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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 56






    PROPYLENE 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


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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR PROPYLENE OXIDE

 1. SUMMARY

 2. PROPERTIES AND ANALYTICAL METHODS

     2.1. Identity
     2.2. Chemical and physical properties of propylene 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
     4.3. Occupational exposure

 5. KINETICS AND METABOLISM

     5.1. Absorption
     5.2. Distribution, metabolic transformation, and excretion

 6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

 7. EFFECTS ON ANIMALS

     7.1. Single exposures
          7.1.1. Oral exposure
          7.1.2. Skin and eye irritation
          7.1.3. Inhalation exposure
     7.2. Repeated exposures
          7.2.1. Oral exposure
          7.2.2. Inhalation exposure
     7.3. Mutagenicity and related end-points
     7.4. Carcinogenicity
          7.4.1. Oral exposure
          7.4.2. Inhalation exposure
          7.4.3. Subcutaneous exposure
     7.5. Effects on reproduction and teratogenicity

 8. EFFECTS ON MAN

     8.1. Exposure of skin and eyes; skin sensitization
     8.2. Accidental inhalation exposure
     8.3. Occupational inhalation exposure
     8.4. Mortality studies
     8.5. Mutagenicity and related end-points

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

10. RECOMMENDATIONS FOR FURTHER RESEARCH

11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

WHO TASK GROUP ON PROPYLENE OXIDE

 Members

Dr R. Bruce, Environmental and Criteria Assessment Office, US
   Environmental Protection Agency, Research Triangle Park,
   North Carolin, 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

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 propylene 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 propylene 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 PROPYLENE OXIDE

    The WHO Task Group for the Environmental Health Criteria
for Propylene 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
propylene 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

    Propylene oxide is a colourless, highly volatile, and flammable 
liquid at room temperature and normal atmospheric pressure.  It is 
very reactive towards nucleophiles.  The compound can be determined 
in air, by gas chromatography, with a detection limit of 0.06 µg/m3 
and, in food, with a limit of 0.1 mg/kg.  Detection limits of 
various other methods include 0.3 µg/litre in biological fluids and 
30 mg/kg in synthetic materials.

    World production of propylene oxide exceeds 2000 kilotonnes per 
year, most of which is used as a chemical intermediate.  Small 
amounts are used for the sterilization of medical equipment and for 
the fumigation of foodstuffs.  About 0.07% of all the propylene 
oxide used is lost to the atmosphere.  The compound can be removed 
from the atmosphere by slow oxidation and by rain.  It evaporates 
from water and is not expected to bioaccumulate.  Aerobic 
biodegradation is slow. 

    The main route of human exposure is through inhalation at the 
workplace.  No published data have been found on ambient levels 
away from point sources.  Eight-hour time-weighted average 
occupational exposure levels are normally less than 5 mg/m3.  
However, peak exposures of up to 9010 mg/m3 have been recorded.

    Analyses of fumigated foodstuffs revealed that the propylene 
oxide derivatives, chloropropanols and 1,2-propane-diol, were 
present at levels ranging from 4 to 47 mg/kg and 29 to 2000 mg/kg, 
respectively.  However, in pure lipids, where degradation is 
minimal, levels of propylene oxide of over 4000 mg/kg have been 
determined.  Levels of up to 6260 mg/kg have been found in wrapping 
materials. 

    Available LC50 values for propylene oxide in various fish
species range between 89 and 215 mg/litre for a 96-h exposure.

    From  in vitro studies, it would appear that propylene oxide 
is metabolized by glutathione epoxide transferase to  S-(2-hydroxy-
1-propyl)glutathione.  It is converted to 1,2-propanediol by epoxide 
hydrolase and non-enzymic hydrolysis, but both of these reactions 
are slow.  The diol can be oxidized to lactic and pyruvic acid. 

    The oral LD50 has been reported to be 630 mg/kg body weight 
for the mouse, 660 mg/kg for the guinea-pig, and from 520 to 
1140 mg/kg for the rat.  Damage to the stomach mucosa and liver was 
observed in rats exposed to such levels.         

    The 4-h LC50s for the rat and the mouse via inhalation were 
9500 and 4100 mg/m3, respectively.  At these concentrations, 
there was severe eye and nose irritation, laboured breathing, and 
central nervous system depression. 

    With repeated exposure (6 h/day, 5 days/week, for 2 weeks) to 
propylene oxide concentrations ranging from 110 - 3400 mg/m3 
(rats) and 50 - 1150 mg/m3 (mice), dyspnoea was observed in rats 
exposed to 3400 mg/m3 and in mice exposed to 460 mg/m3 and 
1150 mg/m3.  Reduced activity was observed in both species, and 
irregular limb movement was seen in rats.  After exposure to 
concentrations of propylene oxide of 240, 460, or 1080 mg/m3 for 
112 - 218 days (7 h/day, 5 days/week), monkeys and rabbits did not 
show any adverse effects, but irritation of the eyes and respiratory 
passages was observed in rats and guinea-pigs at 1080 mg/m3.  
Internally, changes were found only in the lungs in both species 
and consisted of oedema and haemorrhage.  In addition, an increase 
in lung weight was observed in female guinea-pigs exposed at 
460 mg/m3.

    A dose-related increase in the incidence of inflammatory 
lesions and proliferative lesions in the nasal epithelium was
observed in Fischer 344/N rats and B6C3F1 mice exposed to 470 or 
940 mg/m3, for 6 or 7 h per day, 5 days/week, for 2 years.
Similar inflammatory lesions and hyperplasia were also observed at 
240 mg/m3 in another study on Wistar rats exposed for 6 h/day, 
5 days per week, for 124 weeks.  Non-neoplastic effects were not 
observed in the nasal mucosa or internal organs of rats exposed to 
70 mg/m3.

    Axonal dystrophy was observed in the nucleus gracilis in
cynomolgus monkeys, 2 per group, exposed to 237 and 717 mg
propylene oxide/m3 (7 h/day, 5 days/week) for 2 years.  One of
two untreated monkeys also showed such changes.  The changes in 
the treated groups were more pronounced than those in the controls.

    A dose-related increase in the incidence of squamous cell 
carcinoma of the forestomach was observed in rats treated by gavage 
for 112 weeks with 0, 15, or 60 mg propylene oxide/kg body weight 
dissolved in salad oil.  The numbers of rats affected were 0 
(controls), 2, and 19, respectively.  When propylene oxide, 
dissolved in trycaprylin, was administered subcutaneously to mice, 
once a week, for 106 weeks, only local sarcomas were induced.  The 
numbers of animals exhibiting sarcomas were 0/200 in untreated 
controls, 4/200 in tri-caprylin controls, and 3/100, 2/100, 12/100, 
and 15/100 in mice treated with 0, 0.1, 0.3, 1.0, and 2.5 mg per 
injection, respectively. 

    The carcinogenicity of propylene oxide inhalation exposure has 
been investigated in rats and mice.  Two studies have been conducted 
on Fischer 344 rats using groups of 80 - 100 animals, for 2 years.  
In one study, exposure was to concentrations of 470 and 940 mg/m3, 
6 h/day, for 5 days per week, over 103 weeks; in the second, exposure 
was to concentrations of 237 - 717 mg propylene oxide/m3, for
7 h/day, 5 days/week, over 2 years.  A few adenomas were observed 
in the nasal cavity in both studies at the highest level of treatment.  
When Wistar rats were treated with 70, 242, or 712 mg/m3, 6 h/day, 
5 days per week, for 124 weeks, no nasal tumours were reported, but

a dose-related increase in the incidence of multiple mammary 
fibroadenoma was observed.  There was no increased incidence of 
brain tumours.

    In mice, malignant nasal tumours were induced.  Groups of 50 
B6C3F1 mice of each sex were exposed to 470 and 940 mg/m3 
propylene oxide, for 6 h/day, 5 days/week, over 103 weeks.  Tumours 
in the nasal cavity occurred in both sexes.  Haemangiosarcomas were 
observed in the nasal cavity of 5 male and 2 female mice at the 
higher concentration, and haemangiomas appeared in 5 males and 3 
females at the same site.  In addition, one squamous cell carcinoma 
and one papilloma appeared in high-dose males and 2 adenocarcinomas 
in high-dose females, at the same site.  No treatment-related 
tumours were observed at the lower dose.

