s

Toxicological Profile for

Ethylene Oxide

Draft for Public Comment

September 2020
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DISCLAIMER

Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic 

Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human 

Services.

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy.
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FOREWORD

This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary.

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for these toxic substances described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is 

also presented, but is 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.

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile 

begins with a relevance to public health discussion which would allow a public health professional to 

make a real-time determination of whether the presence of a particular substance in the environment 

poses a potential threat to human health. The adequacy of information to determine a substance's health 

effects is described in a health effects summary. Data needs that are of significance to the protection of 

public health are identified by ATSDR and EPA.

Each profile includes the following:

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a toxic substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, intermediate, 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 the levels of exposure that present a 

significant risk to human health due to acute, intermediate, and chronic duration exposures; 

and

(C) Where appropriate, identification of toxicologic testing needed to identify the types or levels 

of exposure that may present significant risk of adverse health effects in humans.

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. ATSDR plans

to revise these documents in response to public comments and as additional data become available. 

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submitting comments.

Written comments may also be sent to: Agency for Toxic Substances and Disease Registry

Office of Innovation and Analytics

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Atlanta, Georgia 30329-4027
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The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to “...effectuate and implement the health related 

authorities” of the statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that 

pose the most significant potential threat to human health, as determined by ATSDR and the EPA. 

Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a 

toxicological profile for each substance on the list. In addition, ATSDR has the authority to prepare 

toxicological profiles for substances not found at sites on the NPL, in an effort to “...establish and 

maintain inventory of literature, research, and studies on the health effects of toxic substances” under 

CERCLA Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as 

otherwise necessary to support the site-specific response actions conducted by ATSDR. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel

and is being made available for public review. Final responsibility for the contents and views expressed 

in this toxicological profile resides with ATSDR.

Patrick N. Breysse, Ph.D., CIH

Director, National Center for Environmental Health and

Agency for Toxic Substances and Disease Registry

Centers for Disease Control and Prevention

Christopher M. Reh, PhD

Associate Director

Agency for Toxic Substances and Disease Registry

Centers for Disease Control and Prevention
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VERSION HISTORY

Date Description

September 2020 Draft for public comment toxicological profile released

December 1990 Final toxicological profile released
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CONTRIBUTORS & REVIEWERS

CHEMICAL MANAGER TEAM

Jennifer Przybyla, Ph.D. (Lead) David W. Wohlers, Ph.D.

Nickolette Roney, M.P.H. Lynn Barber, M.S.

Henry Abadin, M.S.P.H. Gary L. Diamond, Ph.D.

Breanna Alman, M.P.H. Mario Citra, Ph.D.

ATSDR, Office of Innovation and Analytics, Toxicology 

Section, Atlanta, GA

SRC, Inc., North Syracuse, NY

REVIEWERS

Interagency Minimal Risk Level Workgroup: 

Includes ATSDR; National Center for Environmental Health (NCEH); National Institute for 

Occupational Safety and Health (NIOSH); U.S. Environmental Protection Agency (EPA); National 

Toxicology Program (NTP).

Additional reviews for science and/or policy: 

ATSDR, Office of Community Health and Hazard Assessment; ATSDR, Office of Capacity 

Development and Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of 

Laboratory Science; NCEH, Division of Environmental Health Science and Practice; EPA.

PEER REVIEWERS

1. Thomas E. McKone, Ph.D.; Professor Emeritus; School of Public Health; University of 

California; Berkeley, California

2. Kyle Steenland, Ph.D.; Professor, Department of Environmental Health; Professor, Department of 

Epidemiology; Rollins School of Public Health; Emory University; Atlanta, Georgia

3. Lewis Weinstock, Project Manager; Office of Air and Radiation; Office of Air Quality Planning 

& Standards; U.S. Environmental Protection Agency; Research Triangle Park, North Carolina

4. Timothy R. Fennell, Ph.D.; Senior Director, Analytical Chemistry and Pharmaceutics; RTI 

International; Durham, NC

5. Ivan Rusyn, M.D., Ph.D.; Professor, Department of Veterinary Integrative Biosciences; College 

of Veterinary Medicine & Biomedical Sciences; Texas A&M University; College Station, Texas 

6. James Wagner, Ph.D.; Associate Professor, Pathobiology and Diagnostic Investigation; College 

of Veterinary Medicine; Michigan State University; East Lansing, Michigan

These experts collectively have knowledge of toxicology, chemistry, and/or health effects. All reviewers 

were selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, 

Compensation, and Liability Act, as amended.

ATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the 

profile based on comments. The peer reviewers’ comments and responses to these comments are part of 

the administrative record for this compound.
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The listing of peer reviewers should not be understood to imply their approval of the profile's final 

content. The responsibility for the content of this profile lies with ATSDR.
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CONTENTS

DISCLAIMER..............................................................................................................................................ii

FOREWORD...............................................................................................................................................iii

VERSION HISTORY...................................................................................................................................v

CONTRIBUTORS & REVIEWERS...........................................................................................................vi

CONTENTS .............................................................................................................................................viii

LIST OF FIGURES ......................................................................................................................................x

LIST OF TABLES.......................................................................................................................................xi

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH .................................................................................1

1.1 OVERVIEW AND U.S. EXPOSURES.........................................................................................1

1.2 SUMMARY OF HEALTH EFFECTS...........................................................................................2

1.3 MINIMAL RISK LEVELS (MRLs)..............................................................................................7

CHAPTER 2. HEALTH EFFECTS..............................................................................................................9

2.1 INTRODUCTION..........................................................................................................................9

2.2 DEATH ........................................................................................................................................37

2.3 BODY WEIGHT..........................................................................................................................37

2.4 RESPIRATORY ..........................................................................................................................38

2.5 CARDIOVASCULAR.................................................................................................................39

2.6 GASTROINTESTINAL...............................................................................................................40

2.7 HEMATOLOGICAL ...................................................................................................................40

2.8 MUSCULOSKELETAL..............................................................................................................41

2.9 HEPATIC.....................................................................................................................................41

2.10 RENAL ........................................................................................................................................42

2.11 DERMAL.....................................................................................................................................42

2.12 OCULAR .....................................................................................................................................43

2.13 ENDOCRINE...............................................................................................................................44

2.14 IMMUNOLOGICAL ...................................................................................................................44

2.15 NEUROLOGICAL.......................................................................................................................45

2.16 REPRODUCTIVE .......................................................................................................................47

2.17 DEVELOPMENTAL...................................................................................................................48

2.18 OTHER NONCANCER...............................................................................................................49

2.19 CANCER......................................................................................................................................49

2.20 GENOTOXICITY........................................................................................................................68

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL 

INTERACTIONS.................................................................................................................75

3.1 TOXICOKINETICS.....................................................................................................................75

3.1.1 Absorption.............................................................................................................................76

3.1.2 Distribution ...........................................................................................................................76

3.1.3 Metabolism............................................................................................................................77

3.1.4 Excretion ...............................................................................................................................78

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models.............79

3.1.6 Animal-to-Human Extrapolations.........................................................................................88

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.....88

3.3 BIOMARKERS OF EXPOSURE AND EFFECT.......................................................................89

3.3.1 Biomarkers of Exposure........................................................................................................90
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3.3.2 Biomarkers of Effect ............................................................................................................. 91

3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 91

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 92

4.1 CHEMICAL IDENTITY ............................................................................................................. 92

4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 92

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ......................................................................... 94

5.1 OVERVIEW ................................................................................................................................ 94

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .................................................. 96

5.2.1 Production ............................................................................................................................. 96

5.2.2 Import/Export ........................................................................................................................ 98

5.2.3 Use ........................................................................................................................................ 98

5.2.4 Disposal ................................................................................................................................. 99

5.3 RELEASES TO THE ENVIRONMENT ..................................................................................... 99

5.3.1 Air ....................................................................................................................................... 100

5.3.2 Water ................................................................................................................................... 103

5.3.3 Soil ...................................................................................................................................... 104

5.3.4 Other Sources ...................................................................................................................... 104

5.4 ENVIRONMENTAL FATE ...................................................................................................... 104

5.4.1 Transport and Partitioning ................................................................................................... 104

5.4.2 Transformation and Degradation ........................................................................................ 105

5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 107

5.5.1 Air ....................................................................................................................................... 109

5.5.2 Water ................................................................................................................................... 112

5.5.3 Sediment and Soil ............................................................................................................... 113

5.5.4 Other Media ........................................................................................................................ 113

5.6 GENERAL POPULATION EXPOSURE.................................................................................. 114

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 115

CHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 120

6.1 INFORMATION ON HEALTH EFFECTS ............................................................................... 120

6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 122

6.3 ONGOING STUDIES ................................................................................................................ 127

CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 128

CHAPTER 8. REFERENCES .................................................................................................................. 130

APPENDICES

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR ETHYLENE OXIDE ........................ B-1 

APPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS 

DATA FOR ETHYLENE OXIDE ................................................................................. C-1 

APPENDIX D. USER’S GUIDE ............................................................................................................. D-1 

APPENDIX E. QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... E-1 

APPENDIX F. GLOSSARY .................................................................................................................... F-1 

APPENDIX G. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ................................................. G-1
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LIST OF FIGURES

1-1. Health Effects Found in Animals Following Inhalation Exposure to Ethylene Oxide.........................3

1-2. Health Effects Found in Animals Following Oral Exposure to Ethylene Oxide..................................4

1-3. Summary of Sensitive Targets of Ethylene Oxide – Inhalation ...........................................................7

2-1. Overview of the Number of Studies Examining Ethylene Oxide Health Effects...............................12

2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation.........................................................26

2-3. Levels of Significant Exposure to Ethylene Oxide – Oral..................................................................34

2-4. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene 

Oxide and Leukemia...........................................................................................................................57

2-5. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene 

Oxide and Non-Hodgkin's Lymphoma...............................................................................................59

2-6. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene 

Oxide and Breast Cancer....................................................................................................................60

2-7. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene 

Oxide and Lympho-Hematopoietic Cancer........................................................................................61

2-8. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene 

Oxide and Myeloma-Multiple Myeloma............................................................................................63

2-9. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene 

Oxide and Lymphosarcoma/Reticulosarcoma Cancer........................................................................64

3-1. Metabolism of Ethylene Oxide...........................................................................................................78

3-2. Physiologically Based Toxicokinetic Model for Inhaled Ethylene and Inhaled or Metabolically 

Formed Ethylene Oxide......................................................................................................................80

5-1. Number of NPL Sites with Ethylene Oxide Contamination...............................................................94

6-1. Summary of Existing Health Effects Studies on Ethylene Oxide By Route and Endpoint..............121
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LIST OF TABLES

1-1. Minimal Risk Levels (MRLs) for Ethylene Oxide ...............................................................................8

2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation.........................................................13

2-2. Levels of Significant Exposure to Ethylene Oxide – Oral..................................................................33

2-3. Study Design Details for Selected Cohorts of Workers Exposed to Ethylene Oxide.........................51

2-4. Genotoxicity of Ethylene Oxide in Humans.......................................................................................69

2-5. Genotoxicity of Ethylene Oxide in Experimental Test Species In Vivo.............................................71

2-6. Genotoxicity of Ethylene Oxide In Vitro............................................................................................73

3-1. Physiological and Physicochemical Parameters Used in the Physiologically Based 

Toxicokinetic Model.........................................................................................................................81

3-2. Biochemical Parameters Used in the Physiologically Based Toxicokinetic Model ........................82

4-1. Chemical Identity of Ethylene Oxide .................................................................................................92

4-2. Physical and Chemical Properties of Ethylene Oxide ........................................................................93

5-1. Facilities that Produce, Process, or Use Ethylene Oxide....................................................................97

5-2. Releases to the Environment from Facilities that Produce, Process, or Use Chemical 

Ethylene Oxide .................................................................................................................................100

5-3. Ethylene Oxide Emissions from the National Emissions Inventory.................................................102

5-4. Lowest Limit of Detection Based on Standards...............................................................................108

5-5. Summary of Environmental Levels of Ethylene Oxide....................................................................108

5-6. Historical Ambient Air Monitoring Data from Selected States........................................................108

5-7. Ethylene Oxide Ambient Air Levels from NATA............................................................................110

5-8. Ethylene Oxide Ambient Air Concentrations at National Air Toxics Trends Stations and 

Urban Air Toxics Monitoring Program Stations October 1, 2018 to March 31, 2019.....................111

5-9. Geometric Mean and Selected Percentiles of Blood Ethylene Oxide Hemoglobin Adduct 

Levels (pmol/g hemoglobin) Among Nonsmokers in the U.S. Population from the National 

Health and Nutrition Examination Survey (NHANES) 2013–2016.................................................116

5-10. Geometric Mean and Selected Percentiles of Blood Ethylene Oxide Hemoglobin Adduct 

Levels (pmol/g hemoglobin) Among Cigarette Smokers in the U.S. Population from the 

National Health and Nutrition Examination Survey (NHANES) 2013–2016................................117

7-1. Regulations and Guidelines Applicable to Ethylene Oxide..............................................................128
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CHAPTER 1. RELEVANCE TO PUBLIC HEALTH

1.1 OVERVIEW AND U.S. EXPOSURES

Ethylene oxide is a flammable gas with a sweet odor. It dissolves easily in water, alcohol, and most 

organic solvents. Ethylene oxide is produced in large volumes and is primarily used to make other 

chemicals, particularly ethylene glycol, a chemical that is used to make antifreeze and polyester. Most 

ethylene oxide is used in the factories where it is produced. A small amount is used to control insects on 

stored agricultural products, to sterilize food and cosmetics, and in hospitals and factories to sterilize 

medical equipment and supplies. The U.S. Environmental Protection Agency (EPA 2008) Registration 

Eligibility Decision document (RED) indicates that approximately 1,900 hospitals in the United States

have ethylene oxide sterilization chambers. 

When ethylene oxide is produced or used, some of the gas is released to air and water. If it is released 

into the air, it will break down within several months. In water, ethylene oxide will either evaporate 

quickly, break down by hydrolysis, or be destroyed by bacteria within a few days.

You are not likely to be exposed to high levels of ethylene oxide in the general environment; low levels of 

ethylene oxide have been measured in the air in many areas of the United States. There is no evidence 

that ethylene oxide is commonly found in water. The most likely way to be exposed to ethylene oxide is 

by working where it is used or produced. Heath care workers, such as nurses, doctors, and technicians in 

hospitals and offices may contact ethylene oxide, as it is used to sterilize medical equipment. Factory 

workers where ethylene oxide is produced or used to make other chemicals, and those working in 

sterilization facilities, may have contact with ethylene oxide. Residents living near facilities producing or 

using ethylene oxide may also be exposed to higher than background levels via emissions or accidental 

releases.

The U.S. Environmental Protection Agency (EPA) has determined that there is reasonable certainty that 

dietary and drinking water risks from supported registered uses of ethylene oxide will not harm any 

population subgroup (EPA 2006). Levels of ethylene oxide 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.
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Ethylene oxide is endogenously produced in the body via oxidation of ethylene produced during normal 

oxidation processes such as lipid peroxidation, methionine and heme oxidation, and metabolic activity of 

intestinal bacteria. A study comparing the relative contribution of exogenous and endogenous sources of 

ethylene oxide suggests that a substantial proportion of ethylene oxide in the body of nonsmoking 

individuals with no occupational exposure to ethylene oxide is derived from endogenously produced 

ethylene oxide (Kirman and Hays 2017).

1.2 SUMMARY OF HEALTH EFFECTS

Information on the toxicity and carcinogenicity of ethylene oxide comes from epidemiological studies and 

studies conducted in experimental animals. Most human studies evaluated only cancer endpoints; 

inhalation was the presumed exposure route. These studies evaluated the carcinogenicity of inhaled 

ethylene oxide in cohorts involved in ethylene oxide production and/or workers in areas where ethylene 

oxide was used as a sterilizer. Information on noncancer health effects primarily comes from 

experimental animal studies. Nearly 90% of the animal studies employed the inhalation exposure route. 

The limited information available regarding ethylene oxide toxicity following dermal exposure suggests

that it is a contact dermal and ocular irritant in humans and animals. As illustrated in Figures 1-1 and 1-2, 

the most sensitive noncancer targets of ethylene oxide toxicity appear to be hematological, endocrine, 

neurological, reproductive, and developmental endpoints; cancer effects also occur at lower exposure 

levels. 

A systematic review of noncancer endpoints (see Appendix C for details) resulted in the following hazard 

identification conclusions:

• Respiratory effects represent a presumed health effect endpoint for humans

• Hematological effects represent a suspected health effect endpoint for humans

• The endocrine system is a suspected health effect endpoint for humans

• Neurotoxicity is a presumed health effect for humans

• Reproductive toxicity is a presumed health effect for humans

• Developmental toxicity is a presumed health effect for humans

Respiratory 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 

relatively low-level chronic exposure (estimated long-term average of 5–10 ppm) (Joyner 1964). Adverse 

respiratory effects such as labored breathing, nasal discharge, dyspnea, histopathologic pulmonary 
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lesions, rhinitis, and/or pulmonary edema were observed in multiple animal species exposed to 113–

841 ppm ethylene oxide vapor once or intermittently for up to 2 years (Hollingsworth et al. 1956; 

Jacobson et al. 1956; NTP 1987).

Figure 1-1. Health Effects Found in Animals Following Inhalation Exposure to 

Ethylene Oxide
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Figure 1-2. Health Effects Found in Animals Following Oral Exposure to Ethylene 

Oxide*
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Hematological Effects. Decreases in hemoglobin, hematocrit, erythrocyte count, packed cell volume, 

and/or increased reticulocytes were reported in experimental animals (rats, mice, dogs) repeatedly 

exposed to ethylene oxide vapor at 250–500 ppm for 6–13 weeks (Fujishiro et al. 1990; Jacobson et al. 

1956; Snellings et al. 1984a). Splenic extramedullary hematopoiesis was reported in rats repeatedly 

exposed at 50 or 100 ppm for 104 weeks and splenic focal fibrosis was noted at 100 ppm (Lynch et al. 

1984a, 1984b).

Endocrine Effects. Pale coloration and enlargement of adrenals, and numerous fat vacuoles in adrenal 

cortex were reported in rats and guinea pigs exposed two or three times to ethylene oxide vapor at 

841 ppm for 7 hours per exposure (Hollingsworth et al. 1956). Multifocal cortical vacuolation and 

hyperplasia were observed in adrenal glands from rats intermittently exposed to ethylene oxide vapor at 

50 ppm for up to 104 weeks (Lynch et al. 1984a, 1984b).

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 

>50 years (Blackwood and Erskine 1938; Sexton and Henson 1949; von Oettingen 1939). Reliable 

exposure levels are generally not available in these cases. Peripheral neuropathy, impaired hand-eye 

coordination, and memory loss have been reported in 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 (monkeys, rats, mice, rabbits) at moderately high levels of 

ethylene oxide (200–375 ppm) for 6–7 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). An 8-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 demyelination in the brain of monkeys 

(Lynch et al. 1984a). This result raises concerns that similar morphological effects may occur in humans.

Reproductive Effects. Limited human data are available. 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. Abrahams (1980) reported 

decreased sperm counts in ethylene oxide workers. In laboratory animals, inhalation exposure to ethylene 
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oxide was associated with adverse male reproductive effects such as decreases in male reproductive organ 

weights, germ cell survival, and sperm count, as well as histopathologic lesions (Hollingsworth et al. 

1956; Kaido et al. 1992; Lynch et al. 1984a; Mori et al. 1991a, 1991b). Decreased numbers of 

implantation sites and increased resorptions have been reported in studies of ethylene oxide-exposed rats 

(NIOSH 1982; Snellings et al. 1982b).

Developmental Effects. No data on potential human developmental effects of ethylene oxide exposure 

have been located. However, embryo and fetal toxicity were reported in the offspring of rats exposed to 

100–150 ppm during gestation; the neonates were smaller in both length and weight and had reduced 

ossification of the skull and sternebrae (Neeper-Bradley and Kubena 1993; NIOSH 1982; Snellings et al. 

1982a). Decreases in pup body weight and increases in post-implantation losses were observed in rats at 

33 ppm (EPA 1994). Therefore, the offspring of humans exposed to ethylene oxide may be at risk for 

fetal and embryo toxicity. 

Cancer. The carcinogenicity of ethylene oxide has been evaluated in a number of cohorts (ethylene oxide 

production and/or uses in sterilization) (Bisanti et al. 1993; Coggon et al. 2004; Hogstedt 1988; Hogstedt 

et al. 1986; Kiesselbach et al. 1990; Mikoczy et al. 2011; Morgan et al. 1981; Norman et al. 1995; Olsen 

et al. 1997; Steenland et al. 2003, 2004; Swaen et al. 2009; Wong and Trent 1993). Some investigators 

suggested that exposure to ethylene oxide increased the risk of selected cancer types (e.g., 

lymphohematopoietic cancer, leukemia, breast cancer).

In laboratory animals exposed by inhalation, ethylene oxide was associated with a variety of cancer types 

(leukemia, mesotheliomas, lymphomas, tumors of lungs, brain, Harderian gland, and female mammary 

gland and reproductive organs) (Lynch et al. 1984a, 1984b; NTP 1987; Snellings et al. 1984b). 

Forestomach cancer (at the application site) was reported in rats administered ethylene oxide by gavage 

(Dunkelberg 1982).

The Department of Health and Human Services (HHS) has classified ethylene oxide as known to be a 

human carcinogen (NTP 2016). The EPA characterized ethylene oxide as “carcinogenic to humans” by 

the inhalation exposure route (EPA 2016a). The International Agency for Research on Cancer (IARC)

has designated ethylene oxide as carcinogenic to humans (Group 1) (IARC 1987, 2012).
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1.3 MINIMAL RISK LEVELS (MRLs)

The inhalation database was considered adequate for derivation of provisional acute- and intermediate--

duration inhalation MRLs for ethylene oxide. The database was not considered adequate for derivation of 

a chronic-duration inhalation MRL. As presented in Figure 1-3, the available inhalation data for ethylene 

oxide suggest that respiratory, hematological, endocrine, neurological, reproductive, and developmental 

endpoints are sensitive targets of toxicity following inhalation exposure.

The oral database was not considered adequate for derivation of provisional acute-, intermediate-, or 

chronic-duration oral MRLs. 

Figure 1-3. Summary of Sensitive Targets of Ethylene Oxide – Inhalation

Hematological, endocrine, neurological, and reproductive endpoints are the most sensitive 

noncancer targets of ethylene oxide inhalation exposure.

Numbers in circles are the lowest LOAELs for all health effects in animals; no exposure-response human 

data were identified.
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The provisional MRL values for ethylene oxide are summarized in Table 1-1 and discussed in greater 

detail in Appendix A.

Table 1-1. Minimal Risk Levels (MRLs) for Ethylene Oxidea

Exposure 

duration MRL Critical effect

Point of departure/

human equivalent 

concentration

Uncertainty 

and modifying 

factors Reference

Inhalation exposure (ppm)

Acute

(provisional)

0.4 Depressed fetal 

weight

BMCL10: 45.12

(BMCLHEC: 11.28)

UF: 30 Snellings et 

al. 1982a

Intermediate

(provisional)

0.02 Neurotoxicity NOAEL: 10

(NOAELHEC: 1.8)

UF: 30

MF: 3

Snellings et 

al. 1984a

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information.

BMCL = 95% lower limit of benchmark concentration; HEC = human equivalent concentration; MF = modifying 

factor; NOAEL = no-observed-adverse-effect level; UF = uncertainty factor
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CHAPTER 2. HEALTH EFFECTS

2.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of ethylene oxide. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

When available, mechanisms of action are discussed along with the health effects data; toxicokinetic 

mechanistic data are discussed in Section 3.1.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

To help public health professionals and others address the needs of persons living or working near hazardous 

waste sites, the information in this section is organized by health effect. These data are discussed in terms of 

route of exposure (inhalation, oral, and dermal) and three exposure periods: acute (≤14 days), intermediate 

(15–364 days), and chronic (≥365 days).

As discussed in Appendix B, a literature search was conducted to identify relevant studies examining health 

effect endpoints. Figure 2-1 provides an overview of the database of studies in humans or experimental 

animals included in this chapter of the profile. These studies evaluate the potential health effects associated 

with inhalation, oral, or dermal exposure to ethylene oxide, but may not be inclusive of the entire body of 

literature. A systematic review of the scientific evidence of the health effects associated with exposure to 

ethylene oxide was also conducted; the results of this review are presented in Appendix C.

Animal inhalation studies are presented in Table 2-1 and Figure 2-2, and animal oral studies are presented 

in Table 2-2 and Figure 2-3; limited dermal data were identified for ethylene oxide.

Levels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-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. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 
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or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an endpoint should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these endpoints. ATSDR believes 

that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less 

serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. Levels of exposure associated with cancer (Cancer Effect Levels, CELs) of 

ethylene oxide are indicated in Tables 2-1 and 2-2 and Figures 2-2 and 2-3.

A User's Guide has been provided at the end of this profile (see Appendix D). This guide should aid in 

the interpretation of the tables and figures for LSEs and MRLs.

The health effects of ethylene oxide have been evaluated in a number of occupational cohorts and a 

variety of animal studies. As illustrated in Figure 2-1, the inhalation exposure route was employed in the 

majority of animal studies; inhalation was assumed to be the predominant exposure route in the 

occupational cohort studies. The most examined endpoints in animal studies were body weight and 

neurotoxicity. Cancer was the most examined endpoint in epidemiological studies.

Human and/or animal studies suggest that relatively sensitive noncancer targets of ethylene oxide include 

respiratory, hematological, endocrine, neurological, reproductive, and developmental endpoints (see 

Appendix C for more information on the systematic review and for definitions of evidence 

levels). Human and animal studies have also reported carcinogenic effects.

• Respiratory Endpoints: Respiratory effects are a presumed health effect for humans based on a 

moderate level of evidence in workers and a high level of evidence in experimental animal 

studies. Compromised respiratory function has been reported in workers exposed to high levels 

of ethylene oxide. Inhalation studies in experimental animals have reported several respiratory 

effects including labored breathing, nasal discharge, pulmonary lesions, rhinitis, and pulmonary 

edema.

• Hematological Endpoints: Hematological effects are a suspected health effect for humans based 

on a moderate level of evidence in animal studies. Repeated exposure of experimental animals to 

ethylene oxide vapor has resulted in hematological effects such as decreases in hemoglobin, 
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hematocrit, erythrocyte count, packed cell volume, and/or reticulocytes, and splenic 

extramedullary hematopoiesis.

• Endocrine Endpoints: Adrenal gland effects are a suspected health effect in humans based on a 

moderate level of evidence in animal studies. Adverse effects (gross and/or histopathologic 

changes in the adrenal gland) have been observed in rats and guinea pigs following acute- and/or 

chronic-duration exposure to ethylene oxide vapor. 

• Neurological Endpoints: Neurological effects are a presumed health effect in humans based on 

a low level of evidence in occupational exposure studies and a high level of evidence in animal 

studies. Clinical signs of neurotoxicity (e.g., neuropathy, weakness in extremities, impaired 

hand-eye coordination, cognitive dysfunction, memory loss, headache, lethargy) were reported 

among workers exposed to ethylene oxide for various durations. Sural nerve biopsies revealed 

axonal degeneration and regeneration in two studies. Neurological effects such as ataxia, 

impaired sensory reflexes, hindlimb paralysis, and/or degenerative histopathologic lesions have 

been observed among laboratory animals exposed to ethylene oxide by inhalation.

• Reproductive Endpoints: Male reproductive effects are a presumed health effect in humans 

based on a moderate level of evidence in occupational exposure studies and a high level of 

evidence in animal studies. Limited human data suggest possible ethylene oxide-related effects 

on sperm production. Animal studies provide convincing evidence of ethylene oxide-induced

effects on the male reproductive system (e.g., decreases in male reproductive organ weights, germ 

cell survival, and sperm count; histopathologic lesions).

• Developmental Endpoints: Ethylene oxide is a presumed developmental toxicant in humans 

based on animal studies that demonstrated ethylene oxide-induced developmental effects such as 

depressed fetal weight, delayed ossification, fetal fluid retention, and ocular defects.

• Cancer: The carcinogenicity of ethylene oxide has been evaluated in a number of cohorts 

involved in ethylene oxide production and/or uses in sterilization. Results from some cohort 

studies suggest that exposure to ethylene oxide may increase the risk of selected cancer types 

(e.g., lymphohematopoietic cancer, leukemia, breast cancer). In laboratory animals exposed by 

inhalation, ethylene oxide was associated with a variety of cancer types (leukemia, 

mesotheliomas, lymphomas, tumors of lungs, Harderian gland, and female mammary gland and 

reproductive organs). Forestomach cancer was reported in rats treated by the oral exposure route.
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Figure 2-1. Overview of the Number of Studies Examining Ethylene Oxide Health Effects

Most studies examined the potential body weight, neurological, and cancer effects of ethylene oxide

Fewer studies evaluated health effects in humans than animals (counts represent studies examining endpoint)

*Includes studies discussed in Chapter 2. A total of 124 studies (including those finding no effect) have examined toxicity; most studies examined multiple 

endpoints. Chronic exposure was considered the most prevalent exposure duration for human occupational studies.
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

ACUTE EXPOSURE

1 Rat, mouse,

guinea pig, 

rabbit, 

monkey

(NS)

1–10 (NS)

Up to 10 days

Up to 

8 exposures

7 hours/exposure

0, 841 GN, HP, LE Death 841 100% mortality for each species

Hollingsworth et al. 1956

2 Rat, guinea 

pig (NS)

5/sex/species

2 or 3 exposures

7 hours/exposure

0, 841 HP, LE Resp 841 Slight to moderate edema; slight 

hemorrhage and congestion in lungs

Hepatic 841 Light coloration and slight fatty 

degeneration

Renal 841 Enlarged kidney; slight congestion and 

cloudy swelling of convoluted tubules

Endocr 841 Pale coloration and enlargement in 

adrenals; numerous fat vacuoles in 

adrenal cortex

Hollingsworth et al. 1956

3 Rat (NS)

10/sex Mouse

(NS)

10 F

9 days

7 exposures

7 hours/exposure

0, 357 BW, GN, LE Death 357 Death of 2/20 rats and 4/20 mice

Bd wt 357 Moderate body weight loss (not 

otherwise described)

Resp 357 Severe lung injury (not otherwise 

described)

Hollingsworth et al. 1956

4 Rat

(White)

10 M

Once for 4 hours 882, 1,343, 

1,648, 

1,843, 

1,992, 

2,298

CS, LE Death 1,460 4-hour LC50

Jacobson et al. 1956
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

5 Rat

(CD)

25 F

GDs 6–15

6 hours/day

0, 50, 125, 

225

BW, CS, DX, 

FI, FX, LE, 

MX, OF, OW

Bd wt 225

Develop 50 125 5% depressed mean fetal weight/litter

Neeper-Bradley and Kubena 1993

6 Rat (SpragueDawley)

39 or 41 F

GDs 7–16

7 hours/day

0, 150 BW, DX, HP, 

OW

Bd wt 150

Develop 150 5–6% depressed fetal body weight;

decreased crown-rump length;

delayed ossification (skull, sternebrae)

NIOSH 1982

7 Rat (SpragueDawley)

20–21 F

GDs 6–15

1 time/day

30 minutes

0, 400, 

800, 1,200

BW, DX, FX, 

LE, MX

Bd wt 1,200

Develop 800 1,200 Increased incidence of dilation in renal 

pelvis and ureter

Saillenfait et al. 1996

8 Rat (SpragueDawley)

18 F

GDs 5–16

3 times/day

30 minutes each

0, 200, 400 BW, DX, FX, 

LE, MX

Bd wt 400 NOAEL is for three 30-minute 

exposures at 400 ppm per day

Develop 400 NOAEL is for three 30-minute 

exposures at 400 ppm per day

Saillenfait et al. 1996

9 Rat (SpragueDawley)

21 F

GDs 6–15

3 times/day

30 minutes each

0, 800, 

1,200

BW, DX, FX, 

LE, MX

Bd wt 800 1,200 70% depressed mean maternal body 

weight gain for GDs 6–16

Develop 800 4–7% depressed mean fetal weight

Saillenfait et al. 1996

10 Rat

(Fischer- 344)

22 F

GDs 6–15

6 hours/day

0, 0, 10, 

33, 100

CS, DX Develop 33b 100 3–9% depressed fetal body weight; 

BMCL05 of 45.12 ppm

Snellings et al. 1982a
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

11 Rat (SpragueDawley)

5 M or 5 F

Once for 1 hour M: 4,827, 

5,546, 

6,161; F: 

3,966, 

4202, 

4,827

CS, LE Death 5,748 M 

4,439 F

1-hour LC50

Snellings et al. 2011

12 Rat (SpragueDawley)

5 M or 5 F

Once for 4 hours M: 1,850, 

2,026, 

2,182; F: 

1,443, 

1,637, 

1,850

CS, LE Death 1,972 M

1,537 F

4-hour LC50

Snellings et al. 2011

13 Mouse

(White)

10 F

Once for 4 hours 533, 860, 

882, 960, 

1,343, 

1,365

CS, LE Death 835 4-hour LC50

Jacobson et al. 1956

14 Mouse 

(B6C3F1)

5 M, 5 F

Once for 4 hours 100, 200, 

400, 800, 

1,600

CS, LE Death 800 5/5 males and 4/5 females died at 

800 ppm and 5/5 males and 

5/5 females died at 1,600 ppm

Resp 800 1,600 LOAEL: Dyspnea observed after 

4 hours of exposure to 800 ppm

Serious LOAEL: Dyspnea observed 

after 3 hours of exposure to 

1,600 ppm; dyspnea graded as severe 

in the 1,600 ppm after 3.5 hours of 

exposure.

Neuro 1,600 Incoordination after 3 hours and semiconsciousness after 3.5 hours of 

exposure to 1,600 ppm

NTP 1987
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

15 Mouse

(B6C3F1)

10 M, 10 F

Up to 2 weeks 

during a 14-week 

study

5 days/week

6 hours/day

0, 50, 100, 

200, 400, 

600

BW, CS, GN, 

HP, LE

Death 400 100% mortality at 400 and 600 ppm, 

deaths occurred during first 2 weeks of 

exposure

Resp 400 Rhinitis

Renal 400 Renal tubular degeneration and 

necrosis

Immuno 600 Lymphocyte necrosis in thymus

NTP 1987

16 Mouse 

(B6C3F1)

5 M, 5 F

2 weeks

5 days/week

6 hours/day

0, 50, 100, 

200, 400, 

800

BW, CS, GN, 

HP, LE

Death 800 100% mortality

Bd wt 400

NTP 1987

17 Mouse

(Hybrid)

22–55 F

Once for 

1.5 hours

1, 6, 9, or 

25 hours 

postmating

0, 1,200 DX, FX Develop 1,200 Fetal defects (predominantly hydrops 

and eye defects)

Rutledge and Generoso 1989

18 Dog

(Beagle)

3 M

Once for 4 hours 327, 710, 

1,393, 

2,830

CS, LE Death 960 4-hour LC50

Jacobson et al. 1956

19 Rabbit

(New 

Zealand)

20 or 21 F

GDs 7–19

7 hours/day

0, 150 BW, DX, HP, 

OW

Bd wt 150

Develop 150

NIOSH 1982

INTERMEDIATE EXPOSURE

20 Monkey

(NS)

3 M, 1 F

60 or 140 days

38–41 or 

94 exposures

7 hours/exposure

0, 357 BW, CS, HP, 

LE

Musc/skel 357 Muscular atrophy in hindlimbs

Neuro 357 Impaired sensory reflexes, paralysis of 

hindlimbs

Hollingsworth et al. 1956
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

21 Rat

(CD)

28 M, 28 F

6 hours/day, 

5 days/week for 

10 weeks premating; 

6 hours/day, 

5 days/week 

during mating, 

GDs 0–20, and 

LDs 5–28

0, 10, 33, 

100

CS, BW, 

OW, HP, DX, 

RX

Bd wt 10 33 Decreased body weight (7–11%) in F1 

males

Resp 100

Hepatic 100

Neuro 100

Repro 10 33 Post implantation loss in F0 rats; 

decreased number of live pups per 

litter in F1 and F2 generations at 

100 ppm

Develop 10 33 Decreased pup body weight in F1 and 

F2 generations

EPA 1994

22 Rat

(Wistar)

8 M

13 weeks

3 days/week

6 hours/day

0, 500 BW, EA, HE, 

OF, OW, UR

Bd wt 500

Hemato 500 Decreases in hemoglobin, hematocrit, 

erythrocyte count; increased 

reticulocytes

Fujishiro et al. 1990

23 Rat

(White)

20 M

6 weeks

5 days/week

6 hours/day

0, 406 BW, CS, GN, 

LE

Death 406 13/20 rats died during the 6-week 

exposure period

Resp 406 Labored breathing, nasal discharge

Neuro 406 Loss of hindquarter usefulness

Jacobson et al. 1956

24 Rat

(White)

20 M

6 months

5 days/week

6 hours/day

0, 102 BW, CS, GN, 

LE

Resp 102

Neuro 102

Jacobson et al. 1956

25 Rat 

(Wistar)

6 or 8 M 

(28 M 

controls)

Up to 13 weeks

3 days/week

6 hours/day

0, 500 BW, CS, OF, 

OW

Neuro 500 Awkward gait

Repro 500 Decreased testicular weight, 

decreased germ cell survival, 

degenerative effects on germ cells

Kaido et al. 1992
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

26 Rat

(Wistar)

Up to 9 M

12 weeks

3 days/week

6 hours/day

0, 500 BW, CS, EA Bd wt 500

Neuro 500 Ataxic gait

Matsuoka et al. 1990

27 Rat

(Wistar)

6 or 12 M

13 weeks

5 days/week

6 hours/day

0, 50, 100, 

250

BW, EA, OF, 

OW

Bd wt 250

Repro 100 250 20% decreased epididymal weight, 

73% decreased epididymal sperm 

count, histopathologic lesions in 

seminiferous tubules

Mori et al. 1991a

28 Rat

(Wistar)

8 M

6 weeks

3 days/week

6 hours/day

0, 500 BW, EA, OF, 

OW

Bd wt 500

Repro 500 26% decreased testicular weight, 32% 

decreased epididymal weight, 87% 

decrease in sperm counts, increased 

sperm head abnormalities

Mori et al. 1991b

29 Rat (SpragueDawley) 

39 or 41 F

GDs 1–16

7 hours/day

0, 150 BW, DX, FX, 

HP, OW

Bd wt 150

Resp 150

Hepatic 150

Renal 150

Repro 150 Increased incidence of resorptions

Develop 150 7–9% decreased fetal body weight; 

delayed ossification (skull, sternebrae)

NIOSH 1982
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

30 Rat (SpragueDawley) 

32–45 F

3 weeks 

premating and 

GDs 1–16

7 hours/day

0, 150 BW, DX, FX, 

OW

Bd wt 150

Resp 150

Hepatic 150

Renal 150

Repro 150 Increased incidence of resorptions

Develop 150 10–12% decreased fetal weight, 

decreased crown-rump length, 

delayed ossification (skull, sternebrae)

NIOSH 1982

31 Rat

(Wistar)

5 M

13 weeks

3 days/week

6 hours/day

0, 500 CS, HP, OF Bd wt 500

Neuro 500 Peripheral neuropathy

Ohnishi et al. 1985

32 Rat

(Wistar)

7 M

9 months

5 days/week

6 hours/day

0, 250 CS, HP, OF Neuro 250 Retarded growth and maturation of 

myelinated fibers in hindleg nerves 

and mild axonal degeneration in 

absence of clinical signs of neuropathy

Ohnishi et al. 1986

33 Rat

(Fischer- 344)

30 M, 20 F

12 weeks 

premating, 

2 weeks mating, 

and throughout 

gestation and 

lactation

5 or 7 days/week

6 hours/day

0, 0, 10, 

33, 100

BW, DX, FX Bd wt 100

Repro 33 100 Decreases in the number of pups/litter 

and the ratio of fetuses born to 

implantation sites

Develop 100

Snellings et al. 1982b
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

34 Rat, mouse,

rabbit, 

monkey

(NS)

1–10 (NS)

48–85 days

33–59 exposures

7 hours/exposure

0, 357 CS, LE Death 357 Death of 18/20 rats, 

10/10 mice,1/2 rabbits

Bd wt 357 Markedly subnormal growth of each 

species (not otherwise described)

Musc/skel 357 Muscular atrophy in hindlimbs of rats, 

rabbits, and monkey

Neuro 357 Impaired sensory and motor function; 

paralysis in hindlimbs of rats, rabbits, 

monkey

Hollingsworth et al. 1956

35 Rat, mouse,

monkey, 

guinea pig

(NS)

2–20 (NS)

176–226 days

122–

157 exposures

7 hours/exposure

0, 113 BW, CS, HP, 

LE, OF, OW

Bd wt 113 F 113 M 13% depressed final body weight in 

male rats

Resp 113 20–22% increased relative lung weight 

in male and female rats

Hollingsworth et al. 1956

36 Rat, mouse,

rabbit, 

monkey, 

guinea pig

(NS)

2–20 (NS)

176–226 days

122–

157 exposures

7 hours/exposure

0, 204 BW, CS, HP, 

LE, OF, OW

Death 204 Death of 14/20 male and 8/20 female 

rats

Bd wt 204 20, 13, and 10% depressed final body 

weight among male and female rats 

and female guinea pigs, respectively

Resp 204 18–31% increased relative lung weight 

among male and female rats and 

female guinea pigs

Musc/skel 204 Muscular atrophy in hindlimbs of 

monkeys

Neuro 204 Impaired sensory reflexes and partial 

paralysis in hind quarters and back of 

monkeys; slight to marked paralysis in 

hindlegs of rabbits

Hollingsworth et al. 1956
ETHYLENE OXIDE 21

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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

37 Mouse

(A/J)

30 F

6 months

5 days/week

6 hours/day

0, 70, 200 HP, LE Cancer 70 CEL: Lung tumors

Adkins et al. 1986

38 Mouse

(White)

30 F

6 weeks

5 days/week

6 hours/day

0, 406 BW, CS, GN, 

LE

Death 406 24/30 mice died

Jacobson et al. 1956

39 Mouse

(White)

30 F

6 months

5 days/week

6 hours/day

0, 102 BW, CS, GN, 

LE

Bd wt 102

Jacobson et al. 1956

40 Mouse 

(B6C3F1)

10 M, 10 F

Up to 14 weeks

5 days/week

6 hours/day

0, 50, 100, 

200, 400, 

600

BW, CS, GN, 

HP, LE

Bd wt 200

Resp 100 200 Rhinitis in males and females

Renal

100 F

100 M

200 F

Renal tubular degeneration (5/10 M; 

8/10 F)

NTP 1987

41 Mouse

(B6C3F1)

30 M, 30 F

10–11 weeks

5 days/week

6 hours/day

0, 10, 50, 

100, 250

BC, BW, HE, 

HP, MX

Bd wt 250

Hemato 100 250 Males: decreases in hemoglobin

Females: decreases in RBC count, 

hemoglobin, packed cell volume, 

mean corpuscular hemoglobin 

concentration

Musc/skel 250

Hepatic 250

Neuro 10c 50 Males: reduced locomotor activity

Females: hunched posture during gait

Repro 250 M

Snellings et al. 1984a
ETHYLENE OXIDE 22

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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

42 Dog

(Beagle)

3 M

6 months

5 days/week

6 hours/day

0, 102 BC, BW, CS, 

HE, LE

Bd wt 102

Hemato 102 Signs indicative of normochromic 

anemia in 2/3 dogs

Jacobson et al. 1956

43 Dog

(Beagle)

3 M

6 weeks

5 days/week

6 hours/day

0, 292 BC, BW, CS, 

GN, HE

Bd wt 292

Resp 292 Pulmonary congestion, moderate 

alveolar collapse; consistent with mild 

irritation of lung parenchyma

Hemato 292 Decreases in erythrocyte count, 

hemoglobin, hematocrit

Musc/skel 292 Fatty changes consistent with 

muscular atrophy

Neuro 292 Slight tremors, hindleg weakness

Jacobson et al. 1956

44 Rabbit

(New 

Zealand)

21 or 23 F

GDs 1–19

7 hours/day

0, 150 BW, DX, HP, 

OW

Bd wt 150

Resp 150

Hepatic 150

Renal 150

Develop 150

NIOSH 1982
ETHYLENE OXIDE 23

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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

CHRONIC EXPOSURE

45 Monkey

(Cynomolgus)

12 M

Up to 2 years

5 days/week

7 hours/day

0, 50, 100 BC, BW, GN, 

HE, HP, LE, 

OF, OP, UR

Cardio 100

Hemato 100

Repro 50 Decreased sperm count and motility

Lynch et al. 1984a

46 Rat

(Fischer-344)

120 M, 120 F

Up to 2 years

5 days/week

6 hours/day

0, 0, 10, 

33, 100

BW, HP, LE Death 100 Increase in mortality in months 22–23

Bd wt 33 100 M: Up to 12% depressed body weight 

gain

F: 12–18% depressed body weight 

gain

Cancer 33 CEL: Mononuclear leukemia in 

females at ≥33 ppm; peritoneal 

mesothelioma in males at 100 ppm; 

subcutis fibroma in males at 100 ppm; 

brain tumors in males and females at 

≥33 ppm

Garman et al. 1986; Snellings et al. 1984b

47 Rat

(Fischer- 344)

80 M

Up to 2 years

5 days/week

7 hours/day

0, 50, 100 BC, BW, GN, 

HE, HP, UR

Death 100 Decreased survival

Bd wt 50 100 16% decrease in body weight gain

Cardio 100

Gastro 100

Hemato 50 Splenic extramedullary hematopoiesis 

at ≥50 ppm and splenic focal fibrosis 

at 100 ppm; no alterations in 

hematological parameters

Musc/skel 50 100 Multifocal myopathy in skeletal muscle

Hepatic 100

Renal 100

Ocular 100
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Endocr 50 Multifocal cortical vacuolation and 

hyperplasia in the adrenal gland

Neuro 100

Repro 100

Cancer 50 CEL: Mononuclear cell leukemia at 

≥50 ppm; peritoneal mesotheliomas 

and brain gliomas at 100 ppm

Lynch et al. 1984a, 1984b

48 Mouse

(B6C3F1)

50 M, 50 F

102 weeks

5 days/week

6 hours/day

0, 50, 100 BW, CS, GN, 

HP, LE

Bd wt 100

Resp 100

Cardio 100

Gastro 100

Musc/skel 100

Hepatic 100

Renal 100

Dermal 100

Endocr 100

Neuro 100

Repro 100
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Table 2-1. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Cancer 50 M CEL: Harderian gland papillary 

cystadenoma in males at ≥50 ppm and 

females at 100 ppm; mammary gland 

tumors in females at 50 ppm; lung 

alveolar/bronchiolar adenoma or 

carcinoma, malignant lymphomas 

(females only), and uterine 

adenocarcinomas at 100 ppm

NTP 1987

aThe number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in Figure 2-2. 

Where such differences exist, only the levels of effect for the most sensitive sex are presented. bUsed to derive a provisional acute-duration inhalation minimal risk level (MRL) of 0.4 ppm for ethylene oxide; based on a rat BMCLHEC of 11.28 ppm (BMCL05 of 

45.12 ppm adjusted for intermittent exposure and converted to a human equivalent concentration) and an uncertainty factor of 30 (3 for extrapolation from animals to 

humans using dosimetric adjustment and 10 for human variability); see Appendix A for more detailed information regarding the provisional MRL. cUsed to derive a provisional intermediate-duration inhalation MRL of 0.02 ppm for ethylene oxide; based on a NOAELHEC of 1.8 ppm (NOAEL of 0.02 ppm adjusted for 

intermittent exposure and converted to a human equivalent concentration), an uncertainty factor of 30 (3 for extrapolation from animals to humans using dosimetric 

adjustment and 10 for human variability), and a modifying factor of 3 for lack of neurotoxicity data; see Appendix A for more detailed information regarding the provisional 

MRL.

Principal studies for the MRLs.

