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ETHYLENE OXIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ethylene oxide is a compressed gas that is very reactive.

Specific Substances

    1) Amprolene
    2) Anprolene
    3) Dimethylene oxide
    4) 1,2-Epoxyethane
    5) Ethene oxide
    6) ETO
    7) Merpol
    8) Oxacyclopropane
    9) Oxane
    10) Oxidoethane
    11) Oxirane
    12) Oxyfume
    13) T-gas
    14) CAS 75-21-8
    15) E.O. (ETHYLENE OXIDE)
    16) EPOXYETHANE (FRENCH)
    17) ETO (ETHYLENE OXIDE)
    1.2.1) MOLECULAR FORMULA
    1) C2-H4-O CH2-CH2-O

Available Forms Sources

    A) FORMS
    1) Ethylene oxide is generally available in grades of 99.7% purity (as technical grade) or higher (100% with no acetylene as commercial grade) (CGA, 1999; HSDB , 2002).
    2) Ethylene oxide in gas form is explosive at concentrations above 3 percent, and it must be mixed with carbon dioxide or fluorocarbon (HSDB , 2002):
    a) Carboxide is a nonflammable mixture of 10% by weight of ethylene oxide in carbon dioxide. Sterilant 12 is a nonflammable mixture of 12% by weight in fluorocarbon 12.
    B) SOURCES
    1) Ethylene oxide does not occur naturally. Ethylene oxide is produced by the oxidation of ethylene. It is also produced as a product of the combustion of hydrocarbon fuels and naturally-occurring hydrocarbons (Ashford, 2001; Harbison, 1998) Howard, 1990).
    C) USES
    1) Ethylene oxide is used as a chemical intermediate in the production of ethylene glycol and higher glycols (Budavari, 1996; CGA, 1999).
    2) It is used as a fumigant (fungicide and insecticide) and disinfectant (NTP , 2001a).
    a) It is used to fumigate furniture, carpets, books and paper, motor oil, soil, animal bedding, clothing (leather, furs, textile), beekeeping equipment, and transport vehicles (Hayes, 1982; (NTP , 2001a). Honey samples have also been shown to show ethylene oxide residues (NTP , 2001a).
    b) Although a much smaller amount of ethylene oxide is used as sterilant, it is this use that the highest occupational exposure levels have been measured (IARC, 1997; (Zenz, 1994)
    1) It is used in gas sterilizers at health care facilities. Substantial quantities of ethylene oxide may remain in treated materials after gas sterilization. An aeration phase is required, the length of which depends on the material being treated (Grant, 1993; HSDB , 2002). Such use in sterilization was starting to be replaced by other systems by the mid-1990s, (NTP , 2001a), and in Germany, severe restrictions are in place regarding the use as sterilant (Personal Communication, 1996).
    2) It is used as a fumigant in foods such as cocoa, flour, dried egg powder, nuts, coconut, fruits, dehydrated vegetables, spices, and seasoning. Residual amounts of ethylene oxide may be found temporarily on the foods treated. Ethylene oxide may generate ethylene glycol under the temperature and pressure used for sterilization. Additionally, it may react with foods being treated (for example, with water and inorganic halides from foods and produce glycols and halohydrins). Persistence of ethylene oxide and its by-products depends on the grain size; type of food aeration procedures and temperature; and storage conditions and cooking conditions (Hayes, 1982; (NTP , 2001a).
    a) Black and herb teas have also been shown to show ethylene oxide residues (NTP , 2001a).
    b) It is used to accelerate the maturation of tobacco leaves (NTP , 2001a).
    3) Ethylene oxide has been investigated for use as an agent to improve wood durability (NTP , 2001a).
    4) It is used as a petroleum demulsifier (Lewis, 1998).
    5) It is used as a rocket propellant (Lewis, 1998).
    6) It is used to lower the viscosity of water for fire fighting (Lewis, 1998).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Early signs and symptoms of exposure to ethylene oxide (ETO) may include eye, nose, and throat irritation and noticing a sweet or peculiar taste in the mouth.
    B) Delayed effects may include headache, nausea, vomiting, diarrhea, abdominal pain, dyspnea, cough, weakness, lethargy, numbness, incoordination and vertigo. Acute effects such as pneumonia, pulmonary edema, respiratory failure, asthma, cardiac arrhythmias, seizures, allergic reaction, paralysis and coma may also be seen.
