EPA/600/8-86/007F
June 1987
Summary Review of the Health Effects
Associated With Propylene Oxide
Health Issue Assessment
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U. S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NC 27711
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Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade names
or commercial products does not constitute endorsement or recommendation
for use.
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Table of Contents
Page
List of Tables jv
Abstract v
Authors, Contributors, and Reviewers vi
1. Background Information 1
1.1 Chemical Characterization and Measurement 1
1.2 Environmental Release, Transformation and Exposure .. 2
1.3 Environmental Effects 4
2. Health Effects 6
2.1 Pharmacokinetics and Metabolism 6
2.2 Biochemical Effects 7
2.3 Acute Toxicity '.'.'.'.'.'.'.'. Q
2.4 Subchronic Toxicity '.'.'.'.'.'.'.'.'.'.'.'. 8
2.5 Chronic Toxicity '.'.'.'.'.'.'.'.' Q
2.6 Mutagenicity '.'.'.'.'.'.'.'.'.'.'.' 11
2.7 Carcinogenicity '.'.'.'.'.'.'" 14
2.8 Teratogenicity and Reproductive Effects ............... is
2.9 Neurotoxicity 21
2.10 Effects on Humans '.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 21
3. Summary and Conclusions 23
4. References 26
in
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List of Tables
No.
1-1 Propylene oxide emissions by process type 3
2-1 Acute toxicity values for propylene oxide 9
2-2 Results of subchronic inhalation exposure to propylene
oxide in rats, guinea pigs, rabbits, and monkeys 10
2-3 Injection site tumors in NMRI mice receiving propylene
oxide 15
2-4 Incidence of stomach tumors and nonneoplastic changes
in rats intragastrically administered propylene oxide 15
Incidence of mammary gland tumors in female rats
exposed to propylene oxide vapor 17
Incidence of nasal cavity lesions in rats exposed to
propylene oxide via inhalation 17
Incidence of thyroid lesions in female rats exposed to
propylene oxide via inhalation 18
Incidence of nasal cavity epithelial lesions in mice
exposed to propylene oxide via inhalation 19
2-5
2-6
2-7
2-8
2-9 Data for derivation of q*
2-10 Calculated q," values for propylene oxide
20
20
IV
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Abstract
Propylene oxide's major use is as an intermediate in the production of
polyurethane foams and propylene glycol. Average atmospheric concentrations
at a distance of 20 km or greater from production facilities are estimated to be
less than 0.0001 ppt (10'7 ppb). The calculated atmospheric half-life is 6.1
days. Propylene oxide is likely to be readily absorbed through the
gastrointestinal and respiratory tracts. The LC50 for a 4-hour inhalation
exposure was 9486 mg/m3 in rats and 4126 mg/m3 in mice. The lowest
concentrations at which effects were seen in experimental animals with acute or
subchronic exposures were in the. range of approximately 400 to 500 ppm
propylene oxide. The no-observed-adverse-effect level for prolonged
repeated 6- to 7-hour daily exposure is 70 mg/m3 (29 ppm). The published
literature shows evidence for carcinogenic and genotoxic effects. The NTP
carcinogenicity study which exposed rats and mice to propylene oxide
concentrations of 200 to 400 ppm showed evidence of carcinogenicity.
Propylene oxide is tentatively placed in the B-2 category of the Agency's
classification system for carcinogenicity evidence because of the positive
animal data together with the absence of epidemiological studies. Limited
information on air concentrations indicates typical annual average ambient air
concentrations for propylene oxide of < 1 ppt.
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Authors, Contributors, and Reviewers
The following personnel of Dynamac Corporation were involved in the
preparation of this document: Finis Cavender, Ph.D. (Department Director);
Nicolas P. Hajjar, Ph.D. (Project Manager); James Konz (Task Coordinator);
William McLellan, Ph.D., and Chris Dippel (Authors); Norbert Page, Ph.D.
(Reviewer); Anne Gardner (Technical Editor); and Gloria Fine (Information
Specialist). This document was prepared by Dynamac Corp. under contract to
the Environmental Criteria and Assessment Office, Research Triangle Park, NC
(Dennis J. Kotchmar, M.D., Project Manager).
This document has also been reviewed for scientific and technical merit by
the following scientists: Dr. Dennis Lynch, Experimental Toxicology Branch,
NIOSH, Cincinnati, OH; Dr. Michael Farrow, Vienna, VA; Professor Robert
Duncan, University of Miami, School of Medicine, Miami, FL; Dr. Gary Kimmel
and Dr. Sheila Rosenthal, Reproductive Effects Assessment Group, EPA,
Washington, DC; and Dr. Arthur Chiu, Carcinogen Assessment Group, EPA,
Washington, DC.
VI
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1. Background Information
This overview provides a brief summary of the data available on the health
effects of exposure to propylene oxide. Emphasis is placed on determining
whether there is evidence to suggest that propylene oxide exerts effects on
human health under conditions and at concentrations commonly experienced by
the general public. Both acute and chronic effects are addressed, including
general toxicity, teratogenicity, mutagenicity, and carcinogenicity. To place the
health effects discussion in perspective, this report also summarizes air quality
aspects of propylene oxide in the United States, including sources, distribution
fate, and concentrations associated with certain point sources.
1.1. CHEMICAL CHARACTERIZATION AND MEASUREMENT
Propylene oxide (CAS No. 75-56-9) belongs to a class of ethers known
as the epoxyalkanes. It is a colorless liquid at ambient temperatures with a
molecular weight of 58.08. It is very soluble in water (405 g/l @ 20°C) and has a
low density (0.825 g/ml @ 25°C) and a high vapor pressure (445 torr & 20°C)
(Windholz et al., 1983; Hawley, 1981; Weast, 1984).
Propylene oxide released into the environment may be measured by a
variety of analytical methods. These include spectrophotometry, gas
chromatography, electron impact spectroscopy, and colorimetric methods
(International Agency for Research on Cancer, 1976). A multigas analyzer
utilizing microwave spectroscopy has also been developed to monitor proovlene
oxide in air (Kirk and Dempsey, 1982).
The method of the National Institute for Occupational Safety and Health for
analysis of propylene oxide in air involves the adsorption of the compound on
activated charcoal in a sampling tube, desorption with carbon disulfide and
analysis using a gas chromatograph equipped with a flame ionization detector
The method has been validated over the range of 121-482 mg/m3 using a 5-
liter sample. The average value obtained with this method was 94 4 percent of
the concentration (240 mg/m3) analyzed.
Russell (1975) discussed -the use of gas chromatography with flame
ionization detection for the analysis of propylene oxide in air. This method uses
sampling tubes packed with a porous polymer gas chromatographic adsorbent
(Porapak N) to collect the propylene oxide. The collected compound is then
thermally desorbed directly into the gas chromatograph for analysis. Recovery
is 100 ± 3 percent for samples analyzed up to 3 weeks after collection. This
technique is most appropriate for concentrations of less than 100 ppm in a 1-
liter air sample, and has a sensitivity of approximately 1 ppb.
A method for the determination of propylene oxide in air has also been
reported by Gronsberg (1981). The method is based on the hydrolysis of
propylene oxide to form propylene glycol, which is then oxidized to
formaldehyde with periodic acid and determined photometrically following
reaction with chromotropic acid. The detection limit of the method is 1 pg, and
the minimum measurable concentration is 0.5 mg/m3.
Gas chromatography may also be used to determine the levels of
propylene oxide in food, cellulose, and plastic products (International Agency for
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Research on Cancer, 1976). Methods for the analysis of propylene oxide in
water were not reported in the available literature.
1.2. ENVIRONMENTAL
EXPOSURE
RELEASE, TRANSFORMATION AND
Of the top 50 chemicals ranked by U.S. production volume, propylene
oxide was 44th in 1980 with a total production volume of 1.77 billion pounds
(Storck, 1981). Propylene oxide is manufactured at four locations in the Gulf
Coast region of the United States by Dow Chemical USA and ARCO Chemical
Company. The total combined capacity, including the scheduled 1984
expansion by ARCO, is approximately 3 billion pounds (SRI International, 1984).
The major use of propylene oxide is in the production of polyether polyols,
the primary component of polyurethane foams, and in the production of
propylene glycol. Smaller amounts are used in the fumigation of foodstuffs and
plastic medical instruments and in the manufacture of dipropylene glycol and
glycol ethers, or as pesticides (International Agency for Research on Cancer,
1976).
Propylene oxide has also been reported to be an effective soil sterilant
(Skipper and Westermann, 1973) but is not used commercially to sterilize soil.
The major release of propylene oxide is expected to occur into the
atmosphere during its production or use as an intermediate or as a fumigant
and a sterilant. The distribution of released propylene oxide into the
environmental compartments has not been reported. Estimates for the analog
ethylene oxide indicate that 95 percent is released into air, 2 percent into water,
and 3 percent into deep wells (Brown et at., 1975).
It has been estimated that 1.3 million pounds of propylene oxide is released
into the atmosphere annually (Anderson, 1983). Based on model plant analyses,
levels of propylene oxide emissions from various production processes have
been determined (Table 1-1). These levels are intended to represent typical
emissions from a well-designed and well-operated plant without specific
emission control devices other than those for economy and safety (Peterson,
1980).
