Toxicological
Profile
for
ETHYLENE OXIDE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-16
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TOXICOLOGICAL PROFILE FOR
ETHYLENE OXIDE
Prepared by:
Life Systems, Inc.
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990
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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.
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FOREWORD
The Superfund Amendments and Reauthorization Act (SARA) of 1986
(Public Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law directed the Agency for Toxic Substances and Disease
Registry (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 ReEister 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.
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iv
Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the public health statement is
information concerning significant health effects associated with exposure
to the substance. The adequacy of information to determine a substance's
health effects is described. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program (NTP) of the Public Health Service, and EPA. The focus
of the profiles is on health and toxicological information; therefore, we
have included this information in the beginning of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed
by scientists from ATSDR, the Centers for Disease Control, the NTP, and
other federal agencies. It-has also been reviewed by a panel of
nongovernment peer reviewers and is being made available for public
review. Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR.
Wi i.
Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS ETHYLENE OXIDE? 1
1.2 HOW MIGHT I BE EXPOSED TO ETHYLENE OXIDE? 2
1.3 HOW CAN ETHYLENE OXIDE ENTER AND LEAVE MY BODY? 2
1.4 HOW CAN ETHYLENE OXIDE AFFECT MY HEALTH? 3
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE
BEEN EXPOSED TO ETHYLENE OXIDE? 8
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? 8
1.8 WHERE CAN I GET MORE INFORMATION? 9
2. HEALTH EFFECTS 11
2.1 INTRODUCTION 11
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 11
2.2.1 Inhalation Exposure 12
2.2.1.1 Death 12
2.2.1.2 Systemic Effects 13
2.2.1.3 Immunological Effects 22
2.2.1.4 Neurological Effects 22
2.2.1.5 Developmental Effects 24
2.2.1.6 Reproductive Effects 24
2.2.1.7 Genotoxic Effects 25
2.2.1.8 Cancer 26
2.2.2 Oral Exposure 27
2.2.2.1 Death 27
2.2.2.2 Systemic Effects 27
2.2.2.3 Immunological Effects 30
2.2.2.4 Neurological Effects 30
2.2.2.5 Developmental Effects 30
2.2.2.6 Reproductive Effects 30
2.2.2.7 Genotoxic Effects 30
2.2.2.8 Cancer 30
2.2.3 Dermal Exposure 31
2.2.3.1 Death 31
2.2.3.2 Systemic Effects 31
2.2.3.3 Immunological Effects 32
2.2.3.4 Neurological Effects 32
2.2.3.5 Developmental Effects 32
2.2.3.6 Reproductive Effects 33
2.2.3.7 Genotoxic Effects 33
2.2.3.8 Cancer 33
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2.3 TOXICOKINETICS 33
2.3.1 Absorption 33
2.3.1.1 Inhalation Exposure 33
2.3.1.2 Oral Exposure 33
2.3.1.3 Dermal Exposure 33
2.3.2 Distribution 33
2.3.2.1 Inhalation Exposure 33
2.3.2.2 Oral Exposure 34
2.3.2.3 Dermal Exposure 34
2.3.3 Metabolism 34
2.3.4 Excretion 35
2.3.4.1 Inhalation Exposure 35
2.3.4.2 Oral Exposure 36
2.3.4.3 Dermal Exposure 35
2.4 RELEVANCE TO PUBLIC HEALTH ' " 35
2.5 BIOMARKERS OF EXPOSURE AND EFFECT 42
2.5.1 Biomarkers Used to Identify or Quantify Exposure to
Ethylene Oxide 43
2.5.2 Biomarkers Used to Characterize Effects Caused by
Ethylene Oxide 43
2.6 INTERACTIONS WITH OTHER CHEMICALS ' * ' 43
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ' 43
2.8 ADEQUACY OF THE DATABASE ' , | 43
2.8.1 Existing Information on the Health Effects of
Ethylene Oxide 44
2.8.2 Identification of Data Needs 44
2.8.3 On-going Studies 49
3. CHEMICAL AND PHYSICAL INFORMATION 51
3.1 CHEMICAL IDENTITY 51
3.2 PHYSICAL AND CHEMICAL PROPERTIES 51
4. PRODUCTION, IMPORT, USE AND DISPOSAL 55
4.1 PRODUCTION | ^ ^ 55
4.2 IMPORT ' 55
4.3 USE 55
4.4 DISPOSAL ' * 56
5. POTENTIAL FOR HUMAN EXPOSURE 57
5.1 OVERVIEW 57
5.2 RELEASES INTO THE ENVIRONMENT 57
5.2.1 Air 'I 57
5.2.2 Water 53
5.2.3 Soil ' 59
5.2.4 Other Sources 59
5.3 ENVIRONMENTAL FATE 59
5.3.1 Transport and Partitioning 59
5.3.2 Transformation and Degradation 60
5.3.2.1 Air * 60
5.3.2.2 Water 61
5.3.2.3 Soil 6l
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 61
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5.4.1 Air 61
5.4.2 Water 62
5.4.3 Soil 62
5.4.4 Other Media 62
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 63
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 64
5.7 ADEQUACY OF THE DATABASE 64
5.7.1 Identification of Data Needs 65
5.7.2 On-going Studies 67
6. ANALYTICAL METHODS 69
6.1 BIOLOGICAL MATERIALS 69
6.2 ENVIRONMENTAL SAMPLES 69
6.3 ADEQUACY OF THE DATABASE 70
6.3.1 Identification of Data Needs 73
6.3.2 On-going Studies 74
7. REGULATIONS AND ADVISORIES 75
8. REFERENCES 79
9. GLOSSARY 103
APPENDIX 109
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LIST OF FIGURES
2-1 Levels of Significant Exposure to Ethylene Oxide - Inhalation ... 18
2-2 Levels of Significant Exposure to Ethylene Oxide - Oral 29
2-3 Existing Information on the Health Effects of Ethylene Oxide ... 45
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LIST OF TABLES
1-1 Human Health Effects from Breathing Ethylene Oxide 4
1-2 Animal Health Effects from Breathing Ethylene Oxide 5
1-3 Human Health Effects from Eating or Drinking Ethylene Oxide .... 6
1-4 Animal Health Effects from Eating or Drinking Ethylene Oxide .... 7
2-1 Levels of Significant Exposure to Ethylene Oxide - Inhalation ... 14
2-2 Levels of Significant Exposure to Ethylene Oxide - Oral 28
2-3 Genotoxicity of Ethylene Oxide In Vitro 41
3-1 Chemical Identity of Ethylene Oxide 52
3-2 Physical and Chemical Properties of Ethylene Oxide 53
6-1 Analytical Methods for Determining Ethylene Oxide in Biological
Materials 71
6-2 Analytical Methods for Determining Ethylene Oxide in
Environmental Media 72
7-1 Regulations and Guidelines Applicable to Ethylene Oxide 76
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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 ETO 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
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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 ic 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 whore 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 ppra) 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
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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 1-1. This MRL
was derived from animal data for long-term exposure, as described in
Chapter 2 and in Table 2-1. 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
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing Ethylene Oxide*
Short-term Exposure
(less than or equal to 14 days)
Levels in Air
Leneth of Exposure
Description of Effects
The health effects result-
ing from short-term
exposure of humans to
air containing specific
levels of ethylene
oxide are not known.
Long-term Exposure
(greater than 14 days)
Levels in Air (ppnO
Length of Exposure
Description of Effects"
0.09
14 weeks
Minimum risk level (MRL)
for intermediate
exposure to ethylene
oxide. Based on a study
i n in ice .
3-430
5-20 years
Problems with hand/eye
coordinat ion.
10-400
2 years
Eye and nose irritation.
700
2. months
Seizures, cataracts.
*See Section 1.2 for a discussion of exposures encountered in daily life
**These effects are listed at the lowest level at: which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Ethylene Oxide
Short-term Exposure
(less than or equal to 14
days)
Levels in Air
(ppm)
Length of Exposure
DescriDtion of Effects*
100
10 days of
pregnancy
Decreased litter size
and smaller newborn
rats.
800
4 days
Death in mice.
Long-term Exposure
(greater than 14 days)
Levels in Air
(ppm)
Length of Exposure
Description of Effects*
50
10-11 weeks
Decreased physical
activity in mice.
100
200
14 weeks
14 weeks
Kidney damage in mice.
Nasal inflammation in
mice.
400
14 weeks
Death in mice.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking Ethylene Oxide*
Short-term Exposure
(less than or equal to 14 days)
I.p.vels in Food
Length of Exposure
t oirol g in Water
Description of Effects
The health effects result-
ing from short-term
exposure of humans to
food containing specific
levels of ethylene oxide
are not known.
The health effects result-
ing from short-term
exposure of humans to
water containing
specific levels of
ethylene oxide are not
known.
Long-term Exposure
(greater than 14 days)
Levels in Food
Length of Exposure
Description of Effects
T.ftvels in Water
The health effects result-
ing from long-terra
exposure of humans to
food containing specific
levels of ethylene oxide
are not known.
The. health effects result
ing from long-term
exposure of humans to
water containing
specific levels of
ethylene oxide are not
known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking Ethylene Oxide
Short-term Exposure
(less than or equal to 14 days)
Levels in Food fppnO
Length of Exposure
Description of Effects*
4,000
1 day
Death in rats.
Levels in Water
The health effects result-
ing from short-term
exposure of animals to
water containing
specific levels of
ethylene oxide are not
known.
Long-term Exposure
(greater than 14 days)
Levels in Food
Length of Exposure
Description of Effects
2,000
21-30 days
Liver damage and stomach
irritation in rats.
Levels in Water
The health effects result-
ing from long-term
exposure of animals to
water containing
specific levels of
ethylene oxide are not
known.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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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.
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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.
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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.
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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 10~7)j 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 2-1 and plotted in Figure 2-1-
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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 2-1 and plotted in Figure 2~1.
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,
-------
TABIJK 2-1. Levels of Significant Exposure to Ethylene - Inhalation
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Keya Species Duration Effect (ppm) (ppm) (ppm) Reference
ACUTE EXPOSURE
Death
1 Mouse
Developmental
2 Rat
Reproductive
3 Rat
INTERMEDIATE EXPOSURE
Death
4 Mouse
Systemic
5 Mouse
6 Mouse
7 Mouse
4 hr
12 vk
GdO-19
6hr/d
12 wk +
GdO-19
6hr/d
14 vk
5d/wk
6hr/d
10-11 vk Hepatic
5d/vk Hemato
6hr/d
14 vk
5d/vk
6hr/d
14 vk
5d/vk
6hr/d
Resp
Renal
400
33
33
200
250
100 250 (decreased
RfiCs, Hb)
100 200b (nasal
inflammation)
50° 100b (tubular
degeneration)
800b (80-100X death) NTP 1987
100^ (decreased fetal
weight)
Snelllngs et al.