    C) Direct contact with the eye can cause severe ocular damage. Direct dermal contact with the gas or liquid ethylene oxide can cause blistering, severe chemical burns and tissue necrosis. Evaporation of the liquid from the skin may cause frostbite.
    D) Occupational exposure to ethylene oxide may be linked with spontaneous abortions and other adverse reproductive effects. ETO is known to cause cancer in laboratory animals and is a probable human carcinogen. Leukemia and non-Hodgkin's lymphoma have been primarily associated with ETO. Cases of Hodgkin's disease, stomach, breast and pancreatic cancer, lymphosarcoma and reticulosarcoma have also been reported.
    E) CNS and musculoskeletal abnormalities have been reported in the offspring of laboratory animals.
    0.2.3) VITAL SIGNS
    A) Pulmonary irritation is likely after inhalation; dyspnea may occur.
    0.2.4) HEENT
    A) Ocular irritation and conjunctivitis may be seen on splash contact with the eyes. ETO has been implicated as a causal agent for the formation of cataracts.
    B) Irritation of eyes, nose and throat, as well as a peculiar taste, are the early symptoms of ethylene oxide exposure.
    0.2.5) CARDIOVASCULAR
    A) Ethylene oxide has no appreciable effect on the cardiovascular system until respiratory compromise is serious enough to cause anoxia.
    0.2.6) RESPIRATORY
    A) Pulmonary irritation is a common symptom after inhalation. Pulmonary edema may be seen with acute exposures. Pneumonia may be a complication of ethylene oxide exposure. A rare report of asthma has also been reported.
    0.2.7) NEUROLOGIC
    A) Convulsive movements, twitching, malaise, lethargy, headache, seizures, and dizziness have been reported. Serious exposure may result in coma. Chronic exposure may result in peripheral and central nervous system effects, including neuropsychiatric symptoms, cognitive dysfunction, and polyneuropathies.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, and diarrhea may occur.
    0.2.10) GENITOURINARY
    A) Severe cases of ethylene oxide exposure may result in renal damage.
    0.2.13) HEMATOLOGIC
    A) Severe cases of ethylene oxide exposure may result in cyanosis.
    B) Anemia developed in rats after chronic exposure.
    0.2.14) DERMATOLOGIC
    A) Pure anhydrous ETO does not injure dry skin, but solutions have a vesicant action. Exposure to the liquid or gas may cause irritation or burns to moist skin. ETO may also cause contact dermatitis, allergic contact dermatitis, thermal burns, frostbite, edema, erythema, vesiculation, blebs, and desquamation.
    0.2.20) REPRODUCTIVE
    A) Ethylene oxide has been fetotoxic and teratogenic in experimental animals.
    0.2.21) CARCINOGENICITY
    A) Ethylene oxide has been linked with leukemia, stomach, brain and pancreatic cancer, lymphatic cancer, hematopoietic cancer, non-Hodgkin lymphoma, and Hodgkin disease.
    B) The evidence for human and animal carcinogenicity and for genotoxicity has been extensively reviewed (Their & Bolt, 2000).

Laboratory Monitoring

    A) Chest film should be considered to evaluate the extent of pulmonary involvement after inhalation.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS - Oral exposure to ethylene oxide is unusual. Because of the volatility of the liquid, and the extreme reactivity of ethylene oxide, it is questionable whether emesis would be of value. Activated charcoal may be of more benefit.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) CATHARTIC - Ethylene oxide is irritating and probably serves as its own cathartic.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) Clothing should be removed and washed thoroughly.
    C) TREATMENT - If significant amounts of ethylene oxide have been inhaled, immediate hospitalization and observation for 72 hours are recommended. There may be delayed onset of pulmonary edema.
    D) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION - If liquid is spilled on the skin, allow ethylene oxide to vaporize before washing with water. Dermal exposure should be washed with water, from a hose or shower. A physician should examine the exposed area if irritation or pain persists after the area is washed.

