Ethylene oxide (EO)

Catherine J Shelp, BASF Corporation, Florham Park, NJ, United States

© 2024 Elsevier Inc. All rights reserved.

This is an update of R.J. Parod, Ethylene Oxide, Editor(s): Philip Wexler, Encyclopedia of Toxicology (Third Edition), Academic Press, 2014, pp. 535-538,
ISBN 9780123864550, https://doi.org/10.1016/B978-0-12-386454-3.00021-X.

Chemical profile 489

Background 490
Uses 490
Environmental fate and behavior 490
Exposure and exposure monitoring 490
Toxicokinetics 491
Mechanism of toxicity 491
Acute and short-term toxicity 491
Animal 491
Human 492
Chronic toxicity 492
Animal 492
Human 492
Immunotoxicity 492
Reproductive toxicity 492
Genotoxicity 493
Carcinogenicity 493
Animal 493
Human 494
Clinical management 494
Ecotoxicology 494
Other hazards 494
Exposure standards and guidelines 494
References 495
Further reading 496

Abstract

The aim of this work is to present the most recent data for Ethylene Oxide. Ethylene oxide is a colorless gas at room
temperature and pressure with a sweet etherial odor that can be detected at 500 ppm. The primary human health concern
with ethylene oxide under typical workplace exposure conditions is its potential carcinogenicity. Although ethylene oxide
exhibits a low carcinogenic potency in animal models, epidemiological studies have not conclusively linked exposures to
ethylene oxide with carcinogenic outcomes in humans.

Keywords

Alkylating agent; Clastogen; DNA adduct; Endogenous; Epoxide hydrolase; Ethylene glycol; Ethylene oxide; Exogenous;
Glutathione

Chemical profile

• Name: Ethylene Oxide

• Chemical Abstracts Service Registry Number: 75-21-8
• Molecular Formula: C2H4O
• Chemical Structure:

Encyclopedia of Toxicology 4th Edition https://doi.org/10.1016/B978-0-12-824315-2.01013-7 489

490 Ethylene oxide (EO)

Background

Ethylene Oxide (EO) is a colorless and flammable gas with a faint sweet ether-like odor. EO is a strong alkylating agent that can
readily react with cellular nucleophiles to inactivate a variety of cellular macromolecules. Ethylene oxide occurs naturally in the
body due to its conversion from ethylene, which results from normal metabolic processes and the consumption of plants where it is
a natural hormone. Ethylene oxide can also be detected in background air due to the combustion of fossil fuels, its presence in
tobacco smoke, and the decay of organic material. These air emission sources are expected to be negligible relative to the fugitive
emissions from industrial and medical facilities. Ethylene oxide is a bacterial, fungicidal, and sporicidal disinfectant. It is used as a
fumigant for foodstuffs, textiles, and as an agent for the gaseous sterilization of heat-liable pharmaceutical and surgical materials.
The sterilant properties of EO are similar to those of heat, except that the effects are largely superficial due to limited penetration.
Ethylene oxide is typically manufactured by the oxidation of ethylene in the presence of silver catalyst.

Uses

A majority of ethylene oxide (65%) is produced and consumed in the production of ethylene glycol, a chemical that is used to make
antifreeze. EO is also used in the production of nonionic surfactants, polyester resins, soaps, and detergents as well as specialty
solvents (polyethylene glycols, glycol ethers, acrylonitrile, ethanolamines, adhesives, drugs, polyurethane foams, and mixed
polyglycols) (IARC, 2012). Due to its antimicrobial activity, a small percentage of ethylene oxide (<0.1%) is used as a sterilant
for heat-sensitive medical devices and hospital supplies, pharmaceuticals, cosmetics, as a fumigant for pests, insects, microbes, as
well as for stored foods such as herbs and spices (IARC, 2012).