1982a
100® (decreased fetal Snelllngs et al.
implants)
1982b
400 (100X mortality) NTP 1987
400 (necrosis)
Snellings et al.
1984a
NTP 1987
600 (tubular necrosis) NTP 1987
as
pi
>
r
H
se
P3
T!
PI
O
H
W
-------
TABLE 2-1 (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key" Species Duration Effect Cppm) c ppra) (ppm) Reference
Immunological
8 Mouse
U vk
5d/wk
6hr/d
100 200 (hypoplasia)
600 (thymic lymph,
necros is)
NTP 1987
Neurological
9 Mouse
Developmental
10 Rabbit
Reproductive
11 Rat
CHRONIC EXPOSURE
Death
12 Human
13
14
Mouse
Monkey
10-11 wk
5d/vk
6hr/d
13-19 d
7hr/d
16-37 d
7hr/d
5+ yr
5d/wk
8hr/d
2 yr
5d/wk
6hr/d
24 mo
5d/vk
7hr/d
10 50 (decreased
locomotor
activity)
150
150 (increased
resorption)
100
100
Snellings et al.
1984 a
Hardin et al.
1983
Hardin et al.
1983
Morgan et al.
1981
NTP 1987
Lynch et al.
1984a
a
>
5
a
n
o
H
w
-------
Exposure
Figure Frequency/
Key* Species Duration Effect
NOAEL
(ppm)
Systemic
15 Human
16
Human
11 yr
5d/vk
8hr/d
2 yr
Renal
Resp
10
17
Human
2 yr
Hemato
10
18
19
20
21
Human
Mouse
Monkey
Monkey
Neurological
22 Human
23
Human
11 yr
5d/vk
8hr/d
2 yr
5d/vk
6hr/d
2 A mo
5d/vk
7hr/d
2 A mo
5d/vk
7hr/d
5-20 yr
5d/vk
8hr/d
2 yr
Hepatic
Renal
Cardio
Hemato
10
100
100
100
24
Monkey
24 mo
5d/vk
7hr I d
50
TABLE 2-1 (Continued)
LOAEL (Effect)
Less Serious Serious
(ppm) (ppm) Reference
Joyner 1964
10^ (nasal irritation) ZampoLlo et al.
1984
ro
SC
M
>
r
H H-1
X On
pa
pi
n
H
LO
Lynch et al.
1984a
Zaxnpollo et al.
1984
Joyner 1964
NTP 1987
Lynch et al.
1984a
3^ (hand/eye Estrin et al.
coordination) 1987
10 (peripheral Zampollo et al.
neuropathy) 1984
100 (slight
demyelination)
Lynch et al
1984a
-------
TABLE 2-1 (Continued)
Figure
Keya
Species
Exposure
Frequency/ NOAEL
Duration Effect (ppm)
LOAEL (Effect)
Less Serious
(ppm)
Serious
(ppm)
Reference
Reproduct ive
25 Monkey
24 rao
5d/wk
7hr/d
50 (decreased sperm
counts and
motility)
Lynch et al.
1984a
Cancer
26 Rat
27
28
Rat
Mouse
2 yr
5d/wk
7hr/d
24 mo
5d/vk
6hr/d
2 yr
5d/wk
6hr/d
50 CEL (peritoneal Lynch et al.
mesothelioma, 1984b
MNCL)
100 CEL (brain)
33 CEL (brain, MNCL, Snellings et al.
mesothelioma) 1984b
50 CEL (hard, gland,
lung)
50 CEL (F:mammary)
100 CEL (F:lymphoma,
uterine gland)
NTP 1987
SC
£
5
X
m
m
o
H
w
aThe number corresponds to entries in Figure 2-1.
^Presented in Table 1-2,
°Used to derive the intermediate inhalation MRL; dose adjusted for Intermittent exposure and divided by an uncertainty factor of
100 (10 for extrapolation from animals to humans, and 10 for human variability), resulting in an MRL of 0.09 ppm. This MRL
has been presented in Table 1-1.
^Presented in Table 1-1.
LOAEL a* lowest-observed-adverse effect levelt NOAEL * no-observed-adverse effect level; hr = hour; Gd = gestational day;
d = day; vk « week; mo * months RBC ¦ red blood cells; Hb * hemoglobin; Hemata » hematological} lymph « lymphocyte;
Resp * respiratory; yr * year; Cardio = cardivascular; CEL * cancer effect level; F = females; MNCL *= mononuclear cell leukemia
-------
ACUTE
($14 Days)
INTERMEDIATE
(15-364 Days)
/ /
(ppm)
1,000
100
10
* /
.////
^ «/ /C / ,
/./ /J
#lm
Olm
0.1
0.01 L
#7m #Bm
#4m #6m
04m 36m ®5"' °5m 38m
•2t «3r
02r 03r
06m Osm
37m 08m
07m 39m
O9">
OlOh #11r
Key
r Rat
• LOAEL for serious effects (animals)
m Mouse
3 LOAEL for less serious effects (animals)
h Rabbit
O NOAEL (animals)
k Monkey
; Minimal risk level 1or
The number next to each point corresponds to i effects other than cancer
entries in Table 2-1
FIGURE 2-1. Levels of Significant Exposure to Ethylene Oxide - Inhalation
-------
CHRONIC
fe365 Days)
/
(ppm)
1,000
100
/
/ .
/ ci>"
^ -V
nV
/
/
&>
/
/ /
l«kOl3m
O20k
021k
Ol9f
324k
O 24k
~ 28m ~ 26r
(25k ^ 28m +26r
~ 27r
Al6
Al7
Aib Al5
A 23
&Z2
£
5
sc
PJ
T!
PI
n
H
!*)
Key
r Rat
m Mouse
h Rabbit
k Monkey
The number next to each point corresponds to entries in Table 2-1
• LOAEL for serious effects (animals) A LOAEL for less serious effects (humans)
3 LOAEL for less serious effects (animals) A NOAEL (humans)
O NOAEL (animals) ~ CEL-Cancer Effect Level
FIGURE 2-1 (Continued)
-------
20
2. HEALTH EFFECTS
monkeys (Lynch et al. 1984a) and mice (NTP 1987) have reported that
chronic exposures 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 humans
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 seven-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 2-1. 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 N0AEL values and all
reliable LOAEL values for renal effects in each species and duration
category are presented in Table 2-1 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 v°roiting 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 10-11 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 2-1 and plotted in Figure 2-1.
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 2-1 and plotted in Figure 2-1.
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 "C-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 N0AEL 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 2-1 and plotted in Figure 2-1.
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 1 (mg/kg/day)'1 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 B1 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.
-------
TABLE 2-2. Levels of Significant: Exposure to Ethylene Oxide - Oral
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Keya Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference
ACUTE EXPOSURE
Death
1 Rat
(G) 1 d
100
200b (all died)
Hollingsvorth
et al. 1956
INTERMEDIATE EXPOSURE
Systemic
2 Rat
3 Rat
CHRONIC EXPOSURE
Death
4 Rat
(G) 21-30 d
5d/vk
(G)
21-30 d
5d/vk
(G) 150 vk
2d/vk
Gastro 30 100c (gastric
irritation)
Hepatic 30 100c (slight damage)
7.5
Hollingsvorth
et al. 1956
Hollingsvorth
et al. 1956
30 (earlier death) Dunkelberg 1982
NJ
r
H
2C
PJ
W
o
H
CO
ho
00
Cancer
5 Rat
(G)
150 vk
2d/vk
7.5 CEL (forestomach) Dunkelberg 1982
*The number corresponds to entries in Figure 2-2.
^Converted to 4,000 ppm in food for presentation in Table 1-4.
cConverted to 2,000 ppo in food for presentation in Table 1-4.
LOAEL " lovest-observed-adverse effect level; NOAEL - no-observed-adverse-effect level: d - day; (G) - gavage; vk « week;
Gastro ™ gastrointestinal; CEL « cancer effect level.
-------
ACUTE INTERMEDIATE CHRONIC
($14 Days) (15-364 Days) (;>365 Days)
(mg/kg/day)
1,000 r
/
cf ~
J?
c/
Mr
100
Olr
®2r 33r
02r Q3r
10
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m
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r
H
EC
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~n
pi
o
H
W
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V£>
Key
r Rat
The number next
to each point
corresponds to
entries in Table 2-2
• LOAEL for serious effects (animals)
3 LOAEL for less serious effects (animals)
O NOAEL (animals)
~ CEL-Cancer Effect Level (animals)
FIGURE 2-2. Levels of Significant Exposure to Ethylene Oxide - Oral
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30
2. HEALTH EFFECTS
These values have been presented in Table 2-2 and plotted
Figure 2-2.
Hematological Effects. No studies were located regaling
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 fQr ora]^
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.
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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 rag/kg/day by gavage for 2 days/week for 3 years developed a dose-
related 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).
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32
2. HEALTH EFFECTS
Shupack et al. (1981) demonstrated that human skin factions to
ethylene oxide in patch materials were directly related to the total
dose.
CorneaL 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 corneal 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, corneal 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 with
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
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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.
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34
2. HEALTH EFFECTS
Tyler and McKelvey (1982) found that in rats administered
^C-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 uC-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 intra-
venous 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.
Tardif 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
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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
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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 1*C-ethylene oxide elimination was urine (mean value of 59% recovered
uC-activity), followed by expired C02 (12%), feces (4.5%), and expired
ethylene oxide (1%). Cumraing 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 UC-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.
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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
hujnans 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). Corneal 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).
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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 10-11 weeks resulted in hunched posture, reduced locomotion,
and abnormal righting reflexes in mice (Snellings et al. 1984a). A
9-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 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
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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 epididyrnal 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.
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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 mamniary 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 °f the forestomach (the site of application) only, but
not at any distal sites (Dunkelberg 1982). Ethylene oxide is ranked as
a Group B1 carcinogen (i.e., a probable human carcinogen) by EPA's
-------
TABLE 2-3, Genotoxicity of Ethylene Oxide In Vitro
Results
End Point
Species (Test System)
With
Activation
Without
Activation
Reference
Prokaryotic organisms:
Gene mutation
Salmonella typhimurlum
TA1535
S. typhimurlum
TA98
TAX 00
TA1S35
TA1537
Rannug et al. 1976
Pfeiffer and
Dunkelberg 1980
Eukaryotic organisms:
Plant:
Gene mutation
Insects:
Gene mutation
Matnnalian cells:
Gene mutation
Bacillus subtllis
HA101
TRJ 5211
TKJ 8201
Neurospora crassa
Schlzosaccharomvces pombe
Barley
Rice
Drosophila melanonaster
sex-linked recessive lethal
D. melanoRaster-sfex-llhked
recessive lethal and
heritable translocation
D. melanoaaster-sex-1inked
recessive lethal and gonadal
L5178Y TK
Mouse lymphoma
gene mutation assay
CEO-K1-BHA
Chinese hamster ovary
cell gene mutation assay
Tanooka 1979
Kolmark and
Kilbey 1968
Migliore et al- 1982
Ehrenberg et al. 1956
Jana and Roy 1975
Bird 1952
Watson 1966
Lee 1980
Brown et al. 1979
Tan et al. 1981
£
ac
w
•n
pi
o
H
+ « positive result: ND = no data; - = negative result; ( + ) ¦= positive or marginal result.