    No teratogenic or fetotoxic effects were observed when pregnant 
New Zealand rabbits were exposed through inhalation to 1190 mg 
propylene oxide/m3, for 7 h/day, during days 1 - 19 days 7 - 19 
of gestation.  An increase in the number of resorptions was found 
when Sprague Dawley rats were exposed to 1190 mg propylene oxide/m3, 
for 7 h/day, during days 7 - 16 of gestation.  Some reduction in 
ossification in vertebrae and ribs and wavy ribs were found when 
pregnant Sprague Dawley rats were similarly exposed on days 1 - 16 
of gestation.  When rats were exposed for 3 weeks prior to mating 
and on days 1 - 16 of gestation, the numbers of corpora lutea, 
implantations per dam, and live fetuses were decreased compared 
with those in the other groups.

    Propylene oxide is mutagenic to microorganisms and insects and 
produced mutations, DNA damage, and chromosomal effects in mammalian 
cells  in vitro.  Negative results in such studies have never been 
reported.   In vivo, propylene oxide induced a 5-fold increase in 
micronuclei in mice, when given intraperitoneally (ip) at a 
concentration of 300 mg/kg body weight, but not at 150 or 75 mg/kg 
body weight, nor when administered orally.  No dominant-lethal 
effects were observed, when propylene oxide was administered via 
inhalation to male rats at 720 mg/m3 for 5 days prior to mating, 
or, when it was administered daily, by the oral route, to male mice 
at 50 or 250 mg/kg body weight for 2 weeks prior to mating.  No 
increase in chromosome aberrations or sister chromatid exchanges in 
peripheral lymphocytes were observed in male Cynomolgus monkeys 
exposed to 237 or 717 mg propylene oxide/m3 air, for 7 h/day, 5 
days per week, for 2 years. 

    No sperm head abnormalities were detected in mice after 
exposure for 7 h/day, for 5 days, to 720 mg propylene oxide/m3 or 
in cynomolgus monkeys exposed to 240 or 710 mg/m3 for 2 years.

    There are no adequate epidemiological studies to assess the 
toxic effects of propylene oxide on man.  Taking into account the 

body of available data - the alkylating nature of propylene oxide, 
the formation of DNA adducts, the positive responses in  in vitro 
mutagenesis assays, the carcinogenic effects in animals at sites of 
entry into the body, and the absence of adequate data on cancer in 
human beings - propylene oxide should be considered as a possible 
human carcinogen.  Therefore, propylene oxide should be regarded, 
for practical purposes, as presenting a carcinogenic risk for man, 
and levels in the environment should be kept as low as feasible.

2.  PROPERTIES AND ANALYTICAL METHODS

2.1.  Identity

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

Molecular formula:        C3H6O

Abbreviation:             PO

Common synonyms:          1,2-epoxypropane, methyl ethylene
                          oxide, methyl oxirane (IUPAC and
                          CAS name), propene oxide, propylene
                          epoxide, 1,2-propylene oxide

CAS registry number:      75-56-9

RTECS registry number:    TZ2975000

2.2.  Chemical and Physical Properties of Propylene Oxide

    Propylene oxide is a colourless, highly-volatile liquid at
room temperature and normal atmospheric pressure.  It is highly 
flammable.  The vapour will form an explosive mixture with air.  
The substance may polymerize violently.  Ring opening occurs in 
reactions with nucleophiles, such as water, alcohols, amines, 
halides, and sulfhydryl compounds.  Propylene oxide is very 
reactive, particularly with chlorine, ammonia, strong oxidants, 
and acids.  Some physical and chemical data on propylene oxide are 
given in Table 1.

    Conversion factor   1 ppm = 2.37 mg/m3 air at 25 °C
                        and 101.3 kPa (760 mm Hg)

Table 1.  Some physical and chemical data on propylene oxide
-------------------------------------------------------------------
physical state                  liquid                                   
                                                                         
colour                          colourless                               
                                                                         
odour                           ethereal                                 
                                                                         
odour threshold                 20 mg/m3 for perception and              
                                80 - 470 mg/m3 for recognitiona          
                                                                         
relative molecular mass         58.08                                    
                                                                         
melting point                   -104 °C                                  
                                                                         
boiling point                   34 °C                                    
                                                                         
water solubility                405 g/litre, 20 °C                       
                                                                         
log  n-octanol-water partition   -0.13                                   
 coefficient

density                         0.83 g/ml, 20 °C                         
                                                                         
relative vapour density         2.0                                      
                                                                         
vapour pressure                 59 kPa (445 mm Hg), 20 °C                
                                                                         
flash point                     -37 °C (open-cup)                        
                                                                         
flammable limits                2 - 37% by volume in air                 
------------------------------------------------------------------- 
a  From: Jacobson et al. (1956) and Hellman & Small (1974).

2.3.  Analytical Methods

    A summary of methods for the sampling and determination of
propylene oxide in air, water, food, synthetic materials (including, 
e.g., medical equipment), and biological media is presented in 
Table 2.  However, the methods for the determination in water, 
synthetic materials, or biological media are not specific for 
propylene oxide.

    It was proposed that, as for ethylene oxide (Ehrenberg et al., 
1974; Osterman-Golkar et al., 1976, 1983), the determination of the 
degree of alkylation of amino acids, and specifically histidine, in 
haemoglobin could be used for monitoring the tissue doses of propylene 
oxide.  Assuming even distribution, dose is defined as the integral 
of the calculated concentration of free propylene oxide in the 
tissues over a specified period of time (Farmer et al., 1982; 
Svensson & Osterman-Golkar, 1984).  Methods for the  determination 
of  N3-(2-hydroxypropyl)histidine in rat haemoglobin have been
described using gas chromatography with mass spectrometry (Farmer 
et al., 1982) and high-performance liquid chromoatography after

derivatization with fluorescamine (Svensson & Osterman-Golkar, 
1984).  In rats, the alkylation of haemoglobin was found to 
increase linearly with the level of exposure to propylene oxide 
vapour, with a detection limit of 0.002 mg alkylated histidine/kg 
haemoglobin (Farmer et al., 1982).  Human haemoglobin has a life-
span of about 4 months and, therefore, will integrate the dose of 
propylene oxide over a long period.  The method was applied to 
samples from industrial workers by Osterman-Golkar et al. (1984).  
A low background level of alkylation was observed, which may limit
the resolving power of detection at average exposures below 
0.7 mg/m3.  More work is needed to establish the relationship
between propylene oxide exposure and haemoglobin alkylation in
human beings.


Table 2.  Sampling, preparation, analysis
---------------------------------------------------------------------------------------------------------
Medium      Sampling        Analytical method        Detection     Comments             Reference                              
            method                                   limit                                                                                
---------------------------------------------------------------------------------------------------------
Air         adsorption      gas chromatography       0.06 µg/m3    suitable for         Krost et al.                           
            on Tenax-       with mass spectrometric                analysis of          (1982)                                 
            GC, thermal     detection                              ambient air                                                            
            desorption,                                                                                                                                                                                               
            cryofocusing                                                                                                                                                                                              
                                                                                                                                          
Air         adsorption      gas chromatography                     recommended for      NIOSH (1977)                           
(work-      on coconut      with flame ionization                  the range                                                        
place)      charcoal,       detection                              25-720 mg/m3;                                                          
            desorption                                             suitable                                                               
            by carbon                                              for personal                                                           
            disulfide                                              and area sampling                                           
                                                                                                                                          
Air         adsorption on   gas chromatography       2 µg/m3                            Russell (1975)                                    
            Tenax or        with flame ionization                                                                                        
            Porapak N,      detection                                                                                          
            thermal                                                                                                                                                                                                   
            desorption                                                                                                                                                                                                
                                                                                                                               
Water                       colorimetry using        detection     the method is        Mishmash & Meloan                      
                            cadmium iodide after     limit in the  not specific         (1972)                                            
                            hydrolysis and           nmole range                                                                          
                            reaction with periodate                                                                                       
                            in the solvent system                                                                                         
                            1,2-dimethoxyethane-                                                                                         
                            water                                                                                              
                                                                                                                                          
Water                       potentiometric ti-                     the method is not    Swan (1954)                                       
                            tration using hydro-                   specific                                                               
                            chloric acid after                                                                                            
                            reaction with sodium                                                                                         
                            sulfite                                                                                            
---------------------------------------------------------------------------------------------------------

Table 2.  (contd.)
---------------------------------------------------------------------------------------------------------
Medium      Sampling        Analytical method        Detection     Comments             Reference                              
            method                                   limit                                                                                
---------------------------------------------------------------------------------------------------------
Food        extraction      gas chromatography       0.1 mg/kg     sample size          Heuser & Scudamor                                 
            by 5:1          with beta-ionization     wet weight    5-10 g               (1969)                                           
            acetone-water   detection                                                                                              
            by volume                                                                                                                                                                                                 
            for 24 h                                                                                                                                                                                                  

