TOXICOLOGICAL PROFILE FOR
 

ETHYLENE OXIDE
 

Agency for Toxic Substances and Disease Registry
 

U.S. Public Health Service
 

December 1990
 
ii
 

DISCLAIMER
 

The use of company or product name(s) is for identification only
 

and does not imply endorsement by the Agency for Toxic Substances and
 

Disease Registry.
 
iii
 

FOREWORD
 

The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public
 

Law 99-499) extended and amended the Comprehensive EnvironmentalResponse,
 

Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public
 

law directed the Agency for Toxic Substances and DiseaseRegistry (ATSDR) to
 

prepare toxicological profiles for hazardous substances which are most
 

commonly found at facilities on the CERCLA National Priorities List and which
 

pose the most significant potential threat to human health, as determined by
 

ATSDR and the Environmental Protection Agency (EPA). The lists of the 250
 

most significant hazardous substances were published in the Federal Register
 

on April 17, 1987, on October 20, 1988, on October 26, 1989, and on October
 

17, 1990.
 

Section 104(i)(3) of CERCLA, as amended, directs the Administrator of
 

ATSDR to prepare a toxicological profile for each substance on the list.
 

Each profile must include the following content:
 

(A) An examination, summary, and interpretation of available
 

toxicological information and epidemiological evaluations on the
 

hazardous substance in order to ascertain the levels of significant
 

human exposure for the substance and the associated acute, subacute,
 

and chronic health effects,
 

(B) A determination of whether adequate information on the health
 

effects of each substance is available or in the process of
 

development to determine levels of exposure which present a
 

significant risk to human health of acute, subacute, and chronic health
 

effects, and
 

(C) Where appropriate, an identification of toxicological testing
 

needed to identify the types or levels of exposure that may present
 

significant risk of adverse health effects in humans.
 

This toxicological profile is prepared in accordance with guidelines
 

developed by ATSDR and EPA. The original guidelines were published in the
 

Federal Register on April 17, 1987. Each profile will be revised and
 

republished as necessary, but no less often than every three years, as
 

required by CERCLA, as amended.
 

The ATSDR toxicological profile is intended to characterize succinctly
 

the toxicological and adverse health effects information for the hazardous
 

substance being described. Each profile identifies and reviews the key
 

literature (that has been peer-reviewed) that describes a hazardous
 

substance's toxicological properties. Other pertinent literature is also
 

presented but described in less detail than the key studies. The profile is
 

not intended to be an exhaustive document; however, more comprehensive
 

sources of specialty information are referenced.
 









1
 

1. PUBLIC HEALTH STATEMENT
 

This Statement was prepared to give you information about ethylene
 

oxide and to emphasize the human health effects that may result from exposure
 

to it. The Environmental Protection Agency (EPA) has identified 1,177 sites
 

on its National Priorities List (NPL). Ethylene oxide has not been definitely
 

identified at any NPL site. However, it has been tentatively identified at
 

three of these sites. As EPA evaluates more sites, the number of sites at
 

which ethylene oxide is found may change. This information is important for
 

you to know because ethylene oxide may cause harmful health effects and
 

because these sites are potential or actual sources of human exposure to
 

ethylene oxide.
 

When a chemical is released from a large area, such as an
 

industrial plant, or from a container, such as a drum or bottle, it
 

enters the environment as a chemical emission. This emission, which is
 

also called a release, does not always lead to exposure. You can be
 

exposed to a chemical only when you come into contact with the chemical.
 

You may be exposed to it in the environment by breathing, eating, or
 

drinking substances containing the chemical or from skin contact with
 

it.
 

If you are exposed to a hazardous substance such as ethylene oxide,
 

several factors will determine whether harmful health effects will occur
 

and what the type and severity of those health effects will be. These
 

factors include the dose (how much), the duration (how long), the route
 

or pathway by which you are exposed (breathing, eating, drinking, or
 

skin contact), the other chemicals to which you are exposed, and your
 

individual characteristics such as age, sex, nutritional status, family
 

traits, life style, and state of health.
 

1.1 WHAT IS ETHYLENE OXIDE?
 

Ethylene oxide (also known as ET0 or oxirane) is a flammable gas
 

with a somewhat sweet odor. It dissolves easily in water, alcohol, and
 

most organic solvents.
 

Ethylene oxide is produced in large volumes and is used to make
 

other chemicals, especially ethylene glycol, a chemical used to make
 

antifreeze and polyester. Most ethylene oxide is used up in the
 

factories where it is produced. A very small amount (less than 1%) is
 

used to control insects on stored agricultural products such as nuts and
 

spices. Ethylene oxide is also used in very small amounts in hospitals
 

to sterilize medical equipment and supplies.
 

When ethylene oxide is produced or used, some of the gas is released
 

to air and water. If it is released into the air, humidity and sunlight
 
2
 

1. PUBLIC HEALTH STATEMENT
 

cause it to break down within a few days. In water, ethylene oxide will
 

either break down or be destroyed by bacteria within a few days.
 

Further information on the properties and uses of ethylene oxide
 

can be found in Chapters 3, 4 and 5.
 

1.2 HOW MIGHT I BE EXPOSED TO ETHYLENE OXIDE?
 

You are not likely to be exposed to ethylene in the general
 

environment. In studies of the air quality in Texas and California, no
 

ethylene oxide was found. There is also no evidence that ethylene oxide
 

is commonly found in water. Because of the limited information about
 

ethylene oxide in air, water, or soil at hazardous waste sites, we do
 

not know how likely it is that you might be exposed to ethylene oxide at
 

or near these sites.
 

You may be exposed to ethylene oxide if you work where it is
 

produced or used. Health care workers, such as technicians, nurses, and
 

physicians in hospitals and clinics, may have contact with ethylene
 

oxide because it is used to sterilize medical equipment and supplies.
 

Since ethylene oxide is used as a fumigant to spray agricultural
 

products, if you are a farmer or work on a farm where ethylene oxide is
 

used, you may also be exposed to this substance.
 

It is not known if food crops are a source of exposure to ethylene
 

oxide for the general public. Ethylene oxide has been found at levels
 

up to 3.5 parts of ethylene oxide per one million parts of food
 

(3.5 ppm) in some foods shortly after being sprayed with pesticide that
 

contains it. These levels decrease with time as ethylene oxide
 

evaporates or breaks down into other substances, and thus little or none
 

may remain when the food is eaten.
 

Further information on the ways that you can be exposed to ethylene
 

oxide is presented in Chapter 5.
 

1.3 HOW CAN ETHYLENE OXIDE ENTER AND LEAVE MY BODY?
 

Ethylene oxide can enter your body when air containing this
 

substance is breathed into your lungs. Because ethylene oxide
 

evaporates very easily, it is unlikely that it remains in or on food or
 

remains dissolved in water long enough to be eaten or swallowed,
 

although this is not known for certain. It is not known if ethylene
 

oxide can enter the body through the skin.
 

After a person has been exposed to ethylene oxide, it leaves the
 

body through the urine or feces or by breathing it out through the
 

lungs. This probably occurs very rapidly, perhaps within 2 or 3 days.
 
3
 

1. PUBLIC HEALTH STATEMENT
 

1.4 HOW CAN ETHYLENE OXIDE AFFECT MY HEALTH?
 

Ethylene oxide can cause a wide variety of harmful health effects
 

in exposed persons. In general, with higher levels of exposure to this
 

chemical, more severe effects will occur. The major effects seen in
 

workers exposed to ethylene oxide at low levels for several months or
 

years are irritation of the eyes, skin, and mucous membranes and
 

problems in the functioning of the brain and nerves. At higher levels
 

of exposure to ethylene oxide, which may result from accidents or
 

equipment breakdown, the types of effects are similar, but they are more
 

severe and harmful. There is also some evidence that exposure to
 

ethylene oxide can cause an increased rate of miscarriages in female
 

workers exposed to ethylene oxide.
 

Studies in animals have shown that breathing ethylene oxide at high
 

levels can interfere with their ability to reproduce. Litter sizes have
 

been smaller than usual, and the babies of exposed animals have weighed
 

less than normal and have had delayed bone formation.
 

Some studies of workers exposed to ethylene oxide in ethylene oxide
 

factories or hospital sterilizing rooms have shown an increased
 

incidence of leukemia, stomach cancer, cancer of the pancreas and
 

Hodgkin's disease. Ethylene oxide has also been shown to cause cancer
 

in laboratory animals. Leukemia, brain tumors, lung tumors and tumors
 

of the tear glands of the eye have been found.
 

Further information on the health effects of ethylene oxide is
 

presented in Chapter 2.
 

1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
 

Tables 1-1 through 1-4 show the relationship between exposure to
 

ethylene oxide and known health effects. Skin contact with ethylene
 

oxide can result in blisters and burns that may appear to be similar to
 

frostbite. With longer times of contact, there is a more severe
 

reaction. Eye damage can also result from ethylene oxide contact.
 

It is possible to smell ethylene oxide if it is present in water at
 

or above 140 mg per liter (about one quart) of water. It can also be
 

smelled in air if it is present at or above 430 ppm (430 parts of
 

ethylene oxide per million parts of air).
 

A Minimal Risk Level (MRL) is also included in Table l-l. This MRL
 

was derived from animal data for long-term exposure, as described in
 

Chapter 2 and in Table 2-l. The MRL provides a basis for comparison
 

with levels that people might encounter in the air. If a person is
 

exposed to ethylene oxide at an amount below the MRL, it is not expected
 

that harmful (noncancer) health effects will occur. Because this level
 




 

8
 

1. PUBLIC HEALTH STATEMENT
 

is based only on information currently available, some uncertainty is
 

always associated with it. Also, because the method for deriving MRLs
 

does not use any information about cancer, an MRL does not imply
 

anything about the presence, absence, or level of risk for cancer.
 

Further information on exposure levels of ethylene oxide that cause
 

health effects in humans and animals is presented in Chapter 2.
 

1.6	 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
 

ETHYLENE OXIDE?
 

There are two kinds of tests that can determine if you have been
 

exposed to ethylene oxide within the last couple of days. These tests
 

are not routinely done in a doctor's office, but can be done in a
 

special laboratory. One test measures this substance in blood, the
 

other measures it in air that you breathe out of your lungs. If you
 

were exposed to ethylene oxide more than two or three days ago, there
 

may be no ethylene oxide remaining in your body. In addition, if you
 

have been exposed to very low levels of ethylene oxide, these tests may
 

not detect it. The results of these tests cannot be used to predict the
 

type or severity of health effects resulting from exposure.
 

Further information on this topic is presented in Chapter 2 and 6.
 

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
 

HEALTH?
 

In order to protect the general population from exposure to
 

ethylene oxide, the federal government has established a number of
 

guidelines and regulations related to its use and disposal.
 

The EPA is considering listing ethylene oxide as a hazardous air
 

pollutant and regulating industrial emissions. The Food and Drug
 

Administration (FDA) has set limits on the levels of ethylene oxide that
 

may remain on food products fumigated with this chemical. In order to
 

protect workers who use ethylene oxide while on the job, the
 

Occupational Safety and Health Administration (OSHA) has established a
 

limit of 1 ppm in workplace air for an 8-hour work day and a limit of
 

5 ppm for a 15-minute period.
 

More detailed information on federal and state regulations
 

regarding ethylene oxide is given in Chapter 7.
 
9
 

1. PUBLIC HEALTH STATEMENT
 

1.8 WHERE CAN I GET MORE INFORMATION?
 

If you have any more questions or concerns not covered here, please
 

contact your State Health or Environmental Department or:
 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology
 

1600 Clifton Road, E-29
 

Atlanta, Georgia 30333
 

This agency can also give you information on the location of the
 

nearest occupational and environmental health clinics. Such clinics
 

specialize in recognizing, evaluating, and treating illnesses that
 

result from exposure to hazardous substances.
 

11
 

2. HEALTH EFFECTS
 

2.1 INTRODUCTION
 

This chapter contains descriptions and evaluations of studies and
 

interpretation of data on the health effects associated with exposure to
 

ethylene oxide. Its purpose is to present levels of significant
 

exposure for ethylene oxide based on toxicological studies,
 

epidemiological investigations and environmental exposure data. This
 

information is presented to provide public health officials, physicians,
 

toxicologists and other interested individuals and groups with (1) an
 

overall perspective of the toxicology of ethylene oxide and (2) a
 

depiction of significant exposure levels associated with various adverse
 

health effects.
 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
 

To help public health professionals address the needs of persons
 

living or working near hazardous waste sites, the data in this section
 

are organized first by route of exposure -- inhalation, oral and dermal
 

-- and then by health effect -- death, systemic, immunological,
 

neurological, developmental, reproductive, genotoxic and carcinogenic
 

effects. These data are discussed in terms of three exposure periods -­

acute, intermediate and chronic.
 

Levels of significant exposure for each exposure route and duration
 

(for which data exist) are presented in tables and illustrated in
 

figures. The points in the figures showing no-observed-adverse-effect
 

levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)
 

reflect the actual doses (levels of exposure) used in the studies.
 

LOAELs have been classified into "less serious" or "serious" effects.
 

These distinctions are intended to help the users of the document
 

identify the levels of exposure at which adverse health effects start to
 

appear, determine whether or not the intensity of the effects varies
 

with dose and/or duration and place into perspective the possible
 

significance of these effects to human health.
 

The significance of the exposure levels shown on the tables and
 

figures may differ depending on the user's perspective. For example,
 

physicians concerned with the interpretation of clinical findings in
 

exposed persons or with the identification of persons with the potential
 

to develop such disease may be interested in levels of exposure
 

associated with "serious" effects. Public health officials and project
 

managers concerned with response actions at Superfund sites may want
 

information on levels of exposure associated with more subtle effects in
 

humans or animals (LOAELs) or exposure levels below which no adverse
 

effects (NOAELs) have been observed. Estimates of levels posing minimal
 

risk to humans (Minimal Risk Levels, MRLs) are of interest to health
 

professionals and citizens alike.
 
12
 

2. HEALTH EFFECTS
 

For certain chemicals, levels of exposure associated with
 

carcinogenic effects may be indicated in the figures. These levels
 

reflect the actual doses associated with the tumor incidences reported
 

in the studies cited. Because cancer effects could occur at lower
 

exposure levels, the figures also show estimated excess risks, ranging
 

from a risk of one in 10,000 to one in 10,000,000 (10-4 to l0-7), as
 

developed by EPA.
 

Estimates of exposure levels posing minimal risk to humans (MRLs)
 

have been made, where data were believed reliable, for the most
 

sensitive noncancer end point for each exposure duration. MRLs include
 

adjustments to reflect human variability and, where appropriate, the
 

uncertainty of extrapolating from laboratory animal data to humans.
 

Although methods have been established to derive these levels (Barnes
 

et al. 1987; EPA 1989), uncertainties are associated with the
 

techniques.
 

2.2.1 Inhalation Exposure
 

Most information on the health effects of ethylene oxide is derived
 

from animal inhalation studies or epidemiological or case studies of
 

persons in occupational settings. The most relevant route of exposure
 

to a volatile compound such as ethylene oxide in an occupational setting
 

is via inhalation. It is important to note, however, that there may be
 

dermal exposure, either directly or through the air, and any food on the
 

premises may similarly be contaminated, resulting in possible oral
 

exposure.
 

2.2.1.1 Death
 

The available studies on humans exposed to ethylene oxide in the
 

workplace indicate that there is no increase in mortality associated
 

with those exposures (Gardner et al. 1989; Greenberg et al. 1990;
 

Kiesselbach et al. 1990).
 