Bd wt or BW = body weight; BMCL = 95% lower confidence limit on the BMC (subscripts denote benchmark response: i.e., 10 = exposure concentration associated with 

10% extra risk); Cardio = cardiovascular; CEL = cancer effect level; CS = clinical signs; Develop = developmental; DX = developmental toxicity; EA = enzyme activity; 

Endocr = endocrine; F = female(s); FI = food intake; FX = fetal toxicity; Gastro = gastrointestinal; GD = gestation day(s); GN = gross necropsy; HE = hematology; 

HEC = human equivalent concentration; Hemato = hematological; HP = histopathology; Immuno = immunological; LC50 = lethal concentration, 50% kill; LD = lactation day; 

LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); Musc/skel = musculoskeletal; MX = maternal toxicity; Neuro = neurological; NOAEL = noobserved-adverse-effect level; NS = not specified; OF = organ function; OP = ophthalmology; OW = organ weight; RBC = red blood cell; Repro = reproductive; 

Resp = respiratory; RX = reproductive effects; UR = urinalysis
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Figure 2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Acute (≤14 days)
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Figure 2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Acute (≤14 days)
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Figure 2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Intermediate (15-364 days)
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Figure 2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Intermediate (15-364 days)
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Figure 2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Intermediate (15-364 days)
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Figure 2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Chronic (≥365 days)
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Figure 2-2. Levels of Significant Exposure to Ethylene Oxide – Inhalation

Chronic (≥365 days)
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Table 2-2. Levels of Significant Exposure to Ethylene Oxide – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effects

ACUTE EXPOSURE

1 Rat (NS)

5 M, 5 F

Once

(GO)

100, 200 BW, LE Death 200 100% mortality

Bd wt 100

Hollingsworth et al. 1956

2 Rat (Wistar) 

10 M

Once

(GW)

NS LE Death 330 LD50

Smyth et al. 1941

3 Guinea pig

(NS)

NS M, NS F

Once

(GW)

NS LE Death 270 LD50

Smyth et al. 1941

INTERMEDIATE EXPOSURE

4 Rat (NS)

5 F

15 times in 

21 days

(100 mg/kg/day)

22 times in 

30 days

(3, 10, 

30 mg/kg/day)

(GO)

0, 3, 10, 30, 

100

BW, GN, HE, 

HP, OW

Bd wt 30 100 Weight loss, magnitude not 

reported

Gastro 30 100 Gastric irritation; no 

additional information

Hemato 30

Hepatic 30 100 Slight liver damage; no 

additional information

Hollingsworth et al. 1956

CHRONIC EXPOSURE

5 Rat

(SpragueDawley)

50 F

150 weeks

2 times/week

(GO)

0, 7.5, 30 HP, LE Death 30 Decreased survival

Cancer 7.5 CEL: Forestomach 

squamous cell carcinoma

Dunkelberg 1982

aThe number corresponds to entries in Figure 2-3.

Bd wt or BW = body weight; CEL = cancer effect level; F = female(s); (GO) = gavage in oil; (GW) = gavage in water; Gastro = gastrointestinal; GN = gross necropsy; 

HE = hematology; Hemato = hematological; HP = histopathology; LD50 = lethal dose, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); 

NOAEL = no-observed-adverse-effect level; NS = not specified
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Figure 2-3. Levels of Significant Exposure to Ethylene Oxide – Oral

Acute (≤14 days)
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Figure 2-3. Levels of Significant Exposure to Ethylene Oxide – Oral

Intermediate (15-364 days)
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Figure 2-3. Levels of Significant Exposure to Ethylene Oxide – Oral

Chronic (≥365 days)
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2.2 DEATH

Results from a number of epidemiological studies involving occupational exposure to ethylene oxide and 

risk of death from various cancer types (particularly all cancers, lymphohematopoietic cancer, leukemia, 

stomach cancer, pancreatic cancer, and brain and nervous system cancer) are summarized in Section 2.19.

Information regarding death in experimental animals following inhalation exposure to ethylene oxide is 

available. Limited information is available for the oral exposure route. No information was located for 

the dermal exposure route. 

For rats exposed once to ethylene oxide vapor, 1-hour LC50 values were 5,748 and 4,439 ppm for males 

and females, respectively; 4-hour LC50 values were 1,972 and 1,537, respectively (Snellings et al. 2011). 

A 4-hour LC50 of 1,460 ppm was reported for male rats (Jacobson et al. 1956). Mice and dogs were more 

sensitive to acute lethality than rats; reported 4-hour LC50 values were 835 and 960 ppm, respectively 

(Jacobson et al. 1956). Lethality occurred in rats, mice, rabbits, guinea pigs, and monkeys following 

single or repeated inhalation exposure at 204–841 ppm for periods up to 6 weeks (Hollingsworth et al. 

1956; Jacobson et al. 1956; NTP 1987). Studies that employed repeated exposure of rats for up to 2 years 

reported increased mortality at exposures as low as 100 ppm (Garman et al. 1986; Lynch et al. 1984a, 

1984b; Snellings et al. 1984b).

Hollingsworth et al. (1956) reported 100% mortality among rats (5/sex) gavaged once at 200 mg/kg. 

Dunkelberg (1982) reported decreased length of survival among 50 female rats gavaged at 30 mg/kg/day, 

2 times/week, for up to 150 weeks. 

2.3 BODY WEIGHT

No studies were located regarding body weight effects in humans following inhalation, oral, or dermal 

exposure to ethylene oxide.

Information for the inhalation exposure route is available for body weight effects in experimental animals. 

Limited information is available for the oral exposure route. No information was located for the dermal 

exposure route.
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Depressed body weight was reported in a few acute-duration studies of rats or mice repeatedly exposed to 

ethylene oxide vapor at levels in the range of 357–1,200 ppm (Hollingsworth et al. 1956; Saillenfait et al. 

1996) and in mature F1 males exposed to 33 ppm during a 10-week mating period (EPA 1994). 

Decreases in final body weights (10–20%) were observed in rats and guinea pigs exposed to 113–

204 ppm ethylene oxide for up to 226 days (Hollingsworth et al. 1956). Hollingsworth et al. (1956) also 

reported “markedly subnormal growth” (magnitude not reported) among rats, mice, rabbits, guinea pigs, 

and/or monkeys intermittently exposed to ethylene oxide vapor at 357 ppm for up to 85 days. Other 

acute- and intermediate-duration inhalation studies of rats, mice, and/or rabbits found no body weight 

effects at exposure levels in the range of 100–500 ppm (Jacobson et al. 1956; Matsuoka et al. 1990; Mori 

et al. 1991a, 1991b; Neeper-Bradley and Kubena 1993; NTP 1987; Ohnishi et al. 1985; Saillenfait et al. 

1996; Snellings et al. 1982a, 1982b). In 2-year rat studies that employed repeated exposure to ethylene 

oxide vapor, 12–18% depressed body weight gain was reported at an exposure level of 100 ppm (Garman 

et al. 1986; Lynch et al. 1984a, 1984b). No body weight effects were observed for mice repeatedly 

exposed at up to 100 ppm for 102 weeks (NTP 1987).

Hollingsworth et al. (1956) found no body weight effects among rats gavaged once at 100 mg/kg/day. 

Repeated dosing of female rats at 100 mg/kg/day resulted in an unspecified magnitude of weight loss; the 

NOAEL was 30 mg/kg/day.

2.4 RESPIRATORY

Limited data are available regarding ethylene oxide-related respiratory effects in humans. 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 (Thiess 1963). Deschamps et al. (1992) reported a case of 

persistent asthma in a 35-year-old male who was highly exposed to ethylene oxide from a leaky railroad 

tank. Pulmonary function remained compromised when tested 1 and 3 years after the accidental 

exposure. There was no evidence of increased risk of death from non-malignant respiratory disease 

within various cohorts of workers involved in production or use of ethylene oxide (Bisanti et al. 1993; 

Coggon et al. 2004; Hogstedt 1988; Morgan et al. 1981; Steenland et al. 1991; Swaen et al. 2009; Wong 

and Trent 1993).

Information is available regarding respiratory effects in experimental animals following inhalation 

exposure to ethylene oxide. No information was located for oral or dermal exposure routes.
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Dyspnea was observed after 4 hours of exposure of mice to ethylene oxide vapor at a lethal exposure level 

of 800 ppm (NTP 1987). Adverse respiratory effects (e.g., dyspnea, pulmonary edema, pulmonary 

hemorrhage and congestion, “severe lung injury”) were reported for experimental animals (rats, mice, 

and/or guinea pigs) exposed to 357–841 ppm ethylene oxide vapor for acute durations (Hollingsworth et 

al. 1956; NTP 1987). Rhinitis was also observed in mice exposed to 400 ppm ethylene oxide for up to 

2 weeks (NTP 1987). Intermediate-duration studies reported labored breathing and nasal discharge in rats 

exposed to 406 ppm for 6 weeks (Jacobsen et al. 1956), an increase in relative lung weight in rats and 

guinea pigs exposed to 113–204 ppm for up to 226 days (Hollingsworth et al. 1956), rhinitis in mice 

exposed to 200 ppm for up to 14 weeks (NTP 1987), and pulmonary congestion and alveolar collapse in 

dogs exposed to 292 ppm for 6 weeks (Jacobsen et al. 1956). Acute bronchopneumonia, chronic 

pneumonia, pulmonary edema, and suppurative rhinitis were observed in rats exposed at 50 ppm for 

104 weeks (Lynch et al. 1984a, 1984b). However, all groups of rats in this study (including controls) 

experienced a pulmonary bacterial infection as early as 8 months into the treatment period and were 

treated at months 8, 16, and 20. The infection likely played a significant role in the reported respiratory 

effects. There were no indications of exposure-related respiratory effects in rats exposed to 100 ppm as 

part of a 2-generation reproduction study (EPA 1994) or in mice repeatedly exposed at up to 100 ppm for 

102 weeks (NTP 1987).

2.5 CARDIOVASCULAR

Limited data are available regarding ethylene oxide-related cardiovascular effects in humans. There was 

no evidence of increased risk of death from cardiovascular or cerebrovascular diseases within various 

cohorts of workers involved in production or use of ethylene oxide (Bisanti et al. 1993; Coggon et al. 

2004; Hagmar et al. 1991; Hogstedt 1988; Kiesselbach et al. 1990; Morgan et al. 1981; Olsen et al. 1997; 

Steenland et al. 2004; Swaen et al. 2009; Wong and Trent 1993).

Limited information is available regarding cardiovascular endpoints in experimental animals following 

inhalation exposure to ethylene oxide. No information was located for oral or dermal exposure routes.

Lynch et al. (1984b) found no effects on electrocardiograms of male monkeys during repeated exposure 

to ethylene oxide vapor at 50 or 100 ppm for up to 2 years. There was no histopathological evidence of 

ethylene oxide-induced cardiovascular effects in mice repeatedly exposed at 100 ppm for 102–104 weeks 

(Lynch et al. 1984a, 1984b; NTP 1987).
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2.6 GASTROINTESTINAL

Limited information is available regarding the potential for ethylene oxide-induced gastrointestinal effects 

in humans. 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. There 

was no evidence of increased risk of death from gastrointestinal effects within cohorts of workers with 

potential for ethylene oxide exposure (Bisanti et al. 1993; Morgan et al. 1981; Steenland et al. 1991; 

Wong and Trent 1993).

Limited information is available regarding gastrointestinal effects in experimental animals following 

inhalation or oral exposure to ethylene oxide. No information was located for the dermal exposure route.

There was no histopathological evidence of gastrointestinal effects in rats or mice repeatedly exposed to 

ethylene oxide vapor at 100 ppm for 102–104 weeks (Lynch et al. 1984a, 1984b; NTP 1987). 

Hollingsworth et al. (1956) reported gastric irritation in female rats following repeated gavage exposure at 

100 mg/kg/day; the NOAEL was 30 mg/kg/day.

2.7 HEMATOLOGICAL

Limited human data are available. Joyner (1964) reported no effects on hemoglobin levels or red blood 

cell (RBC) or white blood cell (WBC) counts in workers exposed to ethylene oxide at about 5–10 ppm for 

approximately 10 years.

Information is available regarding hematological effects in experimental animals following inhalation or 

oral exposure to ethylene oxide. No information was located for the dermal exposure route.

Decreases in hemoglobin, hematocrit, erythrocyte count, packed cell volume, and/or increased 

reticulocytes were reported in experimental animals (rats, mice, dogs) repeatedly exposed to ethylene 

oxide vapor at 250–500 ppm for 6–13 weeks (Fujishiro et al. 1990; Jacobson et al. 1956; Snellings et al. 

1984a). Hematological alterations indicative of normochromatic anemia were also observed in dogs 

exposed to 102 ppm for 6 months (Jacobson et al. 1956). Splenic extramedullary hematopoiesis was 

reported in rats repeatedly exposed at 50 or 100 ppm for 104 weeks and splenic focal fibrosis was noted at 

100 ppm (Lynch et al. 1984a, 1984b). There was no histopathological evidence of ethylene oxide-
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induced hematological effects in mice intermittently exposed at 100 ppm for up to 102 weeks (NTP 

1987).

Hollingsworth et al. (1956) found no evidence of exposure-related hematological effects in female rats 

repeatedly gavaged with ethylene oxide at up to 30 mg/kg/day.

2.8 MUSCULOSKELETAL

No studies were located regarding musculoskeletal effects in humans exposed to ethylene oxide.

Information is available regarding musculoskeletal effects in experimental animals following inhalation 

exposure to ethylene oxide. No information was located for oral or dermal exposure routes.

Histopathologic indicators of muscular atrophy were reported for experimental animals (rats, rabbits, 

monkeys, dogs) repeatedly exposed to ethylene oxide vapor for 6 weeks to 226 days at exposure levels in 

the range of 204–357 ppm (Hollingsworth et al. 1956; Jacobson et al. 1956). There was no indication of 

musculoskeletal effects in mice repeatedly exposed to ethylene oxide vapor for up to 14 weeks at 

250 ppm (Snellings et al. 1984a). However, multifocal myopathy in skeletal muscle was reported in rats 

following inhalation exposure at 100 ppm for 104 weeks; the NOAEL was 50 ppm (Lynch et al. 1984a, 

1984b). See Section 2.15 for a discussion of neuromuscular alterations. 

2.9 HEPATIC

Information regarding hepatic effects in humans after inhalation exposure to ethylene oxide is limited to a 

report by Joyner (1964). The results suggested that workers exposed to about 5–10 ppm for 10.7 years 

did not have major signs of hepatic toxicity such as jaundice or palpable liver.

Limited information is available regarding hepatic effects in experimental animals following inhalation or 

oral exposure to ethylene oxide. No information was located for the dermal exposure route.

Hollingsworth et al. (1956) reported slight discoloration and fatty degeneration in livers from rats and 

guinea pigs exposed to ethylene oxide vapor at 841 ppm for two or three 7-hour exposures. 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 
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this and all other lower exposure levels for both sexes in this study. No evidence for hepatic effects were 

seen among rats or mice repeatedly exposed at 100 ppm during a 10-week premating period (EPA 1994) 

or for 50 or 100 ppm for up to 102–104 weeks (Lynch et al. 1984a, 1984b; NTP 1987).

Slight liver damage (no further details) was reported in rats following repeated gavage exposure to 

ethylene oxide at 100 mg/kg/day, but not in animals dosed at ≤30 mg/kg/day (Hollingsworth et al. 1956).

2.10 RENAL

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 a mean exposure time of 10.7 years. 

Information is available regarding renal effects in experimental animals following inhalation exposure to 

ethylene oxide. No information was located for oral or dermal exposure routes.

Hollingsworth et al. (1956) reported enlargement, slight congestion, and cloudy swelling of convoluted 

tubules in kidneys from rats and guinea pigs exposed to ethylene oxide vapor at 841 ppm for two or three 

7-hour exposures. In a 14-week study of mice repeatedly exposed to ethylene oxide vapor, renal tubular 

degeneration was observed in 5/10 and 6/10 males exposed at 100 and 200 ppm, respectively, and in 

8/10 females exposed at 200 ppm (NTP 1987). Renal tubular necrosis was observed in 1/10 males of the 

100 and 200 ppm exposure groups. Lethal exposure levels (400 and 600 ppm) resulted in increased 

incidences of necrosis in both sexes exposed for up to 2 weeks. There were no indications of renal effects 

in rats or mice exposed at 50 or 100 ppm for up to 102–104 weeks (Lynch et al. 1984a, 1984b; NTP 

1987).

2.11 DERMAL

Data related to human dermal exposure to ethylene oxide are generally associated with case reports of 

industrial accidents, some of which occurred in the 1930s and 1940s. 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).
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A study using 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; Karacalar and Karacalar 2000). 

Shupack et al. (1981) demonstrated that human skin reactions to ethylene oxide in patch materials were 

directly related to the total dose.

Limited information is available regarding dermal effects in experimental animals following inhalation or 

dermal exposure to ethylene oxide. No information was located for the oral exposure route.

NTP (1987) found no evidence of dermal effects in mice repeatedly exposed to ethylene oxide vapor for 

up to 102 weeks at up to 100 ppm. Dermal application of ethylene oxide (10 and 50% aqueous solutions) 

to rabbits for ≥6 minutes resulted in hyperemia and edema (Hollingsworth et al. 1956). Dermal 

application of undiluted ethylene oxide to the back of rabbits (0.5 mL for 4 hours under occluded 

conditions) resulted in severe erythema and edema, subdermal hemorrhages, and chemical burns during 

72 hours postapplication; the chemical was considered corrosive (Celanese Chem Co. 1972).

2.12 OCULAR

There is some evidence that occupational exposure to high levels of ethylene oxide can result in cataracts 

and corneal burns (McLaughlin 1946; Thiess 1963). For example, cataracts developed in four sterilizer 

operators who were exposed to ethylene oxide from a leaking sterilizer for up to 2 months (Gross et al. 

1979; Jay et al. 1982). Because these persons could intermittently smell the fumes, a level of ≥700 ppm 

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 (31–35 years old) who had no systemic or ocular disease that might be 

associated with cataract formation.
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Ocular instillation of a 1% solution of ethylene oxide-to eyes of rabbits resulted in slight corneal 

cloudiness (severity score 0.8–1.9; maximum possible score of 4.0) during 48 hours postinstillation 

(McDonald et al. 1977). Lynch et al. (1984a, 1984b) reported cataracts in monkeys and rats intermittently 

exposed to ethylene oxide vapor for 2 years. Incidences in 50 and 100 ppm groups of monkeys were 

2/11 and 3/12, respectively, compared to 0/11 among controls. Incidences in 50 and 100 ppm groups of

rats were 3/79 and 9/78, respectively, compared to 2/77 among controls.

2.13 ENDOCRINE

No information was located regarding endocrine effects in humans associated with ethylene oxide 

exposure.

Information is available regarding endocrine effects in experimental animals following inhalation 

exposure to ethylene oxide. No information was located for oral or dermal exposure routes.

Hollingsworth et al. (1956) reported pale coloration and enlargement of adrenals, and numerous fat 

vacuoles in adrenal cortex from rats and guinea pigs exposed two or three times to ethylene oxide vapor at 

841 ppm for 7 hours per exposure. Lynch et al. (1984a, 1984b) reported multifocal cortical vacuolation 

and hyperplasia in adrenal glands from rats intermittently exposed to ethylene oxide vapor at 50 ppm for 

up to 104 weeks. There was no histopathological evidence of ethylene oxide-induced effects on thyroid, 

parathyroid, adrenals, or pituitary of mice intermittently exposed at 100 ppm for up to 102 weeks (NTP 

1987).

2.14 IMMUNOLOGICAL

The immunological effects of human inhalation exposure to ethylene oxide were studied in workers 

employed for up to 14 years in an ethylene oxide manufacturing plant. Workplace concentrations were 

generally <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. However, 
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ethylene oxide was implicated as a skin sensitizer in studies of volunteers following dermal exposure 

(Sexton and Henson 1950; Shupack et al. 1981). Contact dermatitis and delayed-type hypersensitivity 

dermatitis have been observed in case reports of ethylene oxide-exposed health care workers and patients 

(Alomar et al. 1981; Belen and Polat 2015; Brashear et al. 1996; Caroli et al. 2005; Dagregorio and 

Guillet 2004; Kerre and Goossens 2009; Lerman et al. 1995; Romaguera and Vilaplana 1998).

Limited information is available regarding immunological effects in experimental animals following 

inhalation exposure to ethylene oxide. No information was located for oral or dermal exposure routes.

Thymic lymphocytic hypoplasia was reported for male and female mice intermittently exposed to 

ethylene oxide vapor at 400 ppm for up to 2 weeks; at 600 ppm, necrosis was observed in the thymus 

(males and females) and spleen (males) (NTP 1987).

2.15 NEUROLOGICAL

Neurological effects have frequently been reported in association with human and animal exposure to 

ethylene oxide via inhalation at a wide range of concentrations and exposure durations.

In humans exposed to high levels of ethylene oxide in occupational settings, headache, nausea, and 

vomiting were reported (Blackwood and Erskine 1938; Sexton and Henson 1949; von Oettingen 1939). 

Exposure levels were not measured or estimated in these situations.

Neuropathy, impaired hand-eye coordination, cognitive dysfunction, memory loss, headache, and hand 

numbness were reported in case studies of workers exposed to ethylene oxide for various durations 

(Brashear et al. 1996; Crystal et al. 1988; Dretchen et al. 1992; Estrin et al. 1987; Finelli et al. 1983; 

Kuzuhara et al. 1983; Salinas et al. 1981; Schröder 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. Sural nerve biopsies revealed axonal degeneration and 

regeneration in two studies (Kuzuhara et al. 1983; Schröder 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. Headaches, nausea, vomiting, clumsiness, 

blunting of the senses, lethargy, numbness, and weakness in the extremities were reported among four 

sterilizer operators exposed to ethylene oxide for up to 2 months on an intermittent basis at levels of 
ETHYLENE OXIDE 46

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approximately 700 ppm (estimated by the authors based on the fact that the exposed workers could smell 

the vapors emitted from a leaking apparatus) (Gross et al. 1979). One of the operators experienced 

recurrent major motor seizures at 20–30-minute intervals near the end of the work shift; nerve conduction 

testing indicated sensorimotor neuropathy.

Information is available regarding neurological effects in experimental animals following inhalation 

exposure to ethylene oxide. No information was located for oral or dermal exposure routes.

Incoordination and semiconsciousness were reported during a 4-hour exposure of mice to ethylene oxide 

vapor at 1,600 ppm (NTP 1987). Repeated inhalation exposures of experimental animals resulted in 

neurological effects at lower exposure levels. Effects including impaired sensory and motor function 

(particularly in hindlimbs), altered gait, slight tremors, various degrees of hindlimb paralysis, and 

peripheral neuropathy have been reported in experimental animals intermittently exposed to ethylene 

oxide vapor at 100–500 ppm for periods in the range of 48–226 days (Hollingsworth et al. 1956; Jacobson 

et al. 1956; Kaido et al. 1992; Matsuoka et al. 1990; Ohnishi et al. 1985; Snellings et al. 1984a). 

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

myelinated fibers and mild axonal degeneration in hindleg nerves were observed in the absence of clinical 

signs of neuropathy (Ohnishi et al. 1986). Snellings et al. (1984a) reported clinical signs of neurotoxicity 

(hunched posture during gait, reduced locomotor activity) in mice intermittently exposed to ethylene 

oxide vapor for 10–11 weeks at an exposure level as low as 50 ppm. There were no indications of 

ethylene oxide exposure-related neurological effects in a 2-generation study of rats exposed to 

concentrations as high as 100 ppm (EPA 1994) or in a 2-year study of mice intermittently exposed at 

airborne concentrations as high as 100 ppm (NTP 1987). Lynch et al. (1984a) reported axonal dystrophy 

in the brain of 1/2 control monkeys and 2/2 and 1/2 monkeys exposed at 50 and 100 ppm, respectively. 

Demyelination was reported in 1/2 monkeys at the 50 and 100 ppm exposure levels. However, the results 

could not be specifically attributed to ethylene oxide exposure due to the small number of animals 

evaluated and the reported histopathologic brain lesion in a control animal.

Nagata et al. (1992) designed a study to investigate potential mechanisms of ethylene oxide neurotoxicity 

in the rat. Groups of male Wistar rats (5/group) were exposed to ethylene oxide vapor at 0 or 500 ppm for 

6 hours/exposure, 3 days/week, for 15 weeks. Following the final exposure period, 35S-methionine was 

injected into the right dorsal root ganglion to evaluate rapid anterograde axonal transport. The velocity in 

the ethylene oxide-exposed rats was 33% slower than that of controls. Morphometric analysis of selected 
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portions of sural and peroneal nerve preparations revealed significantly greater incidental degeneration of 

myelinated fibers from the ethylene oxide-exposed rats than from controls. The study authors suggested 

that the morphological changes and decreased axonal transport velocity might play a causative role in the 

development of peripheral neuropathy from chronic ethylene oxide exposure.

2.16 REPRODUCTIVE

Limited information is available regarding reproductive effects in humans associated with ethylene oxide 

exposure. In an epidemiological study by Hemminki et al. (1982), the spontaneous abortion rates in 

ethylene oxide sterilizer workers in hospitals in Finland were 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. Limitations in the design and implementation of this study include recall bias, prior 

knowledge of the questionnaires, and analysis based on too few pregnancies. 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.

Rowland et al. (1996) evaluated possible associations between ethylene oxide exposure and the risk of 

spontaneous abortion, preterm birth, and postterm birth in a cross-sectional study of 1,320 female dental 

assistants (32 with self-reported ethylene oxide exposure and 1,288 unexposed). After adjusting for age, 

relative risks (RRs) were 2.5 (95% confidence interval [CI] 1.0–6.3) for spontaneous abortion, 2.7 (95% 

CI 0.8–8.8) for preterm birth, and 2.1 (95% CI 0.7–5.9) for postterm birth. Gresie-Brusin et al. (2007) 

evaluated risks of spontaneous abortion and pregnancy loss within 98 singleton pregnancies among 

women with ethylene oxide exposure in sterilizing units of 22 hospitals in South Africa. The study 

subjects were grouped according to “high” exposure (sterilizer operators) and “low” exposure (not 

directly involved in ethylene oxide sterilization). Prevalence odds ratios (PORs) were 20.8 (95% CI 2.1–

199) for risk of spontaneous abortion and 8.6 (95% CI 1.8–43.7) for pregnancy loss.

Information is available regarding reproductive effects in experimental animals following inhalation 

exposure to ethylene oxide. No information was located for oral or dermal exposure routes.

Increased incidence of resorptions, decreased numbers of pups per litter, and decreased numbers of 

fetuses born relative to numbers of implantation sites were reported in a study of female rats 

intermittently exposed to ethylene oxide vapor at 150 ppm for 3 weeks premating and during gestation 
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days 1–16 (NIOSH 1982). In a 2-generation study, increased post-implantation loss was observed in F0 

rats exposed to 33 ppm (EPA 1994) and decreased numbers of live pups per litter were observed at 

100 ppm in the F1 and F2 generations (EPA 1994). Exposure-related effects on male reproductive organs 

(decreases in testicular and epididymal weights, germ cell survival, sperm count; histopathologic lesions 

in seminiferous tubules) have been reported for rats following intermittent inhalation exposure to ethylene 

oxide vapor for 6–13 weeks at exposure levels in the range of 250–500 ppm (Kaido et al. 1992; Mori et 

al. 1991a, 1991b). Intermittent inhalation exposure of monkeys to ethylene oxide vapor at 50 ppm (the 

lowest exposure level tested) for 24 months resulted in decreases in sperm count (28% less than controls) 

and motility (32% less than controls); however, reproductive function was not tested (Lynch et al. 1984a). 

There was no evidence of histopathological lesions in reproductive organs of rats or mice intermittently 

exposed for 102–104 weeks at 100 ppm (highest exposure level tested) (Lynch et al. 1984a, 1984b; NTP 

1987).

2.17 DEVELOPMENTAL

No studies were located regarding developmental effects in humans after inhalation exposure to ethylene 

oxide.

Information is available regarding developmental effects in experimental animals following inhalation 

exposure to ethylene oxide. No information was located for oral or dermal exposure routes.

Decreases in fetal body weight and crown-rump length and increased incidence of reduced ossification 

were reported following intermittent exposure of maternal rats to ethylene oxide vapor at 150 ppm (the 

only exposure level tested) for 3 weeks premating and during gestation days 1–16 (NIOSH 1982). 

Depressed fetal weight (3–9% less than controls) was noted in other studies of maternal rats intermittently 

exposed to ethylene oxide vapor in the range of 100–800 ppm during gestation (Neeper-Bradley and 

Kubena 1993; NIOSH 1982; Saillenfait et al. 1996; Snellings et al. 1982a). Decreases in the number of 

pups/litter and the ratio of fetuses born to implantation sites were reported in a study of rats intermittently 

exposed to ethylene oxide vapor at 100 ppm for 12 weeks prior to mating and throughout gestation and 

lactation periods (Snellings et al. 1982b). In a 2-generation study, decreased pup body weight was

observed in the F1 and F2 generations at 33 and 100 ppm (EPA 1994). Saillenfait et al. (1996) reported 

increased incidence of dilation in renal pelvis and ureter of rat fetuses following intermittent maternal 

exposure at 1,200 ppm during gestation days 6–15. Fetal defects (predominantly hydrops and ocular 

defects) were reported following maternal exposure of mice to ethylene oxide vapor at 1,200 ppm for a 
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single 1.5-hour exposure at timepoints between 1 and 25 hours postmating (Rutledge and Generoso 

1989). There were no indications of ethylene oxide exposure-related developmental effects in rabbit 

fetuses following intermittent inhalation exposure of their mothers at 150 ppm during gestation days 7–19

or 1–19 (NIOSH 1982).

2.18 OTHER NONCANCER

No information was located regarding other noncancer effects in humans or animals following exposure 

to ethylene oxide.

2.19 CANCER

A number of epidemiological studies have examined possible associations between occupational exposure 

to ethylene oxide and risk of cancer. Epidemiological data for ethylene oxide include limitations such as 

lack of personal estimations of ethylene oxide exposure levels, concomitant exposure to other toxic 

substances, small numbers of subjects, and/or small numbers of selected cancer deaths.

Ethylene oxide was first produced using a chlorohydrin process (reaction of ethylene gas with 

hypochlorous acid to produce ethylene chlorohydrin, which was reacted with calcium oxide to produce 

ethylene oxide). Workers involved with this process were exposed to a variety of chemicals, including 

organochlorine byproducts. The chlorohydrin process was inefficient and was gradually replaced with a 

direct vapor phase oxidation process (oxidation of ethylene gas in the presence of oxygen and silver 

catalyst at 10–30 atmospheres of pressure). Workers involved in the oxidation process did not experience 

exposures to the various chemicals used or produced during the chlorohydrin process. Available 

epidemiological studies include evaluation of cancer risk among cohorts of production workers involved 

in the chlorohydrin process and/or the ethylene oxidation process. Sterilization processes using ethylene 

oxide do not include exposures to the variety of chemicals encountered in the chlorohydrin process of 

ethylene oxide production.

IARC and EPA have evaluated ethylene oxide for carcinogenicity (EPA 2016a; IARC 2008, 2012). Both 

agencies concluded that the most convincing evidence for increased risk among workers exposed to 

ethylene oxide is for lymphohematopoietic cancers and female breast cancer. The discussion of the 

epidemiological database in this toxicological profile focuses on evaluations of ethylene oxide and risk of 

lymphohematopoietic cancers, leukemia, myeloma/multiple myeloma, non-Hodgkin’s lymphoma, 
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lymphosarcoma/reticulosarcoma, and breast cancer. Results from a few epidemiological studies and 

animal studies suggested associations between ethylene oxide exposure and cancer at other sites (e.g., 

stomach, pancreas, nervous system). 

Selected study details for cohorts evaluated for possible associations between exposure to ethylene oxide 

and selected cancer endpoints are presented in Table 2-3. Study results for leukemia, non-Hodgkin’s 

lymphoma, breast cancer, lymphohematopoietic cancer, myeloma/multiple myeloma, and 

lymphosarcoma/reticulosarcoma are summarized in Figures 2-4, 2-5, 2-6, 2-7, 2-8, and 2-9, respectively. 

Figures 2-4, 2-5, 2-6, 2-7, 2-8, and 2-9 include information on cohort size, exposure via production or use 

in sterilization processes, number of observed cancers/expected number, and the plotted risk estimates 

with 95% CIs. The footnote (1

) is used to identify cohorts exposed during ethylene oxide production via 

the chlorohydrin process. The footnote (2

) is used to identify cohorts exposed during ethylene oxide 

production via the nonchlorohydrin process. Some studies included cohorts that may have been exposed 

during production of ethylene oxide by the chlorohydrin process in earlier years and by direct oxidation 

during later years; therefore, these cohorts were not assigned a footnote. The study of Kiesselbach et al. 

(1990) did not specify a method of ethylene oxide production.

Case Reports. Hogstedt et al. (1979a) reported 3 cases of leukemia within a group of 230 workers at a 

Swedish facility where hospital equipment was sterilized using ethylene oxide. The study authors 

estimated an 8-hour time-weighted average (TWA) ethylene oxide level of 20±10 ppm in a storage 

hallway, which was considered higher than levels in the sterilization area. According to national 

statistics, 0.2 leukemia cases would have been expected. In a 5-year update of the study, 4 cases of 

lymphohematopoietic cancer (0.3 expected) were observed among 203 of the workers employed ≥1 year 

(Hogstedt et al. 1986).

Tompa et al. (1999) reported 8 cases of breast cancer within a group of 98 nurses exposed to ethylene 

oxide for 5–15 years in a hospital in Hungary. Reported ethylene oxide concentrations in the working 

area ranged from 5 to 150 mg/m3 (2.75–82.5 ppm). However, the study did not account for natural low 

dose radioactivity from radon in local drinking water, genetic predisposition, or effects of potential 

environmental, occupational, and/or lifestyle confounders.
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Table 2-3. Study Design Details for Selected Cohorts of Workers Exposed to Ethylene Oxide

Reference/cohort description Comments

Hogstedt et al. 1979b

241 male workers at a Swedish ethylene oxide production 

facility using the chlorohydrin method of production

Workers employed ≥1 year; 10-year latency applied; study included years 1961–

1977; expected deaths based on Swedish national rates:

66 unexposed workers (955 person-years) O/E ratio 0/0 for leukemia; no reported SMR

89 full-time production workers (1,324 person-years) O/E ratio 2/0.14 for leukemia; no reported SMR

86 maintenance workers (1,211 person-years) O/E ratio 1/0.13 for leukemia; no reported SMR

Hogstedt et al. 1986 (5-year update of Hogstedt et al. 1979b subcohort)

89 full-time production workers (chlorohydrin method) 

employed ≥1 year with 10-year latency

Results for leukemia and lymphohematopoietic cancers are summarized in 

Figures 2-4 and 2-7, respectively; update included the years 1961–1982; expected 

deaths based on Swedish national rates; the study authors noted that excess 

mortality was most pronounced among workers with ≥10 years of exposure.

Hogstedt 1988 (8-year update of Hogstedt et al. 1979b cohort)

233 male workers at a Swedish ethylene oxide production 

facility using the chlorohydrin method of production

Update included the years 1962–1985; restricted to male production workers at 

chlorohydrin unit and employed ≥1 year:

66 unexposed workers O/E ratio 0/0.1 for leukemia; no reported SMR

89 exposed operators O/E ratio 2/0.2 for leukemia; no reported SMR

78 exposed repairmen O/E ratio 1/0.2 for leukemia; no reported SMR

167 exposed operators and repairmen O/E ratio 3/0.4 for leukemia reported SMR 7.03 (no reported 95% CI)

Hogstedt 1988 (follow-up of combined cohorts of Hogstedt et al. 1979a, 1979b, 1986)

709 workers (539 men, 170 women) at production facility 

using the chlorohydrin process, a production facility using 

ethylene oxidation process, and an ethylene oxide 

sterilization unit

Update performed through 1985; most excess mortality attributed to the facility 

using chlorohydrin method to produce ethylene oxide.

O/E ratio for leukemia 7/0.8; SMR 9.21 (no 95% CI)

O/E ratio for blood/lymphatic cancers 9/2; SMR 4.59 (no 95% CI)

539 male workers only Results for leukemia and lymphohematopoietic cancers are summarized in 

Figures 2-4 and 2-7, respectively.
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Table 2-3. Study Design Details for Selected Cohorts of Workers Exposed to Ethylene Oxide

Reference/cohort description Comments

Hagmar et al. 1991

2,170 ethylene oxide-exposed workers (58,220 personyears) at two Swedish plants producing disposable medical 

equipment; 1,151 workers (594 men, 557 women) at plant A 

employed ≥12 months during 1964–1985; 1,019 workers 

(267 men, 752 women) at plant B employed ≥12 months 

during 1964–1985

Results for leukemia, female breast cancer, and lymphohematopoietic cancers are 

summarized in Figures 2-4, 2-6, and 2-7, respectively.

Expected cancer incidences based on rates in the surrounding county; exposure 

estimates up to 10–40 ppm during 1970–1981 and ≤3 ppm during 1982–1986 in 

plant A and up to 10–75 ppm during 1964–1975 and ≤4 ppm during 1976–1986 in 

plant B

Hagmar et al. 1995 (4-year update of Hagmar et al. 1991 cohort)

2,170 (1,309 women and 861 men) ethylene oxide-exposed 

workers (24,851 person-years) at plants A and B with no 

induction latency

Results for leukemia, female breast cancer, lymphohematopoietic cancers, and 

multiple myeloma are summarized in Figures 2-4, 2-6, 2-7, and 2-8, respectively.

2 leukemia cases (0.28 expected) among 930 workers with at least 0.14 ppmyears of cumulative exposure to ethylene oxide and ≥10-year induction latency 

considered “minor evidence” of association (SIR 7.14; 95% CI 0.87–25.8). 1,649 ethylene oxide-exposed workers (7,326 person-years) 

at plants A and B with ≥10-year induction latency

Mikoczy et al. 2011 (20-year update of Hagmar et al. 1991 cohort)

2,171 ethylene oxide-exposed workers (58,220 personyears); no induction latency periodResults for leukemia, non-Hodgkin’s lymphoma, female breast cancer, 

lymphohematopoietic cancers, and multiple myeloma are summarized in 

Figures 2-4, 2-5, 2-6, 2-7, and 2-8, respectively.

2,046 ethylene oxide-exposed workers (58,220 personyears; induction latency ≥15 yearsResults for leukemia, non-Hodgkin’s lymphoma, female breast cancer, 

lymphohematopoietic cancers, and multiple myeloma are summarized in 

Figures 2-4, 2-5, 2-6, 2-7, and 2-8, respectively.

Gardner et al. 1989

1,471 workers (1,470 men, 1 woman) in England and Wales 

employed at four companies that produced/used ethylene 

oxide

Result for leukemia is summarized in Figure 2-4.

O/E ratio 2/1.04 for non-Hodgkin’s lymphoma; no reported 95% Cis.

O/E ratio 0/0.06 for breast cancer; no reported 95% Cis.

1,405 workers (394 men, 1,011 women) at hospital 

sterilization units in England and Wales

No leukemia deaths; 0.76 expected.

O/E ratio 2/0.57 for non-Hodgkin’s lymphoma; no reported 95% Cis.

O/E ratio 4/5.91 for breast cancer; no reported 95% Cis.

Study spanned the years 1956–1987; expected deaths based on local and national 

rates; industrial hygiene data not available before 1977, but subsequent TWA 
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Table 2-3. Study Design Details for Selected Cohorts of Workers Exposed to Ethylene Oxide

Reference/cohort description Comments

exposures considered <5 ppm in most jobs and <1 ppm in many of the jobs; 

previous exposures likely somewhat higher.

Coggon et al. 2004 (13-year update of Gardner et al. 1989 cohort)

1,471 workers (1,470 men, 1 woman at 4 four companies 

that produced/used ethylene oxide)

Results for leukemia, non-Hodgkin’s lymphoma, and multiple myeloma are 

summarized in Figures 2-4, 2-5, and 2-8, respectively.

1,405 workers (394 men, 1,011 women) at hospital 

sterilization units in England and Wales

Results for leukemia, non-Hodgkin’s lymphoma, female breast cancer, and multiple 

myeloma are summarized in Figures 2-4, 2-5, 2-6, and 2-8, respectively.

Combined cohort of 2,876 workers (1,864 men, 

1,012 women) at ethylene oxide production facilities and 

hospital sterilization units

Results for leukemia, non-Hodgkin’s lymphoma, female breast cancer, and multiple 

myeloma are summarized in Figures 2-4, 2-5, 2-6, and 2-8, respectively.

Greenberg et al. 1990

Cohort included 2,174 ethylene oxide-exposed workers at 

Union Carbide Corporation chemical production facilities in 

West Virginia (278 workers ever assigned to chlorohydrin 

units; 1,896 workers never assigned to chlorohydrin units)

Study spanned the years 1940–1978; expected deaths based on U.S. general 

population, regional population, and 26,965 unexposed men from the same 

facilities.

Subcohort of male workers (number not specified) 

assigned ≥2 years to chlorohydrin units

Results for leukemia, non-Hodgkin’s lymphoma, lymphohematopoietic cancers, 

and multiple myeloma are summarized in Figures 2-4, 2-5, 2-7, and 2-8, 

respectively.

Subcohort of male workers (number not specified) 

assigned ≥2 years to ethylene oxide areas, but never to 

chlorohydrin units

Results for leukemia, non-Hodgkin’s lymphoma, lymphohematopoietic cancers, 

and multiple myeloma are summarized in Figures 2-4, 2-5, 2-7, and 2-8, 

respectively.

Combined cohort of 2,174 male workers ever assigned to 

ethylene oxide using/producing departments

Results for leukemia, non-Hodgkin’s lymphoma, lymphohematopoietic cancers, 

and multiple myeloma are summarized in Figures 2-4, 2-5, 2-7, and 2-8, 

respectively.

Benson and Teta 1993 (10-year update of Greenberg et al. 1990 subcohort ever assigned to chlorohydrin units)

278 male workers ever assigned to chlorohydrin units Results for lymphohematopoietic cancers are summarized in Figure 2-7.

SMRs not calculated for leukemia or lymphosarcoma/reticulosarcoma (observed 

and/or expected deaths <5).
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Table 2-3. Study Design Details for Selected Cohorts of Workers Exposed to Ethylene Oxide

Reference/cohort description Comments

Teta et al. 1993 (10-year update of a subcohort from the cohort of Greenberg et al. 1990)

1,896 male workers (excludes 278 workers with “low” 

potential for exposure to ethylene oxide)

Results for leukemia and lymphohematopoietic cancers are summarized in 

Figures 2-4 and 2-7, respectively.

SMR not calculated for lymphosarcoma/reticulosarcoma (observed and expected 

deaths <5).

Swaen et al. 2009 (25-year update of subcohort of male workers within original cohort of Greenberg et al. 1990)

Subcohort of 2,063 male workers from the original cohort 

of 2,174 workers

Results for leukemia, non-Hodgkin’s lymphoma, and lymphohematopoietic cancers

are summarized in Figures 2-4, 2-5, and 2-7, respectively.

Update included years 1940–2003; original cohort of 2,174 workers from 

Greenberg et al. 1990 redefined, proportional hazards modeling for leukemia, 

lymphoid malignancies revealed no trends or associations with cumulative 

exposure; estimated 8-hour TWA exposure levels 0.3–21 ppm during 1940–1988 

and up to 70 ppm during 1925–1939.

Steenland et al. 1991 (NIOSH-based cohort)

18,254 workers (8,214 men, 10,040 women) at 14 facilities 

producing sterilized medical supplies and spices; workers 

had at least 90 days of exposure to ethylene oxide

Results for leukemia, non-Hodgkin’s lymphoma, breast cancer, hematopoietic 

cancers, myeloma/multiple myeloma, and lymphosarcoma/reticulosarcoma are 

summarized in Figures 2-4, 2-5, 2-6, 2-7, 2-8, and 2-9, respectively.

Mortality evaluated through 1987 and compared to that of U.S. general population; 

estimated 8-hour TWA exposure levels 4.3 ppm for sterilizer operators and 

2.0 ppm for other workers after 1977, likely several times higher in earlier years.

Stayner et al. 1993 (evaluation includes 13 of the 14 facilities from the NIOSH-based cohort of Steenland et al. 1991) 

Workers at 13 facilities producing sterilized medical 

supplies and spices 

Results for leukemia, non-Hodgkin’s lymphoma, and hematopoietic cancers are 

summarized in Figures 2-4, 2-5, and 2-7, respectively.

One of the original 14 facilities excluded due to inadequate data for historical 

exposure estimation.
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Table 2-3. Study Design Details for Selected Cohorts of Workers Exposed to Ethylene Oxide

Reference/cohort description Comments

Wong and Trent 1993 (evaluation includes the 14 facilities from the NIOSH-based cohort of Steenland et al. 1991)

18,728 workers (8,709 men, 10,019 women) at 14 facilities 

producing sterilized medical supplies and spices

Results for leukemia, female breast cancer, lymphopoietic cancers, and 

lymphosarcoma/reticulosarcoma are summarized in Figures 2-4, 2-6, 2-7, and 2-9, 

respectively.

Mortality evaluated through 1988; 8-hour TWA exposure estimates for sterilizer 

workers (20% of cohort) were 4–5 ppm after 1978 and 16 ppm for earlier times; 

exposure estimates for the rest of the cohort were 2 ppm after 1978 and 5 ppm for 

earlier times; possibly higher short-term exposures.

Steenland et al. 2004 (11-year update of the cohort of Steenland et al. 1991) 

18,235 workers (8,214 men, 10,040 women) at 14 facilities 

using ethylene oxide for sterilization

Results for leukemia, non-Hodgkin’s lymphoma, female breast cancer, 

hematopoietic cancers, and myeloma/multiple myeloma are summarized in 

Figures 2-4, 2-5, 2-6, 2-7, and 2-8, respectively.

Positive trend for hematopoietic cancers in males with a 15-year lag time (driven 

by lymphoid tumors); positive trend for breast cancer using log of cumulative 

exposure and 20-year lag time.

Steenland et al. 2003 (NIOSH-based cohort)

7,576 female workers employed for at least 1 year at 

14 facilities using ethylene oxide for sterilization

Results for breast cancer are summarized in Figure 2-6.

Significant trend (p=0.002) for increased breast cancer incidence with increasing 

cumulative ethylene oxide exposure using a 15-year lag period; breast cancer 

incidences evaluated through 1998; referent rates from non-exposed population in 

NCI’s SEER Program.

Bisanti et al. 1993

1,971 male chemical workers licensed to handle ethylene 

oxide for ≥1 year in northern Italy

Results for leukemia, hematopoietic cancers, and lymphosarcoma/reticulosarcoma

are summarized in Figures 2-4, 2-7, and 2-9, respectively.

Subcohort of 637 workers licensed to handle ethylene oxide 

only

Results for leukemia, hematopoietic cancers, and lymphosarcoma/reticulosarcoma 

are summarized in Figures 2-4, 2-7, and 2-9, respectively.

Evaluation included the years 1938–1984; expected deaths based on rates within 

the regional general population.
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Table 2-3. Study Design Details for Selected Cohorts of Workers Exposed to Ethylene Oxide

Reference/cohort description Comments

Kiesselbach et al. 1990

2,658 employees exposed to ethylene oxide for ≥1 year at 

German chemical companies

Results for leukemia and lymphohematopoietic cancers are summarized in 

Figures 2-4 and 2-7, respectively.

Evaluation included the years 1928–1981; expected deaths based on rates within 

the German general population.

Morgan et al. 1981

767 male workers employed for ≥5 years at ethylene oxide 

production facility (production method not specified)

Evaluation included the years 1955–1977.

No leukemia deaths versus 0.70 expected deaths based on U.S. vital statistics.

Norman et al. 1995

928 female workers employed for any time from July 1, 

1974 through September 30, 1980 at a plant with potential 

for ethylene oxide exposure

Results for breast cancer are summarized in Figure 2-6; evaluated through 

December, 1987; expected incidences based on SEER rates.

Olsen et al. 1997

1,361 male workers employed at Dow Chemical facilities 

for ≥1 year and potentially engaged for ≥1 month in 

ethylene chlorohydrin and/or propylene chlorohydrin 

production

Results for leukemia, lymphohematopoietic cancers, and lymphosarcoma/

reticulosarcoma are summarized in Figures 2-4, 2-7, and 2-9, respectively.

Evaluation included the years 1940–1992; expected death rates based on U.S. 

white males; analyses examining location, production process, duration of 

employment, and 25-year induction latency did not result in significant findings.