Synthetic   distillation    titration using hydro-   30 mg/kg      sample size 2 g;     Gunther (1965)                                    
 materials  of samples      gen bromide in glacial                 the method is                                                          
            in monochloro-  acetic acid                            not specific                                                          
            benzene                                                                                                      
            into glacial                                                                                                                                                                                              
            acetic acid                                                                                                                                                                     
                                                                                                                                               
Biological                  fluorimetry employing    0.3 mg/litre  sample size          Nelis & Sinsheime                                        
 media                      alkylation of nicotin-                 0.1 ml; direct       (1981)                                                  
 (blood,                    amide followed by a                    analysis; inter-                                                       
 urine)                     reaction with aceto-                   ference by other                                                   
                            phenone to a fluor-                    alkylating agents                                           
                            escent compound                                                                                    
---------------------------------------------------------------------------------------------------------
3.  SOURCES IN THE ENVIRONMENT, ENVIRONMENTAL TRANSPORT AND 
DISTRIBUTION

3.1.  Production, Uses, Disposal of Wastes

3.1.1.  Production levels and processes

    Propylene oxide is produced in the USA, western Europe, Japan, 
and several other countries.  In the USA, production increased from 
800 kilotonnes in 1974 to 1020 kilotonnes in 1979.  However, 
production in 1983 was estimated to be 720 kilotonnes (Bogyo et al., 
1980; Webber, 1984; IARC, 1985).  In western Europe, 850 kilotonnes 
were produced in 1979 and 810 kilotonnes in 1982; in Japan, 130 
kilotonnes were produced in 1974 and 190 kilotonnes in 1982 (IARC, 
1976, 1985).

    Propylene oxide can be produced by the chlorohydrin process or 
by peroxidation.  In the first of these processes, 1-chloro-2-
propanol and 2-chloro-1-propanol react with potassium hydroxide or 
calcium oxide to form propylene oxide. In the second process, 
propylene oxide is synthesized through a catalysed reaction between 
propene and tertiary butyl hydroperoxide.  Tertiary butyl hydro-
peroxide is prepared by the oxidation of isobutane (WHO, 1978).  
Common impurities, that may be present in small amounts include 
water, acetic acid, chloride, and aldehydes.  Small amounts of 
monochloroacetone, 1,2-dichloro-3-propanol, and propylene dichloride 
can occur in propylene oxide, produced by the chlorohydrin process
(IARC, 1985).

3.1.2.  Uses

    Most propylene oxide produced is used as an intermediate in 
the production of various chemicals.  In order of importance, in 
the USA, these chemicals are:  polyether polyols for urethanes, 
propylene glycol, mainly for polyester fibres, polypropylene 
glycol, dipropylene glycol, glycol ethers, glycerin, and 
surfactants.  Minor quantities are used for the (antimicrobial) 
sterilization or (insecticidal) fumigation of medical equipment and 
foodstuffs (IARC, 1976; WHO, 1978).  Small quantities are also used 
in the production of modified food starch and alginate and as a 
stabilizer in dichloromethane.

3.1.3.  Disposal of wastes

    The emission of propylene oxide through process vents appears 
to be the most important source of atmospheric pollution.  However, 
the waste gas can be removed from air by scrubbing, and emission 
from liquid wastes can be controlled by incineration.  Little, if 
any, propylene oxide seems to be released in waste water in the 
chlorohydrin process, but an environmental problem is created by 
large amounts of by-products such as calcium chloride and chlorinated 
organic compounds.  No specific solid wastes are associated with the
manufacture of propylene oxide (Bogyo et al., 1980).

3.2.  Transport and Fate in the Environment

    Propylene oxide enters the environment mainly through 
evaporation and in vented gases during production, handling, 
storage, transport, and use.  Most of the propylene oxide applied 
as a sterilant or fumigant will finally enter the atmosphere (Bogyo 
et al., 1980).  In the USA, in 1981, a total loss to the atmosphere 
of almost 600 tonnes of propylene oxide was estimated, or 
approximately 0.07% of total production (Storck, 1981; US EPA, 
1981).

    The major removal of propylene oxide from the atmosphere will 
occur rapidly via oxidation by hydroxyl radicals.  On the basis of 
a theoretical rate constant for this reaction, the atmospheric 
residence time of propylene oxide was calculated to be 8.9 days 
(Cupitt, 1980), but by analogy with ethylene oxide (WHO, 1985), the 
real value is probably an order of magnitude greater.  Because of 
its high solubility in water, propylene oxide levels in air can 
also be reduced via washout by rain (Bogyo et al., 1980).  No data 
were found concerning the rate of evaporation of propylene oxide 
from water.  However, because of its lower vapour pressure and high 
water solubility, it can be assumed that the rate is slower for
propylene oxide than that for ethylene oxide, for which, under
certain specified conditions, a half-life of 1 h has been 
determined (Conway et al., 1983).  Chemical degradation in water 
via ionic reactions appears a slow process under environmental 
conditions.  In neutral fresh water, at 25 °C, propylene oxide will 
react to form 1,2-propanediol with a half-life of approximately 12 
days (Koskikallio & Whalley, 1959).  This reaction is acid catalysed.  
In marine waters, 1-and 2-halopropanols are also formed.  In neutral 
marine water, there is a preference for the formation of 1-halopropan-
2-ol (Addy & Parker, 1963).  Bogyo et al. (1980) estimated the
relative importance of the reaction of propylene oxide with water 
and that with chloride at 25 °C in neutral sea water of 3% salinity.  
According to these calculations, approximately 80% of the propylene 
oxide present will react to form chloropropanol; the remainder will 
react to form 1,2-propanediol.  The overall half-life with respect 
to these reactions is 4 days.

    Microorganisms from the effluent of a biological sanitary
waste treatment plant were found to degrade propylene oxide very 
slowly.  The biological oxygen demand (BOD) over 5 days was 8% of 
the theoretical oxygen demand (Bridié et al., 1979b).  In another 
study, the biological oxygen demand of microorganisms from activated 
sludge was 20% of the chemical oxygen demand (COD) over 4 h, after 
1 month of acclimation (Hatfield, 1957).  The aerobic bacteria 
 Nocardia A60 also oxidized propylene oxide after adaptation.  It 
has been established that the first step in bacterial metabolism is 
the conversion of propylene oxide to 1,2-propanediol by epoxide
hydrolase (EC 3.3.2.3), followed by dehydration and oxidation (Bont 
et al., 1982).

4.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

4.1.  Occurrence in the Environment

    The only available information on atmospheric concentrations of 
propylene oxide are estimates of levels in the vicinity of production 
plants.  The lowest annual average concentration occurring within 
20 km of a specific point source was estimated, using dispersion 
models, to be less than 4.836 x 10-8 mg/m3 (Anderson, 1983).  
No data are available indicating that propylene oxide occurs as a 
natural product.

4.2.  General Population Exposure

   Exposure via food

    The residue levels in food after fumigation or sterilization 
by propylene oxide will depend on factors similar to those 
investigated by Scudamore & Heuser (1971) in their studies on 
ethylene oxide.  Important factors are:  the total amount and 
concentration of propylene oxide, the composition of the treatment 
mixture, temperature, aeration and storage conditions after 
treatment, the type of commodity and its moisture content, pH, 
permeability, and particle size, and the method of packaging.

    Few residue data exist on propylene oxide.  In Japan, propylene 
oxide residues of up to several thousands mg/kg wet weight were 
measured in a variety of foodstuffs.  For example, after 24 h of 
aeration, at 37 °C, levels of over 4000 mg/kg were found in lard 
and oleic acid (Oguma et al., 1968, 1969).  Food wrappings and 
containers were also found to contain propylene oxide residues, 
after fumigation.  Depending on the materials, these levels 
fluctuated between 0 and 6260 mg/kg, 3 h after fumigation (Hirashima 
et al., 1970).  No migration studies were reported.

    Propylene oxide can react with water and chloride in commodities 
to form 1,2-propanediol and chloropropanol, respectively.  In 
commercially-fumigated walnut meat, flour, cocoa, glacé cherries, 
and glacé citrons, 4 - 47 mg 1-chloro-propan-2-ol/kg wet weight 
were measured in the USA (Ragelis et al., 1968).  When dehydrated 
mashed potatoes were sterilized, residues of 12.1 mg chloropropanol, 
mostly 1-chloropropan-2-ol, and 29 mg 1,2-propanediol/kg wet weight 
were measured.  There was no detectable reaction of propylene oxide 
with the starch (Steele & Hadziyev, 1976).  Residues of propylene 
oxide in packed prunes were no longer detectable, 7 days after
treatment.  At this time, over 50% of the propylene oxide added 
appeared to be converted to 1,2-propanediol; residue levels of this 
product exceeded 2000 mg/kg wet weight for many months (Mestres & 
Barrois, 1964).  Residues of 1,2-propanediol of 190 - 900 mg/kg wet 
weight were reported for flour, when wheat was treated with propylene 
oxide, before milling at room temperature.  The amount of residue

increased with the moisture content.  When the flour was treated 
after milling, 1000 mg/kg wet weight was found (Vojnovich & 
Pfeifer, 1967).