Estimates of lethal ethylene oxide inhalation levels in animals
 

depend on the exposure duration. In mice, exposures to 800 ppm for four
 

hours resulted in 80-100% mortality, whereas 400 ppm exposures for
 

14 days did not result in death (NTP 1987). Jacobson et al. (1956)
 

reported that the 4-hour LC50 values for rats, mice and dogs were 1,460,
 

835 and 960 ppm, respectively.
 

In two-year studies using mice (NTP 1987) and monkeys (Lynch et al.
 

1984a), exposure to 100 ppm did not result in increased mortality in the
 

test animals.
 

The highest NOAEL values and all reliable LOAEL values for death in
 

each species are presented in Table 2-l and plotted in Figure 2-1.
 
13
 

2. HEALTH EFFECTS
 

2.2.1.2 Systemic Effects
 

Respiratory Effects. Inhalation of ethylene oxide is irritating to
 

mucous membranes including those associated with the respiratory system.
 

Inhalation exposure of workers to high concentrations of ethylene oxide
 

for brief periods has resulted in bronchitis, pulmonary edema, and
 

emphysema (Theiss 1963). Studies on long-term human exposure to
 

ethylene oxide do not address the incidence of respiratory problems.
 

Respiratory irritation has been reported in animal studies at
 

various exposure levels. In lethality studies, mice exposed to 200 ppm
 

and above for 14 weeks exhibited nasal irritation, necrosis of
 

epithelium, and loss of cilia (NTP 1987). These lesions were not seen
 

in mice exposed to 100 ppm for two years (NTP 1987).
 

The highest NOAEL values and all reliable LOAEL values for
 

respiratory effects in each species and duration category are presented
 

in Table 2-l and plotted in Figure 2-l.
 

Cardiovascular Effects. Studies of humans and animals exposed to
 

ethylene oxide via inhalation have not reported evidence of injury to
 

the cardiovascular system. In a study of male monkeys exposed to
 

ethylene oxide at levels up to 100 ppm for two years, no treatment related
 

changes were observed in routine electrocardiograms taken
 

throughout the study (Lynch et al. 1984a).
 

Gastrointestinal Effects. Studies of humans and animals exposed to
 

ethylene oxide via inhalation have not addressed the potential
 

gastrointestinal effects of these exposures. Nausea and vomiting have
 

been reported, but these are considered to be secondary effects due to
 

neurotoxicity rather than a primary effect of inhaled ethylene oxide on
 

the gastrointestinal tract. (See Section 2.2.1.4)
 

Hematological Effects. Most studies of human exposure to ethylene
 

oxide via inhalation have not examined the potential adverse
 

hematological effects of this compound. Joyner (1964) reported no
 

effects on hemoglobin levels or red or white blood cell counts in
 

workers exposed to ethylene oxide at about 5-10 ppm for approximately
 

10 years. Data reported in case studies of individuals exposed to
 

ethylene oxide in occupational settings do not provide quantifiable
 

information due to the small numbers of subjects and lack of information
 

on the level of ethylene oxide exposure.
 

A 10-week exposure of mice to ethylene oxide at 250 ppm resulted in
 

slight but statistically significant decreases in red blood cell numbers
 

and blood hemoglobin concentrations. These effects were not seen at
 

100 ppm or below (Snellings et al. 1984a). Two-year studies of rats,
 






20
 

2. HEALTH EFFECTS
 

monkey (Lynch et al. 1984a) and mice (NTP 1987) have reported that
 

chronic exposure to 100 ppm did not have any observable hematological
 

effects.
 

Thus, it is not clear if hematological effects are an area of
 

Concern associated with inhalation exposure to ethylene oxide.
 

Musculoskeletal Effects. No studies were located regarding
 

Musculoskeletal effects in humans after inhalation exposure to ethylene
 

oxide.
 

Lynch et al. (1984b) reported an increased incidence of skeletal
 

Muscle myopathy in rats exposed to ethylene oxide at 100 ppm by
 

Inhalation. Lesions consisted of multifocal areas of atrophy and
 

Degeneration of skeletal muscle fibers.
 

Hepatic Effects. Information regarding hepatic effects in humane
 

After inhalation exposure to ethylene oxide is limited to a report by
 

Joyner (1964) which indicated that workers exposed to about 5-10 ppm for
 

10 years did not have major signs of hepatic toxicity such as jaundice
 

or palpable liver.
 

The data on hepatic effects in animal studies are sparse.
 

Qualitative evidence of liver damage is available in an earlier acute-


duration study by Hollingsworth et al. (1956) Rats and guinea pigs
 

given two and three sever-hour exposures, respectively, to ethylene
 

oxide at 841 ppm were reported to have light coloration and fatty
 

degeneration of the liver. Because the authors did not specify which
 

species was observed to have the stated lesions, or what observations
 

were made in control animals, the reported results are difficult to
 

Interpret.
 

Adverse hepatic effects have not been reported in the more recent
 

literature, most notably in the NTP (1987) 14-week study in which mice were
 

exposed to ethylene oxide at doses up to 600 ppm. Snellings et al. (1984a)
 

reported an elevation in the liver to body weight ratio in female mice
 

exposed to ethylene oxide at 250 ppm for 11 weeks; however, histological
 

examination showed that the livers were normal at this and all other lower
 

exposure levels for both sexes in this study. No hepatic effects have been
 

reported in chronic studies.
 

The highest NOAEL value and all reliable LOAEL values for each
 

Species and duration category are presented in Table 2-1 and plotted in
 

Figure 2-1.
 
21
 

2. HEALTH EFFECTS
 

Renal Effects. Information regarding renal effects in humans after
 

inhalation exposure to ethylene oxide is limited to a report by Joyner
 

(1964) which indicates that there was no evidence of nephritis or other
 

parenchymal disease among workers exposed to ethylene oxide at 5-10 ppm
 

for 10 years.
 

In animal studies, qualitative evidence of renal effects resulting
 

from acute exposure was presented in an earlier study, Hollingsworth
 

et al. (1956), in which rats and guinea pigs were given two and three
 

seven-hour exposures, respectively, to ethylene oxide at 841 ppm. Renal
 

enlargement and slight congestion and cloudy swelling of the convoluted
 

tubules were reported. As described previously, there are certain
 

limitations in this study (i.e., the results observed in controls were
 

not indicated and the authors did not indicate the species in which each
 

lesion was observed).
 

Renal lesions have also been reported in a 14-week study in mice by
 

NTP (1987). Exposure to 100 ppm resulted in tubular degeneration in
 

male mice and to 600 ppm in tubular necrosis in both sexes. No renal
 

lesions were observed in mice exposed to ethylene oxide at 50 ppm. This
 

value has been used to calculate the minimum risk level (MRL) for
 

intermediate inhalation exposure as shown in Figure 2-l. Renal lesions
 

seen at 100 ppm in the 14-week study, however, were not observed at that
 

level (the highest tested) in the two-year study in mice by NTP (1987).
 

The authors attributed this disparity to the confounding influence of
 

subtle age-related lesions in the kidneys of mice in the two-year study.
 

Therefore, renal effects appear to be an area of some concern for
 

inhalation exposure to ethylene oxide. The highest NOAEL values and all
 

reliable LOAEL values for renal effects in each species and duration
 

category are presented in Table 2-l and plotted in Figure 2-1.
 

Dermal/Ocular Effects. There is some evidence that occupational
 

exposure to high levels of ethylene oxide can result in cataracts. This
 

is based on the cases of four sterilizer operators who were exposed to
 

ethylene oxide from a leaking sterilizer for up to two months (Gross
 

et al. 1979). In the next 2.5 to 3.5 years, Jay et al. (1982) found
 

that all four men had developed cataracts. Because these persons could
 

intermittently smell the fumes, a level of 700 ppm or more was estimated
 

by the authors in retrospect. Although none of the patients were
 

examined before this accidental exposure, the occurrence of cataracts
 

was viewed as unlikely to be a chance occurrence in all four persons in
 

this age range (31 to 35 years old) who had no systemic or ocular
 

disease that might be associated with cataract formation.
 
22
 

2. HEALTH EFFECTS
 

Lynch et al. (1984a) observed a dose-related but not statistically
 

significant increase in the incidence of cataracts in rats exposed to
 

ethylene oxide at 50 and 100 ppm for two years. Therefore, the
 

potential for adverse ocular effects may be an area of concern in cases
 

of chronic or high level inhalation exposure to ethylene oxide. The
 

available data, however, are not useful to serve as the basis for
 

quantifying effect levels for cataract formation in humans.
 

Other Effects. Proliferative and degenerative lesions of the
 

adrenal cortex, consisting of vacuolation and hyperplasia or hypertrophy
 

of the zona fascicularis, have been reported in rats exposed to ethylene
 

oxide at 50 or 100 ppm in a 2-year study by Lynch et al. (1984b). Focal
 

to multifocal splenic fibrosis and extramedullary hematopoiesis were
 

also reported in these rats.
 

2.2.1.3 Immunological Effects
 

The immunological effects of human inhalation exposure to ethylene
 

oxide were studied in workers in an ethylene oxide manufacturing plant
 

for up to 14 years. Atmospheric concentrations were generally below
 

0.05 ppm (the detection limit of the analytical method) with occasional
 

peaks of 8 ppm during the 4 years that the air was monitored. There was
 

no effect on any of the blood parameters relating to immune function
 

that were investigated, including T and B lymphocyte counts, lymphocyte
 

activation, and serum IgG, IgM, and IgA levels (Van Sittert et al.
 

1985). Theiss (1963) did not observe skin sensitization in ethylene
 

oxide plant workers (average exposure: 10.4 years) who were challenged
 

with a single dermal application of 1% ethylene oxide.
 

In mice exposed to ethylene oxide during a 14-week study,
 

lymphocytic hypoplasia of the thymus was seen in males in the 200 ppm
 

exposure group. At 600 ppm, lymphocytic necrosis of the thymus was seen
 

in most mice of both sexes, and lymphocytic necrosis of the spleen was
 

seen in males.
 

2.2.1.4 Neurological Effects
 

Neurological effects have frequently been reported in association
 

with human and animal exposure to ethylene oxide via inhalation at a
 

wide range of concentrations and exposure durations.
 

In humans exposed to high levels of ethylene oxide in occupational
 

settings, headache, nausea and vomiting have been reported for decades
 

(Blackwood and Erskine 1938; von Oettingen 1939; Sexton and Henson
 

1949). Exposure levels were not measured or estimated in these
 

situations.
 
23
 

2. HEALTH EFFECTS
 

Peripheral neuropathy, impaired hand-eye coordination, and memory
 

loss have also been reported in more recent case studies of workers
 

exposed to ethylene oxide for various durations (Crystal et al. 1988;
 

Estrin et al. 1987; Finelli et al. 1983; Kuzuhara et al. 1983; Salinas
 

et al. 1981; Schroeder et al. 1985; Zampollo et al. 1984). These
 

effects were seen at estimated average exposure levels as low as 3 ppm;
 

however, short-term exposures may have been as high as 700 ppm for some
 

of these workers. Two of these studies indicated that sural nerve
 

biopsies showed axonal degeneration and regeneration (Kuzuhara et al.
 

1983; Schroeder et al. 1985).
 

Information on the neurological effects of inhalation exposure to
 

ethylene oxide has also been derived from case studies of longer-term
 

occupational exposure. Four sterilizer operators exposed to ethylene
 

oxide for up to two months on an intermittent basis at levels of
 

approximately 700 ppm (estimated by the authors based on the fact that
 

the exposed workers could smell the vapors emitted from a leaking
 

apparatus) reported headaches, nausea, vomiting, clumsiness, blunting of
 

the senses, lethargy, numbness and weakness in the extremities, and, in
 

the case of one operator, recurrent major motor seizures at 20- to
 

30-minute intervals near the end of the work shift. Nerve conduction
 

studies indicated sensimotor neuropathy. These conditions were reversed
 

in the case of one of these operators who was returned to a position
 

without ethylene oxide exposure, but the results of nerve conduction
 

studies remained abnormal in the cases of two of the three workers who
 

were returned to positions of lower ethylene oxide exposure (50 ppm or
 

less) (Gross et al. 1979). However, the possibility of occasional
 

short-term exposure to high levels of ethylene oxide after that point
 

was not addressed.
 

In subchronic studies in mice, exposure to ethylene oxide at 50 ppm
 

and above for l0-11 weeks resulted in hunched posture, reduced locomotor
 

activity and abnormal righting reflexes (Snellings et al. 1984a).
 

In earlier animal studies, exposures of various species to
 

moderately high levels of ethylene oxide (357 ppm) for up to 6 months
 

resulted in neurological impairment, including reversible hind leg
 

paralysis and atrophy, abnormal knee and extensor reflexes and
 

diminished pain perception (Hollingsworth et al. 1956). The exposure of
 

monkeys to 200 ppm for about 7 months in another phase of this study
 

resulted in partial paralysis, muscular atrophy of the hind legs and
 

suppression of reflexes. Due to inconsistencies in the testing protocol
 

and reporting of results, the Hollingsworth et al. (1956) study can be
 

viewed only as qualitative evidence of a broad range of neurological
 

effects associated with inhalation of ethylene oxide at these levels.
 

In a 9-month study of rats exposed to ethylene oxide at 250 ppm,
 

distal axonal degeneration of myelinated fibers in both sural nerves and
 

gracile fascicles was reported (Ohnishi et al. 1986). Observations of
 
24
 

2. HEALTH EFFECTS
 

neurological effects in two-year studies have ranged from no effects
 

observed in mice exposed to 100 ppm (NTP 1987) to slight demyelination
 

of the brain of monkeys exposed at the same level (Lynch et al. 1984a)
 

and brain lesions seen in rats exposed at 50 ppm (Lynch et al. 1984a,
 

1984b).
 

The highest NOAEL values and all reliable LOAEL values for
 

neurotoxicity in each species and duration category are presented in
 

Table 2-l and plotted in Figure 2-l.
 

2.2.1.5 Developmental Effects
 

No studies were located regarding developmental effects in humans
 

after inhalation exposure to ethylene oxide.
 

Data available from animal studies indicate that ethylene oxide was
 

not teratogenic in rats exposed at 100 ppm during gestation (Snellings
 

et al. 1982a) or in rats or rabbits at an exposure level of 150 ppm
 

during gestation (Hardin et al. 1983).
 

Embryo and fetal toxicities, however, were evident in rats exposed
 

to 100 ppm in the Snellings et al. (1982a) study, as indicated by an
 

increased incidence of resorption and reductions in fetal body weight
 

and crown-rump length and reduced skeletal ossification of the skull and
 

sternebrae. The highest NOAEL values and all reliable LOAEL values for
 

developmental toxicity in each species and duration category are
 

presented in Table 2-l and plotted in Figure 2-l.
 

2.2.1.6 Reproductive Effects
 

There is limited evidence in both animal and human studies that
 

inhalation exposure to ethylene oxide can result in adverse reproductive
 

effects, although there is currently no clear pattern in the nature of
 

those effects.
 

Data in humans are limited. In an epidemiological study by
 

Hemminki et al. (1982), the spontaneous abortion rates in ethylene oxide
 

sterilizer personnel in hospitals in Finland were found to be
 

significantly higher than those of non-exposed workers. Although
 

exposure levels were not measured, the authors estimated that 8-hour
 

weighted mean concentrations ranging from 0.1 to 0.5 ppm with peaks to
 

250 ppm were associated with adverse outcomes. Various limitations have
 

been described in the design and implementation of this study including
 

recall bias, prior knowledge of the questionnaires and analysis based on
 

too few pregnancies (Golberg 1986). Decreased sperm counts in ethylene
 

oxide workers were reported by Abrahams (1980). However, based on the
 

small number of sperm samples obtained, the author viewed the results as
 

inconclusive.
 