Environmental fate and behavior

The primary mode of release of ethylene oxide to the environment is via air emissions to the atmosphere due to EO’s high volatility
(vapor pressure 146 kPa at 20  C) and low boiling point (10.6  C) (NIOSH, 2016). Although ethylene oxide has high water
solubility and dissolves readily in water, it also has the tendency to volatilize rapidly due to its high vapor pressure. It has been
reported that approximately 95% of ethylene oxide mixed in water will volatilize within 4 h (half-life of 1 h) and therefore, is not
found readily in environmental water sources. In the atmosphere, ethylene oxide undergoes oxidation via free hydroxyl radical
formation, with a half-life in air of 2–5 months (69–149 days) (ATSDR, 2022). In freshwater, ethylene oxide is hydrolyzed to form
ethylene glycol (half-life 1 week); in salt water, it is hydrolyzed to ethylene glycol and ethylene chlorohydrin (half-life 2 weeks).
In unacclimated aqueous media, ethylene oxide is also subject to biodegradation with estimated half-lives of 1–6 months (aerobic)
and 4–24 months (anaerobic). However, in the presence of activated sludge, ethylene oxide is readily biodegradable. Due to its high
volatility and water solubility, ethylene oxide is not expected to persist in soil or sediments. The low log Kow (−0.30) for ethylene
oxide indicates a low potential for bioaccumulation of ethylene oxide in animal tissue.

Exposure and exposure monitoring

Ethylene oxide is a gas at room temperature and pressure; therefore, inhalation is the primary route of exposure. Dermal exposures
to liquid ethylene oxide may occur at temperatures below 11  C; however, rapid evaporation minimizes the opportunity for
absorption. Although there are little data on the background levels of ethylene oxide in the environment, estimates based on
measured and modeled data suggest the mean and maximum ambient air concentrations are 0.2 ppb and 2 ppb, respectively.
In the vicinity of ethylene oxide production and sterilization facilities, the predicted annual average concentrations are 6 ppb. The
highest ethylene oxide concentrations are found in production and sterilization facilities. In the 1960s, long-term worker exposures
were estimated to be 5–10 ppm.
However, due to the advent of engineering controls and new work practices introduced around 1980, current exposures have
been reduced to an 8 h time-weighted average (TWA) of 0.1–3 ppm, although operational upsets can result in short-term exposures
(minutes to several hours) as high as 50 ppm. Due to its ability to alkylate nucleophilic groups, exposures to ethylene oxide can be
monitored by measuring the levels of N-(2-hydroxyethyl)valine in hemoglobin and N7-(2-hydroxylethyl)guanine in the DNA of
peripheral lymphocytes. Due to the endogenous production of ethylene oxide in animals and humans, hydroxyethyl adducts in
hemoglobin and DNA occur in the absence of known exposures to ethylene oxide. These background adduct levels must be
considered when assessing exposures to ethylene oxide in ambient air.
Additionally, as EO is formed in the body from endogenous as well as exogenous sources, both sources should be considered in
an exposure assessment.
 Ethylene oxide (EO) 491

Toxicokinetics

Inhaled or ingested ethylene oxide is rapidly absorbed through the respiratory and gastrointestinal tracts (ATSDR, 2022). Due to its
high solubility in blood, ethylene oxide and its metabolites are rapidly distributed to a variety of tissues (ATSDR, 2022). The uptake
of EO is largely dependent on the ventilation rate and the concentration of ethylene oxide in the inspired air. Dermal absorption has
been reported; however, it is not a prominent route of exposure (Bader et al., 2012). Studies in mice indicate that at 0.5 ppm,
100% of the inspired ethylene oxide is absorbed. At higher concentrations, the percentage absorbed decreases from 90%
(10 ppm) to 68% (100 ppm) and falls to 36% at 1000 ppm. Humans exposed to ethylene oxide at levels ranging from 0.1 to
10 ppm absorb 75–80% of the inspired ethylene oxide (Brugnone et al., 1985, 1986). Absorbed ethylene oxide is rapidly
distributed by the blood to a wide variety of tissues throughout the body. In mice exposed by inhalation to radiolabeled ethylene
oxide, distribution was essentially immediate, with the highest postexposure concentrations of ethylene oxide or its metabolites
observed in the liver, kidneys, and lungs. By 4 h after exposure, levels in the liver and kidney had decreased and were comparable
with those detected in the lungs, testes, spleen, and brain. Metabolism of ethylene oxide occurs by two separate pathways, hydrolysis
and glutathione conjugation, via both enzymatic (epoxide hydrolase) and nonenzymatic pathways. Ethylene oxide metabolites
from both pathways are rapidly excreted, primarily in the urine, although some are further metabolized to CO2 and exhaled via the
lungs along with a small amount of unchanged ethylene oxide. While the metabolism of ethylene oxide is qualitatively similar
among species, the glutathione pathway appears to predominate in mice (75%). Rat metabolism is split between the glutathione
and the epoxide hydrolase pathways. Epoxide hydrolase is the primary metabolic pathway in larger species. In humans, hydrolysis
to ethylene glycol is the predominant metabolic pathway. Despite the quantitative metabolic differences among species, when
differences in uptake and metabolism are considered, modeled ethylene oxide blood levels in all three species are comparable at
concentrations used in the rodent cancer bioassays (100 ppm). The estimated half-life of absorbed ethylene oxide in the blood of
mice (3–12 min), rats (9 min), and humans (42 min) is relatively short (Filser et al., 1992; Brown et al., 1998; Filser and
Bolt, 1984).
Ethylene oxide is also produced endogenously from the oxidation of absorbed ethylene or endogenous production of ethylene
during the normal oxidation processes such as lipid peroxidation, oxidation of methionine and heme, and metabolizing activity of
intestinal bacteria (Thier and Bolt, 2000). Isotope labeling can be used to differentiate between exogenous EO vs endogenously
produced EO. The toxicokinetic of exogeneous ethylene oxide can be measured using a radiolabeled isotope (i.e., 14C-ethylene
oxide), where the radiolabel is monitored to determine the extent of absorption, distribution, and excretion related to exogenous
exposure to 14C-ethylene oxide (ATSDR, 2022).
The relative contributions of exogenous vs. endogenous sources of ethylene oxide were evaluated vs. the production of the
adduct hemoglobin, N-(2-hydroxyethyl)-valine (HEV) (Kirman and Hays, 2017). This indicated that the endogenously produced
ethylene oxide provides a substantial proportion of ethylene oxide in the body.