Range Of Toxicity

    A) 30 mg/kg caused nausea, vomiting, and diarrhea for 2 hours in animals. The permissible exposure limit in air is 1 ppm as an eight hour TWA. The OSHA action level is 0.5 ppm.

Clinical Effects

Summary Of Exposure

    A) Early signs and symptoms of exposure to ethylene oxide (ETO) may include eye, nose, and throat irritation and noticing a sweet or peculiar taste in the mouth.
    B) Delayed effects may include headache, nausea, vomiting, diarrhea, abdominal pain, dyspnea, cough, weakness, lethargy, numbness, incoordination and vertigo. Acute effects such as pneumonia, pulmonary edema, respiratory failure, asthma, cardiac arrhythmias, seizures, allergic reaction, paralysis and coma may also be seen.
    C) Direct contact with the eye can cause severe ocular damage. Direct dermal contact with the gas or liquid ethylene oxide can cause blistering, severe chemical burns and tissue necrosis. Evaporation of the liquid from the skin may cause frostbite.
    D) Occupational exposure to ethylene oxide may be linked with spontaneous abortions and other adverse reproductive effects. ETO is known to cause cancer in laboratory animals and is a probable human carcinogen. Leukemia and non-Hodgkin's lymphoma have been primarily associated with ETO. Cases of Hodgkin's disease, stomach, breast and pancreatic cancer, lymphosarcoma and reticulosarcoma have also been reported.
    E) CNS and musculoskeletal abnormalities have been reported in the offspring of laboratory animals.

Vital Signs

    3.3.1) SUMMARY
    A) Pulmonary irritation is likely after inhalation; dyspnea may occur.
    3.3.2) RESPIRATIONS
    A) Pulmonary irritation is likely after inhalation; dyspnea may occur.

Heent

    3.4.1) SUMMARY
    A) Ocular irritation and conjunctivitis may be seen on splash contact with the eyes. ETO has been implicated as a causal agent for the formation of cataracts.
    B) Irritation of eyes, nose and throat, as well as a peculiar taste, are the early symptoms of ethylene oxide exposure.
    3.4.3) EYES
    A) CONJUNCTIVITIS - Ocular irritation and conjunctivitis may be seen if ethylene oxide liquid is splashed in the eyes (Fisher, 1984), or if patients are exposed to the gas (Jay et al, 1982).
    B) CATARACT FORMATION - ETO has been implicated as a causal agent for the formation of cataracts following chronic exposures (Jay et al, 1982).
    1) Cataracts were reported in men who worked on a leaking sterilizer and in hospital-sterilizing-unit workers who were exposed to levels up to 90 ppm (Bingham et al, 2001).
    C) CORNEAL DAMAGE - Authors have reported corneal injury with splash contacts. High concentrations of the vapor have been irritating to the eyes of both animals and humans (Bingham et al, 2001).
    1) Ethylene oxide induced moderate eye irritation in rabbits in the Standard Draize Test (RTECS , 2001).
    2) At approximately 600 ppm, eye irritation begins (Baselt, 2001).
    D) BURNS - Eye contact with ethylene oxide may cause severe burns (Sittig, 1991).
    E) NECROSIS - Necrosis of the eyes may result from exposure to dilute ethylene oxide solutions (Bingham et al, 2001).
    F) CORNEAL OPACITY - Corneal opacities have been seen in guinea pigs and monkeys after ethylene oxide exposure (Bingham et al, 2001).
    3.4.5) NOSE
    A) Nose irritation occurs at approximately 600 ppm (Baselt, 2000).
    B) Transient blunting of the sense of smell was noted in a man exposed to ethylene oxide (Hayes & Laws, 1991).