25
 

2. HEALTH EFFECTS
 

Various adverse reproductive effects have also been noted in animal
 

studies, including a decreased number of implantation sites in rats
 

exposed to ethylene oxide at 100 ppm during gestation (Snellings et al.
 

1982b), decreased testicular weights in mice exposed to 50 ppm or more
 

for 10 weeks (Snellings et al. 1984a), decreased testicular weights and
 

testicular degeneration in guinea pigs exposed to 375 ppm for about
 

6 months, and testicular degeneration in rats exposed to 204 ppm for
 

about 6 months (Hollingsworth et al. 1956). In Cynomolgus monkeys
 

exposed to ethylene oxide at 50 or 100 ppm for two years, sperm
 

concentration, motility and drive range, as well as decreased testicular
 

and epididymal weights, were observed (Lynch et al. 1984a). Appelgren
 

et al. (1977) demonstrated that in mice intravenously injected with
 

14C-ethylene oxide, the 14C-label was detected in the testes and
 

epididymis (at undetermined levels) within four hours. This study
 

indicates that ethylene oxide or one of its degradation products can be
 

distributed to the male reproductive system.
 

Therefore, it appears that both female and male reproductive
 

systems are potential targets of ethylene oxide toxicity.
 

The highest NOAEL values and all reliable LOAEL values for
 

reproductive toxicity in each species and duration category are
 

presented in Table 2-1 and plotted in Figure 2-1.
 

2.2.1.7 Genotoxic Effects
 

In studies of workers exposed to ethylene oxide, analysis of
 

peripheral blood lymphocytes resulted in the detection of various
 

chromosomal aberrations including breaks, gaps, and exchanges and
 

supernumerary chromosomes (Pero et al. 1981; Galloway et al. 1986; Sarto
 

et al. 1984a; Theiss et al. 1981). An increased incidence of sister
 

chromatid exchange (SCE) in the peripheral lymphocytes of ethylene oxide
 

workers has also been reported by Galloway et al. (1986), Garry et al.
 

(1979), Lambert and Lindblad (1980), Sarto et al. (1984a, 1984b),
 

Stolley et al. (1984), and Yager et al, (1983).
 

Inhalation studies with rats indicate that ethylene oxide at 50 ppm
 

or more for 3 days resulted in an increase in SCE (Kligerman et al.
 

1983). Increased incidences of SCE and chromosomal aberrations in the
 

peripheral blood of monkeys exposed to ethylene oxide at 500 or 100 ppm
 

were reported by Lynch et al. (1984a). A follow-up study in these same
 

monkeys by Kelsey et al. (1988) indicated that high SCE counts persisted
 

6 years after exposure.
 

In dominant lethal assays, ethylene oxide administered via
 

inhalation has resulted in a positive response in mice (Cumming and
 

Michaud 1979; Generoso et al. 1986, 1988) and rats (Embree et al. 1977).
 

Dose-rate studies by Generoso et al. (1986) have demonstrated that short
 
26
 

2. HEALTH EFFECTS
 

bursts of ethylene oxide at high concentrations, such as those that may
 

occur in the workplace, may present a greater risk to germ cell damage
 

than does cumulative, long-term exposure to lower levels. Data from
 

these studies are viewed as providing support to the concern for the
 

potential genotoxicity of this compound.
 

2.2.1.8 Cancer
 

There is some evidence from inhalation data in both humans and
 

animals that ethylene oxide is carcinogenic by this route. However, the
 

available data in humans are considered to be limited and inconclusive.
 

Epidemiological studies of workers exposed to ethylene oxide in hospital
 

sterilizing operations and in manufacturing plants (Hogstedt et al.
 

1979, 1986) have reported increased incidences of leukemia and stomach
 

cancer. The Hogstedt data are viewed as having certain limitations,
 

however, such as the small cohort size, the small number of deaths that
 

occurred, and uncertainties about the exposure levels (Golberg 1986).
 

Data (originally reported as negative) by Morgan et al. (1981), when
 

reanalyzed by EPA (1985a), showed an increased rate of mortality from
 

pancreatic cancer and Hodgkin's disease in ethylene oxide-exposed
 

workers. No clear excess in any of these cancers, however, was found by
 

Gardner et al. (1989), Greenberg et al. (1990) or Kiesselbach et al.
 

(1990).
 

In two-year studies of rats exposed to ethylene oxide at 33 to
 

100 ppm and 50 to 100 ppm, increased incidences of mononuclear cell
 

leukemia, peritoneal mesotheliomas, and various brain tumors have been
 

reported at all dose levels tested (Lynch et al. 1984b; Snellings et al.
 

1984b). The finding of mononuclear cell leukemia in rats may be of
 

dubious significance to humans because this is a spontaneous tumor in
 

Fischer-344 rats and because the human equivalent of this disease is
 

T-gamma lymphoproliferative disease (lymphocytosis), not leukemia.
 

In an NTP (1987) two-year inhalation study of mice at 50 and
 

100 ppm, alveolar/bronchiolar carcinomas and adenomas, papillary
 

cystadenomas of the harderian gland, malignant lymphomas, uterine
 

adenocarcinomas, and mammary gland tumors were increased in one or more
 

exposure groups. The cancer effect levels (CEL'S) are presented in
 

Table 2-l and plotted in Figure 2-l.
 

On the basis of the combined incidence of mononuclear cell leukemia
 

and gliomas in female rats in the Snellings et al. (1984b) inhalation
 

study, an upper-limit carcinogenicity potency value for ethylene oxide
 

has been calculated as 3.5 x 10-l (mg/kg/day)-l by EPA (1985a) using the
 

linearized multistage model.
 
27
 

2. HEALTH EFFECTS
 

EPA's Cancer Assessment Group has found the evidence in animal
 

studies to be "sufficient" and the human evidence to be "limited"
 

bordering on inadequate to establish ethylene oxide as a probable human
 

carcinogen (EPA 1985a). This results in a Group Bl bordering on B2
 

carcinogenicity classification for this compound. Similarly, according
 

to IARC guidelines, ethylene oxide has been classified in Group 2A
 

bordering on 2B due to the limitations in human evidence (IARC 1987).
 

2.2.2 Oral Exposure
 

Data on the toxic effects following oral administration of ethylene
 

oxide are extremely limited and no studies are considered appropriate
 

for the calculation of Minimal Risk Levels. As mentioned previously,
 

inhalation is considered to be the most important route of exposure for
 

this chemical.
 

2.2.2.1 Death
 

No information was located on the lethal effects in humans after
 

oral exposure to ethylene oxide.
 

In a study using rats, Hollingsworth et al. (1956) found that a
 

single gavage dose of ethylene oxide at 200 mg/kg resulted in the death
 

of all test animals. At 100 mg/kg, all animals survived 15 doses
 

administered in 21 days. Based on these results, the oral LD50 would
 

probably be somewhere between these two dosage levels. It should be
 

noted that this study used a small number of test animals (5/dose) and
 

the results should be viewed in consideration of this study limitation.
 

These values are presented in Table 2-2 and plotted in Figure 2-2.
 

2.2.2.2 Systemic Effects
 

No studies were located on the respiratory, cardiovascular,
 

musculoskeletal, renal or dermal effects in humans or animals after oral
 

exposure to ethylene oxide.
 

Gastrointestinal Effects. No studies were located on the
 

gastrointestinal effects in humans after oral exposure to ethylene
 

oxide.
 

Hollingsworth et al. (1956) reported gastric irritation in female
 

rats receiving 15 doses of ethylene oxide by gavage at 100 mg/kg/day for
 

21 days. This effect was not observed at doses of 30 mg/kg/day or below
 

in rats dosed 22 times in 30 days. Due to the small number of test
 

animals used (5/dose) and the lack of detail in reporting results,
 

especially in control animals, the value of this study is limited.
 


30
 

2. HEALTH EFFECTS
 

These values have been presented in Table 2-2 and plotted in
 

Figure 2-2.
 

Hematological Effects. No studies were located regarding the
 

hematological effects in humans after oral exposure to ethylene oxide.
 

Hollingsworth et al. (1956) reported that there were no adverse
 

hematological effects in female rats receiving ethylene oxide by gavage
 

at levels up to 100 mg/kg/day at 15 doses in 21 days. No other details
 

were provided.
 

Based on the limitations of the available data, it is not clear if
 

hematological effects would be an area of potential concern for oral
 

exposure to ethylene oxide.
 

Hepatic Effects. No studies were located regarding hepatic effects
 

in humans after oral exposure to ethylene oxide.
 

Slight liver damage (no further details) was reported by
 

Hollingsworth et al. (1956) in rats exposed by gavage to ethylene oxide
 

at 100 mg/kg/day for 15 doses in 21 days, but not in animals receiving
 

up to 30 mg/kg/day for 22 doses in 30 days. Because of various
 

limitations in the scope and reporting of this study, it can be viewed
 

only as suggestive evidence that oral exposure to ethylene oxide can
 

result in hepatic effects.
 

These values have been presented in Table 2-2 and plotted in
 

Figure 2-2.
 

No studies were located regarding the following health effects in
 

humans or animals after oral exposure to ethylene oxide:
 

2.2.2.3 Immunological Effects
 

2.2.2.4 Neurological Effects
 

2.2.2.5 Developmental Effects
 

2.2.2.6 Reproductive Effects
 

2.2.2.7 Genotoxic Effects
 

2.2.2.8 Cancer
 

No studies were located regarding carcinogenic effects in humans
 

after oral exposure to ethylene oxide.
 
31
 

2. HEALTH EFFECTS
 

In the only animal study available via this route, Dunkelberg
 

(1982) reported that female rats dosed with ethylene oxide at 7.5 or
 

30 mg/kg/day by gavage for 2 days/week for 3 years developed a d
 

oserelated incidence of local tumors, mainly squamous-cell carcinoma of the
 

forestomach, a tumor commonly seen following long-term gavage
 

administration of irritant chemicals. No tumors were found at sites
 

away from the point of administration.
 

These levels are presented in Table 2-2, and 7.5 mg/kg/day is
 

plotted as the Cancer Effect Level for ethylene oxide in Figure 2-2.
 

2.2.3 Dermal Exposure
 

2.2.3.1 Death
 

No studies were located regarding lethal effects in animals or
 

humans after dermal exposure to ethylene oxide.
 

2.2.3.2 Systemic Effects
 

No studies were located regarding the respiratory, cardiovascular,
 

gastrointestinal, hematological, musculoskeletal, hepatic or renal
 

effects in humans or animals after dermal exposure to ethylene oxide.
 

Dermal/Ocular Effects. Data related to human dermal exposure to
 

ethylene oxide are generally associated with case reports of industrial
 

accidents, some of which occurred in the 1930's and 1940's.
 

Concentrated ethylene oxide evaporates rapidly from the skin and
 

produces a freezing effect, often compared to frostbite, leaving burns
 

ranging from first to third-degree severity (Taylor 1977). Workers
 

drenched with a 1% solution developed large vesiculated blisters (Sexton
 

and Henson 1949). Nausea and vomiting were also reported in this case
 

study, but might have resulted from inhalation of the vapors rather than
 

from dermal contact.
 

A study using human volunteers by Sexton and Henson (1950) showed
 

that the magnitude of skin injury was related to the concentration of
 

ethylene oxide in solution but peaked at about 50%. This was attributed
 

to the rapid evaporation of the more concentrated solutions, which
 

prevented more prolonged skin contact.
 

Case reports of patients whose intact skin or wounds had contact
 

with gauze or other hospital supplies that had been sterilized with
 

ethylene oxide indicated that the observed skin reactions included
 

erythema, blister formation, scaling, crusted ulcerations and second
 

degree burns (Alomar et al. 1981; Hanifin 1971).
 
32
 

2. HEALTH EFFECTS
 

Shupack et al. (1981) demonstrated that human skin reactions to
 

ethylene oxide in patch materials were directly related to the total
 

dose.
 

Cornea1 burns (McLaughlin 1946; Thiess 1963) and cataracts (Gross
 

et al. 1979; Jay et al. 1982) have been reported in cases of
 

occupational exposure to ethylene oxide. Although the cornea1 burns
 

were due to direct ocular contact with ethylene oxide, it was not clear
 

in the cases of cataracts whether they could be attributed to ocular
 

contact with ethylene oxide vapor or were a systemic effect resulting
 

from inhalation of ethylene oxide.
 

Dermal application of ethylene oxide on rabbits and guinea pigs has
 

resulted in hyperemia (the presence of an increased amount of blood),
 

edema (Hollingsworth et al. 1956), and skin irritation (Bruch 1973;
 

Woodard and Woodard 1971).
 

Ocular effects in rabbits after ocular instillation of ethylene
 

oxide solution have been reported as congestion, swelling, discharge,
 

iritis, cornea1 cloudiness, and irritation (McDonald et al. 1977;
 

Woodard and Woodard 1971).
 

2.2.3.3 Immunological Effects
 

Theiss (1963) did not observe skin sensitization in ethylene oxide
 

plant workers (average exposure: 10.4 years) who were challenged with a
 

single dermal application of 1% ethylene oxide. Dermal application
 

studies using human volunteers by Sexton and Henson (1950) and Shupack
 

et al. (1981) however, have provided some evidence that ethylene oxide
 

is a skin sensitizer. A case study of a hospital patient diagnosed wit1
 

allergic contact dermatitis in response to ethylene oxide also suggests
 

skin sensitization (Alomar et al. 1981). However, ethylene chlorhydrin
 

may also have contacted the patient's skin.
 

Skin sensitization studies in guinea pigs by Woodard and Woodard
 

(1971), however, were negative.
 

No other data on the potential immunologic effects of dermal
 

exposure to ethylene oxide were located, and it is not clear if
 

immunological effects are of concern following dermal exposure to
 

ethylene oxide.
 

No studies were located regarding the following health effects in
 

humans or animals after dermal exposure to ethylene oxide:
 

2.2.3.4 Neurological Effects
 

2.2.3.5 Developmental Effects
 
33
 

2. HEALTH EFFECTS
 

2.2.3.6 Reproductive Effects
 

2.2.3.7 Genotoxic Effects
 

2.2.3.8 Cancer
 

No studies were located regarding carcinogenic effects in humans
 

after dermal exposure to ethylene oxide.
 

In a lifetime skin painting study, application of a 10% solution of
 

ethylene oxide to the backs of mice did not result in skin tumors or
 

irritation (Van Duuren et al. 1965).
 

2.3 TOXICOKINETICS
 

2.3.1 Absorption
 

2.3.1.1 Inhalation Exposure
 

In a study of hospital workers by Brugnone et al. (1985), alveolar
 

ethylene oxide concentrations were highly correlated with ambient
 

ethylene oxide concentrations. The average alveolar retention of
 

ethylene oxide was approximately 75% of the ambient concentration.
 

Animal studies have shown that ethylene oxide is rapidly absorbed by the
 

respiratory systems of the rat (Koga et al. 1987; Matsuoka 1988;
 

Nakashima et al. 1987; Tardif et al. 1987), mouse (Cumming et al. 1981;
 

Ehrenberg et al. 1974; Tardif et al. 1987), and rabbit (Tardif et al.
 

1987).
 

2.3.1.2 Oral Exposure
 

No studies were located regarding absorption of ethylene oxide
 

after oral exposure.
 

2.3.1.3 Dermal Exposure
 

No studies were located regarding absorption of ethylene oxide
 

after dermal exposure.
 

2.3.2 Distribution .
 

2.3.2.1 Inhalation Exposure
 

No studies were located regarding the distribution of ethylene
 

oxide in human tissue after inhalation exposure. Ehrenberg et al.
 

(1974) reported that 75 minutes after exposing mice, the highest
 

concentrations of ethylene oxide were observed in the lungs, liver and
 

kidneys. Lesser amounts were found in the spleen, brain and testes.
 