Data from a 1983 emissions inventory for four manufacturing plants that use
propylene oxide in the Philadelphia, PA, area report that a total of 849 pounds of
propylene oxide is released from these plants each year (production volumes
not stated) (Lazenka et al., 1983).
The only available information on atmospheric concentrations of propylene
oxide is estimates of levels in the vicinity of propylene oxide production plants.
The annual average atmospheric concentration at a distance of 20 km or greater
from production plants was estimated to be less than 0.0001 ppt (1Q-7 ppb)
(Anderson, 1983). The only available data on water concentrations are
measurements from the discharge pipe of an epoxyalkane production plant on
the Ohio River. The measured concentration of propylene oxide at the discharge
pipe from this plant was 0.047 mg/l (STORET, 1980). However, due to
substantial dilution in the Ohio River, actual downstream concentrations would
be expected to be much lower.
Tolerance levels for propylene oxide in foods have been set by the Food
and Drug Administration. A maximum allowable concentration of 700 mg/kg (as
propylene glycol) has been established for fruits and 300 mg/kg for cocoa,
gums, nutmeats, spices, and starch (Code of Federal Regulations, 1985a).
Propylene oxide has been detected in food products fumigated with a 1:4
propylene oxide:carbon dioxide mixture. Levels of 4147 and 5910 mg/kg were
found in lard and oleic acid, respectively, 24 hours after fumigation. Propylene
oxide residues as high as 2000 mg/kg were also detected in various plastic and
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Table 1-1. Propylene Oxide Emissions by Process Type
Plant Capacity.
1000 metric
Production Process tonslyr
Chlorohydrination
Isobutone
hydroperoxide
Ethylbenzene
hydroperoxide
68
417
181
Propylene oxide
emissions
g/kga
0.0549
0.02 r 7
0.0005
kg/hr
0.8365
1.0300
0.0100
a Grams of emissions per kilogram of propylene oxide
produced.
Source: Peterson (1980).
cellulose products used for food storage up to 3 hours following fumigation
(International Agency for Research on Cancer, 1976).
Analysis of wheat fumigated with propylene oxide indicated levels of
several hundred parts per million of propylene glycol. Propylene oxide can also
combine with the natural inorganic chloride content of foodstuffs, forming
propylene chlorohydrin, which is toxic and persistent under food processing
conditions (Lindgren et al., 1968).
Propylene oxide has also been detected as one of the volatile organic
compounds produced from plastics during a test simulating an electrical circuit
overheat situation. The test was conducted at 250°C to simulate real-life
electrical overload conditions (Rigby, 1981).
Occupational exposures to propylene oxide have also been reported.
NIOSH (1977) estimated that about 270,000 workers are occupationally exposed
to propylene oxide in the United States. OSHA (Code of Federal Regulations,
1985b) and The American Conference of Governmental Industrial Hygienists
(ACGIH) have established limits on atmospheric concentrations of propylene
oxide in the workplace. OSHA has set an 8-hour TWA of 100 ppm (240
mg/m3), whereas The ACGIH (1984) recommends a TLV-TWA of 20 ppm (50
mg/m3) over an 8-hour period.
Typical average daily occupational exposure to propylene oxide in 1979
was 2 ppm for workers involved in its production and storage. Peak exposures
in 1979 ranged as high as 3,800 ppm (about 9,000 mg/m3); however, with
proper engineering controls, these peak levels have been reduced to less than 1
ppm (2.37 mg/m3; Flores, 1983). Results of a four-plant sampling program by
BASF Wyandotte Corporation indicated propylene oxide levels ranging from
less than 0.18 to 20.3 mg/m3 with an average concentration of 1.53 mg/m3
(McClellan, 1979).
Propylene oxide may be released into the atmospheric and aquatic
compartments of the environment from point sources such as manufacturing
plants and from numerous nonpoint sources such as areas where products are
treated. Accidental loss may also occur during transport, handling, and storage.
Propylene oxide released into the environment is expected to be very mobile
due to its water solubility, high volatility, and teachability, although degradative
processes will probably limit its transport.
The atmospheric fate and residence time for propylene oxide has been
reported by Cupitt (1980). A measured rate constant for the OH radical reaction
of 1.3 x 1012 cm3/molecule-sec has been reported. The calculated
atmospheric residence time is 8.9 days with a half-life of 6.1 days. Expected
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degradation products include CH3C(O)OCHO, CH3C(0)CHO, formaldehyde
(H2CO), and HC(O)OCHO.
Products identified from free-radical reactions of propylene oxide initiated
by ultraviolet light include acetone, isopropyl alcohol, propionaldehyde, and
propyl alcohol (Gritter and Sabatino, 1964).
In water, propylene oxide hydrolyzes under environmental conditions to
form propylene glycol (Long and Pritchard, 1956), which is highly soluble and
relatively less toxic than propylene oxide. The estimated hydrolysis half-life of
propylene oxide in water at pH 5-9 (25 °C) ranges from 7 to 12 days (Zafran et
al., 1980).
Propylene oxide also reacts readily with chloride ions. The estimated half-
life for this reaction indicates that this is an important degradative process in
water with high chlorine concentrations, such as seawater. Similar reactions
appear to occur in food products and medical equipment sterilized with
propylene oxide. The half-lives of these reactions in water at pH 5-9 are as
follows: freshwater, 6170-8440 days; estuarine, 4.2-6.2 days; and seawater,
3.3 days (Zafran et al., 1980).
Biodegradation data suggest that propylene oxide is not very readily
biodegradable. A 5-day BOD removal rate of 17 percent, a COD value of 1.77,
and a theoretical oxygen demand of 2.21 were reported by Bridie et al. (1979b).
According to the degradability index (ratio of 5-day BOD to COD) of Lyman et
al. (1982), propylene oxide is considered "relatively undegradable."
The log octanol/water partition coefficient for propylene oxide was reported
to be -0.13 (Padding et al., 1977). Because of its low log P value and moderate
to rapid biological and chemical degradation, it is not expected to
bioconcentrate or bioaccumulate.
Based on the equation of Briggs (1973), propylene oxide can be classified
as very mobile in soil. Thus, it is expected that releases of the compound to the
soil would be readily transported to air or water.
1.3. ENVIRONMENTAL EFFECTS
The available literature on the ecological effects of propylene oxide is very
limited. No information was found on the effects of propylene oxide on aquatic
plants, invertebrates, micro-organisms, or terrestrial plants. In addition, no
chronic or life-cycle effects on ecological species have been reported. Chronic
effects would not be expected, since propylene oxide is water-soluble,
teachable, and volatile, and reacts with water; in addition, it is hydrolyzed into
other water-soluble substances and is not expected to persist, bioconcentrate,
or bioaccumulate.
Limited data were found on the acute toxicity of propylene oxide to fish and
its effects on soil chemistry. For freshwater fish, the 96-hour LC5o values were
141 mg/l for the mosquito fish ( Gambusia affinis) and 215 mg/l for the bluegill (
Lepomis macrochirus) (Crews, 1974). The 24-hour LC50 for goldfish (
Carassius auratus) was 170 mg/l (Bridie et al., 1979a). For marine fish, the 96-
hour LC5rj for mullet ( Mugil cephalus) was 89 ppm (Crews, 1974).
Sterilization of three types of soil with propylene oxide resulted in pH
changes and increased concentrations of some of the available plant nutrients
(Skipper and Westermann, 1973). The pH increased by 0.5-0.8 units after
treatment. These increases were attributed to reactions of propylene oxide with
labile H-atoms in the organic and inorganic fractions of the soil. There were
also increases in extractable manganese levels in two soil types and an
increase in extractable nitrogen in one; however, the pattern of change was not
consistent among the three soils. Available phosphorus concentrations
increased in one soil, but not in the second, and were not tested in the third soil
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because of its high initial phosphorus content. Treatment with propylene oxide
did not affect either extractable potassium or extractable calcium levels in any
of the tested soils. The increases in some of the nutrient concentrations in
certain soils were attributed to either the solubilization of inorganic forms or the
release from organic matter or microbial cells.
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2. Health Effects
2.1. PHARMACOKINETICS AND METABOLISM
No studies were identified in the literature on the absorption, distribution,
metabolism, or excretion of propylene oxide. Several studies were found on the
interaction of propylene oxide with cellular constituents that provide information
on the behavior of propylene oxide at the cellular level. These studies are
discussed below. In the absence of data on the metabolism of propylene oxide,
data are presented on structurally similar compounds such as propylene,
epichlorohydrin, and other epoxides. The data provide some information on the
possible uptake and metabolism of propylene oxide, since it is expected that
propylene oxide would behave similarly to these compounds.