Cardiovascular

    3.5.1) SUMMARY
    A) Ethylene oxide has no appreciable effect on the cardiovascular system until respiratory compromise is serious enough to cause anoxia.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Ethylene oxide has no appreciable effect on the cardiovascular system until respiratory compromise is serious enough to cause anoxia (Bingham et al, 2001; Clayton & Clayton, 1993) Marchard et al, 1958).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ECG ABNORMAL
    a) Overexposure to ethylene oxide may cause ECG abnormalities (Budavari, 1996).
    1) Baselt et al (2001) report that there is no evidence of cardiovascular effects, such as ECG changes, after ethylene oxide exposure.

Respiratory

    3.6.1) SUMMARY
    A) Pulmonary irritation is a common symptom after inhalation. Pulmonary edema may be seen with acute exposures. Pneumonia may be a complication of ethylene oxide exposure. A rare report of asthma has also been reported.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) Pulmonary irritation is a common symptom after inhalation of ethylene oxide. A typical case was described by Glaser (1977). Symptoms may range from mild irritation of the nasal passages and bronchioles to severe cough and dyspnea.
    2) Respiratory tract irritation has been reported after exposure to ethylene oxide at unknown concentrations (Sittig, 1991).
    3) CASE REPORT - A case of asthma secondary to ethylene oxide sensitivity has been reported. The patient reacted to latex gloves and had a positive RAST to ethylene oxide and negative responses to latex exposure. The exposure was presumed to be from the ethylene oxide used to sterilize the latex gloves (Verraes & Michel, 1995).
    B) ACUTE LUNG INJURY
    1) Pulmonary edema may occur in severe cases (Lewis, 1997). It also may be seen with acute exposure. One case in which an autopsy was done on a human fatality reported congested lungs (Gross et al, 1979).
    2) Fluid in the lungs has been reported after exposures to ethylene oxide at unknown concentrations (Sittig, 1991).
    C) PNEUMONIA
    1) Pneumonia or a secondary lung infection can occur as a complication of exposure to ethylene oxide (Bingham et al, 2001)
    D) DYSPNEA
    1) Dyspnea may occur when ethylene oxide fumes are inhaled (Lewis, 1997).
    E) REACTIVE AIRWAYS DYSFUNCTION SYNDROME
    1) Reactive airway dysfunction syndrome (RADS), an asthma-like illness, may occur in individuals who inhale ethylene oxide in a single high-dose exposure (Goldfrank, 1998).