34
 

2. HEALTH EFFECTS
 

Tyler and McKelvey (1982) found that in rats administered
 14C-ethylene oxide, the highest concentrations of 14C-activity were found
 

in the urinary bladder, liver, packed blood cells, and adrenal glands,
 

with the lowest concentration found in the fat.
 

Tyler (1983) evaluated the fate of ethylene oxide in pre-exposed
 

rats and their respective controls. Urine, feces and expired air were
 

collected during and 18 hours after exposure to 14C-ethylene oxide.
 

There were no significant differences in the concentration of
 

radioactivity in either group of animals, except that the radioactivity
 

associated with the red blood cells was 1.3 times greater in animals
 

that were not pre-exposed.
 

2.3.2.2 Oral Exposure
 

No studies were located regarding distribution of ethylene oxide
 

after oral exposure.
 

2.3.2.3 Dermal Exposure
 

No studies were located regarding distribution of ethylene oxide
 

after dermal exposure.
 

2.3.3 Metabolism
 

The metabolism of ethylene oxide is not completely known. Data
 

from animal studies indicate two possible pathways for the metabolism of
 

ethylene oxide: hydrolysis to ethylene glycol and glutathione
 

conjugation to form mercapturic acid and meththio-metabolites. Martis
 

et al. (1982) identified 1,2-ethanediol (ethylene glycol), a hydrolysis
 

product, in the plasma and urine of beagle dogs one hour after intravenous
 

administration of ethylene oxide. Ethylene glycol was the major
 

metabolite of ethylene oxide, with 7 to 24% of the administered dose
 

excreted in the urine within 24 hours. Koga et al. (1987) identified
 

ethylene glycol, 2-hydroxymercapturic acid, 2-methylthioethanol and
 

2-mercaptoethanol as metabolites in the urine of rats.
 

Tardi.f et al. (1987) studied the qualitative and quantitative
 

urinary disposition of some metabolites of ethylene oxide in three
 

rodent species: mouse, rat and rabbit. Important differences were
 

observed among the three species in the urinary metabolic disposition of
 

ethylene oxide. After an intravenous injection of ethylene oxide at
 

20 mg/kg, mice excreted significantly higher quantities of
 

N-acetyl-S-(2-hydroxyethyl)-L-cysteine, S-(2-hydroxyethyl)-L-cysteine,
 

S-carboxymethyl-L-cysteine and ethylene glycol (8.3, 5.8, 1.9 and 3.3%
 

of the administered dose, respectively, in 24 hours), whereas in rats,
 

only N-acetyl-S- (2-hydroxyethyl)-L-cysteine (31%) and ethylene glycol
 

(6%) were apparent. In contrast, the rabbits were found to excrete only
 
35
 

2. HEALTH EFFECTS
 

ethylene glycol (2%). This study further revealed species-related
 

differences in the urinary excretion of N-acetyl-S-(2-hydroxyethyl)­

L-cysteine and ethylene glycol during the two collection periods. The
 

observed differences among the three species in the metabolic
 

disposition of ethylene oxide were found to be qualitatively independent
 

of the route of exposure, (i.e., inhalation at 200 ppm or intravenous
 

injection of 20 or 60 mg/kg). These results suggest that care should be
 

exercised when using any single animal species as a model for human
 

disposition of ethylene oxide.
 

Tyler (1983) evaluated the fate of ethylene oxide in pre-exposed
 

rats and their respective controls. Urine, feces and expired air were
 

collected during and 18 hours after exposure to 14C-ethylene oxide.
 

There were no significant differences between the non-pre-exposed or
 

pre-exposed animals in the metabolic profiles. The data indicate that
 

prolonged exposure of rats to ethylene oxide has little effect on the
 

metabolism of the chemical.
 

Matsuoka (1988) reported that in rats exposed to ethylene oxide for
 

three months, the cytochrome P-450 enzyme systems in the lung and brain
 

were not affected. However, hepatic cytochrome P-450 and protoheme
 

decreased by 28% and 19%, respectively. Hepatic total microsomal
 

protein, cytochrome b5, NADPH-cytochrome c reductase and NADH-ferricyanide
 

reductase were not affected. The activity of hepatic heme
 

oxygenase showed a two-fold increase. These results suggest that the
 

heme moiety of hepatic cytochrome P-450 was primarily affected by
 

exposure of ethylene oxide and the cellular heme balance in liver was
 

altered.
 

Nakashima et al. (1987) found that in rats exposed to ethylene
 

oxide for 12 weeks, the concentration of the reduced form of glutathione
 

(GSH) in the liver was not significantly different from that of
 

controls. However, the hepatic GSH levels in rats subjected to a 4 hour
 

exposure to a high concentration of ethylene oxide (2,500 ppm) were
 

markedly decreased. These data suggest the involvement of glutathione
 

in the detoxication of ethylene oxide, at least in the rat.
 

McKelvey and Zemaitis (1986) exposed rats and mice to different,
 

atmospheric concentrations of ethylene oxide for 4 hours. In mice
 

sacrificed immediately after exposure to ethylene oxide, there was a
 

concentration-related decrease in the GSH levels of all tissues
 

examined. Similar findings were obtained in rats immediately after
 

exposure to ethylene oxide, except that blood GSH levels were not
 

affected at any exposure concentration. In both species, lung and liver
 

GSH levels were depressed at all exposure concentrations. Twenty-four
 

hours after exposure to ethylene oxide, the GSH concentrations of rat
 

bone marrow and testis had not returned to control levels. Only blood
 

GSH levels remained depressed in mice 48 hours after exposure to
 
36
 

2. HEALTH EFFECTS
 

ethylene oxide. The results indicate a marked species difference
 

between rats and mice regarding the effects of ethylene oxide exposure
 

on blood GSH levels.
 

2.3.4 Excretion
 

2.3.4.1 Inhalation Exposure
 

No studies were located regarding excretion of ethylene oxide in
 

humans after inhalation exposure.
 

Tyler and McKelvey (1982) found that in the rat, the primary route
 

of 14C-ethylene oxide elimination was urine (mean value of 59% recovered
 14C-activity), followed by expired CO, (12%), feces (4.5%), and expired
 

ethylene oxide (1%). Cumming et al. (1981) reported that ethylene oxide
 

was rapidly eliminated by mice that had been exposed to radio-labeled
 

ethylene oxide. Ehrenberg et al. (1974) reported that in mice ethylene
 

oxide has a biological half-life of approximately 9 minutes. Seventy-eight
 

percent of the administered dose was eliminated within 48 hours,
 

suggesting rapid urinary excretion. Filser and Bolt (1984) found that
 

ethylene oxide administered in a closed-system inhalation chamber
 

exhibited first-order elimination kinetics.
 

Tyler (1983) evaluated the fate of ethylene oxide in pre-exposed
 

rats and their respective controls. Urine, feces and expired air were
 

collected during and 18 hours after exposure to 14C-ethylene oxide.
 

There were no significant differences between the nonpre-exposed or
 

pre-exposed animals in the routes of elimination.
 

2.3.4.2 Oral Exposure
 

No studies were located regarding excretion of ethylene oxide after
 

oral exposure.
 

2.3.4.3 Dermal Exposure
 

No studies were located regarding excretion of ethylene oxide after
 

dermal exposure.
 

2.4 RELEVANCE TO PUBLIC HEALTH
 

As discussed previously in Section 2.2, the main route of exposure
 

to ethylene oxide in humans is via inhalation, and the main health
 

effects are central nervous system depression and irritation of the eyes
 

and mucous membranes.
 
37
 

2. HEALTH EFFECTS
 

Reproductive effects have been observed in animal studies but there
 

is no clear evidence of these effects in humans. Similarly, ethylene
 

oxide is clearly a carcinogen in animals, and epidemiological studies in
 

humans have shown limited evidence of carcinogenic effects in
 

occupationally exposed populations.
 

Death. The available reports (Gardner et al. 1989; Greenberg
 

et al. 1989) indicate that there is no increased incidence of human
 

death in association with ethylene oxide exposure. In mice, four-hour
 

exposures to 800 ppm resulted in a high rate of mortality (80-100%)
 

whereas 400 ppm exposures for 14 days did not result in death (NTP
 

1987). A level of 100 ppm for two years did not result in increased
 

lethality of mice (NTP 1987) or monkeys (Lynch et al. 1984a).
 

Based on the available data, lethality due to inhalation of
 

ethylene oxide may not be a health concern in occupational settings,
 

except with the use of damaged or leaking equipment.
 

Systemic Effects. Bronchitis, pulmonary edema and emphysema have
 

been reported in workers after acute high-level exposure (Theiss 1963),
 

but respiratory problems have not been reported to occur with chronic
 

exposure (Joyner 1964). Evidence of the potential for respiratory
 

irritation resulting from ethylene oxide inhalation comes mainly from
 

animal studies.
 

Based on data in mice, it appears that exposure level is more
 

important than duration of exposure with respect to respiratory effects.
 

Mice exposed to 200 ppm or more for 14 days suffered from rhinitis, loss
 

of polarity of olfactory and respiratory epithelial cells, epithelial
 

necrosis, loss of cilia and accumulation of purulent exudate. These
 

lesions were not seen by the same investigators in mice exposed to
 

100 ppm for two years NTP (1987).
 

Thus it appears that, at least in animals and possibly in humans,
 

there is a critical concentration of ethylene oxide that is necessary to
 

elicit respiratory irritation and the resulting lesions.
 

Dermal and ocular irritation have been reported in several case
 

studies of individuals occupationally exposed to ethylene oxide. Dermal
 

contact results in skin burns of varying severity depending on the
 

concentration of ethylene oxide and the length of contact (Sexton and
 

Henson 1949; Shupack et al. 1981). Cornea1 burns have been reported in
 

workers whose eyes have been splashed with ethylene oxide in solution or
 

blasted by the vapor (McLaughlin 1946; Thiess 1963).
 
38
 

2. HEALTH EFFECTS
 

Cataracts have also been associated with occupational exposure to
 

ethylene oxide when workers were exposed to a leaky sterilizer (Gross
 

et al. 1979; Jay et al. 1982). It is not clear whether the development
 

of cataracts was a response to direct ocular contact with the vapor or
 

was a systemic response to inhaled ethylene oxide.
 

Dermal application studies in animals have confirmed that ethylene
 

oxide is a dermal irritant (Bruch 1973; Hollingsworth et al. 1956;
 

Woodard and Woodard 1971) and ocular irritant (McDonald et al. 1977;
 

Woodard and Woodard 1971).
 

Immunological Effects. There is no clear evidence in animals or
 

humans that exposure to ethylene oxide via the inhalation, oral, or
 

dermal route is associated with immunological effects.
 

Neurological Effects. Central nervous system effects are
 

frequently associated with human exposure to ethylene oxide in
 

occupational settings. Headache, nausea and vomiting have been reported
 

for more than fifty years (Blackwood and Erskine 1938; von Oettingen
 

1939; Sexton and Henson 1949). Reliable exposure levels are generally
 

not available in these cases. Peripheral neuropathy, impaired hand-eye
 

coordination and memory loss have been reported in more recent case
 

studies of chronically-exposed workers (Crystal et al. 1988; Estrin
 

et al. 1987; Kuzuhara et al. 1983; Zampollo et al. 1984) at estimated
 

average exposure levels as low as 3 ppm (with possible short-term peaks
 

as high as 700 ppm).
 

In studies using several animal species at moderately high levels
 

of ethylene oxide (200-375 ppm) for 6 to 7 months, hind leg paralysis
 

and atrophy, abnormal knee and extensor reflexes, and diminished pain
 

perception were reported (Hollingsworth et al. 1956). Even levels of
 

50 ppm for l0-11 weeks resulted in hunched posture, reduced locomotion,
 

and abnormal righting reflexes in mice (Snellings et al. 1984a). A
 

g-month exposure to 250 ppm resulted in distal axonal degeneration of
 

myelinated fibers in both sural nerves and gracile fascicles in rats
 

(Ohnishi et al. 1986). Chronic exposures to ethylene oxide at 100 ppm
 

resulted in slight demyelination of the brains of monkeys and exposure
 

to 500 ppm resulted in brain lesions in rats (Lynch et al. 1984a).
 

These results raise concerns that similar morphological effects may
 

occur in humans.
 

Based on the body of available data from both human and animal
 

studies, the neurotoxic effects of ethylene oxide are an occupational
 

health concern for a wide range of exposure levels and durations. Both
 

chronic low level exposure associated with years of normal employment
 
39
 

2. HEALTH EFFECTS
 

conditions, as well as the brief or even protracted exposure duration to
 

high ethylene oxide levels due to industrial accidents or faulty
 

equipment, can lead to a broad spectrum of adverse neurological effects.
 

Developmental Effects. No data on the potential human
 

developmental effects of ethylene oxide exposure have been located and
 

the available data in animal studies (Hackett et al. 1982; Snellings
 

et al. 1982a) do not indicate that inhalation exposure to ethylene oxide
 

is associated with teratogenic effects. However, embryo and fetal
 

toxicity were reported in the offspring of rats exposed to 100 ppm
 

during gestation; the neonates were smaller in both length and weight
 

and had reduced ossification of the skull and sternebrae (Snellings
 

et al. 1982a). Intravenous administration of ethylene oxide to pregnant
 

mice resulted in decreased fetal weight and increases in dead and
 

resorbed fetuses and in fetal malformations (La Borde and Kimmel 1980).
 

Therefore, the offspring of humans exposed to ethylene oxide may be at
 

risk for teratogenicity and fetal and embryo toxicity.
 

Reproductive Effects. Based on the available human and animal
 

studies, inhalation exposure to ethylene oxide is associated with
 

numerous adverse reproductive effects in both males and females. In an
 

epidemiological study, Hemminki et al. (1982) reported that the
 

spontaneous abortion rates of ethylene oxide sterilizer operators in
 

Finnish hospitals were significantly higher than those of non-exposed
 

workers. Exposure levels were estimated to be as low as 0.1 to 0.5 ppm.
 

However, there were various limitations to the interpretation of this
 

study, as described in Section 2.2.1.6. Abrahams (1980) reported
 

decreased sperm counts in ethylene oxide workers, but as stated
 

previously, the small number of sperm samples obtained for analysis
 

precluded firm interpretation of the findings.
 

Decreased numbers of implantation sites have been reported in rats
 

exposed to ethylene oxide at 100 ppm during gestation (Snellings et al.
 

1982b). Reproductive effects in males have been reported in at least
 

three species of animals. Decreased testicular weights and testicular
 

degeneration have been observed in rats and guinea pigs exposed to
 

ethylene oxide for 6 to 7 months at 204 and 357 ppm, respectively
 

(Hollingsworth et al. 1956). In monkeys exposed at 50 ppm for two
 

years, decreased sperm concentration and drive range and reductions in
 

testicular and epididymal weights have been reported (Lynch et al.
 

1984a). An autoradiography study in mice by Appelgren et al. (1977)
 

indicates that ethylene oxide or one of its degradation products has
 

access to the male gonads (testes and epididymis) in this species within
 

four hours of intravenous exposure.
 
40
 

2. HEALTH EFFECTS
 

The potential for adverse reproductive effects is apparently an
 

area which warrants attention in terms of human exposure to ethylene
 

oxide.
 

Genotoxic Effects. Ethylene oxide has been demonstrated to be
 

genotoxic in a wide variety of prokaryotic and eukaryotic test systems.
 

A summary of the available in vitro genotoxicity studies for ethylene
 

oxide is presented in Table 2-3.
 