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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
copper, 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 physiology signs of dysfunction such as increased
blood pressure or decreased lung capacity. Note that these markers are
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A3
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
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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
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45
2. HEALTH EFFECTS
SYSTEMIC
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
FIGURE 2-3. Existing Information on Health Effects of Ethylene Oxide
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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
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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 ppra 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.
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2. HEALTH EFFECTS
Biomarkers of Exposure and Effect. Measurement of ethylene oxide
or its addition products, N-(2-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.
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2. HEALTH EFFECTS
2.8.3 On-going Studies
The NTP Annual Plan for FY 1988 (NTP 1988a) indicated that ethylene
ox4de 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
(CUT), 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.
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3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Tables 3-1 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.
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3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Ethylene Oxide
Value
Reference
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO
Shipping
HSDB
NCI
Ethylene oxide
Oxirane; dihydro-
oxirene; dimethylene
oxide; epoxyethane;
ethene oxide; ETO
Anprolene
Oxyfume; T-Gas
C2H«0
H H
I I
H-C-C-H
\ I
O
75-21-8
KX2450000
U115
7216724
UN 1040
IMCO. 2.3
170
C50088
NLM 1988
NLM 1988
NLM 1988
NLM 1988
NLM 1988
HSDB 1988
NLM 1988
HSDB 1988
NLM 1988
HSDB 1938
NLM 1988
NLM 1988
CAS - Chemical Abstracts Service; NIOSH - National Institute for
Occupational Safety and Health; RTECS - Registry of Toxic Effects of
Chemical Substances; EPA - Environmental Protection Agency; OHM/TADS -
Oil and Hazardous Materials/Technical Assistance Data System;
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North
America/International Maritime Dangerous Goods Code; HSDB - Hazardous
Substances Data Bank; NCI - National Cancer Institute.
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3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Ethylene Oxide
Property
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 10°C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 20°C
Organic solvents
Partition coefficients;
Log octanol/water
Log Koc
Vapor Pressure at 20°C
Henry's law constant
Autoignition temperature
Flashpoint
Flaramability limits
Conversion factors
44.05
Colorless
Gas
-111°C
11°C
0.8824
Sweet, olefinic
140 mg/L
787 mg/m3
1 x 106 mg/L
Soluble in alcohol,
ether, acetone,
benzene
-0.22
0.342
1.095 x 103 mmHg
7.56 x 10~5 atm-m3/mol
429°C
<-18°C
No data
1 ppm - 1.83 mg/m3
1 mg/m3 — 0.55 ppm
Weast 1985
Verschueren 1983
Verschueren 1983
Weast 1985
Verschueren 1983
Weast 1985
Verschueren 1983
Amoore and
Hautala 1983
Amoore and
Hautala 1983
PHRED 1988
Weast 1985
PHRED 1988
PHRED 1988
Verschueren 1983
PHRED 1988
HSDB 1988
HSDB 1988
Verschueren 1983
Verschueren 1983
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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 (1%), 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; NI0SH 1981; SRC 1982; SRI 1984; WHO 1985).
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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).
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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
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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 Mg/L and a
groundwater site with 21 A«g/L (mean of two samples) (CLPSD 1988) .
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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 jxg/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 (Km)
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.
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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 (1984b) 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 7-1).
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 UV light. Studies by Goner 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 UV-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 10"16 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-UV 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
UV 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.
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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 103 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
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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 |ig/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.
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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) .
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64
5. POTENTIAL FOR HUMAN EXPOSURE
Other medical equipment such as adhesive dressings and cotton wool pads
may also retain ethylene oxide at 2 xng/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 tiine-
weighted-average limit is 1 ppm and the 15-minute excursion limit is
5 ppm. 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 -1).
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.
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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
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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
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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.
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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 6-1.
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
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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 heptafluorobutyryl-
imidazole 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.
-------
TABLE 6-1. Analytical Methods for Determining Ethylene Oxide in Biological Materials
Sample
Detection
Sample Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Blood
No data
GC
No data
No data
Brugnone
et al. 1986
Alveolar air
No data
GC
No data
No data
Brugnone
et al. 1986
Hemoglobin
adducts from
blood
Hemoglobin
Separation of erythrocytes, GC/MS
derivatization of N-(2-hydroxy
ethyl)histidine or
N- (2-hydroxy ethyl) val ine
Separation of erythrocytes, HRGC/MS
derivatization of N-(2-hydroxy-
ethyl)histidine
2 ng/mL
No data
No data
No Data
Farmer
et al. 1986
Bailey
et al. 1987
GC * gas chromatography; MS « mass spectrometry; HRGC * High Resolution Gas Chromatography.
>
5
H
M -J
O (-•
>
r
K
PI
H
ac
o
o
-------
TABLE 6-2. Analytical Methods for Determining Etbflene Oxide In Environment:a 1 Samples
Sample
Detection
Sample Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Air
Direct injection of air sample GC/FID
<1 ppb by
volume
No data
Bond and Dumas
1982
Air
Direct injection of air sample GC/FID
No data
No data
Collins and
Barker 1983
Air
Collect on HBr-coated charcoal
tube forming 2-bromoethanol,
desorb with dimethylf ormamide to
produce volatile derivative
GC/ECD
0.1 ppm
(volume)
97X Rec.
of 2 ppm
Cummins
et al. 1987
Air
Collect on charcoal, desorb
with carbon disulfide
GC
No data
No data NIOSH 1977
Air
Soil
Water
Derivatize to 2-bromoethanol
No data
No data
GC/ECD
Partition
infrared
Partition
infrared
0.45 /igI
sample
>40 ppm
40-400 ppm
No data NIOSH 1987
No data APHA 1985
NR
APHA 1985
GC = gas chromatography; FTP = flame ionization detector; ECD = electron captive detector; Rec. =¦= recovery; NR * not reported.
>
5
H
M «-J
n ro
>
r
s
M
1-3
sc
o
o
t/5
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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.
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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 MB/l- in drinking water,
1 ug/~L in surface water, and 10 /ig/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.
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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 7-1.
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76
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Ethylene Oxide
Agency
Description
Value
Reference
IARC
Carcinogenic classification
Group 2Aa IARC 1987
National
Regulations:
a. Air:
EPA OAQPS
Hazardous air pollutant
notice of intent to list
No data
EPA 1985b
OSHA
PEL
TWA
Excursion limit (15 min)
1 ppm
5 ppm
OSHA 1988b
29 CFR 1910.1047
b. Nonspecific media:
EPA OERR
EPA OPP
EPA OSW
EPA OTS
FDA
Reportable quantity
Reportable quantity (proposed)
Extremely hazardous substance
threshold planning quantity
Tolerances for residues on raw
agricultural commodities
Hazardous waste constituent
(Appendix VIII)
Land disposal restrictions
Health and safety data
reporting rule
Preliminary assessment
information rule
Toxic chemical release
reporting
Fumigant for spices permitted
Tolerance for residue in
ground spices
Maximum residue limits in
medical devices (proposed)
Maximum residue limits in
drug products (proposed)
Maximum daily exposure level
to residues in drug
products (proposed)
1 lb
10 lb
1000 lb
50 ppm
No data
No data
No data
No data
No data
50 ppm
5-250 ppm
5-35 ppm
30 ^g/kg/day
30 days
EPA 1985c
(40 CFR 302.4)
EPA 1987a
EPA 1987b
(40 CFR 355)
40 CFR 180.151
EPA 1980
(40 CFR 261)
EPA 1989
EPA 1988a (40
CFR 716.120)
EPA 1982b (40
CFR 712.30)
EPA 1988b
(40 CFR 372)
21 CFR 193.200
FDA 1978
FDA 1978
FDA 1978
Guidelines:
a. Air;
ACGIH
NIOSH
b. Other:
EPA
TLV TWA
Suspected human carcinogen
IDLH
Recommended exposure limits
TWA
Ceiling (10 min/day)
Carcinogenic classification group Bll
1 ppm
(2 mg/m3)
800 ppm
<0.1 ppm
5 ppm
ACGIH 1986
NIOSH 1985b
NIOSH 1988
EPA 1985a
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77
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
Agency
Description
Value
Reference
State
Regulations:
a. Air:
Connecticut
Indiana
Nevada
New York
North Carolina
North Dakota
Pennsylvania (Philadelphia)
Rhode Island
South Carolina
South Dakota
Virginia
Acceptable ambient air concentration
20 ng/ro3 (8 hr)
450 jjg/m3 (8 hr)
0.048 mg/m3 (8 hr)
6.67 pg/m3 (1 yr)
0.10 pg/m3 (annual)
0.0 (bact)
A. 87 #ig/m3
0.01 jig/m3
10 pg/m3 (24 hr)
20 Mg/m3 (8 hr)
20 jig/m3 (24 hr)
NATICH 1988
(1 yr)
(annual)
a Group 2A: Probably carcinogenic to humans,
k Group Bl: Probable human carcinogen.
IARC = International Agency for Research on Cancer; EPA «¦ Environmental Protection Agency; OAQPS -
Office of Air Quality, Planning and Standards; OSHA - Occupational Safety and Health Administration;
PEL = Permissible Exposure Limit; TWA - Time-Weighted Average; OAQPS » Office of Air Quality
Planning and Standards; OERR ¦ Office of Emergency and Remedial Response; OPP » Office of Pesticide
Programs; OSW = Office of Solid Wastes; OTS ¦ Office of Toxic Substances; FDA * Food and Drug
Administration; ACGIH = American Conference of Governmental Industrial Hygienists; TLV - Threshold
Limit Value; NIOSH » National Institute for Occupational Safety and Health; IDLH * Immediately
Dangerous to Life or Health Level.
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79
8. REFERENCES
Abrahams RH. 1980. Recent studies with workers exposed to ethylene
oxide. In: Jorkasky JF, ed. Safe use of ethylene oxide. Proceedings
of the Educational Seminar. Washington DC: Health Industries
Manufacturers Association, 27-38, 211-220. HIMA Report No. 80-4.
