International programme on chemical safety




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INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


ENVIRONMENTAL HEALTH CRITERIA 55


ETHYLENE OXIDE


This report contains the collective views of an international group of

experts and does not necessarily represent the decisions or the stated

policy of the United Nations Environment Programme, the International

Labour Organisation, or the World Health Organization.


Published under the joint sponsorship of

the United Nations Environment Programme,

the International Labour Organisation,

and the World Health Organization


World Health Orgnization

Geneva, 1985


The International Programme on Chemical Safety (IPCS) is a

joint venture of the United Nations Environment Programme, the

International Labour Organisation, and the World Health

Organization. The main objective of the IPCS is to carry out and

disseminate evaluations of the effects of chemicals on human health

and the quality of the environment. Supporting activities include

the development of epidemiological, experimental laboratory, and

risk-assessment methods that could produce internationally

comparable results, and the development of manpower in the field of

toxicology. Other activities carried out by the IPCS include the

development of know-how for coping with chemical accidents,

coordination of laboratory testing and epidemiological studies, and

promotion of research on the mechanisms of the biological action of

chemicals.


ISBN 92 4 154195 4


The World Health Organization welcomes requests for permission

to reproduce or translate its publications, in part or in full.

Applications and enquiries should be addressed to the Office of

Publications, World Health Organization, Geneva, Switzerland, which

will be glad to provide the latest information on any changes made

to the text, plans for new editions, and reprints and translations

already available.


(c) World Health Organization 1985


Publications of the World Health Organization enjoy copyright

protection in accordance with the provisions of Protocol 2 of the

Universal Copyright Convention. All rights reserved.


The designations employed and the presentation of the material

in this publication do not imply the expression of any opinion

whatsoever on the part of the Secretariat of the World Health

Organization concerning the legal status of any country, territory,

city or area or of its authorities, or concerning the delimitation

of its frontiers or boundaries.


The mention of specific companies or of certain manufacturers'

products does not imply that they are endorsed or recommended by the

World Health Organization in preference to others of a similar

nature that are not mentioned. Errors and omissions excepted, the

names of proprietary products are distinguished by initial capital

letters.


CONTENTS


ENVIRONMENTAL HEALTH CRITERIA FOR ETHYLENE OXIDE


1. SUMMARY


2. PROPERTIES AND ANALYTICAL METHODS


2.1. Identity

2.2. Chemical and physical properties of ethylene oxide

2.3. Analytical methods


3. SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT

AND DISTRIBUTION


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. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE


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. KINETICS AND METABOLISM


5.1. Absorption

5.2. Distribution

5.3. Metabolic transformation and excretion


6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT


7. EFFECTS ON ANIMALS


7.1. 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. EFFECTS ON MAN


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


9. EVALUATION OF THE HEALTH RISKS FOR MAN AND EFFECTS ON

THE ENVIRONMENT


10. RECOMMENDATIONS FOR FURTHER RESEARCH


11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES


REFERENCES




WHO TASK GROUP ON ETHYLENE OXIDE


Members


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-

Chairman)


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


Observers


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

Kingdom


Secretariat


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

Adviser)


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

Lyons, France


-------------------------------------------------------------------

a IPCS Consultant.


PREFACE


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.


ENVIRONMENTAL HEALTH CRITERIA FOR ETHYLENE OXIDE


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

oxide.


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

PUBLIC HEALTH AND ENVIRONMENTAL HYGIENE, Bilthoven, the

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.


1. SUMMARY


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

levels.


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
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