The kinetics of the uptake of inhaled propylene were investigated by
Svensson and Osterman-Golkar (1984), whose data suggested that propylene
is rapidly metabolized to propylene oxide. In this study, groups of 15 male CBA
mice (average weight 31 g) were placed in closed, all-glass, 11-liter inhalation
chambers filled with propylene atmospheres ranging in concentration from 95 to
1715 ppm. The depletion of propylene from the chamber was monitored by gas
chromatography at regular intervals over a period of time equivalent to at least
one half-life. The results indicated that the uptake process was saturable and
enzymatic over the tested range (i.e., resulting from metabolism) and followed
Michaelis-Menton kinetics. The authors calculated the Km and Vmax to be 800
± 600 ppm and 8 ± 0.5 mg (kg body weight)-1 hr1, respectively. In a second
experiment, Svensson and Osterman-Golkar exposed 12 mice to 14C-labeled
propylene for 1 hour and looked for the binding of label to hemoglobin and DNA
from the liver, testes, spleen, lungs, and kidneys. They identified labeled amino
acids and guanine and attributed the label to the metabolism of propylene to
propylene oxide and subsequent alkylation of proteins and DNA.
The absorption, distribution, and metabolism of epichlorohydrin have been
thoroughly investigated. Epichlorohydrin differs from propylene oxide in that the
former has a chlorine-bearing C-3 carbon and hence two electrophilic
reactive sites (the halogenated carbon and the C-1 carbon of the epoxide ring),
whereas propylene oxide has one.
Studies in rats have indicated that epichlorohydrin is readily absorbed after
oral or inhalation exposures. Weigle et al. (1978) conducted a distribution study
in Charles River CD rats that were administered 10 mg/kg labeled
epichlorohydrin by oral gavage; peak tissue concentrations were found 2 hours
after dosing. Label from the epichlorohydrin was distributed to the kidneys, liver,
pancreas, adrenals, and spleen in descending order of the tissue concentration
of label. Male Fischer 344 rats were administered 1 or 100 mg/kg labeled
epichlorohydrin by gavage or by inhalation (Smith et al., 1979). Administration
by both routes resulted in a dose-related absorption of the label; at 72 hours
after dosing, 46-54 percent of the label had been excreted in the urine and
25-42 percent was exhaled as carbon dioxide regardless of the dose or route.
Smith et al. reported the distribution of label 3 hours after a single oral dose of
100 mg/kg epichlorohydrin and after a 6-hour inhalation exposure at 100 ppm.
After the oral dose, the highest levels of label were in the stomach, small
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intestine, kidneys, and large intestine. After inhalation, the highest levels were
found in the nasal turbinates, lacrimal glands, kidneys, large intestine, and liver.
A metabolic pathway for epichlorohydrin was proposed by Fakhouri and
Jones (1979). In the proposed pathway, the primary route of detoxification is by
conjugation with glutathione, with the end products being N-acetyl-S-(2 3-
dihydroxypropanol) cysteine and 1,3-(bis-N-acetyl cysteinyl) propan-2-ol
Jones and O'Brien (1980) performed a similar study and proposed an
alternative pathway in which epichlorohydrin is hydrolyzed via epoxide hydrase
and then phosphorylated to form 3-chloroglycerophosphate or oxidized to
beta-chloro-lactate and oxalate.
In general, it is expected that the metabolism of propylene oxide in rodents
would be similar to that of other epoxides; i.e., it is likely to be readily absorbed
through the gastrointestinal and respiratory tracts and distributed to the kidneys
liver, pancreas, adrenals, and spleen. Excretion is likely to be via the urine and
expired air, which would involve conjugation with glutathione and conversion to
carbon dioxide, respectively.
2.2. BIOCHEMICAL EFFECTS
Three in vitro studies were conducted on the interaction of propylene oxide
with subcellular constituents, primarily nucleotides and DNA. Lawley and
Jarman (1972) found that propylene oxide reacts with DNA under physiological
conditions (neutral pH) to form two alkylated adducts, identified as 7-(2-
hydroxypropyl) guanine and 3-(2-hydroxypropyl)adenine. The molar ratio of
the products 3-alkyladenine and 7-alkylguanine was found to be 1-5 The
yield was relatively low compared to the high concentrations of reagents used-
e.g., 16 mM-DNA P incubated with 230 mM-propylene oxide for 7 days gave
6.2 mmol of 2-hydroxypropyl/mol of DNA P; similarly, 7-alkylguanine gave 33
mmol of the 2-hydroxypropyl derivative/mol of DNA P. These adducts
hydrolyze out of the alkylated DNA at neutral pH values at 37°C. The order of
reactivity of the various ring-N atoms of adenine was N-3 > N-1 >N-9; no
evidence for reaction at N-7 was found, whereas guanosine was alkylated at
N-7. It was suggested that product formation indicated a bimolecular reaction
mechanism, binding to the N-7 of guanine and the N-3 of adenine.
Hemminki and Vainio (1980) studied the in vitro alkylation of guanosine and
deoxyguanosme (nucleotides) by epoxides and glycidyl ethers. Propylene oxide
was found to be one of the least active alkylating agents, having an alkylation
rate that was 28 percent of the most reactive compound, phenyl glycidyl ether-
other data were not presented. It was also found that epoxides, including
propylene oxide, alkylate deoxyguanosine faster than single-stranded DNA at
equal concentrations of guanine (Hemminki, 1979). In another study, Hemminki
et al. (1980) characterized the reaction products of a series of epoxides with
deoxyribonucleosides in order to investigate whether differences in adduct
formation would explain the differential mutagenic potency of the epoxides The
reactions were conducted at near-saturation conditions for 3 hours in order to
identify the products, and thus reaction rates were not determined. Propylene
oxide reacted with N-7 of deoxyguanosine to yield one product, and with N-6
of deoxyadenosine to yield one major reaction product.
Farmer et al. (1982) conducted an in vivo study to determine if exposure to
propylene oxide would produce measurable levels of alkylated hemoglobin
Female LAC Porton-derived Wistar rats (170-200 g body weight) were
exposed by inhalation to propylene oxide at 0-2000 ppm (four animals per
dose) for 4 hours. After exposure, hemoglobin was isolated from red blood cells
and hydrolyzed; the amino acids were separated by thin-layer
chromatography, and the level of N-3'-(2-hydroxypropyl)histidine, an
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alkylation product of the protein, was then quantified. A linear dose-related
increase in alkylation, with a maximum of 10.5 yg of the histidine derivative, was
found per gram of hemoglobin. The authors suggested that measurement of
hemoglobin alkylation could be developed as an assay to monitor worker
exposure to propylene or propylene oxide.
2.3. ACUTE TOXICITY
Several studies have been conducted to determine the acute effects of
propylene oxide. The acute toxicity values (LD5rj, LC5rj, and LC[_0) are
presented in Table 2-1.
Rowe et al. (1956) reported the acute effects of propylene oxide following
oral administration in female rats, skin contact in rabbits, and inhalation in
female rats and guinea pigs. In female rats, single oral doses of 1.0 g/kg
resulted in 100 percent mortality while no deaths occurred at 0.3 g/kg.
In rabbits, skin contact with undiluted propylene oxide and with 10 and 20
percent aqueous solutions resulted in hyperemia and edema following exposure
for 6 minutes or longer (Rowe et al., 1956). The intensity of response increased
with increasing exposure time. Some evidence indicated that the diluted
solutions were more irritating than the undiluted ones.
Female rats and guinea pigs exposed to propylene oxide vapors at
concentrations ranging from 2,000 to 16,000 ppm for 0.25-7 hours showed
irritation of the respiratory passages and eyes as well as weight loss (Rowe et
al., 1956). In rats, no effects were noted after single exposures at 1000 ppm for
7 hours, 2000 ppm for 2 hours, or 4000 ppm for 0.5 hour.
The NTP (National Toxicology Program, 1985) reported results of single
4-hour exposure inhalation studies of propylene oxide using F344/N rats and
B6C3F, mice of both sexes. The calculated acute toxicity values are listed in
Table 2-1. Rats (five animals/sex/dose) were exposed to propylene oxide
concentrations of 1277, 2970, 3794, and 3900 ppm (3033, 7055, 9012, and 9204
mg/m3), with mortalities of 0/5, 1/5, 4/5, and 3/5 for the males and 0/5, 2/5, 4/5,
and 3/5 for the females, respectively. Clinical observations in animals exposed
at the three higher concentrations included dyspnea and red nasal discharge.
Male and female mice (five animals/sex/dose) were exposed to propylene
oxide concentrations of 387, 859, 1102, 1277, and 2970 ppm (919, 2041, 2618,
3033. and 7054 mg/m3), with mortalities of 0/5, 0/5, 2/5, 2/5, and 5/5 for the
males and 1/5, 0/5, 4/5, 5/5, and 5/5 for the females. Dyspnea occurred in
animals of all groups; narcosis was observed in animals exposed to the two
highest doses, and lacrimation occurred in animals exposed to the highest dose
(National Toxicology Program, 1985).
2.4. SUBCHRONIC TOXICITY
Following repeated oral doses in female rats (18 doses in 24 days), a slight
loss of body weight, gastric irritation, and slight liver damage were seen at 0.3
g/kg; no effects were noted at the 0.2 or 0.1 g/kg levels (Rowe et al., 1956).