Mechanism of toxicity

In general, the toxic effects of ethylene oxide are due to its ability to react with cellular molecules, altering function. Attempts to link
the carcinogenicity of ethylene oxide noted in experimental animals to ethylene oxide-induced DNA adducts, including the major
adduct formed (N7-hydroxyethyl guanine), have been unsuccessful. Research on the mode of action for ethylene oxide-induced
carcinogenicity includes work focused on the potential role of glutathione depletion and the resulting oxidative stress, events that
can occur after exposure to high levels of ethylene oxide.

Acute and short-term toxicity

Animal
The acute 4-h oral 50% lethal concentration (LD50) of EO in rats and mice range from less than 200 to 350 mg/kg, in male and
female guinea pigs, the LD50 was 270 mg/kg (ECHA, 2020). Additionally, the oral LD50 in rabbits was 630 mg/kg (ECHA, 2020).
Inhalation is the most relevant route of exposure to EO. The acute 4-h inhalation LC50 value in rats was 1972 ppm in males and
1537 ppm in females (1741 ppm for combined sexes) (Snellings et al., 2011). One-hour LD50 values were 5748 ppm for males and
4439 ppm for females (5029 combined males and females) (Snellings et al., 2011). The lowest 4-h LC50 was 660 ppm for female
mice (NTP, 1987) and 960 for dogs (Rusch et al., 2009). For both routes of exposure, the dose–response curve for mortality is steep.
Effects associated with overexposure via inhalation include eye and respiratory tract irritation, central nervous system (CNS)
depression, salivation, vomiting, incoordination, and convulsions. Mortality shortly after exposure is typically associated with
pulmonary edema, while later deaths are thought to result from secondary lung infections with a potential contribution from
systemic toxicity. Study survivors may exhibit bronchitis, pneumonia, dyspnea, and muscle paralysis, particularly of the hind legs.
Histopathological examinations show damage to the lung, liver, kidney, spleen, and brain. Aqueous solutions of ethylene oxide are
irritating to the skin but have not been definitively associated with sensitization. Corneal opacities have been noted in some species.
492 Ethylene oxide (EO)

Human
At high concentrations (200 ppm), ethylene oxide acts as an eye, respiratory and mucous membrane irritant as well as a CNS
depressant. Symptoms of overexposure include nausea, vomiting, and neurological effects. Pulmonary edema may result several
days after an acute exposure. Contact with liquid ethylene oxide or its solutions may result in irritation and burns as well as frostbite
from evaporative cooling.