4.3.  Occupational Exposure

    Levels of propylene oxide were measured by personal sampling in 
8 plants in the Federal Republic of Germany, where alkene oxides 
were produced between 1978 and 1980.  In each case, the time-
weighted averages were reported to be far below 240 mg/m3, though 
higher concentrations were measured for brief periods (Thiess et 
al., 1981a).

    More detailed results were reported for a propylene oxide-
producing plant in the USA in 1979, where daily, time-weighted 
average exposures were found to range from 0.5 to 4.7 mg/m3.  
Peak air concentrations in that year were 24 - 9010 mg/m3 (Flores, 
1983).

    In a factory in Sweden, in 1981, where starches were alkylated 
with propylene oxide, the time-weighted average for 5 of the 
workers, potentially exposed to the highest levels of propylene 
oxide during their work, varied between 1.4 and 28 mg/m3.  The 
work with propylene oxide occupied 25 - 75% of the total working 
time.  Short-term exposures of up to 2370 mg/m3 were recorded 
for some workers (Pero et al., 1982).

5.  KINETICS AND METABOLISM

5.1.  Absorption

    No experimental data on the absorption of propylene oxide are 
available.

5.2.  Distribution, Metabolic Transformation, and Excretion

    There are no  in vivo data on the distribution and metabolism 
of propylene oxide.  On the basis of  in vitro experiments, 2 
metabolic pathways have been suggested (Tachizawa et al., 1982).  
Propylene oxide was found to be a substrate for rat liver 
glutathione epoxide transferase (EC 4.4.1.7), while nonenzymic 
conjugation was negligible (Fjellstedt et al., 1973).  It was also 
observed to be hydrolysed to 1,2-propanediol by epoxide hydrolase
(EC 3.3.2.3) from rat liver microsomes, but at a low rate 
(Guengerich & Mason, 1980; Dent & Schnell, 1981).  Propylene 
oxide was found to be a poor substrate for human liver epoxide
hydrolase (Oesch, 1974).  The nonenzymatic hydrolysis to 1,2-
propanediol is rather slow.  At 37 °C, the half-life for the 
uncatalysed reaction in a neutral medium was found to be 87 h 
(Ross, 1950).

    Propanediol can be excreted unchanged via the kidneys and can 
be oxidized to lactic and pyruvic acid (Ruddick, 1972).  The data 
are summarized in Fig. 1.

    Propylene oxide is a direct-acting agent, and  in vitro 
alkylation of DNA deoxynucleosides has been found.  A total of
15 different calf thymus DNA adducts of propylene oxide were
detected, which altered 1.3% of the nucleosides in the DNA
molecule (Randerath et al., 1981).  Guanosine and, to a lesser
extent, adenosine were alkylated to  N7-(2-hydroxypropyl)-
guanosine and  N3- or  N6-(2-hydroxypropyl)adenosine,
respectively (Lawley & Jarman, 1972; Walles, 1974; Hemminki et
al., 1980).  In rats, haemoglobin alkylation was established at 
the amino acids, cysteine, valine, and histidine (Farmer et al., 
1982; Svensson & Osterman-Golkar, 1984).  Histidine alkylation was 
found to increase linearly with the level of vapour exposure.  
Exposure of rats for 4 h to 3080 mg/m3 resulted in 10.5 mg 
hydroxypropylhistidine/kg haemoglobin (Farmer et al., 1982).

    On the basis of the haemoglobin alkylation data of Farmer et 
al. (1982), a half-life of approximately 40 min can be calculated 
for the elimination of propylene oxide from rat tissues, assuming 
100% alveolar absorption and first order kinetics.

FIGURE 1

6.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    In an acute toxicity test on goldfish  (Carassius auratus), 
in static fresh water, at 20 °C, pH between 6 and 8, and a 
dissolved oxygen content greater than 4 mg/litre, the 24-h LC50 
for propylene oxide was 170 mg/litre (Bridié et al., 1979a).  In 
other static tests, with the fresh water species bluegill sunfish 
 (Lepomis machrochirus) and mosquito fish  (Gambusia affinis), 
96-h LC50 values for propylene oxide were 215 and 141 mg/litre,  
respectively,  at 23 °C.  For the common mullet  (Mugil cephalus), 
a marine fish, a static 96-h LC50 for propylene oxide of 89 
mg/litre was determined at 23 °C and a water salinity of 1.5% (no 
water analysis was reported) (Crews, 1974).  The 24-h LC50 for 
1,2-propanediol (a product of propylene oxide) for goldfish was 
over 5000 mg/litre (Bridié et al., 1979a).  Propylene oxide is very
soluble in aqueous media; the log  n-octanol water partition 
coefficient was reported to be -0.13 (Radding et al., 1977) and, 
therefore, it is not expected to bioaccumulate.

7.  EFFECTS ON ANIMALS

7.1.  Single Exposures

7.1.1.  Oral exposure

    In 2 studies, the oral LD50s for the rat were reported to be 
1140 mg/kg body weight and 520 mg/kg body weight for males, and 
540 mg/kg for females (Smyth et al., 1941; Antonova et al., 1981); 
the difference between 16 and 84% mortality was caused by a dose of 
only approximately 300 mg/kg body weight, indicating a rather steep 
dose-effect relationship.  In one of these studies, oral LD50s for 
male mice and guinea-pigs were 630 and 660 mg/kg body weight, 
respectively (Antonova et al., 1981).

    At lethal oral doses, necrosis of the stomach mucosa was
observed in rats.  Succinate dehydrogenase (EC 1.3.99.1) activity 
was reported to be decreased in the stomach mucosa.  The liver 
cells showed oedema and fatty changes.  In serum, alanine amino-
transferase (EC 2.6.1.2) and aspartate aminotransferase (EC 2.6.1.1) 
activity and histamine levels were increased.  Kidney function was 
disturbed.  Mature lymphocytes were reduced in the spleen (Antonova 
et al., 1981).

7.1.2.  Skin and eye irritation

    Solutions of 100 or 200 g propylene oxide/litre water, applied 
under a plastic cover on the intact skin of rabbits produced hyper-
aemia, oedema, and finally scars after 6 or more min of exposure.  
The intensity of the effects was proportional to the exposure time 
(Rowe et al., 1956).

    No, or only slight, irritation was observed when undiluted
1,2-propanediol, a possible reaction product of propylene oxide in 
water, was applied to the skin of various animals under occlusive 
conditions for 24 or 72 h (Davies et al., 1972).

    When 5 µl of undiluted propylene oxide was applied once on the 
centre of the cornea of rabbits, a severe burn resulted with 
necrosis (Weil et al., 1963).

7.1.3.  Inhalation exposure

    In inhalation studies, the 4-h LC50s for rats and mice were 
9500 and 4100 mg/m3, respectively (Jacobson et al., 1956).  The 
lowest lethal concentration (US NTP, 1984) or the 0.1% mortality 
level (Jacobson et al., 1956) for 4-h exposures was approximately 
5250 mg/m3 for rats and 900 mg/m3 for mice.  In both species, 
100% mortality was reached after 4 h of exposure at levels above 
17 000 mg/m3 (Jacobson et al., 1956).  In rats, 100% mortality 
was also reported after a 30-min exposure to 38 000 mg/m3 or a 
7-h exposure to 9500 mg/m3 (Rowe et al., 1956).

    After inhalation of propylene oxide, rodents showed eye and 
nose irritation, nasal discharge, dyspnoea, and depression of the 
central nervous system, the severity of which increased with 
increasing level and length of the exposure (effect levels not 
specified) (Rowe et al., 1956).  Gross pathology revealed 
distension of the stomach only at lethal concentrations (Jacobson 
et al., 1956).  No organ damage was observed in rats exposed to 
2370 mg/m3 for 7 h, 4740 mg/m3 for 4 h, or 9480 mg/m3 for 0.5 h 
(Rowe et al., 1956).  In 4 groups, each containing 3 dogs, exposed 
for 4 h to propylene oxide concentrations of 3230, 4750, 4810, or 
5880 mg/m3, lachrymation, salivation, nasal discharge, and vomiting
occurred.  Congestion in the lungs and trachea, oedema of pulmonary 
tissues, and necrosis of bronchiolar epithelium were observed at 
4810 and 5880 mg/m3.  Deaths occurred in the groups exposed to 
concentrations of 4750 mg/m3 or more (Jacobson et al., 1956).