ACGIH. 1986. Documentation of the threshold limit values and
biological exposure indices. 5th ed. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH.
Alexander M. 1977. Introduction to soil microbiology. 2nd ed. New
York, NY: John Wiley & Sons, 207.
Alomar A, Camarasa JM, Noguera J, et al. 1981. Ethylene oxide
dermatitis. Contact Dermatitis 7:205-207.
Anoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor
thresholds compared with threshold limit values and volatilities for
214 industrial chemicals in air and water dilution. J Appl Toxicol
3:272-290.
Anbar M, Neta P. 1967. A compilation of specific biomolecular rate
constants for the reactions of hydrated electrons, hydrogen atoms and
hydroxyl radicals with inorganic and organic compounds in aqueous
solution. Int J Appl Radiat Isot 18:493-523.
Anderson SR. 1971. Ethylene oxide toxicity: A study of tissue
reactions to retained ethylene oxide. J Lab Clin Med 77:346-356.
Anonymous. 1977. NIOSH asks for better control of ethylene oxide.
Association of Operating Room Nurses J 26:1152-1156.
Anonymous. 1979. Has any recent research shown ethylene or ethylene
oxide to be carcinogenic? If so, in what concentrations? Br Med J
1:1194.
Anonymous. 1986. Ethylene oxide--a human carcinogen? [Editorial],
Lancet 2:201-202.
APHA. 1985. Method 503B. Standard methods for the examination of
water and wastewater. 16th ed. Washington, DC: American Public Health
Association, 498.
* - cited in text.
-------
80
8. REFERENCES
Appelgren L, Eneroth G, Grant C. 1977. Studies on ethylene oxide:
Whole body autoradiography and dominant lethal test in mice. Proc Eur
Soc Toxicol 18:315-317.
Ashby J, Richardson, CR. 1985. Tabulation and assessment of 113 human
surveillance cytogenetic studies conducted between 1965 and 1984.
Mutat Res 154:111-133.
Austin SB. 1987. Carcinogenicity of ethylene oxide. JAMA 258:1733.
Austin SG, Sielken RL Jr. 1988. Issues in assessing the carcinogenic
hazards of ethylene oxide. J Occup Med 30:236-245.
Back KC, Thomas AA, MacEwen JD. 1972. Reclassification of materials
listed as transportation health hazards. Washington, DC: Department of
Transportation, Office of Hazardous Materials. NTIS No. PB 214270.
Bailey E, Farmer PB, Shuker DE. 1987. Estimation of exposure to
alkylating carcinogens by the GC-MS determination of adducts to
hemoglobin and nucleic acid bases in urine. Arch Toxicol 60:187-191.
Bainova A. 1986. New data on the biological activity of ethylene
oxide. Suvrem Med 37:11-16. (Russian)
Barnard JA, Lee RK. 1972. Combustion of n-pentane in a shock tube.
Combustion Sci and Technol 6:143-150.
Barnes D, Bellin J, DeRosa C, et al. 1987. Reference dose (RfD):
Description and use in health risk assessments. Volume I, Appendix A:
Integrated risk information system supportive documentation.
Washington, DC: U.S. Environmental Protection Agency, Office of Health
and Environmental Assessment. EPA/600/8 -86/032a.
Beliles RP, Parker JC. 1987. Risk assessment and oncodynamics of
ethylene oxide as related to occupational exposure. Toxicol Ind Health
3:371-382.
Berck B. 1975. Analysis of fumigants and fumigant residues. J
Chromatogr Sci 13:256-267.
Berg GL, ed. 1984. Farm chemicals handbook 1984. Willoughby, OH:
Meister Publishing Co., C97.
Binder H. 1974. [Ethylene oxide and chlorohydrin in tobacco and its
smoke.] Fachliche Mitt Oesterr Tabakregie 15:294-301. (German)
-------
81
8. REFERENCES
Binder H, Lindner W. 1972. [Determination of ethylene oxide in the
smoke of treated and untreated cigarettes.] Fachliche Mitt Oesterr
Tabakregie 13:215-220. (German)
Bird M. 1952. Chemical production of mutations in Drosonhila:
Comparison of techniques. J of Genet 50:480-485.
Blackwood JD Jr, Erskine EB. 1938. Carboxide poisoning. U.S. Navy Med
Bull 36:44-45.
Bogan DJ, Hand CW. 1978. Absolute rate constant, kinetic isotope
effect, and mechanism of the reaction of ethylene oxide with oxygen (3P)
atoms. J Phys Chem 82:2067-2073.
Bogyo DA, Lande SS, Meylan WM, et al. 1980. Investigation of selected
potential environmental contaminants: Epoxides. Report to U. S.
Environmental Protection Agency, Office of Toxic Substances, Washington,
DC, by Syracuse Research Corporation, Syracuse, NY. EPA-560/11-80-005.
NTIS No. PB80-183197.
Bond EJ, Dumas T. 1982. A portable gas chromatograph for macro- and
microdetermination of fumigants in the field. J Agric Food Chem 30:986-
988.
Bridie AL, Wolff CJ, Winter M. 1979. BOD and COD of some
petrochemicals. Water Res 13:627-630.
Brodzinsky RB, Singh HB. 1983. Volatile organic chemicals in the
atmosphere: An assessment of available data. Research Triangle Park,
NC: U.S. Environmental Protection Agency, Office of Research and
Development. EPA-600/3-83-027(A).
Brown AM, Bruch C, Jackson E, et al. 1979. Increased mutation
frequency due to ethylene oxide absorbed to plastics. In Vitro 15:220-
221.
Bruch C, Koesterer M. 1961. The microbicidal activity of gaseous
propylene oxide and its application to powdered or flaked foods. J Food
Sci 26:428.
Bruch CW. 1973. Factors determining choice of sterilizing procedure.
In: Phillips GB, Miller WS, eds. Industrial sterilization. Durham,
NC: Duke University Press, 119-123.
Brugnone F, Perbellini L, Faccini G, et al. 1985. Concentration of
ethylene oxide in the alveolar air of occupationally exposed workers.
Am J Ind Med 8:67-72.
-------
82
8. REFERENCES
Brugnorie F, Perbellirii L, Faccini GB, et al. 1986. Ethylene oxide
exposure: Biological monitoring by analysis of alveolar air and blood.
Int Arch Occup Environ Health 58:105-112.
CCTTE. 1988. Computerized listing of chemicals being tested for toxic
effects. United Nations Environment Programme, International Programme
on Chemical Safety, International Register of Potentially Toxic
Chemicals. Geneva, Switzerland.
Clansky KB, ed. Chemical guide to the OSHA hazard communication
standard. Burlingame, CA: Roytech Publications, Inc., 50, B-3, C-7, E-
4, F-4.
Clare MG, Dean BJ, de Jong G, et al. 1985. Chromosome analysis of
lymphocytes from workers at an ethylene oxide plant. Mutat Res 156:109-
116.
Clarke CP, Davidson WL, Johnston JB. 1966. Haemolysis of blood
following exposure to an Australian manufactured plastic tubing
sterilized by means of ethylene-oxide gas. Aust NZ J Surg 36:53-56.
CLC. 1988. Coordinated list of chemicals. U.S. Environmental
Protection Agency, Office of Research and Development, Washington, DC.
CLPSD. 1988. Contract Laboratory Program Statistical Database. Viar
and Company, Management Services Division, Alexandria, VA. December
1988.
Collins M, Barker NJ. 1983. Direct monitoring of ambient air for
ethylene oxide and ethylene dibromide. Am Lab (July):72-81.
Conway RA, Waggy GT, Spiegel MH, et al. 1983. Environmental fate and
effects of ethylene oxide. Environ Sci Technol 17:107-112.
Crystal HA, Schaumburg HH, Grober E, et al. 1988. Cognitive impairment
and sensory loss associated with chronic low-level ethylene oxide
exposure. Neurology 38:567-569.
Cumming RB, Sega GA, Horton CY, et al. 1981. Degree of alkylation of
DNA in various tissues of the mouse following inhalation exposure to
ethylene oxide [Abstract], Environ Mutagen 3:343.
Cumming RB, Michaud TA. 1979. Mutagenic effects of inhaled ethylene
oxide in male mice [Abstract]. Environ Mutagen 1:166-167.
Cummins KJ, Schultz GR, Lee JS, et al. 1987. The development and
evaluation of a hydrobromic acid-coated sampling tube for measuring
occupational exposure to ethylene oxide. Am Ind Hyg Assoc J 48:563-573.
-------
83
8. REFERENCES
Darby TD. 1984. Pharmacokinetics in a safety evaluation of ethylene
oxide. In: Inhospital ethylene oxide sterilization. Potential health
effects, regulatory initiatives. Safe use. Arlington, VA: AAMI
Technology Assessment Report No. 8-84, 11-14.
Dauvois C, Chaigneau M, Le Moan G. 1982. [Sterilization of dressings
by ethylene oxide. I. Physisorption.] Ann Pharm Fr 40:125-132.
(French)
De Bont JA, Albers RA. 1976. Microbial metabolism of ethylene.
Antonie van Leeuwenhoek 42:78-80.
De Bont JA, Harder W. 1978. Metabolism of ethylene by Mycobacterium E
20. FEMS Microbiol Lett 3:89-93.
DeGarmo P, Varnas V. 1933. Ethylene oxide: A hazard to health care
workers. Oreg Nurse 48:11-13.
Deleixhe A, Balsat A, Laurent C. 1986. [Acute ethylene oxide
poisoning. Apropos of five cases.] Arch Belg Med Soc 44:478-488.
(French)
Denk B, Filser JG, Oesterle D, et al. 1988. Inhaled ethylene oxide
induces preneoplastic foci in rat liver. J Cancer Res Clin Oncol
114:35-38.
Dunkelberg H. 1982. Carcinogenicity of ethylene oxide and 1,2-
propylene oxide upon intragastric administration to rats. Br J Cancer
46:924-933.
Dunkelberg H. 1987. [Carcinogenic activity of ethylene oxide and its
reaction products 2 -chloroethanol, 2-bromoethanol, ethylene glycol and
diethylene glycol. III. Research on ethylene glycol and diethylene
glycol for carcinogenic effects.] Zentralbl Bakteriol Mikrobiol Hyg [B]
183:358-365. (German)
ECETOC. 1982. Technical report no. 5: Toxicity of ethylene oxide and
its relevance to man. Brussels, Belgium: European Chemical Industry
Ecology and Toxicology Centre.
ECETOC. 1984. Technical report no. 11: Ethylene oxide toxicology and
its relevance to man: An updating of ECETOC technical report no. 5.