Rowe et al. also reported the results of subchronic inhalation studies with
rats, guinea pigs, rabbits, and monkeys (Table 2-2). No toxic effects were
observed following repeated exposure to propylene oxide vapor at 195 ppm for
128-154 7-hour exposures. In one experiment using a 457-ppm exposure
level, growth of guinea pigs and rats was suppressed after 25-27 7-hour
exposures over 37-39 days. At the same exposure level, after 79-138 7-hour
exposures, some rats developed pneumonia and died; and after 110 7-hour
exposures, guinea pigs showed eye and respiratory tract irritation as well as
slight growth depression, but no deaths occurred.
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Table 2-1. Acute Toxicify Values for Propylene Oxide
Species/strain
(sex)
Mouse/NR* (M)
Rat/Wistar (M)
Rat/NR
Rat/NR (M/F)
Rat/NR (F)
Guinea Pig (M,F)
Guinea Pig (M)
Mouse/NR (M)
Mouse/B6C3F,
Atouse/86C3F;
Rat/NR (M)
Rat/F344/N (M)
Rat/F344/N (F)
Guinea Pig (F)
Dog/Beagle (M)
Rabbit/NR
Route
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Dermal
Exposure
protocol
NR
NR
NR
NR
NR
NR
NR
7 doses, 10
mice/dose
5 doses, 5
mice/dose
5 doses, 5
mice/dose
6 doses, 10
rats/dose
4 doses, 5
rats/dose
4 doses, 5
rats/dose
2 doses, 5
orlOpigs/dose
4 doses, 3
dogs/dose
NR
Acute toxicity
value
LD50 630mg/kg
LD50 1l40mg/kg
LD50 930mg/kg
LD50 520mg/kg
t-D50 540mg/kg
LD50 690mg/kg
LD50 660mg/kg
LC50 4i26mg/m3/4
hr
LC50 3540mg/m3/4
hrc
LC50 2420mg/m3/4
hrc
LC50 9486mg/m3/4
hr
LC50 8265mg/m3/4
hrc
LC50 7697mgtm3/4
hrc
LC^ 9486mg/m3/4
hr
L.CLO 4750mg/m3/4
hr
LD50 i.SmUkg
Reference
Antonova et
al.,1981
Smyth et
al.,1941
Smyth et
a/., 7970
Antonova et
al.,1981
Antonova et
al.,1981
Smyth et
al.,1941
Antonova et
al.,1981
Jacobson et
at., 1956
NTP, 1985
NTP, 1985
Jacobson et
al.,1956
NTP, 1985
NTP, 1985
Rowe et at.,
1956
Jacobson et
al.,1956
Smyth et a/., 7969
A subchronic inhalation study in male and female Cpb:WU rats indicated
that exposure to propylene oxide at 600 ppm for 6 hours/day for 3 months
caused decreased weight gain and degenerative and hyperplastic epithelial
changes in the nasal, passages (Reuzel and Kuper, 1983). At 300 pprn there
was slight growth retardation. This study was used to set levels for a life-time
study in rats.
2.5. CHRONIC 1OXICITY
Reuzel and Kuper (1983) performed an inhalation chronic
r?XK^,??*C,°?eniCity study in wtlich 9rouPs of 10° male and 100 female
Cpb:WU Wistar rats were exposed to propylene oxide at 0, GO, 100 or 300 ppm
for 6 hours/day, 5 days/week for 123 weeks (females) or 124 weeks (males)
Ten rats/sex/group were sacrificed at 12, 18, and 24 months. There were
-------
Table 2-2. Results of Subchronic Inhalation Exposure to Propylene Oxide in
Rats, Guinea Pigs, Rabbits, and Honkeys
Vapor No. of
cone..
Species/Sex
Rat/M.F
Guinea pig/M.F
Rat/M.F
Guinea pig/M.F
RabbitlM.F
Monkey/F
Rat/M
Rat/F
Guinea pig/M
Guinea pig/F
RabbitlM.F
Monkey/F
Source: Rowe et a/.
ppm
102
102
195
195
195
195
457
457
457
457
457
457
(1956).
7-hour
Exposures
138
128
138
128
154
154
79
138
110
110
154
154
Mortality
9/40
0/16
7/40
0/16
0/4
012
5110
7/10
018
0/8
0/2
0/1
Pathologic findings
None
None
None
None except lungs of females;
slightly heavy
None
None
Eye and respiratory irritation;
growth depression; increased
mortality; lung injury
Eye and respiratory irritation;
growth depression; increased
mortality; lung injury
Eye and respiratory irritation;
growth depression;
slight liver injury
Eye and respiratory irritation;
growth depression;
slight lung injury
None
None
considerable decreases in weight gain in both males and females exposed at
300 ppm propylene oxide during the first year of the study. However, the
animals adapted and body weights were similar between control and dosed
groups during the second year of the study. There was increased mortality in
both males and females receiving 300 ppm propylene oxide as compared to
controls but no effects were noted in hematology, blood chemistry, or urinary
parameters. At sacrifice, male rats exposed at 300 ppm had increased adrenal,
spleen liver, and lung weights as compared to controls, but there were no
accompanying histopathologic changes in these organs. Histologic changes in
the nasomaxillary turbinates o* exposed rats were observed, consisting of
degenerative changes in th'j olfactory epithelium and thickening of the
submucosa and a dose-related increase in focal hyperplasia of the nasal
epithelium. At 300 ppm, dilated renal tubules were found in the kidneys of 7 of
69 female rats but none was found in the controls. In addition, there was
mvocardial degeneration in 10 of 69 females at 300 ppm compared to an
incidence of 3 of 69 in controls; 9 of 69 males at 300 ppm had thrombi in the
heart whereas the incidence in controls was 2 of 70. Preneoplastic changes
were noted in that high-dose males also had prosoplasia in the exorbital
lacrimal glands. Neoplastic findings are discussed in Section 2.7.
Lynch et at. (1984a) studied the chronic toxicity of inhaled propylene oxide
in which groups of 80 male Fischer 344 rats were exposed to 0, 100, or 300
ppm propylene oxide vapor for 6.9 hours (average)/day, 5 days/week for 2 years
10
-------
(488 days of exposure). There were significant decreases in mean body weights
in rats exposed at 300 ppm from week 2 of the study and in rats exposed at 100
ppm from week 37 of the study. The median survival time was 700 days for
controls, 705 days for rats exposed at 100 ppm, and 675 days for rats exposed
at 300 ppm propylene oxide. For both groups of exposed rats, hemoglobin
concentrations were elevated compared with controls. There were changes in
differential leukocyte counts, but these changes were probably caused by
outbreaks of Mycoplasma pneumonia at 8 and 16 months of the study. There
were no dose-related changes in clinical chemistry or urinalysis parameters. At
study termination, there were statistically significant increases in lung weights
and lung-to-body weight ratios in both dosed groups, an increased adrenal-
to-body ratio, and a decrease in testes weights and testes-to-body weight
ratios in both dosed groups as compared to controls. The changes in the
adrenals were correlated with histopathologic changes. Nonneoplastic
histppathologic changes were seen in the respiratory system. There was a
statistically significant increase in the incidence of chronic focal pneumonia (66
of 80 and 53 of 80 at 100 and 300 ppm, respectively, compared to 6 of 79 in
controls); edema of the lungs (6 of 80 and 11 of 80 at 100 and 300 ppm
respectively, compared to 0 of 79 in controls); suppurative rhinitis of the nasai
cavity (21 to 77 and 44 of 78 at 100 and 300 ppm, respectively, compared to 12
of 76 in controls); complex epithelial hyperplasia of the nasal passages (11 of 78
at 300 ppm compared to 0 of 76 in controls); and an increased incidence of
lymphoid hyperplasia in the tracheobronchial lymph nodes (41 of 76 and 41 of
79 at 100 and 300 ppm, respectively, compared to 3 of 73 in controls)
Neoplastic changes in these rats are discussed in Section 2.7.
Renne et al. (1986) discussed the results of the National Toxicology
Program (1985) studies. In this bioassay, F344/N rats and B6C3F! mice were
exposed to propylene oxide vapors at concentrations of 200 or 400 ppm 6
hours/day, 5 days/week for 2 years. Mean body weight decreased when
compared with that of control groups, during the second year of exposure in
both mice and rats exposed to the higher dose (400 ppm) of propylene oxide
However, mean body weight at terminal sacrifice for rats exposed to 400 ppm
was within 10% of chamber control group values. There was a decrease (P
< 0.005) in survival at the end of the study in both male and female mice
exposed to 400 ppm propylene oxide. Only 29 of 50 (58%) male mice and 10 of
50 (20%) female mice exposed to 400 ppm survived to terminal sacrifice
compared with 42 of 50 (84%) male control mice and 38 of 50 (76%) female
control mice. No statistically significant trends in survival were observed among
groups of male or female rats. The significant decrease in survival and body
weight in mice exposed to 400 ppm propylene oxide indicates that chronic
exposure to this concentration is toxic to mice. Neoplastic findinqs are
discussed in Section 2.7.
The World Health Organization (1985) summarized the results of animal
studies (excluding mutagenic, carcinogenic, and reproductive effects) They
indicate a no-observed-adverse-effect level for prolonged repeated 6- to
7-hour daily exposure at a concentration of 70 mg/m3 (29 ppm).