Neurologic

    3.7.1) SUMMARY
    A) Convulsive movements, twitching, malaise, lethargy, headache, seizures, and dizziness have been reported. Serious exposure may result in coma. Chronic exposure may result in peripheral and central nervous system effects, including neuropsychiatric symptoms, cognitive dysfunction, and polyneuropathies.
    3.7.2) CLINICAL EFFECTS
    A) SPASMODIC MOVEMENT
    1) Convulsive movements, twitching and random muscle spasms have been reported (Salinas et al, 1981).
    B) SEIZURE
    1) Seizures have been reported after ethylene oxide exposure at unknown concentrations (Sittig, 1991).
    2) Seizures occurred in an individual accidentally exposed to an estimated 500 ppm for 2 or 3 minutes (Grant, 1993).
    3) After being exposed to leaking ethylene oxide for 3 weeks at up to 70 hours per week, a man experienced recurrent major motor seizures at intervals of 20-30 minutes (Hayes & Laws, 1991).
    4) Convulsions have been cited as possible human systemic effects of inhalation exposure to ethylene oxide (Lewis, 2000).
    a) A 43-year old female experienced convulsive movements of legs and arms after being exposed to no more than 500 ppm ethylene oxide for 2 to 3 minutes (Hayes & Laws, 1991).
    C) MALAISE
    1) Malaise and lethargy may occur immediately or for up to one week after exposure (Salinas et al, 1981).
    2) Malaise was reported by a patient 2 weeks after exposure to ethylene oxide (Hayes & Laws, 1991).
    D) DIZZINESS
    1) Dizziness has been reported after a two- to three-minute exposure to a broken vial (Hayes & Laws, 1991; Salinas et al, 1981).
    E) HEADACHE
    1) Headache is a common symptom seen after exposure (ACGIH, 1991) Brashear et al, 1995; Glaser, 1997; (Lewis, 1997).
    F) DROWSY
    1) Drowsiness may follow inhalation exposure (Lewis, 1997).
    G) COMA
    1) Serious exposure may result in stupor progressing to coma (Marchand et al, 1958).
    2) Temporary unconsciousness occurred in an individual accidentally exposed to an estimated 500 ppm for 2 to 3 minutes (Grant, 1993).
    H) NEUROPATHY
    1) Chronic exposures may result in disabling neuropathies of both the upper and lower limbs. Full partial recovery may occur after several months (Bingham et al, 2001; Salinas et al, 1981).
    a) Symptoms include numbness of the feet, leg buckling, weakness and incoordination of lower extremities, tingling of extremities, cramps, absent or decreased reflexes, nervousness, difficulty in sleeping, nystagmus, ataxia, slurred speech, stocking-and-glove sensory loss and loss of Achilles tendon reflex (Bingham et al, 2001; Estrin et al, 1990; Finelli et al, 1983; Goldfrank, 1998).
    b) CASE SERIES - Hospital workers with 6-month to 10-year exposure to ethylene oxide showed slower psychomotor speed but similar nerve conduction velocities and EEG spectral analysis compared with a control group of unexposed hospital workers (Estrin et al, 1990).
    c) CASE SERIES - Twelve nurses with occupational exposure to ethylene oxide demonstrated peripheral and central nervous system toxicity. Findings of axonal injury included sensory dysesthesias and grip weakness (Brashear et al, 1995).
    d) CASE SERIES - Symptoms of multiple neuropathy were reported in four of six workers chronically exposed to ethylene oxide in a Japanese factory producing medical appliances. Symptoms noted were sensory desturbance of the lower limbs gradually extending to the upper limbs and other parts of the body, irregular gait, posterior symptoms, motor neuron symptoms and cranial nerve and autonomic nerve disturbance. When workers were removed from ethylene oxide exposure, the symptoms disappeared (ACGIH, 1991).
    e) CASE SERIES - Cases of subacute motor polyneuropathy have been found in sterilizing workers that were exposed to ethylene oxide. Signs included loss of reflexes, weakness, bilateral foot drop, neuropathologic changes on EMG in the lower extremities, and, in some cases, axonal degeneration (shown by sural nerve biopsy). Once removed from exposure, symptoms were resolved in 1-7 months. Sensory loss has also been associated with the subacute motor polyneuropathy (Hathaway et al, 1996).
    f) CASE SERIES - Of four men exposed to an intermittently leaking sterilizer at approximately 500 ppm for 2-8 weeks, three developed a reversible peripheral neuropathy (Baxter et al, 2001).
    I) AMNESIA
    1) Cognitive impairment, including emotional lability, impaired concentration, and memory impairment were described in a 29-year-old woman who worked for 10 years adjacent to an ethylene oxide sterilizer. The 8-hour time-weighted average (TWA) was 2.4 ppm (OSHA standard 0.5 ppm), and concentrations next to the sterilizer were 4.2 ppm (Crystal et al, 1988).
    2) CASE SERIES - Hospital workers with chronic ethylene oxide exposure showed poorer neuropsychological performance among those exposed (Estrin et al, 1990).
    a) A 6-month to 10-year history of working in proximity to ethylene oxide gas sterilizers qualified the 10 hospital workers as exposed. Spot air sampling in the sterilizing room showed levels of 15 and 250 ppm on two separate determinations.
    b) The exposed group performed more poorly on the Wechsler Memory Scale visual reproduction subtest.
    3) CASE SERIES - Of 12 nurses exposed to ethylene oxide, 10 reported memory disturbances. Generalized cerebral atrophy on MRI was observed in 2 patients (Brashear et al, 1995).
    J) MOOD SWINGS
    1) Higher levels of anxiety and depression were reported among hospital workers with prolonged exposure to ethylene oxide (Estrin et al, 1990).
    K) INSOMNIA
    1) Sleeplessness has been reported after ethylene oxide exposures (Baxter et al, 2000).
    L) DISTURBANCE IN THINKING
    1) A group of individuals exposed to ethylene oxide at concentrations of 15-250 ppm had a statistically significant lower P300 amplitude, as well as a poorer performance on neuropsychological test involving psychomotor speed, than the control group (ACGIH, 1991).
    M) TOXIC ENCEPHALOPATHY
    1) Of four men exposed to an intermittently leaking sterilizer (approximately 500 ppm), one developed acute encephalopathy (Baxter et al, 2000).
    N) FATIGUE
    1) Increased fatiguability has been reported by individuals exposed to ethylene oxide for 2 to 4 years (Hayes & Laws, 1991).
    O) CHRONIC POISONING
    1) Both peripheral and central nervous system effects may be reported after chronic exposure, including peripheral nerve dysfunction and axonal injury with polyneuropathy, sensory dysesthesias and grip weakness, neuropsychiatric symptoms, cognitive dysfunction and generalized cerebral atrophy on MRI.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, and diarrhea may occur.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) Doses of 30 mg/kg caused nausea, vomiting and diarrhea for two hours (Clayton & Clayton, 1981). Vomiting may occur after oral or inhalation exposures (Bingham et al, 2001; Glaser ZR, 1977).
    2) Nausea and vomiting can occur after exposure to unknown concentrations of ethylene (Sittig, 1991).
    3) Nausea and vomiting occurred in three of six men after a 3- to 4-hour dermal exposure to a 1-percent solution of aqueous ethylene oxide (Hayes & Laws, 1991).
    4) In cases of severe inhalation exposure, protracted vomiting and nausea may occur 2 to 4 hours after exposure (Baselt, 2000).
    5) Nausea and vomiting were experienced by an individual exposed to ethylene oxide for 3 weeks for as much as 70 hours/week (Hayes & Laws, 1991).