Brussels, Belgium: European Chemical Industry Ecology and Toxicology
Centre.
Echter E. 1972. [A few clinical examples: Part 2. Clinical
incidences following the use of ethylene oxide,] Ann Anesthesiol Fr
13:376. (French)
-------
84
8. REFERENCES
Ehrenberg L, 1979. Risk assessment of ethylene oxide and other
compounds. In: McElheny VK, Abrahamson S, eds. Banbury report: 1.
Assessing chemical mutagens: The risk to humans. Cold Spring Harbor,
NY: Cold Spring Harbor Laboratory, 157-190.
Ehrenberg L, Gustafsson A, Lundqvist U. 1956. Chemically induced
mutation and sterility in barley. Acta Chem Scand 10:492-494.
Ehrenberg L, Hiesche KD, Osterman-Golkar S, et al. 1974. Evaluation of
genetic risks of alkylating agents: Tissue doses in the mouse from air
contaminated with ethylene oxide. Mutat Res 24:83-103.
Embree JW, Lyon JP, Hine CH. 1977. The mutagenic potential of ethylene
oxide using the dominant-lethal assay in rats. Toxicol Appl Pharmacol
40:261-267.
Environment Canada. 1985. Ethylene oxide: Environmental and technical
information for problem spills. Ottawa, Ontario: Environmental
Protection Service, Technical Services Branch.
EPA. 1980. U.S. Environmental Protection Agency. Federal Register.
45:33084-33133.
EPA. 1982a. Chemical hazard information profile: Draft report:
Ethylene oxide. Cas No. 75-21-8. Washington, DC: U.S. Environmental
Protection Agency.
EPA. 1982b. U.S. Environmental Protection Agency. Federal Register
47:26992-27008.
EPA. 1984a. U.S. Environmental Protection Agency. Federal Register
49:200-205.
EPA. 1984b. Health and environmental effects profile for oxirane.
Cincinnati, OH: U.S. Environmental Protection Agency, Office of
Research and Development. EPA/600/X-84/222. NTIS No. PB88-162318,
EPA. 1985a. Health assessment document for ethylene oxide. Research
Triangle Park, NC: U.S. Environmental Protection Agency, Office of
Research and Development. EPA-600/8-84-009F.
EPA, 1985b. U.S. Environmental Protection Agency: Part II. Federal
Register. 50:13456-13522.
EPA. 1985c. U.S. Environmental Protection Agency. Federal Register
50:40286-40289.
-------
85
8. REFERENCES
EPA. 1986. Reference values for risk assessment. Final draft.
Cincinnati, OH: U.S. Environmental Protection Agency, Office of Solid
Waste. ECA0-CIN-477.
EPA. 1987. Toxic air pollutant/source crosswalk: A screening tool for
locating possible sources emitting toxic air pollutants. Research
Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air
Quality Planning and Standards. EPA-450/4-87-023a.
EPA. 1987a. U.S. Environmental Protection Agency: Part II. Federal
Register. 52:8140.
EPA. 1987b. U.S. Environmental Protection Agency: Part II. Federal
Register. 52:13378-13410.
EPA. 1988. U.S. Environmental Protection Agency: Part V. Federal
Register. 53:38642-38654.
EPA. 1989. U.S. Environmental Protection Agency. Part II. Federal
Register 54:1056-1119.
Estrin WJ, Cavalieri SA, Wald P, et al. 1987. Evidence of neurologic
dysfunction related to long-term ethylene oxide exposure. Arch Neurol
44:1283-1286.
Farmer PB, Bailey E, Gorf SM, et al. 1986. Monitoring human exposure
to ethylene oxide by the determination of haemoglobin adducts using gas
chromatography-mass spectrometry. Carcinogenesis 7:637-640.
Filser JG, Bolt HM. 1984. Inhalation pharmacokinetics based on gas
uptake studies: VI. Comparative evaluation of ethylene oxide and
butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-
butadiene in rats. Arch Toxicol 55:219-223.
Finelli PF, Morgan TF, Yaar I, et al. 1983. Ethylene oxide-induced
polyneuropathy: A clinical and electrophysiologic study. Arch Neurol
40:419-421.
Fisher AA. 1984. Ethylene oxide dermatitis. Cutis 34:20,22,24.
Flores GH. 1983. Controlling exposure to alkene oxides. Chem Eng Prog
79:39-43.
Flury F. 1930. [Uber athylenoxyd (T-gas)]. Naunyn-Schmiedeberg Arch
Exp Pathol Pharmakol 157:107-108. (German)
-------
86
8. REFERENCES
Fritz B, Lorenz K, Steinert W, et al. 1982. Laboratory kinetic
investigations of the tropospheric oxidation of selected industrial
emissions. Commission of the European Communities, 192-202.
Fukushima T, Abe K, Nakagawa A, et al. 1986. Chronic ethylene oxide
poisoning in a factory manufacturing medical appliances. J Soc Occup
Med 36:118-123.
Gallo FP. 1978. [Methyl bromide, ethylene oxide and ethylene
formaldehyde: Biological and toxicological problems and problems
related to treatment of library materials.] Nuovi Ann Ig Microbial
29:51-82. (Italian)
Galloway SM, Berry PK, Nichols WW, et al. 1986. Chromosome aberrations
in individuals occupationally exposed to ethylene oxide, and in a large
control population. Mutat Res 170:55-74.
Gardner MJ, Coggon D, Pannett B, et al. 1989. Workers exposed to
ethylene oxide: A follow up study. Br J Ind Med 46:860-865.
Garman RH, Snellings WM, Maronpot RR. 1985. Brain tumors in F344 rats
associated with chronic inhalation exposure to ethylene oxide.
Neurotoxicology 6:117-138.
Garry VF, Hozier J, Jacobs D, et al. 1979. Ethylene oxide: Evidence
of human chromosomal effects. Environ Mutagen 1:375-382.
Garry VF, Wiencke JK, Nelson RL. 1984. Ethylene oxide and some factors
affecting the mutagen sensitivity of sister chromatid exchange in
humans. Basic Life Sci 29(Pt B):975-985.
Generoso WM, Cain KT, Hughes LA, et al. 1986. Ethylene oxide dose and
dose-rate effects in the mouse dominant-lethal test. Environ Mutagen
8:1-7.
Generoso WM, Rutledge JC, Cain KT, et al. 1988. Mutagen-induced fetal
anomalies and death following treatment of females within hours after
mating. Mutat Res 199:175-181.
Gennart JP, Dutrieux M, Lauwerys R. 1983. Toxicity of ethylene oxide.
Review of the literature. Arch Mai Prof 44:269-274.
Gerhardt U, Ladd Effio JC. 1983. [Ethylene oxide residue in spices.]
Fleisch Wirtsch 63:606-608. (German)
-------
87
8. REFERENCES
Glaser ZR. 1977. Special occupational hazard review with control
recommendations for the use of ethylene oxide as a sterilant in medical
facilities. Rockville, MD: U.S. Department of Health, Education, and
Welfare, Public Health Service, Centers for Disease Control, National
Institute for Occupational Safety and Health. DHEW (NIOSH) Publication
No. 77-200.
Glaser ZR. 1979. Ethylene oxide: Toxicology review and field study
results of hospital use. J Environ Path Toxicol 2:173-207.
Golberg L. 1986. Hazard assessment of ethylene oxide. Boca Raton, FL
CRC Press.
Gomer R, Noyes WA Jr. 1950. Photochemical studies. XLII. Ethylene
oxide. J Am Chem Soc 72:101-108.
Gosselin RE, Smith RP, Hodge HC, et al. 1984. Clinical toxicology of
commercial products. 5th ed. Baltimore, MD: Williams and Wilkins, II
97.
Gramiccioni L, Esposito G, Arena C, et al. 1982. [Ethylene oxide:
toxicity, hazard, and retention in sterilized materials.] Rass Chim
34:109-115. (Italian)
Grammer LC, Paterson BF, Roxe D, et al. 1985. IgE against ethylene
oxide-altered human serum albumin in patients with anaphylactic
reactions to dialysis. J Allergy Clin Immunol 76:511-514.
Greaves Walker WJ, Greeson CE. 1932. The toxicity of ethylene oxide.
J Hyg 32;409-416.
Greenberg HL, Ott MG, Shore RE. 1990. Men assigned to ethylene oxide
production or other ethylene oxide related chemical manufacturing: A
mortality study. Br J Ind Med 47:000-000.
Greife A, Morawetz J, Stayner L. 1986. Industrywide studies report of
walk-through survey at Johnson and Johnson (Ethicon), Somerville, NJ.
Cincinnati, OH: National Institute for Occupational Safety and Health,
Centers for Disease Control. NTIS No. PB87-164406.
Gross JA, Haas ML, Swift TR. 1979. Ethylene oxide neurotoxicity:
Report of four cases and review of the literature. Neurology 29:978-
983.
-------
88
8. REFERENCES
Guriter BJ. 1987a. Health hazard evaluation report: HETA-87-365-1848,
Memorial Hospital of Southern Oklahoma, Ardmore, Oklahoma. Cincinnati,
OH: U.S. Department of Health and Human Services, Public Health
Service, Centers for Disease Control, National Institute for
Occupational Safety and Health.
Gunter BJ, Daniels WJ. 1987b. Health hazard evaluation report: HETA
87-013-1803, West Seattle Community Hospital, Seattle, Washington.
Cincinnati, OH: U.S. Department of Health and Human Services, Public
Health Service, Centers for Disease Control, National Institute for
Occupational Safety and Health.
Hackett PL, Brown MG, Buschbom RL, et al. 1982. Teratogenic study of
ethylene and propylene oxide and n-butyl acetate. Cincinnati, OH: U.S.
Department of Health and Human Services, Public Health Service, Centers
for Disease Control, National Institute for Occupational Safety and
Health. NTIS No. PB83-258038.
Hanifin JM. 1971. Ethylene oxide dermatitis (Letter], J Am Med Assoc
217:213.
Hansch C, Leo A. 1979. Substituent constants for correlation analysis
in chemistry and biology. New York, NY: John Wiley & Sons, Inc., 176.
Hansen JP, Allen J, Brock K, et al. 1984. Normal sister chromatid
exchange levels in hospital sterilization employees exposed to ethylene
oxide. J Occup Med 26:29-32.
Hardin BD, Niemeier RW, Sikov MR, et al. 1983. Reproductive -
toxicologic assessment of the epoxides ethylene oxide, propylene oxide,
butylene oxide, and styrene oxide. Scand J Work Environ Health 9:94-
102.
Hatch GG, Conklin PM, Christensen CC, et al. 1986. Mutation and
enhanced virus transformation of cultured hamster cells by exposure to
gaseous ethylene oxide. Environ Mutagen 8:67-76.