95% CI = 95% confidence interval; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; O/E = observed deaths or 

incidences/expected deaths or incidences; RR = rate ratio; SEER = Surveillance Epidemiology and End Results; SIR = standardized incidence ratio; 

SMR = standardized mortality ratio; TWA = time-weighted average
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Figure 2-4. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Leukemia
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Figure 2-4. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Leukemia (continued)
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Figure 2-5. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Non-Hodgkin's Lymphoma
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Figure 2-6. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Breast Cancer
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Figure 2-7. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Lympho-Hematopoietic Cancer
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Figure 2-7. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Lympho-Hematopoietic Cancer (continued)
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Figure 2-8. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Myeloma-Multiple Myeloma 
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Figure 2-9. Summary of Epidemiological Studies Evaluating Associations between Inhaled Ethylene Oxide and 

Lymphosarcoma/Reticulosarcoma Cancer

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Swaen et al. (1996) investigated a cluster of 10 cases of Hodgkin’s lymphoma within a large chemical 

manufacturing complex in Belgium. Among 214 different chemical substances evaluated, 5 chemicals 

exhibited elevated odds ratios (ORs) (ammonia, benzene, ethylene oxide, sodium hydroxide, and oleum). 

The cluster of cases could not be specifically associated with ethylene oxide exposure.

Meta-Analyses of Epidemiological Studies. Shore et al. (1993) conducted a review and meta-analysis on 

cohorts from previously-published studies. The meta-analysis for leukemia was conducted using data 

from Bisanti et al. (1993), Gardner et al. (1989), Hagmar et al. (1991), Hogstedt (1988), Kiesselbach et al. 

(1990), Teta et al. (1993), Wong and Trent (1993), and an unpublished study (update to Greenberg et al. 

1990). The reported O/E ratio was 1.06 (95% CI 0.73–1.48) based on 31 incident cases or deaths versus 

29.31 expected. The meta-analysis for non-Hodgkin’s lymphoma was conducted using data from Bisanti 

et al. (1993), Gardner et al. (1989), Hagmar et al. (1991), Hogstedt (1988), Teta et al. (1993), Thiess et al. 

(1981), Wong and Trent (1993), and an unpublished study (update to Greenberg et al. 1990). The 

reported O/E ratio was 1.35 (95% CI 0.93–1.90) based on 31 incident cases or deaths versus 

22.93 expected.

Teta et al. (1999) updated the meta-analysis of Shore et al. (1993) by including results from Hagmar et al. 

(1995) and Olsen et al. (1997) and excluding results from Greenberg et al. (1990), Morgan et al. (1981), 

and Thiess et al. (1981). The updated meta-analysis included nearly 33,000 workers and more than 

800 cancers. For leukemia and non-Hodgkin’s lymphoma risks, reported standardized mortality ratios 

(SMRs) were 1.08 (95% CI 0.61–1.93) based on 35 deaths versus 32 expected, and 1.34 (95% CI 0.96–

1.89) based on 33 deaths versus 25 expected, respectively; neither leukemia nor non-Hodgkin’s 

lymphoma results exhibited positive trends with duration, intensity, or latency. The study authors 

considered the results inconclusive for leukemia and for non-Hodgkin’s lymphoma. 

Marsh et al. (2019) conducted a systematic literature review of occupational exposure to ethylene oxide 

and risk of lymphohematopoietic cancer and breast cancer and identified 13 studies that were included in 

a meta-analysis. Overall meta-relative risks (meta-RRs) were 1.48 (95% CI 1.07–2.05) for 

lymphohematopoietic cancer and 0.97 (95% CI 0.80–1.18) for breast cancer. For lymphohematopoietic 

cancer, the study authors reported meta-RRs of 1.46 (95% CI 0.85–2.50) among ethylene oxide 

production workers and 1.07 (95% CI 0.87–1.30) among ethylene oxide sterilization workers. Higher 

risks of lymphohematopoietic cancer were noted for earlier published studies, compared to more recent 

studies.
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Animal Studies. Animal studies examining the carcinogenicity of ethylene oxide have reported increased 

incidences of several tumor types. Significantly increased incidence of brain gliomas (5/79 versus 

0/76 controls; p<0.05) and peritoneal mesotheliomas (21/79 versus 3/78 controls; p<0.01) were reported 

among male Fischer 344 rats intermittently exposed by inhalation for up to 2 years at 100 ppm (Lynch et 

al. 1984a, 1984b). An increase in the incidence of mononuclear cell leukemia was also observed at 

50 ppm (38/79 versus 24/77 controls, p<0.01).

Significantly increased incidence of spleen mononuclear cell leukemia was observed in female rats 

exposed to ethylene oxide vapor for up to 2 years at 100 ppm (58% versus 8 or 11% controls; p<0.01)

(Garman et al. 1985, 1986; Snellings et al. 1984b). Although the incidence was only statistically 

significantly elevated at 100 ppm, increased incidences were also observed at 10 ppm (11/54 versus 

11/115 in controls) and 33 ppm (14/48). When incidences among rats dying early or killed in moribund 

condition were included, there were significant mortality-adjusted trends for mononuclear cell leukemia 

in males and females at ≥33 ppm (incidence data not reported). Male rats of the 100 ppm exposure group 

exhibited significant increases in peritoneal mesothelioma when rats that died or were killed in moribund 

condition were included (no incidence reported) and subcutis fibroma (36% versus 2 and 4% control; 

0.01>p>0.001). A significant trend for primary brain neoplasms was observed in males (p<0.01) and 

females (p<0.05).

In a 2-year inhalation study of male and female B6C3 F1 mice, ethylene oxide exposure at 100 ppm

resulted in significantly increased incidence of alveolar/bronchiolar carcinoma (16/50 versus 

6/50 controls, p=0.048 according to life table analysis) in males, and significantly increased incidences of 

alveolar/bronchiolar adenoma (17/49 versus 2/49 controls; p=0.001) and alveolar/bronchiolar carcinoma 

(7/49 versus 0/49 controls, p=0.019) in female mice (NTP 1987). Incidences of Harderian gland papillary 

cystadenoma were increased at 50 ppm in males (9/44, p=0.014) and females (6/46, p=0.052) and at 

100 ppm in males (8/42, p=0.021) and females (8/47, p=0.039). The 100 ppm group of female mice also 

exhibited marginally significantly increased incidence of malignant lymphoma in the hematopoietic 

system (22/49 versus 9/49 controls; p=0.049) and uterine adenocarcinoma (5/49 versus 0/49 controls; 

p=0.058). The 50 ppm (but not 100 ppm) group of female mice also exhibited increased incidences of 

hepatocellular adenoma (8/48 versus 1/49; p=0.021) and mammary gland adenocarcinoma or 

adenosquamous carcinoma combined (8/48 versus 1/49 controls; p=0.020). Picut et al. (2003) reevaluated the pathology and tumor incidence data from NTP (1987) and confirmed the results.
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Significantly increased incidences of lung adenomas were reported among female A/J mice intermittently 

exposed to ethylene oxide vapor for 6 months at 70 or 200 ppm; lung adenoma incidences were 16/28 and 

25/29, respectively, compared to 8/30 controls (Adkins et al. 1986). Incidences were statistically 

significantly increased in both ethylene oxide-exposed groups. In a replicate study that included controls 

and 200 ppm groups, incidences of lung adenomas in surviving mice were 9/29 (29%) and 12/28 (42%), 

respectively.

Dose-related increased incidence of malignant tumors of the forestomach was reported among female rats 

administered ethylene oxide by gavage at 7.5 or 30 mg/kg/day for 2 days/week for 150 weeks; incidences 

were 8/50 and 31/50, respectively, compared to no stomach tumors among 50 vehicle and 50 untreated 

controls (Dunkelberg 1982). A total of 37 of the 39 tumors were squamous cell carcinomas. 

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 (Van Duuren et al. 1965).

Carcinogenicity Assessments. The HHS has classified ethylene oxide as known to be a human 

carcinogen (NTP 2016) based on sufficient evidence of carcinogenicity from studies in humans 

(increased risk of cancer in workers exposed to ethylene oxide during its synthesis, production, and use), 

and evidence for a common mechanism of carcinogenesis in humans and experimental animals (similar 

genetic damage in cells of animals and workers exposed to ethylene oxide).

EPA (2016a) characterized ethylene oxide as “carcinogenic to humans” by the inhalation exposure route, 

based on the total weight of evidence including epidemiological evidence of lymphohematopoietic 

cancers and breast cancer in ethylene oxide-exposed workers, lymphohematopoietic cancers in rats and 

mice and mammary carcinomas in mice, clear evidence that ethylene oxide is genotoxic and sufficient 

evidence to support a mutagenic mode of action for ethylene oxide carcinogenicity, and strong evidence 

for occurrence of key precursor events and progression to tumors in humans. EPA derived unit risk 

estimates were based on results from the National Institute for Occupational Safety and Health (NIOSH)

study (Steenland et al. 2003, 2004) that evaluated cancer risk in a cohort of workers exposed to ethylene 

oxide. The authors found positive exposure responses for breast cancer mortality in females for log 

cumulative exposure and a 20-year lag. There was also a positive exposure response for lymphoid tumors 

(non-Hodgkin’s lymphoma, myeloma, and lymphocytic leukemia) in both sexes for cumulative exposure. 

The adult-based unit risk estimates were 2.6x10-3

per μg/m3 4.8x10-3 per ppb) for lymphoid cancer, 

7.0x10-4 per μg/m3 (1.3x10-3 per ppb) for female breast cancer, and 3.0x10-3 per μg/m3 (5.5x10-3 per ppb) 
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for both cancer types combined. Application of standard age-dependent adjustment factors yields a full 

lifetime total cancer unit risk estimate of 5.0x10-3 per μg/m3 (9.1x10-3 per ppb) (EPA 2016a). The 

commensurate lifetime chronic (lower bound) exposure level of 2x10-4 μg/m3 (1x10-4 ppb) corresponds to 

an increased cancer risk of 10-6 (1 in 1,000,000). The unit risk estimate was developed for environmental 

ethylene oxide exposures up to about 40 μg/m3 (20 ppb) and is not applicable to higher exposure levels 

that may occur in occupational exposure scenarios. Maximum likelihood estimates of extra risk of 

lymphoid cancer and breast cancer (combined) occupational exposure scenarios in the range of 0.1–1 ppm 

for an 8-hour TWA for 35 years range from 0.037 to 0.11 (upper bound estimates 0.081–0.22).

IARC has produced several reports on the carcinogenicity of ethylene oxide (IARC 1976, 1985, 1987, 

1994, 2008, 2012). IARC has designated ethylene oxide as carcinogenic to humans (Group 1) (IARC 

1987, 2012) based on limited evidence for a causal association between exposure to ethylene oxide and 

lymphatic and hematopoietic cancers and breast cancer in humans, sufficient evidence for carcinogenicity 

in animals, and strong evidence for a genotoxic mechanism of action for ethylene oxide carcinogenicity. 

2.20 GENOTOXICITY

Ethylene oxide has been demonstrated to be genotoxic in human and animal studies in vivo and a wide 

variety of test systems in vitro. Extensive reviews are available regarding the genotoxicity of ethylene 

oxide (see EPA 2016a; IARC 1994, 2008, 2012). Studies evaluating the genotoxicity of ethylene oxide in 

humans and in vivo studies using experimental test species are summarized in Tables 2-4 and 2-5, 

respectively. Results from selected in vitro assays are summarized in Table 2-6. Available data 

collectively demonstrate the mutagenicity and clastogenicity of ethylene oxide both in vitro and in vivo. 

Ethylene oxide induced gene mutation, chromosomal aberrations, sister chromatid exchange, 

micronucleus formation, deoxyribonucleic acid (DNA) strand breaks, unscheduled DNA synthesis, and 

cell transformation in vitro. Ethylene oxide induced gene mutation, specific locus mutation, 

chromosomal aberrations, sister chromatid exchange, micronucleus formation, dominant lethal mutation, 

and heritable translocation in test species and/or occupationally-exposed humans.

In addition to these genotoxic effects, in vitro studies in mammal tissues, in vivo studies in rats and mice, 

and studies in humans have demonstrated the formation of DNA adducts. Ethylene oxide is an alkylating 

agent that forms adducts with DNA, ribonucleic acid (RNA), and proteins. The primary DNA adduct 

formed is N7-(2-hydroxyethyl)guanine (7-HEG). Other DNA adducts have been found in lesser amounts, 

these include N3-(2-hydroxyethyl)adenine and O6

-(2-hydroxyethyl)guanine (EPA 2016a; IARC 2012). 
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7-HEG has been detected in various tissues of rats exposed via inhalation to ethylene oxide for up to 

4 weeks (Walker et al. 1990). Duration-related increases were observed in the brain, lungs, spleen, 

kidneys, leukocytes, liver, and testes. 

Table 2-4. Genotoxicity of Ethylene Oxide in Humans

Ethylene oxide exposure group Test system Endpoint Result Reference

Factory sterilization workers Blood DNA Gene mutation + Kamel et al. 2011

Hospital, factory sterilization 

workers

Lymphocytes Gene mutation – Tates et al. 1991

Chemical manufacturing workers Lymphocytes Gene mutation – Tates et al. 1995

Occupationally-exposed workers Lymphocytes Chromosomal aberrations + Abrahams 1980

Sterilization plant workers Lymphocytes Chromosomal aberrations + Galloway et al. 

1986

Production workers Lymphocytes Chromosomal aberrations + Högstedt et al. 

1990

Production, sterilization workers Lymphocytes Chromosomal aberrations + Karelová et al. 

1987

Hospital sterilization workers Lymphocytes Chromosomal aberrations + Lerda and Rizzi 

1992

Sterilization workers Lymphocytes Chromosomal aberrations + Richmond et al. 

1985

Hospital, factory sterilization 

workers

Lymphocytes Chromosomal aberrations + Tates et al. 1991

Chemical industry workers Lymphocytes Chromosomal aberrations + Thiess et al. 1981

Sterilization plant workers Lymphocytes Chromosomal aberrations (+) Pero et al. 1981

Hospital sterilization workers Lymphocytes Chromosomal aberrations (+) Sarto et al. 1984

Chemical industry workers Lymphocytes Chromosomal aberrations – Clare et al. 1985

Hospital sterilization workers Lymphocytes Chromosomal aberrations – Högstedt et al. 

1983

Hospital sterilization workers Lymphocytes Chromosomal aberrations – Mayer et al. 1991

Chemical production workers Lymphocytes Chromosomal aberrations – Ribeiro et al. 1994

Chemical industry workers Lymphocytes Chromosomal aberrations – van Sittert et al. 

1985

Occupationally-exposed workers Lymphocytes Sister chromatid exchange + Abrahams 1980

Hospital sterilization workers Lymphocytes Sister chromatid exchange + Garry et al. 1979

Highly-exposed sterilization 

workers

Lymphocytes Sister chromatid exchange + Laurent 1988

Hospital sterilization workers Lymphocytes Sister chromatid exchange + Laurent et al. 

1984

Hospital sterilization workers Lymphocytes Sister chromatid exchange + Lerda and Rizzi 

1992

Hospital sterilization workers Lymphocytes Sister chromatid exchange + Mayer et al. 1991

Hospital workers Lymphocytes Sister chromatid exchange + Richmond et al. 

1985
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Table 2-4. Genotoxicity of Ethylene Oxide in Humans

Ethylene oxide exposure group Test system Endpoint Result Reference

Hospital sterilization workers Lymphocytes Sister chromatid exchange + Sarto et al. 1984

Sanitary workers Lymphocytes Sister chromatid exchange + Sarto et al. 1987

Hospital sterilization workers Lymphocytes Sister chromatid exchange + Schulte et al. 

1992

Sterilization plant workers Lymphocytes Sister chromatid exchange + Stolley et al. 1984

Hospital, factory sterilization 

workers

Lymphocytes Sister chromatid exchange + Tates et al. 1991

Hospital sterilization workers Lymphocytes Sister chromatid exchange + Yager et al. 1983

Sterilization plant workers Lymphocytes Sister chromatid exchange (+) Lambert and 

Lindblad 1980

Hospital sterilization workers Lymphocytes Sister chromatid exchange ± Sarto et al. 1991

Hospital sterilization workers Lymphocytes Sister chromatid exchange – Hansen et al. 

1984

Hospital sterilization workers Lymphocytes Sister chromatid exchange – Högstedt et al. 

1983

Production workers Lymphocytes Sister chromatid exchange – Tates et al. 1995

Hospital workers Lymphocytes Sister chromatid exchange – Tomkins et al. 

1993

Production workers Lymphocytes Micronucleus formation + Högstedt et al. 

1990

Hospital, factory sterilization 

workers

Lymphocytes Micronucleus formation + Tates et al. 1991

Hospital sterilization workers Lymphocytes Micronucleus formation – Mayer et al. 1991

Hospital sterilization workers Lymphocytes Micronucleus formation – Schulte et al. 

1992

Hospital sterilization, preparation 

workers

Lymphocytes Micronucleus formation – Sarto et al. 1991

Production workers Lymphocytes Micronucleus formation – Tates et al. 1995

Hospital sterilization workers Bone marrow 

cells

Micronucleus formation + Högstedt et al. 

1983

Chemical production workers Buccal cells Micronucleus formation – Ribeiro et al. 1994

Factory sterilization workers Buccal cells Micronucleus formation – Sarto et al. 1990

Hospital sterilization, preparation 

workers

Buccal cells Micronucleus formation – Sarto et al. 1991

Factory sterilization workers Nasal cells Micronucleus formation + Sarto et al. 1990

Hospital sterilization workers Lymphocytes DNA adducts (+) Yong et al. 2007

Hospital sterilization workers DNA strand breaks – Mayer et al. 1991

Hospital sterilization workers DNA cross-links + Popp et al. 1992
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Table 2-4. Genotoxicity of Ethylene Oxide in Humans

Ethylene oxide exposure group Test system Endpoint Result Reference

Commercial, hospital sterilization 

workers

Peripheral 

blood 

mononuclear 

cells

DNA damage + Fuchs et al. 1994

– = negative result; + = positive result; (+) = weakly positive result; ± = inconclusive

Table 2-5. Genotoxicity of Ethylene Oxide in Experimental Test Species In Vivo

Species (test system) Endpoint Results Reference

Drosophila melanogaster Sex-linked recessive lethal 

mutation

+ Bird 1952; Fahmy and Fahmy 

1956; Nakao and Auerbach 

1961, as cited in IARC 1994; 

Vogel and Nivard 1997, 

1998; Watson 1966; Zijlstra 

and Vogel 1988

D. melanogaster Somatic mutation + Fahmy and Fahmy 1970

D. melanogaster Heritable translocation + Nakao and Auerbach 1961, 

as cited in IARC 1994

D. melanogaster Heritable translocation + Watson 1966

D. melanogaster DNA adducts + Nivard et al. 2003

Rat splenic, thymic T-lymphocytes Gene mutation + Walker et al. 1997

Rat splenic T-lymphocytes Gene mutation (+) Tates et al. 1999

Mouse splenic T-lymphocytes Gene mutation + Walker and Skopek 1993

Mouse lung lymphocytes Gene mutation + Sisk et al. 1997

Mouse bone marrow, germ cells Gene mutation + Recio et al. 2004

Mouse bone marrow, splenic 

lymphocytes

Gene mutation – Sisk et al. 1997

Mouse germ cells Gene mutation – Sisk et al. 1997

Mouse germ cells Specific locus gene mutation – Russell et al. 1984

+ Lewis et al. 1986, 1990

Rat lymphocytes Chromosomal aberrations – Kligerman et al. 1983

Rat lymphocytes Chromosomal aberrations – van Sittert et al. 2000

Mouse lymphocytes Chromosomal aberrations + Donner et al. 2010

Rat bone marrow cells Chromosomal aberrations – Union Carbide Corp. 1980

Mouse bone marrow cells Chromosomal aberrations + Ribeiro et al. 1987a; Farooqi 

et al. 1993

Mouse spermatocytes Chromosomal aberrations + Ribeiro et al. 1987a

Monkey lymphocytes Chromosomal aberrations + Lynch et al. 1984c

Rat lymphocytes Sister chromatid exchange + Kligerman et al. 1983

Rat bone marrow, splenic cells Sister chromatid exchange + Lorenti Garcia et al. 2001; 

Ong et al. 1993
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Table 2-5. Genotoxicity of Ethylene Oxide in Experimental Test Species In Vivo

Species (test system) Endpoint Results Reference

Mouse bone marrow cells Sister chromatid exchange + Farooqi et al. 1993

Rabbit lymphocytes Sister chromatid exchange + Yager 1987; Yager and Benz 

1982

Monkey lymphocytes Sister chromatid exchange + Kelsey et al. 1988; Lynch et 

al. 1984c

Rat bone marrow cells Micronucleus formation + Appelgren et al. 1978, as 

cited in IARC 1994

Rat bone marrow, splenic cells Micronucleus formation + Hochberg et al. 1990; Lorenti 

Garcia et al. 2001

Mouse bone marrow cells Micronucleus formation + Appelgren et al. 1978, as 

cited in IARC 1994; Farooqi 

et al. 1993; Jensen and 

Ramel 1980

Rat splenic T-lymphocytes Micronucleus formation (+) Tates et al. 1999

Rat lymphocytes Micronucleus formation – van Sittert et al. 2000

Mouse sperm Single strand breaks + Sega and Generoso 1988

Mouse spermatids Single strand breaks + Sega et al. 1988

Mouse lymphocytes Reciprocal translocation (+) Donner et al. 2010

Mouse (germ cells) Heritable translocation + Generoso et al. 1980, 1990

Chinese hamster V79 cells Heritable translocation + Generoso et al. 1980, 1990

Rat Dominant lethal mutation + Embree et al. 1977

Mouse Dominant lethal mutation + Generoso et al. 1980, 1983, 

1986, 1990

Mouse Dominant lethal mutation – Appelgren et al. 1977

Rat liver, testis DNA DNA adducts + Osterman-Golkar et al. 1983

Rat DNA DNA adducts + Potter et al. 1989

Rat brain, spleen, liver DNA DNA adducts + Rusyn et al. 2005

Rat brain, lung, spleen, kidney, 

liver, testis DNA

DNA adducts + Walker et al. 1992b

Rat lymphocyte DNA DNA adducts (+) van Sittert et al. 2000

Mouse DNA DNA adducts + Ehrenberg et al. 1974

Rat brain, lung, spleen, kidney, 

liver, testis DNA

DNA adducts + Walker et al. 1990

Mouse germ cell DNA DNA adducts + Sega et al. 1991

Mouse DNA DNA adducts + Segerbäck 1983

– = negative result; + = positive result; (+) = weakly positive result
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Table 2-6. Genotoxicity of Ethylene Oxide In Vitro

Species (test system) Endpoint

Results

Reference

Activation

With Without

Prokaryotic organisms:

Salmonella typhimurium

TA100, TA1535 Gene mutation + Agurell et al. 1991

TA100, TA1535 Gene mutation + + De Flora 1981

TA98, TA1537, TA1538 Gene mutation – – De Flora 1981

TA100, TA102 Gene mutation + Hughes et al. 1987

TA98, TA100, TA1535, TA1537 Gene mutation + Pfeiffer and Dunkelberg 1980

TA1535 Gene mutation + Rannug et al. 1976

TA100, TA1535 Gene mutation + Simmon 1981

TA100 Gene mutation + + Victorin and Ståhlberg 1988

Escherichia coli

WU36-10, WU36-10-89 Gene mutation + Kolman 1984; Kolman et al. 

1989a

KMBL 3835 Gene mutation + Kolman 1985

WP2, WP2 uvrA, WP6 Gene mutation + Kolman and Näslund 1987

Bacillus subtilis

HA101, TKJ5211, TKJ8201 Gene mutation + Tanooka 1979

Eukaryotic organisms:

Saccharomyces cerevisiae RS112 Gene mutation + Agurell et al. 1991

Schizosaccaromyces pombe Gene mutation + + Migliore et al. 1982

Streptomyces griseoflavus Gene mutation – Mashima and Ikeda 1958

Aspergillus nidulans Gene mutation (+) Morpurgo 1963

Neurospora crassa Gene mutation + de Serres and Brockman 

1995; Kilbey and Kolmark 

1968; Kolmark and Kilbey 

1968; Kolmark and 

Westergaard 1953

Aspergillus nidulans Somatic crossingover– Morpurgo 1963

Mammalian cells:

Chinese hamster

V79 cells Gene mutation + Hatch et al. 1986

SP5/V79 cells Gene mutation – Zhang and Jenssen 1994

K1-BH4 ovary cells Gene mutation + + Tan et al. 1981

Mouse L5178Y TK cells Gene mutation + Brown et al. 1979; Krell et al. 

1979

Human fibroblasts Gene mutation + Bastlová et al. 1993; Kolman 

et al. 1992; Lambert et al. 

1994
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Table 2-6. Genotoxicity of Ethylene Oxide In Vitro

Species (test system) Endpoint

Results

Reference

Activation

With Without

Chinese hamster V79 cells Chromosomal 

aberrations

+ Zhong et al. 1991

Monkey lymphocytes Chromosomal 

aberrations

+ Lynch et al. 1984c

Human transformed amniotic cells Chromosomal 

aberrations

+ Poirier and Papadopoulo 1982

Monkey lymphocytes Sister chromatid 

exchange

+ Kelsey et al. 1989; Lynch et al. 

1984c

Human lymphocytes Sister chromatid 

exchange

+ Agurell et al. 1991; Garry et al. 

1982; Hallier et al. 1993; 

Tucker et al. 1986

Chinese hamster V79 cells Micronucleus 

formation

+ Zhong et al. 1991

Mouse C3H10T1/2 cells Cell transformation + Kolman et al. 1989b, 1990

SA7/Syrian hamster embryo cells Cell transformation + Hatch et al. 1986

Chinese hamster V79 cells DNA single strand 

breaks

+ Herrero et al. 1997

Human fibroblasts + Nygren et al. 1994

Human fibroblasts DNA double strand 

breaks

+ Nygren et al. 1994

Human lymphocytes + Hengstler et al. 1997

Human lymphocytes Unscheduled DNA 

synthesis

+ Pero et al. 1981

Human peripheral blood 

mononuclear cells

DNA damage + Godderis et al. 2006

Calf thymus DNA DNA adducts + Li et al. 1992

Calf thymus DNA DNA adducts + Segerbäck 1990

– = negative result; + = positive result; (+) = weakly positive result
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CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, 

BIOMARKERS, CHEMICAL INTERACTIONS

3.1 TOXICOKINETICS 

• Inhaled or ingested ethylene oxide is readily absorbed through the lung and by the gastrointestinal 

tract.

• Following absorption, ethylene oxide and its metabolites are rapidly distributed by the blood to a 

wide variety of tissues.

• As a reactive epoxide, ethylene oxide forms hydroxyethyl adducts with proteins (including 

hemoglobin) and deoxyribonucleic acid (DNA).

• Metabolism of ethylene oxide occurs by two separate pathways; hydrolysis and glutathione 

conjugation. 

• Ethylene oxide metabolites are rapidly excreted, predominantly in urine.

Ethylene oxide is produced endogenously via oxidation of absorbed ethylene or endogenous production 

of ethylene during normal oxidation processes such as lipid peroxidation, oxidation of methionine and 

heme, and metabolizing activity of intestinal bacteria (Thier and Bolt 2000). Isotope labeling is one way 

to differentiate between absorbed ethylene oxide from exogenous sources from endogenously-produced 

ethylene oxide. The toxicokinetics of exogenous ethylene oxide is commonly measured using a 

radiolabeled isotope (typically 14C-ethylene oxide). In such studies, the radiolabel is monitored to 

determine the extent of absorption, distribution, and excretion related to exogenous exposure to 

14C-ethylene oxide.

Kirman and Hays (2017) evaluated the relative contributions of exogenous and endogenous sources of the 

ethylene oxide to the production of the adduct hemoglobin, N-(2-hydroxyethyl)-valine (HEV). 

Endogenous equivalent values (based on meta-analysis of data from published literature characterizing 

the distribution of HEV) in nonsmoking populations were derived and compared to levels of HEV in 

ethylene oxide-exposed populations of smokers (tobacco smoke is an exogenous source of ethylene oxide 

exposure). For controls (nonsmokers without occupational exposure to ethylene oxide), mean HEV 

values ranged from 12.9 to 117 pmol/g hemoglobin. For smokers and occupationally exposed workers, 

mean HEV values ranged from 19.2 to 15,472 pmol/g hemoglobin. Fixed and random models predicted 

mean and standard deviation HEV values of 20.5±14.0 and 21.1±14.6 pmol/g hemoglobin, respectively. 

For smokers, modeled mean HEV values were 29.9±29.5 and 205±193 pmol/g hemoglobin, respectively. 
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These results indicate that endogenously-produced ethylene oxide provides a substantial proportion of 

ethylene oxide in the body.

3.1.1 Absorption 

In a study of hospital workers exposed to ethylene oxide in the workplace air at concentrations ranging 

from 0.2 to 24.1 mg/m3 (0.11–13.2 ppm), approximately 75% of the inhaled ethylene oxide was absorbed 

into the bloodstream (Brugnone et al. 1985, 1986). Blood:air coefficients were 2.5–3.3 measured from 

venous blood samples collected 4 hours after the workshift.

Inhaled ethylene oxide was rapidly absorbed through the respiratory system of the rat (Filser and Bolt 

1984; 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). Absorption 

approached 100% among mice exposed to ethylene oxide for up to 2 hours at 2–55 mg/m3 (1.1–30 ppm) 

(Ehrenberg et all 1974).

No human or animal data were located regarding absorption of ethylene oxide after oral exposure. 

Available information regarding dermal absorption of ethylene oxide is limited to a reported permeation 

rate of 0.125 mg/(cm-hour) for absorption through excised human skin exposed to a 1% ethylene oxide 

solution (Baumbach et al. 1987, as cited in IARC 2008).

3.1.2 Distribution 

No studies were located regarding the distribution of ethylene oxide in humans. However, studies in 

experimental animals demonstrate that absorbed ethylene oxide is readily distributed to a wide variety of 

tissues.

Brown et al. (1996) exposed rats and mice to ethylene oxide by 4-hour inhalation at 100 or 300 ppm and 

studied its distribution and elimination from blood, muscle, and brain. Tissue concentrations of ethylene 

oxide were calculated from headspace ethylene oxide concentrations using the appropriate air:tissue 

partition coefficient (Krishnan et al. 1992). For the 100 ppm exposure concentration, peak tissue 

concentrations averaged 0.57–0.60 μg/g for male rats, 0.56–0.72 μg/g for female rats, 0.29–0.36 μg/g for 

male mice, and 0.35–0.41 μg/g for female mice. Half-times of elimination of ethylene oxide from blood 

were 13.8 and 10.8 minutes for male and female rats, respectively, and 3.12 and 2.4 minutes for male and 
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female mice, respectively. Peak ethylene oxide concentrations in the testes were approximately 20% 

lower in rats and 50% lower in mice compared to concentrations in blood, muscle, and brain. Saturation 

kinetics were observed in mice (but not rats) exposed to ethylene oxide at 300 ppm for 4 hours. Brown et 

al. (1998) reported a linear increase in ethylene oxide levels in blood with increasing exposure 

concentrations in mice exposed to 50–200 ppm ethylene oxide for 4 hours; steady state was achieved with 

the first 2 hours of exposure. At higher concentrations (300 and 400 ppm), blood ethylene oxide levels 

increased sublinearly and continued to increase during the 4-hour exposure. The sublinear increase in 

blood levels correlated with tissue glutathione depletion. Ehrenberg et al. (1974) reported that 75 minutes 

after exposing mice to radiolabeled ethylene-[1,2-

3

H] oxide, the highest levels of radioactivity were 

observed in the lungs, liver, and kidneys. Lesser amounts were found in the spleen, brain, and testes.

Krishnan et al. (1992) demonstrated relatively similar ethylene oxide tissue distribution for male Fischer 

rats based on calculated in vitro tissue:air partition coefficients for fat (44.1), brain (48.3), lung (60.9), 

liver (61.6), blood (64.1), and testes (83). Tyler and McKelvey (1982) reported the highest concentrations 

of 14C-activity in urinary bladder, liver, packed blood cells, and adrenal glands, and the lowest 

concentration in fat from rats exposed to 14C-ethylene oxide.

No studies were located regarding distribution of ethylene oxide after oral or dermal exposure.

3.1.3 Metabolism 

Ethylene oxide metabolism has been evaluated in a variety of experimental mammal systems in vivo and 

in vitro, and has resulted in the proposed metabolic scheme shown in Figure 3-1 (from IARC 2008; see 

also Popp et al. 1994; Scheick et al. 1997; Wolfs et al. 1983, as cited in IARC 2008). Metabolism is 

initiated via two separate pathways. One pathway involves enzymatic and nonenzymatic hydrolysis to 

ethylene glycol and subsequent conversion to oxalic acid, formic acid, and carbon dioxide. The other 

pathway involves glutathione conjugation to form mercapturic acid and meththio metabolites, some of 

which are converted to thiodiacetic acid. Metabolites recovered from the urine of ethylene oxide-exposed 

rats include ethylene glycol, 2-hydroxyethylmercapturic acid, and thiodiacetic acid (Scheick et al. 1997).

The relative contribution of each major pathway is species dependent. Results from a physiologically 

based pharmacokinetic (PBPK) model (Fennell and Brown 2001) designed to simulate the uptake and 

metabolism of ethylene oxide in rats, mice, and humans suggest that approximately 80% (rats), 60% 

(mice), and 20% (humans) of metabolized ethylene oxide occurs via glutathione conjugation and 20% 
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(rats), 40% (mice), and 80% (humans) occurs via the hydrolytic pathway. Although PBPK model 

simulations produced these species-specific differences in the relative contribution of each metabolic 

pathway, after accounting for species differences in uptake and metabolism, simulated peak blood 

concentrations were relatively similar for rats, mice, and humans (Fennell and Brown 2001). The order of 

area under the curve (AUC) values was humans>rats>mice.

Figure 3-1. Metabolism of Ethylene Oxide

Source: IARC 2008

3.1.4 Excretion 

No studies were located regarding excretion in humans following inhalation, oral, or dermal exposure to 

ethylene oxide. No animal studies were located regarding excretion of ethylene oxide and/or its 

metabolites following oral or dermal exposure.

In a study of rats exposed to 14C-ethylene oxide by inhalation, 59% of the 14C-activity was recovered in 

the urine, 12% expired as 14CO2, 4.5% in feces, and 1% expired unchanged (Tyler and McKelvey 1982). 
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Ethylene oxide and its metabolites are rapidly excreted in urine. In a study of mice exposed to 

radiolabeled ethylene oxide for 60–75 minutes, an average of 78% of the absorbed radioactivity was 

eliminated in the urine within 48 hours (Ehrenberg et al. 1974). Filser and Bolt (1984) found that 

ethylene oxide administered in a closed-system inhalation chamber exhibited first-order elimination 

kinetics. Metabolites recovered in urine from rats exposed to airborne ethylene oxide include ethylene 

glycol, 2-hydroxyethylmercapturic acid, and thiodiacetic acid (Scheick et al. 1997).

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

PBPK models use mathematical descriptions of the uptake and disposition of chemical substances to 

quantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK 

models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in 

risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that 

will be delivered to any given target tissue following various combinations of route, dose level, and test 

species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use 

mathematical descriptions of the dose-response function to quantitatively describe the relationship 

between target tissue dose and toxic endpoints. 

Several PBPK models of ethylene oxide have been reported. These include models of humans, mice, and 

rats (Csanady et al. 2000; Fennell and Brown 2001; Filser and Klein 2018a, 2018b; Krishnan et al. 1992; 

NIOSH 1987). The models simulate species differences in metabolism of ethylene oxide thought to 

contribute to interspecies differences in dose-response relationships for carcinogenicity. The model 

reported by Filser and Klein (2018a, 2018b) is an extension and enhancement of a model reported by 

Csanady et al. (2000) and includes simulations of adduct formation, thought to be important in the 

mechanism of carcinogenicity of ethylene oxide. The model reported by Fennell and Brown (2001) is an 

extension and enhancement of a model reported by Krishnan et al. (1992).

Filser and Klein (2018a, 2018b) Models of Human, Mouse, and Rat. Filser and Klein (2018a, 2018b) 

developed a model for simulating the kinetics of inhaled ethylene and ethylene oxide in humans, mice, 

and rats. The model is an extension and enhancement of a model reported by Csanady et al. (2000). The 

major enhancements made to the Csanady et al. (2000) model were as follows: (1) including glutathione 

transferase activity to extra-hepatic tissues; (2) including suicide substrate (ethylene) inhibition of hepatic 

CYP2E1-mediated metabolism; (3) expanding metabolism pathways to include non-enzymatic hydrolysis 

and glutathione conjugation; and (4) updating some parameter values based on new data. The general 
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structure of the model is depicted in Figure 3-2. Parameter values for the model are presented in 

Tables 3-1 and 3-2. Complete lists of parameters and parameter values and the basis for parameter values 

and evaluations of model predictions in comparison to observations are described in Filser and Klein 

(2018a, 2018b).

Figure 3-2. Physiologically Based Toxicokinetic Model for Inhaled Ethylene and 

Inhaled or Metabolically Formed Ethylene Oxide*

*Compartments in solid lines are characterized by defined volumes; the air compartment (dotted lines) can have a 

defined volume or can be infinitely large, depending on the exposure condition. Dashed arrows indicate transport in 

the blood; solid arrows indicate uptake or elimination

CYP2E1 = cytochrome P450 2E1; EH = microsomal epoxide hydrolase; EO = ethylene oxide; ET = ethylene; 

ET(OH)2 = ethylene glycol; ET(OH)SG = S-(2-hydroxyethyl)glutathione; GSH = glutathione; GST = cytosolic 

glutathione S-transferase; RPTG = richly perfused tissue group

Source: Filser and Klein 2018a, 2018b (permission: Creative Commons CC BY 4.0, 

https://creativecommons.org/licenses/by/4.0/; minor revisions)
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Table 3-1. Physiological and Physicochemical Parameters Used in the 

Physiologically Based Toxicokinetic Model

Parameter Abbreviation Mouse Rat Human

Body weight (kg) BW 0.025 0.25 70

Alveolar ventilation at rest 

(L/hour)

Qalv 1.2 7.02 300

Cardiac output at rest (L/hour) Qcard 1.02 5.04 372

Blood flow (L/hour)

RPTG Qr 0.355 x Qcard 0.355 x Qcard 0.285 x Qcard

Kidneys Qk 0.155 x Qcard 0.155 x Qcard 0.155 x Qcard

Muscle Qm 0.223 x Qcard 0.223 x Qcard 0.250 x Qcard

Fat Qa 0.017 x Qcard 0.017 x Qcard 0.050 x Qcard

Liver QL 0.250 x Qcard 0.250 x Qcard 0.260 x Qcard

Compartment volumes (L)

Arterial blood Vart 0.0159 x BW 0.0241 x BW 0.0257 x BW

Venous blood Vvnb 0.0331 x BW 0.050 x BW 0.0533 x BW

RPTG Vr 0.026 x BW 0.0377 x BW 0.038 x BW

Kidneys Vk 0.0167 x BW 0.0073 x BW 0.0044 x BW

Lung Vp 0.0073 x BW 0.005 x BW 0.0076 x BW

Muscle Vm 0.66 x BW 0.676 x BW 0.541 x BW

Fat Va 0.10 x BW 0.07 x BW 0.19 x BW

Liver VL 0.055 x BW 0.04 x BW 0.026 x BW

Water content as fraction of compartment volume

Blood wfb 0.842 0.842 0.830

RPTG wfr 0.783 0.783 0.76

Kidneys wfk 0.771 0.771 0.827

Lung wfp 0.842 0.842 0.790

Muscle wfm 0.756 0.756 0.756

Fat wfa 0.183 0.183 0.100

Liver wfL 0.705 0.705 0.683

Partition coefficients of ET

Blood:air Pbair 0.48 0.48 0.22

RPTG:blood Prb 1.04 1.04 2.18

Kidney:blood Pkb 1.04 1.04 2.18

Lung:blood Ppb 1.04 1.04 2.18

Muscle:blood Pmb 1.31 1.31 2.95

Fat:blood Pab 4.29 4.29 8.73

Liver:blood PLb 1.19 1.19 2.05

Partition coefficients of EO

Blood:air PEObair 61 61 61

RPTG:blood PEOrb 1.03 1.03 1.03

Kidney:blood PEOkb 1.03 1.03 1.03

Lung:blood PEOpb 1.03 1.03 1.03
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Table 3-1. Physiological and Physicochemical Parameters Used in the 

Physiologically Based Toxicokinetic Model

Parameter Abbreviation Mouse Rat Human

Muscle:blood PEOmb 1.08 1.08 1.08

Fat:blood PEOab 0.70 0.70 0.70

Liver:blood PEOLb 0.89 0.89 0.89

Wash-in–wash-out effect

Fraction of inhaled ET 

reaching the alveoli

fET 0.6 0.6 1.0

Fraction of inhaled EO 

reaching the alveoli

fEO 0.6 0.6; 0.3 0.8

EO = ethylene oxide; ET = ethylene; PTRG = richly perfused tissue group

Source: Filser and Klein 2018a, 2018b (permission: Creative Commons CC BY 4.0, 

https://creativecommons.org/licenses/by/4.0/; minor revisions)

Table 3-2. Biochemical Parameters Used in the Physiologically Based 

Toxicokinetic Model

Parameter Abbreviation Mouse Rat Human

Metabolism of ET in the liver

Rate constant of CYP2E1 catalyzed formation of 

EO from ET (hour-1)

k3 260 420 50

Rate constant of suicide inhibition of CYP2E1 by 

ET (hour-1)

k4 1.9 0.8 1.1

Apparent Michaelis constant of ET oxidation in 

venous liver blood (mmol/L)

Kmmo 0.001 0.003 0.003

Rate constant of physiological degradation of 

CYP2E1 (hour-1)

ke 0.187 0.120 0.0139

Initial concentration of CYP2E1 (mmol/kg liver) CYPo 0.00288 0.001074 0.002115

Metabolism of EO

EH in the liver

Maximum rate of hydrolysis of EO catalyzed by 

EH (mmol/hour/kg liver)

VmaxEOEH 2.70 3.60 25.83

Apparent Michaelis constant of EO hydrolysis in 

the liver (mmol/L)

KmapEO 0.2 0.2 0.46

Intrinsic Michaelis constant of EO hydrolysis in 

the endoplasmic reticulum (mmol/L)

KmihEO 0.1999 0.1999 0.31

GST in the liver

Maximum metabolic elimination rate of EO 

catalyzed by GST in the liver (mmol/hour/kg liver)

VmaxgstL 1,431 272 58.4

Apparent Michaelis-constant of EO with GST in the 

liver (mmol/L)

KmEOL 9 9 9

Apparent Michaelis constant of GSH with GST in the 

liver (mmol/L)

KmgshL 0.1 0.1 0.1
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Table 3-2. Biochemical Parameters Used in the Physiologically Based 

Toxicokinetic Model

Parameter Abbreviation Mouse Rat Human

Elimination rate constant for GSH turnover in the 

liver (hour-1)

kdgshL 0.2 0.2 0.2

Initial concentration of cytosolic GSH in the liver 

(mmol/L)

CgshoL 8.62 6.4 5.9

GST in the lung

Maximum metabolic elimination rate of EO 

catalyzed by GST in the lung (mmol/hour/kg lung)

Vmaxgstp 97.6 27.5 5.84

Apparent Michaelis-constant of EO with GST in the 

lung (mmol/L)

KmEOp 9 9 9

Apparent Michaelis constant of GSH with GST in the 

lung (mmol/L)

Kmgshp 0.1 0.1 0.1

Elimination rate constant for GSH turnover in the 

lung (hour-1)

kdgshp 1.3 1.8 2.0

Initial concentration of cytosolic GSH in the lung 

(mmol/L)

Cgshop 1.86 1.7 1.95

GST in the kidneys

Maximum metabolic elimination rate of EO 

catalyzed by GST in the kidneys (mmol/hour/kg 

kidney)

Vmaxgstk 264 172 5.0

Apparent Michaelis-constant of EO with GST in the 

kidneys (mmol/L)

KmEOk 9 9 9

Apparent Michaelis constant of GSH with GST in the 

kidneys (mmol/L)

Kmgshk 0.1 0.1 0.1

Elimination rate constant for GSH turnover in the 

kidneys (hour-1)

kdgshk 0.2 0.2 0.2

Initial concentration of cytosolic GSH in the kidneys 

(mmol/L)

Cgshok 3.06 2.6 0.5

GST in the RPTG

Maximum metabolic elimination rate of EO 

catalyzed by GST in the RPTG (mmol/hour/kg 

RPTG)

Vmaxgstr 43 8.16 1.75

Apparent Michaelis-constant of EO with GST in the 

RPTG (mmol/L)

KmEOr 9 9 9

Apparent Michaelis constant of GSH with GST in the 

RPTG (mmol/L)

Kmgshr 0.1 0.1 0.1

Elimination rate constant for GSH turnover in the 

RPTG (hour-1)

kdgshr 0.2 0.2 0.2

Initial concentration of cytosolic GSH in the RPTG 

(mmol/L)

Cgshor 2.29 2.85 1.20

GST in blood

Maximum metabolic elimination rate of EO 

catalyzed by GST in the blood (mmol/hour/L blood)

Vmaxgstb 57.24 10.88 2.33

Apparent Michaelis-constant of EO with GST in the 

blood (mmol/L)

KmEOb 9 9 9
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Table 3-2. Biochemical Parameters Used in the Physiologically Based 

Toxicokinetic Model

Parameter Abbreviation Mouse Rat Human

Apparent Michaelis constant of GSH with GST in the 

blood (mmol/L)

Kmgshb 0.1 0.1 0.1

Elimination rate constant for GSH turnover in the 

blood (hour-1)

kdgshb 0.2 0.2 0.2

Initial concentration of cytosolic GSH in the blood 

(mmol/L)

Cgshob 1.255 0.945 0.766

Non-enzymatic GSH conjugation of EO

Rate constant of the conjugation reaction (L/(mmol 

GSHxhour))

kEOG 0.01248 0.01248 0.01248

Non-enzymatic hydrolysis of EO 

Rate constant of EO hydrolysis (hour-1) kEOh 0.06 0.06 0.06

CYP2E1 = cytochrome P450 2E1; EH = microsomal epoxide hydrolase; EO = ethylene oxide; ET = ethylene; 

SH = glutathione; GST = cytosolic glutathione S-transferase; PTRG = richly perfused tissue group

Source: Filser and Klein 2018a, 2018b (permission: Creative Commons CC BY 4.0, 

https://creativecommons.org/licenses/by/4.0/; minor revisions)

The ethylene oxide model includes compartments representing venous and arterial blood, lung, kidney, 

liver, muscle, fat, and a lumped compartment representing all other richly perfused tissues. Absorption 

from the respiratory tract is simulated as a flow-limited transfer from the upper respiratory tract governed 

by the fraction of inhaled ethylene oxide reaching the alveolar region of the lung, the alveolar-blood 

concentration difference, alveolar ventilation rate, cardiac output, and the blood:air partition coefficient. 

Reported blood:air partition coefficients are 61 for humans (Csanady et al. 2000) and 64.1 for rats 

(Krishnan et al. 1992). Exchanges between ethylene oxide in tissues and blood are assumed to be flowlimited (governed by blood flow) with equilibrium determined by the tissue:blood partition coefficient. 

Elimination of ethylene oxide is simulated as exhalation and metabolism. Four metabolism pathways are 

simulated: (1) conversion to ethylene glycol mediated by liver microsomal epoxide hydrolase in liver; 

(2) conversion to S-(2-hydroxyethyl)glutathione mediated by cytosolic glutathione S-transferase in lung, 

kidney, liver, and richly perfused tissue; (3) non-enzymatic conversion to ethylene glycol in all tissues; 

and (4) non-enzymatic conjugation with glutathione in all tissues. 

The epoxide-hydrolase pathway is simulated as a capacity-limited process governed by a maximum rate 

(Vmax, mmol/hour/kg liver) and a Michaelis half-saturation constant (Km, mmol/L). The non-enzymatic 

hydrolysis pathway is unlimited and governed by a first-order rate constant (hour-1

). The glutathione 

transferase pathway is simulated as a capacity-limited process governed by a maximum (Vmax, 

mmol/hour/kg liver) and Michaelis constants (Km, mmol/L) for ethylene oxide and reduced glutathione 
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(GSH). Conjugation with glutathione is limited by availability of GSH, which is consumed by 

conjugation with ethylene oxide as well as physiologic GSH turnover unrelated to conjugation. 