Chronic toxicity
Animal
Nonneoplastic effects associated with long-term exposures to ethylene oxide have not been extensively investigated. In lifetime
studies, rats were exposed to airborne ethylene oxide concentrations of 10, 33, or 100 ppm for 6 h/day, 5 days/week. Body weight
gain was depressed at 33 and 100 ppm; mortality was increased at 100 ppm. In a 2-year study, no noncancer effects were observed in
mice exposed to ethylene oxide vapor at concentrations of 50 and 100 ppm for 6 h/day, 5 days/week. Neurological effects
(abnormal posture during gait and decreased locomotor activity) were observed in mice after 10 weeks of exposure to ethylene
oxide concentrations 50 ppm; paralysis and axonal degeneration have been noted in rodents exposed for several months to higher
concentrations (250–500 ppm). Although demyelination and histological alteration of axons were initially reported in monkeys
exposed to 50 and 100 ppm ethylene oxide for 2 years, the final report stated there were no treatment-related differences between
exposed and control monkeys.

Human
Studies of chronically exposed populations suggest that ethylene oxide may cause allergic contact dermatitis and cataracts at high
concentrations well above the 1 ppm TLV (Goldberg, 1986; Sobaszek et al., 1999). Neuropsychological, peripheral, and CNS
deficits have been reported among hospital workers exposed to ethylene oxide prior to the advent of engineering controls and better
work practices. However, a dose–response relationship for this effect is difficult to establish due to multiple confounders, including
the observation that exposed workers frequently reported smelling ethylene oxide (i.e., exposures exceeded 500 ppm) (RAC, 2017).

Immunotoxicity

Repeated exposures of mice to 200 ppm ethylene oxide for 14 weeks, an exposure level at which nonlinear kinetics result in a
disproportionately higher blood level of ethylene oxide in the mouse, resulted in lymphocytic hypoplasia of the thymus in males
and lymphocytic necrosis of the thymus in both sexes at 600 ppm. Blood parameters related to immune function (e.g., lymphocyte
counts and activation, immunoglobulin levels) were not affected in ethylene oxide production workers exposed for up to 10 years to
airborne concentrations that ranged from <0.05 ppm (the detection limit of the analytical method) to an occasional peak of 8 ppm
during the 4 years that the air was monitored (van Sittert et al., 1985). 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).

Reproductive toxicity

Ethylene oxide is a reproductive and developmental toxicant in rodents at concentrations approximating those associated with
neoplastic effects. In two reproduction studies, male and female rats were exposed to ethylene oxide vapor at concentrations of 10,
33, and 100 ppm 6 h/day 5 days per week, for 10–12 weeks prior to mating and then daily during mating. After mating, females
were exposed 6 h/day, 7 days/week from gestation day 0 to 19 and then from lactation day 5 to day 21–28 postpartum. Fetotoxicity
(i.e., increased post implantation loss and decreased fetal body weight gain) was observed at 33 ppm, resulting in a no observable
adverse effect concentration (NOAEC) for reproduction of 10 ppm. Adverse effects in the parental animals were not observed.
In two developmental studies, pregnant rats were exposed to ethylene oxide at concentrations between 10 and 225 ppm for 6 h/day
on days 6–15 of gestation. The developmental NOAECs were 33–50 ppm based on the significant decrement in fetal body weight
seen on gestational day 20 at 100 ppm; the incidence of malformations was not increased at any concentration (Snellings et al.,
1982; Chun and Neeper-Bradley, 1993). Very high exposures (>1200 ppm) can produce teratogenicity. Ethylene oxide causes
comparable effects in mice.
There are limited epidemiological data in humans that suggest occupational exposures to ethylene oxide during pregnancy may
result in reproductive effects (e.g., spontaneous abortions) (ATSDR, 1996).
 Ethylene oxide (EO) 493

Genotoxicity

Ethylene oxide is regarded as a direct-acting mutagen and/or clastogen in a wide range of organisms from bacteria to mammalian
cells. In vivo, ethylene oxide is considered weakly genotoxic.
The available genotoxicity data demonstrate the mutagenic and clastogenic properties of ethylene oxide, both in vitro and
in vivo. EO induced gene mutation, chromosomal aberrations, sister chromatid exchange, micronucleus formation, deoxyribonu-
cleic acid (DNA) stand breaks, unscheduled DNA synthesis, and cell transformation in vitro. In addition, EO induced gene
mutation, specific locus mutation, chromosomal aberrations, sister chromatid exchange, micronucleus formation, dominant lethal
mutation, and heritable translocation in test species as wee a in occupationally-exposed humans (IARC, 1994, 2008, 2012; USEPA
(United States Environmental Protection Agency), 2016). The overall results from human studies indicate that ethylene oxide is
genotoxic in humans, despite some confounding factors and conflicting results that were observed in occupational studies (IARC,
2012; USEPA (United States Environmental Protection Agency), 2016).
In addition to genotoxic effects, in vitro and in vivo animal studies in rats and mice, as well as studies in humans have
demonstrated the formation of DNA adducts. EO is an alkylating agent that forms adducts with DNA, ribonucleic acid (RNA), and
proteins. The primary DNA adduct formed is N7-(2-hydroxyethl)guanine (7-HEG). Other adducts have been found I smaller
amounts, including N3-(2-hydroxyethyl)adenine and O6-(2-hydroxyethyl)guanine (EPA, 2016; IARC, 2012). In rats exposed via
inhalation to EO for up to 4 weeks, 7-HEG has been detected in various tissues (ATSDR, 2022).