Peripheral blood studies of exposed workers have indicated that
 

ethylene oxide exposure is associated with an elevated incidence of
 

chromosomal aberrations including breaks, gaps, and exchanges and
 

supernumerary chromosomes (Galloway et al. 1986; Pero et al. 1981; Sarto
 

et al. 1984a; Theiss et al. 1981). An increased incidence of sister
 

chromatid exchange (SCE) in the peripheral lymphocytes of ethylene oxide
 

workers has also been reported by Galloway et al. (1986), Garry et al.
 

(1979), Lambert and Lindblad (1980), Sarto et al. (1984 and 1984b) and
 

Yager et al. (1983).
 

Increased and persistent elevations of SCE have also been observed
 

in the peripheral blood lymphocytes of monkeys, (Kelsey et al. 1988;
 

Lynch et al. 1984a) exposed to ethylene oxide for two years, providing
 

additional concern for the carcinogenic potential of this compound for
 

humans exposed via inhalation.
 

Cancer. There is evidence from both human and animal studies that
 

inhalation exposure to ethylene oxide can result in a wide range of
 

carcinogenic effects. Epidemiological studies in ethylene oxide factory
 

workers and sterilizer operators have indicated that leukemia, stomach
 

cancer (Hogstedt et al. 1979, 1986) pancreatic cancer and Hodgkin's
 

disease (Morgan et al. 1981) were elevated in exposed individuals. As
 

described in Section 2.2.1.8, the Hogstedt data are viewed as having
 

certain limitations. Other studies (Gardner et al. 1989; Greenberg
 

et al. 1990; Kiesselbach et al. 1990) have not found these associations.
 

Inhalation studies in animals have resulted in mononuclear cell
 

leukemia, peritoneal mesotheliomas, and various brain tumors in rats
 

(Lynch et al. 1984b; Snellings et al. 1984b) at levels as low as 33 ppm.
 

Lung tumors, tumors of the harderian gland, malignant lymphomas and
 

uterine and mammary gland tumors were also found in mice (NTP 1987).
 

In the only located animal study using the oral route, female rats
 

dosed with ethylene oxide by gavage at 7.5 mg/kg/day developed squamous
 

cell carcinomas of the forestomach (the site of application) only, but
 

not at any distal sites (Dunkelberg 1982). Ethylene oxide is ranked as
 

a Group Bl carcinogen (i.e., a probable human carcinogen) by EPA's
 

42
 

2. HEALTH EFFECTS
 

Carcinogen Assessment Group (IRIS 1989) and a 2A carcinogen by IARC
 

(1987). These classifications are based on adequate evidence in animal
 

studies but limited or inadequate evidence in humans (EPA 1985a).
 

Ethylene oxide was not found to cause skin tumors in a skin painting
 

study using mice (Van Duuren et al. 1965).
 

Data from in vitro studies indicate that ethylene oxide is
 

mutagenic in several prokaryotic and eukaryotic systems.
 

Based on the available data, carcinogenicity is an area of major
 

concern in relation to humans chronically exposed to ethylene oxide via
 

inhalation in occupational settings.
 

2.5 BIOMARKERS OF EXPOSURE AND EFFECT
 

Biomarkers are broadly defined as indicators signaling events in
 

biologic systems or samples. They have been classified as markers of
 

exposure, markers of effect, and markers of susceptibility (NAS/NRC
 

1989).
 

A biomarker of exposure is a xenobiotic substance or its
 

metabolite(s) or the product of an interaction between a xenobiotic
 

agent and some target molecule or cell that is measured within a
 

compartment of an organism (NAS/NRC 1989). The preferred biomarkers of
 

exposure are generally the substance itself or substance-specific
 

metabolites in readily obtainable body fluid or excreta. However,
 

several factors can confound the use and interpretation of biomarkers of
 

exposure. The body burden of a substance may be the result of exposures
 

from more than one source. The substance being measured may be a
 

metabolite of another xenobiotic (e.g., high urinary levels of phenol
 

can result from exposure to several different aromatic compounds).
 

Depending on the properties of the substance (e.g., biologic half-life)
 

and environmental conditions (e.g., duration and route of exposure), the
 

substance and all of its metabolites may have left the body by the time
 

biologic samples can be taken. It may be difficult to identify
 

individuals exposed to hazardous substances that are commonly found in
 

body tissues and fluids (e.g., essential mineral nutrients such as
 

cower, zinc and selenium). Biomarkers of exposure to ethylene oxide
 

are discussed in Section 2.5.1.
 

Biomarkers of effect are defined as any measurable biochemical,
 

physiologic, or other alteration within an organism that, depending on
 

magnitude, can be recognized as an established or potential health
 

impairment or disease (NAS/NRC 1989). This definition encompasses
 

biochemical or cellular signals of tissue dysfunction (e.g., increased
 

liver enzyme activity or pathologic changes in female genital epithelium
 

cells), as well as physiologic signs of dysfunction such as increased
 

blood pressure or decreased lung capacity. Note that these markers are
 
43
 

2. HEALTH EFFECTS
 

often not substance specific. They also may not be directly adverse,
 

but can indicate potential health impairment (e.g., DNA adducts).
 

Biomarkers of effects caused by ethylene oxide are discussed in
 

Section 2.5.2.
 

A biomarker of susceptibility is an indicator of an inherent or
 

acquired limitation of an organism's ability to respond to the challenge
 

of exposure to a specific xenobiotic. It can be an intrinsic genetic or
 

other characteristic or a preexisting disease that results in an
 

increase in absorbed dose, biologically effective dose, or target tissue
 

response. If biomarkers of susceptibility exist, they are discussed in
 

Section 2.7, "POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE."
 

2.5.1 Biomarkers Used to Identify or Quantify Exposure to Ethylene


 Oxide
 

Ethylene oxide can be measured in blood (Bailey et al. 1987;
 

Brugnone et al. 1986; Farmer et al. 1986) and alveolar air (Brugnone
 

et al. 1986). Because ethylene oxide is very reactive in biological
 

systems, it is usually necessary to measure its addition products (e.g.,
 

N-(2-hydroxyethyl)histidine or N-(2-hydroxyethyl)valine) in blood.
 

However, based on the currently available information, the levels
 

of these substances in biological media cannot be used to calculate or
 

estimate corresponding levels of exposure to ethylene oxide.
 

2.5.2 Biomarkers Used to Characterize Effects Caused by Ethylene Oxide
 

There are currently no subtle or sensitive biomarkers of effects
 

associated with ethylene oxide.
 

2.6 INTERACTIONS WITH OTHER CHEMICALS
 

No data have been located that identify the interactions of
 

ethylene oxide with other chemicals in the environment.
 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
 

No population has been identified that is more at risk from
 

ethylene oxide exposure based on biological differences.
 

2.8 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in
 

consultation with the Administrator of EPA and agencies and programs of
 

the Public Health Service) to assess whether adequate information on the
 

health effects of ethylene oxide is available. Where adequate
 

information is not available, ATSDR, in conjunction with the National
 
44
 

2. HEALTH EFFECTS
 

Toxicology Program (NTP), is required to assure the initiation of a
 

program of research designed to determine the health effects (and
 

techniques for developing methods to determine such health effects) of
 

ethylene oxide.
 

The following categories of possible data needs have been
 

identified by a joint team of scientists from ATSDR, NTP, and EPA. They
 

are defined as substance-specific informational needs that, if met would
 

reduce or eliminate the uncertainties of human health assessment. In
 

the future, the identified data needs will be evaluated and prioritized,
 

and a substance-specific research agenda will be proposed.
 

2.8.1 Existing Information on the Health Effects of Ethylene Oxide
 

The existing data on health effects of inhalation, oral, and dermal
 

exposure of humans and animals to ethylene oxide are summarized in
 

Figure 2-3. The purpose of this figure is to illustrate the existing
 

information concerning the health effects of ethylene oxide. Each dot
 

in the figure indicates that one or more studies provide information
 

associated with that particular effect. The dot does not imply anything
 

about the quality of the study or studies. Gaps in this figure should
 

not be interpreted as "data needs" information.
 

As indicated in Figure 2-3, most of the available information on
 

the health effects of ethylene oxide is related to the inhalation route.
 

Most of the data on humans are related to case studies based on normal
 

or accidental occupational exposure.
 

Studies in animals have been more comprehensive, but as described
 

in the previous section, much of the information is considered to be
 

limited in its usefulness for a variety of reasons.
 

2.8.2 Identification of Data Needs
 

Acute-Duration Exposure. Information on acute-duration exposure of
 

humans to ethylene oxide indicates that irritation reactions involving
 

the mucous membranes of the respiratory system and the skin are the
 

result of inhalation and dermal exposure, respectively. Available
 

information in animals is limited to lethality data in mice via the
 

inhalation route and in rats via the oral route, as well as information
 

on dermal/ocular effects after local administration. The data were not
 

considered to be adequate to calculate an MRL by any route. Further
 

animal studies using acute-duration inhalation exposure to ethylene
 

oxide may be useful in identifying the mechanism of lethality. This
 

information would be relevant to the safety of workers in industrial or
 

hospital settings. Data on acute-duration exposure via the oral route
 

would also be helpful. Some of the currently available studies were
 

46
 

2. HEALTH EFFECTS
 

conducted 30 to 50 years ago, and improvements in experimental
 

technology since then may result in more accurate estimates of exposure
 

levels and analysis of results.
 

Intermediate-Duration Exposure. The currently available data on
 

intermediate-duration exposure to ethylene oxide in humans also indicate
 

that irritation reactions are the major effects resulting from
 

inhalation or dermal exposure. Data in animals via inhalation are
 

useful in assessing its potential effects on a variety of organ systems.
 

An MRL for renal effects in mice exposed via inhalation has been
 

calculated for this duration period. Although intermediate-duration
 

studies via the oral and dermal routes are not currently available,
 

there is no indication that they would be a valuable contribution to the
 

data base for this chemical.
 

Chronic-Duration Exposure and Cancer. Studies are available for
 

this duration period for both humans and animals exposed via inhalation
 

and for animals exposed via the oral route. However, the data were not
 

considered to be adequate to calculate an MRL for any route of exposure.
 

Data on the carcinogenic potential of ethylene oxide in
 

occupationally exposed humans are inconclusive, with both positive and
 

negative results reported in the available studies. The currently
 

available studies on the chronic exposure of various animal species to
 

ethylene oxide have established that this chemical is clearly
 

carcinogenic via the inhalation route. If it were determined that
 

ethylene oxide residues still remain in or on various agricultural
 

commodities when they are consumed by humans, a chronic feeding study in
 

animals might also be useful. Also, further epidemiologic assessments
 

of the carcinogenic and other health effects in occupationally exposed
 

humans, including dermal effects, would also provide valuable data.
 

Based on the results of such studies, dermal carcinogenicity studies in
 

animals might be relevant to the welfare of occupationally exposed
 

workers.
 

Genotoxicity. The genotoxicity of ethylene oxide has been
 

established in a number of in vitro tests using various prokaryotic and
 

eukaryotic systems as well as in vivo studies of human peripheral blood.
 

Further studies in this area do not currently appear to be necessary.
 

Reproductive Toxicity. Available data on ethylene oxide's
 

reproductive effects on occupationally exposed males are considered
 

inconclusive; further investigation of these individuals would be
 

extremely useful. Further data on occupationally exposed women would
 

also be helpful since the currently available data are limited to a
 

single study of spontaneous abortions in Finnish hospital workers. The
 

currently available reproductive toxicity data from inhalation studies
 
47
 

2. HEALTH EFFECTS
 

in animals indicate that this may be an area of concern for inhalation
 

exposure to ethylene oxide. Reproductive toxicity studies in animals
 

via the oral route may also be useful. Studies using the dermal route
 

would probably not be useful unless systemic absorption via skin
 

application is first demonstrated.
 

Developmental Toxicity. There are no data on developmental
 

toxicity in the offspring of humans exposed to ethylene oxide via
 

inhalation, oral, or dermal routes. The currently available data in
 

rats indicate that fetal and embryo toxicity can result from inhalation
 

exposure to ethylene oxide, and fetal abnormalities have been increased
 

in studies using intravenous administration. No studies in this area
 

using oral or dermal exposure have been located. Studies to assess the
 

developmental effects of exposure to ethylene oxide via the inhalation
 

and the oral routes would be useful in assessing the potential risks to
 

offspring of persons exposed to this chemical in the workplace or in the
 

vicinity of hazardous waste sites. Studies using the dermal route would
 

probably not be useful unless systemic absorption can be demonstrated to
 

result from dermal application.
 

Immunotoxicity. The currently available information does not
 

indicate that this is an area of potential concern for ethylene oxide
 

exposure via any route.
 

Neurotoxicity. Ethylene oxide has been established as a neurotoxin
 

in both humans and animals via the inhalation route; therefore, further
 

studies using this route would not appear to be a priority. Studies in
 

animals using the oral route may provide useful information if it is
 

first determined that ethylene oxide residues still remain in or on
 

agricultural commodities when they are consumed by humans. Studies
 

using the dermal route would probably not be useful unless systemic
 

absorption via skin application can first be demonstrated.
 

Epidemiological and Human Dosimetry Studies. Although ethylene
 

oxide has been shown to be toxic to humans in several studies, the
 

related air concentrations have not been sufficiently established.
 

Estimates provided in some studies range from as low as 0.1 ppm for
 

chronic exposure to as high as 700 ppm for intermediate exposure.
 

Dosimetry studies would be valuable in providing retrospective insights
 

into the data reported in human case and epidemiological studies as well
 

as in attempting to determine the most relevant range of exposures at
 

which to conduct any further animal studies. Epidemiological studies of
 

occupationally exposed persons would be useful in determining the risks
 

of cancer, reproductive effects, and neurological effects associated
 

with long-term exposure to ethylene oxide.
 
48
 

2. HEALTH EFFECTS
 

Biomarkers of Exposure and Effect. Measurement of ethylene oxide
 

or its addition products, N-(Z-hydroxyethyl)histidine or N­

(2-hydroxyethyl)valine, in blood may provide an adequate qualitative
 

indication of recent exposure to ethylene oxide. The development of
 

methods that could be used to calculate or estimate levels of exposure
 

to ethylene oxide from the levels of these substances in biological
 

fluids would be extremely useful.
 

There are currently no subtle or sensitive biomarkers of effects
 

caused by ethylene oxide. It would be useful to have information to
 

correlate levels of ethylene oxide addition products in blood or other
 

biological media with the onset of adverse health effects.
 

Absorption, Distribution, Metabolism and Excretion. The absorption
 

of ethylene oxide administered via inhalation has been extensively
 

studied in humans and several species of animals. Data on its
 

absorption when administered via the oral and dermal routes would also
 

be valuable.
 

Data are available on the distribution of ethylene oxide after
 

inhalation by rats and mice. Studies that provide information on its
 

distribution after oral and dermal administration would also be helpful.
 

The metabolism of ethylene oxide is not completely known. Studies to
 

further characterize the two possible pathways for the metabolism of
 

ethylene oxide, hydrolysis and glutathione conjugation, and to identify,
 

if possible, the species in which metabolism most resembles that in
 

humans would be useful. It may also be helpful to characterize
 

unidentified urinary metabolites that have been reported in several
 

studies.
 

Excretion data are available only for rats and mice exposed to
 

ethylene oxide via inhalation. Studies using the oral and dermal routes
 

may also provide useful information.
 

Comparative Toxicokinetics. The available toxicokinetic studies
 

are limited and it is not possible to determine if there are any major
 

differences in the kinetics of ethylene oxide absorption, distribution,
 

metabolism or excretion across species. It would be useful to
 

investigate patterns of distribution, to identify target organs, to
 

measure rates of excretion in several species, and to identify blood
 

metabolites in humans and animals in order to understand what, if any,
 

relationships exist. Studies in this area would also be helpful in
 

putting the results of all available toxicity studies into perspective
 

in terms of their relevance to the potential human health effects of
 

ethylene oxide under similar conditions of exposure.
 