Physiologic turnover of GSH is governed by a first-order elimination rate constant (hour-1

). The nonenzymatic glutathione conjugation pathway is unlimited and governed by a clearance constant (L/mmol 

GSH/hour). The Filser and Klein (2018a, 2018b) ethylene oxide model is connected to a similar model 

for ethylene. The ethylene model simulates production of ethylene oxide in the liver mediated by the 

microsomal CYP2E1 system and includes suicide inhibition of CYP2E1 by ethylene. Production of 

ethylene oxide is governed by a first-order rate constant (hour-1

) for the reaction with ethylene, a firstorder rate constant for suicide inhibition of CYP2E1 by ethylene (hour-1

), and a first-order rate constant 

for physiologic turnover of CYP2E1 (hour-1

). The model simulates the formation of adducts between 

ethylene oxide and HEV and DNA guanine (N7-(2-hydroxyethyl)guanine; HEG). Adduct formation is 

governed by clearance terms (L/hour/g Hb or DNA).

Partition coefficients were estimated from in vitro head-space studies (Csanady et al. 2000). Parameters 

(Vmax, Km) for liver epoxide hydrolase and tissue-specific glutathione transferase activity were derived 

from in vitro studies, with Vmax scaled to whole tissue from estimates of rates per unit mass of protein 

(Filser and Klein 2018a, 2018b). Parameters for liver epoxide hydrase were subsequently calibrated to fit 

data on blood ethylene oxide concentration in mice, rats, or humans exposed to ethylene or ethylene oxide 

(Brugnone et al. 1986; Fennell et al. 2004; Filser et al. 2013). Calibration was achieved by visual 

inspection of plots of observed and predicted values. The rate of non-enzymatic conjugation with GSH 

was estimated from in vitro studies (Fennell and Brown 2001). The rate of non-enzymatic hydrolysis was 

estimated by model calibration to blood ethylene oxide concentrations measured in workers exposed to 

ethylene oxide (Fennell and Brown 2001). Adduct formation rates were derived from in vitro studies of 

adduct formation (Segerback 1990; Walker et al. 1992b).

The calibrated model was evaluated against observations of blood ethylene oxide concentrations and rates 

of uptake from closed space air obtained from studies in which mice, rats, or humans were exposed to 

ethylene or ethylene oxide (Brown et al. 1998; Brugnone et al. 1986; Filser and Bolt 1984; Filser et al. 

1992, 2013, 2015). Exposures to ethylene oxide were 9–2,500 ppm in mice, 140–1,450 ppm in rats, and 

2–10 ppm in humans. Goodness-of-fit was assessed by the sum of squared errors from observations and 

comparison of plotted predictions and observations.

The model predicts that, over a range of exposures (0.5–500 ppm for 6 hours), the epoxide hydrolase 

pathway will dominate metabolism in the human relative to the glutathione transferase pathway (EH/GST 
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ratio: 85/15). In mice and rats, the glutathione transferase pathway is predicted to dominate; however, 

depletion of the glutathione will limit the capacity for conjugation at concentrations exceeding 100 ppm 

in the mouse and 200 ppm in the rat. The model predicts that clearance of ethylene oxide in the mouse is 

capacity limited. At exposure concentrations below 200 ppm, rates of uptake of ethylene oxide from 

closed chambers (an indicator of systemic clearance) are predicted to be similar in mice and rats. 

However, at exposure concentrations exceeding 200 ppm, uptake rates in mice are slower than those 

predicted for rats, indicating slower clearance by mice. The model also predicts that exposure 

concentrations exceeding 200 ppm in mice would result a super-linear increase in blood ethylene oxide 

concentrations (i.e., an increase in blood concentration larger than the proportional increase in exposure 

concentration). The predicted differences in the exposure-clearance and exposure-blood concentration 

relationship in mice agree with observations (Filser and Klein 2018a, 2018b). These differences in 

metabolic pathways and systemic clearance could contribute to species differences in dose-response 

relationships for toxicity endpoints that derive from metabolites of ethylene oxide. The model was 

applied to estimating exposure concentrations of ethylene and ethylene oxide that would result in the 

same HEV or HEG levels. The model predicts that an inhalation exposure of humans to 0.3 ppm ethylene 

oxide (8 hours/day, 5 days/week) would produce the same levels of HEV or HED as a similar exposure to 

200 ppm ethylene.

Fennell and Brown (2001) Models of Human, Mouse, and Rat. Fennell and Brown (2001) developed a 

model for simulating the kinetics of inhaled ethylene oxide in humans, mice, and rats. The model is an 

extension and enhancement of a model reported by Krishnan et al. (1992). The major enhancements 

made to the Krishnan et al. (1992) model were as follows: (1) including a kidney compartment; 

(2) simulating enzymatic hydrolysis (liver) and glutathione conjugation (liver, kidney, testes) as capacity 

limited (Vmax, Km); (4) simulating exchanges between blood and testes as diffusion-limited; and 

(4) updating some parameter values based on new data. Complete lists of parameters and parameter 

values and the basis for parameter values and evaluations of model predictions in comparison to 

observations are described in Fennell and Brown (2001).

The model includes compartments representing venous and arterial blood, lung, kidney, liver, brain,

testes, fat, and lumped compartments representing all other richly perfused tissues or slowly perfused 

tissues. Absorption from the respiratory tract is simulated as a flow-limited transfer from a gas exchange 

compartment of the lung to a metabolic lung compartment, governed by an uptake fraction, concentration 

difference across the lung compartments, alveolar ventilation rate, cardiac output, and the blood:air 

partition coefficient. Exchanges between ethylene oxide in blood and all tissues except testes are 
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assumed to be flow-limited (governed by blood flow) with equilibrium determined by a tissue:blood 

partition coefficient. Exchange between blood and testes was simulated as a diffusion-limited process 

governed by a permeability coefficient (hour

-1

). The diffusion-limited assumption was needed to 

accurately predict the observed testes concentrations of ethylene oxide. Elimination of ethylene oxide is 

simulated as exhalation and metabolism. Three metabolism pathways are simulated: (1) conversion to 

ethylene glycol mediated by liver microsomal epoxide hydrolase in liver; (2) conversion to S-(2-hydroxyethyl)glutathione mediated by cytosolic glutathione S-transferase in lung, kidney, and testes; and (3) nonenzymatic hydrolysis in all other tissues except fat. The epoxide hydrolase pathway is simulated as a 

capacity-limited process governed by a maximum rate (Vmax, mmol/hour) and a Michaelis halfsaturation constant (Km, mmol/L). The non-enzymatic hydrolysis pathway is unlimited and governed by 

a first-order rate constant (hour

-1

). The glutathione transferase pathway is simulated as a capacity-limited 

process governed by a maximum (Vmax, mmol/hour) and Michaelis half-saturation constants (Km, 

mmol/L) for ethylene oxide and GSH. Conjugation with glutathione is limited by availability of GSH,

which is consumed by conjugation with ethylene oxide as well as physiologic GSH turnover unrelated to 

conjugation. Physiologic turnover of GSH is governed by first-order synthesis and elimination rates 

(hour

-1

). The model simulates the formation of adducts between ethylene oxide and the protein and DNA 

in kidney, liver, and testes, governed by first-order binding rates (hour

-1

).

Partition coefficients were estimated from in vitro head-space studies (Csanady et al. 2000; Filser et al.

1992; Krishnan et al. 1992). Parameters (Vmax, Km) for liver epoxide hydrolase and tissue-specific 

glutathione transferase activity were derived from in vitro studies, with Vmax scaled to whole tissue from 

estimates of rates per unit mass of protein (Brown et al. 1996; Fennell and Brown 2001). Other 

parameters were calibrated to achieve better agreement with observations. These included the pulmonary 

uptake factor, the diffusion permeability coefficient for testes, partition coefficients, and various 

physiological parameters. The model was calibrated with observations made in mice and rats on kinetics 

of ethylene oxide concentrations in closed exposure chamber air, blood, and tissues; and blood GSH 

concentrations (Brown et al. 1996, 1998; Krishnan et al. 1992). The human model was calibrated with 

observations of blood ethylene oxide concentrations exposed to work room air (Brugnone et al. 1986).

The model predicts that, over a range of exposures (20–500 ppm for 4 hours), the hydrolysis pathway will 

dominate metabolism in the human relative to the glutathione transferase pathway (EH/GST ratio: 60/20). 

In mice and rats, the glutathione transferase pathway is predicted to dominate; however, depletion of the 

glutathione will limit the capacity for conjugation at concentrations exceeding 200 ppm in the mouse. 

The EH/GST ratio was relatively constant (30:60) in the rat. The model predicts that clearance of 
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ethylene oxide in the mouse is capacity limited. At exposure concentrations below 200 ppm, blood 

ethylene oxide concentrations are predicted to be similar in mice, rats, and humans. However, at 

exposure concentrations exceeding 200 ppm, blood ethylene oxide concentrations in mice exceed those 

predicted for rats and humans. The predicted differences in the exposure-blood concentration relationship 

in mice and rats agree with observations (Fennell and Brown 2001). These differences in metabolic 

pathways and clearance could contribute to species differences in dose-response relationships for toxicity 

endpoints that derive from metabolites of ethylene oxide. However, at exposure concentrations below 

100 ppm, the models predict similar peak and blood ethylene oxide concentrations and areas under the 

curve (AUCs) in mice, rats, and humans (Fennell and Brown 2001).

3.1.6 Animal-to-Human Extrapolations 

The disposition and metabolism of inhaled ethylene oxide is species dependent. Species differences exist 

regarding the relative contribution of the metabolic pathways discussed in Section 3.1.3 (the 

nonenzymatic hydrolysis pathway and the glutathione conjugation pathway) (Fennell and Brown 2001). 

Although ethylene oxide exposure concentrations <200 ppm are predicted to result in similar blood levels 

among rats, mice, and humans, higher exposure concentrations would result in higher blood levels in mice 

compared to rats and humans. The higher blood levels in mice are likely the result of glutathione 

depletion. Interspecies extrapolation would need to account for species differences in metabolic 

pathways, species-specific contribution of exposure concentration, and the identity of the toxicant or 

toxicants (ethylene oxide itself and/or its metabolite[s]) responsible for a particular toxic effect.

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans. Potential effects on offspring resulting from exposures of parental 

germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal 

exposure during gestation and lactation. Children may be more or less susceptible than adults to health 

effects from exposure to hazardous substances and the relationship may change with developmental age. 

This section also discusses unusually susceptible populations. A susceptible population may exhibit 

different or enhanced responses to certain chemicals than most persons exposed to the same level of these 

chemicals in the environment. Factors involved with increased susceptibility may include genetic 
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makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters can reduce detoxification or excretion or compromise organ function. 

Populations at greater exposure risk to unusually high exposure levels to ethylene oxide are discussed in 

Section 5.7, Populations with Potentially High Exposures.

No data were located regarding age-related differences in susceptibility to ethylene oxide toxicity or 

carcinogenicity. However, because detoxification of ethylene oxide occurs via hydrolytic and 

glutathione-S-transferase pathways, very young children with incomplete development of these 

detoxification pathways (McCarver and Hines 2002; Zhong et al. 2018) may exhibit increased 

susceptibility to ethylene oxide toxicity. Limited data do not suggest significant sex-related differences in 

ethylene oxide metabolism (Fennell and Brown 2001; Mertes et al. 1985). Individuals with genetic 

deficiencies in activities of detoxification enzymes would likely be at increased risk of ethylene oxide 

toxicity/carcinogenicity. For example, ethylene oxide hemoglobin adduct levels in occupationallyexposed workers were 2-fold greater among individuals expressing a null GSTT1 genotype than those 

expressing a nonnull GSTT1 genotype (Yong et al. 2001). Haufroid et al. (2007) reported increased 

urinary excretion of an ethylene oxide glutathione conjugate among nonnull GSTT1 genotype hospital 

workers, suggestive of increased ethylene oxide detoxification. People with DNA repair deficiencies 

might experience increased sensitivity to DNA-damaging effects of ethylene oxide.

3.3 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as biomarkers of exposure, biomarkers of effect, and biomarkers 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(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. Biomarkers of 

exposure to ethylene oxide are discussed in Section 3.3.1. The National Report on Human Exposure to 

Environmental Chemicals provides an ongoing assessment of the exposure of a generalizable sample of 

the U.S. population to environmental chemicals using biomonitoring (see http://www.cdc.gov/
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exposurereport/). If available, biomonitoring data for ethylene oxide from this report are discussed in 

Section 5.6, General Population Exposure. 

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 epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effect caused 

by ethylene oxide are discussed in Section 3.3.2.

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 substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.2, Children and Other Populations that are Unusually Susceptible.

3.3.1 Biomarkers of Exposure

Ethylene oxide is a direct acting alkylating agent that can form adducts with macromolecules such as 

DNA and hemoglobin. The primary DNA adduct formed is 7-HEG (EPA 2016a; IARC 2012). Studies in 

rats and mice have found concentration- and duration-related increases in 7-HEG levels following 

inhalation exposure (Rusyn et al. 2005; Walker et al. 1993). EPA (2016a) notes that DNA adducts are 

less reliable measures of exposure because they can be repaired or fixed as mutations. The ethylene oxide 

hemoglobin adduct, hydroxylated N-terminal valine (HOEtVal), has been widely used as a biomarker of 

occupational exposure to ethylene oxide (see Angerer et al. 1998; Boogaard 2002; Boogaard et al. 1999). 

Occupational exposure studies have found a correlation between ambient air levels of ethylene oxide and 

HOEtVal levels (Angerer et al. 1998; Boogaard 2002). Studies in rats and mice have reported increases 

in HOEtVal levels following a single inhalation exposure (Walker et al. 1992a) or intraperitoneal 

injection (Tates et al. 1999; Walker et al. 1992a) or repeated inhalation (Tates et al. 1999; Walker et al. 

1992a, 1993) or drinking water (Tates et al. 1999) exposures. A 4-week inhalation exposure to 3–33 ppm 

resulted in a linear increase in HOEtVal levels; at 100 ppm, the slope estimated from the 3–33 ppm 

exposure underpredicted the HOEtVal levels by 20 and 25% in rats and mice, respectively (Walker et al. 
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1992a). In humans, HOEtVal blood levels are influenced by endogenous production of ethylene oxide, 

genetic status of the polymorphic glutathione transferases hGSST1 (Fennell et al. 2000; Müller et al. 

1998; Thier et al. 1999, 2001; Yong et al. 2001), and smoking status (Bono et al. 1999; Fennell et al. 

2000; Müller et al. 1998; Thier et al. 1999). hGSTM1 genotypes did not influence HOEtVal blood levels 

(Fennell et al. 2000; Müller et al. 1998; Their et al. 1999). 

The urinary metabolite, HEMA (S-[2-hydroxyethyl]mercapturic acid), has also been used as a biomarker 

of exposure to ethylene oxide (Alwis et al. 2012; Eckert et al. 2011; Popp et al. 1994), including 

occupational levels <1 ppm (Haufroid et al. 2007). However, HEMA is not specific to ethylene oxide; it 

is also a metabolite of acrylonitrile and vinyl chloride. Ethylene oxide can be measured in blood and 

alveolar air (Brugnone et al. 1986).

3.3.2 Biomarkers of Effect

No information was located regarding specific biomarkers of effect for ethylene oxide.

3.4 INTERACTIONS WITH OTHER CHEMICALS

No information was located regarding toxicologically-relevant interactions between ethylene oxide and 

other substances. Although no specific data were identified, chemicals that deplete glutathione levels 

may interfere with the metabolism of ethylene oxide and could result in an increased internal dose and 

toxicity.
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CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY

Ethylene oxide is both a manmade substance and a natural substance produced in the body via oxidation 

of absorbed or endogenously produced ethylene during normal oxidation processes.

Table 4-1 lists common synonyms, trade names, and other pertinent identification information for 

ethylene oxide.

Table 4-1. Chemical Identity of Ethylene Oxide

Characteristic Information Reference

Chemical name Ethylene oxide HSDB 2010

Synonym(s) and registered 

trade name(s)

Oxirane; dihydro-oxirane; dimethylene 

oxide; epoxyethane; ETO; Anprolene; 

Oxyfume; T-Gas; 1,2-epoxyethane; ethene 

oxide; diethylene oxide; E.O.; oxane; 

oxidoethane

HSDB 2010; Parod 2014; 

WHO 2003 

Chemical formula C2H4O EPA 2017b

Chemical structure

CAS Registry Number 75-21-8 WHO 2003

CAS = Chemical Abstracts Service 

4.2 PHYSICAL AND CHEMICAL PROPERTIES

Ethylene oxide is a colorless, flammable gas. It is highly soluble in water (1x106 mg/L at 20°C) and 

possesses a high vapor pressure (1.095x103 mm Hg at 20°C).

Table 4-2 lists important physical and chemical properties of ethylene oxide.

H C C H

O

H H
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Table 4-2. Physical and Chemical Properties of Ethylene Oxide

Property Information Reference

Molecular weight 44.05 g/mol WHO 2003

Color Colorless WHO 2003

Physical state Gas NIOSH 2007

Melting point -111.7°C HSDB 2010

Boiling point 51°F (10.6°C) NIOSH 2016

Density at 10°C 0.8824 HSDB 2010; Weast 1985

Odor Sweet, olefinic; ether-like NIOSH 2007; Verschueren 1983

Odor threshold:

Water 140 mg/L Amoore and Hautala 1983

Air 787 mg/m3 (432.85 ppm) Amoore and Hautala 1983

Solubility:

Water at 20°C 1x106 mg/L EPA 2017b

Organic solvents Soluble in alcohol, ether, 

acetone, benzene

EPA 2017b

Partition coefficients:

Log Kow -0.22 EPA 2017b

Log Koc 1.204 WHO 2003

Vapor pressure at 20°C 1.095x103 mm Hg EPA 2017b

Henry's law constant at 25°C 1.48x10-4 atm-m3/mol HSDB 2010

Autoignition temperature 429°C HSDB 2010

Flashpoint <-18°C (open cup) HSDB 2010

Flammability limits Lower: 3.0%

Upper: 100%

HSDB 2010

Conversion factors 1 ppm=1.83 mg/m3

1 mg/m3=0.55 ppm

WHO 2003

Explosive limits Lower: 3.0%

Upper: 100%

HSDB 2010
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CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Ethylene oxide has been identified in at least 2 of the 1,867 hazardous waste sites that have been proposed 

for inclusion on the EPA National Priorities List (NPL) (ATSDR 2019). However, the number of sites in 

which ethylene oxide has been evaluated is not known. The number of sites in each state is shown in 

Figure 5-1.

Figure 5-1. Number of NPL Sites with Ethylene Oxide Contamination

• People can be exposed to ethylene oxide through:

o Inhalation of contaminated air near production and use facilities

o Inhalation of contaminated air during sterilization/fumigation practices

o Inhalation of tobacco smoke

o Dermal contact during sterilization/fumigation practices

o Use of medical devices and cosmetics sterilized with ethylene oxide

o Preparation and ingestion of foods sterilized with ethylene oxide

• Environmental exposure of ethylene oxide can occur: 

o During production of ethylene oxide and its involvement in the production of other 

chemicals

o Following use of ethylene oxide in sterilization/fumigation operation

o By breathing air contaminated with tobacco smoke
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• In the environment, ethylene oxide is expected to:

o Oxidize in the atmosphere 

o Evaporate or hydrolyze from water

o Volatilize from soil

o React with nucleophilic groups such as carboxyl, amino, and phenolic groups, as well as 

strong acids

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

(WHO 2003). 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. In the air, oxidation via free radical formation 

is the most probable degradation pathway; the estimated half-life of this reaction ranges from 2 to 

5 months. The half-life estimates for other degradation pathways for atmospheric ethylene oxide vary 

widely. In water, ethylene oxide would likely degrade 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 <15 days, depending on environmental conditions. Ultraviolet-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, infinite solubility in water, and reaction with 

mineral surfaces. Soil microorganisms may also convert it to glycols.

Data on the levels of ethylene oxide in the environment are very limited. There is a limited amount of 

ethylene oxide air monitoring data in the United States; EPA has begun to measure ethylene oxide at the 

National Air Toxics Trends Stations and the Urban Air Toxics Monitoring Program networks. There are 

no data to indicate that ethylene oxide is a common constituent of 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.
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There are limited data to evaluate the general population's exposure levels to ethylene oxide. 

Environmental exposures may include ethylene oxide from 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 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2.1 Production

Ethylene oxide is primarily produced through ethylene oxidation with silver catalyst (Khan et al. 2002; 

Parod 2014). Ethylene and oxygen combine at 10–30 atmospheres and 400–500°F in a fixed bed catalytic 

reactor, which contains tubes with silver catalyst. The off-gas from the reactor is processed by CO2

scrubbers followed by ethylene oxide scrubbers. Ethylene oxide is recovered from the resulting liquid by 

a desorber and then distilled (Khan et al. 2002). The EPA Chemical Data Reporting tool lists eight

manufacturers of ethylene oxide in the United States at 11 different locations (EPA 2014, 2017a). Only 

two manufacturers (LG America and Shell Petroleum Inc.) reported actual production volume data with 

the other manufacturers declaring their production volumes confidential business information (CBI). In 

2010 and 2011, LG Chemicals America reported production volumes of 3,368 and 26,479 pounds 

(1.5 and 12.0 metric tons), respectively. Shell Petroleum reported production volumes of 1,012,190,974, 

925,329,789, and 1,012,190,974 pounds (0.45, 0.42, and 0.46 million metric tons) in 2009, 2010, and 

2011, respectively. For 2015, the national domestic aggregate production of ethylene oxide was 

estimated to range from 5,000,000,000 to 10,000,000,000 pounds (2.3–4.6 million metric tons) (EPA 

2014, 2017a). According to the American Chemistry Council (ACC) Economics and Statistics 

Department, in 2018, it was reported that there were 15 process plants in the United States that produced 

ethylene oxide with a total production volume of 2.92 million metric tons (6,400 million pounds) (ACC

2019). Total production capacity is about 3.5 million metric tons (7,700 million pounds) but is expected 

to increase by another 1.8 million metric tons (4,000 million pounds) by 2023 due to market demand 

(ACC 2019).

Ethylene oxide is produced naturally in negligible quantities by degradation of ethylene in certain plants 

and microorganisms. It can also emanate from water-logged soil, manure, and sewage sludge (WHO 

2003).
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Table 5-1 summarizes information on U.S. companies that reported the manufacture or use of ethylene 

oxide in 2017 (TRI17 2018). Based on reported company names, seven of the companies were likely 

involved in sterilization processes; another nine companies were associated with medical devices. Toxics 

Release Inventory (TRI) data should be used with caution since only certain types of industrial facilities 

are required to report. This is not an exhaustive list.

Table 5-1. Facilities that Produce, Process, or Use Ethylene Oxidea

Stateb

Number of 

facilities

Minimum amount on 

site in poundsc

Maximum amount on 

site in poundsc Activities and usesd

AR 1 1,000 9,999 12

AZ 1 1,000 9,999 11

CA 1 1,000,000 9,999,999 6

CO 1 1,000 9,999 11

CT 1 1,000 9,999 12

DE 1 1,000,000 9,999,999 6, 7

GA 4 1,000 999,999 6, 11, 12

IA 1 1,000,000 9,999,999 6

IL 4 100,000 999,999 6, 7

IN 2 1,000 999,999 6, 11

KS 1 1,000,000 9,999,999 6

KY 1 1,000,000 9,999,999 6

LA 13 100 49,999,999 1, 3, 4, 5, 6, 7, 9, 12, 14

MD 2 1,000 9,999 12

MI 3 1,000 999,999 6, 11, 12

MN 1 10,000 99,999 7, 12

MO 3 10,000 9,999,999 1, 3, 6, 9, 12

MS 1 100,000 999,999 6

NC 4 1,000 49,999,999 6, 11

NE 1 1,000 9,999 12

NJ 2 1,000,000 9,999,999 6

NV 1 100 999 12

NY 1 10,000 99,999 9

OH 1 1,000 9,999 12

OK 1 1,000,000 9,999,999 6, 7

PA 5 1,000 9,999,999 6, 9, 11, 12

PR 3 1,000 9,999 2, 3, 6, 12

SC 7 100,000 9,999,999 6, 9

TN 2 1,000 999,999 6, 12

TX 24 100 499,999,999 1, 3, 4, 5, 6, 7, 11, 12, 13, 14

UT 1 1,000 9,999 2, 3, 11
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Table 5-1. Facilities that Produce, Process, or Use Ethylene Oxidea

Stateb

Number of 

facilities

Minimum amount on 

site in poundsc

Maximum amount on 

site in poundsc Activities and usesd

VA 3 1,000 999,999 6, 11

WI 3 100,000 999,999 6

WV 5 1,000 9,999,999 6, 14

aThe TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.

bPost office state abbreviations used. cAmounts onsite reported by facilities in each state using predefined ranges. dActivities/uses:

1.Produce

2.Import

3.Used Processing

4.Sale/Distribution

5.Byproduct

6.Reactant

7.Formulation Component

8.Article Component

9.Repackaging

10.Chemical Processing Aid

11.Manufacture Aid

12.Ancillary

13.Manufacture Impurity

14.Process Impurity

Source:TRI17 2018 (Data are from 2017)

Estimated total production of ethylene oxide in the United States for the year 2004 was nearly 9 billion 

pounds (IARC 2008).

5.2.2 Import/Export

Due to its high reactivity, most ethylene oxide that is produced is also used onsite to create other products 

(ethylene oxide derivatives). There are little import or export volumes of ethylene oxide; however, there 

is substantial trade involving ethylene oxide derivatives such as monoethylene glycol (MEG) (ACC

2019). In 2018, approximately one-third of the MEG produced in the United States from ethylene oxide 

was exported to other nations. In 2018, the United States exported 0.831 million metric tons 

(1,800 million pounds) of ethylene oxide derivatives and also imported 1.2 million metric tons 

(2,600 million pounds) of ethylene oxide derivatives. Shell Petroleum exported 825,320 pounds of 

ethylene oxide in 2010; however, the other U.S. producers reported either zero export and import volumes 

or declared this as CBI (EPA 2014, 2017a). 

5.2.3 Use

Greater than 97% of ethylene oxide production involves its use as a chemical intermediate for the 

production of other chemicals. The ACC reported the following consumption patterns of ethylene oxide 

in 2018: 34% to produce MEG; 28% in the production of ethoxylates; 16% used to produce 
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ethanolamines; 6% in the production of glycol ethers; 4% to produce polyether polyols; and 12% for other 

uses, which include medical sterilization and microbial reduction in spices (ACC 2019). At one time, 

ethylene oxide was used in the production of acrylonitrile, but that process was discontinued in 1966 

(EPA 1984a, 1985a; NIOSH 1981; WHO 1985). Ethylene oxide is 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 (EPA 2017b; Parod 2014; Ribeiro 1994; WHO 2003). Ethylene oxide is highly 

effective as a sterilant gas where it can penetrate packaging (such as cardboard, shrink wrap, paper, and 

other wrappings) and destroy bacteria and viruses (EPA 2004). Ethylene oxide is the primary 

fumigation/sterilization method for reducing bacteria levels in spices/herbs and black walnuts. According 

to the EPA (2008) RED, approximately 8.2 million pounds of ethylene oxide are used annually in the 

United States for commercial fumigation/sterilization. Of the 8.2 million pounds, approximately 

7.4 million pounds are used annually for sterilization of medical and laboratory items/equipment; an 

estimated 800,000 pounds are used annually for fumigation of herbs and spices (EPA 2008). 

5.2.4 Disposal

Because ethylene oxide is listed as a hazardous substance, disposal of wastes containing this compound is 

controlled by a number of federal regulations. 

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; WHO 

1985).

5.3 RELEASES TO THE ENVIRONMENT

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ ≥10 full-time employees; if 

their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 1081, and 

1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the purpose of 

generating electricity for distribution in commerce), 4931 (limited to facilities that combust coal and/or 

oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to facilities that 
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combust coal and/or oil for the purpose of generating electricity for distribution in commerce), 4953 

(limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 5169, 5171, and 

7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities primarily engaged in 

solvents recovery services on a contract or fee basis); and if their facility produces, imports, or processes 

≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI chemical in a calendar 

year (EPA 2005).

5.3.1 Air

Estimated releases of 240,092 pounds (~109 metric tons) of ethylene oxide to the atmosphere from (106) 

domestic manufacturing and processing facilities in 2017, accounted for about 99% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI17 2018). These releases are 

summarized in Table 5-2.

Table 5-2. Releases to the Environment from Facilities that Produce, Process, 

or Use Chemical Ethylene Oxidea

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and offsite

AR 1 5,013 0 0 0 No data 5,013 No data 5,013

AZ 1 492 0 0 0 No data 492 No data 492

CA 1 15 0 0 0 No data 15 No data 15

CO 1 2,544 0 0 0 No data 2,544 No data 2,544

CT 1 255 0 0 0 No data 255 No data 255

DE 1 2,318 0 0 0 No data 2,318 No data 2,318

GA 4 9,989 0 0 0 No data 9,989 No data 9,989

IA 1 499 0 0 0 No data 499 No data 499

IL 4 2,399 0 0 0 No data 2,399 0 2,399

IN 2 748 0 0 0 No data 748 No data 748

KS 1 535 0 0 0 No data 535 No data 535

KY 1 1,977 9 0 0 No data 1,986 No data 1,986

LA 13 67,911 116 4 0 No data 68,027 4 68,031

MD 2 109 0 0 0 No data 109 No data 109

MI 3 2,024 2 0 3 No data 2,029 No data 2,029

MN 1 1 0 0 0 No data 1 No data 1

MO 3 9,807 0 0 0 No data 9,807 No data 9,807

MS 1 4 0 0 0 No data 4 No data 4
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Table 5-2. Releases to the Environment from Facilities that Produce, Process, 

or Use Chemical Ethylene Oxidea

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and offsite

NC 4 189 0 0 0 No data 66 No data 66

NE 1 66 0 0 0 No data 43 No data 43

NJ 2 214 0 0 0 No data 214 No data 214

NV 1 43 0 0 0 No data 8 No data 8

NY 1 8 0 0 0 No data 189 No data 189

OH 1 0 0 0 0 No data 0 No data 0

OK 1 9 0 0 0 No data 9 No data 9

PA 5 6,185 0 0 0 No data 6,185 No data 6,185

PR 3 599 0 0 0 No data 599 No data 599

SC 7 4,742 0 0 68 No data 4,742 68 4,810

TN 2 148 0 0 0 No data 148 No data 148

TX 24 104,625 2,158 0 47 No data 106,785 45 106,830

UT 1 42 0 0 0 No data 42 No data 42

VA 3 8,834 0 0 0 No data 8,834 No data 8,834

WI 3 1,111 0 0 0 0 6,639 0 6,639

WV 5 6,639 0 0 0 8 1,111 8 1,119

Total 106 240,092 2,285 4 118 8 242,382 124 242,506

aThe TRI data should be used with caution since only certain types of facilities are required to report. This is not 

an exhaustive list. Data are rounded to nearest whole number.

bData in TRI are maximum amounts released by each facility. cPost office state abbreviations are used.

dNumber of reporting facilities.

eThe sum of fugitive and point source releases are included in releases to air by a given facility.

f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) 

(metal and metal compounds).

gClass I wells, Class II-V wells, and underground injection. hResource Conservation and Recovery Act (RCRA) subtitle C landfills; other onsite landfills, land treatment, 

surface impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 

disposal, unknown. j

The sum of all releases of the chemical to air, land, water, and underground injection wells. kTotal amount of chemical transferred off-site, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI17 2018 (Data are from 2017)

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 during its 
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storage and handling in industrial settings. Industrial emissions of ethylene oxide are due to uncontrolled 

fugitive emissions or venting with other gases (EPA 1980, 2017b).

Other known 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 annually (EPA 1980), and losses during disinfection of hospital equipment (EPA 2017b).

Ethylene oxide could be released to the atmosphere during catastrophic events. In 1987, an explosion in 

an ethylene oxide purification column in Antwerp, Germany occurred due to decomposition of ethylene 

oxide (Khan et al. 2002).

EPA’s National Emission Inventory (NEI) database contains information regarding sources that emit 

criteria air pollutants (CAPs) and their precursors, and hazardous air pollutants (HAPs) for the 50 United 

States, Washington DC, Puerto Rico, and the U.S. Virgin Islands. This database documents and estimates 

emission data from multiple sources, including state and local environmental agencies; the TRI database; 

computer models for on- and off-road emissions; and databases related to EPA's Maximum Achievable 

Control Technology (MACT) programs to reduce emissions of HAPs. Ethylene oxide emissions 

estimated from the 2014 inventory are summarized in Table 5-3.

Table 5-3. Ethylene Oxide Emissions from the National Emissions Inventory

Emission sector

Amount of ethylene oxide emitted to 

air (pounds)

Fuel combustion, commercial/institutional, natural gas 17

Fuel combustion, commercial/institutional, oil 0.0009

Fuel combustion, electric generation, natural gas 45

Fuel combustion, industrial boilers, ICEs, natural gas 33

Fuel combustion, industrial boilers, ICEs, other 8

Industrial processes, chemical manufacturing 123,520

Industrial processes, not elsewhere classified 86,367

Industrial processes, petroleum refineries 0.040

Industrial processes, pulp and paper 125

Industrial processes, storage and transfer 6,707

Solvent, degreasing 1,368

Solvent, graphic arts 23
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Table 5-3. Ethylene Oxide Emissions from the National Emissions Inventory

Emission sector

Amount of ethylene oxide emitted to 

air (pounds)

Solvent, industrial surface coating and solvent use 2,502

Waste disposal 2,386

Source: EPA 2020a

Additional nonquantified sources of air emission of ethylene oxide may be bacterial degradation products, 

photochemical smog, tobacco smoke, and hydrocarbon combustion (EPA 1980). Barnard and Lee (1972) 

and EPA (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.

The World Health Organization (WHO 2003) reported that the estimated air emissions due to sterilization 

and fumigation operations, production, medical facility use, and ethoxylation resulted in 57, 31, 8, and 

4% of total ethylene oxide emissions, respectively. 

5.3.2 Water

Estimated releases of 2,285 pounds (~1.036 metric tons) of ethylene oxide to surface water from 

106 domestic manufacturing and processing facilities in 2017, accounted for about 0.9% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI17 2018). This estimate 

includes releases to waste water treatment and publicly owned treatment works (POTWs) (TRI17 2018). 

These releases are summarized in Table 5-2.

Although recent data were not located, historically, ethylene oxide discharges into water appeared to be 

primarily industry-related. WHO (1985) indicated that biological treatment of waste waters containing 

ethylene oxide appeared to be successful in the removal of this chemical from reaching waterways. 

Recent data concerning discharge of ethylene oxide to water were not located.
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5.3.3 Soil

Estimated releases of 118 pounds (~0.0535 metric tons) of ethylene oxide to soil from 106 domestic 

manufacturing and processing facilities in 2017, accounted for about 0.05% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI17 2018). An additional 

4 pounds (~0.002 metric tons), accounted for about <0.01% of the total environmental emissions, were 

released via underground injection (TRI17 2018). These releases are summarized in Table 5-2.

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. Data concerning levels of ethylene oxide in soil were not found. 

5.3.4 Other Sources

Solid or liquid wastes containing measurable amounts of ethylene oxide, as defined in Part 261 of CFR 40 

(EPA 1984c), can be classified as hazardous with ignitable and toxic properties. However, according to 

EPA (1980), no specific wastes containing large amounts of ethylene oxide associated with the 

manufacture of ethylene oxide have been identified.

5.4 ENVIRONMENTAL FATE

5.4.1 Transport and Partitioning

Air. 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 (51°F [10.6°C]) (NIOSH 2016). A fugacity model

estimated that ethylene oxide will persist in the atmosphere over a densely populated area of Canada for 

approximately 3 days, localized to the area of discharge (WHO 2003).

Water. Although ethylene oxide dissolves in water in any proportion, it also has the tendency to 

volatilize due in part to its high vapor pressure. Conway et al. (1983) reported that about 95% of ethylene 
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oxide mixed with water volatilizes within 4 hours (its half-life is about 1 hour), and thus is not prevalent 

in environmental water sources

Sediment and Soil. The reported log of the octanol/water partition coefficient (Kow) for ethylene oxide 

is -0.30 (Hansch and Leo 1979), indicating that ethylene oxide is a very polar chemical. From its 

chemical and physical properties, it can be inferred that ethylene oxide in soil will volatilize as water 

evaporates, leach through the soil, or be removed by runoff during rainstorms. It is, therefore, unlikely 

that ethylene oxide will accumulate in soils or sediments (WHO 2003). No data on the accumulation 

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

Other Media. EPA (1984b) indicated that there are no data on the bioaccumulation of ethylene oxide in 

animal tissue.

Ethylene oxide is used as a fumigant for some food commodities. EPA has set tolerances of 7 ppm on 

herbs and spices, licorice roots, dried peppermint tops, sesame seeds, dried spearmint tops, and dried 

vegetables. A 50 ppm tolerance was set for walnuts (EPA 2018a).

Staples and Gulledge (2006) used a level III multi-media fate model to calculate ethylene oxide 

concentrations in air, water, soil, and sediment given an estimated annual emission rate using six different 

environmental scenarios meant to represent different climatic regions of the United States. Mass 

transport parameters such as the erosion and runoff mass transport velocities as well as rainfall rates and 

composition of the four main environmental compartments were varied in these six scenarios. The 

modeled output concentrations in air, water, and sediment were not highly sensitive to the changes in 

environmental parameters. However, modeled soil levels were shown to be fairly sensitive to changes in 

the input parameters, most likely the 10-fold changes in the soil erosion and runoff mass transport 

parameters. In all cases, hazard quotients calculated for target species were much lower than 1, 

suggesting low adverse risk to aquatic and terrestrial wildlife at the given emissions used in the model.

5.4.2 Transformation and Degradation

Ethylene oxide undergoes numerous reactions. It hydrolyzes in water and reacts with other nucleophiles 

with a half-life of approximately 10 days, forming ethylene glycol and ethylene chlorohydrin in saltwater 

(e.g., oceans). It also undergoes biodegradation, some of the measurable biological oxygen demand 

(BOD) is likely from the degradation of its reaction products. These rates have been measured in closed 
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systems to prevent volatilization. Under most environmental conditions, volatilization from water or soil 

will be more rapid than hydrolysis, biodegradation, or reaction with other nucleophiles.

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). Atmospheric half-lives 

based on reaction with hydroxyl radicals were also estimated as ranging from 38 to 382 days (WHO 

2003). 

According to EPA (1984b), measurements of the absolute rate constant, determined to be about 

6x10-16 cm3

/mole/second 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 

ethylene oxide oxidation to be hydrogen, water, carbon monoxide, carbon dioxide, and formaldehyde. 

Joshi et al. (1982) determined ethylene oxide to have a low reactivity with atmospheric nitrogen dioxide 

under W radiation and at 25°C. Using ethylene oxide:nitrogen dioxide ratios similar to those found in 

urban and rural air, these researchers reported the ethylene oxide half-life to be >53 hours.

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.

Water. If released to water, ethylene oxide would likely evaporate, hydrolyze, or biodegrade aerobically 

(and to a lesser extent, anaerobically) (WHO 2003). Ethylene oxide hydrolyzes in water to form glycols 

(Long and Pritchard 1956). EPA (1980) reported the hydrolysis rate constant (acid catalyzed) to be about 

19.9x10-3 L/mol-second 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. 

The hydrolysis half-life of ethylene oxide ranges from 12 to 14 days in sterile, deionized, and natural river 

water (Conway et al. 1983; EPA 2017b; WHO 2003). Increased water salinity (up to 3% sodium 

chloride) was found to decrease the half-life of ethylene oxide to 9 days (Conway et al. 1983), producing 

ethanediol and chloroethanol. The volatilization half-life is estimated to be approximately 1 hour (WHO 

2003). 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 
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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.

The estimated aerobic biodegradation half-life for ethylene oxide in water is expected to be 20 days to 

6 months, while the anaerobic biodegradation half-life is estimated as 4 months to 2 years (WHO 2003). 

The aqueous aerobic biodegradation half-life from a BOD test was about 20 days. A 5-day BOD was 3% 

of the theoretical oxygen demand (1.82 g/g) (WHO 2003). With an initial concentration of 100 mg/L, 

ethylene oxide was found to hydrolyze in water over a 4-week period (J-CHECK 2019).

Sediment and 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 and via reactivity with mineral surfaces.

Ethylene oxide is expected to volatilize rapidly from soil, with estimated hydrolysis half-lives of 10.5 and 

11.9 days for soil and groundwater, respectively. While volatilization is expected to be the predominant 

mechanism by which ethylene oxide is removed from soil, it may also undergo fairly rapid hydrolysis and 

biodegradation. It is not expected to be sorbed by soil or sediment (WHO 2003).

Other Media. While no reports of ethylene oxide in biota were located, bioaccumulation of ethylene 

oxide is not expected, based on the very low log Kow (WHO 2003).

5.5 LEVELS IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to ethylene oxide depends, in part, on the 

reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of ethylene oxide in unpolluted atmospheres and in pristine surface waters are often so 

low as to be near the limits of current analytical methods. In reviewing data on ethylene oxide levels 

monitored or estimated in the environment, it should also be noted that the amount of chemical identified 

analytically is not necessarily equivalent to the amount that is bioavailable.
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Table 5-4 shows the lowest limit of detections that are achieved by analytical analysis in environmental 

media. An overview summary of the range of concentrations detected in environmental media is 

presented in Table 5-5.

Table 5-4. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Air NAb EPA 2019b

Drinking water 9 μg/L EPA 2007

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.

bMethod detection limits are regularly updated.

Table 5-5. Summary of Environmental Levels of Ethylene Oxide

Media Low High For more information

Outdoor air 0.4 μg/m3 (0.22 ppb) 11 μg/m3 (6.05 ppb) Parod 2014

Surface water Not applicable 2 mg/L EPA 1984b

Food <0.05 μg/g 1,800 μg/g WHO 2003

Historical ambient air levels are shown in Table 5-6. The samples were collected in areas with no known 

ethylene oxide sources and ranged from below the reporting level to 5.3 μg/m3 (2.92 ppb).

Table 5-6. Historical Ambient Air Monitoring Data from Selected Statesa

Location (sampling time frame) Number of valid samplesb Median(s)c Range

California (1989–1990) 58 0.08 μg/m3

(0.044 ppb)

0.03–0.54 μg/m3

(0.017–0.30 ppb)

Coloradod 16 0.276 μg/m3

(0.153 ppb)e

<RL–1.05 μg/m3

(<RL–0.580 ppb)

Illinois (2018) 72 0.19–0.20 μg/m3

(0.105–0.11 ppb)f

<RL–1.1 μg/m3

(<RL–0.61 ppb)

Massachusetts (1999–2016) 1,433 0.15–0.18 μg/m3

(0.083–0.099 ppb)g

<RL–5.3 μg/m3

(<RL–2.92 ppb)

New Hampshire (2002–2008) 578 0.22–0.27 μg/m3

(0.12–0.15 ppb)g

<RL–1.61 μg/m3

(<RL–0.89 ppb)
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Table 5-6. Historical Ambient Air Monitoring Data from Selected Statesa

Location (sampling time frame) Number of valid samplesb Median(s)c Range

Rhode Island (1999–2010) 11,280 0.14–0.20 μg/m3

(0.077–0.11 ppb)g

<RL–1.68 μg/m3

(<RL–0.92 ppb)

a Different analytical methods with different detection limits were used. bSamples were reported be nonvalid by the instrument operators for reasons including, but not limited to, instrument 

malfunction or collection error.

cNon-detect values and values below the RL may have been substituted with the detection limit/2. dPost-control samples only from background sites. eReported average assuming 1⁄2 MDL for non-detected samples. f

Ranges reflect 12-hour and grab sampling. gRanges reflect estimates at different sampling locations.

MDL = minimum detection level; NA = not applicable; RL = reporting level

Sources: CARB 1992; CDPHE 2018; EPA 2018a; Ramboll 2019

No data are available on levels of ethylene oxide in air, water, or soil at NPL sites (ATSDR 2019). 

5.5.1 Air

The National Air Toxics Assessment (NATA) program is a comprehensive screening assessment released 

by EPA in 2018 (EPA 2018b). NATA data, which are based on computer modeling not ambient air 

modeling, provide a snapshot of outdoor air toxic emissions; they are annual. The data are used by public 

health officials to screen air toxic concentrations for further evaluation of public health risk and reduction 

activities in areas where concentrations are elevated. This assessment utilized emission estimates from 

the 2014 NEI discussed in Section 5.3.1 to calculate ambient concentrations of air toxics across the 

United States, Puerto Rico, and the Virgin Islands (EPA 2018c). A statistical breakdown of the calculated 

annual concentrations of ethylene oxide in ambient outdoor air at the census tract level is provided in 

Table 5-7. The mean calculated national concentration of ethylene oxide in ambient air was 2.92x10-4

μg/m3 (1.61x10-4 ppb) and the maximum level measured was 0.144 ug/m3 (0.079 ppb). 
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Table 5-7. Ethylene Oxide Ambient Air Levels from NATAa

Mean level 5th percentile 25th percentile 50th percentile 75th percentile 95th percentile

2.9x10-4 μg/m3

(1.6x10-4 ppb)

5.7x10-6 μg/m3

(3.2x10-6 ppb)

4.0x10-5 μg/m3

(2.2x10-5 ppb)

8.7x10-5 μg/m3

(4.8x10-5 ppb)

1.5x10-4 μg/m3

(0.85x10-4 ppb)

9.5x10-4 μg/m3

(5.2x10-4 ppb)

aLevels are primarily from stationary point sources; emissions estimates from 2014 NEI.

NATA = National Air Toxics Assessment; NEI = National Emission Inventory

Source: EPA 2018b

The NATA report indicated that the predicted levels of ethylene oxide in ambient air for the communities 

surrounding industrial sources of ethylene oxide were associated with an elevated level of estimated 

cancer risks, including the Sterigenics commercial sterilizing facility in Willowbrook, Illinois. To verify 

the predicted levels, EPA conducted a limited sampling of ethylene oxide in ambient air in both 

residential areas and locations in close proximity to the Sterigenics facility. The maximum 12-hour 

residential sample concentration was 2.1 μg/m3 (1.56 ppb) and the maximum 12-hour for a general 

workplace concentration was 9.09 μg/m3 (5.0 ppb). ATSDR reviewed the data to assess potential health 

risks to the surrounding community in a health consultation document (ATSDR 2018). The EPA Office 

of Air Quality Planning and Standards Office of Air and Radiation released a risk assessment report for 

this facility, which consisted of both monitoring data and modeled levels of ethylene oxide from the 

Gaussian dispersion model AERMOD (EPA 2019c). Sampling was conducted at eight locations in 

Willowbrook, two locations approximately 100 m from the facility and six locations in the surrounding 

community, from November 2018 to March 2019. Ethylene oxide levels at the two locations near the 

facility reached maximum 24-hour values of 26.4 and 17.3 μg/m3 (14.5 and 9.5 ppb) for samples 

collected on February 5, 2019, while background levels 1.7 km away for this date were 0.174 μg/m3

(0.096 ppb) (EPA 2019c).

Ethylene oxide concentrations were monitored in a facility in Brazil that utilizes the chemical in the 

production of polyethylene glycol. Ambient air concentrations, determined using passive air sampling 

pumps with activated charcoal tubes, were analyzed for over a 3-month period. TWAs for an 8-hour 

working day were determined to be 2–5 ppm (4–10 mg/m3

) (Ribeiro 1994). In 1993, it was estimated that 

the average ground-level ethylene oxide concentrations could be >12 μg/m3 (>6.6 ppb) for 17 hours/year 

around a Canadian production facility, although no measured data were provided (WHO 2003).
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Ethylene oxide was detected in only 1 of 50 samples of indoor air in a study of residences by Health 

Canada; the concentration was determined to be 4 μg/m3 (2.2 ppb) in the 24-hour sample (WHO 2003). It 

was also detected at levels of 5 μg/m3 in 3 of 24 personal air samples collected from an occupant of each 

of the 50 residences.

Parod (2014) reported that mean and maximum concentrations of ethylene oxide in ambient air were 

<0.2 and 2 ppb (0.37 and 4.37 μg/m3

), respectively, based on measured and estimated data. The average 

concentration may be slightly higher (≤11 μg/m3 [≤6.05 ppb]) near production and sterilization facilities 

utilizing ethylene oxide (Parod 2014). Limitations of the report include lack of information regarding the 

number of samples evaluated, limit of detection, number of samples below the limit of detection, and 

whether the mean value was geometric or arithmetic.

EPA (2019a) reported ethylene oxide average concentrations from ambient air samples collected at 

8 National Air Toxics Trends Stations (NATTS) and 10 Urban Air Toxics Monitoring Program

(UATMP) sampling sites between October 2018 and September 2019. Results are summarized in Table 

5-8. Measured average ethylene oxide concentrations ranged from 0.136 μg/m3 (0.075 ppb) in Pinellas 

Park, Florida to 0.407 μg/m3 (0.224 ppb) in Phoenix, Arizona. EPA has added ethylene oxide to 

pollutants to be measured at all existing, longstanding monitoring sites in the NATTS and the UATMP

networks (a total of 34 sites).