2.6. MUTAGENIC1TY
Propylene oxide was found to be mutagenic, causing base-pair
substitutions in Salmonella typhimurium strains TA 100 and TA 1535 without S9
metabolic activation. The compound did not cause frameshift mutations in
strains TA 1537, TA 1538, and TA 98 (Bootman et al.. 1979; McMahon et al
1979; Hemminki and Falck, 1979; Pfeiffer and Dunkelberg 1980)
11
-------
There was a dose-related increase in mutants at levels of propylene oxide
between 40 and 1000 yg/ml in strain TA 100, when the assay was carried out in
liquid culture in sealed tubes (1-hour incubation) and the cells plated and
incubated in a sealed container. At 1000 yg/ml, there were 227 his +
revertants/107 surviving bacteria (Bootman et at., 1979). Wade et al. (1978)
reported that propylene oxide produced 166 his+ revertants/yg in Salmonella
strain TA 100 and 22 revertants/yg in strain T\ 1535. Propylene oxide was also
mutagenic without activation in spot tests in Escherichia coli strain WP2
(Bootman et al., 1979; Hemminki and Falck, 1979), £. coli strains CM891 (uvrA,
pKM 101 plasmid) and CM871 (exr A-, uvr A-, rec A;) (Bootman et al., 1979),
and Klebsiella pneumoniae (Voogd et al., 1981). Migliore et al. (1982) reported
that propylene oxide caused forward mutations (5 ade loci) in
Schizosaccharomyces pombe, when the yeast was incubated for 6 hours in
sealed test tubes with levels of propylene oxide between 3 and 30 mM.
Mutation frequencies were similar in the absence and presence of an S9 mix.
Kolmark and Giles (1955) found that propylene oxide caused reverse mutations
in a purple adenine auxotrophic strain of Neurospora. In this test, reversion to
adenine independence is usually accompanied by a lack of production of purple
pigment. A maximum number of reversions was achieved by treating
macroconidia with 0.5 M propylene oxide for 60 minutes. This produced 80
revertants/106 survivors and 27 percent survival.
Djuric et al. (1986) studied mutagenicity dose response for propylene
oxides in Salmonella typhimurium tests systems TA100 and TA1535. Of three
propylene oxides (propylene oxide, epichlorohydrin, and glycidol), propylene
oxide produced the lowest dose-mutagenicity response. However, the fourth
propylene oxide studied (trichloropropylene) produced inconsistent results.
Hardin et al. (1983b) tested propylene oxide for mutagenic activity in the
Drosophila sex-linked recessive lethal test. Male flies were exposed statically
to propylene oxide at 645 ppm (1530 mg/m3) for 24 hours and mated with
Muller-5(Basc) females on days 2-3 and 7-8 postoxposure. F-\ females,
heterozygous for the control or propylene oxide-treated, wild-type X-
chromosome, were mated with Muller-5 males and cultures scored for wild-
type F2 males. The total incidence of sex-linked recessive lethal mutations
was significantly increased in propylene oxide-exposed flies (4.28 percent)
compared to controls (0.25 percent). The increase was observed in developing
spermatocytes (broods at days 2-3) and mature sperm (broods at days 7-8).
Zamora et al. (1983) evaluated the mutagenicity of propylene oxide in the
vapor phase in the in vitro Chinese hamster-HGPRT assay. Cells were grown
on collagen gels in glass culture flasks. Medium was removed, the flasks
inverted, and cold propylene oxide added. The propylene oxide was vaporized
by briefly heating the bottle and the cells were incubated for 1 hour at 37°C.
Propylene oxide caused a dose-related increase in mutants. At 32 yg/cnv
(13,376 ppm), there was a 30 percent survival of cells and 88 mutants/106
survivors. Cells attached to glass did not survive exposure to propylene oxide in
the absence of medium.
Propylene oxide was also tested for genotoxic activity in the mouse
spermhead morphology test by exposing groups of 10 male C3H-He mice (10
weeks old) at 300 ppm (711 mg/m3) for 7 hours/day for 5 days; five control
groups of 10 mice each were also included. Groups of 10 mice were sacrificed
at weeks 1, 3, 5, 7, and 9 postexposure. Cauda epididimides were removed and
minced, and then the sperm were isolated; about 2000 sperm per mouse were
scored for abnormal morphologies by microscopic examination. No statistically
significant abnormalities were noted.
12
-------
The same investigators tested propylene oxide for genotoxic activity usinq
the dominant lethal test in a group of 10 male Sprague-Dawley rats exposed to
propylene oxide at 300 ppm (711 mg/m3) for 7 hours/day for 5 days; a control
group of 10 males was also included. Two days after exposure, each male was
caged with two virgin females of the same strain. Mating was for 5 days with a
2-day rest period, and each week, for 6 consecutive weeks, another pair of
virgin females was introduced. No clear genotoxic effects were evident
Experimental groups differed from controls only in the first week of mating but
the control group had an unusually low rate of implantation when compared to
subsequent control groups.
Bootman et al. (1979) tested propylene oxide in a dominant lethal test in
which groups of 10 male CD-1 mice received 14 daily doses of 50 or 250
mg/kg propylene oxide by gavage; control groups received 0.5 percent gum
tragacanth (vehicle control) or three daily doses of 200 mq/kq
ethylmethanesulfonate (EMS). Males were then mated for 7 days with two virgin
female CD-1 mice. There were six successive weekly matings. Females were
sacrificed 18 days after mating initiation, and implants, early deaths and late
deaths were recorded for each female. Pregnancy rates, total implants/sire, and
post-implantation loss were not different in negative control groups and
propylene oxide-treated groups. Females of the positive control group had a
significant reduction in pregnancy rate in weeks 2 and 5 and an increase in
implant deaths after weeks 1 and 2 of mating. There was no evidence of
genotoxic effects on sperm.
Bootman et al. (1979) also tested propylene oxide in the mouse
micronucleus test. Groups of male CD-1 mice were administered two doses of
propylene oxide by gavage at 30 and 6 hours before sacrifice or were given two
doses intrapentoneally on the same schedule. The doses administered orally
were 100, 250, or 500 mg/kg, and those injected intraperitoneally were 75 150
or 300 mg/kg at each dosing. Appropriate vehicle control (05 percent
tragacanth) and positive control (2 x 55 mo Kg cyclophosphamide) groups were
included. The numbers of micronucleated cells per 103 polychromatic
erythrocytes were scored. No effects were noted after oral administration but
there was a significant increase in micronucleated cells in mice receiving two
300-mg/kg doses of propylene oxide intraperitoneally as compared to vehicle
controls.
The same investigators (Bootman et al., 1979) conducted cytogenetic
studies in cultured human lymphocytes. Growing cultures were incubated for 24
hours with 1.85 or 9.25 yg/ml propylene oxide. Control cultures had sterile water,
added, and positive controls were incubated with 0.93 yg/ml chlorambucil
Colcemid (4 yg) was added 3 hours before cells were harvested After
harvesting, the cells were fixed and stained with Giemsa, and slides prepared
for chromosomal analysis. There was a dose-related increase in the frequency
or chromosomal aberrations following propylene oxide exposure The largest
increases occurred as chromatid gaps and breaks and as chromosome breaks
Propylene oxide at 9.25 yg/ml produced an incidence of aberrations similar to
the positive controls (0.93 ug/ml chlorambucil) when gaps were not scored
(Bootman et al., 1979).
Dean and Hodson-Walker (1979) tested the genotoxicity of propylene
oxide in an in vitro chromosome assay utilizing rat liver epithelial cells. This
system was shown not to require an extrinsic metabolic activating system Cells
were exposed to propylene oxide at concentrations between 25 and 100 yq/ml
for 24 hours and treated with colcemid (0.3 yg/ml) in the final 2 hours of
incubation. There was a dose-related increase in chromatid gaps (11 53
17.5, 31.3, and 53.7 percent at 0, 25, 50, 75, and 100 yg/ml, respectively) and in
13
-------
chromatid deletions (0.3, 1.3, 3.3, and 6.0 percent at 0. 25, 50, and 75 yg/ml,
respectively); however, there were no increases in chromosomal aberrations.
These results strongly suggest clastogenic activity of propylene oxide.
Lynch et al. (1984b) assayed sister-chromatid exchanges (SCE's) and
chromosomal aberrations in cultured lymphocytes from cynomolgus monkeys
that had been exposed to propylene oxide vapors. Groups of 12 adult male
monkeys were exposed to propylene oxide at 0, 100, or 300 ppm for 7
hours/day, 5 days/week for 2 years. Blood was collected in the 24th month and
lymphocyte cultures established. To measure SCE's, 5-bromodeoxyuridine (50
pmol/ml BrdUrd) was added to the cultures; to measure chromosomal
aberrations, BrdUrd was omitted. There were no significant increases in the
incidence of SCE's or in the incidence of chromosomal aberrations in propylene
oxide-exposed groups of monkeys compared to controls. In comparison,
exposure of cynomolgus monkeys to ethylene oxide at 50 or 100 ppm,
however did result in a significant increase in SCE's and chromosomal
aberrations. In addition, Lynch et al. (1983) also studied the spermatogenic
function of these monkeys at the end of the 2-year study. Statistically
significant (p value not reported) decreases in sperm counts and sperm motility
and increases in drive range were seen in all treated groups of monkeys.
