC, 1985) evaluated the carcinogenicity of ethylene oxide and 
concluded that: 

    "There is sufficient evidence for the carcinogenicity of
ethylene oxide to experimental animals; there is limited
evidence for the carcinogenicity to humans of exposures to
ethylene oxide in combination with other chemicals; there is
inadequate evidence for the carcinogenicity to humans of
exposures to ethylene oxide alone.  Taken together, the data
indicate that ethylene oxide is probably carcinogenic to


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    See Also:
       Toxicological Abbreviations
       Ethylene oxide (HSG 16, 1988)
       Ethylene oxide (ICSC)
       ETHYLENE OXIDE (JECFA Evaluation)
       Ethylene oxide (FAO Meeting Report PL/1965/10/2)
       Ethylene oxide (FAO/PL:1968/M/9/1)
       Ethylene oxide (WHO Pesticide Residues Series 1)
       Ethylene oxide (CICADS 54, 2003)
       Ethylene Oxide (IARC Summary & Evaluation, Volume 60, 1994)