Table 5-8. Ethylene Oxide Ambient Air Concentrations at National Air Toxics 

Trends Stations and Urban Air Toxics Monitoring Program Stations 

October 2018 to September 2019

Location AQS Site ID Station ID

Average concentration 

in μg/m3 (ppb)

Phoenix, Arizona 04-013-9997

04-013-4003

National Air Toxics Trend

Urban Air Toxics

0.407 (0.224)

0.323 (0.177)

Grand Junction, Colorado 08-077-0018 National Air Toxics Trend 0.306 (0.168)

Valrico, Florida 12-057-3002 National Air Toxics Trend 0.144 (0.079)

St. Petersburg, Florida 12-103-0018 Urban Air Toxics 0.14 (0.077)

Pinellas Park, Florida 12-106-0026 National Air Toxics Trend 0.136 (0.075)

Schiller Park, Illinois 17-031-3103 Urban Air Toxics 0.343 (0.189)

Northbrook, Illinois 17-031-4201 National Air Toxics Trend 0.279 (0.153)

Ashland, Kentucky 21-019-0017 Urban Air Toxics 0.284 (0.156)

Grayson, Kentucky 21-043-0500 National Air Toxics Trend 0.246 (0.135)
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Table 5-8. Ethylene Oxide Ambient Air Concentrations at National Air Toxics 

Trends Stations and Urban Air Toxics Monitoring Program Stations 

October 2018 to September 2019

Location AQS Site ID Station ID

Average concentration 

in μg/m3 (ppb)

Smithland, Kentucky 21-139-0004 Urban Air Toxics 0.306 (0.168)

Calvert City, Kentucky 21-157-0014 Urban Air Toxics 0.295 (0.162)

Dearborn, Michigan 26-163-0033 National Air Toxics Trend 0.241 (0.132)

St Louis, Missouri 29-510-0085 National Air Toxics Trend 0.264 (0.145)

Camden, New Jersey 34-007-0002 Urban Air Toxics 0.313 (0.193)

E. Brunswick, New Jersey 34-023-0011 Urban Air Toxics 0.301 (0.165)

Chester, New Jersey 34-027-3001 Urban Air Toxics 0.342 (0.188)

Elizabeth, New Jersey 34-039-0004 Urban Air Toxics 0.298 (0.164)

Albany, New York 36-001-0013 New York 0.188 (0.103)

Bronx, New York 36-005-0110

36-005-0133

National Air Toxics Trend

New York

0.169 (0.093)

0.15 (0.082)

Rochester, New York 36-055-1007 National Air Toxics Trend 0.179 (0.098)

Queens, New York 36-081-0124 New York 0.138 (0.076)

Pinnacle, New York 36-101-0003 New York 0.182 (0.100)

Bountiful, Utah 49-011-0004 National Air Toxics Trend 0.251(0.138)

Seattle, Washington 53-033-0080 National Air Toxics Trend 0.167 (0.092)

Lacey, Washington 53-067-0013 Urban Air Toxics 0.203 (0.112)

AQS = Air Quality System; ID = identification

Source: EPA 2020b

5.5.2 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. The intake 

fraction (iF) is the modeled portion of chemical mass releases into the environment that will be inhaled, 

ingested, or absorbed by the population. The water iF for ethylene oxide is 1.32x10-5 compared to the air 

intake fraction of 1.99x10-5

, suggesting similar efficiency of population intake via water compared to air 

(Bennett et al. 2002).
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5.5.3 Sediment and 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.

5.5.4 Other Media

Ethylene oxide may be found in tobacco, some food and spices, skin care products, and medical devices 

as a result of its use as a fumigant and a sterilizing agent. Measurable amounts of ethylene oxide were

detected in both fumigated and unfumigated tobacco and its smoke; the ethylene oxide concentration in 

smoke from unfumigated tobacco was 1 μg/g (EPA 1980). More recently, it was also detected in smoke 

from fumigated and unfumigated tobacco at 0.3 and 0.02 μg/mL (0.17 and 0.011 ppm), respectively 

(WHO 2003). Skin care products may contain up to 1 μg/g of ethylene oxide (WHO 2003). As a result 

of sterilization, medical devices have been found to contain ethylene oxide concentrations of 1–2%, 

which generally decrease rapidly upon aeration; however, levels >180 mg/m3 (>99 ppm) have been 

identified after aeration (WHO 2003). There is evidence that some foods such as flour and spices retain 

measurable ethylene oxide and byproducts several months after fumigation (NIOSH 1981; Parod 2014; 

EPA 2017b). 

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 commodities experimentally fumigated (to kill 

microorganisms) had levels of ethylene oxide <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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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 of 53–116 mg/kg (ppm) and ~25 mg/kg (ppm) at 2 and 26 days after 

fumigation, respectively, have been reported (WHO 1985).

Food product samples obtained from retail stores in Denmark in 1985 were found to contain ethylene 

oxide in concentrations ranging from <0.05 to 1800 μg/g (in 96 of 204 samples). Spice samples also 

contained ethylene oxide at a maximum concentration of 580 μg/g (mean: 84 μg/g) (WHO 2003).

5.6 GENERAL POPULATION EXPOSURE

The general population's exposure to ethylene oxide occurs primarily via inhalation and food ingestion. 

There is no information to indicate that ethylene oxide is a common contaminant of drinking water 

supplies. 

Some foods retain ethylene oxide after fumigation (EPA 2017b; NIOSH 1981; Parod 2014), thereby 

resulting in exposure to the general population. Ethylene oxide is naturally occurring in the body, as it is 

formed from ethylene conversion during metabolic processes (Bono 2002; Parod 2014). WHO estimated 

that potential maximum exposure levels of ethylene oxide for the general population are about 0.34 and 

0.17 μg/m3 (0.19 and 0.094 ppb) for outdoor and indoor air, respectively. For those residing near point 

sources, the levels may be significantly higher (estimated as 2, 11, and 20.1 μg/m3 [1.1, 6.05, and 

11.06 ppb) for near hospitals, sterilization facilities, and production facilities of ethylene glycol, 

respectively (WHO 2003). 

Exposure to ethylene oxide from environmental tobacco smoke and via maternal transfer has been 

demonstrated in several studies. In a study of 3–13-year-old children, the levels of HOEtVal (ethylene 

oxide hemoglobin adduct) was correlated to the number of cigarettes passively smoked by the children 

(Bono et al. 2005). The levels of HOEtVal were also correlated to urinary cotinine (a nicotine metabolite) 

levels. Similarly, studies of newborns of mothers have found correlations between HOEtVal levels in 

maternal blood and cord blood (Farmer et al. 1996; Von Stedingk et al. 2011) or newborn blood levels 

(Tavares et al. 1994). The cord blood levels were 5 times higher in smokers than nonsmokers (Farmer et 

al. 1996) and newborn blood levels were about 3 times higher in smokers (Tavares et al. 1994).
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Ethylene oxide monitoring data were collected during the 2013–2014 and 2015–2016 National Health and 

Nutrition Examination Survey (NHANES). The hemoglobin adduct levels for the nonsmoking and the 

smoking populations are presented in Tables 5-9 and 5-10, respectively.

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

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 1988; EPA 2017b). Reported odor threshold concentrations of 

ethylene oxide in air are in the range of 430–700 ppm (786.9–1,281 mg/m3

) (Amoore and Hautala 1983; 

OSHA 2018a), which is well above the Occupational Safety and Health Administration (OSHA)

permissible exposure limit (PEL) of 1 ppm (1.83 mg/m3

) (OSHA 2018a, 2018b, 2018c). Thus, odor does 

not provide adequate warning of hazardous concentrations. Worker exposure to ethylene oxide can be 

determined only through routine air monitoring. The TWA concentration for ethylene oxide exposure in 

occupational settings was determined to be around 90 mg/m3 (49.5 ppm) (WHO 2003).

Hospital workers and patients may be exposed to residual levels of ethylene oxide during procedures 

where medical supplies that have been sterilized with ethylene oxide are used. During sterilization, 

plastics can absorb ethylene oxide and release it when the product is used, resulting in exposure by 

inhalation, dermal contact, or direct release to the blood stream (Chien 2009). Some sterilized plastics 

may retain concentrations of ethylene oxide ranging from 3 to 443 mg/kg (ppm) even after 7 days of 

aeration (WHO 1985). Medical equipment such as adhesive dressings and cotton wool pads may also 

retain ethylene oxide at ≤2 mg/kg (ppm) for 7–8 days after sterilization (Dauvois et al. 1982). 

Technicians involved in routine disinfection of medical equipment in hospitals may be exposed to 

relatively high levels of ethylene oxide.

Short-term area concentrations of ethylene oxide were detected in the air of a central supply department 

of a Midwestern U.S. hospital at levels up to 77 ppm (141 mg/m3

) (measured at breathing zone height). 

TWA personal exposure concentrations in this proximity were determined to be 0.23–0.56 ppm (0.42–

1.0 mg/m3

). Adjustment of the ventilation system, added exhaust hoods, and addition of an ethylene 

oxide monitoring system mitigated the elevated air levels of ethylene oxide (Zey et al. 1994). A study of 

9 hospital workers and 15 factory workers exposed to ethylene oxide during sterilization of medical 
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Table 5-9. Geometric Mean and Selected Percentiles of Blood Ethylene Oxide Hemoglobin Adduct Levels 

(pmol/g hemoglobin) Among Nonsmokers in the U.S. Population from the National Health and Nutrition 

Examination Survey (NHANES) 2013–2016

Survey 

yearsa

Geometric 

mean (95% CI)

Selected percentiles (95% CI)

50 Sample size th 75th 90th 95th

Total 2013–2014

2015–2016

27.8 (26.3–29.4)

27.0 (25.4-28.7)

28.3 (26.9–29.7)

25.8 (24.6–27.0)

36.4 (34.4–38.6)

33.7 (31.8–35.6)

48.6 (45.4–51.3)

46.4 (42.7–51.8)

58.9 (54.2–67.5)

61.8 (52.4–77.6)

1,945

1,896

Age 6–11 years 2013–2014

2015–2016

33.0 (30.7–35.3)

32.2 (30.9–33.5)

32.3 (29.4–35.8)

31.3 (29.9–32.8)

41.6 (36.8–46.5)

38.7 (36.7–40.8)

51.0 (47.3–54.5)

50.4 (45.2–56.8)

61.0 (54.1–73.7)

58.4 (54.3–62.2)

321

301

Age 12–19 years 2013–2014

2015–2016

28.5 (26.7–30.4)

26.9 (24.5–29.5)

28.8 (26.7–30.3)

26.3 (24.6–28.5)

35.4 (33.4–38.8)

34.3 (30.4–38.0)

47.5 (42.8–55.1)

44.9 (39.5–52.3)

58.4 (46.6–77.3)

52.4 (44.9–58.5)

358

328

Age 20+ years 2013–2014

2015–2016

27.1 (25.6–28.7)

26.5 (24.8–28.3)

27.8 (26.2–29.)

25.0 (23.5–26.5)

35.8 (33.6–37.7)

32.8 (31.1–35.2)

47.7 (43.2–52.5)

46.1 (41.8–52.4)

58.9 (52.5–67.5)

63.8 (52.4–80.1)

1,266

1,267

Males 2013–2014

2015–2016

28.3 (26.5–30.1)

28.4 (26.8–30.0)

29.4 (27.5–30.4)

26.6 (25.0–27.9)

37.3 (34.9–39.2)

35.4 (33.4–36.7)

49.0 (44.0–51.3)

49.7 (44.4–55.2)

58.5 (51.3–68.9)

77.6 (58.6–80.4)

897

882

Females 2013–2014

2015–2016

27.3 (25.8–29.0)

25.9 (24.1–27.9)

27.8 (26.2–28.9)

25.1 (23.5–26.6)

35.6 (33.9–37.5)

32.3 (30.8–34.6)

48.1 (44.3–53.9)

45.2 (39.3–51.0)

58.9 (53.0–67.5)

55.2 (47.5–66.0)

1,048

1,014

Non-Hispanic blacks 2013–2014

2015–2016

30.5 (28.4–32.8)

31.0 (29.3–32.7)

30.0 (27.9–32.8)

29.9 (27.3–32.7)

42.6 (36.9–46.5)

39.4 (36.9–43.1)

56.5 (50.1–67.0)

52.3 (46.2–61.7)

75.9 (60.0–105)

63.6 (53.5–76.7)

376

340

Non-Hispanic whites 2013–2014

2015–2016

26.5 (24.4–28.8)

25.4 (23.4–27.7)

27.4 (25.5–29.4)

24.4 (23.0–25.9)

34.9 (31.7–38.0)

31.3 (28.9–33.3)

46.6 (40.9–51.3)

41.8 (38.7–47.4)

57.4 (48.1–67.5)

61.8 (45.0–80.5)

680

569

All Hispanics 2013–2014

2015–2016

29.4 (28.1–30.8)

28.3 (27.0–29.6)

29.2 (28.4–30.4)

26.9 (25.7–28.6)

36.1 (34.1–38.4)

34.7 (33.1–36.3)

47.6 (43.1–52.1)

46.0 (40.8–56.5)

57.4 (51.0–70.8)

60.8 (47.9–92.3)

585

654

aThe limits of detection (LODs) for survey years 2013–2014 and 2015–2016 were 12.9 and 12.9 pmol/g hemoglobin, respectively.

CI = confidence interval

Source: CDC 2020
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Table 5-10. Geometric Mean and Selected Percentiles of Blood Ethylene Oxide Hemoglobin Adduct Levels 

(pmol/g hemoglobin) Among Cigarette Smokers in the U.S. Population from the National Health and 

Nutrition Examination Survey (NHANES) 2013–2016

Survey yearsa

Geometric 

mean (95% CI)

Selected percentiles (95% CI)

50 Sample size th 75th 90th 95th

Total 2013–2014

2015–2016

193 (171–217)

186 (155–223)

219 (201–236)

220 (185–249)

342 (314–378)

361 (298–405)

508 (448–591)

515 (442–565)

653 (589–863)

652 (557–773)

416

377

Age 18–49 years 2013–2014

2015–2016

191 (170–214)

146 (110–195)

208 (171–242)

174 (131–235)

342 (303–385)

286 (238–374)

517 (424–627)

448 (329–565)

700 (517–894)

565 (431–728)

271

220

Age 50+ years 2013–2014

2015–2016

197 (150–259)

280 (237–331)

235 (177–296)

290 (220–368)

333 (294–423)

429 (362–546)

493 (423–652)

585 (496–778)

635 (432–1,210)

778 (557–1,480)

145

157

Males 2013–2014

2015–2016

193 (168–222)

171 (129–226)

207 (176–242)

219 (169–263)

370 (297–423)

348 (284–431)

558 (420–721)

522 (437–583)

717 (558–1,020)

585 (550–662)

231

231

Females 2013–2014

2015–2016

192 (154–240)

207 (173–248)

222 (179–255)

220 (167–257)

324 (280–375)

370 (286–417)

486 (390–627)

513 (379–890)

629 (473–894)

737 (419–1,480)

185

146

aThe limits of detection (LODs) for survey years 2013–2014 and 2015–2016 were 12.9 and 12.9 pmol/g hemoglobin, respectively.

CI = confidence interval

Source: CDC 2020
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equipment showed that elevated concentrations typically occurred in short bursts. Concentrations ranged 

from 22 to 72 ppm (40–132 mg/m3

) for hospital settings and from 14 to 400 ppm (26–732 mg/m3) in 

factories (Tates et al. 1991). Instantaneous environmental air concentrations from the breathing zone near 

a hospital sterilizer unit ranged from 0.4 to 22.5 mg/m3 (0.22–12.38 ppm) (Brugnone et al. 1986). An 

analysis of historical data pertaining to occupational exposure in various United Kingdom industries 

concluded that ethylene oxide concentrations ranged from <0.1 to 16 mg/m3 (<0.055–8.8 ppm), with a 

mean concentration of 2.0 mg/m3 (1.1 ppm) for 17 measurements (Cherrie et al. 2001).

Air samples collected at two commercial sterilization facilities contained ethylene oxide in concentrations 

ranging from 0.7 to 32 ppm (1.3–59 mg/m3

) and from 0.5 to 1.6 ppm (0.9–2.9 mg/m3) for 15-minute and 

8-hour durations, respectively (Cummins et al. 1993). A composite study presented airborne ethylene 

oxide concentrations in hospital sterilization facilities in various countries, with data collection ranging 

from 1977 to 1987. TWAs ranged from not detectable to 72 mg/m3 (39.6 ppm), with peak levels ranging 

from not detectable to 1,431 mg/m3 (787 ppm). The study also reported 8-hour TWAs and peak levels, 

measured in 1987 for six Dutch and Belgian hospitals, ranging from not detectable to 28 mg/m3

(15.4 ppm) and from not detectable to 700 mg/m3 (385 ppm), respectively (Florack and Zielhuis 1990). 

Air concentrations, measured in seven Swiss hospitals with sterilization units from March 2003 to March 

2004, ranged from not detectable to 0.59 ppm (1.08 mg/m3

) (Haufroid et al. 2007).

In facilities utilizing ethylene oxide in sterilizing applications, concentrations in air are typically high for 

very short time periods (i.e., after opening a sterilizer), thereby resulting in low TWA exposures despite 

high initial concentrations. A survey of 26 exposure scenarios at 18 hospitals with ethylene oxide 

sterilizers determined that air concentrations peak within 20 seconds of opening portable sterilizers and 

within 78 seconds of opening built-in sterilizers. In a confined space, a peak ethylene oxide value of 

24 ppm (43.9 mg/m3

) was reported following the opening of a built-in sterilizer (Yoshida et al. 1989). A 

2005 study by the Taiwan Institute of Occupational Safety and Health of the medical supplies 

manufacturing industry monitored ethylene oxide concentration and exposure at 10 factories. Ethylene 

oxide concentrations in air were determined by collecting samples on hydrobromic acid (HBr)-coated 

charcoal tubes, followed by analysis with gas chromatography/mass spectrometry (GC/MS). It was 

determined that workers operating sterilizers were exposed to short-term ethylene oxide air concentrations 

of 27.61 ppm (50.53 mg/m3

), with mean TWA workshift exposures of 7.35 ppm (13.45 mg/m3). 

Additional measurements were obtained near the aeration, sterilizer, and warehouse areas of the facility, 

where mean ethylene oxide air concentrations were 10.19, 5.75, and 8.78 ppm (18.65, 10.52, and 

16.07 mg/m3

), respectively (Chien et al. 2007).
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A study of an Egyptian facility using ethylene oxide for sterilization of medical products found 

concentrations ranging from 4.20 to 7.10 ppm (7.87–12.9 mg/m3

) in the sterilization and aeration room 

and from 0.70 to 2.50 ppm (1.3–4.58 mg/m3

) in the final inspection room. The mean concentration in the 

assembly and injection room was reported as 0.21 ppm (0.38 mg/m3

) (Kamel et al. 2011).

Studies of worker exposures in five hospital sterilization rooms in the United States indicate that the timeaveraged exposures range from <0.1 to 4.3 ppm (<0.183–7.87 mg/m3

), with peaks as high as 795 ppm 

(1,455 mg/m3

) (Hansen et al. 1984). Brugnone et al. (1985) reported alveolar concentrations of ethylene 

oxide to be about 75% of the environmental concentrations of ethylene oxide in a hospital sterilizing unit 

(0.1–7.8 ppm or 0.183–14.27 mg/m3

).
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CHAPTER 6. ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, 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 NTP, is required to assure the initiation of a program of 

research designed to determine the adverse health effects (and techniques for developing methods to 

determine such health effects) of ethylene oxide.

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

uncertainties of human health risk assessment. This definition should not be interpreted to mean that all 

data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.1 INFORMATION ON HEALTH EFFECTS

Studies evaluating the health effects of inhalation, oral, and dermal exposure of humans and animals to 

ethylene oxide that are discussed in Chapter 2 are summarized in Figure 6-1. The purpose of this figure is 

to illustrate the information concerning the health effects of ethylene oxide. The number of human and 

animal studies examining each endpoint is indicated regardless of whether an effect was found and the 

quality of the study or studies.

Most of the information concerning health effects in humans is reported in occupational studies that are 

difficult to interpret because of limitations in study design (e.g., exposure levels and duration cannot be 

quantified and concurrent exposure to other toxic substances cannot be ruled out). Cancer was the 

endpoint most often evaluated in human studies. No human oral studies were located. Human dermal 

studies evaluated dermal or ocular irritation endpoints and dermal sensitization potential. Most animal 

studies evaluated the effects of inhalation exposure to ethylene oxide. Body weight, respiratory, 

neurological, reproductive, and developmental endpoints were the most studied. Limited animal oral data 

indicated local irritative effects rather than systemic effects. Limited dermal studies in animals confirmed 

that ethylene oxide as a dermal and ocular irritant.
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Figure 6-1. Summary of Existing Health Effects Studies on Ethylene Oxide By 

Route and Endpoint* 

Potential body weight, neurological, and cancer effects were the most studied endpoints 

The majority of the studies examined inhalation exposure in animals (versus humans) 

*Includes studies discussed in Chapter 2; the number of studies include those 

finding no effect; many studies examined multiple endpoints
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6.2 IDENTIFICATION OF DATA NEEDS

Missing information in Figure 6-1 should not be interpreted as a “data need.” A data need, as defined in 

ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological 

Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public 

health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature.

Acute-Duration MRLs. The inhalation database was considered adequate for derivation of an acuteduration inhalation MRL for ethylene oxide. The oral database was not considered adequate for 

derivation of an acute-duration oral MRL for ethylene oxide. No dose-response data are available for 

humans. Available oral animal data are restricted to a single study in which 100% mortality occurred in 

rats treated with ethylene oxide by single gavage dose at 200 mg/kg; treatment at 100 mg/kg did not affect 

body weight (Hollingsworth et al. 1956). An acute-duration inhalation study is needed to extensively 

examine neurological effects including function and histopathology. An acute-duration oral study could 

be designed to examine exposure-response relationships for a comprehensive set of endpoints. However, 

human oral exposure scenarios resulting in adverse health effects are not likely.

Intermediate-Duration MRLs. The inhalation database was considered adequate for derivation of an 

intermediate-duration inhalation MRL for ethylene oxide. The oral database was not considered adequate 

for derivation of an intermediate-duration oral MRL for ethylene oxide. No dose-response data are 

available for humans. Available oral animal data are restricted to a single study in which gavage dosing 

of rats at 100 mg/kg/day for 15 or 22 treatments in 15 or 30 days resulted in weight loss, gastric irritation, 

and slight liver damage (not otherwise described); the noncancer NOAEL was 30 mg/kg/day 

(Hollingsworth et al. 1956). An intermediate-duration oral study could be designed to examine exposureresponse relationships for a comprehensive set of endpoints. However, human oral exposure scenarios 

resulting in adverse health effects are not likely.

Chronic-Duration MRLs. The inhalation database was not considered adequate for derivation of a 

chronic-duration inhalation MRL for ethylene oxide. No adequate exposure-response data were available 

for humans. Several studies evaluated the effects of chronic-duration inhalation exposure to ethylene 

oxide in experimental animals. The lowest LOAEL from chronic-duration inhalation studies in animals is 

50 ppm for body weight, respiratory, hematological, and endocrine effects in rats (Lynch et al. 1984a, 

1984b) and for decreases in sperm count and motility in cynomolgus monkeys (Lynch et al. 1984b, 
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1984c). The studies did not identify NOAELs for these effects. The lowest LOAEL of 50 ppm for 

respiratory effects in the rats of Lynch et al. (1984b) is considered a serious LOAEL and was not 

considered a suitable point of departure for an MRL. A potential chronic-duration inhalation MRL based 

on endocrine effects in the rat study of Lynch et al. (1984b) resulted in a higher value than the provisional 

intermediate-duration inhalation MRL based on signs of neurotoxicity in male mice (Snellings et al. 

1984a). Furthermore, there is some degree of uncertainty regarding the role a chronic respiratory

infection may have played in the systemic effects observed in the rats of Lynch et al. (1984b). A chronicduration inhalation animal study should be designed to evaluate a comprehensive set of endpoints, 

including neurological endpoints.

The oral database was not considered adequate for derivation of a chronic-duration oral MRL for ethylene 

oxide. No dose-response data are available for humans. Available oral animal data are restricted to a 

single study in which gavage dosing at 30 mg/kg/day, 2 times/week for up to 150 weeks resulted in 

decreased survival; forestomach squamous cell carcinoma was reported at 7.5 mg/kg/day (Dunkelberg 

1982). A chronic-duration oral animal study could be designed to evaluate a comprehensive set of 

endpoints. However, human oral exposure scenarios resulting in adverse health effects are not likely.

Health Effects. 

Hematological effects. Ethylene oxide has been shown to affect the hematological system in 

animals exposed via inhalation. The effects on the hematological system appear to have been 

adequately addressed. Additional animal studies are not necessary at this time. However, 

ethylene oxide-exposed human populations should be monitored for possible exposure-related 

hematological effects.

Endocrine effects. One acute-duration inhalation study reported adrenal gland effects at an 

exposure level of 841 ppm. Adrenal gland effects were reported in a 2-year rat study, but the 

animals were compromised by a pulmonary infection at times. Additional evaluation of ethylene 

oxide exposure-related adrenal gland effects is needed. Ethylene oxide-exposed human 

populations should be monitored for possible exposure-related effects on the endocrine system.

Neurotoxicity. Ethylene oxide exposure has been demonstrated to result in clinical signs of 

neurotoxicity in both occupational cohort studies and animal studies. However, neurological 

function has not been adequately assessed. A repeated-exposure study in animals employing the 
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inhalation exposure route should be designed to more critically evaluate the neurotoxicity of 

ethylene oxide; the study should include multiple exposure levels designed to evaluate the 

threshold of ethylene oxide-induced neurological effects. Additional studies should be designed 

to evaluate mechanisms of ethylene oxide neurotoxicity.

Reproductive toxicity. Limited human data indicate that occupational exposure to ethylene 

oxide may result in effects such as increased spontaneous abortions and decreased sperm count. 

Available animal studies indicate that inhaled ethylene oxide may cause effects such as decreases 

in numbers of implantations, testicular weight, and sperm production, and testicular degeneration. 

An additional animal study employing the inhalation exposure route should be designed to 

comprehensively evaluate the potential of ethylene oxide to affect reproductive function.

Epidemiology and Human Dosimetry Studies. Most of the available information on the adverse 

effects of ethylene oxide in humans comes from occupational studies of workers exposed during ethylene 

oxide production and/or related to its uses in sterilization. Limitations include unquantifiable exposure 

levels and durations, exposures to other potentially hazardous substances, small sample sizes, and/or 

small numbers of workers exhibiting selected adverse effects (particularly cancer endpoints). Additional 

occupational cohorts should be evaluated for ethylene oxide exposure-related health effects; reliable

historical exposure levels should be determined for these cohorts. Also, epidemiological studies should 

be conducted in communities located near facilities releasing ethylene oxide to the atmosphere. The 

ethylene oxide NIOSH cohort should continue to be followed.

Biomarkers of Exposure and Effect. Several biomarkers of exposure have been identified for 

ethylene oxide. These include the hemoglobin adduct HOEtVal, DNA adduct 7-HEG, and the urinary 

metabolite HEMA. The HOEtVal and 7-HEG are specific to ethylene oxide, whereas HEMA is a 

metabolite for several compounds. There are no known biomarkers of effect that are unique to ethylene 

oxide exposure. Additional data on the biomarkers of exposure, particularly HOEtVal, would be valuable 

for animal to human dose extrapolation. 

Absorption, Distribution, Metabolism, and Excretion. Toxicokinetic properties of inhaled 

ethylene oxide have been widely evaluated in animal models and, to a lesser extent, in humans. 

Additional studies could be designed to evaluate the toxicokinetics of ethylene oxide following oral and 

dermal exposure. However, the oral exposure route for ethylene oxide is not of particular human concern.
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Comparative Toxicokinetics. Similarities and differences in toxicokinetic properties of ethylene 

oxide have been studied across species, particularly among rats, mice, and humans. PBPK models have 

been developed to predict the internal dose metrics of inhaled ethylene oxide (Csanady et al. 2000; 

Fennell and Brown 2001; Filser and Klein 2018a, 2018b; Krishnan et al. 1992; NIOSH 1987). The 

proximal toxicant(s) responsible for ethylene oxide-induced noncancer effects (e.g., neurological effects) 

should be identified in order to apply PBPK modeling to derivation of MRLs for ethylene oxide.

Children’s Susceptibility. No data were located regarding age-related differences in susceptibility to 

ethylene oxide toxicity or carcinogenicity. However, very young children with incomplete development 

of detoxification pathways that are known to metabolize ethylene oxide might be at increased 

susceptibility to ethylene oxide exposure-related effects. Additional studies are needed to assess possible 

age-related toxicokinetic differences.

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 4). However, limited data exist on the properties related to its fate in the environment. 

For example, there are no recent studies that verify the degradation rates of ethylene oxide in 

environmental media, and many current studies simply reiterate data from past studies. 

Production, Import/Export, 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, aside from noting that the primary mechanism of release of 

ethylene oxide to the atmosphere is through sterilization and fumigation practices, 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.

Environmental Fate. Data on the fate of ethylene oxide in the atmosphere are limited. The half-life 

estimates of this chemical should be updated. Historical data on the fate of ethylene oxide in the water 

environment are available but are very limited, and current studies were not found. 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 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 
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transport and degradation of ethylene oxide would be helpful in determining its potential contamination of 

water supplies. Many studies rely on outdated estimates for fate and transport of ethylene oxide in 

environmental media. Current experimental data are needed to better understand the fate and 

transformation of ethylene oxide in water, soil, air, and biota.

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) 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, 

although estimates based on the low log Kow indicate that bioaccumulation is not expected. 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 5.5.3, 

and because it is also an atmospheric pollutant.

Exposure Levels in Environmental Media. Little recent environmental monitoring data were 

found for ethylene oxide in soil, air, or water. Ambient concentrations of ethylene oxide in high density 

urban and industrial areas that have potentially large sources of ethylene oxide would be helpful in 

determining the ambient concentrations of ethylene oxide so that exposure estimates can be made for the 

general population. Additionally, monitoring data from rural and/or remote locations would provide 

valuable information on background levels.

Exposure Levels in Humans. Available data indicate that some work environments provide 

continuous exposure to ethylene oxide at levels that may exceed OSHA regulations. While the majority 

of the monitoring data found were for sterilization facilities, data on other industrial workers such as 

building and agricultural fumigators, construction workers, and the general population located near 

sources of ethylene oxide would be useful. Estimates of the exposure levels of the general population 

would also be helpful.
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Exposures of Children. There are limited data available that specifically measured environmental 

exposures of ethylene oxide to children; the 2013–2014 and 2015–2016 NHANES measured ethylene 

oxide hemoglobin adducts in children aged 6–11 and 12–19 years (CDC 2020). Additional monitoring 

data would be useful, particularly in younger children and infants.

6.3 ONGOING STUDIES

Mark L. Rubenstein, M.D., of the University of California, San Francisco, is evaluating the levels of 

toxicants, including ethylene oxide, in adolescent users of electronic nicotine delivery systems

(RePORTER 2019).
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CHAPTER 7. REGULATIONS AND GUIDELINES

Pertinent international and national regulations, advisories, and guidelines regarding ethylene oxide in air, 

water, and other media are summarized in Table 7-1. This table is not an exhaustive list, and current 

regulations should be verified by the appropriate regulatory agency.

ATSDR develops MRLs, which are substance-specific guidelines intended to serve as screening levels by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. See Section 1.3 and Appendix A for detailed information on 

the MRLs for ethylene oxide.

Table 7-1. Regulations and Guidelines Applicable to Ethylene Oxide

Agency Description Information Reference

Air

EPA RfC Not assessed IRIS 2019

OEHHA RfC (chronic) 30 μg/m3 (18 ppb) OEHHA 2008

WHO Air quality guidelines No data WHO 2010

Water & Food

EPA Drinking water standards and health 

advisories 

No data EPA 2018d

National primary drinking water regulations No data EPA 2009

RfD Not assessed EPA 2016a

WHO Drinking water quality guidelines No data WHO 2017

FDA Substances Added to Food No longer FEMA GRASa FDA 2018

Cancer

HHS Carcinogenicity classification Known to be a human 

carcinogen

NTP 2016

EPA Carcinogenicity classification Carcinogenic to humans EPA 2016a

Inhalation unit risk (adult-based for

lymphoid and female breast cancer 

combined)

3.0x10-3 per μg/m3

(9.1x10-3 per ppb) for 

environmental ethylene 

oxide exposures up to 

about 40 μg/m3 (20 ppb)

IARC Carcinogenicity classification Group 1b IARC 2012

Occupational

OSHA PEL (8-hour TWA) for general industry, 

shipyards, and construction

1 ppm (1.83 mg/m3) OSHA 2018a, 2018b, 

2018c

Excursion limitc (15-minute) for general 

industry, shipyards, and construction

5 ppm (9.15 mg/m3)

NIOSH REL (up to 10-hour TWA) <0.1 ppmd (<0.183 mg/m3) NIOSH 2016

Ceiling REL (10-minute/day) 5 ppm (9.15 mg/m3)

IDLH 800 ppmd (1,464 mg/m3) NIOSH 1994
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Table 7-1. Regulations and Guidelines Applicable to Ethylene Oxide

Agency Description Information Reference

Emergency Criteria

EPA AEGLs-aire EPA 2016b

AEGL 2f

10-minute 80 ppm (146.4 mg/m3)

30-minute 80 ppm (146.4 mg/m3)

60-minute 45 ppm (82.35 mg/m3)

4-hour 14 ppm (25.62 mg/m3)

8-hour 7.9 ppm (14.46 mg/m3)

AEGL 3f

10-minute 360 ppm (658.8 mg/m3)

30-minute 360 ppm (658.8 mg/m3)

60-minute 200 ppm (366 mg/m3)

4-hour 63 ppm (115.29 mg/m3)

8-hour 35 ppm (64.05 mg/m3)

DOE PACs-air DOE 2018b

PAC-1g 5 ppm (9.15 mg/m3)

PAC-2g 45 ppm (82.35 mg/m3)

PAC-3g 200 ppm (366 mg/m3)

aThe Substances Added to Food inventory replaces EAFUS and contains the following types of ingredients: food and 

color additives listed in FDA regulations, flavoring substances evaluated by FEMA or JECFA, GRAS substances 

listed in FDA regulations, substances approved for specific uses in food prior to September 6, 1958, substances that 

are listed in FDA regulations as prohibited in food, delisted color additives, and some substances "no longer FEMA 

GRAS." bGroup 1: carcinogenic to humans.

cExposure not to exceed 5 ppm as averaged over a sampling period of 15 minutes. dPotential occupational carcinogen. eNo recommendations for AEGL 1 due to insufficient data. f

Definitions of AEGL terminology are available from EPA (2018e).

gDefinitions of PAC terminology are available from DOE (2018a).

AEGL = acute exposure guideline level; DOE = Department of Energy; EAFUS = Everything Added to Food in the 

United States; EPA = Environmental Protection Agency; FAO = Food and Agricultural Organization of the United 

Nations; FDA = Food and Drug Administration; FEMA = Flavor and Extract Manufacturers Association; 

GRAS = generally recognized as safe; HHS = Department of Health and Human Services; IARC = International 

Agency for Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information 

System; JECFA = Joint FAO/WHO Expert Committee on Food Additives; NIOSH = National Institute for 

Occupational Safety and Health; NTP = National Toxicology Program; OEHHA = California’s Office of Environmental 

Health Hazard Assessment; OSHA = Occupational Safety and Health Administration; PAC = protective action 

criteria; PEL = permissible exposure limit; REL = recommended exposure limit; RfC = inhalation reference 

concentration; RfD = oral reference dose; TWA = time-weighted average; WHO = World Health Organization
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ETHYLENE OXIDE A-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS

MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the 

most sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an 

estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk 

of adverse noncancer health effects over a specified route and duration of exposure. MRLs are based on 

noncancer health effects only; cancer effects are not considered. These substance-specific estimates, 

which are intended to serve as screening levels, are used by ATSDR health assessors to identify 

contaminants and potential health effects that may be of concern at hazardous waste sites. It is important 

to note that MRLs are not intended to define clean-up or action levels.

MRLs are derived for hazardous substances using the NOAEL/uncertainty factor approach. They are 

below levels that might cause adverse health effects in the people most sensitive to such chemicalinduced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic 

(≥365 days) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal 

route of exposure are not derived because ATSDR has not yet identified a method suitable for this route 

of exposure. MRLs are generally based on the most sensitive substance-induced endpoint considered to 

be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or 

birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not 

mean that adverse health effects will occur.

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals.
ETHYLENE OXIDE A-2

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Office of Innovation and Analytics, Toxicology Section, expert panel peer reviews, and agency-wide 

MRL Workgroup reviews, with participation from other federal agencies and comments from the public. 

They are subject to change as new information becomes available concomitant with updating the 

toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously 

published MRLs. For additional information regarding MRLs, please contact the Office of Innovation 

and Analytics, Toxicology Section, Agency for Toxic Substances and Disease Registry, 1600 Clifton 

Road NE, Mailstop S102-1, Atlanta, Georgia 30329-4027.
ETHYLENE OXIDE A-3

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Ethylene Oxide

CAS Numbers: 75-21-8

Date: September 2020

Profile Status: Final for Public Comment

Route: Inhalation

Duration: Acute

MRL: 0.4 ppm (provisional)

Critical Effect: Depressed fetal weight

Reference: Snellings et al. 1982a

Point of Departure: BMCL05 of 45.12 ppm (BMCLHEC of 11.28 ppm)

Uncertainty Factor: 30

LSE Graph Key: 10

Species: Rat

MRL Summary: A provisional acute-duration inhalation MRL of 0.4 ppm has been derived for ethylene 

oxide based on depressed mean male fetal weight following exposure of pregnant Fischer 344 rats to 

ethylene oxide vapor for 6 hours/day during gestation days 6–15 (Snellings et al. 1982a). The BMCL05 of 

45.12 ppm was adjusted for intermittent exposure and converted to a human equivalent concentration 

(BMCLHEC) of 11.28 ppm and divided by a total uncertainty factor of 30 (3 for extrapolation from animals 

to humans using dosimetric adjustment and 10 for human variability).

Selection of the Critical Effect: No adequate exposure-response human data are available. Two rat 

studies were designed to evaluate acute lethality following single 1- or 4-hour exposure (Jacobson et al. 

1956; Snellings et al. 2011). NTP (1987) evaluated the effects of repeated inhalation exposure of rats and 

mice for 2 weeks or up to 2 weeks during 14-week studies. Several studies were designed to evaluate the 

effects of maternal exposure during periods of gestation (Neeper-Bradley and Kubena 1993; NIOSH 

1982; Rutledge and Generoso 1989; Saillenfait et al. 1996; Snellings et al. 1982a).

Selected results from the studies that evaluated sublethal effects (potential candidates for MRL 

derivation) are summarized in Table A-1. Several studies were considered inadequate for the purpose of 

deriving an acute-duration inhalation MRL for ethylene oxide. NTP (1987) reported a respiratory effect 

(rhinitis) at an exposure level (71.4 ppm) resulting in 90% mortality during 2 weeks of repeated 

exposures. The study of Rutledge and Generoso (1989) employed only a single high ethylene oxide 

exposure concentration (1,200 ppm) for an exposure period of 1.5 hours. The studies of Saillenfait et al. 

(1996) employed short exposure durations (30 minutes/day or three 30-minute periods/day).

In two developmental toxicity studies, pregnant rats were exposed to ethylene oxide vapors for 

6 hours/day during gestation days 6–15. The studies reported fetal weight data as mean of litter means. 

Sprague-Dawley rats were used in the study of Neeper-Bradley and Kubena (1993); the study identified a 

NOAEL of 50 ppm and a LOAEL of 125 ppm for 5% depressed mean fetal weight. Fischer 344 rats were 

used in the study of Snellings et al. (1982a); the study identified a NOAEL of 33 ppm and a LOAEL of 

100 ppm for up to 9% depressed mean fetal weight.
ETHYLENE OXIDE A-4

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-1. Summary of Selected NOAELs and LOAELs from Acute-Duration Studies in Animals Exposed to 

Ethylene Oxide by Inhalation

Species Exposure scenario

NOAEL

(ppm)

LOAEL

(ppm)

NOAELADJa

(ppm)

LOAELADJa

(ppm) Effect Reference

Respiratory effects

B6C3F1 

mouse

Up to 2 weeks during a 

14-week study

5 days/week

6 hours/day

0, 50, 100, 200, 400, 600 ppm

ND 400b ND 71.4 Rhinitis NTP 1987

Developmental effects

Fischer 

344 rat

GDs 6–15

6 hours/day

0, 0, 10, 33, 100 ppm

33 F 100 F 8.3 F 25 F Up to 9% depressed mean fetal 

weight

Snellings et al. 

1982a

SpragueDawley 

rat

GDs 6–15

30 minutes/day

0, 400, 800, 1,200 ppm

800 F 1,200 F 16.7 25 F Increased incidence of dilation in 

renal pelvis and ureter of fetuses

Saillenfait et al. 

1996

SpragueDawley 

rat

GDs 6–15

6 hours/day

0, 50, 125, 225 ppm

50 125 12.5 31.3 5% depressed mean fetal weight Neeper-Bradley 

and Kubena 

1993

SpragueDawley 

rat

GDs 7–16

7 hours/day

0, 150 ppm

ND 150 F ND 43.8 F 5–6% depressed mean fetal 

weight; decreased crown-rump 

length; delayed ossification 

(skull, sternebrae)

NIOSH 1982

SpragueDawley 

rat

GDs 6–15

3x30 minutes/day

0, 800, 1,200 ppm

ND 800 F ND 50 F 4–7% depressed mean fetal 

weight at maternally toxic 

exposure level

Saillenfait et al. 

1996

Hybrid 

mouse

Once for 1.5 hours

0, 1,200 ppm

ND 1,200 F ND 75 F Selected fetal defects (mostly 

hydrops and eye defects)

Rutledge and 

Generoso 1989

aDuration-adjusted from intermittent exposure to a continuous exposure scenario. bLethal exposure level.

ADJ = adjusted; F = female(s); GD = gestation day; LOAEL = lowest observed adverse effect level; ND = not determined; NOAEL = no-observed-adverse-effect 

level 
ETHYLENE OXIDE A-5

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Selection of the Principal Study: The mean fetal weight data in the developmental toxicity study of 

Fischer 344 maternal rats (Snellings et al. 1982a) were selected to represent the critical effect of acuteduration inhalation exposure to ethylene oxide because the fetal weight data represent the lowest LOAEL 

(100 ppm); the corresponding NOAEL was 33 ppm. As shown in Table A-1, duration adjustment (to 

account for a continuous exposure scenario) of NOAELs and LOAELs from the various studies did not 

result in a more appropriate principal study or critical effect.

Summary of the Principal Study: 

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.

Groups of 22 pregnant Fischer 344 rats were exposed to 0, 0, 10, 33, or 100 ppm ethylene oxide 

6 hours/day on gestation days 6–15 and sacrificed on gestation day 20. Parameters used to assess toxicity

included number of implantation sites, viable fetuses, dead fetuses, early resorption sites, and late 

resorption sites, number of corpora lutea, fetal body weight, sex, crown-to-rump length, external fetal 

abnormalities, and internal and skeletal abnormalities in both control and 100 ppm groups (examined in 

10 and 33 ppm groups if effects were noted at 100 ppm).

No overt signs of toxicity were observed in the dams. No alterations in preimplantation loss or embryo or 

fetal resorptions were observed. Significant decreases in fetal body weight were observed at 100 ppm 

(approximately 6–9% in males and 3–6% in females), but there were no differences in crown-rump 

length. An increase in the occurrence of vertebrae ossification variations was observed at 100 ppm, but 

the incidence was not significantly different from controls. No other developmental alterations were 

observed. The fetal weight data are presented in Table A-2. Although there are no established guidelines 

as to what minimal change in a continuous endpoint such as body weight is biologically significant, a 

10% change is generally used for adult body weight. However, because fetal or neonatal organisms may 

be more susceptible than adults, a ≥5% decrease in fetal body weight relative to controls was selected to 

represent an adverse effect.

Table A-2. Fetal Weight Data (Mean of Litter Means) for Fetuses of Maternal 

Fischer 344 Rats Exposed to Ethylene Oxide Vapor for 6 Hours/Day During 

Gestation Days 6–15 

Ethylene oxide exposure level (ppm)

0 (control I) 0 (control II) 10 33 100

Number of litters 21 17 20 21 19

Mean fetal weight (g) M: 3.4±0.4a

F: 3.1±0.3

M: 3.3±0.2

F: 3.0±0.2

M: 3.3±0.3

F: 3.0±0.3

M: 3.3±0.3

F: 3.1±0.3

M: 3.1b±0.2

F: 2.9b±0.1

aMean of litter means ± standard deviation.

bSignificantly different from each sex-matched control group by Duncan’s multiple range test (p<0.05).

F = female; M = male

Source: Snellings et al. 1982a

Selection of the Point of Departure for the MRL: A benchmark dose (BMD) approach was considered 

for deriving an acute-duration inhalation MRL for ethylene oxide. The male fetal weight data were fit to 

all available continuous variable models in the EPA Benchmark Dose Software (BMDS, version 3.1) 
ETHYLENE OXIDE A-6

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

using a benchmark response (BMR) of 5% change from control and the assumption of constant variance. 

The following procedure for fitting continuous data was used. Adequate model fit was judged by three 

criteria: χ2 goodness-of-fit p-value (p≥0.1), visual inspection of the dose-response curve, and scaled 

residual (>-2 and <+2) at the data point (except the control) closest to the predefined BMR. Among 

models providing adequate fit to the data, the lowest BMCL was selected as the point of departure (POD) 

when the difference between the BMCLs estimated from these models was >3-fold; otherwise, the BMCL 

from the model with the lowest Akaike’s Information Criterion (AIC) was chosen.

Table A-3 summarizes the results. Among models providing viable results, the Linear model-predicted 

BMCL05 of 45.12 ppm was selected as a potential point of departure because it provided the lowest AIC.

Table A-3. Results from BMD Analysis (Constant Variance) of Male Fetal Weight 

Following Maternal Exposure of Fischer 344 Rats to Ethylene Oxide Vapor for 

6 Hours/Day During Gestation Days 6–15

Model

Test for 

significant 

difference 

p-valuea

Variance

p-valueb

Means

p-valueb

Scaled residualsc

AIC

BMC05

(ppm)

BMCL05

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Exponential 

(model 2)d

0.018 0.13 0.81 0.472 -0.125 -0.756 40.984 67.69 43.76

Exponential 

(model 3)d

0.018 0.13 0.55 0.215 -0.029 0.876 42.909 74.59 44.00

Exponential 

(model 4)d

0.018 0.13 0.51 0.472 -0.125 0.745 40.984 67.69 43.76

Exponential 

(model 5)d

0.018 0.13 NA 0.215 -0.029 0.876 44.909 74.59 44.00

Hilld 0.018 0.13 0.49 -0.000 0.000 1.01 43.038 38.10 33.28

Lineare,f 0.018 0.13 0.82 0.450 -0.112 0.752 40.965 68.39 45.12

Polynomial 

(2-degree)e

0.018 0.13 0.58 0.187 -0.017 0.868 42.861 76.38 45.43

Polynomial 

(3-degree)e

0.018 0.13 0.60 0.149 -0.005 0.874 42.836 79.24 45.50

Polynomial 

(4-degree)b

0.018 0.13 0.60 0.137 -0.002 0.876 42.827 81.48 45.53

Powerd 0.018 0.13 0.56 0.220 -0.029 0.872 42.904 74.65 45.31

aValues >0.05 fail to meet conventional goodness-of-fit criteria. bValues <0.10 fail to meet conventional goodness-of-fit criteria. cScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose.

dPower restricted to ≥1. eCoefficients restricted to be negative.

f

Best-fitting model (lowest AIC).

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 05 = exposure concentration associated with 5% extra risk); BMD = benchmark dose; 

NA = not applicable
ETHYLENE OXIDE A-7

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

The female fetal weight data were also fit to all available continuous variable models in the EPA BMDS 

(version 3.1) using a BMR of 5% change from control. None of the models provided adequate fit to the 

data using constant variance. Therefore, the data were fit to all models using nonconstant variance. The 

Exponential model 3 and Polynomial models (2-, 3-, and 4-degree) provided viable results (Table A-4). 