Hattis D. 1987. A pharmacokinetic/mechanism-based analysis of the
carcinogenic risk of ethylene oxide. Report to U.S. National Institute
for Occupational Safety and Health, by Massachusetts Institute of
Technology, Center for Technology, Policy and Industrial Development,
Cambridge, MA. NTIS No. PB88-188784.
Hemminki K, Mutinen P, Saloniemi I, et al. 1982. Spontaneous abortions
in hospital staff engaged in sterilizing instruments with chemical
agents. Br Med J 285:1461-1463.
-------
89
8. REFERENCES
Hemminki K, Mutanen P, Niemi M-L. 1983. (Letter to editor). Br Med J
286:1976-1977 .
Henderson PT, van Doom R, Leijdekkers CM, et al. 1984. Excretion of
thloethers in urine after exposure to electrophilic chemicals. IARC Sc
Publ 59:173-187.
Hertz-Picciotto I, Neutra RR, Collins JF. 1987. Ethylene oxide and
leukemia. JAMA 257:2290.
Hine C, Rowe VK, White ER, et al. 1981. Epoxy compounts. In: Clayto
GD, Clayton FE, eds. 1981. Patty's industrial hygiene and toxicology.
3rd ed. Vol. 2A: Toxicology. New York, NY: John Wiley and Sons,
2166-2257.
Hogstedt C, Malmqvist N, Wadraan B. 1979. Leukemia in workers exposed
to ethylene oxide. JAMA 241:1132-1133.
Hogstedt C, Aringer L, Gustavsson A. 1984. [Ethylene oxide and cancer
review of the literature and follow-up of two studies.] Solna, Sweden:
Arbetarskyddsstyrelsen, Publikationsservice. (Swedish)
Hogstedt C, Aringer L, Gustavsson A. 1986. Epidemiologic support for
ethylene oxide as a cancer-causing agent. JAMA 255:1575-1578.
Hollingsworth RL, Rowe VK, Oyen F, et al. 1956. Toxicity of ethylene
oxide determined on experimental animals. AMA Archives of Industrial
Health 13:217-227.
Honkanen E, Makela P, Bjorksten F, et al. 1987. [Ethylene oxide and
hemodialysis anaphylaxis.] Duodecim 103:694-699. (Swedish)
HSDB. 1988. Hazardous Substances Data Bank. National Library of
Medicine, National Toxicology Information Program, Bethesda, MD.
December 1988.
Hunt WF Jr, Faoro RB, Freas W. 1986. Interim data base for state and
local air toxic volatile organic chemical measurements. Research
Triangle Park, NC: U.S. Environmental Protection Agency, Office of Air
Quality Planning and Standards. EPA 450/4-86-012. NTIS No. PB87-
168779.
IARC. 1976. Monographs on the evaluation of carcinogenic risk of
chemicals to man: Cadmium, nickel, some epoxides, miscellaneous
industrial chemicals and general considerations of volatile
anaesthetics. Vol. II. International Agency for Research on Cancer,
Lyon, France, 157-167.
-------
90
8. REFERENCES
IARC. 1982. I ARC monographs on the evaluation of the carcinogenic risk
of chemicals to humans. Vol. 1-29 (Supplement 4): Chemicals,
industrial processes and industries associated with cancer in humans.
World Health Organization, Lyon, France.
IARC. 1987. IARC monographs on the evaluation of carcinogenic risks to
humans. Vol. 1-42 (Supplement 7): Overall evaluations of
carcinogenicity: An updating of IARC monographs. World Health
Organization, Lyon, France.
IRIS. 1989. Integrated Risk Information System. U.S. Environmental
Protection Agency. Washington, D.C.
IRPTC 1989. IRPTC data profile: Ethylene oxide. International
Register of Potentially Toxic Chemicals, United Nations Environment
Programme. Geneva, Switzerland January 1989.
Jacobson KH, Hackley EB, Feinsilver L. 1956. The toxicity of inhaled
ethylene oxide and propylene oxide vapors. AMA Arch Ind Health 13:237-
244.
Jaffe S. 1971. Photooxidation of ethylene oxide and propionaldehyde in
the presence of N02 and light. In: Englund HM, Berry WT, eds.
Proceedings of the Second International Clean Air Congress. New York,
NY: Academic Press, 316-324.
Jana MK, Roy K. 1975. Effectiveness and efficiency of ethyl
methanesulfonate and ethylene oxide for the induction of mutations in
rice. Mutat Res 28:211-215.
Jarvinen A. 1979. [Cancer diagnosis In Sweden. Ethylene oxide's
health hazard continually investigated in Finland.] Sairaanhoitaja
55:12-14. (Swedish)
Jay WM, Swift TR, Hull DS. 1982. Possible relationship of ethylene
oxide exposure to cataract formation. Am J Ophthalmol 93:727-732.
Jones-Price C, Marks TA, Ledoux TA, et al. 1983. Teratologic
evaluation of ethylene oxide (Cas No. 75-21-8) in New Zealand white
rabbits. Laboratory study: August 21, 1979 to December 2, 1980.
Research Triangle Park, NC: National Institute of Environmental Health
Sciences. NTIS No. PB83-242016.
Joshi SB, Dodge MC, Bufalini JJ. 1982. Reactivities of selected
organic compounds and contamination effects. Atmos Environ 16:1301-
1310.
-------
91
8. REFERENCES
Joyner RE. 1964. Chronic toxicity of ethylene oxide: A study of human
responses to long-term low-level exposures. Arch Environ Health
8:700-710.
Karelova J, Jablonicka A, Vargova M. 1987. Results of cytogenetic
testing of workers exposed to ethylene oxide. J Hyg Epidemiol Microbiol
Immunol 31:119-126.
Kelsey KT, Wiencke JK, Eisen EA, et al. 1988. Persistently elevated
sister chromatid exchanges in ethylene oxide-exposed primates: The role
of a subpopulation of high frequency cells. Cancer Res 48:5045-5050.
Kiesselbach N, Ulm K, Lange HJ, et al. 1990. A multicentre mortality
study of workers exposed to ethylene oxide. Br J Ind Med 47:182-188,
Kikuchi H, Nakamura A, Tsuji K. 1988. Gas chromatographic
determination with electron capture detection of residual ethylene oxide
in intraocular lenses. J Assoc Off Anal Chem 71:1057-1062.
Kligerman AD, Erexson GL, Phelps ME, et al. 1983. Sister-chromatid
exchange induction in peripheral blood lymphocytes of rats exposed to
ethylene oxide by inhalation. Mutat Res 120:37-44.
Klonne DR, Nachreiner DJ, Dodd DE, et al. 1987. Acute and two-week
inhalation toxicity studies on aerosols of selected ethylene
oxide/propylene oxide polymers in rats. Fundam Appl Toxicol 9:773-784.
Koga M, Hori H, Tanaka I. 1987. [Analysis of urinary metabolites of
rats exposed to ethylene oxide.] Sangyo Ika Daigaku Zasshi 9:267-270.
Kolman A, Naslund M, Calleman CJ. 1986. Genotoxic effects of ethylene
oxide and their relevance to human cancer [Editorial], Carcinogenesis
(London) 7:1245-1250.
Kolmark HG, Kilbey BJ. 1968. Kinetic studies of mutation induction by
epoxides in Neurospora crassa. Mol Gen Genet 101:89-98.
Kuzuhara S, Kanazawa I, Nakanishi T, et al. 1983. Ethylene oxide
polyneuropathy. Neurology 33:377-380.
LaBorde JB, Kimrael CA. 1980. The teratogenicity of ethylene oxide
administered intravenously to mice. Toxicol Appl Pharmacol 56:16-22.
Lambert B, Lindblad A. 1980. Sister chromatid exchange and chromosome
aberrations in lymphocytes of laboratory personnel. J Toxicol Environ
Health 6:1237-1243.
-------
92
8. REFERENCES
Landrigan PJ, Meinhardt TJ, Gordon J, et al. 1984. Ethylene oxide: An
overview of toxicologic and epidemiologic research. Am J Ind Med 6:103-
115.
Laurent CH, Frederic J, Marechal F. 1982. Etude des effets
cytogenetiques d'intoxication a l'oxyde d'ethylene. CR Soc Biol (Paris)
176:733-735. (French)
Lee, WE.. 1980. Relation of mutation frequency to dose of ethylene
oxide in germ cells. Submitted to South Carolina Pesticides
Epidemiologic Study Center, Preventive Medicine Division, Department of
Family Practice, Medical University of South Carolina.
Lemke HD. 1987. Mediation of hypersensitivity reactions during
hemodialysis by IgE antibodies against ethylene oxide. Artif Organs
11:104-110.
Lewis SE, Barnett LB, Felton C, et al. 1986. Dominant visible and
electrophoretically expressed mutations induced in male mice exposed to
ethylene oxide by inhalation. Environ Mutagen 8:867-872.
Long FA, Pritchard JG. 1956. Hydrolysis of substituted ethylene oxides
in H2018 solutions. J Am Chem Soc 78:2663-2667.
Lynch DW, Lewis TR, Moorman WJ, et al. 1984a. Effects on monkeys and
rats of long-term inhalation exposure to ethylene oxide: Major findings
of the NIOSH study. In: Inhospital ethylene sterilization. Current
issues in ETO toxicity and occupational exposure. AAMI Technology
Assessment Report No. 8-84. Arlington VA: Association for the
Advancement of Medical Instrumentation, 7-10.
Lynch DW, Lewis TR, Moorman WJ, et al. 1984b. Carcinogenic and
toxicologic effects of inhaled ethylene oxide and propylene oxide in
F344 rats. Toxicol Appl Pharmacol 76:69-84.
Manware RA, Fell M. 1984. Current status of Occupational Safety and
Health Administration regulation of ethylene oxide. In: Inhospital
ethylene oxide sterilization. Potential health effects, regulatory
initiatives, safe use. AAMI Technology Assessment Report No. 8-84,
Arlington VA: Association for the Advancement of Medical
Instrumentation, 37-41.
Markel HL Jr. 1988. Health hazard evaluation report no. HETA-87-210-
1862, Earl K. Long Memorial Hospital, Baton Rouge, Louisiana.
Cincinnati, OH: Public Health Service, Centers for Disease Control,
National Institute for Occupational Safety and Health.
-------
93
8. REFERENCES
Martis L, Kroes R, Darby TD, et al. 1982. Disposition kinetics of
ethylene oxide, ethylene glycol, and 2-chlorethanol in the dog. J
Toxicol Environ Health 10:847-856.