However, no differences in the number of sperm head abnormalities were
detected between exposed and control monkeys.
Tucker et al. (1986) exposed phytohemagglutinin-stimulated human
peripheral lymphocyte cultures to propylene oxide at a concentration of 2.5
percent to examine the induction of SCE's. The SCE frequency was increased
from 8.74 per cell in the control to 22.74 per cell in the treated cells
demonstrating its genotoxicity.
2.7. CARCINOGENICITY
Walpole (1958) tested the ability of various alkylating agents to cause
sarcomas at the site of injection in rats. When propylene oxide in arachis oil was
injected subcutaneously in rats (sex not specified), a total dose of 1500 mg/kg
given over 325 days caused injection-site sarcomas in 8 of 12 rats, whereas
injection of propylene oxide in water, using the same regimen, produced
sarcomas in 3 of 12 rats. It could not be determined if propylene oxide was a
direct carcinogen, an initiator, or a promoter.
Dunkelberg (1981) investigated the carcinogenic potential of propylene
oxide in groups of 100 female NMRI mice injected subcutaneously with 0.1, 0.3,
10 or 2 5 mg propylene oxide in tricaprylin once a week for 95 weeks. A
positive control group (100 mice) received benzo(a)pyrene (2.5 ug/mouse) from
week 32. Groups of 200 mice served as the untreated controls and vehicle
controls (0.1 ml tricaprylin). There was a dose-related increase in tumors at the
injection site (Table 2-3); the first tumor appeared at 39 weeks in the high-
dose group. Tumors at sites away from the site of injection occurred
sporadically, and their incidences were similar in control and dosed groups.
Dunkelberg (1982) tested the carcinogenicity of intragastrically
administered propylene oxide in female Sprague-Dawley rats. Groups of 50
rats were administered propylene oxide in salad oil at 0, 15, or 60 mg/kg body
weight 2 times a week for 150 weeks. Survival was about 60 percent in all
groups at 2 years. Propylene oxide induced local tumors, primarily squamous
cell carcinomas of the forestomach. In addition, there was an increase in
papillomas and reactive changes in the squamous epithelium of the
forestomach (Table 2-4). The first stomach tumor appeared at week 79 in the
high-dose group. The incidence of tumors at sites away from the site of
administration was similar in dosed and control groups.
14
-------
Table 2-3. Injection Site Tumors in NMRI Mice Receiving Propylene Oxide
Propylene oxide, mo/animal
Untreated
controls
Vehicle
controls
0.1
0.3
1.0 2.5 B(a)Pa
No. of mice
No. of tumors
at injection site
Fibrosarcoma
200
0
200
5
100 100 100 100 100
4 4 14 20 83
10
a Benzo(a)pyrene.
b Data not available.
Source: Dunkelberg (1981).
Table 2-4.
Incidence of Stomach Tumors and
Nonneoplastic Changes in Rats
Intragastrically Administered
Propylene Oxide
Histologic findings
Dose, mg/kg
15
60
Squamous cell carcinoma
Adenocarcinoma
Carcinoma in situ
Hyperkeratosis, hyperplasia,
and papilloma
0
0
0
0
2
0
0
7
19
1
1
17
13
74
Pleomorphic
sarcoma
Lymphoma
infiltrate
Adenocarcinoma
Cystic granuloma
1-22
1 1222
1
2
7
2
_
-
Source: Dunkelberg (1982).
Reuzel and Kuper (1983) exposed CpbrWU Wistar rats (100
animals/sex/group) to propylene oxide at atmospheric concentrations of 0 30
100, or 300 ppm for 6 hours/day, 5 days a week for 123 weeks (female) or 124
weeks (males). After 12, 18, and 24 months, 10 rats/sex/group were sacrificed
for interim information. No differences in site, type, or incidences of tumors
were found between the groups at any of the interim sacrifices. However an
increased incidence in mammary gland tumors was noted in exposed females
at the terminal sacrifice (Tah'j 2-5). There was a dose-related increase in
multiple fibroadenomas (statistically significant trend using Cox's time-to-
tumor analysis) and a significant increase in the number of females with total
fibroadenomas or carcinomas at 300 ppm when compared to controls There
were no tumors in the nasal turbinates, although there was a dose-related
increase in focal hyperplasia. Incidences of tumors at other sites were similar
between exposed and control groups of males and females. The authors
15
-------
suggested that propylene oxide was not a direct acting carcinogen but, rather, it
"enhanced the development of malignant neoplasms by an indirect mechanism
such as immunosuppression or disturbed hormonal balance."
Lynch et al. (1984a) tested the carcinogenicity of inhaled propylene oxide in
male Rscher 344 rats. Groups of 80 rats were exposed to 0, 100, or 300 ppm
propylene oxide vapor for 6.9 hours (average)/day, 5 days/week for 2 years (488
days of exposure). There was a statistically significant increase in the incidence
of pheochromocytomas of the adrenal glands (25 of 78 and 22 of 80 at 100 and
300 ppm, respectively, compared to 8 of 7j in controls) but no dose-related
trend. Two adenomas of the nasal passages were found at 300 ppm and none
at 100 ppm or in controls. No increases in other respiratory tract neoplasms
were noted. There was, however, a statistically significant increased incidence
of epithelial hyperplasia in the nasal cavities of rats exposed to propylene oxide
at 300 ppm (11 of 78) compared to controls (0 of 76).
The finding of increased proliferative lesions was stated by the authors to
be similar to that of a bioassay performed by the National Toxicology Program
(1985) and Renne et al. (1986). In this bioassay, F344/N rats and B6C3FT mice
were exposed to propylene oxide vapors at concentrations of 200 or 400 ppm, 6
hours/day, 5 days/week for 2 years. The rats tolerated the exposure with no
increase in mortality when compared to controls. In the high-dose group, 58
percent of the males and 62 percent of the females survived until study
termination. The terminal mean body weights of males and females exposed at
400 ppm were 8 and 6 percent lower than those of the controls, respectively.
In female rats, "some evidence" of compound-related carcinogenicity was
reported based on a positive trend (p <0.04) in papillary adenomas of the nasal
cavity (Table 2-6). There were also dose-related increases in inflammatory
and preneoplastic lesions in the nasal cavities of both males and females. The
epithelial hyperplasia lesions were"'morphologically similar but less focal than
the papillary adenomas. In addition, there was an increased incidence of thyroid
C-cell adenomas and C-cell carcinomas in females receiving 400 ppm;
however, only the combined incidence of these tumors was significantly
different from that of the controls (Table 2-7). The combined incidence of
endometrial stromal polyps or sarcomas of the uterus was increased in the
dosed groups, but the incidence in the concurrent controls was low compared to
historical controls.
In addition, dose-related increases in the following nonneoplastic lesions
were observed: in male rats, acinar cell atrophy of the pancreas (1 of 47, 12 of
49, and 17 of 47) and testicular atrophy (18 of 49, 40 of 50, and 24 of 50) in the
control, low, and high-dose groups, respectively; and in female rats,
cytomegaly of the adrenals (1 of 48, 6 of 49, and 11 of 48) in the control, low,
and high-dose groups, respectively.
In mice, a significant increase in mortality occurred in the dosed animals.
Survival at the high dose was 58 percent in males and 20 percent in females
compared to 84 and 54 percent for the controls, respectively. The terminal
mean body weights of males and females exposed at 400 ppm were 21 and 10
percent lower than those of the controls, respectively.
The incidence of histopathologic lesions in the nasal cavities of mice is
summarized in Table 2-8. Based on the increased incidences of hemangiomas
and hemangiosarcomas in the nasal cavities, propylene oxide can be
considered a site-specific carcinogen. Inflammation of the respiratory
epithelium was observed, but no significant hyperplasia or metaplasia was
noted. There was also an increased incidence of mammary gland
adenocarcinomas (3 of 50 and 3 of 50 at 200 and 400 ppm, respectively,
compared to 0 of 50 in the controls); this increase was not statistically
16
-------
Table 2-5. Incidence of Mammary Gland Tumors in Female Rats Exposed to
Propylene Oxide Vapor^
Exposure level; ppm
Fibroadenoma Single
Fibroadenoma
Multiple
Fibroadenoma Total
Adenoma
Fibroma
Carcinoma
(tubulopapillary)
0
25
7
32
0
0
3
30
11
1&>
30
0
0
6
WO
15
23b
39
0
1
5
300
13
33"
470
1
2
8C
a Tumor incidences are based on examination of all tissues of control and high-dose
groups and all gross lesions of low and mid-dose groups. Fifty animals! sex/group
were examined, excluding animals at the interim sacrifice.
° Statistically significant trend using a chi-square test.
c Statistically significant (p <0.05) using Cox's test adjusting for time to tumor
Source: Reuzel and Kuper (1983).