Among these models, the 4-degree Polynomial model-predicted BMCL05 of 87.08 ppm was selected as a 

potential point of departure because the model provided the lowest AIC.

Table A-4. Results from BMD Analysis (Nonconstant Variance) of Female Fetal 

Weight Following Maternal Exposure of Fischer 344 Rats to Ethylene Oxide 

Vapor for 6 Hours/Day During Gestation Days 6–15

Model

Test for 

significant 

difference 

p-valuea

Variance

p-valueb

Means

p-valueb

Scaled residualsc

AIC

BMC05

(ppm)

BMCL05

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Exponential 

(model 2)d

<0.001 0.54 0.01

Exponential 

(model 3)d

<0.001 0.54 0.39 0.215 -0.029 0.876 -2.143 99.98 90.86

Exponential 

(model 4)d

<0.001 0.54 0.00

Exponential 

(model 5)d

<0.001 0.54 NA

Hilld <0.001 0.54 NA

Lineare <0.001 0.54 0.01

Polynomial 

(2-degree)e

<0.001 0.54 0.31 0.187 -0.017 0.868 -2.542 98.07 82.73

Polynomial 

(3-degree)e

<0.001 0.54 0.57 0.149 -0.005 0.874 -3.742 99.52 86.09

Polynomial 

(4-degree)b,f

<0.001 0.54 0.65 0.137 -0.002 0.876 -4.024 99.83 87.08

Powerd <0.001 0.54 0.39 0.220 -0.029 0.872 -2.143 ND ND

aValues >0.05 fail to meet conventional goodness-of-fit criteria. bValues <0.10 fail to meet conventional goodness-of-fit criteria. cScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose. dPower restricted to ≥1. eCoefficients restricted to be negative.

f

Best-fitting model (lowest AIC).

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 05 = exposure concentration associated with 5% extra risk); BMD = benchmark dose; 

NA = not applicable; ND = not determined (computation failed)

The fetal weight data from the study of Neeper-Bradley and Kubena (1993; see Table A-5) were also 

subjected to BMD analysis (BMDS Version 3.1) using constant variance. All models provided adequate 

fit to the data (Table A-6). The Exponential model 3 was selected as the best-fitting model (lowest AIC) 

and provided a BMCL05 of 92.20 ppm.
ETHYLENE OXIDE A-8

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-5. Fetal Weight per Litter Following Maternal Exposure of SpragueDawley Rats to Ethylene Oxide Vapor for 6 Hours/Day on Gestation Days 6–15

Ethylene oxide concentration (ppm)

0 50 125 225

Number of litters 23 20 20 24

Fetal weight per litter (g) 5.161±0.2480a 4.972±0.2766b 4.891±0.2745b 4.644±0.2899c

aMean ± standard deviation.

bSignificantly different from control group by t- test (p<0.05). cSignificantly different from control group by t- test (p<0.01).

Source: Neeper-Bradley and Kubena 1993

Table A-6. Results from BMD Analysis (Constant Variance) of Fetal Weight per 

Litter Following Maternal Exposure of Sprague-Dawley Rats to Ethylene 

Oxide Vapor for 6 Hours/Day During Gestation Days 6–15

Model

Test for 

significant 

difference 

p-valuea

Variance

p-valueb

Means

p-valueb

Scaled residualsc

AIC

BMC05

(ppm)

BMCL05

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Exponential 

(model 2)d

<0.001 0.90 0.54 -0.877 0.519 -0.877 23.925 115.38 92.06

Exponential 

(model 3)d,e

<0.001 0.90 0.54 -0.878 0.519 0.876 23.925 115.38 92.20

Exponential 

(model 4)d

<0.001 0.90 0.27 -0.829 0.614 -0.829 25.908 110.93 59.60

Exponential 

(model 5)d

<0.001 0.90 0.27 -0.828 0.616 -0.828 25.908 110.84 59.60

Hilld <0.001 0.90 0.27 -0.818 0.630 -0.818 25.903 110.12 54.95

Linearf <0.001 0.90 0.53 -0.906 0.457 -0.906 23.954 118.32 95.55

Polynomial 

(2-degree)f

<0.001 0.90 0.53 -0.906 0.457 -0.906 23.954 118.32 95.55

Polynomial 

(3-degree)f

<0.001 0.90 0.53 -0.906 0.457 -0.906 23.954 118.32 95.55

Powerd <0.001 0.90 0.53 -0.906 0.457 -0.906 23.954 118.32 95.55

aValues >0.05 fail to meet conventional goodness-of-fit criteria. bValues <0.10 fail to meet conventional goodness-of-fit criteria. cScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose.

dPower restricted to ≥1. eBest-fitting model (lowest AIC). f

Coefficients restricted to be negative.

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 05 = exposure concentration associated with 5% extra risk); BMD = benchmark dose
ETHYLENE OXIDE A-9

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Potential points of departure for deriving an acute-duration inhalation MRL for ethylene oxide include:

• BMCL05 of 92.20 ppm from the fetal weight data of Neeper-Bradley and Kubena (1993)

• BMCL05 of 87.08 ppm from the female fetal weight data of Snellings et al. (1982a)

• BMCL05 of 45.12 ppm from the male fetal weight data of Snellings et al. (1982a)

The Linear model-derived BMCL05 of 45.12 ppm from the male fetal weight data of Snellings et al. 

(1982a) was selected as the point of departure for deriving an acute-duration inhalation MRL for ethylene 

oxide because it represents the most conservative (health-protective) point of departure. The fit of the 

Linear model to the dataset is presented in Figure A-1.

Figure A-1. Fit of Linear Model to Data on Male Fetal Weight Following Maternal 

Exposure of Fischer 344 Rats to Ethylene Oxide Vapor for 6 Hours/Day 

During Gestation Days 6–15

Calculations

Intermittent Exposure: The BMCL05 of 45.12 ppm was adjusted from intermittent exposure to account 

for a continuous exposure scenario:

BMCLADJ = BMCL05 of 45.12 ppm x (6 hours/24 hours) = 11.28 ppm.

Human Equivalent Concentration: A PBPK modeling approach was initially considered to calculate a 

human equivalent to the rat BMCL05ADJ. However, a PBPK modeling approach was rejected due to a lack 

of experimental data regarding the proper dose metric (proximate toxicant) for ethylene oxide-induced 

developmental toxicity. Therefore, the rat BMCL05ADJ was converted to a BMCLHEC (human equivalent 

concentration) using the following equation:

BMCLHEC = BMCL05ADJ x ([Hb/g]A/[Hb/g]H)

[Hb/g]A = animal blood/air partition coefficient = 64.1 for rats according to Krishnan et al. (1992)

[Hb/g]H = human blood/air partition coefficient = 61 according to Csanady et al. (2000)

0

0.5

1

1.5

2

2.5

3

3.5

4

0 10 20 30 40 50 60 70 80 90 100

Response

Concentration (ppm)

Estimated Probability Response at BMD Data BMD BMDL
ETHYLENE OXIDE A-10

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

A default value of 1 is used for the ratio of blood/air partition coefficients because the animal value is 

greater than the human value.

BMCLHEC = 11.28 ppm x 1 = 11.28 ppm

Uncertainty Factor: The BMCLHEC of 11.28 ppm was divided by a total uncertainty factor of 30:

• 3 for extrapolation from animals to humans using dosimetric adjustment

• 10 for human variability

Provisional MRL = BMCLHEC ÷ uncertainty factors

11.28 ppm ÷ (3 x 10) = 0.4 ppm

Other Additional Studies or Pertinent Information that Lend Support to this MRL: Other 

developmental toxicity studies in rats identified fetal body weight effects as well (Neeper-Bradley and 

Kubena 1993; NIOSH 1982; Saillenfait et al. 1996), albeit at LOAELs somewhat higher than the LOAEL 

of Snellings et al. (1982a).

Agency Contacts (Chemical Managers): Jennifer Przybyla
ETHYLENE OXIDE A-11

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Ethylene Oxide

CAS Numbers: 75-21-8

Date: September 2020

Profile Status: Final for Public Comment

Route: Inhalation

Duration: Intermediate

MRL: 0.02 ppm (provisional)

Critical Effect: Clinical signs of neurotoxicity

Reference: Snellings et al. 1984a

Point of Departure: NOAEL of 10 ppm (NOAELHEC of 1.8 ppm)

Uncertainty Factor: 30

Modifying Factor: 3 

LSE Graph Key: 41

Species: Mouse

MRL Summary: A provisional intermediate-duration inhalation MRL of 0.02 ppm has been derived for 

ethylene oxide based on signs of neurotoxicity (hunched posture during gait, reduced locomotor activity) 

among B6C3F1 mice exposed to ethylene oxide vapor for 6 hours/day, 5 days/week for 10–11 weeks 

(Snellings et al. 1984a). The MRL is based on a NOAEL of 10 ppm that was adjusted to continuous 

exposure and converted to a human equivalent concentration (NOAELHEC) of 1.8 ppm, divided by a total 

uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric adjustment and 

10 for human variability) and modifying factor of 3 (for insufficient animal data regarding functional 

neurotoxicity endpoints).

Selection of the Critical Effect: No adequate exposure-response human data are available. Case studies 

of workers have reported a number of neurological effects including headache, neuropathy, impaired 

hand-eye coordination, hand numbness, cognitive dysfunction, and memory loss (Brashear et al. 1996; 

Crystal et al. 1988; Dretchen et al. 1992; Estrin et al. 1987; Finelli et al. 1983; Kuzuhara et al. 1983; 

Salinas et al. 1981; Schröder 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. Several animal studies evaluated sublethal effects of intermediateduration inhalation exposure in laboratory animals (EPA 1994; Fujishiro et al. 1990; Matsuoka et al. 

1990; Mori et al. 1991a, 1991b; NIOSH 1982; NTP 1987; Ohnishi et al. 1985, 1986; Snellings et al. 

1982b, 1984a).

Table A-7 summarizes selected NOAELs and LOAELs from intermediate-duration inhalation studies in 

laboratory animals. Several rat studies (Fujishiro et al. 1990; Kaido et al. 1992; Matsuoka et al. 1990; 

NIOSH 1982; Ohnishi et al. 1985, 1986) employed a single ethylene oxide exposure level and are not 

preferred for MRL derivation. Five studies employed multiple exposure levels. Mori et al. (1991a) 

reported adverse male reproductive effects (decreases in epididymal weight and sperm count; 

seminiferous tubule lesions) in rats intermittently exposed for 13 weeks at a LOAEL of 100 ppm 

(equivalent to 44.6 ppm for a continuous exposure scenario). The mouse study of NTP (1987) identified 

LOAELs of 200 ppm for rhinitis, and 100 and 200 ppm for renal tubular degeneration in males and 

females, respectively. In a 1-generation reproductive study of rats, decreases in number of pups/litter and 

fetuses born/implantation sites were reported at a LOAEL of 100 ppm (Snellings et al. 1982b). A 

2-generation study reported increases in post-implantation losses and decreases in pup body weight at 

33 ppm (EPA 1994).
ETHYLENE OXIDE A-12

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-7. Summary of Selected NOAELs and LOAELs from Intermediate-Duration Studies in Animals Exposed 

to Ethylene Oxide by Inhalation

Species Exposure scenario

NOAEL

(ppm)

LOAEL

(ppm)

NOAELADJa

(ppm)

LOAELADJa

(ppm) Effect Reference

Respiratory effects

B6C3F1 mouse Up to 14 weeks

5 days/week

6 hours/day

0, 50, 100, 200, 400, 

600 ppm

100 200 17.9 35.7 Rhinitis NTP 1987

Hematological effects

B6C3F1 mouse 10–11 weeks

5 days/week

6 hours/day

0, 10, 50, 100, 

250 ppm

100 250 17.9 44.6 Decreases in hemoglobin, 

erythrocyte count, packed cell 

volume, and/or mean corpuscular 

hemoglobin

Snellings et al. 

1984a

Wistar rat 13 weeks

5 days/week

6 hours/day

0, 500 ppm

ND 500 M ND 89.3 M Decreases in hemoglobin, 

hematocrit, erythrocyte count; 

increased reticulocytes

Fujishiro et al. 

1990

Renal effects

B6C3F1 mouse Up to 14 weeks

5 days/week

6 hours/day

0, 50, 100, 200, 400, 

600 ppm

NR M

100 F

100 M

200 F

ND M

17.9 F

17.9 M

35.7 F

Renal tubular degeneration NTP 1987
ETHYLENE OXIDE A-13

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-7. Summary of Selected NOAELs and LOAELs from Intermediate-Duration Studies in Animals Exposed 

to Ethylene Oxide by Inhalation

Species Exposure scenario

NOAEL

(ppm)

LOAEL

(ppm)

NOAELADJa

(ppm)

LOAELADJa

(ppm) Effect Reference

Neurological effects

B6C3F1 mouse 10–11 weeks

5 days/week

6 hours/day

0, 10, 50, 100, 

250 ppm

10 50 1.8 8.9 Hunched posture during gait, 

reduced locomotor activity

Snellings et al. 

1984a

Wistar rat 9 months

5 days/week

6 hours/day

0, 250 ppm

ND 250 ND 44.6 Retarded growth and maturation 

of myelinated fibers in hindleg 

nerves; mild axonal degeneration

Ohnishi et al. 

1986

Wistar rat Up to 13 weeks

3 days/week

6 hours/day

0, 500 ppm

ND 500 ND 53.6 Awkward gait Kaido et al. 

1992

Wistar rat 12 weeks

3 days/week

6 hours/day

0, 500 ppm

ND 500 ND 53.6 Ataxic gait Matsuoka et al. 

1990

Wistar rat 13 weeks

3 days/week

6 hours/day

0, 500 ppm

ND 500 ND 53.6 Peripheral neuropathy Ohnishi et al. 

1985

Reproductive effects

CD rat 10 weeks premating 

(6 hours/day, 

5 days/week) and 

during mating, 

gestation, and 

lactation (6 hours/day, 

7 days/week)

10 33 2.1b 6.89b Increased post-implantation loss 

in F0 rats 

EPA 1994
ETHYLENE OXIDE A-14

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-7. Summary of Selected NOAELs and LOAELs from Intermediate-Duration Studies in Animals Exposed 

to Ethylene Oxide by Inhalation

Species Exposure scenario

NOAEL

(ppm)

LOAEL

(ppm)

NOAELADJa

(ppm)

LOAELADJa

(ppm) Effect Reference

Fischer 344 rat ~19 weeks

12 weeks premating, 

up to 2 weeks mating, 

GDs 0–19, lactation 

days 5–21

5 or 7 days/week

6 hours/day

0, 0, 10, 33, 100 ppm

33 100 5.9–8.25 17.9–25 Decreases in number of 

pups/litter and fetuses 

born:implantation sites

Snellings et al. 

1982b

Sprague-Dawley 

rat

37 days 

3 weeks premating, 

GDs 1–16

7 hours/day

0, 150 ppm

ND 150 F ND 43.8 F Increased incidence of 

resorptions

NIOSH 1982

Wistar rat 13 weeks

5 days/week

6 hours/day

0, 50, 100, 250 ppm

100 250 17.9 44.6 Decreases in epididymal weight 

and sperm count; seminiferous 

tubule lesions

Mori et al. 

1991a

Wistar rat Up to 13 weeks

3 days/week

6 hours/day

0, 500 ppm

ND 500 ND 53.6 Decreases in testicular weight 

and germ cell survival; 

degenerative germ cell lesions

Kaido et al. 

1992

Wistar rat 6 weeks

3 days/week

6 hours/day

0, 500 ppm

ND 500 ND 53.6 Decreased testicular and 

epididymal weights

Mori et al. 

1991b
ETHYLENE OXIDE A-15

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-7. Summary of Selected NOAELs and LOAELs from Intermediate-Duration Studies in Animals Exposed 

to Ethylene Oxide by Inhalation

Species Exposure scenario

NOAEL

(ppm)

LOAEL

(ppm)

NOAELADJa

(ppm)

LOAELADJa

(ppm) Effect Reference

Developmental effects

CD rat 10 weeks premating 

(6 hours/day, 

5 days/week) and 

during mating, 

gestation, and 

lactation (6 hours/day, 

7 days/week)

10 33 2.1b 6.89b Decreased pup body weight in 

F1 and F2 generations

EPA 1994

Sprague-Dawley 

rat

GDs 1–16

7 hours/day

0 or 150 ppm

ND 150 F ND 43.8 F 7–9% depressed mean fetal 

weight; delayed ossification 

(skull, sternebrae)

NIOSH 1982

Sprague-Dawley 

rat

37 days 

3 weeks premating, 

GDs 1–16

7 hours/day

0 or 150 ppm

ND 150 F ND 43.8 F 10–12% depressed mean fetal 

weight; decreased crown-rump 

length; delayed ossification 

(skull, sternebrae)

NIOSH 1982

aDuration-adjusted from intermittent exposure to a continuous exposure scenario. bDuration-adjusted to continuous exposure using the time-weighted average for the exposure frequency (5.85 hours/week, 6 hours/day).

ADJ = adjusted; F = female(s); GD = gestation day; LOAEL = lowest observed adverse effect level; M = male(s); ND = not determined; NOAEL = no-observedadverse-effect level; NR = not reported
ETHYLENE OXIDE A-16

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Selection of the Principal Study: Among available intermediate-duration inhalation studies in laboratory 

animals, the mouse study of Snellings et al. (1984a) and EPA (1994) identified the lowest LOAELs

(50 ppm; equivalent to 8.9 ppm for a continuous exposure scenario and 33 ppm; equivalent to 6.89 ppm 

for a continuous exposure scenario) for clinical signs of neurotoxicity (hunched posture during gait, 

reduced motor activity) and reproductive/developmental toxicity (increased post-implantation loss and 

decreased pup body weight); the corresponding NOAEL values were 10 ppm (equivalent to 1.8 ppm for a 

continuous exposure scenario) for the Snellings et al. (1984a) study and 10 ppm (equivalent to 2.1 ppm 

for a continuous exposure scenario). The Snellings et al. (1984a) study was selected as the principal 

study for deriving an intermediate-duration inhalation MRL for ethylene oxide over the EPA (1994) study 

because it identified a slightly lower NOAEL.

Summary of the Principal Study:

Snellings WM, Weil CS, Maronpot RR. 1984a. A subchronic inhalation study of the toxicologic 

potential of ethylene oxide in B6C3F1 mice. Toxicol Appl Pharmacol 76:510-518.

Groups of 30 male and 30 female B6C3F1 mice were exposed to 0, 10, 50, 100, or 250 ppm ethylene 

oxide 6 hours/day, 5 days/week for 10 (males) or 11 (females) weeks; actual concentrations were 0, 10, 

48, 104, and 236 ppm. Neuromuscular screening tests, which assess locomotor activity, patterns of 

respiration, corneal response, gait, tail and toe pinch reflex, and righting reflex, were conducted in five

mice after 6 weeks of exposure (females only) and near termination (males and females). At termination, 

urinalysis, hematology (RBC and WBC counts, hemoglobin, hematocrit, packed cell volume, mean

corpuscular volume, mean corpuscular hemoglobin concentration, and differential leukocyte count), 

serum clinical chemistry (glucose, blood urea nitrogen [BUN], creatinine, protein, albumin, alkaline 

phosphatase, alanine aminotransferase [ALT], aspartate aminotransferase [AST]), organ weights, and 

necropsy evaluations were conducted in 10 mice per group. Histopathological examinations were 

conducted for the sciatic nerve, gastrocnemius muscle, brain and spinal cord, testes, liver (females only), 

sternal marrow (females only), and spleen (females only).

No alterations in survival, clinical signs, or body weight were observed. Abnormal righting reflex 

response was observed in 100% of females exposed to 100 or 250 ppm for 6 weeks and in 80% of males 

and females exposed to 250 ppm for 10–11 weeks; abnormal reflexes were observed in 20% of controls at 

6 weeks and 0% at termination. Hunched posture during gait was observed at 6 weeks in females 

exposed to 100 or 250 ppm (100% incidence versus 20% in controls) and at termination in males exposed 

to 100 or 250 ppm (100% compared to 0% in controls) and in females at 50, 100, or 250 ppm (80, 100, 

and 100% compared to 0% in controls). Reductions in locomotor activity were observed at termination in 

males at 50, 100, and 250 ppm (80, 100, and 100% compared to 0% in controls) and in females at 100 and 

250 ppm (100 and 100% compared to 0% in controls). Reduced or no toe pinch reflex was observed in 

100% of 250 ppm females at 6 weeks (0% in controls) and 100% of 250 ppm males at termination (0% in 

controls). Alterations in hematological parameters included significant decreases in RBC and 

hemoglobin levels in males at 250 ppm and decreases in RBC, packed cell volume, hemoglobin, and 

mean corpuscular hemoglobin concentration in females at 250 ppm. No alterations in serum clinical 

chemistry or urinalysis parameters were observed. Alterations in organ weight included decreases in 

absolute and relative spleen weights in males and females at 250 ppm, decreased absolute testes weight at 

250 ppm, and increased relative liver weight in females at 250 ppm.

Selection of the Point of Departure for the MRL: Among intermediate-duration inhalation studies in 

laboratory animals, the study of Snellings et al. (1984a) identified the lowest LOAEL (50 ppm; equivalent 

to 8.9 ppm for a continuous exposure scenario) for clinical signs of neurotoxicity; the corresponding 

NOAEL was 10 ppm (equivalent to 1.8 ppm for a continuous exposure scenario). The incidence data for 

hunched posture during gait and for reduced motor activity are presented in Table A-8.
ETHYLENE OXIDE A-17

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-8. Incidence Data for Selected Neurotoxicity Screening Tests in Male 

and Female B6C3F1 Mice Exposed to Ethylene Oxide Vapor for 6 Hours/Day, 

5 Days/Week for 10 Weeks (Males) or 11 Weeks (Females)

Test

Ethylene oxide exposure level (ppm)

0 10 50 100 250

Males

Hunched posture during gait

Reduced motor activity

0/5

0/5

1/5

2/5

2/5

4/5b

5/5a

5/5a

5/5a

5/5a

Females

Hunched posture during gait

Reduced motor activity

0/5

0/5

NE

NE

4/5b

3/5

4/5b

5/5a

5/5a

5/5a

aSignificantly different from control incidence by Duncan’s multiple range test (p<0.01). bSignificantly different from control incidence by Duncan’s multiple range test (p<0.05).

NE = not evaluated

Source: Snellings et al. 1984a

BMD analysis was initially considered to evaluate the datasets for clinical signs of neurotoxicity. 

However, only 5 mice/sex/exposure concentration were evaluated in the neurotoxicity screening tests. 

Male and female data could not be combined because: (1) females of the 10-ppm exposure group were 

not evaluated in the neurotoxicity screening tests, and (2) males were exposed for 10 weeks, whereas 

females were exposed for 11 weeks. Therefore, a NOAEL/LOAEL approach was considered using the 

NOAEL of 10 ppm as a potential point of departure to derive an intermediate-duration inhalation MRL 

for ethylene oxide.

Other datasets considered as potential points of departure for deriving an intermediate-duration inhalation 

MRL for ethylene oxide include mouse data for rhinitis and for renal tubular degeneration from the study 

of NTP (1987), data for ratios of pups to litter and fetuses born to implantation sites among rats of the 

study of Snellings et al. (1982b), and data for selected hematological changes in mice from the study of 

Snellings et al. (1984a). BMD analysis was initially considered for each of these datasets.

The data for rhinitis (NTP 1987) are not amenable to BMD analysis because the 400- and 600-ppm 

groups exhibited 100% mortality during the first 2 weeks of the 14-week study and histopathologic lesion 

data were not reported for the 50 ppm exposure group. Similarly, the dataset for renal tubular 

degeneration (NTP 1987) is not amenable to BMD analysis because incidences of degeneration observed 

at 100 and 200 ppm in males and females, respectively, decreased at 400 and 600 ppm (likely due to 

increasing incidences of necrosis at these exposure levels). Also, 100% mortality was noted for the 

400 and 600 ppm groups during the first 2 weeks of the study. The data for decreases in the ratios of pups 

to litter and fetuses born to implantation sites (Snellings et al. 1982b) were not amenable to BMD analysis 

because the effect occurred only at the highest exposure level. Furthermore, the study report did not 

provide the numbers of pups at birth on a per litter basis.

Data for hematological effects were considered amenable to BMD analysis. Table A-9 summarizes 

selected hematological changes in mice (RBC count and hemoglobin content in males and females; 

packed cell volume [PCV] and mean corpuscular hemoglobin in females) following repeated exposure to 
ETHYLENE OXIDE A-18

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

ethylene oxide vapor for 6 hours/day, 5 days/week for 10 weeks (males) or 11 weeks (females) (Snellings 

et al. 1984a). These parameters exhibited exposure concentration-response characteristics and each 

parameter in the highest exposure group was significantly different from that of controls.

Table A-9. Selected Hematology Results for B6C3F1 Mice Exposed to Ethylene 

Oxide Vapor for 6 Hours/Day, 5 Days/Week for 10–Weeks (Males) or 11 Weeks 

(Females)

Blood value

Ethylene oxide exposure level (ppm)

0 10 50 100 250

Males

RBC concentration (x106/mm3) 9.346

(0.530)

9.335

(0.432)

9.174

(0.316)

8.534

(1.908)

8.922a

(0.332)

Hemoglobin content (g/dL) 15.16

(0.75)

15.04

(0.58)

14.81

(0.56)

14.02

(2.58)

14.48a

(0.60)

Females

RBC concentration (x106/mm3) 9.539

(0.365)

9.514

(0.316)

9.429

(0.201)

9.228

(0.510)

8.694a

(0.451)

Packed cell volume (%) 48.2

(3.5)

47.9

(2.1)

47.6

(2.3)

47.0

(2.9)

44.7a

(4.0)

Hemoglobin content (g/dL) 15.54

(0.47)

15.53

(0.35)

15.40

(0.65)

15.35

(0.51)

14.76a

(0.64)

Mean corpuscular hemoglobin (pg) 16.2

(0.4)

16.2

(0.4)

16.2

(0.4)

16.5

(0.7)

17.0a

(0.8)

aSignificantly different from control incidence by Duncan’s multiple range test (p<0.01).

RBC = red blood cell

Source: Snellings et al. 1984a

Each dataset was subjected to BMD analysis using all available continuous variable models in BMDS 

version 3.1. A BMR of 1 standard deviation change from control was applied in the absence of a 

rationale for considering an alternative BMR. Adequate model fit was judged by three criteria: goodnessof-fit p-value (p>0.1), visual inspection of the dose-response curve, and scaled residual at the data point 

(except the control) closest to the predefined BMR. Among all of the models providing adequate fit to 

the data, the lowest BMCL (95% lower confidence limit on the BMC) was selected as the point of 

departure when the difference between the BMCLs (95% lower confidence limits on the BMD) estimated 

from these models was >3-fold; otherwise, the BMCL from the model with the lowest AIC was chosen.

None of the models provided adequate fit to the data for the male mice (RBC concentration, hemoglobin 

content) using either constant or nonconstant variance. Table A-10 summarizes BMD results (constant 

variance) for RBC count in the female mice. All models provided adequate fit to the data. The Linear 

model was selected as the best-fitting model (lowest AIC).
ETHYLENE OXIDE A-19

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-10. Results from BMD Analysis (Constant Variance) of RBC Count in 

Female B6C3F1 Mice Exposed to Ethylene Oxide Vapor for 6 Hours/Day, 

5 Days/Week for 11 Weeks

Model

Test for 

significant 

difference 

p-valuea

Test for

variance

p-valueb

Test for 

means

p-valuec

Scaled residualsd

AIC

BMC1SD

(ppm)

BMCL1SD

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Exponential 

(model 2)e

<0.0001 0.06 0.97 0.130 -0.127 0.359 47.127 103.67 77.64

Exponential 

(model 3)e

<0.0001 0.06 0.97 -0.131 0.0190 0.183 48.949 119.16 78.33

Exponential 

(model 4)e

<0.0001 0.06 0.89 0.359 0.130 0.359 49.127 103.67 77.64

Exponential 

(model 5)e

<0.0001 0.06 0.82 -0.130 0.019 0.183 50.949 119.16 78.33

Hille <0.0001 0.06 0.91 -0.008 0.0007 -0.0874 50.908 114.77 61.09

Polynomial 

(2-degree)e

<0.0001 0.06 0.96 -0.148 0.0145 0.232 48.975 119.11 81.04

Polynomial 

(3-degree)e

<0.0001 0.06 0.96 -0.148 0.0145 0.232 48.975 119.11 81.04

Polynomial 

(4-degree)e

<0.0001 0.06 0.96 -0.148 0.0145 0.232 48.975 119.11 81.04

Powere <0.0001 0.06 0.97 -0.139 0.0196 0.191 48.954 119.45 81.12

Linearf <0.0001 0.06 0.97 0.077 -0.092 0.333 47.074 106.41 80.66

aValues >0.05 fail to meet conventional goodness-of-fit criteria. bValues <0.05 fail to meet conventional goodness-of-fit criteria. cValues <0.1 fail to meet conventional goodness-of-fit criteria. dScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose. eRestricted model. f

Recommended model (lowest AIC).

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 1SD = exposure concentration associated with a 1 standard deviation change from the 

control)
ETHYLENE OXIDE A-20

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-11 summarizes BMD results (constant variance) for PCV in blood samples from the female 

mice. All models provided adequate fit to the data. The Linear model was selected as the best-fitting 

model (lowest AIC).

Table A-11. Results from BMD Analysis (Constant Variance) of Packed Cell 

Volume (PCV) in Female B6C3F1 Mice Exposed to Ethylene Oxide Vapor 

for 6 Hours/Day, 5 Days/Week for 11 Weeks

Model

Test for 

significant 

difference 

p-valuea

Test for

variance

p-valueb

Test for 

means

p-valuec

Scaled residualsd

AIC

BMC05

(ppm)

BMCL05

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Exponential 

(model 2)e

0.07 0.22 0.99 0.203 -0.098 0.203 254.073 209.83 131.46

Exponential 

(model 3)e

0.07 0.22 0.98 0.036 -0.008 -0.137 256.010 218.83 132.05

Exponential 

(model 4)e

0.07 0.22 0.95 0.203 -0.098 0.203 256.073 209.83 131.46

Exponential 

(model 5)e

0.07 0.22 0.85 0.037 -0.008 -0.137 258.010 218.80 132.05

Hille 0.07 0.22 0.85 0.051 -0.017 -0.141 258.011 218.24 102.18

Polynomial 

(2-degree)e

0.07 0.22 0.99 0.012 -0.002 -0.122 256.001 219.94 135.37

Polynomial 

(3-degree)e

0.07 0.22 0.88 0.002 -0.001 -0.119 257.999 221.56 135.37

Polynomial 

(4-degree)e

0.07 0.22 0.99 0.007 0.0006 -0.118 255.990 223.99 135.39

Powere 0.07 0.22 0.98 0.034 -0.008 -0.136 256.009 219.02 135.30

Linearf 0.07 0.22 0.99 0.182 -0.083 -0.183 254.058 210.83 134.85

aValues >0.05 fail to meet conventional goodness-of-fit criteria. bValues <0.05 fail to meet conventional goodness-of-fit criteria. cValues <0.1 fail to meet conventional goodness-of-fit criteria. dScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose.

eRestricted model. f

Recommended model (lowest AIC).

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 05 = exposure concentration associated with 5% extra risk)
ETHYLENE OXIDE A-21

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-12 summarizes BMD results (constant variance) for hemoglobin content in blood samples from 

the female mice. All models provided adequate fit to the data. The Linear model was selected as the 

best-fitting model (lowest AIC).

Table A-12. Results from BMD Analysis (Constant Variance) of Hemoglobin 

Content in Female B6C3F1 Mice Exposed to Ethylene Oxide Vapor for 

6 Hours/Day, 5 Days/Week for 11 Weeks

Model

Test for 

significant 

difference 

p-valuea

Test for

variance

p-valueb

Test for 

means

p-valuec

Scaled residualsd

AIC

BMC1SD

(ppm)

BMCL1SD

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Exponential 

(model 2)e

0.02 0.32 0.93 0.576 -0.217 0.576 80.668 162.62 110.91

Exponential 

(model 3)e

0.02 0.32 0.93 0.196 -0.023 -0.310 82.378 187.21 112.91

Exponential 

(model 4)e

0.02 0.32 0.80 0.576 -0.217 0.576 82.668 162.62 110.91

Exponential 

(model 5)e

0.02 0.32 0.70 0.195 -0.023 -0.310 84.378 187.20 112.91

Hille 0.02 0.32 0.70 0.205 -0.027 -0.304 84.377 186.77 89.62

Polynomial 

(2-degree)e

0.02 0.32 0.95 0.170 -0.016 -0.274 82.345 189.43 114.95

Polynomial 

(3-degree)e

0.02 0.32 0.96 0.129 -0.006 0.129 82.318 195.02 115.14

Polynomial 

(4-degree)e

0.02 0.32 0.96 0.112 -0.002 -0.118 82.307 200.05 115.21

Powere 0.02 0.32 0.93 0.195 -0.022 -0.307 82.375 187.46 114.72

Linearf 0.02 0.32 0.94 0.558 -0.201 0.558 80.639 163.78 112.93

aValues >0.05 fail to meet conventional goodness-of-fit criteria. bValues <0.05 fail to meet conventional goodness-of-fit criteria. cValues <0.1 fail to meet conventional goodness-of-fit criteria. dScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose.

eRestricted model. f

Recommended model (lowest AIC).

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 1SD = exposure concentration associated with a 1 standard deviation change from the 

control)

Using constant variance, none of the models provided adequate fit to the data for mean corpuscular 

hemoglobin in blood samples from the female mice. Therefore, the BMD modeling exercise was 

repeated using nonconstant variance (Table A-13). Among the models providing viable results, the 

Linear model was selected as the best-fitting model (lowest AIC).
ETHYLENE OXIDE A-22

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-13. Results from BMD Analysis (Nonconstant Variance) of Mean 

Corpuscular Hemoglobin in Female B6C3F1 Mice Exposed to Ethylene 

Oxide Vapor for 6 Hours/Day, 5 Days/Week for 11 Weeks

Model

Test for 

significant 

difference 

p-valuea

Test for

variance

p-valueb

Test for 

means

p-valuec

Scaled residualsd

AIC

BMC1SD

(ppm)

BMCL1SD

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Exponential 

(model 2)e

0.002 0.85 0.56 0.152 0.113 -0.779 80.913 121.75 76.78

Exponential 

(model 3)e

0.002 0.85 <0.0001

Exponential 

(model 4)e

0.002 0.85 <0.0001

Exponential 

(model 5)e

0.002 0.85 <0.0001

Hille 0.002 0.85 1.00 0.047 -0.510 -0.510 82.85 99.47 54.98

Polynomial 

(2-degree)e

0.002 0.85 0.56 0.152 0.166 -0.791 80.892 121.56 74.86

Polynomial 

(3-degree)e

0.002 0.85 0.56 0.152 0.166 -0.791 82.318 121.56 74.86

Polynomial 

(4-degree)e

0.002 0.85 0.56 0.154 0.172 -0.791 80.89 121.75 74.86

Powere 0.002 0.85 0.36 0.183 0.138 -0.762 82.375 124.39 74.90

Linearf 0.002 0.85 0.56 0.156 0.176 0.373 80.892 121.89 74.86

aValues >0.05 fail to meet conventional goodness-of-fit criteria. bValues <0.05 fail to meet conventional goodness-of-fit criteria. cValues <0.1 fail to meet conventional goodness-of-fit criteria. dScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose.

eRestricted model. f

Recommended model (lowest AIC).

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 1SD = exposure concentration associated with a 1 standard deviation change from the 

control)

The intermediate-duration inhalation study in male and female B6C3F1 mice (Snellings et al. 1984a) 

provides several candidate points of departure for deriving an intermediate-duration inhalation MRL for 

ethylene oxide (Table A-14).
ETHYLENE OXIDE A-23

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-14. Candidate Points of Departure for Deriving an Intermediate-Duration 

Inhalation MRL for Ethylene Oxide

Effect description Candidate point of departure

Clinical signs of neurotoxicity in male mice NOAEL of 10 ppm

Mean corpuscular hemoglobin in blood of female mice BMCL1SD of 74.86 ppm

RBC count in blood of female mice BMCL1SD of 80.66 ppm

Hemoglobin content in blood of female mice BMCL1SD of 112.93 ppm

PCV in blood of female mice BMCL1SD of 134.85 ppm

BMCL = 95% lower confidence limit on the BMC (subscripts denote benchmark response: i.e., 1SD = exposure 

concentration associated with 1 standard deviation change); MRL = Minimal Risk Level; NOAEL = no-observedadverse-effect level; PCV = packed cell volume; RBC = red blood cell

The NOAEL of 10 ppm is the lowest point of departure for deriving an intermediate-duration inhalation 

MRL for ethylene oxide.

Calculations

Intermittent Exposure: The NOAEL of 10 ppm was adjusted from intermittent exposure to account for a 

continuous exposure scenario:

NOAELADJ = 10 ppm x (6 hours/24 hours) x (5 days/7 days) = 1.8 ppm.

Human Equivalent Concentration: A PBPK modeling approach was initially considered to calculate a 

human equivalent to the mouse NOAELADJ. Available PBPK models for ethylene oxide are described in 

Section 3.1.5. However, a PBPK modeling approach was rejected due to a lack of experimental data 

regarding the proper dose metric (proximate toxicant) for ethylene oxide-induced neurotoxicity. 

Therefore, the mouse NOAELADJ was converted to a NOAELHEC using the following equation:

NOAELHEC = NOAELADJ x ([Hb/g]A/[Hb/g]H)

[Hb/g]A = animal blood/air partition coefficient = 78 (Fennell and Brown 2001) 

[Hb/g]H = human blood/air partition coefficient = 61 according to Csanady et al. (2000)

A default value of 1 for the ratio of blood/air partition coefficients for mice and humans was used because 

the mouse blood/air partition coefficient was greater than the value for humans.

NOAELHEC = 1.8 ppm x 1 = 1.8 ppm

Uncertainty Factor and Modifying Factor: The NOAELHEC of 1.8 ppm was divided by a total 

uncertainty factor of 30 and a modifying factor of 3 for insufficient animal data assessing functional 

neurological endpoints. Case studies of workers have reported a number of neurological effects such as 

cognitive dysfunction and memory loss, which have not been evaluated in animal studies. The 

epidemiological studies do not provide adequate exposure-response data. The modifying factor of 3 is 

used to address concern that these effects could occur at lower concentrations than those associated with 

gait alterations and decreased locomotor activity:

• 3 for extrapolation from animals to humans using dosimetric adjustment

• 10 for human variability
ETHYLENE OXIDE A-24

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

• 3 for insufficient assessment of functional neurological endpoints 

Provisional MRL = NOAELHEC ÷ (total uncertainty factor x modifying factor)

Provisional MRL = 1.8 ppm ÷ (30 x 3) = 0.02 ppm

Other Additional Studies or Pertinent Information that Lend Support to this MRL: Human and animal 

data provide supporting evidence for the neurotoxicity of ethylene oxide. Neuropathy, impaired hand-eye 

coordination, cognitive dysfunction, memory loss, headache, and hand numbness were reported after 

occupational exposure to ethylene oxide (Brashear et al. 1996; Crystal et al. 1988; Dretchen et al. 1992; 

Estrin et al. 1987; Finelli et al. 1983; Kuzuhara et al. 1983; Salinas et al. 1981; Schröder et al. 1985; 

Zampollo et al. 1984). Sural nerve biopsies performed on two occupational groups revealed axonal 

degeneration and regeneration (Kuzuhara et al. 1983; Schröder et al. 1985). Peripheral neuropathy, 

retarded growth and maturation of myelinated fibers in hindleg nerves, and mild axonal degeneration 

were observed in Wistar rats (Ohnishi et al. 1985, 1986).

Agency Contacts (Chemical Managers): Jennifer Przybyla
ETHYLENE OXIDE A-25

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Ethylene Oxide

CAS Numbers: 75-21-8

Date: September 2020

Profile Status: Final for Public Comment

Route: Inhalation

Duration: Chronic

MRL Summary: A chronic-duration inhalation MRL was not derived for ethylene oxide.

Rationale for Not Deriving an MRL: As demonstrated below, evaluation of available chronic-duration 

animal studies that employed the inhalation exposure route resulted in the calculation of a potential 

chronic-duration inhalation MRL of 0.03 ppm, which is slightly higher than the provisional intermediateduration inhalation MRL of 0.02 ppm. Therefore, a chronic-duration inhalation MRL was not derived for 

ethylene oxide. ATSDR considers the intermediate-duration inhalation MRL to be protective of chronicduration inhalation exposure to ethylene oxide.

No adequate exposure-response data were available for humans. Neuropathy, impaired hand-eye 

coordination, cognitive dysfunction, memory loss, headache, and hand numbness were reported after 

occupational exposure to ethylene oxide (Brashear et al. 1996; Crystal et al. 1988; Dretchen et al. 1992; 

Estrin et al. 1987; Finelli et al. 1983; Kuzuhara et al. 1983; Salinas et al. 1981; Schröder et al. 1985; 

Zampollo et al. 1984). Sural nerve biopsies performed on two occupational groups revealed axonal 

degeneration and regeneration (Kuzuhara et al. 1983; Schröder et al. 1985). Table A-15 summarizes 

results from chronic-duration inhalation studies in experimental animals.

In cynomolgus monkeys intermittently exposed to ethylene oxide vapor for 2 years, decreased sperm 

count (28% less than controls) and motility (32% less than controls) were noted at the lowest exposure 

level tested (50 ppm) (Lynch et al. 1984a). It is not known whether these alterations would result in 

decreases in fertility as the study did not evaluate reproductive function. Although the study employed 

11 monkeys/group, evaluation of sperm parameters at cessation of exposures at 24 months included only 

2 monkeys per group. The remaining nine animals/group were evaluated at unspecified timepoints up to 

9 weeks following cessation of ethylene oxide exposures. Although the study report included mean and 

standard deviation for the 11 monkeys/group, the variation in timepoints at which sperm parameters were 

evaluated resulted in considerable uncertainty in mean and standard deviation values and precludes 

meaningful quantitative analysis. Therefore, the monkey study of Lynch et al. (1984a) was not 

considered as a principal study for deriving a chronic-duration inhalation MRL for ethylene oxide.

Approximately 12–18% depressed body weight gain was reported in male and female Fischer 344 rats 

exposed to ethylene oxide vapor at 100 ppm, 6 hours/day, 5 days/week for up to 2 years (Snellings et al. 

1984b).

A 104-week repeated inhalation study of male Fischer 344 rats employed ethylene oxide vapor 

concentrations of 0, 50, and 100 ppm (Lynch et al. 1984b). Reported effects at 50 ppm included 

respiratory effects (acute bronchopneumonia, chronic pneumonia, pulmonary edema, suppurative 

rhinitis), hematological effects (splenic extramedullary hematopoiesis), and endocrine effects (adrenal 

gland multifocal cortical vacuolation and hyperplasia). The respiratory tract of the rats may have been 

compromised by a pulmonary infection that occurred in controls and ethylene oxide-exposed groups as 

early as month 8 and resulted in treatment for the infection at 8, 16, and 20 months. Therefore, the 

respiratory effects were not considered as potential critical effects for MRL derivation. However, the 
ETHYLENE OXIDE A-26

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-15. Summary of Selected NOAELs and LOAELs from Chronic-Duration Studies in Animals Exposed 

to Ethylene Oxide by Inhalation

Species Exposure scenario

NOAEL

(ppm)

LOAEL

(ppm)

NOAELADJa

(ppm)

LOAELADJa

(ppm) Effect Reference

Body weight effects

Fischer 344 rat 104 weeks

5 days/week

7 hours/day

0, 50, 100 ppm

50 100 ND 20.8 13% depressed body weight 

gain

Lynch et al. 

1984b

Fischer 344 rat 2 years

5 days/week

6 hours/day

0, 0, 10, 33, 100 ppm

33 100 5.9 17.9 Males: up to 12% depressed 

body weight gain

Females: 12–18% depressed 

body weight gain

Garman et al. 

1986; 

Snellings et al. 

1984b

Hematological effects

Fischer 344 rat 104 weeks

5 days/week

7 hours/day

0, 50, 100 ppm

ND 50 ND 10.4 Splenic extramedullary 

hematopoiesis

Lynch et al. 

1984b

Musculoskeletal effects

Fischer 344 rat 104 weeks

5 days/week

7 hours/day

0, 50, 100 ppm

50 100 10.4 20.8 Multifocal myopathy Lynch et al. 

1984b

Endocrine effects

Fischer 344 rat 104 weeks

5 days/week

7 hours/day

0, 50, 100 ppm

ND 50 ND 10.4 Multifocal cortical vacuolation 

and hyperplasia in adrenal gland

Lynch et al. 

1984b

aDuration-adjusted from intermittent exposure to a continuous exposure scenario.

ADJ = adjusted; LOAEL = lowest observed adverse effect level; ND = not determined; NOAEL = no-observed-adverse-effect level
ETHYLENE OXIDE A-27

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

hematological and endocrine effects are considered representative of ethylene oxide exposure-related 

effects. These hematological and endocrine effects were selected as candidate critical effects because 

they were observed at the lowest LOAEL (50 ppm).

Table A-16 summarizes incidence data for selected hematological and endocrine effects in the rats of 

Lynch et al. (1984b). 

Table A-16. Incidences of Selected Nonneoplastic Lesions in Male Fischer 344 

Rats Exposed to Ethylene Oxide Vapor for 7 Hours/Day, 5 Days/Week for 

104 Weeks

Lesion

Ethylene oxide exposure level (ppm)

0 50 100

Adrenal gland

Multifocal cortical vacuolation

Multifocal cortical hyperplasia

Cortical nodular hyperplasia

0/78

0/78

0/78

25/77a

16/77a

2/77

42/78a

36/78a

14/78a

Spleen

Extramedullary hematopoiesis

Focal fibrosis

34/77

6/77

53/79a

9/79

46/76a

23/76a

aSignificantly different from control incidence by Duncan’s multiple range test (p<0.01).

Source: Lynch et al. 1984b

BMD analysis was considered to evaluate datasets for each lesion type in the adrenal gland and the 

spleen.

Significantly increased incidences of cortical nodular hyperplasia in the adrenal gland and splenic focal 

fibrosis occurred only at the highest ethylene oxide exposure level (100 ppm) and failed to exhibit 

meaningful exposure-response data. The dataset for splenic extramedullary hematopoiesis exhibited 

nearly 50% incidence in controls and 67% and 60% incidences at 50 and 100 ppm, respectively. 

Therefore, BMD analysis was not considered for adrenal gland cortical nodular hyperplasia or for splenic

lesions.

The datasets for multifocal cortical vacuolation and multifocal cortical hyperplasia in the adrenal gland 

(Table A-16) were subjected to BMD analysis using BMDS version 3.1. All dichotomous models were 

fitted to the incidence data using a BMR of 10% change from controls. Adequate model fit was judged 

by three criteria: goodness-of-fit p-value (p>0.1), visual inspection of the dose-response curve, and scaled 

residual at the data point (except the control) closest to the predefined BMR. Among all of the models 

providing adequate fit to the data, the lowest BMCL (95% lower confidence limit on the BMC) was 

selected as the point of departure when the difference between the BMCLs (95% lower confidence limits 

on the BMD) estimated from these models was >3-fold; otherwise, the BMCL from the model with the 

lowest AIC was chosen. The results are summarized in Table A-17 for vacuolation and Table A-18 for 

hyperplasia.
ETHYLENE OXIDE A-28

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-17. Results from BMD Analysis of Multifocal Cortical Vacuolation in 

Adrenal Gland from Male Fischer 344 Rats Exposed to Ethylene Oxide 

Vapor for 7 Hours/Day, 5 Days/Week for 104 Weeks

Model DF χ2

χ2

Goodnessof-fit 

p-valuea

Scaled residualsb

AIC

BMD10

(ppm)

BMDL10

(ppm)

Dose 

below 

BMD

Dose 

above 

BMD

Overall 

largest

Gammac 1 1.2x10-6 0.95 -0.001 0.047 0.047 208.75 13.55 11.11

LogLogistic 1 1.2x10-6 1.00 -0.001 -10x10-9 -10x10-9 208.74 15.91 8.10

Multistage 

(2-degree)d,e

2 0.0036 1.00 -0.001 0.047 0.047 206.75 13.55 11.11

Multistage 

(1-degree)d,e

2 0.0036 1.00 -0.001 0.047 0.047 206.75 13.55 11.11

Weibullc 1 0.0036 0.95 -0.001 0.047 0.047 208.75 13.55 11.11

Dichotomous 

Hillf

-1 1.2x10-6 65,535

Logistic 1 10.13 0.001

LogProbitg 0 1.2x10-6 NA

Probit 1 8.80 0.003

aValues <0.1 fail to meet conventional goodness-of-fit criteria. bScaled residuals at doses immediately below and above the BMC; also the largest residual at any dose. cSlope restricted to ≥1. dPower restricted to ≥1. eAmong models providing adequate fit to the data, BMCL10 values varied by <3-fold; therefore, the model with the 

lowest AIC was selected as the best-fitting model (1- and 2-degree Multistage). f

Invalid degrees of freedom and χ2 values.

gBetas restricted to ≥0.