Matsuoka M. 1988. [Effects of chronic exposure of ethylene oxide,
especially on heme metabolism.] Sangyo Ika Daigaku Zasshi (J UOEH)
10:77-88. (Japanese)
Mattia MA. 1983. Hazards in the hospital environment. The sterilants
ethylene oxide and formaldehyde. Am J Nurs 83:240-243.
McDonald TO, Kasten K, Hervey R. 1977. Acute ocular toxicity for
normal and irritated rabbit eyes and subacute ocular toxicity for
ethylene oxide, ethylene chlorohydrin, and ethylene glycol. Bull
Parenter Drug Assoc 31:25-32.
McKelvey JA, Zemaitis MA, 1986, The effect of ethylene oxide exposure
on tissue glutathione levels in rats and mice. Drug Chem Toxicol
9:51-66.
McLaughlin RS. 1946. Chemical burns of the human cornea. Am J
Ophthalmol 29:1355-1362.
McNally ME, Wheeler JR. 1988. Supercritical fluid extraction coupled
with supercritical fluid chromatography for the separation of
sulfonylurea herbicides and their metabolites from complex matrices. J
Chromatogr 435:63-71.
Meinhardt T, Carrano A, Moore D, et al. 1985. Cytogenetic study of
workers exposure to ethylene oxide: Analysis of the chromosomal
aberration data and overall conclusions from the analyses of sister
chromatid exchanges and chromosomal aberrations. Cincinnati, OH: U.S.
Department of Health and Human Services, National Institute for
Occupational Safety and Health. No. 00156828.
Meister RT, ed. 1988. Farm chemicals handbook. 74th ed. Willoughby,
OH: Meister Publishing Co., C96.
Michael LC, Pellizzari ED, Wiseman RW. 1988. Development and
evaluation of a procedure for determining volatile organics in water.
Environ Sci Technol 22:565-570.
Migliore L, Rossi AM, Loprieno N. 1982. Mutagenic action of
structurally related alkene oxides on Schizosaccharomvces pombe: The
influence, 'in vitro', of mouse-liver metabolizing system. Mutat Res
102:425-437.
-------
94
8. REFERENCES
Morawetz J, Steenland K. 1987. Industrywide studies report of walk-
through survey of Schilling, McCormick and Company, Incorporated,
Salinas, CA. Cincinnati, OH: National Institute for Occupational
Safety and Health, Centers for Disease Control. NTIS No. PB87-164398.
Morgan RW, Claxton KW, Divine BJ, et al. 1981. Mortality among
ethylene oxide workers. J Occup Med 23:767-770.
Nakashima K, Furutani A, Higashi K, et al. 1987. Glutathione contents
in rat livers after acute and chronic exposure to ethylene oxide.
Sangyo Ika DaigaKu Zasshi 9:355-359.
NAS/NRC. 1989. Biologic markers in reproductive toxicology.
Washington, DC: National Academy of Sciences, National Research
Council, National Academy Press.
NATICH. 1988. NATICH data base report on state, local and EPA air
toxic activities. Research Triangle Park, NC: U.S. Environmental
Protection Agency, Office of Air Quality Planning and Standards,
National Air Toxics Information Clearinghouse. EPA 450/5-88-007. NTIS
No. PB89-106983.
NIOSH. 1977. NI0SH manual of analytical methods. 2nd ed. Part II:
Standards completion program validated methods. Vol 3. Cincinnati, OH:
U.S. Department of Health, Education, and Welfare, Public Health
Service, Centers for Disease Control, National Institute for
Occupational Safety and Health, S286-1-S286-9.
NIOSH. 1981. NIOSH current intelligence bulletin 35: Ethylene oxide
(EtO): Evidence of carcinogenicity. Cincinnati, OH: U.S. Department
of Health and Human Services, Public Health Service, Centers for Disease
Control, National Institute for Occupational Safety and Health. DHHS
(NIOSH) Publication No. 81-130.
NIOSH. 1985a. Ethylene oxide: Method: 1607. In: NIOSH manual of
analytical methods. 3rd ed. Vol. 1. Cincinnati, OH: U.S. Department
of Health and Human Services, Public Health Service, Centers for Disease
Control, National Institute for Occupational Safety and Health.
NIOSH. 1985b. NIOSH pocket guide to chemical hazards. Washington, DC:
U.S. Department of Health and Human Services, Public Health Service,
Centers for Disease Control, National Institute for Occupational Safety
and Health.
NIOSH. 1987. Ethylene oxide: Method: 3702. In: NIOSH manual of
analytical methods. Cincinnati, OH: U.S. Department of Health and
Human Services, Public Health Service, Centers for Disease Control,
National Institute for Occupational Safety and Health.
-------
95
8. REFERENCES
NIOSH. 1988. National occupational exposure survey. Cincinnati, OH:
National Institute for Occupational Safety and Health.
NIOSH. 1988. National occupational hazard survey, Cincinnati, OH:
National Institute for Occupational Safety and Health.
NIOSH. 1988. NIOSH recommendations for occupational safety and health
standards. MMWR Suppl 37:14. Atlanta, GA: U.S. Department of Health
and Human Services, Public Health Service, Centers for Disease Control,
National Institute for Occupational Safety and Health.
N.J. Dept. of Health. 1986. Hazardous substance fact sheet. Trenton,
NJ: N.J. Department of Health. CAS No. 75-21-8. DOT No. UN 1040.
NLM. 1988. Chemline. National Library of Medicine, Bethesda, MD.
December 1988.
NTP. 1985. Fourth annual report on carcinogens: Summary National
Toxicology Program. Research Triangle Park, NC: U.S. Department of
Health and Human Services, Public Health Service. NTP 85-002.
NTP. 1987. Toxicology and carcinogenesis studies of ethylene oxide
(CAS No. 75-21-8) in B6C3F! mice (inhalation studies). National
Toxicology Program. Technical report series no. 326. Research Triangle
Park, NC: U.S. Department of Health and Human Services, Public Health
Service, National Institutes of Health. NIH Publication No. 88-2582.
NTP. 1988a. National Toxicology Program: Fiscal year 1988 annual
plan. Research Triangle Park, NC: U.S. Department of Health and Human
Services, Public Health Service.
NTP. 1988b. National Toxicology Program: Review of current DHHS, DOE,
and EPA research related to toxicology: Fiscal year 1988. Research
Triangle Park, NC: U.S. Department of Health and Human Services,
Public Health Service.
O'Leary RK, Guess WL. 1968a. The toxicogenic potential of medical
plastics sterilized with ethylene oxide vapors. J Biomed Mater Res
2:297-311.
O'Leary RK, Guess WL. 1968b. Toxicological studies on certain medical
grade plastics sterilized by ethylene oxide. J Pharm Sci 57:12-17.
O'Leary RK, Watkins WD, Guess WL. 1969. Comparative chemical and
toxicological evaluation of residual ethylene oxide in sterilized
plastics. J Pharm Sci 58:1007-1010.
-------
96
8. REFERENCES
Ohnishi A, Inoue N, Yamamoto T, et al. 1986. Ethylene oxide neuropathy
in rats: Exposure to 250 ppm. J Neurol Sci 74:215-221.
OSHA. 1988a. U.S. Department of Labor. Occupational Safety and Health
Administration: Part IV. Federal Register. 53:1724-1737.
OSHA. 1988b. U.S. Department of Labor. Occupational Safety and Health
Administration: Part IV. Federal Register. 53:11414-11438.
OSHA. 1989. U.S. Department of Labor, Occupational Safety and Health
Administration: Part III. Federal Register. 54:2332-2983.
Perera F. 1987. Molecular epidemiology: A novel approach to the
investigation of pollutant-related chronic disease. In: Draggan S,
Cohrssen JJ, Morrison RE, eds. Environmental impacts on human health-
The agenda for long-term research and development. New York, NY:
Praeger Publishers, 61-88.
Pero RW, Widegren B, Hogstedt B, et al. 1981. In vivo and in vitro
ethylene oxide exposure of human lymphocytes assessed by chemical
stimulation of unscheduled DNA synthesis. Mutat Res 83:271-289.
Pfeiffer E, Dunkelberg H. 1980. Mutagenicity of ethylene oxide and
propylene oxide and of the glycols and halohydrins formed from them
during the fumigation of foodstuffs. Toxicology 18:115-118.
PHRED. 1988. Public Health Risk Evaluation Database. U.S.
Environmental Protection Agency, Washington, DC. March 1988.
Popp DM, Popp RA, Lock S, et al. 1986. Use of multiparameter analysis
to quantitate hematological damage from exposure to a chemical (ethylene
oxide). J Toxicol Environ Health 18:543-565.
Prat-Marin A, Sanz-Gallen P. 1987. [Toxicological aspects of exposure
to ethylene oxide.] Rev Saude Publica 21:523-528. (Spanish)
Puskar MA, Hecker LH. 1989. Field validation of passive dosimeters for
the determination of employee exposures to ethylene oxide in hospital
product sterilization facilities. Am Ind Hyg Assoc J 50:30-36.
Quint J. 1982. Toxicity of ethylene oxide with emphasis on
carcinogenic, reproductive and genetic effects. Berkeley, CA:
Department of Health Services/Department of Industrial Relations, Hazard
Evaluation System and Information Service, State of California.
Rajendran S, Muthu M. 1981. Detection of acrylonitrile and ethylene
oxide in air and fumigated foodstuffs. Bull Environ Contain Toxicol
27:426-431.
-------
97
8. REFERENCES
Rannug U, Goethe R, Wachtraeister CA. 1976. The mutagenicity of
chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and
chloroacetic acid, conceivable metabolites of vinyl chloride. Chem Biol
Interact 12:251-263.
Rathbun RE, Tai DY. 1984. Comment on "Environmental fate and effects
of ethylene oxide". Environ Sci Technol 18:133-134.
Ribeiro LR, Salvadori DM, Pereira CA, et al. 1987. Activity of
ethylene oxide in the mouse sperm morphology test. Arch Toxicol 60:331-
333.
Richmond GW, Abrahams RH, et al. 1985. An evaluation of possible
effects on health following exposure to ethylene oxide. Arch Environ
Health 40:20-25.
Romano SJ, Renner JA. 1979. Analysis of ethylene oxide-worker
exposure. Am Ind Hyg Assoc J 40:742-745.
Salinas E, Sasish L, Hall DH, et al. 1981. Acute ethylene oxide
intoxication. Drug Intell Clin Pharm 15:384-386.
Sarto F, Cominato I, Pinton AM, et al. 1984a. Cytogenetic damage in
workers exposed to ethylene oxide. Mutat Res 138:185-195.
Sarto F, Cominato I, Pinton AM, et al. 1984b. Workers exposed to
ethylene oxide have increased incidence of sister chromatid exchange.