7.2.  Repeated Exposures

7.2.1.  Oral exposure

    Propylene oxide was administered in the drinking-water to 4 
groups of rats of both sexes at dose levels calculated by the 
authors to be 0.52, 5.2, 52, or 520 µg/kg body weight per day, over 
a 26-week period.  At the highest dose level, polyuria, haematological 
abnormalities, lowering of serum-albumin, increased serum-beta-
globulin levels, and increased activity of gastrointestinal mucosal 
enzymes were observed.  Mild haematological abnormalities occurred 
at the next lower dose, while no adverse effects were noted at the 
two lowest doses (Antonova et al., 1981).

7.2.2.  Inhalation exposure

    In range-finding tests for a carcinogenicity study, groups of 5 
male and 5 female Fischer 344/N rats were exposed to 0, 110, 230, 
460, 1150, or 3400 mg propylene oxide/m3 air for 5 days per week, 
and 6 h per day, during a 2-week exposure period.  B6C3F1 mice were 
exposed for the same period to 0, 50, 110, 230, 460, or 1150 mg/m3.  
All animals were necropsied on the 12th day.  No pathological 
effects were observed.  Body weights were not affected.  Dyspnoea 
and gasping were observed in rats, one of which died at 3400 mg/m3.  
Mice showed dyspnoea at 460 and 1150 mg/m3.  Both species were 
less active at the highest exposure.  Rats also showed irregular 
limb movements and diarrhoea.  After 13 weeks of a similar exposure
regime up to concentration of 1150 mg/m3, rats and mice did not 
show any gross- or histopathological effects.  Body weights were 
reduced at 1150 mg/m3 only (US NTP, 1984).

    Groups of 10 - 20 rats, 8 guinea-pigs, 1 or 2 rabbits of both 
sexes, and 1 or 2 female Rhesus monkeys were exposed to 0, 240, 
460, or 1080 mg propylene oxide/m3 air for 112 - 218 days, for 
7 h per day, and 5 days per week.  Rabbits and monkeys did not 

show any adverse effects with regard to appearance, behaviour, 
mortality rate, growth, organ weights, and gross- and histopathology.  
Rats showed irritation of the eyes and respiratory passages and an 
increased mortality rate due to pneumonia at 1080 mg/m3.  Guinea-
pigs also showed irritation of the eyes and respiratory passages at 
this exposure level, but no increase in mortality rate.  In 
addition, the growth of the female guinea-pigs was reduced.  Livers 
exhibited slight fatty degeneration in male guinea-pigs.  The 
relative weights of the lungs of the guinea-pigs were slightly, but 
significantly, increased in both sexes at 1080 mg/m3, and in 
females at 460 mg/m3.  It should be noted that control lung 
weights were low.  Histopathological findings were alveolar 
haemorrhages and oedema, and interstitial oedema and hyperaemia in 
the lungs of guinea-pigs after 157 days of exposure to 1080 mg/m3.  
After 37 - 39 days of exposure to 1080 mg/m3, these histopatho-
logical effects had also been observed in rats (Rowe et al., 1956). 

    The possibility of the induction of neuropathological effects 
by propylene oxide was investigated in groups of 12 male Cynomolgus 
monkeys.  The animals were exposed to actual concentrations of 0, 
237, and 717 mg/m3 propylene oxide, 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 neuropathological lesions found were in the medulla 
oblongata of the brain.  Axonal dystrophy was observed in the 
nucleus gracilis in all of the 4 treated monkeys examined, without 
any apparent dose-effect relationship.  The same lesion was observed 
in one of the two control monkeys (Sprinz et al., 1982).

7.3.  Mutagenicity and Related End-Points

    A summary of mutagenicity tests with positive results is 
presented in Table 3.  Propylene oxide is mutagenic in bacteria, 
fungi, and insects; no such studies with negative results have been 
reported.


Table 3.  Mutagenic tests for propylene oxide with positive resultsa
---------------------------------------------------------------------------------------------------------
Test description                        System description                      Reference
                                    Organism          Strain/cell type                                         
---------------------------------------------------------------------------------------------------------
Gene mutations                                                                                                                                                    
                                                                                                                                                                  
   Forward mutations                virus              Bacillus subtilis         Garro & Phillips (1980)b       
                                                      phage phi 105                                            
                                                                                                                                                                  
   Reverse mutations (base-pair     bacterium          Escherichia coli WP2      McMahon et al. (1979)c         
   substitutions)                                      Escherichia coli WP2      McMahon et al. (1979)c         
                                                       Escherichia coli WP2      Hemminki & Falck (1979)        
                                                                                                                                                                  
                                                       Escherichia coli WP2      Bootman et al. (1979)c         
                                                      CM871, CM891                                             
                                                       Bacillus subtilis         Phillips et al. (1980)         
                                                       Salmonella typhimurium    Wade et al. (1978)             
                                                      TA 1535, TA 100           McMahon et al. (1979)c;        
                                                                                Bootman et al. (1979)c;        
                                                                                Pfeiffer & Dunkelberg          
                                                                                (1980)d                        
                                                                                                                                                                  
   Reverse mutations                bacterium          Escherichia coli SD4      Hussain & Osterman-Golkar      
                                                                                (1984)                         
   Forward mutations                                   Klebsiella pneumoniae     Voogd et al. (1981)            
   Reverse mutations                fungus             Neurospora crassa W40     Kolmark & Giles (1955)         
                                                      macroconidia                                             
                                                       Schizosaccharomyces       Heslot (1962)                  
                                                       pombe                                                              
   Forward mutations                fungus             Schizosaccharomyces       Migliore et al. (1982)c        
                                                       pombe Pl                                                 
                                                                                                                                                                  
   Sex-linked recessive lethals     insect             Drosophila melanogaster   Hardin et al. (1983)           
                                                                                                                                                                  
   Forward mutations on specific    mammal            Chinese hamster           Zamora et al. (1983);          
   locus                            (in vitro)        ovary cells                                              
---------------------------------------------------------------------------------------------------------

Table 3.  (contd.)
-------------------------------------------------------------------------------------------------------------------
Test description                       System description                       Reference
                                 Organism             Strain/cell type
-------------------------------------------------------------------------------------------------------------------
DNA damage

   Single-strand breaks          bacterium             Bacillus subtilis         Phillips et al. (1980)b

                                 mammal  (in vitro)    rat hepatocytes           Sina et al. (1983)
                                                      calf thymus DNA           Walles (1974)

Chromosome damage

   Chromatid gaps and breaks,    mammal  (in vitro)    human lymphocytes         Bootman et al. (1979)
   Chromosome breaks, fragments

   Chromatid gaps, deletions,    mammal  (in vitro)    epithelial rat liver      Dean & Hodson-Walker
    exchanges                                         cells                     (1979)c

   Micronuclei                   mammal (ip)          mouse polychromatic       Bootman et al. (1979)
                                 (2 x 300 mg/kg)      erythrocytes
-------------------------------------------------------------------------------------------------------------------
a  For details of these studies, see text and data profile (IRPTC, 1984).
b  Treatment of isolated DNA  in vitro, followed by transformation (bacteria) or transfection (virus).
c  A similar or slightly reduced effect after metabolic activation by S9 rat or mouse liver fraction.
d  Chloropropanols were also mutagenic, but not as mutagenic as propylene oxide; 1,2-propanediol was not 
   mutagenic.
    Propylene oxide causes single-strand breaks in isolated calf 
thymus DNA, probably by alkylation of the phosphodiester bond 
(Walles, 1974).  Single-strand breaks were observed in the DNA of 
isolated rat hepatocytes at concentrations that were not toxic 
(Sina et al., 1983).

    Propylene oxide caused chromosome aberrations in mammalian 
cells  in vitro, in particular, chromatid gaps and breaks (Bootman 
et al., 1979; Dean & Hodson-Walker, 1979).  However, no increases 
in chromosome aberrations or sister-chromatid exchanges were found 
in peripheral lymphocytes of male Cynomolgus monkeys, after long-
term vapour exposure,  in vivo.  The animals were exposed in 
groups of 12 to concentrations of 0, 237, and 717 mg propylene 
oxide/m3 air, for 7 h per day, 5 days per week, for 2 years 
(Lynch et al., 1984b).

    Two oral doses of up to 500 mg propylene oxide/kg body weight, 
in gum tragacanth, administered within 24 h to mice, did not induce 
micronuclei in the polychromatic erythrocytes.  In contrast, 2 
intraperitoneal doses of 300 mg/kg body weight in water, administered 
within 24 h, gave a 5-fold increase over controls.  No effects were 
observed following ip administration of 2 doses of 75 mg/kg or 150 
mg/kg (Bootman et al., 1979).