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure dose associated with the 

selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote benchmark 

response: i.e., 10 = exposure dose associated with 10% extra risk); DF = degrees of freedom; NA = not applicable 

(degrees of freedom = 0; model saturated; goodness-of-fit not calculated)
ETHYLENE OXIDE A-29

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-18. Results from BMD Analysis of Multifocal Cortical Hyperplasia in 

Adrenal Gland from Male Fischer 344 Rats Exposed to Ethylene Oxide 

Vapor for 7 Hours/Day, 5 Days/Week for 104 Weeks

Model DF χ2

χ2

Goodness

-of-fit 

p-valuea

Scaled residualsb

AIC

BMC10

(ppm)

BMCL10

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Gammac 1 1.2x10-6 1.00 -0.001 -4.9x10-5 -4.9x10-5 190.37 29.27 15.83

LogLogistic 1 1.2x10-6 1.00 -0.001 -2.8x10-5 -2.8x10-5 190.37 30.24 13.65

Multistage 

(2-degree)d

0 1.2x10-6 NA

Multistage 

(1-degree)d,e

2 0.894 0.64 -0.001 -0.754 -0.754 189.28 18.77 15.03

Weibullc 1 1.2x10-6 1.00 -0.001 1.7x10-6 1.3x10-6 190.37 28.49 15.65

Dichotomous 

Hill

0 1.2x10-6 NA

Logistic 1 4.936 0.03

LogProbitd 0 18.07 NA

Probit 1 3.84 0.05

aValues <0.1 fail to meet conventional goodness-of-fit criteria. bScaled residuals at doses immediately below and above the BMC; also the largest residual at any dose. cSlope restricted to ≥1.

dBetas restricted to ≥0.

eAmong models providing adequate fit to the data, BMCL10 values varied by <3-fold; therefore, the model with the 

lowest AIC was selected as the best-fitting model (1-degree Multistage). f

Power restricted to ≥1.

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure dose associated with the 

selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote benchmark 

response: i.e., 10 = exposure dose associated with 10% extra risk); DF = degrees of freedom; NA = not applicable 

(degrees of freedom = 0; model saturated; goodness-of-fit not calculated)

Candidate points of departure for deriving a potential chronic-duration inhalation MRL for ethylene oxide 

include BMD results for multifocal cortical vacuolation in the adrenal gland (BMCL10 of 11.11 ppm) and 

for multifocal cortical hyperplasia in the adrenal gland (BMCL10 of 15.03 ppm). The LOAEL of 50 ppm 

for splenic extramedullary hematopoiesis was initially considered as a candidate point of departure. 

However, the dataset was not amenable to BMD analysis (ethylene oxide exposure levels of 50 and 

100 ppm only, relatively high incidence among controls, and a lower incidence at 100 ppm than at 

50 ppm). Results from BMD analysis of incidences of histopathologic lesions in the adrenal gland was 

considered a more scientific approach to deriving a chronic-duration inhalation MRL than a NOAEL/

LOAEL approach using incidence data for splenic extramedullary hematopoiesis. Among BMD results, 

the lowest BMCL10 (11.11 ppm for multifocal cortical vacuolation) was selected as a potential point of 

departure for deriving a chronic-duration inhalation MRL for ethylene oxide.

The BMCL10 of 11.11 ppm was adjusted from intermittent exposure to account for a continuous exposure 

scenario:

BMCL10ADJ = BMCL10 of 11.11 ppm x (7 hours/24 hours x 5 days/7days) = 2.3 ppm.
ETHYLENE OXIDE A-30

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

A PBPK modeling approach was initially considered to calculate a human equivalent to the rat 

BMCL10ADJ of 2.3 ppm. Available PBPK models for ethylene oxide are described in Section 3.1.5. 

However, a PBPK modeling approach was rejected due to a lack of experimental data regarding the 

proper dose metric (proximate toxicant) for ethylene oxide-induced endocrine effects. Therefore, the rat 

BMCL10ADJ was converted to a NOAELHEC using the following equation:

BMCL10HEC = BMCL10ADJ x ([Hb/g]A/[Hb/g]H)

[Hb/g]A = animal blood/air partition coefficient = 64.1 for rats according to Krishnan et al. (1992)

[Hb/g]H = human blood/air partition coefficient = 61 according to Csanady et al. (2000)

A default value of 1 is used for the ratio of blood/air partition coefficients because the animal value is 

greater than the human value.

BMCL10HEC = BMCL10ADJ (2.3 ppm) x 1 = 2.3 ppm

The BMCL10HEC of 2.3 ppm was divided by an uncertainty factor of 30 and a modifying factor of 3 to 

account for lack of data regarding the neurological effects of chronic-duration inhalation exposure to 

ethylene oxide. Intermediate-duration studies in animals and case studies of workers have reported a 

number of neurological effects; however, the potential neurotoxicity of ethylene oxide following chronicduration exposure has not been evaluated in animals:

• 3 for extrapolation from animals to humans using dosimetric adjustment

• 10 for human variability

• 3 for lack of neurological data from chronic-duration exposure

Potential MRL = BMCL10HEC ÷ (uncertainty factor x modifying factor)

(BMCL10HEC of 2.3 ppm ÷ 30 x 3) = 0.03 ppm

As stated previously, a chronic-duration inhalation MRL was not derived for ethylene oxide. The 

intermediate-duration inhalation MRL of 0.02 ppm is considered protective of chronic-duration inhalation 

exposure to ethylene oxide.

Agency Contacts (Chemical Managers): Jennifer Przybyla
ETHYLENE OXIDE A-31

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Ethylene oxide

CAS Numbers: 75-21-8

Date: September 2020

Profile Status: Final for Public Comment

Route: Oral

Duration: Acute

MRL Summary: Available acute-duration oral data were not considered adequate for derivation of an 

acute-duration oral MRL for ethylene oxide.

Rationale for Not Deriving an MRL: No dose-response data are available for humans. Available animal 

data are restricted to a single study in which 100% mortality occurred in rats treated with ethylene oxide 

by single gavage dose at 200 mg/kg; treatment at 100 mg/kg did not affect body weight (Hollingsworth et 

al. 1956).

Agency Contacts (Chemical Managers): Jennifer Przybyla
ETHYLENE OXIDE A-32

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Ethylene oxide

CAS Numbers: 75-21-8

Date: September 2020

Profile Status: Final for Public Comment

Route: Oral

Duration: Intermediate

MRL Summary: The intermediate-duration oral data were not considered adequate for derivation of an 

intermediate-duration oral MRL for ethylene oxide.

Rationale for Not Deriving an MRL: No dose-response data are available for humans. Available animal 

data are restricted to a single study in which gavage dosing of rats at 100 mg/kg/day for 15 or 

22 treatments in 15 or 30 days resulted in weight loss, gastric irritation, and slight liver damage (not 

otherwise described); the NOAEL was 30 mg/kg/day (Hollingsworth et al. 1956). The lack of 

quantitative data precludes derivation of an intermediate-duration oral MRL for ethylene oxide.

Agency Contacts (Chemical Managers): Jennifer Przybyla
ETHYLENE OXIDE A-33

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Ethylene oxide

CAS Numbers: 75-21-8

Date: September 2020

Profile Status: Final for Public Comment

Route: Oral

Duration: Chronic

MRL Summary: The chronic-duration oral data were not considered adequate for derivation of a 

chronic-duration oral MRL for ethylene oxide.

Rationale for Not Deriving an MRL: No dose-response data are available for humans. Available animal 

data are restricted to a single study in which gavage dosing at 30 mg/kg/day, 2 times/week for up to 

150 weeks resulted in decreased survival; forestomach squamous cell carcinoma was reported at 

7.5 mg/kg/day (Dunkelberg 1982).

Agency Contacts (Chemical Managers): Jennifer Przybyla
ETHYLENE OXIDE B-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR ETHYLENE 

OXIDE

The objective of the toxicological profile is to evaluate the potential for human exposure and the potential 

health hazards associated with inhalation, oral, or dermal/ocular exposure to ethylene oxide. 

B.1 LITERATURE SEARCH AND SCREEN 

A literature search and screen was conducted to identify studies examining health effects, toxicokinetics, 

mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical 

properties, production, use, environmental fate, environmental releases, and environmental and biological 

monitoring data for ethylene oxide. ATSDR primarily focused on peer-reviewed articles without 

publication date or language restrictions. Non-peer-reviewed studies that were considered relevant to the 

assessment of the health effects of ethylene oxide have undergone peer review by at least three ATSDRselected experts who have been screened for conflict of interest. The inclusion criteria used to identify 

relevant studies examining the health effects of ethylene oxide are presented in Table B-1.

Table B-1. Inclusion Criteria for the Literature Search and Screen

Health Effects

Species

Human

Laboratory mammals

Route of exposure

Inhalation

Oral

Dermal (or ocular)

Parenteral (these studies will be considered supporting data)

Health outcome

Death

Systemic effects

Body weight effects 

Respiratory effects

Cardiovascular effects

Gastrointestinal effects

Hematological effects

Musculoskeletal effects

Hepatic effects

Renal effects

Dermal effects

Ocular effects

Endocrine effects

Immunological effects

Neurological effects

Reproductive effects

Developmental effects
ETHYLENE OXIDE B-2

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-1. Inclusion Criteria for the Literature Search and Screen

Other noncancer effects

Cancer

Toxicokinetics

Absorption

Distribution

Metabolism

Excretion

PBPK models

Biomarkers

Biomarkers of exposure

Biomarkers of effect

Interactions with other chemicals

Potential for human exposure

Releases to the environment

Air

Water

Soil

Environmental fate

Transport and partitioning

Transformation and degradation

Environmental monitoring

Air

Water

Sediment and soil

Other media

Biomonitoring

General populations

Occupation populations

B.1.1 Literature Search

The current literature search was intended to update the 1990 toxicological profile for ethylene oxide;

thus, the literature search was restricted to studies published between 1989 to June 2018. The following 

main databases were searched in June 2018:

• Medline

• Embase

• Scopus

• Proquest – Agricultural and Environmental Science Database

The search strategy used the chemical names, Chemical Abstracts Service (CAS) numbers, 

synonyms, Medical Subject Headings (MeSH) headings, and keywords for ethylene oxide. The

query strings used for the literature search are presented in Table B-2. 
ETHYLENE OXIDE B-3

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS), 

OSH (Occupational Health and Safety) Reference Collection, and National Institute of Health Research 

Portfolio Online Reporting Tools Expenditures and Results (NIH RePORTER) databases using the 

queries presented in Table B-3. Additional databases were searched in the creation of various tables and 

figures, such as the TRI Explorer, the Substance Priority List (SPL) resource page, and other items as 

needed. Regulations applicable to ethylene oxide were identified by searching international and U.S. 

agency websites and documents.

Review articles were identified and used for the purpose of providing background information and 

identifying additional references. ATSDR also identified reports from the grey literature, which included 

unpublished research reports, technical reports from government agencies, conference proceedings and 

abstracts, and theses and dissertations. 

Table B-2. Database Query Strings 

Database

search date Query string

Medline (OVID)

6/2018 Ethylene oxide OR dimethylene oxide OR 1?2-epoxyethane OR a?beta-oxidoethane OR 

oxirane* OR dihydrooxirene OR oxane OR epoxyethane OR oxacyclopropane OR 

ethene oxide OR amprolene OR anprolene OR anproline OR oxidoethane OR oxyfume 

OR aethylenoxid OR 1?2-epoxyaethan OR merpol OR oxiran OR T-Gas OR oxirene* 

OR ethyl?enoxide OR oxiraan OR epoxy ethane OR Ethylenoxid OR ethyleneoxy OR 

75-21-8.rn

AND

(ae OR to OR po OR pk OR bl OR bi OR ur OR me).fs OR (Health OR illness* OR injur* 

OR adverse OR exposure* OR poison* OR lung* OR respirat* OR thorax OR risk* OR 

endocrine OR hormone* OR metabol* OR genetic* OR gene expression OR antagonist* 

OR inhibitor* OR monitor* OR transcription* OR RNA OR DNA OR biosynthesis OR 

Polymerase Chain Reaction OR PCR OR cancer* OR neoplasm* OR toxic* OR pharma* 

OR inhale* OR inhalation OR gastrointestin* OR nausea OR vomit* OR eye* OR 

muscle* OR kidney* OR ureter OR bladder* OR liver* OR seizure* OR convulsion* OR 

skin OR derma*).ti,ab.

1989- ; English ; Abstracts available

Embase (OVID)

6/2018 Ethylene oxide OR dimethylene oxide OR 1?2-epoxyethane OR a?beta-oxidoethane OR 

oxirane* OR dihydrooxirene OR oxane OR epoxyethane OR oxacyclopropane OR 

ethene oxide OR amprolene OR anprolene OR anproline OR oxidoethane OR oxyfume 

OR aethylenoxid OR 1?2-epoxyaethan OR merpol OR oxiran OR T-Gas OR oxirene* 

OR ethyl?enoxide OR oxiraan OR epoxy ethane OR Ethylenoxid OR ethyleneoxy OR 

75-21-8.rn

AND

(ae OR to OR po OR pk OR bl OR bi OR ur OR me).fs OR (Health OR illness* OR injur* 

OR adverse OR exposure* OR poison* OR lung* OR respirat* OR thorax OR risk* OR 

endocrine OR hormone* OR metabol* OR genetic* OR gene expression OR antagonist* 

OR inhibitor* OR monitor* OR transcription* OR RNA OR DNA OR biosynthesis OR 

Polymerase Chain Reaction OR PCR OR cancer* OR neoplasm* OR toxic* OR pharma* 

OR inhale* OR inhalation OR gastrointestin* OR nausea OR vomit* OR eye* OR 

muscle* OR kidney* OR ureter OR bladder* OR liver* OR seizure* OR convulsion* OR 

skin OR derma*).ti,ab.

1989- ; English ; Abstracts available ; exclude Medline journals
ETHYLENE OXIDE B-4

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings 

Database

search date Query string

Scopus

6/2018 TITLE-ABS-KEY(“Ethylene oxide” OR “dimethylene oxide” OR 1?2-epoxyethane OR 

a?beta-oxidoethane OR oxirane* OR dihydrooxirene OR oxane OR epoxyethane OR 

oxacyclopropane OR “ethene oxide” OR amprolene OR anprolene OR anproline OR 

oxidoethane OR oxyfume OR aethylenoxid OR 1?2-epoxyaethan OR merpol OR oxiran 

OR T-Gas OR oxirene* OR ethyl?enoxide OR oxiraan OR “epoxy ethane” OR 

Ethylenoxid OR ethyleneoxy) OR CASREGNUMBER(75-21-8)

AND

TITLE-ABS-KEY(Health OR illness* OR injur* OR adverse OR exposure* OR poison* 

OR lung* OR respirat* OR thorax OR risk* OR endocrine OR hormone* OR metabol* OR 

genetic* OR “gene expression” OR antagonist* OR inhibitor* OR monitor* OR 

transcription* OR RNA OR DNA OR biosynthesis OR “Polymerase Chain Reaction” OR 

PCR OR cancer* OR neoplasm* OR toxic* OR pharma* OR inhale* OR inhalation OR 

gastrointestin* OR nausea OR vomit* OR eye* OR muscle* OR kidney* OR ureter OR 

bladder* OR liver* OR seizure* OR convulsion* OR skin OR derma*)

AND NOT INDEX(medline)

1989- ; English

Proquest – Agricultural and Environmental Science Database

6/2018 TI,AB(“Ethylene oxide” OR “dimethylene oxide” OR 1?2-epoxyethane OR a?betaoxidoethane OR oxirane* OR dihydrooxirene OR oxane OR epoxyethane OR 

oxacyclopropane OR “ethene oxide” OR amprolene OR anprolene OR anproline OR 

oxidoethane OR oxyfume OR aethylenoxid OR 1?2-epoxyaethan OR merpol OR oxiran 

OR T-Gas OR oxirene* OR ethyl?enoxide OR oxiraan OR “epoxy ethane” OR 

Ethylenoxid OR ethyleneoxy) OR RN(75-21-8)

AND

TI,AB(Health OR illness* OR injur* OR adverse OR exposure* OR poison* OR lung* OR 

respirat* OR thorax OR risk* OR endocrine OR hormone* OR metabol* OR genetic* OR 

“gene expression” OR antagonist* OR inhibitor* OR monitor* OR transcription* OR RNA 

OR DNA OR biosynthesis OR “Polymerase Chain Reaction” OR PCR OR cancer* OR 

neoplasm* OR toxic* OR pharma* OR inhale* OR inhalation OR gastrointestin* OR 

nausea OR vomit* OR eye* OR muscle* OR kidney* OR ureter OR bladder* OR liver* 

OR seizure* OR convulsion* OR skin OR derma*)

AND NOT INDEX(medline)

1989- ; English 

PubMed

2/2020 "ethylene oxide"[mh] AND 2018/06/01:3000[mhda]

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

OSH Reference Collection

6/2018 “Ethylene oxide” OR “dimethylene oxide” OR 1?2-epoxyethane OR a?beta-oxidoethane 

OR oxirane* OR dihydrooxirene OR oxane OR epoxyethane OR oxacyclopropane OR 

“ethene oxide” OR amprolene OR anprolene OR anproline OR oxidoethane OR oxyfume 

OR aethylenoxid OR 1?2-epoxyaethan OR merpol OR oxiran OR T-Gas OR oxirene* OR 

ethyl?enoxide OR oxiraan OR “epoxy ethane” OR Ethylenoxid OR ethyleneoxy
ETHYLENE OXIDE B-5

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

TSCATSa

10/2018 Compounds searched: 75-21-8

NIH RePORTER

2/2019 "Ethylene oxide" OR "dimethylene oxide" OR "1,2-epoxyethane" OR "alpha,betaoxidoethane" OR "oxirane" OR "oxiranes" OR "dihydrooxirene" OR "oxane" OR 

"epoxyethane" OR "oxacyclopropane" OR "ethene oxide" OR "amprolene" OR "anprolene" 

OR "anproline" OR "oxidoethane" OR "oxyfume" OR "aethylenoxid" OR "1,2-epoxyaethan" 

OR "merpol" OR "oxiran" OR "oxirene" OR "oxirenes" OR "ethyleenoxide" OR "oxiraan" 

OR "epoxy ethane" OR "Ethylenoxid" OR "ethyleneoxy" OR "75-21-8" (Advanced)

Search in: Projects AdminIC: All, Fiscal Year: Active Projects

Other Identified throughout the assessment process

aSeveral versions of the TSCATS database were searched, as needed, by CASRN including TSCATS1 via Toxline 

(no date limit), TSCATS2 via https://yosemite.epa.gov/oppts/epatscat8.nsf/ReportSearch?OpenForm (date restricted 

by EPA receipt date), and TSCATS via CDAT (date restricted by ‘Mail Received Date Range’), as well as google for 

recent TSCA submissions.

The 2018 results were: 

• Number of records identified from Medline, Embase, Scopus, Proquest - Agricultural and 

Environmental Science Database and PubMed (after duplicate removal): 4,410

• Number of records identified from other strategies: 189

• Total number of records to undergo literature screening: 4,598

B.1.2 Literature Screening 

A two-step process was used to screen the literature search to identify relevant studies on ethylene oxide: 

• Title and abstract screen

• Full text screen

Title and Abstract Screen. Within the reference library, titles and abstracts were screened manually for 

relevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to the 

second step of the literature screening process. Studies were excluded when the title and abstract clearly 

indicated that the study was not relevant to the toxicological profile. 

• Number of titles and abstracts screened: 4,598

• Number of studies considered relevant and moved to the next step: 428

Full Text Screen. The second step in the literature screening process was a full text review of individual 

studies considered relevant in the title and abstract screen step. Each study was reviewed to determine 

whether it was relevant for inclusion in the toxicological profile. 

• Number of studies undergoing full text review: 428

• Number of studies cited in the pre-public draft of the toxicological profile: 111

• Total number of studies cited in the profile: 356

A summary of the results of the literature search and screening is presented in Figure B-1.
ETHYLENE OXIDE B-6

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Figure B-1. June 2018 Literature Search Results and Screen for Ethylene Oxide
ETHYLENE OXIDE C-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF 

HEALTH EFFECTS DATA FOR ETHYLENE OXIDE

To increase the transparency of ATSDR’s process of identifying, evaluating, synthesizing, and 

interpreting the scientific evidence on the health effects associated with exposure to ethylene oxide, 

ATSDR utilized a slight modification of NTP’s Office of Health Assessment and Translation (OHAT) 

systematic review methodology (NTP 2013, 2015; Rooney et al. 2014). ATSDR’s framework is an eightstep process for systematic review with the goal of identifying the potential health hazards of exposure to 

ethylene oxide:

• Step 1. Problem Formulation

• Step 2. Literature Search and Screen for Health Effects Studies

• Step 3. Extract Data from Health Effects Studies

• Step 4. Identify Potential Health Effect Outcomes of Concern

• Step 5. Assess the Risk of Bias for Individual Studies

• Step 6. Rate the Confidence in the Body of Evidence for Each Relevant Outcome

• Step 7. Translate Confidence Rating into Level of Evidence of Health Effects

• Step 8. Integrate Evidence to Develop Hazard Identification Conclusions

C.1 PROBLEM FORMULATION

The objective of the toxicological profile and this systematic review was to identify the potential health 

hazards associated with inhalation, oral, or dermal/ocular exposure to ethylene oxide. The inclusion 

criteria used to identify relevant studies examining the health effects of ethylene oxide are presented in 

Table C-1. 

Data from human and laboratory animal studies were considered relevant for addressing this objective. 

Human studies were divided into two broad categories: observational epidemiology studies and 

controlled exposure studies. The observational epidemiology studies were further divided: cohort studies 

(retrospective and prospective studies), population studies (with individual data or aggregate data), and 

case-control studies.

Table C-1. Inclusion Criteria for Identifying Health Effects Studies

Species

Human

Laboratory mammals

Route of exposure

Inhalation

Oral

Dermal (or ocular)

Parenteral (these studies will be considered supporting data)

Health outcome

Death

Systemic effects

Body weight effects 

Respiratory effects
ETHYLENE OXIDE C-2

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-1. Inclusion Criteria for Identifying Health Effects Studies

Cardiovascular effects

Gastrointestinal effects

Hematological effects

Musculoskeletal effects

Hepatic effects

Renal effects

Dermal effects

Ocular effects

Endocrine effects

Immunological effects

Neurological effects

Reproductive effects

Developmental effects

Other noncancer effects

Cancer

C.2 LITERATURE SEARCH AND SCREEN FOR HEALTH EFFECTS STUDIES

A literature search and screen was conducted to identify studies examining the health effects of ethylene 

oxide. The literature search framework for the toxicological profile is discussed in detail in Appendix B.

C.2.1 Literature Search

As noted in Appendix B, the current literature search to update the 1990 toxicological profile for ethylene 

oxide; thus, the literature search was restricted to studies published between 1989 and 2018. See 

Appendix B for the databases searched and the search strategy.

A total of 4,598 records relevant to all sections of the toxicological profile were identified (after duplicate 

removal).

C.2.2 Literature Screening

As described in Appendix B, a two-step process was used to screen the literature search to identify 

relevant studies examining the health effects of ethylene oxide.

Title and Abstract Screen. In the Title and Abstract Screen step, 4,598 records were reviewed; 

58 documents were considered to meet the health effects inclusion criteria in Table C-1 and were moved 

to the next step in the process. 

Full Text Screen. In the second step in the literature screening process for the systematic review, a full 

text review of 88 health effect documents (documents identified in the update literature search and 

documents cited in older versions of the profile) was performed. From those 88 documents, 127 studies 

were included in the qualitative review.
ETHYLENE OXIDE C-3

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

C.3 EXTRACT DATA FROM HEALTH EFFECTS STUDIES

Relevant data extracted from the individual studies selected for inclusion in the systematic review were 

collected in customized data forms. A summary of the type of data extracted from each study is presented 

in Table C-2. For references that included more than one experiment or species, data extraction records 

were created for each experiment or species. 

Table C-2. Data Extracted From Individual Studies

Citation

Chemical form

Route of exposure (e.g., inhalation, oral, dermal)

Specific route (e.g., gavage in oil, drinking water)

Species

Strain

Exposure duration category (e.g., acute, intermediate, chronic)

Exposure duration

Frequency of exposure (e.g., 6 hours/day, 5 days/week)

Exposure length

Number of animals or subjects per sex per group 

Dose/exposure levels

Parameters monitored

Description of the study design and method

Summary of calculations used to estimate doses (if applicable)

Summary of the study results

Reviewer’s comments on the study

Outcome summary (one entry for each examined outcome)

No-observed-adverse-effect level (NOAEL) value

Lowest-observed-adverse-effect level (LOAEL) value

Effect observed at the LOAEL value

A summary of the extracted data for each study is presented in the Supplemental Document for Ethylene 

Oxide and overviews of the results of the inhalation, oral, and dermal exposure studies are presented in 

Sections 2.2–2.18 of the profile; results from inhalation and oral exposure studies are presented in the 

Levels Significant Exposures tables in Section 2.1 of the profile (Tables 2-1 and 2-2, respectively).

C.4 IDENTIFY POTENTIAL HEALTH EFFECT OUTCOMES OF CONCERN 

Overviews of the potential health effect outcomes for ethylene oxide identified in human and animal 

studies are presented in Tables C-3 and C-4, respectively. A number of occupational cohorts were 

evaluated for possible associations between ethylene oxide and risk of death from selected noncancer 

endpoints. The noncancer endpoints from occupational studies are summarized in inhalation exposure 

sections below because inhalation was the assumed major exposure route; exposure duration was 

considered chronic, although shorter exposure durations may have been involved as well. Animal studies 

examined a number of endpoints following inhalation exposure. These studies examined most endpoints; 

the most sensitive endpoints were hematological, endocrine (adrenal gland), and neurological effects.
ETHYLENE OXIDE C-4 

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-3. Overview of the Health Outcomes Ethylene Oxide Evaluated In Human Studies Body weight Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Dermal Ocular Endocrine Immunological Neurological Reproductive Developmental

Other NoncancerCaner

Inhalation studies

Cohort 9 10 4 1 1 1 7 4 12 4 23

2 0 0 0 0 0 7 4 10 4 13

Case control

Population

Case series 13

13

Oral studies

Cohort

Case control

Population

Case series

Dermal studies

Cohort

Case control

Population

Case series

Number of studies examining endpoint 0 1 2 3 4 5-9 ≥10

Number of studies reporting outcome 0 1 2 3 4 5-9 ≥10
ETHYLENE OXIDE C-5 

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-4. Overview of the Health Outcomes for Ethylene Oxide Evaluated in Experimental Animal Studies Body weight Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Dermal Ocular Endocrine Immunologicala Neurologicala Reproductivea Developmental Other Noncancer Caner

Inhalation studies

Acute-duration 9 6 2 2 1 2 1 1 8

5 6 2 2 1 2 1 1 6

Intermediate-duration 26 14 1 4 13 3 1 1 1 19 8 3 1

9 6 0 4 6 0 0 0 0 13 7 2 1

Chronic-duration 3 2 3 2 2 2 2 2 1 1 2 3 3 3

2 1 0 0 1 1 0 0 0 0 1 1 1 3

Oral studies

Acute-duration 1

0

Intermediate-duration 1 1 1 1

1 1 0 1

Chronic-duration 1

1

Dermal studies

Acute-duration 1

1

Intermediate-duration

Chronic-duration 1

0

Number of studies examining endpoint 0 1 2 3 4 5-9 ≥10

Number of studies reporting outcome 0 1 2 3 4 5-9 ≥10

aNumber of studies examining endpoint includes study evaluating histopathology, but not evaluating function.
ETHYLENE OXIDE C-6

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Studies examining these potential outcomes (as well as respiratory, reproductive, and developmental 

outcomes) were carried through to Steps 4–8 of the systematic review. Oral data were not available for 

humans. Animal data were limited to results from a solitary study with limited study details. Gavage 

dosing of rats at 30 mg/kg/day, 2 times/week for up to 150 weeks resulted in decreased survival; 

forestomach squamous cell carcinoma was reported at 7.5 mg/kg/day (Dunkelberg 1982). This study was 

not subjected to systematic review because it could not be used as basis for deriving a provisional 

chronic-duration oral MRL for ethylene oxide. There were 127 studies (published in 88 documents) 

examining these potential outcomes carried through to Steps 4–8 of the systematic review.

C.5 ASSESS THE RISK OF BIAS FOR INDIVIDUAL STUDIES

C.5.1 Risk of Bias Assessment

The risk of bias of individual studies was assessed using OHAT’s Risk of Bias Tool (NTP 2015). The 

risk of bias questions for observational epidemiology studies and animal experimental studies are 

presented in Tables C-5 and C-6, respectively. Each risk of bias question was answered on a four-point

scale:

• Definitely low risk of bias (++)

• Probably low risk of bias (+)

• Probably high risk of bias (-)

• Definitely high risk of bias (– –)

In general, “definitely low risk of bias” or “definitely high risk of bias” were used if the question could be 

answered with information explicitly stated in the study report. If the response to the question could be 

inferred, then “probably low risk of bias” or “probably high risk of bias” responses were typically used. 

Table C-5. Risk of Bias Questionnaire for Observational Epidemiology Studies

Selection bias

Were the comparison groups appropriate?

Confounding bias

Did the study design or analysis account for important confounding and modifying variables?

Attrition/exclusion bias

Were outcome data complete without attrition or exclusion from analysis?

Detection bias

Is there confidence in the exposure characterization?

Is there confidence in outcome assessment?

Selective reporting bias

Were all measured outcomes reported?
ETHYLENE OXIDE C-7

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-6. Risk of Bias Questionnaire for Experimental Animal Studies

Selection bias

Was administered dose or exposure level adequately randomized?

Was the allocation to study groups adequately concealed?

Performance bias

Were experimental conditions identical across study groups?

Were the research personnel blinded to the study group during the study?

Attrition/exclusion bias

Were outcome data complete without attrition or exclusion from analysis?

Detection bias

Is there confidence in the exposure characterization?

Is there confidence in outcome assessment?

Selective reporting bias

Were all measured outcomes reported? 

After the risk of bias questionnaires were completed for the health effects studies, the studies were 

assigned to one of three risk of bias tiers based on the responses to the key questions listed below and the 

responses to the remaining questions. 

• Is there confidence in the exposure characterization? (only relevant for observational studies)

• Is there confidence in the outcome assessment? 

• Does the study design or analysis account for important confounding and modifying variables? 

(only relevant for observational studies)

First Tier. Studies placed in the first tier received ratings of “definitely low” or “probably low” risk of 

bias on the key questions AND received a rating of “definitely low” or “probably low” risk of bias on the 

responses to at least 50% of the other applicable questions.

Second Tier. A study was placed in the second tier if it did not meet the criteria for the first or third tiers.

Third Tier. Studies placed in the third tier received ratings of “definitely high” or “probably high” risk of 

bias for the key questions AND received a rating of “definitely high” or “probably high” risk of bias on 

the response to at least 50% of the other applicable questions.

The results of the risk of bias assessment for the different types of ethylene oxide health effects studies 

(observational epidemiology and animal experimental studies) are presented in Tables C-7 and C-8, 

respectively.
ETHYLENE OXIDE C-8

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-7. Summary of Risk of Bias Assessment for Ethylene Oxide—Observational Epidemiology Studies

Reference

Risk of bias criteria and ratings

Selection bias

Confounding 

bias

Attrition / 

exclusion bias Detection bias

Selective 

reporting bias

Comparison groups appropriate?Study design or analysis account for important confoundingand modifying variables?*Outcome data complete without attrition or exclusion from analysis?Confidence in the exposure characterization?*Confidence in the Risk of bias tier

outcome 

assessment?*All measured outcomes reported?

Outcome: Respiratory effects

Cohort

Bisanti et al. 1993 + – + na – + Second

Coggon et al. 2004 + – + na – + Second

Hogstedt 1988 + – + na – + Second

Morgan et al. 1981 + – + na – + Second

Steenland et al. 1991 + – + na – + Second

Swaen et al. 2009 + – + na – + Second

Wong and Trent 1993 + – + na – + Second

Case series

Deschamps et al. 1992 + – + na – + Second

Theiss 1963 + – + na – + Second

Outcome: Neurological effects

Case series

Blackwood and Erskine 1938 + – + na – + Second

Brashear et al. 1996 + – + na – + Second

Crystal et al. 1988 + – + na – + Second

Dretchen et al. 1992 + – + na – + Second

Estrin et al. 1987 + – + na – + Second

Finelli et al. 1983 + – + na – + Second
ETHYLENE OXIDE C-9

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-7. Summary of Risk of Bias Assessment for Ethylene Oxide—Observational Epidemiology Studies

Reference

Risk of bias criteria and ratings

Selection bias

Confounding 

bias

Attrition / 

exclusion bias Detection bias

Selective 

reporting bias

Comparison groups appropriate?Study design or analysis account for important confoundingand modifying variables?*Outcome data complete without attrition or exclusion from analysis?Confidence in the exposure characterization?*Confidence in the Risk of bias tier

outcome 

assessment?*All measured outcomes reported?

Gross et al. 1979 + – + na – + Second

Kuzuhara et al. 1983 + – + na – + Second

Salinas et al. 1981 + – + na – + Second

Schröder et al. 1985 + – + na – + Second

Sexton and Henson 1949 + – + na – + Second

Von Oettingen 1939 + – + na – + Second

Zampollo et al. 1984 + – + na – + Second

Outcome: Reproductive effects

Cohort

Abrahams 1980 + – + na – + Second

Gresie-Brusin et al. 2007 + – + na – + Second

Hemminki et al. 1982 + – + na – + Second

Rowland et al. 1996 + – + na – + Second

++ = definitely low risk of bias; + = probably low risk of bias; – = probably high risk of bias; – – = definitely high risk of bias; na = not applicable
ETHYLENE OXIDE C-10

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-8. Summary of Risk of Bias Assessment for Ethylene Oxide—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion 

bias Detection bias

Selective 

reporting 

bias Other bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in the exposure characterization?Confidence in the outcome assessment?*All measured outcomes reported?Study design or analysis account for important confounding and modifying variables?Risk of bias tier

Outcome: Respiratory effects

Inhalation acute exposure

Hollingsworth et al. 1956 (rat, 841 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (rat, 357 ppm) + + + + + + + + + First

NIOSH 1982 (rat) + + + + + + + + + First

NIOSH 1982 (rabbit) + + + + + + + + + First

NTP 1987 (mouse, 4-hour) + + + + + + + + + First

NTP 1987 (mouse, 2-week) + + + + + + + + + First

Inhalation intermediate exposure

EPA 1994 (rat) ++ + + + + + + + + First

Hollingsworth et al. 1956 (rat, 113 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (mouse, 113 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (monkey, 113 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (guinea pig, 113 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (rat, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (mouse, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (rabbit, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (monkey, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (guinea pig, 204 ppm) + + + + + + + + + First

Jacobson et al. 1956 (rat, 406 ppm) + + + + + + + + + First

Jacobson et al. 1956 (rat, 102 ppm) + + + + + + + + + First

Jacobson et al. 1956 (dog, 292 ppm) + + + + + + + + + First

NIOSH 1982 (rat, GDs 1–16) + + + + + + + + + First
ETHYLENE OXIDE C-11

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-8. Summary of Risk of Bias Assessment for Ethylene Oxide—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion 

bias Detection bias

Selective 

reporting 

bias Other bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in the exposure characterization?Confidence in the outcome assessment?*All measured outcomes reported?Study design or analysis account for important confounding and modifying variables?Risk of bias tier

NIOSH 1982 (rat, 3 weeks premating and 

GDs 1–16)

+ + + + + + + + +

First

NIOSH 1982 (rabbit, GDs 1–19) + + + + + + + + + First

NTP 1987 (mouse, 14-week) + + + + + + + + + First

Inhalation chronic exposure

Lynch et al. 1984b (rat, 2-year) + + + + + + + + + First

NTP 1987 (mouse, 102-week) + + + + + + + + + First

Outcome: Hematological effects

Inhalation intermediate exposure

Fujishiro et al. 1990 (rat, 500 ppm) + + + + + + + + + First

Jacobson et al. 1956 (rat, 102 ppm) + + + + + + + + + First

Jacobson et al. 1956 (dog, 292 ppm) + + + + + + + + + First

Snellings et al. 1984a (mouse, 11-week) ++ + + + + + + + + First

Inhalation chronic exposure

Lynch et al. 1984a (monkey, 2-year) + + + + + + + + + First

Lynch et al. 1984b (rat, 2-year) + + + + + + + + + First

Outcome: Endocrine effects

Inhalation acute exposure

Hollingsworth et al. 1956 (rat, 841 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (guinea pig 841 ppm) + + + + + + + + + First

Inhalation chronic exposure

Lynch et al. 1984b (rat, 2-year) + + + + + + + + + First

NTP 1987 (mouse, 102-week) + + + + + + + + + First
ETHYLENE OXIDE C-12

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-8. Summary of Risk of Bias Assessment for Ethylene Oxide—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion 

bias Detection bias

Selective 

reporting 

bias Other bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in the exposure characterization?Confidence in the outcome assessment?*All measured outcomes reported?Study design or analysis account for important confounding and modifying variables?Risk of bias tier

Outcome: Neurological effects

Inhalation acute exposure

NTP 1987 (mouse, 4-hour) + + + + + + + + + First

Inhalation intermediate exposure

EPA 1994 (rat) ++ + + + + + + + + First

Hollingsworth et al. 1956 (monkey, 357 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (rat, 357 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (mouse, 357 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (rabbit, 357 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (monkey, 357 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (rat, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (mouse, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (rabbit, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (monkey, 204 ppm) + + + + + + + + + First

Hollingsworth et al. 1956 (guinea pig, 204 ppm) + + + + + + + + + First

Jacobson et al. 1956 (rat, 406 ppm) + + + + + + + + + First

Jacobson et al. 1956 (rat, 102 ppm) + + + + + + + + + First

Jacobson et al. 1956 (dog, 292 ppm) + + + + + + + + + First

Kaido et al. 1992 (rat, 500 ppm) ++ + + + + + + + + First

Matsuoka et al. 1990 (rat, 500 ppm) + + + + + + + + + First

Ohnishi et al. 1985 (rat, 13-week) + + + + + + + + + First

Ohnishi et al. 1986 (rat, 9-month) + + + + + + + + + First

Snellings et al. 1984a (mouse, 11-week) ++ + + + + + + + + First
ETHYLENE OXIDE C-13

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-8. Summary of Risk of Bias Assessment for Ethylene Oxide—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion 

bias Detection bias

Selective 

reporting 

bias Other bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in the exposure characterization?Confidence in the outcome assessment?*All measured outcomes reported?Study design or analysis account for important confounding and modifying variables?Risk of bias tier

Inhalation chronic exposure

Lynch et al. 1984a (monkey, 2-year) + + + + + + + + + First

Lynch et al. 1984b (rat, 2-year) + + + + + + + + + First

NTP 1987 (mouse, 102-week) + + + + + + + + + First

Outcome: Reproductive effects

Inhalation intermediate exposure

EPA 1994 (rat) ++ + + + + + + + + First

Kaido et al. 1992 (rat, 13-week) ++ + + + + + + + + First

Mori et al. 1991a (rat, 13-week) + + + + + + + + + First

Mori et al. 1991b (rat, 6-week) + + + + + + + + + First

NIOSH 1982 (rat, GDs 1–16) + + + + + + + + + First

NIOSH 1982 (rat, 3 weeks premating and 

GDs 1–16)

+ + + + + + + + +

First

NIOSH 1982 (rabbit, GDs 1–19) + + + + + + + + + First

Snellings et al. 1982b (rat, 12-week) ++ + + + + + + + + First

Snellings et al. 1984a (mouse, 11-week) ++ + + + + + + + + First

Inhalation chronic exposure

Lynch et al. 1984a (monkey, 2-year) + + + + + + + + + First

Lynch et al. 1984b (rat, 2-year) + + + + + + + + + First

NTP 1987 (mouse, 102-week) + + + + + + + + + First

Outcome: Developmental effects

Inhalation acute exposure

Neeper-Bradley and Kubena 1993 (rat) + + + + + + + + + First
ETHYLENE OXIDE C-14

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-8. Summary of Risk of Bias Assessment for Ethylene Oxide—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion 

bias Detection bias

Selective 

reporting 

bias Other bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in the exposure characterization?Confidence in the outcome assessment?*All measured outcomes reported?Study design or analysis account for important confounding and modifying variables?Risk of bias tier

NIOSH 1982 (rat) + + + + + + + + + First

NIOSH 1982 (rabbit) + + + + + + + + + First

Rutledge and Generoso 1989 (mouse) + + + + + + + + + First

Saillenfait et al. 1996 (rat, 400–1,200 ppm) + + + + + + + + + First

Saillenfait et al. 1996 (rat, 200 or 400 ppm) + + + + + + + + + First

Saillenfait et al. 1996 (rat, 800 or 1,200 ppm) + + + + + + + + + First

Snellings et al. 1982a (rat, 10–100 ppm) ++ + + + + + + + + First

Inhalation intermediate exposure

EPA 1994 (rat) ++ + + + + + + + + First

NIOSH 1982 (rat, GDs 1–16) + + + + + + + + + First

NIOSH 1982 (rat, 3 weeks premating and 

GDs 1–16)

+ + + + + + + + +

First

NIOSH 1982 (rabbit, GD 1–19) + + + + + + + + + First

Snellings et al. 1982b (rat, 12-week) ++ + + + + + + + + First

++ = definitely low risk of bias; + = probably low risk of bias; – = probably high risk of bias; – – = definitely high risk of bias; na = not applicable

*Key question used to assign risk of bias tier
ETHYLENE OXIDE C-15

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

C.6 RATE THE CONFIDENCE IN THE BODY OF EVIDENCE FOR EACH RELEVANT 

OUTCOME

Confidences in the bodies of human and animal evidence were evaluated independently for each potential 

outcome. ATSDR did not evaluate the confidence in the body of evidence for carcinogenicity; rather, the 

Agency defaulted to the cancer weight-of-evidence assessment of other agencies including DHHS, EPA, 

and IARC. The confidence in the body of evidence for an association or no association between exposure 

to ethylene oxide and a particular outcome was based on the strengths and weaknesses of individual 

studies. Four descriptors were used to describe the confidence in the body of evidence for effects or when 

no effect was found:

• High confidence: the true effect is highly likely to be reflected in the apparent relationship

• Moderate confidence: the true effect may be reflected in the apparent relationship

• Low confidence: the true effect may be different from the apparent relationship

• Very low confidence: the true effect is highly likely to be different from the apparent 

relationship

Confidence in the body of evidence for a particular outcome was rated for each type of study: casecontrol, case series, cohort, population, and experimental animal. In the absence of data to the contrary, 

data for a particular outcome were collapsed across animal species, routes of exposure, and exposure 

durations. If species (or strain), route, or exposure duration differences were noted, then the data were 

treated as separate outcomes.

C.6.1 Initial Confidence Rating

In ATSDR’s modification to the OHAT approach, the body of evidence for an association (or no 

association) between exposure to ethylene oxide and a particular outcome was given an initial confidence 

rating based on the key features of the individual studies examining that outcome. The presence of these 

key features of study design was determined for individual studies using four “yes or no” questions, 

which were customized for epidemiology or experimental animal study designs. Separate questionnaires 

were completed for each outcome assessed in a study. The key features for observational epidemiology 

(cohort, population, and case-control) studies and experimental animal studies are presented in Tables C-9

and C-10, respectively. The initial confidence in the study was determined based on the number of key 

features present in the study design: 

• High Initial Confidence: Studies in which the responses to the four questions were “yes”. 

• Moderate Initial Confidence: Studies in which the responses to only three of the questions 

were “yes”. 

• Low Initial Confidence: Studies in which the responses to only two of the questions were “yes”. 

• Very Low Initial Confidence: Studies in which the response to one or none of the questions 

was “yes”. 
ETHYLENE OXIDE C-16

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-9. Key Features of Study Design for Observational Epidemiology 

Studies

Exposure was experimentally controlled 

Exposure occurred prior to the outcome

Outcome was assessed on individual level rather than at the population level

A comparison group was used

Table C-10. Key Features of Study Design for Experimental Animal Studies

A concurrent control group was used

A sufficient number of animals per group were tested

Appropriate parameters were used to assess a potential adverse effect

Appropriate statistical analyses were performed and reported or the data were reported in such a way to 

allow independent statistical analysis

The presence or absence of the key features and the initial confidence levels for studies examining body 

weight effects, respiratory effects, reproductive effects, and developmental effects observed in the 

observational epidemiology and animal experimental studies are presented in Tables C-11 and C-12, 

respectively.