Carcinogenicity

The Department of Human Health Services (DHHS) has classified ethylene oxide as “known to be a human carcinogen” (NTP,
2016) based on sufficient evidence from studies in humans, as well as evidence from mechanistic data in humans and experimental
animals that showed similar genetic damage in the cells of animals and workers exposed to EO. EPA (2016) has also characterized
EO as “carcinogenic to humans,” by the inhalation route of exposure based on the following:

1. Epidemiological evidence of lymphohematopoietic cancers and breast cancer in EO exposed workers (strong but not
conclusive);
2. Evidence of carcinogenicity in laboratory animals (including lymphohematopoietic cancers in rats & mice & mammary
carcinoma in mice following inhalation exposures);
3. Evidence that EO is genotoxic based on sufficient evidence to support a mutagenic mode of action for carcinogenicity;
4. Strong evidence that there are key events that are anticipated to occur and the progression of tumors in humans, including
evidence of chromosome damage in humans exposed to EO.

The unit risk estimates derived by EPA were based on the NIOSH study (Steenland et al., 2003, 2004) that evaluated cancer risk in a
cohort of workers exposed to EO. There was a positive exposure response for breast cancer mortality in females, a positive exposure
response for lymphoid tumors in both sexes for cumulative exposure, with elevated odds rations in males in the highest quartile.
The adult-based unit risk estimates for lymphoid cancer were 2.6  10−3 per mg/m3, 7.0  10−4 per mg/m3 for female breast cancer,
and 3.0  10−3 per mg/m3 for both cancer types combined. After the application of standard age-dependent adjustment factor, the
full lifetime total cancer unit risk was 5.0  10−3 per mg/m3 (EPA, 2016).
IARC has classified ethylene oxide as carcinogenic to humans (Group 1) (IARC, 1987, 2012) based on limited evidence for a causal
association between exposure to EO and the 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 EO carcinogenicity (ATSDR, 2022).
The Texas Commission in Environmental Quality (TCEQ, 2020) assessed the carcinogenicity of EO and came to the conclusion
that ethylene oxide is likely to be a carcinogenic to humans. In addition, the TCEQ determined that the epidemiological data support
the association between EO exposure and lymphohematopoietic tumors, but not the association with breast cancer (ATSDR, 2022).

Animal
Cancer is generally considered the critical end point for chronic exposures to ethylene oxide. Animal studies have reported
incidences of several tumor types related to EO exposure. A significant increase of brain gliomas, peritoneal mesotheliomas, and
mononuclear cell leukemia have been observed in rats exposed by inhalation for up to 2 years at 100 pm and 50 ppm respectively
(Lynch et al., 1984a, 1984b). In lifetime studies, male and female rats exposed to airborne concentrations of 10, 33, or 100 ppm for
6 h day−1, 5 days week−1 exhibited several treatment-related tumors including mononuclear cell leukemia, peritoneal mesotheli-
oma, and brain tumors (Garman et al., 1985, 1986; Snellings et al., 1984). Ethylene oxide also produced carcinogenic responses in
multiple organs (lung, Harderian gland, immune system, uterus, and mammary gland) of mice exposed to ethylene oxide for 102
weeks at concentrations of 50 and 100 ppm for 6 h day−1, 5 days week−1 (NTP, 1987).
494 Ethylene oxide (EO)