49
 

2. HEALTH EFFECTS
 

2.8.3 On-going Studies
 

The NTP Annual Plan for FY 1988 (NTP 1988a) indicated that ethylene
 

oxide testing was scheduled to be ongoing or completed in the following
 

areas:
 

• 	 In vitro microbial testing for mutagenesis and genetic toxicity
 

• 	 In vitro Chinese hamster ovary assay to detect chromosomal


 aberrations and sister chromatid exchange
 

• 	 Drosophila sex-linked lethality assay
 

• 	 Neurological and behavioral toxicity testing
 

• 	 Inhalation testing in mice and rats to study pulmonary and


 immunologic toxicity
 

In addition, the Ethylene Oxide Industry Council (EOIC), a panel of
 

the Chemical Manufacturers Association's CHEM STAR Division, has plans
 

to develop, through the Chemical Industry Institute of Toxicology
 

(CIIT) , a Physiologically-Based Pharmacokinetic (PB-PK) model for the
 

metabolism, disposition and macromolecular reactivity of the ethylene
 

oxide. The PB-PK model is intended to permit extrapolation to predict
 

tissue exposures from various ethylene oxide exposure scenarios and in a
 

variety of animal species, including humans. Eventually, a
 

comprehensive risk assessment will combine the PB-PK model for chemical
 

disposition and tissue dosimetry of DNA adducts with biologically-based
 

descriptions of the cancer process. The completed PB-PK model will be
 

used to interpret the rodent bioassay study results, to support a human
 

risk assessment for exposure, and to interpret exposure assessment
 

studies based on the concentration of hemoglobin adducts in exposed
 

persons.
 

51
 

3. CHEMICAL AND PHYSICAL INFORMATION
 

3.1 CHEMICAL IDENTITY
 

Tables 3-l lists common synonyms, trade names, and other pertinent
 

identification information for ethylene oxide.
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

Table 3-2 lists important physical and chemical properties of
 

ethylene oxide.
 



55
 

4. PRODUCTION, IMPORT, USE AND DISPOSAL
 

4.1 PRODUCTION
 

Ethylene oxide is a major industrial chemical and is one of the 25
 

highest production volume chemicals in the United States There was a
 

gradual increase in the production volume of ethylene oxide in recent
 

years from 1,906,800 kkg (metric tons) in 1973 to a peak of
 

2,610,500 kkg in 1979, and then a gradual decrease to 2,172,530 kkg in
 

1987.
 

Ethylene oxide is produced by 12 chemical companies in the United
 

States in four states; one plant is in Illinois, one in Delaware, four
 

in Louisiana, and six in Texas. The manufacturers of ethylene oxide are
 

also the major users and distributors of the compound.
 

In the United States, all ethylene oxide is produced by the direct
 

oxidation of ethylene by air or oxygen in the presence of a silver oxide
 

catalyst. Another commercial production method, reaction of ethylene
 

chlorohydrin with potassium hydroxide or calcium oxide, was phased out
 

by 1980 (EPA 1985a; SRC 1982; SRI 1984, 1988; USITC 1988; WHO 1985).
 

4.2 IMPORT
 

Imports of ethylene oxide are relatively small, with amounts
 

increasing from 1982 to 1984 from 4,300 kkg to 5,600 kkg. Exports of
 

ethylene oxide increased substantially over the same period, from
 

1,500 kkg in 1982 to 11,200 kkg in 1984 (SRI 1984).
 

4.3 USE
 

Over 99% of the ethylene oxide produced in the United States is
 

used as a chemical intermediate for the production of various chemicals,
 

while less than 1% is used as a sterilant or fumigant. Ethylene oxide
 

is used captively by manufacturers to produce ethylene glycol (64% of
 

ethylene oxide consumption), non-ionic surfactants (11%), glycol ethers
 

(7%), higher glycols (10%), ethanolamines (7%), and miscellaneous
 

chemicals (l%), including choline, polyether polyols, and hydroxyethyl
 

starch. These chemicals are found in antifreeze, textiles, detergents,
 

solvents, polyurethane foam, medicinals, adhesives, and other products.
 

Relatively small amounts of ethylene oxide are used as a fumigant,
 

a sterilant for food (spices) and cosmetics, and in hospital
 

sterilization of surgical equipment and plastic devices that cannot be
 

sterilized by steam. At one time, ethylene oxide was used in the
 

production of acrylonitrile, but that process was discontinued in 1966
 

(EPA 1984a, 1985a; NIOSH 1981; SRC 1982; SRI 1984; WHO 1985).
 
56


 4. PRODUCTION, IMPORT, USE AND DISPOSAL
 

4.4 DISPOSAL
 

Because ethylene oxide is listed as a hazardous substance, disposal
 

of wastes containing this compound is controlled by a number of federal
 

regulations (see Chapter 7). Restrictions are proposed for land
 

disposal of ethylene oxide.
 

The production processes for ethylene oxide do not generate solid
 

wastes and the waste waters are treated or recycled. The production
 

process is a closed system; however, vent gases and fugitive emissions
 

may contain some ethylene oxide. Waste gases may be removed from the
 

air by scrubbers. Wastes containing ethylene oxide may be incinerated
 

by rotary kiln or fluidized bed incineration methods (EPA 1989; HSDB
 

1988; SRC 1982; WHO 1985).
 
57
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.1 OVERVIEW
 

Ethylene oxide is a gas used in the production of other synthetic
 

chemicals such as ethylene glycol. Gaseous releases of ethylene oxide
 

to the environment are the result of uncontrolled industrial emissions.
 

Less than 1% of the industrial production of ethylene oxide is used as a
 

fumigant and sterilizing agent for a variety of purposes and materials
 

which include hospital equipment and certain food.
 

Ethylene oxide degrades in both the air and natural water via
 

radical formation and hydrolysis, leading to the formation of glycols,
 

and halogenated alcohols (in the presence of sodium chloride), which in
 

turn degrade into simpler molecules such as carbon dioxide and water.
 

The half-lives of these reactions range from a few hours to less than 15
 

days, depending on environmental conditions. UV-catalyzed oxidation (in
 

the presence of oxygen and nitrogen dioxide) may also account for some
 

of the ethylene oxide lost in the atmosphere. Ethylene oxide also
 

degrades in wastewater treatment systems with a half-life of about 20
 

days.
 

No data are available on the fate of ethylene oxide in soil.
 

Nonetheless, this chemical is expected to either volatilize or be
 

leached due to its high vapor pressure and infinite solubility in water.
 

Soil organisms may also convert it to glycols.
 

Data on the levels of ethylene oxide in the environment are very
 

limited. There are no data to indicate that ethylene oxide is a common
 

constituent of air or water sources of any type in any geographic
 

location within the United States. Fumigated foods and sterilized
 

hospital equipment may have initially high levels of ethylene oxide,
 

which dissipate and/or degrade into other products within a few days.
 

There are no data on ethylene oxide bioaccumulation in marine organisms.
 

No data are available to determine the general population's
 

exposure levels to ethylene oxide. Environmental exposures may include
 

ethylene oxide from car exhaust and tobacco smoke. The populations
 

with potentially higher than average risk of exposure to ethylene oxide
 

include sterilization technicians and industrial workers involved in the
 

manufacture and/or use of ethylene oxide.
 

5.2 RELEASES INTO THE ENVIRONMENT
 

5.2.1 Air
 

Ethylene oxide is a synthetically produced gas used primarily in
 

the production of other chemicals by the chemical industry. As a
 

result, most of the releases of ethylene oxide to the atmosphere occur
 
58
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

during its storage and handling in industrial settings. Industrial
 

emissions of ethylene oxide are due to uncontrolled fugitive emissions
 

or venting with other gases. Estimates of ethylene oxide losses during
 

production range from 1.3 to 3 million pounds (590 to 1,360 kkg) for
 

1978 and 1980, respectively, as reported in Bogyo et al. (1980). The
 

same report indicated that losses of ethylene oxide during storage might
 

have been about 143,000 pounds (65 kkg) annually.
 

Other sources of ethylene oxide air emissions include its
 

production from combustion of hydrocarbon fuels and its release from
 

commodity-fumigated materials, estimated to be about 10 million pounds
 

(4,500 kkg) annually (Bogyo et al. 1980), and losses during disinfection
 

of hospital equipment.
 

Additional nonquantified sources of air emission of ethylene oxide
 

may be bacterial degradation products, photochemical smog, cigarette
 

smoke and hydrocarbon combustion (Bogyo et al. 1980). Barnard and Lee
 

(1972) and Bogyo et al. (1980) reported finding ethylene oxide in the
 

products of n-pentane combustion, but specific concentrations were not
 

given. EPA (1980) concluded that because pentanes are found in
 

gasoline, significant amounts of ethylene oxide are probably released
 

annually into the atmosphere from automobile exhaust.
 

WHO (1985) reported that the estimated air emissions due to
 

agricultural fumigation and disinfection of medical products were about
 

2% (about 53,000 tons or 48,000 kkg) of the total ethylene oxide
 

production, which was estimated at about 2.4 million tons (2.2 million
 

kkg) in the United States during 1980. The use of ethylene oxide in
 

hospitals was estimated to be less than 0.02% of the total United States
 

production, or about 500 tons (450 kkg) during 1976 (Glaser 1979).
 

5.2.2 Water
 

Ethylene oxide discharges into water also appear to be mostly
 

industry-related. According to EPA (1982a), industrial producers of
 

ethylene oxide estimated that about 800,000 pounds of this compound were
 

discharged into wastewater treatment systems each year in the United
 

States. EPA (1982a) also reported that ethylene oxide was not detected
 

in treated industrial wastewaters discharged into waterways. WHO (1985)
 

also indicated that biological treatment of wastewaters containing
 

ethylene oxide appears to be successful in the removal of this chemical
 

from reaching waterways. Contract Laboratory Program (CLP) statistical
 

data from November 1988 appear to verify this assertion. A review of
 

this data base indicated that of 5,300 water samples collected from 862
 

sites, only two sites had samples contaminated with ethylene oxide,
 

including a surface water site with a concentration of 28 μg/L and a
 

groundwater site with 21 μg/L (mean of two samples) (CLPSD 1988).
 
59
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.2.3 Soil
 

No discharges of ethylene oxide into the soil are reported in the
 

literature. Although ethylene oxide is a potent fumigant and will kill
 

fungi, viruses, and insects, it is not approved as a soil fumigant.
 

However, since ethylene oxide is infinitely soluble in water, it is
 

likely that the soil environment is exposed to this chemical as a result
 

of the atmospheric scrubdown of rainfall and some uncontrolled
 

discharges of liquid wastes containing this chemical. The Contract
 

Laboratory Program Statistical Database (CLPSD 1988) reported that only
 

six soil samples collected from four different sites, out of 862 total
 

sites, had quantifiable amounts of ethylene oxide (mean: 22 μg/kg)
 

(CLPSD 1988).
 

5.2.4 Other Sources
 

Solid or liquid wastes containing measurable amounts of ethylene
 

oxide, as defined in Part 261 of CFR 40 (1984), can be classified as
 

hazardous with ignitable and toxic properties. However, according to
 

Bogyo et al. (1980), no specific wastes containing large amounts of
 

ethylene oxide associated with the manufacture of ethylene oxide have
 

been identified.
 

5.3 ENVIRONMENTAL FATE
 

5.3.1 Transport and Partitioning
 

The primary mode of transport of ethylene oxide is via air 

emissions into the atmosphere. At atmospheric pressure and room 

temperature, ethylene oxide exists as a gas due to its very high vapor 

pressure (1,095 mm Hg at 20°C) and low boiling point (10.4° C) (WHO 

1985). 

The reported log of the octanol/water partition coefficient (KOW)
 

for ethylene oxide is -0.30 (Hansch and Leo 1979), indicating that
 

ethylene oxide is a very polar chemical. From its chemical and physical
 

properties, it can be inferred that ethylene oxide in soil will
 

volatilize as water evaporates, leach through the soil, or be removed by
 

runoff during rainstorms. It is, therefore, unlikely that ethylene
 

oxide will accumulate in soils or sediments. No data on the
 

accumulation and/or fate of ethylene oxide in the soil environment are
 

available.
 

EPA (1984b) indicated that there are no data on the bioaccumulation
 

of ethylene oxide in animal tissue.
 
60
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Although ethylene oxide dissolves in water in any proportion, it
 

also has the tendency to escape (volatilize) due in part to its high
 

vapor pressure. Conway et al. (1983) reported that about 95% of
 

ethylene oxide mixed with water volatilizes within 4 hours (its half-life
 

is about 1 hour).
 

Ethylene oxide is used as a fumigant for some food commodities.
 

The Environmental Protection Agency (198413) reported the use of ethylene
 

oxide to fumigate cocoa, flour, dried fruits, dehydrated vegetables,
 

fish, and bone meal. However, Meister (1988) listed ethylene oxide as a
 

fumigant and sterilizing agent for only three food products: spices,
 

black walnuts and copra. Currently, EPA has set tolerances for residues
 

on these three items (see Table 7-l).
 

5.3.2 Transformation and Degradation
 

5.3.2.1 Air
 

There is limited information on the fate of ethylene oxide in the 

atmosphere. EPA (1984b) reported that the most probable path of 

atmospheric degradation of ethylene oxide is oxidation via free-radical 

formation, and estimated its half-life in air at 25°C to range from 69 

to 149 days, based on data (rate constants and the concentration of OH 

radicals) obtained by Fritz et al. (1982). 

Ethylene oxide also reacts with atmospheric oxygen in the presence 

of nitrogen dioxide and W light. Studies by Gomer and Noyes (1950) 

indicated that photocatalyzed chemical decomposition of ethylene oxide 

would result in the formation of methane, ethane, hydrogen, carbon 

dioxide, and some smaller amounts of simple aldehydes. Jaffe (1971) 

examined ethylene oxide decomposition products and postulated that 

ethylene oxide reacts with W-excited nitrogen dioxide molecules, 

eventually leading to the formation of acetaldehyde, methane, and carbon 

dioxide. According to EPA (1984b), measurements of the absolute rate 

constant, determined to be about 6 x l0-l6 cm3

/mole/sec by Bogan and Hand 

(1978) for the reaction between oxygen and ethylene oxide at 27° C, 

indicate an ethylene oxide half-life of about 1,400 years, assuming an 

atmospheric oxygen concentration of 25,000 molecules/cm3

. Bogan and 

Hand (1978) determined the final products of oxygen-W catalyzed 

ethylene oxide oxidation to be hydrogen, water, carbon monoxide, carbon 

dioxide, and formaldehyde. Joshi et al. (1982) determined ethylene 

oxide to have a low reactivity with atmospheric nitrogen dioxide under 

W radiation and at 25° C. Using ethylene oxide:nitrogen dioxide ratios 

similar to those found in urban and rural air, these researchers 

reported the ethylene oxide half-life to be more than 53 hours. 
61
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

In summary, the few available studies on the photodecomposition of
 

ethylene oxide in the atmosphere suggest that it undergoes measurable
 

rates of degradation into simpler products. However, laboratory
 

estimates of the half-life of ethylene oxide in the atmosphere vary
 

widely.
 

5.3.2.2 Water
 

Ethylene oxide hydrolyzes in water to form glycols (Long and 

Pritchard 1956). Bogyo et al. (1980) reported the hydrolysis rate 

constant (acid catalyzed) to be about 19.9 x l0-3 L/mol-sec at 30° C. 