Table C-11. Presence of Key Features of Study Design for Ethylene Oxide—

Observational Epidemiology Studies

Key features 

Reference

Controlled exposureExposure prior to outcomeOutcomes assessed on an individual level Comparison group

Initial study 

confidence

Outcome: Respiratory effects

Cohort

Bisanti et al. 1993 No Yes Yes Yes Moderate

Coggon et al. 2004 No Yes Yes Yes Moderate

Hogstedt 1988 No Yes Yes Yes Moderate

Morgan et al. 1981 No Yes Yes Yes Moderate

Steenland et al. 1991 No Yes Yes Yes Moderate

Swaen et al. 2009 No Yes Yes Yes Moderate

Wong and Trent 1993 No Yes Yes Yes Moderate

Case series

Deschamps et al. 1992 No No Yes Yes Low

Theiss 1963 No No Yes Yes Low
ETHYLENE OXIDE C-17

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-11. Presence of Key Features of Study Design for Ethylene Oxide—

Observational Epidemiology Studies

Key features 

Reference

Controlled exposureExposure prior to outcomeOutcomes assessed on an individual level Comparison group

Initial study 

confidence

Outcome: Neurological effects

Case series

Blackwood and Erskine 1938 No No Yes No Very low

Brashear et al. 1996 No No Yes No Very low

Crystal et al. 1988 No No Yes No Very low

Dretchen et al. 1992 No No Yes No Very low

Estrin et al. 1987 No No Yes No Very low

Finelli et al. 1983 No No Yes No Very low

Gross et al. 1979 No No Yes No Very low

Kuzuhara et al. 1983 No No Yes No Very low

Salinas et al. 1981 No No Yes No Very low

Schröder et al. 1985 No No Yes No Very low

Sexton and Henson 1949 No No Yes No Very low

Von Oettingen 1939 No No Yes No Very low

Zampollo et al. 1984 No No Yes No Very low

Outcome: Reproductive effects

Cohort

Abrahams 1980 No Yes Yes Yes Moderate

Gresie-Brusin et al. 2007 No Yes Yes Yes Moderate

Hemminki et al. 1982 No Yes Yes Yes Moderate

Rowland et al. 1996 No Yes Yes Yes Moderate
ETHYLENE OXIDE C-18

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-12. Presence of Key Features of Study Design for Ethylene Oxide—

Experimental Animal Studies

Key feature

Reference

Concurrent control groupSufficient number of animals per groupAppropriate parameters to assess potential effectAdequate data for statistical analysis

Initial study 

confidence

Outcome: Respiratory effects

Inhalation acute exposure

Hollingsworth et al. 1956 (rat, 841 ppm) Yes Yes No No Low

Hollingsworth et al. 1956 (rat, 357 ppm) Yes Yes No No Low

NIOSH 1982 (rat) Yes Yes No No Low

NIOSH 1982 (rabbit) Yes Yes No No Low

NTP 1987 (mouse, 4-hour) No No Yes No Very low

NTP 1987 (mouse, 2-week) Yes Yes Yes No Moderate

Inhalation intermediate exposure

EPA 1994 (rat) Yes Yes Yes No Moderate

Hollingsworth et al. 1956 (4 species, 113 ppm) Yes No No No Very low

Hollingsworth et al. 1956 (5 species, 204 ppm) Yes No No No Very low

Jacobson et al. 1956 (rat, 406 ppm) Yes No No No Very low

Jacobson et al. 1956 (rat, 102 ppm) Yes No No No Very low

Jacobson et al. 1956 (dog, 292 ppm) Yes No No No Very low

NIOSH 1982 (rat, GDs 1–16) Yes Yes No No Low

NIOSH 1982 (rat, 3 weeks premating and 

GDs 1–16)

Yes Yes No No Low

NIOSH 1982 (rabbit, GDs 1–19) Yes Yes No No Low

NTP 1987 (mouse, 14-week) Yes Yes Yes Yes High

Inhalation chronic exposure

Lynch et al. 1984b (rat, 2-year) Yes Yes Yes No Moderate

NTP 1987 (mouse, 102-week) Yes Yes Yes Yes High

Outcome: Hematological effects

Inhalation intermediate exposure

Fujishiro et al. 1990 (rat, 500 ppm) Yes Yes Yes No Moderate

Jacobson et al. 1956 (rat, 102 ppm) Yes Yes No No Low

Jacobson et al. 1956 (dog, 292 ppm) Yes No No No Very low

Snellings et al. 1984a (mouse, 11-week) Yes Yes Yes No Moderate

Inhalation chronic exposure

Lynch et al. 1984a (monkey, 2-year) Yes Yes Yes No Moderate

Lynch et al. 1984b (rat, 2-year) Yes Yes Yes No Moderate
ETHYLENE OXIDE C-19

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-12. Presence of Key Features of Study Design for Ethylene Oxide—

Experimental Animal Studies

Key feature

Reference

Concurrent control groupSufficient number of animals per groupAppropriate parameters to assess potential effectAdequate data for statistical analysis

Initial study 

confidence

Outcome: Endocrine effects

Inhalation acute exposure

Hollingsworth et al. 1956 (2 species, 841 ppm) Yes Yes No No Low

Inhalation chronic exposure

Lynch et al. 1984b (rat, 2-year) Yes Yes Yes No Moderate

NTP 1987 (mouse, 102-week) Yes Yes Yes Yes High

Outcome: Neurological effects

Inhalation acute exposure

NTP 1987 (mouse, 4-hour) No No Yes No Very low

Inhalation intermediate exposure

EPA 1994 (rat) Yes Yes No No Low

Hollingsworth et al. 1956 (monkey, 357 ppm) Yes No No No Very low

Hollingsworth et al. 1956 (4 species, 357 ppm) Yes No No No Very low

Hollingsworth et al. 1956 (5 species 204 ppm) Yes No No No Very low

Jacobson et al. 1956 (rat, 406 ppm) Yes No No No Very low

Jacobson et al. 1956 (rat, 102 ppm) Yes No No No Very low

Jacobson et al. 1956 (dog, 292 ppm) Yes No No No Very low

Kaido et al. 1992 (rat, 500 ppm) Yes No Yes No Low

Matsuoka et al. 1990 (rat, 500 ppm) Yes Yes No No Low

Ohnishi et al. 1985 (rat, 13-week) Yes No Yes Yes Moderate

Ohnishi et al. 1986 (rat, 9-month) Yes No Yes Yes Moderate

Snellings et al. 1984a (mouse, 11-week) Yes Yes Yes No Moderate

Inhalation chronic exposure

Lynch et al. 1984a (monkey, 2-year) Yes Yes Yes No Moderate

Lynch et al. 1984b (rat, 2-year) Yes Yes Yes No Moderate

NTP 1987 (mouse, 102-week) Yes Yes Yes Yes High

Outcome: Reproductive effects

Inhalation intermediate exposure

EPA 1994 (rat) Yes Yes Yes No Moderate

Kaido et al. 1992 (rat, 13-week) Yes No Yes No Low

Mori et al. 1991a (rat, 13-week) Yes No Yes Yes Moderate

Mori et al. 1991b (rat, 6-week) Yes Yes Yes Yes High

NIOSH 1982 (rat, GDs 1–16) Yes Yes No No Low
ETHYLENE OXIDE C-20

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-12. Presence of Key Features of Study Design for Ethylene Oxide—

Experimental Animal Studies

Key feature

Reference

Concurrent control groupSufficient number of animals per groupAppropriate parameters to assess potential effectAdequate data for statistical analysis

Initial study 

confidence

NIOSH 1982 (rat, 3 weeks premating and 

GDs 1–16)

Yes Yes No No Low

NIOSH 1982 (rabbit, GDs 1–19) Yes Yes No No Low

Snellings et al. 1982b (rat, 1-generation) Yes Yes Yes No Moderate

Snellings et al. 1984a (mouse, 11-week) Yes Yes Yes No Moderate

Inhalation chronic exposure

Lynch et al. 1984a (monkey, 2-year) Yes Yes Yes No Moderate

Lynch et al. 1984b (rat, 2-year) Yes Yes Yes No Moderate

NTP 1987 (mouse, 102-week) Yes Yes Yes Yes High

Outcome: Developmental effects

Inhalation acute exposure

Neeper-Bradley and Kubena 1993 (rat) Yes Yes Yes Yes High

NIOSH 1982 (rat) Yes Yes No No Low

NIOSH 1982 (rabbit) Yes Yes No No Low

Rutledge and Generoso 1989 (mouse) Yes Yes Yes No Moderate

Saillenfait et al. 1996 (rat, 400–1,200 ppm) Yes Yes Yes Yes High

Saillenfait et al. 1996 (rat, 200 or 400 ppm) Yes Yes Yes Yes High

Saillenfait et al. 1996 (rat, 800 or 1,200 ppm) Yes Yes Yes Yes High

Snellings et al. 1982a (rat, 10–100 ppm) Yes Yes Yes Yes High

Inhalation intermediate exposure

EPA 1994 (rat) Yes Yes Yes No Moderate

NIOSH 1982 (rat, GDs 1–16) Yes Yes No No Low

NIOSH 1982 (rat, 3 weeks premating and 

GDs 1–16) Yes Yes No No Low

NIOSH 1982 (rabbit, GDs 1–19) Yes Yes No No Low

Snellings et al. 1982b (rat, 1-generation) Yes Yes Yes Yes High

A summary of the initial confidence ratings for each outcome is presented in Table C-13. If individual 

studies for a particular outcome and study type had different study quality ratings, then the highest 

confidence rating for the group of studies was used to determine the initial confidence rating for the body 

of evidence; any exceptions were noted in Table C-13.
ETHYLENE OXIDE C-21

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-13. Initial Confidence Rating for Ethylene Oxide Health Effects Studies

Initial study 

confidence

Initial confidence 

rating

Outcome: Respiratory effects

Inhalation acute exposure

Animal studies

Hollingsworth et al. 1956 (rat, 841 ppm) Low

Moderate

Hollingsworth et al. 1956 (rat, 357 ppm) Low

NIOSH 1982 (rat) Low

NIOSH 1982 (rabbit) Low

NTP 1987 (mouse, 4-hour) Very low

NTP 1987 (mouse, 2-week) Moderate

Inhalation intermediate exposure

Animal studies

EPA 1994 (rat) Moderate

High

Hollingsworth et al. 1956 (4 species, 113 ppm) Very low

Hollingsworth et al. 1956 (5 species, 204 ppm) Very low

Jacobson et al. 1956 (rat, 406 ppm) Very low

Jacobson et al. 1956 (rat, 102 ppm) Very low

Jacobson et al. 1956 (dog, 292 ppm) Very low

NIOSH 1982 (rat, GDs 1–16) Low

NIOSH 1982 (rat, 3 weeks premating and GDs 1–16) Low

NIOSH 1982 (rabbit, GDs 1–19) Low

NTP 1987 (mouse, 14-week) High

Inhalation chronic exposure

Human studies (cohort)

Bisanti et al. 1993 Moderate

Moderate

Coggon et al. 2004 Moderate

Hogstedt 1988 Moderate

Morgan et al. 1981 Moderate

Steenland et al. 1991 Moderate

Swaen et al. 2009 Moderate

Wong and Trent 1993 Moderate

Human studies (case series)

Deschamps et al. 1992 Moderate

Moderate

Theiss 1963 Moderate

Animal studies

Lynch et al. 1984b (rat, 2-year) Moderate

High NTP 1987 (mouse, 102-week) High

Outcome: Hematological effects

Inhalation intermediate exposure

Animal studies

Fujishiro et al. 1990 (rat, 500 ppm) Moderate

Moderate Jacobson et al. 1956 (rat, 102 ppm) Low

Jacobson et al. 1956 (dog, 292 ppm) Very low

Snellings et al. 1984a (mouse, 11-week) Moderate
ETHYLENE OXIDE C-22

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-13. Initial Confidence Rating for Ethylene Oxide Health Effects Studies

Initial study 

confidence

Initial confidence 

rating

Inhalation chronic exposure

Animal studies

Lynch et al. 1984a (monkey, 2-year) Moderate

Moderate

Lynch et al. 1984b (rat, 2-year) Moderate

Outcome: Endocrine effects

Inhalation acute exposure

Animal studies

Hollingsworth et al. 1956 (2 species, 841 ppm) Low Low

Inhalation chronic exposure

Animal studies

Lynch et al. 1984b (rat, 2-year) Moderate

High NTP 1987 (mouse, 102-week) High

Outcome: Neurological effects

Inhalation acute exposure

Animal studies

NTP 1987 (mouse, 4-hour) Very low Very low

Inhalation intermediate exposure

Animal studies

EPA 1994 (rat) Low

Moderate

Hollingsworth et al. 1956 (monkey, 357 ppm) Very low

Hollingsworth et al. 1956 (4 species, 357 ppm) Very low

Hollingsworth et al. 1956 (5 species 204 ppm) Very low

Jacobson et al. 1956 (rat, 406 ppm) Very low

Jacobson et al. 1956 (rat, 102 ppm) Very low

Jacobson et al. 1956 (dog, 292 ppm) Very low

Kaido et al. 1992 (rat, 500 ppm) Low

Matsuoka et al. 1990 (rat, 500 ppm) Low

Ohnishi et al. 1985 (rat, 13-week) Moderate

Ohnishi et al. 1986 (rat, 9-month) Moderate

Snellings et al. 1984a (mouse, 11-week) Moderate

Inhalation chronic exposure

Human studies

Blackwood and Erskine 1938 Low

Low

Brashear et al. 1996 Low

Crystal et al. 1988 Low

Dretchen et al. 1992 Low

Estrin et al. 1987 Low

Finelli et al. 1983 Low

Gross et al. 1979 Low

Kuzuhara et al. 1983 Low

Salinas et al. 1981 Low

Schröder et al. 1985 Low

Sexton and Henson 1949 Low

Von Oettingen 1939 Low
ETHYLENE OXIDE C-23

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-13. Initial Confidence Rating for Ethylene Oxide Health Effects Studies

Initial study 

confidence

Initial confidence 

rating

Zampollo et al. 1984 Low

Animal studies

Lynch et al. 1984a (monkey, 2-year) Moderate

Lynch et al. 1984b (rat, 2-year) Moderate High

NTP 1987 (mouse, 102-week) High

Outcome: Reproductive effects

Inhalation intermediate exposure

Animal studies

EPA 1994 (rat) Moderate

High

Kaido et al. 1992 (rat, 13-week) Low

Mori et al. 1991a (rat, 13-week) Moderate

Mori et al. 1991b (rat, 6-week) High

NIOSH 1982 (rat, GDs 1–16) Low

NIOSH 1982 (rat, 3 weeks premating and GDs 1–16) Low

NIOSH 1982 (rabbit, GDs 1–19) Low

NTP 1987 (mouse, 14-week) High

Snellings et al. 1982b (rat, 1-generation) Moderate

Snellings et al. 1984a (mouse, 11-week) Moderate

Inhalation chronic exposure

Human studies

Abrahams 1980 Moderate

Moderate Gresie-Brusin et al. 2007 Moderate

Hemminki et al. 1982 Moderate

Rowland et al. 1996 Moderate

Animal studies

Lynch et al. 1984a (monkey, 2-year) Moderate

Lynch et al. 1984b (rat, 2-year) Moderate High

NTP 1987 (mouse, 102-week) High

Outcome: Developmental effects

Inhalation acute exposure

Animal studies

Neeper-Bradley and Kubena 1993 (rat) High

High

NIOSH 1982 (rat) Low

NIOSH 1982 (rabbit) Low

Rutledge and Generoso 1989 (mouse) Moderate

Saillenfait et al. 1996 (rat, 400–1,200 ppm) High

Saillenfait et al. 1996 (rat, 200 or 400 ppm) High

Saillenfait et al. 1996 (rat, 800 or 1,200 ppm) High

Snellings et al. 1982a (rat, 10–100 ppm) High

Inhalation intermediate exposure

Animal studies

EPA 1994 (rat) Moderate

NIOSH 1982 (rat, GDs 1–16) Low Moderate

NIOSH 1982 (rat, 3 weeks premating and GDs 1–16) Low
ETHYLENE OXIDE C-24

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-13. Initial Confidence Rating for Ethylene Oxide Health Effects Studies

Initial study 

confidence

Initial confidence 

rating

NIOSH 1982 (rabbit, GDs 1–19) Low

C.6.2 Adjustment of the Confidence Rating

The initial confidence rating was then downgraded or upgraded depending on whether there were 

substantial issues that would decrease or increase confidence in the body of evidence. The nine properties 

of the body of evidence that were considered are listed below. The summaries of the assessment of the 

confidence in the body of evidence for respiratory, hematological, endocrine, neurological, reproductive, 

and developmental effects are presented in Table C-14. If the confidence ratings for a particular outcome 

were based on more than one type of human study, then the highest confidence rating was used for 

subsequent analyses. An overview of the confidence in the body of evidence for all health effects 

associated with ethylene oxide exposure is presented in Table C-15.

Table C-14. Adjustments to the Initial Confidence in the Body of Evidence 

Initial confidence

Adjustments to the initial 

confidence rating

Final 

confidence

Outcome: Respiratory effects

Human studies Moderate No adjustments Moderate

Animal studies High No adjustments High

Outcome: Hematological effects

Animal studies Moderate No adjustments Moderate

Outcome: Endocrine effects

Animal studies Moderate No adjustments Moderate

Outcome: Neurological effects

Human studies Low No adjustments Low

Animal studies High No adjustments High

Outcome: Reproductive effects

Human studies Moderate No adjustments Moderate

Animal studies High No adjustments High

Outcome: Developmental effects

Animal studies High No adjustments High
ETHYLENE OXIDE C-25

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Table C-15. Confidence in the Body of Evidence for Ethylene Oxide

Outcome

Confidence in body of evidence

Human studies Animal studies

Respiratory effects Moderate High

Hematological effects No data Moderate

Endocrine effects No data Moderate

Neurological effects Low High

Reproductive effects Moderate High

Developmental effects No data High

Five properties of the body of evidence were considered to determine whether the confidence rating 

should be downgraded: 

• Risk of bias. Evaluation of whether there is substantial risk of bias across most of the studies 

examining the outcome. This evaluation used the risk of bias tier groupings for individual studies 

examining a particular outcome (Tables C-7 and C-8). Below are the criteria used to determine 

whether the initial confidence in the body of evidence for each outcome should be downgraded 

for risk of bias:

o No downgrade if most studies are in the risk of bias first tier

o Downgrade one confidence level if most studies are in the risk of bias second tier

o Downgrade two confidence levels if most studies are in the risk of bias third tier

• Unexplained inconsistency. Evaluation of whether there is inconsistency or large variability in 

the magnitude or direction of estimates of effect across studies that cannot be explained. Below 

are the criteria used to determine whether the initial confidence in the body of evidence for each 

outcome should be downgraded for unexplained inconsistency:

o No downgrade if there is little inconsistency across studies or if only one study evaluated 

the outcome

o Downgrade one confidence level if there is variability across studies in the magnitude or 

direction of the effect

o Downgrade two confidence levels if there is substantial variability across studies in the 

magnitude or direct of the effect

• Indirectness. Evaluation of four factors that can affect the applicability, generalizability, and 

relevance of the studies: 

o Relevance of the animal model to human health—unless otherwise indicated, studies in 

rats, mice, and other mammalian species are considered relevant to humans 

o Directness of the endpoints to the primary health outcome—examples of secondary 

outcomes or nonspecific outcomes include organ weight in the absence of histopathology 

or clinical chemistry findings in the absence of target tissue effects

o Nature of the exposure in human studies and route of administration in animal studies—

inhalation, oral, and dermal exposure routes are considered relevant unless there are 

compelling data to the contrary 

o Duration of treatment in animal studies and length of time between exposure and 

outcome assessment in animal and prospective human studies—this should be considered 

on an outcome-specific basis
ETHYLENE OXIDE C-26

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Below are the criteria used to determine whether the initial confidence in the body of evidence for 

each outcome should be downgraded for indirectness:

o No downgrade if none of the factors are considered indirect 

o Downgrade one confidence level if one of the factors is considered indirect 

o Downgrade two confidence levels if two or more of the factors are considered indirect

• Imprecision. Evaluation of the narrowness of the effect size estimates and whether the studies 

have adequate statistical power. Data are considered imprecise when the ratio of the upper to 

lower 95% CIs for most studies is ≥10 for tests of ratio measures (e.g., odds ratios) and ≥100 for 

absolute measures (e.g., percent control response). Adequate statistical power is determined if 

the study can detect a potentially biologically meaningful difference between groups (20% 

change from control response for categorical data or risk ratio of 1.5 for continuous data). Below 

are the criteria used to determine whether the initial confidence in the body of evidence for each 

outcome should be downgraded for imprecision:

o No downgrade if there are no serious imprecisions 

o Downgrade one confidence level for serious imprecisions 

o Downgrade two confidence levels for very serious imprecisions 

• Publication bias. Evaluation of the concern that studies with statistically significant results are 

more likely to be published than studies without statistically significant results. 

o Downgrade one level of confidence for cases where there is serious concern with 

publication bias

Four properties of the body of evidence were considered to determine whether the confidence rating 

should be upgraded: 

• Large magnitude of effect. Evaluation of whether the magnitude of effect is sufficiently large 

so that it is unlikely to have occurred as a result of bias from potential confounding factors. 

o Upgrade one confidence level if there is evidence of a large magnitude of effect in a few 

studies, provided that the studies have an overall low risk of bias and there is no serious 

unexplained inconsistency among the studies of similar dose or exposure levels; 

confidence can also be upgraded if there is one study examining the outcome, provided 

that the study has an overall low risk of bias

• Dose response. Evaluation of the dose-response relationships measured within a study and 

across studies. Below are the criteria used to determine whether the initial confidence in the body 

of evidence for each outcome should be upgraded:

o Upgrade one confidence level for evidence of a monotonic dose-response gradient

o Upgrade one confidence level for evidence of a non-monotonic dose-response gradient 

where there is prior knowledge that supports a non-monotonic dose-response and a nonmonotonic dose-response gradient is observed across studies

• Plausible confounding or other residual biases. This factor primarily applies to human studies 

and is an evaluation of unmeasured determinants of an outcome such as residual bias towards the 

null (e.g., “healthy worker” effect) or residual bias suggesting a spurious effect (e.g., recall bias). 

Below is the criterion used to determine whether the initial confidence in the body of evidence for 

each outcome should be upgraded:

o Upgrade one confidence level for evidence that residual confounding or bias would 

underestimate an apparent association or treatment effect (i.e., bias toward the null) or 

suggest a spurious effect when results suggest no effect
ETHYLENE OXIDE C-27

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

• Consistency in the body of evidence. Evaluation of consistency across animal models and 

species, consistency across independent studies of different human populations and exposure 

scenarios, and consistency across human study types. Below is the criterion used to determine 

whether the initial confidence in the body of evidence for each outcome should be upgraded:

o Upgrade one confidence level if there is a high degree of consistency in the database

C.7 TRANSLATE CONFIDENCE RATING INTO LEVEL OF EVIDENCE OF HEALTH 

EFFECTS

In the seventh step of the systematic review of the health effects data for ethylene oxide, the confidence in 

the body of evidence for specific outcomes was translated to a level of evidence rating. The level of 

evidence rating reflected the confidence in the body of evidence and the direction of the effect (i.e., 

toxicity or no toxicity); route-specific differences were noted. The level of evidence for health effects 

was rated on a five-point scale: 

• High level of evidence: High confidence in the body of evidence for an association between 

exposure to the substance and the health outcome

• Moderate level of evidence: Moderate confidence in the body of evidence for an association 

between exposure to the substance and the health outcome

• Low level of evidence: Low confidence in the body of evidence for an association between 

exposure to the substance and the health outcome

• Evidence of no health effect: High confidence in the body of evidence that exposure to the 

substance is not associated with the health outcome

• Inadequate evidence: Low or moderate confidence in the body of evidence that exposure to the 

substance is not associated with the health outcome OR very low confidence in the body of 

evidence for an association between exposure to the substance and the health outcome

A summary of the level of evidence of health effects for ethylene oxide is presented in Table C-16.

Table C-16. Level of Evidence of Health Effects for Ethylene Oxide

Outcome

Confidence in body 

of evidence

Direction of health 

effect

Level of evidence for 

health effect

Human studies

Respiratory effects Moderate Health effect Moderate

Neurological effects Low Health effect Low

Reproductive effects Moderate Health effect Moderate

Animal studies

Respiratory effects High Health effect High

Hematological effects Moderate Health effect Moderate

Endocrine effects Moderate Health effect Moderate

Neurological effects High Health effect High

Reproductive effects High Health effect High

Developmental effects High Health effect High
ETHYLENE OXIDE C-28

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

C.8 INTEGRATE EVIDENCE TO DEVELOP HAZARD IDENTIFICATION CONCLUSIONS

The final step involved the integration of the evidence streams for the human studies and animal studies 

to allow for a determination of hazard identification conclusions. For health effects, there were four 

hazard identification conclusion categories:

• Known to be a hazard to humans

• Presumed to be a hazard to humans 

• Suspected to be a hazard to humans 

• Not classifiable as to the hazard to humans 

The initial hazard identification was based on the highest level of evidence in the human studies and the 

level of evidence in the animal studies; if there were no data for one evidence stream (human or animal), 

then the hazard identification was based on the one data stream (equivalent to treating the missing 

evidence stream as having low level of evidence). The hazard identification scheme is presented in 

Figure C-1 and described below:

• Known: A health effect in this category would have:

o High level of evidence for health effects in human studies AND a high, moderate, or low 

level of evidence in animal studies.

• Presumed: A health effect in this category would have:

o Moderate level of evidence in human studies AND high or moderate level of evidence in 

animal studies OR

o Low level of evidence in human studies AND high level of evidence in animal studies

• Suspected: A health effect in this category would have:

o Moderate level of evidence in human studies AND low level of evidence in animal 

studies OR

o Low level of evidence in human studies AND moderate level of evidence in animal 

studies

• Not classifiable: A health effect in this category would have:

o Low level of evidence in human studies AND low level of evidence in animal studies
ETHYLENE OXIDE C-29

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Figure C-1. Hazard Identification Scheme

Other relevant data such as mechanistic or mode-of-action data were considered to raise or lower the level 

of the hazard identification conclusion by providing information that supported or opposed biological 

plausibility. 

Two hazard identification conclusion categories were used when the data indicated that there may be no 

health effect in humans:

• Not identified to be a hazard in humans

• Inadequate to determine hazard to humans

If the human level of evidence conclusion of no health effect was supported by the animal evidence of no 

health effect, then the hazard identification conclusion category of “not identified” was used. If the 

human or animal level of evidence was considered inadequate, then a hazard identification conclusion 

category of “inadequate” was used. As with the hazard identification for health effects, the impact of 

other relevant data was also considered for no health effect data. 

The hazard identification conclusions for ethylene oxide are listed below and summarized in Table C-17. 

Ethylene oxide is a presumed hazard to humans for respiratory effects, neurological effects, reproductive 

effects, and developmental effects. Ethylene oxide is a suspected hazard to humans for hematological 

effects and endocrine effects.
ETHYLENE OXIDE C-30

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

Presumed

• Respiratory effects

o Occupational exposures, presumably to relatively high concentrations in workplace air, 

have resulted in compromised respiratory function (Deschamps et al. 1992; Theiss 1963).

o Inhalation exposures of laboratory animals to ethylene oxide vapor concentrations ≥100 

ppm have resulted in adverse respiratory effects (Hollingsworth et al. 1956; Jacobson et 

al. 1956; NTP 1987).

• Neurological effects

o Clinical signs and symptoms of neurological effects have been reported in occupational 

exposure scenarios that included estimated ethylene oxide levels as low as 3 ppm, 

although most reports indicated exposures at much higher levels (Blackwood and Erskine 

1938; Brashear et al. 1996; Crystal et al. 1988; Dretchen et al. 1992; Estrin et al. 1987; 

Finelli et al. 1983; Gross et al. 1979; Kuzuhara et al. 1983; Salinas et al. 1981; Schröder

et al. 1985; Sexton and Henson 1949; von Oettingen 1939; Zampollo et al. 1984).

o Impaired neurological function and histopathologic lesions have been reported in 

laboratory animals exposed to ethylene oxide by inhalation at concentrations ≥100 ppm 

(Hollingsworth et al. 1956; Jacobson et al. 1956; Kaido et al. 1992; Lynch et al. 1984b; 

Matsuoka et al. 1990; NTP 1987; Ohnishi et al. 1985, 1986; Snellings et al. 1984a) 

• Reproductive effects

o Limited human data indicate potential for ethylene oxide-induced reproductive effects 

among occupationally-exposed persons (Abrahams 1980; Gresie-Brusin et al. 2007; 

Hemminki et al. 1982).

o Adverse male reproductive effects have been reported in laboratory animals exposed to 

ethylene oxide by inhalation at concentrations ≥33 ppm (EPA 1994; Kaido et al. 1992; 

Lynch et al. 1984b; Mori et al. 1991a, 1991b). Decreased numbers of viable pups have 

been reported in rats repeatedly exposed to ethylene oxide vapor at 100 ppm prior to 

mating and throughout gestation and lactation periods (Snellings et al. 1982b).

• Developmental effects

o No human data are available on the potential for developmental effects of ethylene oxide.

o Developmental effects such as depressed fetal weight, delayed ossification, dilatation in 

fetal renal pelvis and ureter, and fetal fluid retention and ocular defects have been 

associated with inhalation exposure to ethylene oxide by parental laboratory animals at 

exposure levels ≥33 ppm (EPA 1994; Neeper-Bradley and Kubena 1993; NIOSH 1982; 

Rutledge and Generoso 1989; Saillenfait et al. 1996; Snellings et al. 1982a).

Suspected

• Hematological effects

o No human studies have associated ethylene oxide exposure with hematological effects.

o Inhalation exposure of laboratory animals to ethylene oxide vapor concentrations as low 

as 50 ppm resulted in splenic histopathology (Lynch et al. 1984a, 1984b); higher 

exposure concentrations were associated with changes in selected hematology parameters 

(Fujishiro et al. 1990; Jacobson et al. 1956; Snellings et al. 1984a).

• Endocrine effects

o No human data are available regarding ethylene oxide exposure and endocrine effects.
ETHYLENE OXIDE C-31

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

o Inhalation exposure of laboratory animals to ethylene oxide vapor concentrations as low 

as 50 ppm resulted in histopathologic lesions in adrenal glands (Lynch et al. 1984a, 

1984b).

Table C-17. Hazard Identification Conclusions for Ethylene Oxide

Outcome Hazard identification 

Respiratory effects Presumed

Hematological effects Suspected

Endocrine effects Suspected

Neurological effects Presumed

Reproductive effects Presumed

Developmental effects Presumed
ETHYLENE OXIDE D-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX D. USER'S GUIDE

Chapter 1. Relevance to Public Health

This chapter provides an overview of U.S. exposures, a summary of health effects based on evaluations of 

existing toxicologic, epidemiologic, and toxicokinetic information, and an overview of the minimal risk 

levels. This is designed to present interpretive, weight-of-evidence discussions for human health 

endpoints by addressing the following questions:

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern to humans?

3. What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites?

Minimal Risk Levels (MRLs)

Where sufficient toxicologic information is available, ATSDR derives MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans.

MRLs should help physicians and public health officials determine the safety of a community living near 

a hazardous substance emission, given the concentration of a contaminant in air or the estimated daily 

dose in water. MRLs are based largely on toxicological studies in animals and on reports of human 

occupational exposure.

MRL users should be familiar with the toxicologic information on which the number is based. 

Section 1.2, Summary of Health Effects, contains basic information known about the substance. Other 

sections, such as Section 3.2 Children and Other Populations that are Unusually Susceptible and 

Section 3.4 Interactions with Other Substances, provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to 

protect sensitive subpopulations (people who are most susceptible to the health effects caused by the 

substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, 

these individual uncertainty factors are multiplied together. The product is then divided into the 

inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a 
ETHYLENE OXIDE D-2

APPENDIX D

***DRAFT FOR PUBLIC COMMENT***

substance-specific MRL are provided in the footnotes of the levels of significant exposure (LSE) tables

that are provided in Chapter 2. Detailed discussions of the MRLs are presented in Appendix A.

Chapter 2. Health Effects

Tables and Figures for Levels of Significant Exposure (LSE)

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species and MRLs to humans for noncancer 

endpoints. The LSE tables and figures can be used for a quick review of the health effects and to locate 

data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction 

with the text. All entries in these tables and figures represent studies that provide reliable, quantitative 

estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE tables and figures follow. The numbers in the left column of the legends correspond to 

the numbers in the example table and figure.

TABLE LEGEND

See Sample LSE Table (page D-5)

(1) Route of exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. 

Typically, when sufficient data exist, three LSE tables and two LSE figures are presented in the 

document. The three LSE tables present data on the three principal routes of exposure

(i.e., inhalation, oral, and dermal). LSE figures are limited to the inhalation and oral routes. Not 

all substances will have data on each route of exposure and will not, therefore, have all five of the 

tables and figures. Profiles with more than one chemical may have more LSE tables and figures.

(2) Exposure period. Three exposure periods—acute (<15 days), intermediate (15–364 days), and 

chronic (≥365 days)—are presented within each relevant route of exposure. In this example, two 

oral studies of chronic-duration exposure are reported. For quick reference to health effects 

occurring from a known length of exposure, locate the applicable exposure period within the LSE 

table and figure.

(3) Figure key. Each key number in the LSE table links study information to one or more data points 

using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 51 identified NOAELs and less serious LOAELs (also see the three

"51R" data points in sample LSE Figure 2-X).

(4) Species (strain) No./group. The test species (and strain), whether animal or human, are identified 

in this column. The column also contains information on the number of subjects and sex per 

group. Chapter 1, Relevance to Public Health, covers the relevance of animal data to human 

toxicity and Section 3.1, Toxicokinetics, contains any available information on comparative 

toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated 

to equivalent human doses to derive an MRL.

(5) Exposure parameters/doses. The duration of the study and exposure regimens are provided in 

these columns. This permits comparison of NOAELs and LOAELs from different studies. In 

this case (key number 51), rats were orally exposed to “Chemical X” via feed for 2 years. For a 
ETHYLENE OXIDE D-3

APPENDIX D

***DRAFT FOR PUBLIC COMMENT***

more complete review of the dosing regimen, refer to the appropriate sections of the text or the 

original reference paper (i.e., Aida et al. 1992).

(6) Parameters monitored. This column lists the parameters used to assess health effects. Parameters 

monitored could include serum (blood) chemistry (BC), behavioral (BH), biochemical changes 

(BI), body weight (BW), clinical signs (CS), developmental toxicity (DX), enzyme activity (EA), 

food intake (FI), fetal toxicity (FX), gross necropsy (GN), hematology (HE), histopathology 

(HP), lethality (LE), maternal toxicity (MX), organ function (OF), ophthalmology (OP), organ 

weight (OW), teratogenicity (TG), urinalysis (UR), and water intake (WI).

(7) Endpoint. This column lists the endpoint examined. The major categories of health endpoints 

included in LSE tables and figures are death, body weight, respiratory, cardiovascular, 

gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, ocular, endocrine, 

immunological, neurological, reproductive, developmental, other noncancer, and cancer. "Other

noncancer" refers to any effect (e.g., alterations in blood glucose levels) not covered in these 

systems. In the example of key number 51, three endpoints (body weight, hematological, and 

hepatic) were investigated.

(8) NOAEL. A NOAEL is the highest exposure level at which no adverse effects were seen in the 

organ system studied. The body weight effect reported in key number 51 is a NOAEL at

25.5 mg/kg/day. NOAELs are not reported for cancer and death; with the exception of these two 

endpoints, this field is left blank if no NOAEL was identified in the study.

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused an adverse health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific endpoint used to 

quantify the adverse effect accompanies the LOAEL. Key number 51 reports a less serious 

LOAEL of 6.1 mg/kg/day for the hepatic system, which was used to derive a chronic exposure, 

oral MRL of 0.008 mg/kg/day (see footnote "c"). MRLs are not derived from serious LOAELs. 

A cancer effect level (CEL) is the lowest exposure level associated with the onset of 

carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious 

effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report 

doses not causing measurable cancer increases. If no LOAEL/CEL values were identified in the 

study, this field is left blank.

(10) Reference. The complete reference citation is provided in Chapter 8 of the profile.

(11) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. For example, footnote "c" indicates that the LOAEL of 6.1 mg/kg/day in key 

number 51 was used to derive an oral MRL of 0.008 mg/kg/day.

FIGURE LEGEND

See Sample LSE Figure (page D-6)

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods.

(13) Exposure period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the chronic exposure period are illustrated.
ETHYLENE OXIDE D-4

APPENDIX D

***DRAFT FOR PUBLIC COMMENT***

(14) Endpoint. These are the categories of health effects for which reliable quantitative data exist. 

The same health effect endpoints appear in the LSE table.

(15) Levels of exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day.

(16) LOAEL. In this example, the half-shaded circle that is designated 51R identifies a LOAEL 

critical endpoint in the rat upon which a chronic oral exposure MRL is based. The key number 

51 corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 6.1 mg/kg/day (see entry 51 in the sample LSE table) to 

the MRL of 0.008 mg/kg/day (see footnote "c" in the sample LSE table).

(17) CEL. Key number 59R is one of studies for which CELs were derived. The diamond symbol 

refers to a CEL for the test species (rat). The number 59 corresponds to the entry in the LSE 

table.

(18) Key to LSE figure. The key provides the abbreviations and symbols used in the figure.
ETHYLENE OXIDE D-5

APPENDIX D

***DRAFT FOR PUBLIC COMMENT***
ETHYLENE OXIDE D-6 

APPENDIX D

***DRAFT FOR PUBLIC COMMENT***
ETHYLENE OXIDE E-1 

***DRAFT FOR PUBLIC COMMENT***

APPENDIX E. QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances may find the following information helpful for fast 

answers to often-asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Relevance to Public Health: The Relevance to Public Health Section provides an overview 

of exposure and health effects and evaluates, interprets, and assesses the significance of toxicity 

data to human health. A table listing minimal risk levels (MRLs) is also included in this chapter.

Chapter 2: Health Effects: Specific health effects identified in both human and animal studies are 

reported by type of health effect (e.g., death, hepatic, renal, immune, reproductive), route of 

exposure (e.g., inhalation, oral, dermal), and length of exposure (e.g., acute, intermediate, and 

chronic). 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. 

Pediatrics: 

Section 3.2 Children and Other Populations that are Unusually Susceptible

Section 3.3 Biomarkers of Exposure and Effect

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) 

Internet: http://www.atsdr.cdc.gov 

The following additional materials are available online: 

Case Studies in Environmental Medicine are self-instructional publications designed to increase primary 

health care providers’ knowledge of a hazardous substance in the environment and to aid in the 

evaluation of potentially exposed patients (see https://www.atsdr.cdc.gov/csem/csem.html). 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident (see https://www.atsdr.cdc.gov/MHMI/index.asp). Volumes I and II are planning guides 

to assist first responders and hospital emergency department personnel in planning for incidents 

that involve hazardous materials. Volume III—Medical Management Guidelines for Acute 

Chemical Exposures—is a guide for health care professionals treating patients exposed to 

hazardous materials.

Fact Sheets (ToxFAQsTM) provide answers to frequently asked questions about toxic substances (see 

https://www.atsdr.cdc.gov/toxfaqs/Index.asp).
ETHYLENE OXIDE E-2 

APPENDIX E

***DRAFT FOR PUBLIC COMMENT***

Other Agencies and Organizations

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA 

30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015 • Web Page: 

https://www.cdc.gov/nceh/. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 395 E Street, S.W., Suite 9200, 

Patriots Plaza Building, Washington, DC 20201 • Phone: 202-245-0625 or 1-800-CDC-INFO 

(800-232-4636) • Web Page: https://www.cdc.gov/niosh/. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212 • Web Page: 

https://www.niehs.nih.gov/. 

Clinical Resources (Publicly Available Information) 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/.

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266 • Web Page: 

http://www.acoem.org/. 

The American College of Medical Toxicology (ACMT) is a nonprofit association of physicians with 

recognized expertise in medical toxicology. Contact: ACMT, 10645 North Tatum Boulevard, 

Suite 200-111, Phoenix AZ 85028 • Phone: 844-226-8333 • FAX: 844-226-8333 • Web Page: 

http://www.acmt.net.

The Pediatric Environmental Health Specialty Units (PEHSUs) is an interconnected system of specialists 

who respond to questions from public health professionals, clinicians, policy makers, and the 

public about the impact of environmental factors on the health of children and reproductive-aged 

adults. Contact information for regional centers can be found at http://pehsu.net/findhelp.html. 

The American Association of Poison Control Centers (AAPCC) provide support on the prevention and 

treatment of poison exposures. Contact: AAPCC, 515 King Street, Suite 510, Alexandria VA 

22314 • Phone: 701-894-1858 • Poison Help Line: 1-800-222-1222 • Web Page: 

http://www.aapcc.org/.
ETHYLENE OXIDE F-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX F. GLOSSARY

Absorption—The process by which a substance crosses biological membranes and enters systemic 

circulation. Absorption can also refer to the taking up of liquids by solids, or of gases by solids or liquids.

Acute Exposure—Exposure to a chemical for a duration of ≤14 days, as specified in the Toxicological 

Profiles.

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact.

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by 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.

Benchmark Dose (BMD) or Benchmark Concentration (BMC)—is the dose/concentration 

corresponding to a specific response level estimate using a statistical dose-response model applied to 

either experimental toxicology or epidemiology data. For example, a BMD10 would be the dose 

corresponding to a 10% benchmark response (BMR). The BMD is determined by modeling the doseresponse curve in the region of the dose-response relationship where biologically observable data are 

feasible. The BMDL or BMCL is the 95% lower confidence limit on the BMD or BMC. 

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 period.

Biomarkers—Indicators signaling events in biologic systems or samples, typically classified as markers 

of exposure, effect, and susceptibility.

Cancer Effect Level (CEL)—The lowest dose of a chemical in a study, or group of studies, that 

produces significant increases in the incidence of cancer (or tumors) between the exposed population and 

its appropriate control.

Carcinogen—A chemical capable of inducing cancer.

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-control study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without the outcome.

Case Report—A report that describes a single individual with a particular disease or exposure. These 

reports may suggest some potential topics for scientific research, but are not actual research studies.

Case Series—Reports that describe the experience of a small number of individuals with the same 

disease or exposure. These reports may suggest potential topics for scientific research, but are not actual 

research studies.
ETHYLENE OXIDE F-2

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

Ceiling Value—A concentration that must not be exceeded.

Chronic Exposure—Exposure to a chemical for ≥365 days, as specified in the Toxicological Profiles.

Clastogen—A substance that causes breaks in chromosomes resulting in addition, deletion, or 

rearrangement of parts of the chromosome.

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome, and who are disease-free at start of follow-up. Often, at 

least one exposed group is compared to one unexposed group, while in other cohorts, exposure is a 

continuous variable and analyses are directed towards analyzing an exposure-response coefficient.

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at a specific point in time.

Data Needs—Substance-specific informational needs that, if met, would reduce the uncertainties of 

human health risk assessment.

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.

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the response or amount of the response.

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

effect occurs. Effects include malformations and variations, altered growth, and in utero death.

Epidemiology—The investigation of factors that determine the frequency and distribution of disease or 

other health-related conditions within a defined human population during a specified period. 

Excretion—The process by which metabolic waste products are removed from the body.

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome.

Half-life—A measure of rate for the time required to eliminate one-half of a quantity of a chemical from 

the body or environmental media.

Health Advisory—An estimate of acceptable drinking water levels for a chemical substance derived by 

EPA and 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)—A condition that poses a threat of life or health, or 

conditions that pose an immediate threat of severe exposure to contaminants that are likely to have 

adverse cumulative or delayed effects on health.
ETHYLENE OXIDE F-3

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

Immunotoxicity—Adverse effect on the functioning of the immune system that may result from 

exposure to chemical substances. 

Incidence—The ratio of new cases of individuals in a population who develop a specified condition to 

the total number of individuals in that population who could have developed that condition in a specified 

time period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles.

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.

In Vivo—Occurring within the living organism.

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals.

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population.

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals.

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population.

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 exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control.

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus.

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function.

Metabolism—Process in which chemical substances are biotransformed in the body that could result in 

less toxic and/or readily excreted compounds or produce a biologically active intermediate.

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure.

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1.
ETHYLENE OXIDE F-4

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease in 

a specific population.

Mortality—Death; the mortality rate is a measure of the number of deaths in a population during a 

specified interval of time.

Mutagen—A substance that causes mutations, which are changes in the DNA sequence of a cell’s DNA. 

Mutations can lead to birth defects, miscarriages, or cancer.

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

hazardous substance.

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Although effects may be produced at this dose, 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.

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An odds ratio that is greater than 1 is considered to indicate greater risk of 

disease in the exposed group compared to the unexposed group.

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

regulatory limit on the amount or concentration of a substance not to be exceeded in workplace air 

averaged over any 8-hour work shift of a 40-hour workweek.

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests (insects or other organisms harmful to cultivated plants or animals).

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body.

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic 

endpoints. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
ETHYLENE OXIDE F-5

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

Physiologically Based Pharmacokinetic (PBPK) Model—A type of physiologically based doseresponse model that is comprised of a series of compartments representing organs or tissue groups with 

realistic weights and blood flows. These models require a variety of physiological information, including 

tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly 

membrane permeabilities. The models also utilize biochemical information, such as blood:air partition 

coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry 

models.

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which a group is followed over time and the pertinent 

observations are made on events occurring after the start of the study. 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek.

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation RfC is expressed in units of mg/m3 or ppm.

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily oral exposure of the human population to a potential hazard that is likely to be without risk of 

deleterious noncancer health effects during a lifetime. The oral RfD is expressed in units of mg/kg/day. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). RQs are 

(1) ≥1 pound or (2) for selected substances, an amount established by regulation either under CERCLA or 

under Section 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 hazardous substance. The toxicity may be directed to the reproductive organs and/or 

the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual 

behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the 

integrity of this system.

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort.

Risk—The possibility or chance that some adverse effect will result from a given exposure to a hazardous 

substance.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing health 

condition, or an inborn or inherited characteristic that is associated with an increased occurrence of 

disease or other health-related event or condition.
ETHYLENE OXIDE F-6

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to the 

risk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of disease 

in the exposed group compared to the unexposed group.

Short-Term Exposure Limit (STEL)—A STEL is a 15-minute TWA exposure that should not be 

exceeded at any time during a workday. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population.

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)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which it is believed that nearly all workers may be repeatedly 

exposed, day after day, for a working lifetime without adverse effect. The TLV may be expressed as a 

Time-Weighted Average (TLV-TWA), as a Short-Term Exposure Limit (TLV-STEL), or as a ceiling 

limit (TLV-C).

Time-Weighted Average (TWA)—An average exposure within a given time period. 

Toxicokinetic—The absorption, distribution, metabolism, and elimination of toxic compounds in the 

living organism.

Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases and 

pollution prevention activities reported by industrial and federal facilities. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL),

Reference Dose (RfD), or Reference Concentration (RfC) 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 human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis (3 being the approximate logarithmic 

average of 10 and 1).

Xenobiotic—Any substance that is foreign to the biological system.
ETHYLENE OXIDE G-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX G. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

AAPCC American Association of Poison Control Centers

ACGIH American Conference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ACMT American College of Medical Toxicology

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AEGL Acute Exposure Guideline Level

AIC Akaike’s information criterion 

AIHA American Industrial Hygiene Association 

ALT alanine aminotransferase

AOEC Association of Occupational and Environmental Clinics

AP alkaline phosphatase

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

AWQC Ambient Water Quality Criteria

BCF bioconcentration factor

BMD/C benchmark dose or benchmark concentration

BMDX dose that produces a X% change in response rate of an adverse effect

BMDLX 95% lower confidence limit on the BMDX

BMDS Benchmark Dose Software 

BMR benchmark response

BUN blood urea nitrogen 

C centigrade

CAA Clean Air Act

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

cm centimeter

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DWEL drinking water exposure level

EAFUS Everything Added to Food in the United States

ECG/EKG electrocardiogram

EEG electroencephalogram

EPA Environmental Protection Agency

ERPG emergency response planning guidelines 

F Fahrenheit

F1 first-filial generation

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FR Federal Register
ETHYLENE OXIDE G-2

APPENDIX G

***DRAFT FOR PUBLIC COMMENT***

FSH follicle stimulating hormone

g gram

GC gas chromatography

gd gestational day

GGT γ-glutamyl transferase 

GRAS generally recognized as safe

HEC human equivalent concentration 

HED human equivalent dose 

HHS Department of Health and Human Services 

HPLC high-performance liquid chromatography

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer

IDLH immediately dangerous to life and health

IRIS Integrated Risk Information System 

Kd adsorption ratio

kg kilogram

kkg kilokilogram; 1 kilokilogram is equivalent to 1,000 kilograms and 1 metric ton

Koc organic carbon partition coefficient

Kow octanol-water partition coefficient

L liter

LC liquid chromatography

LC50 lethal concentration, 50% kill

LCLo lethal concentration, low

LD50 lethal dose, 50% kill

LDLo lethal dose, low

LDH lactic dehydrogenase

LH luteinizing hormone

LOAEL lowest-observed-adverse-effect level

LSE Level of Significant Exposure

LT50 lethal time, 50% kill

m meter

mCi millicurie

MCL maximum contaminant level

MCLG maximum contaminant level goal

MF modifying factor

mg milligram

mL milliliter

mm millimeter

mmHg millimeters of mercury

mmol millimole

MRL Minimal Risk Level

MS mass spectrometry

MSHA Mine Safety and Health Administration

Mt metric ton

NAAQS National Ambient Air Quality Standard

NAS National Academy of Science

NCEH National Center for Environmental Health

ND not detected

ng nanogram

NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences
ETHYLENE OXIDE G-3

APPENDIX G

***DRAFT FOR PUBLIC COMMENT***

NIOSH National Institute for Occupational Safety and Health

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-observed-adverse-effect level

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NTP National Toxicology Program

OR odds ratio

OSHA Occupational Safety and Health Administration

PAC Protective Action Criteria

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PEHSU Pediatric Environmental Health Specialty Unit

PEL permissible exposure limit

PEL-C permissible exposure limit-ceiling value

pg picogram

PND postnatal day

POD point of departure

ppb parts per billion

ppbv parts per billion by volume

ppm parts per million

ppt parts per trillion

REL recommended exposure level/limit

REL-C recommended exposure level-ceiling value

RfC reference concentration

RfD reference dose

RNA ribonucleic acid

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SD standard deviation

SE standard error

SGOT serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)

SGPT serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)

SIC standard industrial classification

SMR standardized mortality ratio

sRBC sheep red blood cell

STEL short term exposure limit

TLV threshold limit value

TLV-C threshold limit value-ceiling value

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TWA time-weighted average

UF uncertainty factor

U.S. United States

USDA United States Department of Agriculture

USGS United States Geological Survey

USNRC U.S. Nuclear Regulatory Commission
ETHYLENE OXIDE G-4 

APPENDIX G

***DRAFT FOR PUBLIC COMMENT***

VOC volatile organic compound 

WBC white blood cell

WHO World Health Organization 

> greater than

≥ greater than or equal to

= equal to 

< less than

≤ less than or equal to 

% percent 

α alpha 

β beta 

γ gamma

δ delta

μm micrometer

μg microgram

q1

* cancer slope factor

– negative 

+ positive

(+) weakly positive result

(–) weakly negative result