    The results of the dominant-lethal assay were negative when 
male rats were exposed, for 7 h per day, to propylene oxide vapour 
at a concentration of 720 mg/m3, for 5 days prior to mating 
(Hardin et al., 1983).  A negative result was also obtained in a 
dominant lethal assay in which male mice received, once a day, 0, 
50, or 250 mg propylene oxide/kg body weight in gum tragacanth, by 
gavage, for 2 weeks prior to mating (Bootman et al., 1979).

    No increased frequency of abnormal sperm heads was observed, 
1 - 9 weeks after exposure of mice for 5 days to propylene oxide 
vapour at a concentration of 720 mg/m3, for 7 h per day (Hardin 
et al., 1983).  Similarly, no increase was observed in the frequency 
of abnormal sperm heads in the groups of Cynomolgus monkeys exposed 
for 2 years (Lynch et al., 1984c).  These monkeys were used by 
Sprinz et al. (1982) (section 7.2.2) and Lynch et al. (1984b) 
(section 7.3).

7.4.  Carcinogenicity

7.4.1.  Oral exposure

    Groups of 50 female Sprague Dawley rats received 2 doses of 
15.0 or 60.0 mg propylene oxide/kg body weight per week, by gavage, 
for a total of 112 weeks.  The compound was dissolved in salad oil 
and administered to fasting rats.  Two groups of 50 female rats 
served as vehicle controls or untreated controls.  There was an 
exposure-free period between the 79th and 82nd week because of an 
outbreak of pneumonia.  The rats were observed up to 150 weeks.  
No statistical analysis of the results was reported.  Mortality

rates were not affected by the exposures.  There was a dose-related 
incidence of squamous cell carcinoma of the forestomach.  In 
addition, one early carcinoma of the forestomach was observed.  The 
numbers of rats affected were 0, 2, and 19 in animals receiving 0, 
15, and 60 mg/kg body weight, respectively.  The combined incidences 
of hyperkeratosis, hyperplasia, and papillomas were 0, 7, and 17 at 
0, 15, and 60 mg/kg body weight, respectively.  At the highest dose 
level, one adenocarcinoma of the pylorus was also observed.  There 
was no treatment-related increase of any other tumour type 
(Dunkelberg, 1982). 

7.4.2.  Inhalation exposure

    The following studies have been reported by the US NTP (1984).  
Groups of 50 Fischer 344/N rats and 50 B6C3F1 mice of each sex were 
exposed to average propylene oxide vapour concentrations of 0, 470, 
and 940 mg/m3 air, for 6 h per day, 5 days per week, over a 103-
week period.  Three accidental over-exposures at the highest 
exposure level occurred.  The concentrations did not exceed 15 300 
mg/m3 for a maximum of 12 min during these periods.

    In rats, survival rate was not affected and was over 58% at the 
end of the study, at all exposure levels.  Growth was slightly 
reduced from week 20 onwards.  The respiratory epithelium of the 
nasal turbinates showed a dose-related increase in the incidence of 
suppurative inflammation of the mucosae, hyperplasia, and squamous 
cell metaplasia.  At 940 mg/m3, 2 out of 50 male and 3 out of 50 
female rats had papillary adenomas involving the respiratory 
epithelium and the underlying submucosal glands of the nasal 
turbinates.  No such tumours were observed in controls or low-dose 
animals.  In the thyroid of the female rats, a dose-related increase 
in the combined incidences of C-cell adenomas and carcinomas occurred, 
which was significant at 940 mg/m3.  The combined incidence of 
endometrial stromal polyps and sarcomas was reported to have 
increased, at both exposure levels, in a dose-related manner.  
According to the authors, the C-cell adenomas and C-cell carcinomas 
were not related to treatment.  The incidences of polyps and 
sarcomas were within the historical control range for the species 
tested.  In males, an increase in skin keratoacanthomas was 
observed, with a statistically-significant positive trend.  Induced 
non-neoplastic lesions further included testicular atrophy, acinar 
cell atrophy in the pancreas of males, cytomegaly in the adrenal 
cortex of females, and cystic endometrial hyperplasia (US NTP, 
1984). 

    The survival rate in mice was decreased at 940 mg/m3, from
week 60 onwards and was 58 and 20% for male and female mice,
respectively, at the end of the study, compared with 84 and 76% for 
male and female controls.  Growth was slightly reduced from week 29 
onwards.  In the nasal turbinates, a dose-related increased 
incidence of inflammation occurred.  Squamous cell metaplasia was 
observed in 1 male at 470 mg/m3 and 2 females at 940 mg/m3.  At 
940 mg/m3, haemangiosarcomas were found in the nasal cavity of 5

5 males and 2 females.  Haemangiomas were also observed in the 
nasal cavity of 5 males and 3 females at this dose level.  The 
increases in the incidence of haemangiosarcomas in the males and of 
haemangiomas in both sexes were statistically-significant. 

    One squamous cell carcinoma and one papilloma were induced in 
the nasal cavity of male mice at 940 mg/m3 and 2 adenocarcinomas 
were induced in the nasal cavity of females at 940 mg/m3.  None 
was observed in controls or low-dose animals.  The incidence of 
adenocarcinomas of the mammary gland was increased at 940 mg/m3, 
but did not exceed the historical control range for the species 
tested.  Induced non-neoplastic lesions further included ovarian 
atrophy and suppurative inflammation, mainly of the uterus and 
peritoneum (US NTP, 1984).

    In a combined NIOSH toxicity-carcinogenicity study, groups of 
80 male Fischer 344 rats were exposed to 237 or 717 mg propylene 
oxide/m3, for 7 h per day, 5 days per week, over 2 years.  A 
control group contained 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 was 
increased at both exposure levels, and the increase was significant 
at 717 mg/m3.  The mean survival was 96 weeks at this exposure 
level, compared with 103 weeks for control rats.  Body weights were 
reduced from the 2nd week at 717 mg/m3 and from the 39th week at 
237 mg/m3.  After 2 years, at both concentrations, the relative 
weights of lungs, adrenals, and brain were increased and those of 
the testes decreased.  The only altered biochemical parameters were
increased haemoglobin concentrations in blood at both exposure 
levels and increased activities of serum aspartate aminotransferase 
(EC 2.6.1.1) and serum sorbitol dehydrogenase (EC 1.1.1.14) at 237 
mg/m3.  Dose-related increases in the incidence and severity of 
inflammatory lesions in the lungs, nasal cavity, trachea, and 
middle ear were observed.  In the nasal passages, there was a dose-
related increased incidence of complex epithelial hyperplasia that 
was significant at 717 mg/m3.  Metaplasia was not observed.  Two 
rats showed nasal-cavity adenomas at 717 mg/m3.  At this 
concentration, there was also an increased incidence of multifocal 
areas of atrophy and degeneration of skeletal muscles.  No lesions 
were observed in the nerves.  The only statistically-significant
neoplastic change observed was an increased incidence of adrenal 
phaeochromocytomas at both concentrations.  The incidences were 
8/78 in controls, 25/78 in the low-dose group, and 22/80 in the 
high-dose group (Lynch et al., 1984a).  

    Another study on the possible toxic and carcinogenic properties 
of inhaled propylene oxide was performed on randomly-bred Wistar 
rats.  Groups of 100 rats of each sex were exposed to propylene 
oxide concentrations of 70, 242, or 712 mg/m3, for 6 h per day, 5 
days per week, over a period of 123 - 124 weeks.  Groups of 100 
rats of each sex served as controls.  Ten rats per sex and per 
group were killed for examination after 12, 18, and 24 months of

exposure.  No adverse effects were observed on general health, 
behaviour, food intake, biochemistry, urinalysis, and haematology 
in comparison with control rats.  The mortality rate was increased 
at the highest exposure level from week 73, in males, and from week 
109, in females, and at the end of the exposure to 242 mg/m3 in 
females.  Rats of both sexes gained less weight than controls at 
712 mg/m3, though the difference compared with controls became 
smaller towards the end of the exposure.  The relative and absolute 
weights of adrenals, spleen, liver, and lungs of males were 
increased at 712 mg/m3, but no pathological lesions were observed 
in these organs.  Male rats showed a lower incidence of pale 
exorbital lachrymal glands at this exposure level.  In both sexes, 
the incidences of basal cell hyperplasia and atrophy of the 
olfactory epithelium and the incidence of nest-like infolds of the
respiratory epithelium were increased mainly at the 2 highest
exposure levels.  These changes were also noted at interim kills.  
The severity of the changes increased only slightly, if at all, 
with increasing length of exposure and with age.  Squamous 
metaplasia was not observed.  One rat was found with squamous cell 
carcinoma of the nose.  In female rats, the incidence of benign 
tumours of the mammary glands, mostly fibroadenomas, was increased 
at 712 mg/m3 in comparison to both the concurrent controls and 
the historical controls.  Moreover, the number of females bearing 2 
or more mammary fibroadenomas increased in a dose-related manner 
from the lowest exposure level onwards when compared with controls.
The increased incidence of tubulopapillary mammary carcinomas at 
712 mg/m3 was within the range of historical controls.  With the 
exclusion of mammary tumours, the total incidence of primary 
tumours in females and the number of malignant tumour-bearing rats 
of both sexes was increased at the highest exposure level (Reuzel & 
Kuper, 1983).  Following reports that ethylene oxide had induced 
brain tumours in rats, the histopathological investigation of the 
brain of the rats was extended.  There was no evidence that 
propylene oxide induced such tumours (Reuzel & Kuper, 1984).