IARC Sci Publ 59:413-419.
Sax NI, Lewis RJ Sr. 1987. Hawley's condensed chemical dictionary.
11th ed. New York, NY: Van Nostrand Reinhold Company, 490.
Schroeder JM, Hoheneck M, Weis J, et al. 1985. Ethylene oxide
polyneuropathy: Clinical Follow-up study with morphometric and electron
microscopic findings in a sural nerve biopsy. J Neurol 232:83-90.
Scudamore KA, Heuser SG. 1971. Ethylene oxide and its persistent
reaction products in wheat flour and other commodities: Residues from
fumigation or sterilisation, and effects of processing. Pestic Sci
2:80-91.
Segerback D. 1983. Alkylation of DNA and hemoglobin in the mouse
following exposure to ethene and ethene oxide. Chem Biol Interact
45:139-151.
Sexton RJ, Henson, E. 1949. Dermatological injuries by ethylene oxide.
J Ind Hyg Toxicol 31:297-300.
-------
98
8. REFERENCES
Sexton RJ, Henson EV. 1950. Experimental ethylene oxide human skin
injuries. Ind Hyg Occup Med 32:549-564.
Sheikh K. 1984. Adverse health effects of ethylene oxide and
occupational exposure limits. Am J Ind Med 6:117-127.
Shupack JL, Andersen SR, Romano SJ. 1981. Human skin reactions to
ethylene oxide. J Lab Clin Med 98:723-729.
Sittig M. 1985. Handbook of toxic and hazardous chemicals and
carcinogens. 2nd ed. Park Ridge, HJ: Noyes Publications, 433-434,
Smyth HF Jr, Seaton J, Fischer L. 1941. The single dose toxicity of
some glycols and derivatives. J Ind Hyg Toxicol 23:259-268.
Snellings WM, Pringle JL, Dorko JD, et al. 1979. Teratology and
reproduction studies with rats exposed to 10, 33, or 100 ppm of ethylene
oxide (ETO) [Abstract]. Toxicol Appl Pharmacol 48:A84,
Snellings WM, Maronpot RR, Zelenak JP, et al. 1982a. Teratology study
in Fischer 344 rats exposed to ethylene oxide by inhalation. Toxicol
Appl Pharmacol 64:476-481.
Snellings WM, Zelenak JP, Weil CS. 1982b. Effects on reproduction in
Fischer 344 rats exposed to ethylene oxide by inhalation for one
generation. Toxicol Appl Pharmacol 63:382-388.
Snellings WM, Weil CS, Maronpot RR. 1984a. A subchronxc inhalation
study of the toxicologic potential of ethylene oxide in B6C3F1 mice.
Toxicol Appl Pharmacol 76:510-518.
Snellings WM, Weil CS, Maronpot RR. 1984b. A two-year inhalation study
of the carcinogenic potential of ethylene oxide in Fischer-344 rats.
Toxicol Appl Pharmacol 75:105-11.7.
SRC. 1982. Information profiles on potential occupational hazards:
Epoxy compounds (non-cyclic). Syracuse Research Corporation, Center for
Chemical Hazard Assessment, Syracuse, NY. SRC TR 81-637.
SRI. 1984. CEH manual of current indicators - supplemental data.
Menlo Park, CA: SRI International, 300.5202 N-R, 248-249.
SRI. 1985. Directory of chemical producers: United States of America.
Menlo Park, CA; SRI International, 572.
SRI. 1986. Directory of chemical producers: United States of America.
Menlo Park, CA: SRI International, 645.
-------
99
8. REFERENCES
SRI. 1987. Directory of chemical producers: United States of America.
Menlo Park, CA: SRI International, 628.
SRI. 1987. Directory of chemical producers: United States of America:
Supplement II. Menlo Park, CA: SRI International, 33.
SRI. 1988. Directory of chemical producers: United States of America.
Menlo Park, CA: SRI International, 614.
Star EG. 1980. [Ethylene oxide residues and aeration time after use of
modern heated aerators.] Zentralbl Bakteriol [B] 170:539-547. (German)
Stayner L, Morawetz J, Schober S. 1986. Industrywide studies report:
A walk-through survey of Bristol-Myers Company, Industrial Division,
Syracuse, New York. Cincinnati, OH: National Institute for
Occupational Safety and Health, Centers for Disease Control. NTIS
No. PB87-164349.
Stolley PD, Soper KA, Galloway SM, et al. 1984. Sister-chromatid
exchanges in association with occupational exposure to ethylene oxide.
Mutat Res 129:89-102.
Tan EL, Cummlng RB, Hsie AW. 1981. Mutagenicity and cytotoxicity of
ethylene oxide in the CHO/HGPRT system. Environ Mutagen 3:683-686.
Tanooka H. 1979. Application of Bacillus subtilis spores in the
detection of gas mutagens: A case of ethylene oxide. Mutat Res 64:433-
435.
Taylor JS. 1977. Dermatologic hazards from ethylene oxide. Cutis
19:189-192.
Tardif R, Goyal R, Brodeur J, et al. 1987. Species differences in the
urinary disposition of some metabolites of ethylene oxide. Fundam Appl
Toxicol 9:448-453.
Thiess AM. 1963. [Observations on the health hazards of ethylene
oxide.] Archiv Toxiko 20:127-140. (German)
Thiess AM, Schwegler H, Fleig I, et al. 1981. Mutagenicity study on
workers exposed to alkene oxides (ethylene oxide/propylene oxide) and
derivatives. J Occup Med 23:343-347.
Thomson, WT. 1979. Agricultural chemicals-book III: Miscellaneous
chemicals. Fresno, CA. Thomson Publications.
TPCDB. 1988. Testing Priority Committee Data Base. U.S. Environmental
Protection Agency, Office of Toxic Substances, Washington, DC.
-------
100
8. REFERENCES
Tyler TR. 1983. Metabolism study on ethylene oxide in conjunction with
dominant lethal test. Carnegie Mellon Institute of Research,
Pittsburgh, PA. TSCATS/017059. EPA/OTS Document Number 8782.
Tyler TR, McKelvey JA. 1982. Dose dependent disposition of 1AC labeled
ethylene oxide in rats. Bushy Run Research Center, Export, PA.
TSCATS/017061. EPA/OTS Document Number 878212056.
USITC. 1988. Synthetic organic chemicals: United States production
and sales - 1987: Washington, DC: U.S. International Trade Commission.
USITC Publication 2118.
Van Duuren B, Orris L, Nelson N. 1965. Carcinogenicity of epoxides,
lactones, and peroxy compounds. Part II. J Natl Cancer Inst 35:707-
717.
Van Sittert NJ, De Jong G, Clare MG, et al. 1985. Cytogenetic,
immunological, and haematological effects in workers in an ethylene
oxide manufacturing plant. Br J Ind Med 42:19-26.
Vanderlaan M, Watkins BE, Stanker L. 1988. Environmental monitoring by
immunoassay. Environ Sci Technol 22:247-254.
Vargova M, Karelova J, Jablonicka A, et al. 1988. [On the question of
possible unfavourable effects of occupational exposure to ethylene
oxide.] Cesk Hyg 33:323-328. (Czech)
Verschueren K. 1983. Handbook of environmental data on organic
chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Company, 652-
655.
VIEW Database. 1989. Agency for Toxic Substances and Disease Registry
(ATSDR), Office of External Affairs, Exposure and Disease Registry
Branch, Atlanta, GA. February 2, 1989.
Von Oettingen W. 1939. Ethylene oxide. In: Supplement to occupation
and health: Encyclopedia of Hygiene, Pathology, and Social Welfare.
Geneva, Switzerland: International Labor Office.
Wagner M, Kollorz W. 1987. [Occupational medicine studies of seven
ethylene oxide-exposed endoscopy nursing professionals.] Zentralbl
Bakteriol Mikrobiol Hyg [B] 185:154-163.
Waldrop W. 1984. Current status of EPA regulation of ethylene oxide.
In: Inhospital ethylene oxide sterilization. Potential health effects,
regulatory initiatives, safe use. AAMI Technology Assessment Report
No. 8-84. Arlington, VA: Association for the Advancement of Medical
Instrumentation, 42-43.
-------
101
8. REFERENCES
Walters SM. 1986. Cleanup of samples. In: Zweig G, Sherma J, eds.
Analytical methods for pesticides and plant growth regulators. Vol 15.
New York, NY: Academic Press, 67-110.
Watson, WA. 1966. Further evidence of an essential difference between
the genetical effects of mono- and bifunctional alkylation agents.
Mutat Res 3:455-457.
Weast RC, ed. 1985. CRC handbook of chemistry and physics: A ready-
reference book of chemical and physical data. Boca Raton, FL: CRC
Press, Inc., C-273.
Weiss H. 1981. Carcinogenicity of ethylene oxide [Editorial]. JAMA
258:1733-1734.
WHO. 1985. Environmental health criteria 55: Ethylene oxide. Geneva,
Switzerland: World Health Organization, 3-79.
Willson JE. 1981. Ethylene oxide toxicity: review and update. Steril
Med Prod (Proceedings of the 2nd International Kilmer Memorial
Conference), 129-149.
Wilsnack RE, Meyer FJ, Smith JG. 1973. Human cell culture toxicity
testing of medical devices and correlation to animal tests. Biomater
Med Devices Artif Organs 1:543-562.
Woodard G, Woodard M. 1971. Toxicity of residuals from ethylene oxide
gas sterilization. Proc Health Ind Assoc Tech Symp, Washington, DC,
140-161.
Yager JW, Hines CJ, Spear RC. 1983. Exposure to ethylene oxide at work
increases sister chromatid exchanges in human peripheral lymphocytes.
Science 219:1221-1223.
Zamlauski MJ, Cohen JJ. 1976. The effects of aortic infusion of
ethylene oxide on renal function in the rat. Toxicol Appl Pharmacol
38:283-295.
Zampollo A, Zacchetti 0, Pisati G. 1984. On ethylene oxide
neurotoxicity: Report of two cases of peripheral neuropathy. Ital J
Neurol Sci 5:59-62.
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9. GLOSSARY
Acute Exposure - - Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (K^) -- 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.
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9. GLOSSARY
Embryotoxicity and Fetotoxiclty -- 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^) (LC^,) -- The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration^,,) (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 DoseC^,) (LDlq) -- 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.
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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.
qx* -- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The qx* can
be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually fig/L for
water, mg/kg/day for food, and Kg/m3 for air).
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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 he 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.
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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.
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APPENDIX
APPENDIX
PEER REVIEW
A peer review panel was assembled for ethylene oxide. The panel
consisted of the following members: Dr. 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.
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