Table 2-6. Incidence of Nasal Cavity Lesions in Rats Exposed to Propylene
Oxide via Inhalation3
Males Exposure level,
ppm
Females Exposure level,
ppm
Type of lesion
Suppurative
inflammation
Epithelial hyperplasia
Squamous metaplasia
Papillary adenoma
0
9
0
1
0
200
21
1
3
0
400
38
11
21
2
0
3
1
1
0
200
5
0
2
0
400
23
5
11
3
a Tissues from 50 animals were examined histologicallv in each orouo
Source: NTP (1985).
significant but showed a significant positive trend. An increased incidence of
atrophy of the ovary was also noted (8 of 46 and 20 of 37 at 200 and 400 ppm
respectively, compared to 6 of 40 in the controls).
From the available data, NTP concluded that propylene oxide showed clear
evidence of carcinogenicity in mice and some evidence of carcinoqenicitv in
rats.
The International Agency for Research on Cancer (1985) has evaluated that
there is sufficient evidence for the carcinogenicity of propylene oxide for
experimental animals but inadequate evidence for the carcinogenicity of
propylene oxide for humans. According to EPA's guidelines for classifying
carcinogenic evidence (Federal Register, 1986), propylene oxide would be
17
-------
Table 2-7. Incidence of Thyroid Lesions in
Female Rats Exposed to Propylene
Oxide via Inhalation
Exposure level, ppm
Type of lesion
No. of tissues
examined
C-cell hyperplasia
C-cell adenoma
C-cell carcinoma
Adenoma and
carcinoma
0
45
7
1
1
2
200
35
6
1
1
2
400
37
5
4
3
?a
a Statistically significant (p <0.05) compared to
controls.
Source: National Toxicology Program (1985).
tentatively placed in the B-2 category (Probable Human Carcinogen) because
of positive animal data and an absence of epidemiological studies (Paynter,
1985).
Preliminary unit risk estimation for the carcinogenicity of propylene oxide
for both the gavage and inhalation routes of exposure has been performed by
the EPA (U.S. Environmental Protection Agency, 1985). The q^ values were
calculated using the linearized multistage model of Crump based on the tumor
response data for Sprague-Dawley rats in the gavage study of Dunkelberg
(1982) or based on the tumor response data on B6C3F! male mice in the
National Toxicology Program (1985) inhalation study. The qi* value is a 95
percent upper confidence limit which is taken as an upperbound estimate of the
human cancer potency of the chemical -- the true risk is not likely to be
higher than the estimate, but it could be smaller (Federal Register, 1980). The
pertinent data for the calculations are summarized in Table 2-9. Calculated
values for q^ are presented in Table 2-10. Potency, mg/kg/day, has been
converted to a ug/m3 basis for air concentration. It will be noted that the
inhalation estimate, 3.74 x 10-6(yg/m3)-1, is approximately twentyfold lower
than that calculated for the ingestion data, 6.83 x 10-5(yg/m3)-i. There are
insufficient data on pharmacokinetics to evaluate if the assumption of 50 percent
absorption used in the calculations is reasonable. For air unit risk estimates, it
may be preferable to calculate the value from the inhalation study; however, it
also may be preferable to use the less conservative estimate from the gavage
study. These are only rough estimates to be used as tools for further
preliminary evaluations and should not be construed as Agency policy.
2.3. TERATOGENICITY AND REPRODUCTIVE EFFECTS
Hardin et al. (1983a)'conducted a teratogenicity study with rats and rabbits
exposed to propylene oxide by inhalation and concluded that propylene oxide
was embryotoxic but not teratogenic. The study groups consisted of 32-45
sexually mature female Sprague-Dawley rats that were sperm positive and
23-30 New Zealand white rabbits that were artificially inseminated. Groups of
animals were exposed in a dynamic inhalation chamber at 500 ppm (1118
18
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Table 2-8. Incidence of Nasal Cavity Epithelial Lesions in Mice Exposed to
Propylene Oxide via Inhalation^
Males Exposure level,
ppm
Females Exposure level,
ppm
Type of lesion
Serous inflammation
Suppurative
inflammation
Acute/chronic
inflammation
Squamous
metaplasia
Papilloma
Squamous cell
carcinoma
Adenocarcinoma
Hemangioma
Hemangiosarcoma
Hemangioma and
hemangiosarcoma
0
0
0
1
0
0
0
0
0
0
0
200
13t>
8
14b
1
0
0
0
0
0
0
400
2
4
38b
0
1
1
0
5*>
5b
10*>
0
2
0
0
0
0
0
0
0
0
0
200
6
1(jb
14b
0
0
0
0
0
0
0
400
2
23b
18b
2
0
0
2
3
2
5*>
a Tissues from 50 animals were examined histologically in each group.
b Statistically significant (p < 0.05) compared to controls.
Source: National Toxicology Program (1985).
mg/m3) propylene oxide for 7 hours/day. Rats were exposed in one of three
time periods: for 3 weeks prior to mating and throughout gestation, on days 1-
6 of gestation, or on days 7-16 of gestation. All rats were sacrificed on day 21
of gestation. Groups of rabbits were exposed on days 1-6 or 7-19 of
gestation and sacrificed on day 30. Control groups of animals were exposed to
filtered air. All rat and rabbit fetuses were examined for extdrnal defects, and
half of the fetuses were examined for brain defects.
There was no maternal mortality in either rats or rabbits. However, a
statistically significant decrease in body weight gain and a significant increase
in kidney-to-body weight ratios was observed in exposed rats when
compared with control animals. Similar increases in the relative weights of the
lungs, liver, and spleen of rats were observed, but the increases were not
statistically significant. The effect on relative organ weights was greater in the
group exposed for 3 weeks prior to mating and through gestation than in groups
exposed during gestation only. There was no effect on body or organ weights in
rabbits. A significant (p <0.01) decrease in the numbers of corpora lutea,
implants, and live fetuses in rats exposed to propylene oxide for 3 weeks prior
to mating was noted when compared to the other exposed groups or controls.
There was a significant increase in the number of resorptions in rats exposed
from days 7-16 of gestation but not in other exposed groups when compared
to controls.
19
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Table 2-9. Dafa for Derivation of q,"
Reference
Route, vehicle:
Species, strain, sex:
Body weight (assumed):
Length of exposure:
Length of experiment:
Ufespan of animal:
Tumor site and type:
Experimental doses
Gavaae (219 doses)
60 mg/kg/day
15 mglkglday
0.0 mg/kg/day
Inhalation (6 hours/dav, 5
days/week)
400 ppm
200 ppm
0.0 ppm
Dunkelberg (1982)
gavage, salad oil
rat/Sprague-
Dawley/female
0.35 kg
1029 days
1050 days
1050 days
forestomach, squamous
cell carcinoma
Transformed doses
(mg/kg/day)
10.28
2.58
0.0
UOb
55"
0.0
NTP (1985)
inhalation
moose/B6C3Fr/ male
0.030
721 days
721 days
721 days
nasal cavities:
hemangioma or
hemangio-sarcoma
Tumor incidence
19/50
2/50
0/1 00a
10/50
0/50
0/50
* Combined vehicle and untreated control.
b Assumes 50 percent absorption.
Source: U.S. Environmental Protection Agency (1985).
Table 2-70. Calculated q,* Values for Propylene Oxide
Parameter Units Gavage study Inhalation study
Unadjusted q ;"
Human q;*
Human q*
(mglkgldayr1
(mg/kg/day^'
(liglm3?1
4.08 x ro-2
2.39ax JO-'
6.83C x 70-5
9.84 x 70"*
t.31b x 10-2
3.74 x 1Cr6
a Unadjusted q "x (70/0.35)"3.
^ Unadjusted q, x (70/0.030)»3.
c Human q " (mg/kg/day)-1 x (2.86 x 1Q-4 m^/kg) x (irr3 ng/mg), assuming 70
kg the average human weight and 20 m3 the daily respiratory volume.
20
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in «if ? y We'3ht and crown-to-™mp length were significantly reduced
in all propylene ox.de-exposed rats. There was an increased incidence of rib
dysmorphology (wavy ribs) and decreased skeletal ossification. No embryonic
fetotoxic, or developmental defects were noted in rabbits.
2.9. NEUROTOXICITY
Groups of 12 male monkeys ( Macaca fascicularis) were exposed to
propylene oxide at 0, 100, and 300 ppm for 6 hours/day, 5 days/week for 24
months and tested bimonthly for nerve conduction velocity (Sprinz et al 1982)
At the end of the exposure period, two monkeys from each group were"deeply
anesthetized and perfused with fixative. Brains, spinal cords and ulnar and
sciatic nerves were removed, placed in fixative, and prepared for microscopic
examination. No differences were found between exposed animals and controls
n sections at various levels of the sciatic and ulnar nerves or eight segments of
the spinal cord. There were signs of axonal dystrophy in the area of the nucleus
gracilis and fasciculares gracilis in the medulla oblongata of the brain in
monkeys exposed at 300 ppm. No demyelination was found in monkeys
exposed to propylene, while demyelination was observed in the distal fasciculus
sunnS^H ££ °HHvUr monl!?yS exP°sed to ethylene oxide. The authors
suggested hat additional studies are needed to establish whether neurotoxic
effects result from propylene oxide exposure.