Human
A few early epidemiological studies suggested that ethylene oxide exposures were associated with lymphohematopoietic tissue
cancers (i.e., myeloid and lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma) as well as cancers of the breast,
stomach, pancreas, and brain. However, subsequent studies are either inconclusive in this regard or do not support the earlier
observations. Indeed, the analysis of the combined UCC (Dabney, 1979) and NIOSH (Steenland et al., 2004) occupational cohorts
of over 19,000 industrial and hospital workers with quantitative exposure estimates failed to demonstrate an association between
ethylene oxide exposures and any of the purported carcinogenic effects. Although acknowledging the limited evidence for
carcinogenicity in humans, the International Agency for Research on Cancer (IARC) has classified ethylene oxide as a known
human carcinogen (Group 1) (IARC, 1987, 2012) based on limited evidence regarding exposure to EO and lymphatic and
hematopoietic cancers and breast cancer in humans (ATSDR, 2022) and sufficient evidence in experimental animals and strong
genotoxic mechanism of action for EO carcinogenicity (ATSDR, 2022).

Clinical management

If contact with the liquid or its solutions occurs, affected areas should be flushed thoroughly with water for at least 15 min. The areas
should be observed for burns or resulting irritation. In case of inhalation of ethylene oxide, the victim should be moved to fresh air,
an airway should be established, and respiration should be maintained as necessary. The victim should be monitored for irritation,
bronchitis, and pneumonitis. If excessive exposure occurs, hospitalization and monitoring for delayed pulmonary edema is
recommended.

Ecotoxicology

The 24-, 48-, and 96-h LC50 values for fish range from 84 to 90 mg/L (Conway et al., 1983). For aquatic freshwater invertebrates, the
48-h LC50 value is 212 mg/L (Conway et al., 1983). In a static test conducted according to the method described in EPA-660/3-
75-009 the 48-h EC50 for Daphnia magna was in the range of 137–300 mg/L (freshwater flea and 490–1000 mg/L (brine shrimp))
(Conway et al., 1983). The 16 h half-maximal inhibitory concentration (IC50) for ethylene oxide on activated sludge organisms is
10–100 mg/L. The breakdown products of ethylene oxide in water, ethylene glycol and ethylene chlorohydrin, appear to be less
acutely toxic than ethylene oxide. The 24-h LC50 values in fish, freshwater flea, and brine shrimp for ethylene glycol and ethylene
chlorohydrin are >10,000 to >20,000 mg/L and 675 to >1000 mg/L, respectively (Conway et al., 1983).

Other hazards

Ethylene oxide vapor is extremely flammable at concentrations ranging from 3% to 100% and subject to explosive decomposition.
Being heavier than air, ethylene vapors can travel undetected along the ground. Although liquid ethylene oxide is relatively stable,
contact with acids, bases, or heat, particularly in the presence of metal chlorides and oxides, can lead to violent polymerization.

Exposure standards and guidelines

International occupational exposure limits (OELs) generally range from 0.1 to 39 ppm as an 8-h TWA, with 1 ppm being the most
common value. The US Occupational Safety and Health Administration (OSHA) and the American Conference of Governmental
Industrial Hygienists (ACGIH) have established an 8-h TWA OEL for ethylene oxide of 1 ppm. OSHA has also established a 15-min
excursion limit of 5 ppm as well as an action level of 0.5 ppm, which if met or exceeded as an 8-h TWA for 30 or more days per year
triggers additional requirements. Ethylene oxide has been judged a potential/suspected (ACGIH, National Institute for Occupa-
tional Safety and Health) (NIOSH, 2022) or known (IARC, National Toxicology Program) (NTP, 2021) human carcinogen. For this
reason, NIOSH recommends workplace exposure to be maintained below 0.1 ppm as an 8-h TWA. NIOSH also lists a concentration
of 800 ppm ethylene oxide as immediately dangerous to life or health (OSHA.gov/chemicaldata/575).
In 2016, the US EPA updated the Integrated Risk Information System (IRIS) assessment for Ethylene Oxide (US EPA, 2016). The
IRIS unit risk estimate (URE) of 1-in-a-million extra risk specific concentration was set at 0.1 ppt. This URE is extremely conservative
and falls significantly below the air background levels of EO (in ppb) (Kirman and Hays, 2017; Jain, 2020; TCEQ, 2020). However,
EPA indicated that this level was set to be protective of the general public, from childhood through adulthood and retirement,
(US EPA, 2016) and was not appropriate for occupational settings. TCEQ finalized their own URE of 240 ppt for EO in 2020
(TCEQ, 2020).
 Ethylene oxide (EO) 495