7.4.3.  Subcutaneous exposure

    Groups of 100 female NMRI mice received subcutaneous doses of 
0.1, 0.3, 1.0, or 2.5 mg propylene oxide per animal in tricaprylin 
once a week, for 106 weeks.  These groups were compared with 200 
controls receiving tricaprylin and 200 untreated controls.  In the 
second year of exposure, mice were not treated for 11 weeks.  Body 
weights and survival rates were not affected by treatment.  At the 
site of injection, a dose-related increase in the incidence of 
sarcomas (mainly fibrosarcomas) occurred.  The numbers of mice 
affected were 0/200 in untreated controls, 4/200 in tricaprylin 
controls, and 3/100, 2/100, 12/100, and 15/100 at the 0.1, 0.3, 
1.0, and 2.5 mg dose levels, respectively.  The increases in 
incidence at the 2 highest dose levels were statistically 
significant.  The first tumour appeared in week 38 (Dunkelberg, 
1981).

7.5.  Effects on Reproduction and Teratogenicity

    When B6C3F1 mice of both sexes were exposed repeatedly for 2 
years to propylene oxide at concentrations of 470 and 940 mg/m3 
air (section 7.4.2), the incidence of ovarian atrophy was increased 
at the higher exposure level (US NTP, 1984).  In F344 rats, similarly 
exposed, higher incidences of testicular atrophy were found at both 
exposure levels, but they were not dose-related (US NTP, 1984).  
Decreased relative weights of the testes were reported by Lynch et 
al. (1984a), when male F344 rats were exposed repeatedly for 2 years 
to propylene oxide at levels of 240 and 720 mg/m3 air.

    Sperm head abnormalities were not detected in mice after
exposure for 5 days, 7 h per day, to 720 mg propylene oxide/m3
(Hardin et al., 1983), or in groups of 12 Cynomolgus monkeys,
exposed for 2 years to 240 and 710 mg propylene oxide/m3, for
7 h per day, 5 days per week.  In monkeys, at both exposure levels, 
sperm counts and sperm motility were reduced, and the sperm drive 
range was elevated (Lynch et al., 1984c).

    In a reproduction-teratogenicity study, groups of 41 - 44
female Sprague Dawley rats were exposed to 1190 mg propylene 
oxide/m3 air, for 7 h per day, during days 7 - 16 of gestation
(Group 1), days 1 - 16 of gestation (Group 2), or for 3 weeks
(5 days/week) before mating and on days 1 - 16 of gestation 
(Group 3).  A group of 46 rats served as controls.  The dams were 
sacrificed on day 21.  No deaths of dams occurred, their histology 
was normal, and the percentage of pregnant rats was not affected by 
the exposure.  Toxic effects in dams were expressed as decreased 
body weights and food consumption and increased relative weights of 
kidneys in all exposed groups. The numbers of corpora lutea, 
implantations per dam, and live fetuses were lower in group 3, 
compared with those in the other groups.  In group 1, the number of 
resorptions was increased compared with that in group 2.  The body 
weights and lengths of fetuses were decreased in all exposed groups 
compared with controls, but more so in group 3.  In group 2, 
increases in wavy rib and in reduced ossification, primarily of the 
vertebrae and ribs, were observed (Hackett et al., 1982). 

    Groups of New Zealand rabbits were also exposed to 1190 mg/m3, 
for 7 h per day, during days 1 - 19 or days 7 - 19 of gestation.  
No evidence of toxicity was observed in the mothers, fetuses, or 
embryos, and no developmental defects were noted (Hacket et al., 
1982).

    Female rats administered a single oral dose of 260 mg/kg body 
weight of propylene oxide showed disturbance of the estrus cycle.

    Pregnant female rats administered an identical dose during the
first 2 weeks of gestation exhibited higher embryotoxicity and 
lower offspring body weight compared with the controls.  Male rats 
exposed to a single oral LD50 (520 mg/kg) dose of propylene oxide 
showed reduced sperm motility and damage to primary spermatocytes.  
When such rats were mated with normal female rats, between 2 and 10 
weeks after exposure, 50% of the males were infertile.  The fertility 
of the first generation was reduced by 23% (Antonova et al., 1981).

8.  EFFECTS ON MAN

8.1.  Exposure of Skin and Eyes; Skin Sensitization

    Accidental exposure of the eyes of 3 persons to propylene 
oxide (it was not reported whether this was liquid or vapour) 
resulted in alterations in the cornea and conjunctiva (McLauglin, 
1946). 

    Allergic contact dermatitis was diagnosed in 3 cases of 
exposure to solutions of propylene oxide (Ketel, 1979; Jensen,
1981).  Biopsy on the skin of these patients revealed spongiosis 
in the epidermis, oedema in the cutis, and dense perivascular 
infiltrates with mononuclear cells.

8.2.  Accidental Inhalation Exposure

    No data are available.

8.3.  Occupational Inhalation Exposure

    In the Federal Republic of Germany, 279 employees from 8 
plants where alkene oxides were produced or processed, were
examined during 1978.  They were employed for an average of 10.8
years.  No clinical abnormalities were found that could be related 
to exposure to alkene oxides.  Propylene oxide levels were measured 
by personal sampling over 1 - 10 h, but levels of exposure were not 
reported.  The workers were exposed to many other chemicals, 
including ethylene oxide (Stocker & Thiess, 1979).  Because of the 
mixed exposure and unavailability of propylene oxide exposure data, 
the Task Group was unable to evaluate this study.

8.4.  Mortality Studies

    In the Federal Republic of Germany, 602 workers were
investigated for mortality over the period 1928-80.  The workers
had been employed for at least 6 months in 8 plants producing 
ethylene oxide and propylene oxide, the latter produced only since 
1959.  A subcohort of 351 workers was observed for more than 10 
years.  Control data came from a styrene plant and from national 
statistics.  Propylene oxide levels, measured by personal sampling 
(number of samples not reported), from 1978 to 1980, were far below 
a time-weighted average of 240 mg/m3 over a working shift of 12 h 
(Thiess et al., 1981a).  Higher levels were measured for brief 
periods.  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.  No significant excess of
deaths could be found due to any cause in the cohort of 602 workers.
In the sub-cohort of 351 workers, there was a significant increase 
in mortality rate due to kidney disease (3 compared with 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.  The stomach tumours were observed compared

with 1.8 expected (Thiess et al., 1981b).  Since the workers were 
also exposed to many other chemicals, such as butylene oxide, 
epichlorohydrin, dioxan, dichloropropane, and chlorohydrins, the 
Task Group was unable to evaluate this study in relation to 
propylene oxide. 

8.5.  Mutagenicity and Related End-Points

    In 43 male workers from the cohort of 602 workers discussed in
section 8.4 (Thiess et al., 1981b), no increase in chromosome 
aberration rate was found in 2 groups of workers exposed to alkene 
oxides for average periods of either 12.5 or 17.6 years; in addition, 
workers in the latter group had at least one accidental high exposure 
to ethylene oxide.  The results were also negative in a group of 
workers exposed once for a brief period following an accident.  On 
the other hand, the aberration rate was significantly elevated in 
workers exposed for more than 20 years (Thiess et al., 1981a).

    For the reason mentioned in section 8.4, the Task Group was
 unable to evaluate this study in relation to propylene oxide.

    Unscheduled DNA synthesis, induced  in vitro by the mutagen
 N-acetoxy-2-acetylaminofluorene, was inhibited in the lymphocytes 
of 23 workers from a factory in Sweden, where starch was modified 
with propylene oxide.  The workers had been exposed for 1 - 20 
years.  At the time of the study, exposure was generally below a 
time-weighted average of 28 mg/m3.  However, short-term exposures 
of up to 2370 mg/m3 were recorded for some workers (Pero et al., 
1982). 