According to the same report, all epoxides, including ethylene oxide, 

can react with anions such as chloride and bromide in aqueous solutions, 

forming halogenated alcohols. Conway et al. (1983) determined the 

half-life of ethylene oxide to range from 12 to 14 days in sterile, 

deionized and natural river water. They also reported that increased 

water salinity (up to 3% sodium chloride) decreased the half-life of 

ethylene oxide to 9 days (Conway et al. 1983), and produced ethanediol 

and chloroethanol. 

According to Anbar and Neta (1967), the degradation of ethylene
 

oxide in water via hydroxyl radicals is very slow, with a computed half-life
 

of about 50 years.
 

Conway et al. (1983) reported that the half-life measurements for
 

ethylene oxide in sterile and natural river water were not appreciably
 

different. This may be because hydrolytic degradation of ethylene oxide
 

is more rapid than biodegradation of this compound in aqueous media.
 

5.3.2.3 Soil
 

No studies on the degradation of ethylene oxide in the soil
 

environment have been located. However, it is likely that ethylene
 

oxide would be found in both the water and vapor phases of the soil
 

environment due to its high vapor pressure and very low octanol/water
 

partition coefficient. Thus, ethylene oxide in the soil is likely to
 

undergo at least some degradation via the same types of mechanisms as
 

those that predominate in aquatic environments.
 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
 

5.4.1 Air
 

There is very little information on ethylene oxide levels in air,
 

but the data available indicate that ethylene oxide does not seem to be
 

a contaminant in ambient air. Hunt et al. (1986) conducted an air
 

quality survey in Texas during 1985 and 1986. Quarterly state and local
 

air quality measurements indicated that ethylene oxide was not detected
 
62
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

at concentrations above the detection limit of 0.194 ng/m3

. These
 

authors also reported that ethylene oxide was not detected in a
 

comprehensive air quality survey in the state of California.
 

5.4.2 Water
 

There are very limited data on the presence or absence of ethylene
 

oxide in water (drinking water supplies, groundwater, etc.) on a
 

national scale. EPA (1984b) reported a survey showing ethylene oxide at
 

a concentration of 2 mg/L in the effluent of a chemical plant in
 

Bandenburg, Kentucky.
 

5.4.3 Soil
 

No data are available on the presence or absence of any significant
 

levels of ethylene oxide in soil. However, DeBont and Albers (1976)
 

reported that ethylene oxide is produced by the metabolism of ethylene
 

by an ethylene-oxidizing bacterium. Also, ethylene is a relatively
 

common volatile hydrocarbon in wet soil, where it can be produced by
 

several species of fungi, bacteria, and actinomycetes (Alexander 1977).
 

Therefore, small but constant levels of ethylene oxide may be present in
 

soils under wet conditions. No data are available on ethylene oxide in
 

soils resulting from uncontrolled releases of ethylene oxide liquid
 

waste or from atmospheric depositions of any kind.
 

5.4.4 Other Media
 

Ethylene oxide may be found in tobacco and some food as a result of 

its use as a fumigant and a sterilizing agent. The Farm Chemicals 

Handbook (Meister 1988) lists ethylene oxide for use only as a fumigant 

on three food products: spices, black walnuts and copra. However, 

ethylene oxide may have been used (and may still be used) as a fumigant 

for tobacco and some cosmetics. Measurable amounts of ethylene oxide 

were detected in both fumigated and unfumigated tobacco and its smoke; 

the ethylene oxide concentration in smoke from unfumigated tobacco was 

1 μg/g (Bogyo et al. 1980). 

Residual ethylene oxide may be found in foods temporarily,
 

following fumigation. Scudamore and Heuser (1971) reported that
 

ethylene oxide may react with water and inorganic halides (chloride and
 

bromide) from foods and produce glycols and halohydrins. The same
 

researchers concluded that the persistence or disappearance of ethylene
 

oxide and its byproducts in fumigated commodities depends on the grain
 

size, type of foods, aeration procedures, temperature, and storage and
 

cooking conditions. According to Scudamore and Heuser (1971), most
 

experimentally fumigated commodities had levels of ethylene oxide below
 

1 ppm after 14 days in normal storage conditions. No residues of
 

ethylene oxide were found in commercially fumigated flour or tobacco.
 
63
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Rajendran and Muthu (1981) reported that concentrations of ethylene
 

oxide in 24-hour aerated foods (wheat, rice, spices, dates and peas)
 

(following a 24-hour fumigation period) ranged from 0 to 3.5 ppm. IARC
 

(1976) indicated that food fumigated with ethylene oxide generally had
 

negligible levels of ethylene oxide within a few hours after fumigation,
 

due primarily to loss by volatilization. However, in spices, ethylene
 

oxide levels ranging from 53 to 116 mg/kg (ppm) and about 25 mg/kg (ppm)
 

at 2 days and 26 days after fumigation, respectively have been reported
 

(WHO 1985).
 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
 

The general population's exposure to ethylene oxide may occur via
 

inhalation and food ingestion. There is no information to indicate that
 

ethylene oxide is a common contaminant of drinking water supplies.
 

Since ethylene oxide is used as a sterilant and fumigant, the
 

potential locations of contaminated air include hospitals (ethylene
 

oxide is commonly used to sterilize medical equipment), libraries,
 

museums, and laboratories. Sources include vapors from certain foods,
 

clothing, cosmetics, and beekeeping equipment (NIOSH 1981).
 

Sources of exposure of the general population to ethylene oxide may
 

be the by-products of gasoline combustion and cigarette smoke. There is
 

also some evidence that some foods such as flour and spices retain
 

measurable ethylene oxide and by-products several months after
 

fumigation. Ethylene oxide exposure levels of the general population
 

via air, water, or foods have not been found in the available literature
 

or from national surveys and have not been estimated.
 

Occupational groups exposed to ethylene oxide include workers in
 

ethylene oxide manufacturing or processing plants, sterilization
 

technicians, workers involved in the fumigation of foods, clothing, and
 

cosmetics, and indoor fumigators. OSHA (1988b) estimates that 67,728
 

workers were exposed to ethylene oxide in 1988. OSHA and ACGIH have
 

established an 8-hour workshift exposure limit of 1 ppm (ACGIH 1986;
 

OSHA 1988b). However, NIOSH (1985b) recommends the exposure level to be
 

0.1 ppm or less over 8 hours, not to exceed 5 ppm for more than
 

10 minutes. The odor threshold of ethylene oxide in air is 430 ppm
 

(Amoore and Hautala 1983), which is well above the OSHA PEL (1 ppm).
 

Thus, worker exposure to ethylene oxide can be determined only through
 

routine air monitoring.
 

Hospital workers and patients may be exposed to residual levels of
 

ethylene oxide from the sterilization of hospital equipment. Some
 

sterilized plastics may retain concentrations of ethylene oxide ranging
 

from 3 to 443 mg/kg (ppm) even after seven days of aeration (WHO 1985).
 
64
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Other medical equipment such as adhesive dressings and cotton wool pads
 

may also retain ethylene oxide at 2 mg/kg (ppm) or less for 7 to 8 days
 

after sterilization (Dauvois et al. 1982).
 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
 

Technicians involved in routine disinfection of medical equipment
 

in hospitals may be exposed to relatively high levels of ethylene oxide.
 

Studies of worker exposures in five hospital sterilization rooms in the
 

United States indicate that the time-averaged exposures range from less
 

than 0.1 to 4.3 ppm, with peaks as high as 795 ppm (Hansen et al. 1984).
 

Brugnone et al. (1985) have reported alveolar concentrations of ethylene
 

oxide to be about 75% of the environmental concentrations of ethylene
 

oxide in a hospital sterilizing unit (0.1 to 7.8 ppm); the OSHA timeweightedaverage limit is 1 ppm and the 15-minute excursion limit is
 

5 mm. Occupational exposure levels estimated by OSHA (1988b) range
 

from 0.08 to 3.97 ppm (8-hour TWA) and 0.24 to 32.2 ppm (15-minute) (see
 

Table 7-l).
 

According to Flores (1983), workers in chemical manufacturing
 

plants in the United States may also be exposed to high levels of
 

ethylene oxide in air; typical average daily exposure levels ranging
 

from 0.2 to 2.2 ppm were measured during 1979. Some isolated incidents
 

of very high (peak) worker exposures have also occurred as a result of
 

plant breakdowns (Flores 1983; Thiess et al. 1981). It is expected that
 

occupational exposures will be reduced because of recent OSHA
 

regulations (OSHA 1988b).
 

5.7 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
 

consultation with the Administrator of EPA and agencies and programs of
 

the Public Health Service) to assess whether adequate information on the
 

health effects of ethylene oxide is available. Where adequate
 

information is not available, ATSDR, in conjunction with the NTP, is
 

required to assure the initiation of a program of research designed to
 

determine the health effects (and techniques for developing methods to
 

determine such health effects) of ethylene oxide.
 

The following categories of possible data needs have been
 

identified by a joint team of scientists from ATSDR, NTP, and EPA. They
 

are defined as substance-specific informational needs that, if met would
 

reduce or eliminate the uncertainties of human health assessment. In
 

the future, the identified data needs will be evaluated and prioritized,
 

and a substance-specific research agenda will be proposed.
 
65
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.7.1 Identification of Data Needs
 

Physical and Chemical Properties. Ethylene oxide is commonly used
 

in the synthesis of many other products, and its basic physical and
 

chemical properties are well known and documented (see Chapter 3).
 

However, data on the properties related to its fate in the environment
 

are less reliable or are totally lacking. For example, there are no
 

recent studies that verify the degradation rates of ethylene oxide in
 

air. Also, there is only one study, Conway et al. (1983), that provides
 

data on the rates of degradation and on water to air transfer of
 

ethylene oxide during the 1980s. There are no data on the fate and
 

transport of ethylene oxide in the soil environment. Since ethylene
 

oxide is a gas and a polar solute in water, these types of data are
 

particularly important for media with water-saturated or near saturated
 

conditions, such as landfills. Data on the rates of microbial
 

degradation and toxicity of ethylene oxide in soils are needed.
 

Production, Use, Release, and Disposal. Available production, use,
 

release, and disposal data indicate that most ethylene oxide
 

manufactured in the United states is consumed in the synthesis of other
 

chemicals. However, current quantitative data on the amounts of
 

ethylene oxide released to the environment during ethylene oxide
 

production and use are sparse. This information would be helpful in
 

evaluating the effect of industrial practices on environmental levels of
 

ethylene oxide.
 

According to the Emergency Planning and Community Right to Know Act
 

of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries
 

are required to submit release information to the EPA. The Toxics
 

Release Inventory (TRI), which contains release information for 1987,
 

became available in May of 1989. This database will be updated yearly
 

and should provide a more reliable estimate of industrial production and
 

emission.
 

Environmental Fate. Data on the fate of ethylene oxide in the
 

atmosphere are limited. The half-life estimates of this chemical should
 

be refined and include measurements in the stratosphere. Since ethylene
 

oxide has been shown to slowly react with oxygen, stratospheric
 

measurements should also include data on the potential impact of
 

ethylene oxide on the ozone layer. Data on the fate of ethylene oxide
 

in the water environment are available but are very limited. More
 

information is needed on the rates of transport of ethylene oxide
 

between water and air. Also, more data on the rates of biodegradation
 

of ethylene oxide in natural environments such as lakes, rivers,
 

groundwater, and soil are needed. Data on the fate of ethylene oxide in
 
66
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

the soil environment would be useful. Because all of the ethylene oxide
 

that does not degrade in the atmosphere eventually returns to the soil
 

and water, data on transport and degradation of ethylene oxide would be
 

helpful in determining its potential contamination of water supplies.
 

Bioavailability from Environmental Media. Ethylene oxide has been
 

shown to be absorbed following inhalation of contaminated air. However,
 

there are no data on absorption after oral or dermal administration of
 

this compound. No information was located on the bioavailability of
 

ethylene oxide from contaminated water, soil, or plant material. These
 

data would be useful in determining potential exposure levels for
 

organisms (humans, animals, and plants) that may have contact with
 

ethylene oxide in these media.
 

Food Chain Bioaccumulation. WHO (1985) has concluded that ethylene
 

oxide will not bioaccumulate in animals since it is readily metabolized
 

via hydrolysis and glutathione conjugation and excretion. This
 

conclusion was based on the review of several studies in both humans and
 

animals (terrestrial and marine species). No data are available in the
 

literature that indicate that ethylene oxide bioaccumulates in plants.
 

Research on the possible mechanisms of plant uptake, absorption and
 

assimilation of ethylene oxide would be useful since it may be a common
 

and natural constituent in the soil environment, as discussed in
 

Section 5.4.3, and because it is also an atmospheric pollutant.
 

Exposure Levels in Environmental Media. Neither environmental
 

monitoring nor background data are available for ethylene oxide in soil,
 

air, or water. Ambient concentrations of ethylene oxide are not known
 

in high density urban and industrial areas which have potentially large
 

sources of ethylene oxide such as car exhaust or point sources
 

(industrial). These data would be helpful in determining the ambient
 

concentrations of ethylene oxide so that exposure estimates can be made
 

for the general population.
 

Exposure Levels in Humans. Available data indicate that some work
 

environments provide continuous exposure to ethylene oxide at levels
 

that may exceed OSHA regulations. Data on other industrial workers such
 

as building and agricultural fumigators and construction workers would
 

be useful.
 

Estimates of the exposure levels of the general population would
 

also be helpful.
 

Exposure Registries. No exposure registries for ethylene oxide
 

were located. This compound is not currently one of the compounds for
 

which a subregistry has been established in the National Exposure
 

Registry. The compound will be considered in the future when chemical
 
67
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

selection is made for subregistries to be established. The information
 

that is amassed in the National Exposure Registry facilitates the
 

epidemiological research needed to assess adverse health outcomes that
 

may be related to the exposure to this compound.
 

5.7.2 On-going Studies
 

No on-going studies related to the potential for human exposure to
 

ethylene oxide were located in the available literature.
 

69
 

6. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods
 

that are available for detecting and/or measuring and monitoring
 

ethylene oxide in environmental media and in biological samples. The
 

intent is not to provide an exhaustive list of analytical methods that
 

could be used to detect and quantify ethylene oxide. Rather, the
 

intention is to identify well-established methods that are used as the
 

standard methods of analysis. Many of the analytical methods used to
 

detect ethylene oxide in environmental samples are the methods approved
 

by federal agencies such as EPA and the National Institute for
 

Occupational Safety and Health (NIOSH). Other methods presented in this
 

chapter are those that are approved by a trade association such as the
 

Association of Official Analytical Chemists (AOAC) and by the American
 

Public Health Association (APHA). Additionally, analytical methods are
 

included that refine previously used methods to obtain lower detection
 

limits, and/or to improve accuracy and precision.
 

6.1 BIOLOGICAL MATERIALS
 

Ethylene oxide is relatively reactive in biological systems and
 

undergoes chemisorption to biological materials to form addition
 

products with compounds that contain hydroxyl, phenolic, carbonyl,
 

amino, or sulfhydryl groups. Therefore, it is usually necessary in
 

biological samples to determine these addition products. Examples of
 

such products that are determined to measure in vivo exposure to
 

ethylene oxide are N-(2-hydroxyethyl)histidine and N­

(2-hydroxyethyl)valine (Bailey et al. 1987; Farmer et al. 1986).
 

Methods have been published for the determination of ethylene oxide in
 

blood and alveolar air (Brugnone et al. 1986).
 

As with other materials in biological samples, samples containing
 

ethylene oxide, its reaction products, and its metabolites must undergo
 

some form of sample cleanup prior to analysis. Cleanup is a separation
 

procedure that ideally isolates the analyte in a mixture, concentrates
 

it, and eliminates most of the sample matrix. The chemical and
 

biochemical reactivity of ethylene oxide complicates the cleanup of the
 

biological samples in which it is contained.
 

Methods for the determination of ethylene oxide and its reaction
 

products in biological samples are summarized in Table 6-l.
 