2.10. EFFECTS ON HUMANS
Two case reports involving contact dermatitis resulting from exposure to
propylene oxide were found in the literature. Van Ketel (1979) described the
£,?« a lf.male
-------
oxide, a known human mutagen. Second, the mean age of this group was 52.5
years while the mean age of the control group was only 38.6 years.
Pero et al (1982) investigated unscheduled DNA synthesis (DMA repair) in
the lymphocytes of workers exposed to propylene oxide for an average of 10
years The study group was composed of 23 workers, ages 25-59 years (mean
41 years) who were exposed to propylene oxide in a factory producing
alkylated starch. Estimates of exposure were obtained using personal and
stationary sampling; the time-weighted average was 0.6-12 ppm for 2-b
hours per day. The control group consisted of 12 workers, ages 21-46 years
(mean 30 years). Unscheduled DNA synthesis (UDS) was measured by
exposing cultured lymphocytes to a standardized dose of N-acetoxy-2-
acetylaminofluorene (NA-AAF) and measuring thymidme incorporation This
value was adjusted for individual variation by dividing it by the level of NA-AAF
binding to DNA as concurrently measured in each individual's lymphocytes. The
NA-AAF-induced UDS was significantly lower (p < 0.001, t-test in the
propylene oxide-exposed group, thus indicating that these individuals had a
reduced capacity to repair DNA damage.
Van Sittert and De Jong (1985) conducted a prospective study of
chromosome aberrations in the lymphocytes of plant workers exposed to
propylene oxide. Precise data on levels of exposure were utilized in this study
of 116 men and 20 controls. The authors concluded that changes in the
frequency of chromosome aberrations in the lymphocytes during the period of
1978-81 were unlikely of occupational origin. They also note that the low levels
under study (below 1 ppm, 8-hour TWA) may be such that the method is not
sensitive enough to detect differences at such levels.
Thiess et al. (1982) carried out a retrospective cohort study ot bu^
employees in eight German production plants where alkylene oxides (ethylene
oxide and propylene oxide) and their derivatives were produced. Mortality of
these employees was compared with that in three subsets of the German
population. Overall, 56 deaths were observed in the study cohort, compared
with 71 5-76.6 expected in the reference populations. No deaths occurred in
any cancer category that were significantly higher than those expected.
Malignant diseases occurred in men who worked in different production areas.
However, exposure to butylene oxide, dioxane epichlorohydrin, dichloropropane,
and other chemicals also existed.
22
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3. Summary and Conclusions
Propylene oxide is an epoxyalkane with a high water solubility and a high
vapor pressure. Its major use is as an intermediate in the production of
polyurethane foams and propylene glycol. It is also used as a fumiqant and as a
pesticide.
-, o °Uhe estimated 1-77 billion pounds of propylene oxide produced annually
i.J million pounds is released to the atmosphere. Average atmospheric
concentrations at a distance of 20 km or greater from production facilities are
estimated to be less than 0.0001 ppt (10-7 ppb). Occupational exposures are
believed to be less than 1 ppm. Propylene oxide has been detected in
fumigated foods and plastics.
Propylene oxide is expected to be very mobile in the environment and is
not expected to bioconcentrate or bioaccumulate. The calculated atmospheric
half-life is 6.1 days. The estimated hydrolysis half-life in water ranges from 7
to 12 days.
The reported ecological effects of propylene oxide are limited to acute
toxicity studies. The reported LC50 values in fish range from 89 to 215 mq/l No
chronic or life-cycle effects have been reported.
No studies were found in the available literature on the absorption
distribution, metabolism, or excretion of propylene oxide. However, based on
available data on structurally similar compounds such as propylene and
epichlorohydrm, it appears that propylene oxide is likely to be readily absorbed
through the gastrointestinal and respiratory tracts and distributed to the kidneys
liver, pancreas, adrenals, and spleen. Metabolism may involve conjugation with
glutathione or hydrolysis by epoxide hydrase. Excretion of propylene oxide and
its metabolites is expected to be primarily through the urine and expired air
Several studies were found on the ability of propylene oxide to alkylate protein
nucleotides, and DNA in vitro and in vivo.
The oral LD50 for propylene oxide was reported to be in a range of 0 52 to
1.14 g/kg in rats and 0.66 to 0.69 g/kg in guinea pigs. The LC50 for a 4-hour
inhalation exposure was from 7697 to 9486 mg/rrn in rats and from 2420 to
4126 mg/m3 in mice. The LCLo for a 4-hour inhalation exposure was 9486
mg/m3 in pigs and 4750 mg/m3 in dogs.
Acute exposure to sublethal concentrations of propylene oxide vapor
caused eye and respiratory tract irritation in experimental animals. The lowest
concentrations at which effects were seen in experimental animals with acute or
subchronic inhalation exposures were in the range of approximately 400-500
ppm propylene oxide. Skin contact with an undiluted or 10 percent solution of
propylene oxide caused skin irritation in rabbits.
Exposure of rats to propylene oxide at 100 or 300 ppm (270 or 711 mg/m3)
for 2 years caused a statistically significant decrease in body weight gain and
increased mortality. There was also an increased incidence of inflammatory
lesions of the lungs, nasal cavity, and trachea. The no-observed-adverse-
effects level for prolonged repeated 6- to 7-hour daily exposure is 70 mq/m3
(29 ppm).
Propylene oxide was found to be a direct acting mutagen, causing base-
pair substitutions in Salmonella (0.04-1.0 mg/ml) and Escherichia coli strains. It
23
-------
was also found to produce forward mutations in the yeast
Schizosaccharomyces pombe and reverse mutations in the bacterium
Klebsiella pneumonias and the fungus Neurospora crassa. It was a positive
mutagen in the Drosophila sex-linked recessive lethal test. No clear genotox.c
effects were reported using the dominant lethal test in rats (inhalation, 300 ppm)
or mice (oral, 50 mg/kg). When given to mice by the intraperitoneal route (but
not by the oral route), propylene oxide (two 300-mg/kg doses) caused an
increase in micronuclei in polychromatic erythrocytes. It was clastogemc in
cultured human lymphocytes, causing chromosomal aberrations. In monkeys
exposed to levels of 100 or 300 ppm for 2 years, propylene oxide did not
induce sister-chromatid exchanges or chromosomal aberrations in the
lymphocytes and did not increase the frequency of abnormal sperm head
morphology, but caused a decrease in sperm counts and motihty.
Repeated subcutaneous injections of propylene oxide (1 mg/kg) caused
sarcomas at the injection site in rats and mice; repeated intragastric
administration (60 mg/kg) induced carcinomas and reactive changes in the
epithelium of the forestomach of rats. No clear oncogenic effects were noted
when rats were exposed by inhalation at 100 or 300 ppm propylene oxide over
their life time. There was an increased incidence of adrenal
pheochromocytomas at both exposure levels but no dose-related trend. Two
adenomas were also found in the nasal passages of rats exposed to propylene
oxide at 300 ppm, whereas none was found in the controls. However, there was
a dose-related increase in complex hyperplasia of the nasal cavities. A
significant increase in the number of female Cpb:WU Wistar rats with total
mammary gland fibroadenomas or carcinomas when compared to controls was
reported in animals exposed to propylene oxide at 300 ppm, 6 hours/day, 5
days a week for 123 weeks. However, it was suggested that propylene oxide
enhanced the development of malignant neoplasms rather than acting as a
carcinogenicity study with F344/N rats and B6C3F! mice
exposed to propylene oxide vapors at concentrations of 200 or 400 ppm 6
hours/day 5 days/week for 2 years, it was concluded that propylene oxide
showed clear evidence of carcinogenicity in mice and some evidence of
carcinogenicity in rats. This conclusion was based on the following findings: a
significant increase in the incidence of hemangiomas and hemangiosarcomas in
the nasal cavities of mice exposed to the high dose and a significant positive
trend in the incidence of papillary adenomas and epithelial hyperplasia in the
nasal cavities of female rats.
According to EPA's Guidelines for Carcinogen Risk Assessment (Federal
Register 1986), propylene oxide would be tentatively placed in the B-2
weight-of-evidence category because of positive animal data and an absence
of epidemiological studies. . .
Propylene oxide was found to be embryotoxic but not teratogenic in rats
and rabbits exposed at 500 ppm prior to and during gestation. One study
indicated that chronic exposure to propylene oxide may cause some
neuropathologic changes in monkeys.
Two case reports indicated that contact dermatitis can result from short-
term human exposure to high levels of propylene oxide. An epidemiology study
with workers occupational^ exposed to propylene oxide indicated that the
ability of the lymphocytes to repair chemically induced DNA damage
{unscheduled DNA synthesis) was significantly lower than that of the control
group; however, the relationship of this reduction in repair proficiency to human
health is unclear.
24
-------
Only limited information was found in regard to air concentrations of
propylene oxide. These indicated typical annual average ambient air
concentrations of <1 ppt. However, no data were available on short-term
ambient concentrations of
-------
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