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

    Exposure of man to propylene oxide mainly occurs through
inhalation at the work-place.

    Data are insufficient to estimate the exposure to propylene 
oxide residues in food after fumigation and sterilization.  The 
main conversion products in foodstuffs are chloropropanols and 
1,2-propanediol, which are more persistent than the parent compound 
(section 4.2).  No adverse effects have been reported due to the 
ingestion of propylene oxide and its reaction products in food. 

    No ambient air monitoring data are available, but the lowest 
annual average concentration at distances of up to 20 km from 
production plants has been assessed, by modelling, to be less than 
4.836 x 10-8 mg/m3(section 4.1).  The risk for human health 
under such conditions of exposure is likely to be negligible.

    Propylene oxide is highly soluble in water but is likely to 
evaporate to a great extent.  However, no data on the rate of 
evaporation are available.  In neutral fresh water, propylene 
oxide is converted to 1,2-propanediol and, in marine waters, to 
halopropanols, but, even in the presence of micro-organisms, these 
processes are slow (section 3.2).  Because of the low log  n-octanol 
water-partition coefficient, propylene oxide and its conversion 
products are unlikely to bioaccumulate (Table 1).  The toxicity of 
propylene oxide for aquatic organisms is low.  The available LC50s 
are above approximately 90 mg/litre (section 6).  Thus, the 
probability of an adverse impact on the aquatic environment is 
considered low. 

    Eight-hour time-weighted occupational exposure in propylene 
oxide production and use is normally below 5 mg/m3, with 
occasional peak exposures up to 9000 mg/m3 (section 4.3).

    Inhaled propylene oxide is probably readily absorbed, 
distributed throughout the body, and rapidly metabolized.  The 
half-life in rat tissues has been estimated to be 40 min (section 
5.2).  There are no data on skin absorption. 

    An aqueous solution of propylene oxide (100 or 200 g/litre) 
is irritating to rabbit skin when applied under occlusive cover 
(section 7.1.2).  In man, corneal and conjunctival damage, and 
allergic contact dermatitis have been reported through accidental 
exposure to propylene oxide vapour (section 8.1). 

    The 4-h LC50s for the rat and the mouse were 9500 mg/m3
and 4100 mg/m3, respectively.  Dogs exposed by inhalation, once
for 4 h, to a concentration of 3230 - 5880 mg/m3 showed 
salivation, lachrymation, nasal discharge, and vomiting.  Deaths 
were observed at 4750 - 5880 mg/m3 but not at 3230 mg/m3 
(section 7.1.3).

    On repeated exposure of various species to propylene oxide 
vapour, 7 h per day, 5 days per week, for 112 - 218 days, at 
concentrations of 0, 240, 460, and 1080 mg/m3, rabbits and 
monkeys did not show any adverse effects on appearance, mortality, 
growth, and histopathology of internal organs.  Rats and guinea-
pigs showed irritation of the respiratory passages and lung damage 
histologically at 1080 mg/m3.  An increase in lung weight was 
observed in female guinea-pigs at concentrations of 460 mg/m3 or 
more.  No effect was observed in any species at a concentration of 
240 mg/m3.  A concentration of 3400 mg/m3 administered for 2 
weeks, 6 h/day, 5 days per week, resulted in dyspnoea and death in 
rats.  In the same study, mice showed dyspnoea at 460 and 1150 mg/m3 
(section 7.2.2). 

    Rats and mice exposed for 2 years showed increased incidences
of inflammatory and proliferative lesions of the nasal epithelium 
from an exposure level of 470 mg/m3.  In rats, the inflammatory 
lesions and hyperplasia were also observed at an exposure level of 
240 mg/m3, but not at 70 mg/m3 (section 7.4.2).

    Depression of the central nervous system, the severity of
which increased with increasing level and length of exposure, was
observed when rats and mice were exposed by inhalation to single 
high concentrations of propylene oxide (section 7.1.3).  Although 
no clinical central nervous system effects were reported when 
monkeys were exposed to 237 and 717 mg/m3 for 2 years, some 
histopathological changes were observed in the treated animals 
(section 7.2.2).  It should be noted that these data cannot be 
evaluated for estimating hazard for man, since only 2 monkeys were 
examined in each of the exposed groups, and the lesion appeared 
also in one of the 2 controls.

    Summarizing the results of animal studies (excluding 
mutagenic, carcinogenic, and reproduction effects) the no-
observed-adverse-effect level for prolonged repeated 6- to 7-h
daily exposure is 70 mg/m3.

    Propylene oxide administered by inhalation for 2 years 
produced ovarian atrophy in mice at 940 mg/m3.  Testicular
atrophy was found at 240 and 720 mg/m3 in rats (section 7.5).

    No sperm head abnormalities were detected in mice after
exposure for 5 days to 720 mg/m3 or in Cynomolgus monkeys
exposed to 240 or 710 mg/m3 for 2 years, but sperm count and
motility were reduced, and sperm drive range (time to traverse a
linear path) increased in the monkeys.  A reduced sperm motility 
and damage to spermatocytes were observed in male rats treated with 
an oral LD50 (520 mg/kg body weight) dose.  A reduced fertility 
was observed when these males were mated between 2 and 10 weeks 
after exposure with normal females (sections 7.3, 7.5). 

    Reduced fetal ossification of vertebrae and ribs and wavy ribs
were observed when pregnant Sprague Dawley rats were exposed to 
1190 mg propylene oxide/m3, 7 h per day, on days 1 - 16 of 
gestation.  When rats were additionally exposed for 3 weeks before 
mating, the numbers of corpora lutea, implantations per dam, and 
live fetuses were decreased.  No teratogenic or fetotoxic effects 
were found in New Zealand rabbits exposed to 1190 mg/m3 (section 
7.5). 

    Propylene oxide is mutagenic in microorganisms and insects and
produces DNA damage and chromosomal aberrations in mammalian cells 
 in vitro.  It produced micronuclei in mouse erythrocytes after 
parenteral injection of 2 doses of 300 mg/kg body weight but not 
after oral exposure.  No chromosomal aberrations or sister 
chromatid exchanges occurred in monkeys exposed by inhalation to 
237 and 717 mg/m3, for 7 h/day, 5 days/week, for 2 years.  No 
dominant-lethal effects were observed in rats or mice following 
inhalation or oral exposure, respectively, in 2 studies (section 
7.3).  No adequate data on chromosomal effects in human beings are 
available. 

    In studies on the carcinogenicity of propylene oxide in rats
and mice, malignant tumours were mainly observed at the site of 
entry into the body:  for stomach, at 15 and 60 mg/kg body weight; 
for subcutaneous tissues, at 1.0 - 2.5 mg; and, for nasal passages, 
at 940 mg/m3.  At the dose levels at which these tumours were 
induced, propylene oxide produced tissue damage.  This damage may 
have played a role in the appearance of the tumours.  Propylene 
oxide also produced an increase in the incidence of multiple benign 
mammary tumours in female rats following inhalation exposure 
(section 7.4).  No adequate epidemiological studies on cancer 
incidence in exposed human populations have been carried out.

    Taking into account the body of available data - the
alkylating nature of propylene oxide, the formation of DNA 
adducts, the positive responses in  in vitro mutagenesis assays,
the carcinogenic effects in animals at the sites of entry into the 
body, and the absence of adequate data on cancer in human beings - 
propylene oxide should be considered as a possible human carcinogen.  
Thus, for practical purposes, propylene oxide should be regarded as 
if it presented a carcinogenic risk for man, and levels in the 
environment should be kept as low as feasible.

10.  RECOMMENDATIONS FOR FURTHER RESEARCH

1.  A thorough detailed study on the absorption, distribution, 
    and metabolism of propylene oxide should be conducted.

2.  Biological indicators should be developed that quantify both 
    the incidence and severity of human exposure.

3.  The epidemiological studies indicating an increased risk of 
    cancer in workers exposed to propylene oxide in combination 
    with other chemicals suggest that additional studies should 
    be conducted on populations whose exposure has been primarily 
    to propylene oxide.  The adequate quantification of past 
    exposures should be a part of these studies.

11.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

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

    "There is sufficient evidence for the carcinogenicity of
propylene oxide to experimental animals; there is inadequate
evidence for its carcinogenicity to humans.  It is noted that,
in the absence of adequate data in humans, it is reasonable,
for practical purposes, to regard chemicals for which there is
sufficient evidence of carcinogenicity in experimental animals
as if they represented a carcinogenic risk to humans."

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See Also:
        Propylene oxide (IARC Summary & Evaluation, Volume 60, 1994)