6.2 ENVIRONMENTAL SAMPLES
 

Ethylene oxide in environmental samples is most commonly determined
 

after derivatization to stable, volatile halogenated species,
 

particularly 2-bromoethanol (Cummins et al. 1987), followed by gas
 

chromatography with an electron capture detector (GC/ECD) for
 
70
 

6. ANALYTICAL METHODS
 

halogenated derivatives, or by gas chromatography/mass spectrometry
 

(GC/MS) (Farmer et al. 1986). Infrared spectrometry may also be used
 

(APHA 1985). A sensitive method for ethylene oxide determination has
 

been published in which the brominated compound is formed in a standard
 

solution of propylene oxide and the chromatographic peak ratios for the
 

brominated ethylene oxide and propylene oxide derivatives are compared
 

(Kikuchi et al. 1988).
 

The most straightforward means of determining ethylene oxide in air
 

is direct analysis of air samples without analyte collection. This has
 

been done with a portable gas chromatograph using clean air as a carrier
 

gas and a photoionization detector (PID) for detection (Bond and Dumas
 

1982; Collins and Barker 1983). Ethylene oxide can be concentrated from
 

air samples with a solid sorbent, desorbed with carbon disulfide, and
 

measured by gas chromatography (NIOSH 1977). A major problem with this
 

approach is the reaction of ethylene oxide with moisture or with
 

halides, resulting in loss of the analyte. However, this reaction
 

tendency can be used to advantage by derivatization of ethylene oxide to
 

2-bromoethanol on a collection column treated with hydrobromic acid,
 

followed by elution of the product with benzene/carbon disulfide and
 

measurement by GC/ECD. In the analysis of ethylene oxide in air by
 

direct GC/ECD determination of 2-bromoethanol formed by reaction of
 

ethylene oxide with HBr on HBr-coated charcoal, reproducibility problems
 

have been encountered as a consequence of interference by unreacted HBr
 

(Cummins et al. 1987). This interference has been overcome by forming a
 

derivative of 2-bromoethanol by reaction with heptafluorobutyrylimidazole
 

and measuring the product with GC/ECD (Cummins et al. 1987).
 

A method for the determination of ethylene oxide in water and in
 

soil by partition infrared spectrophotometry has been reported (APHA
 

1985; Environment Canada 1985).
 

Methods for the determination of ethylene oxide in environmental
 

samples are summarized in Table 6-2.
 

6.3 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
 

consultation with the Administrator of EPA and agencies and programs of
 

the Public Health Service) to assess whether adequate information on the
 

health effects of ethylene oxide is available. Where adequate
 

information is not available, ATSDR, in conjunction with the NTP, is
 

required to assure the initiation of a program of research designed to
 

determine the health effects (and techniques for developing methods to
 

determine such health effects) of ethylene oxide.
 


73
 

6. ANALYTICAL METHODS
 

The following categories of possible data needs have been
 

identified by a joint team of scientists from ATSDR, NTP, and EPA. They
 

are defined as substance-specific informational needs that, if met would
 

reduce or eliminate the uncertainties of human health assessment. In
 

the future, the identified data needs will be evaluated and prioritized,
 

and a substance-specific research agenda will be proposed.
 

6.3.1 Identification of Data Needs
 

Methods for Determining Biomarkers of Exposure and Effect.
 

Ethylene oxide is rapidly metabolized in biological systems and tends to
 

form addition products such as N-(2-hydroxyethyl)histidine and N­

(2-hydroxyethyl)valine. Although existing methodology is adequate to
 

provide qualitative evidence of exposure, it would be useful to have the
 

means to determine corresponding levels of exposure to ethylene oxide
 

from the levels of these substances in biological media.
 

There are currently no available methods that can be used to
 

associate the levels of ethylene oxide in biological media with the
 

onset of adverse health effects. Further information in this area would
 

be useful. It is not known if existing methods are sensitive enough to
 

measure background levels of these compounds in the blood, urine or
 

other biological media of the general population.
 

Supercritical fluid extraction coupled with supercritical fluid
 

chromatography and immunoassay analysis are two areas of intense current
 

activity from which substantial advances in the determination of
 

ethylene oxide metabolites in biological samples can be anticipated.
 

The two techniques are complementary in that supercritical fluid
 

extraction is especially promising for the removal of analytes from
 

sample materials and immunoassay analysis is very analyte selective and
 

sensitive (Vanderlaan 1988). This combination has been described for
 

the determination of sulfonylurea herbicides and their metabolites in
 

complex media including soil, plant materials, and a cell culture medium
 

(McNally and Wheeler 1988). This technique should be applicable to many
 

other toxicologically and environmentally significant analytes including
 

ethylene oxide metabolites.
 

Methods for Determining Parent Compounds and Degradation Products
 

in Environmental Media. Methods are available for the determination of
 

ethylene oxide in a clean, dry, gas-phase matrix. However, because of
 

ethylene oxide's reactivity, its determination in air, water and soil
 

matrices is difficult. The development of methods for analysis of
 

ethylene oxide that have improved sensitivity and selectivity would be
 

useful.
 
74
 

6. ANALYTICAL METHODS
 

There is an ongoing effort to develop a "Master Analytical Scheme" 

for organic compounds in water (Michael et al. 1988). The overall goal 

is the development of technology capable of detecting and measuring 

organic compounds present at levels of 0.1 μg/L in drinking water, 

1 μg/L in surface water, and 10 μg/L in effluent waters. In addition to 

volatile compounds (bp < 150° C), analytes are to include numerous 

semivolatile compounds and some compounds that are sparingly soluble in 

water. 

Determination of the degradation products of ethylene oxide in
 

environmental media is difficult, not because of analytical problems,
 

but because the fundamental environmental chemistry of these compounds
 

in water, soil, air, and biological systems is not known.
 

The development of analytical methods to measure ethylene oxide in
 

situ in water and other environmental media could contribute to
 

environmental studies of this compound.
 

6.3.2 On-going Studies
 

Studies designed to improve methods for the determination of
 

environmental contaminants may provide refinements and improvements in
 

the determination of ethylene oxide. The current high level of activity
 

in supercritical fluid extraction of solid and semisolid samples should
 

yield improved recoveries and sensitivities for the determination of
 

ethylene oxide and its environmental degradation products in solid
 

wastes, and these compounds should be amenable to supercritical fluid
 

chromatographic analysis. Immunoassay analysis (Vanderlaan 1988) is an
 

area of intense current activity from which substantial advances in the
 

determination of ethylene oxide in environmental samples can be
 

anticipated.
 
75
 

7. REGULATIONS AND ADVISORIES
 

Because of its potential to cause adverse health effects in exposed
 

persons, a number of regulations and advisories have been established
 

for ethylene oxide by various international, national, and state
 

agencies. These regulations and advisories are summarized in Table 7-l.
 



____________ 

79
 

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* Appelgren L, Eneroth G, Grant C. 1977. Studies on ethylene oxide:


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 Austin SB. 1987. Carcinogenicity of ethylene oxide. JAMA 258:1733.


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103
 

9. GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or
 

less, as specified in the Toxicological Profiles.
 

Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical
 

adsorbed per unit weight of organic carbon in the soil or sediment to
 

the concentration of the chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment
 

or soil (i.e., the solid phase) divided by the amount of chemical in the
 

solution phase, which is in equilibrium with the solid phase, at a fixed
 

solid/solution ratio. It is generally expressed in micrograms of
 

chemical sorbed per gram of soil or sediment.
 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a
 

chemical in aquatic organisms at a specific time or during a discrete
 

time period of exposure divided by the concentration in the surrounding
 

water at the same time or during the same time period.
 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
 

group of studies which produces significant increases in incidence of
 

cancer (or tumors) between the exposed population and its appropriate
 

control.
 

Carcinogen -- A chemical capable of inducing cancer.
 

Ceiling value (CL) -- A concentration of a substance that should not be
 

exceeded, even instantaneously.
 

Chronic Exposure -- Exposure to a chemical for 365 days or more, as
 

specified in the Toxicological Profiles.
 

Developmental Toxicity -- The occurrence of adverse effects on the
 

developing organism that may result from exposure to a chemical prior to
 

conception (either parent), during prenatal development, or postnatally
 

to the time of sexual maturation. Adverse developmental effects may be
 

detected at any point in the life span of the organism.
 
104
 

9. GLOSSARY
 

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as
 

a result of prenatal exposure to a chemical; the distinguishing feature
 

between the two terms is the stage of development during which the
 

insult occurred. The terms, as used here, include malformations and
 

variations, altered growth, and in utero death.
 

EPA Health Advisory -- An estimate of acceptable drinking water levels
 

for a chemical substance based on health effects information. A health
 

advisory is not a legally enforceable federal standard, but serves as
 

technical guidance to assist federal, state, and local officials.
 

Immediately Dangerous to Life or Health (IDLH) -- The maximum
 

environmental concentration of a contaminant from which one could escape
 

within 30 min without any escape-impairing symptoms or irreversible
 

health effects.
 

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
 

days, as specified in the Toxicological Profiles.
 

Immunologic Toxicity -- The occurrence of adverse effects on the immune
 

system that may result from exposure to environmental agents such as
 

chemicals.
 

In Vitro -- Isolated from the living organism and artificially
 

maintained, as in a test tube.
 

In Vivo -- Occurring within the living organism.
 

Lethal Concentration(LO) (LCLO) -- The lowest concentration of a chemical
 

in air which has been reported to have caused death in humans or
 

animals.
 

Lethal Concentration(50) (LC50) -- A calculated concentration of a
 

chemical in air to which exposure for a specific length of time is
 

expected to cause death in 50% of a defined experimental animal
 

population.
 

Lethal Dose (LO) (LDLO) -- The lowest dose of a chemical introduced by a
 

route other than inhalation that is expected to have caused death in
 

humans or animals.
 

Lethal Dose(50) (LD50) -- The dose of a chemical which has been
 

calculated to cause death in 50% of a defined experimental animal
 

population.
 
105
 

9. GLOSSARY
 

Lethal Time(50) (LT50) -- A calculated period of time within which a
 

specific concentration of a chemical is expected to cause death in 50%
 

of a defined experimental animal population.
 

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of
 

chemical in a study or group of studies which produces statistically or
 

biologically significant increases in frequency or severity of adverse
 

effects between the exposed population and its appropriate control.
 

Malformations -- Permanent structural changes that may adversely affect
 

survival, development, or function.
 

Minimal Risk Level (MRL) -- An estimate of daily human exposure to a
 

chemical that is likely to be without an appreciable risk of deleterious
 

effects (noncancerous) over a specified duration of exposure.
 

Mutagen -- A substance that causes mutations. A mutation is a change in
 

the genetic material in a body cell. Mutations can lead to birth
 

defects, miscarriages, or cancer.
 

Neurotoxicity -- The occurrence of adverse effects on the nervous system
 

following exposure to a chemical.
 

No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
 

which there are no statistically or biologically significant increases
 

in frequency or severity of adverse effects seen between the exposed
 

population and its appropriate control. Effects may be produced at this
 

dose, but they are not considered to be adverse.
 

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of
 

the concentrations of a chemical in n-octanol and water, in dilute
 

solution.
 

Permissible Exposure Limit (PEL) -- An allowable exposure level in
 

workplace air averaged over an 8-hour shift.
 

q1* -- The upper-bound estimate of the low-dose slope of the dose response
 

curve as determined by the multistage procedure. The q1* can
 

be used to calculate an estimate of carcinogenic potency, the
 

incremental excess cancer risk per unit of exposure (usually μg/L for
 

water, mg/kg/day for food, and μg/m3

 for air).
 
106
 

9. GLOSSARY
 

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps
 

an order of magnitude) of the daily exposure of the human population to
 

a potential hazard that is likely to be without risk of deleterious
 

effects during a lifetime. The RfD is operationally derived from the
 

NOAEL (from animal and human studies) by a consistent application of
 

uncertainty factors that reflect various types of data used to estimate
 

RfDs and an additional modifying factor, which is based on a
 

professional judgment of the entire database on the chemical. The RfDs
 

are not applicable to nonthreshold effects such as cancer.
 

Reportable Quantity (RQ) -- The quantity of a hazardous substance that
 

is considered reportable under CERCLA. Reportable quantities are: (1) 1
 

lb or greater or (2) for selected substances, an amount established by
 

regulation either under CERCLA or under Sect. 311 of the Clean Water
 

Act. Quantities are measured over a 24-hour period.
 

Reproductive Toxicity -- The occurrence of adverse effects on the
 

reproductive system that may result from exposure to a chemical. The
 

toxicity may be directed to the reproductive organs and/or the related
 

endocrine system. The manifestation of such toxicity may be noted as
 

alterations in sexual behavior, fertility, pregnancy outcomes, or
 

modifications in other functions that are dependent on the integrity of
 

this system.
 

Short-Term Exposure Limit (STEL) -- The maximum concentration to which
 

workers can be exposed for up to 15 min continually. No more than four
 

excursions are allowed per day, and there must be at least 60 min
 

between exposure periods. The daily TLV-TWA may not be exceeded.
 

Target Organ Toxicity -- This term covers a broad range of adverse
 

effects on target organs or physiological systems (e.g., renal,
 

cardiovascular) extending from those arising through a single limited
 

exposure to those assumed over a lifetime of exposure to a chemical.
 

Teratogen -- A chemical that causes structural defects that affect the
 

development of an organism.
 

Threshold Limit Value (TLV) -- A concentration of a substance to which
 

most workers can be exposed without adverse effect. The TLV may be
 

expressed as a TWA, as a STEL, or as a CL.
 

Time-weighted Average (TWA) -- An allowable exposure concentration
 

averaged over a normal 8-hour workday or 40-hour workweek.
 

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a
 

route other than inhalation, which is expected to cause a specific toxic
 

effect in 50% of a defined experimental animal population.
 
107
 

9. GLOSSARY
 

Uncertainty Factor (UF) -- A factor used in operationally deriving the
 

RfD from experimental data. UFs are intended to account for (1) the
 

variation in sensitivity among the members of the human population, (2)
 

the uncertainty in extrapolating animal data to the case of humans, (3)
 

the uncertainty in extrapolating from data obtained in a study that is
 

of less than lifetime exposure, and (4) the uncertainty in using LOAEL
 

data rather than NOAEL data. Usually each of these factors is set equal
 

to 10.
 

109
 

APPENDIX
 

APPENDIX
 

PEER REVIEW
 

A peer review panel was assembled for ethylene oxide. The panel
 

consisted of the following members: DK. Martin Alexander, Professor,
 

Department of Agronomy, Cornell University; Dr. Richard Thomas,
 

Consulting Toxicologist, Thomas and Thomas Technologies, Inc.; and
 

Dr. Mohammed Mustafa, School of Public Health, University of California.
 

These experts collectively have knowledge of ethylene oxide's physical
 

and chemical properties, toxicokinetics, key health end points,
 

mechanisms of action, human and animal exposure, and quantification of
 

risk to humans. All reviewers were selected in conformity with the
 

conditions for peer review specified in the Superfund Amendments and
 

Reauthorization Act of 1986, Section 110.
 

A joint panel of scientists from ATSDR and EPA has reviewed the
 

peer reviewers' comments and determined which comments will be included
 

in the profile. A listing of the peer reviewers' comments not
 

incorporated in the profile, with a brief explanation of the rationale
 

for their exclusion, exists as part of the administrative record for
 

this compound. A list of databases reviewed and a list of unpublished
 

documents cited are also included in the administrative record.
 

The citation of the peer review panel should not be understood to
 

imply their approval of the profile's final content. The responsibility
 

for the content of this profile lies with the Agency for Toxic
 

Substances and Disease Registry.