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Further reading
European Chemicals Agency Ethylene Oxide (CAS 75-21-8). https://echa.europa.eu/registration-dossier/-/registered-dossier/15813/. Accessed April 23, 2020.
Evans JS, Rhomberg LR, Williams PL, Wilson AM, and Baird JS (2001) Reproductive and developmental risks from ethylene oxide: A probabilistic characterization of possible regulatory
thresholds. Risk Analysis 21: 697–717.
Fuchs R (2011) Site-specific mutagenicity of O6- and N7-alkylguanine adducts. In: Presented at the 42nd Environmental Mutagen Society Meeting, Quebec, Canada, 15–19 October.
Gresie-Brusin DF, Kielkowski D, Baker A, et al. (2007) Occupational exposure to ethylene oxide during pregnancy and association with adverse reproductive outcomes. International
Archives of Occupational and Environmental Health 80(7): 559–565. https://doi.org/10.1007/s00420-006-0163-y.
Hemminki K, Mutanen P, Saloniemi I, et al. (1982) Spontaneous abortions in hospital staff engaged in sterilizing instruments with chemical agents. British Medical Journal (Clinical
Research Ed.) 285(6353): 1461–1463. https://doi.org/10.1136/bmj.285.6353.1461.
Kirman CR, Li AA, Sheehan PJ, Bus JS, Lewis RC, and Hays SM (2021) Ethylene oxide review: Characterization of total exposure via endogenous and exogeneous pathways and their
implications to risk assessment and risk management. Journal of Toxicology and Environmental Health—Part B: Critical Reviews 24(1): 1–29.
Klees JE, Bowler RM, Shore M, and Becker CE (1990) Neuropsychologic “impairment” in a cohort of hospital workers chronically exposed to ethylene oxide. Journal of Toxicology.
Clinical Toxicology 28: 21–28.
Marsh GM, Keeton KA, Riordan AS, Best EA, and Benson SM (2019) Ethylene oxide and risk of lympho-hematopoietic cancer and breast cancer: A systemic literature review and meta-
anlyisis. International Archives of Occupational and Environmental Health 92: 919–939.
OSHA Occupational Chemical Database (2020) Ethylene Oxide. OSHA. Last updated 12/28/2020. OSHA.gov/chemicaldata/575.
Pottenger LH, Boverhof DR, and Waechter JM (2019) Epoxy compounds—Olefin oxides, aliphatic glycidyl ethers and aromatic monoglycidyl ethers. In: Bingha E and Cohrssen B (eds.)
Patty’s Toxicology, 6th edn. New York: Wiley.
Rowland AS, Baird DD, Shore DL, et al. (1996) Ethylene oxide exposure may increase the risk of spontaneous abortion, preterm birth, and post term birth. Epidemiology 7(4):
363–368. https://doi.org/10.1097/00001648-199607000-00005.
Setzer JV, Brightwell WS, Russo JM, Johnson BL, Lynch DW, Madden G, Burg JR, and Sprinz H (1996) Neurophysiological and neuropathological evaluation of primates exposed to
ethylene oxide and propylene oxide. Toxicology and Industrial Health 12: 667–682.
Snellings WM, Nachreiner DJ, and Pottenger LH (2011) Ethylene oxide: Acute four-hour and one-hour inhalation toxicity testing in rats. Journal of Toxicology 2011: 910180.
Swenberg JA, Lu K, Moeller BC, Gao L, Upton PB, Nakamura J, and Starr TB (2011) Endogenous versus exogenous DNA adducts: Their role in carcinogenesis, epidemiology, and risk
assessment. Toxicological Sciences 120: S130–S145.
Valdez-Flores C, Sielken RL Jr, and Teta MJ (2010) Quantitative cancer risk assessment based on NIOSH and UCC epidemiological data for workers exposed to ethylene oxide.
Regulatory Toxicology and Pharmacology 56: 312–320.

Relevant websites

http://apps.echa.europa.eu/registered/registered-sub.aspx :European Chemicals Agency. Information on Ethylene Oxide.

http://monographs.iarc.fr/index.php :International Agency for Research on Cancer. Monograph on Ethylene Oxide.
http://ntp-server.niehs.nih.gov/ :National Toxicology Program, Report on Carcinogens. Ethylene Oxide.
http://www.atsdr.cdc.gov :Agency for Toxic Substances and Disease Registry. Toxicological Profile for Ethylene Oxide.
http://www.inchem.org :Concise International Chemical Assessment Document 54, search for Ethylene Oxide.