Genitourinary

    3.10.1) SUMMARY
    A) Severe cases of ethylene oxide exposure may result in renal damage.

Hematologic

    3.13.1) SUMMARY
    A) Severe cases of ethylene oxide exposure may result in cyanosis.
    B) Anemia developed in rats after chronic exposure.
    3.13.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) Cyanosis may occur after severe exposure to ethylene oxide (Budavari, 1996) Lewsi, 1997).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) Rats exposed to ethylene oxide 500 ppm 6 hours/day, 3 times a week for 13 weeks developed a normocytic, normochromic anemia. The mechanism was presumed to be interference with heme synthesis because of accumulation of porphyrins (Fujishiro et al, 1990). The significance of this in humans is unknown.

Dermatologic

    3.14.1) SUMMARY
    A) Pure anhydrous ETO does not injure dry skin, but solutions have a vesicant action. Exposure to the liquid or gas may cause irritation or burns to moist skin. ETO may also cause contact dermatitis, allergic contact dermatitis, thermal burns, frostbite, edema, erythema, vesiculation, blebs, and desquamation.
    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) Pure anhydrous ETO does not produce primary injury to dry skin, but solutions have a vesicant action (Fisher, 1984).
    2) Extensive blister formation may occur from contact with a 40 to 80 percent water solution (Sittig, 1991).
    3) Blebs the size of lemons were reported in individuals exposed to a 1 percent solution of ethylene oxide (Hayes & Laws, 1991).
    B) CHEMICAL BURN
    1) Exposure to the liquid or gas may cause irritation or burns of the skin (Marchand et al, 1958).
    2) CASE SERIES - Third-degree burns on the hands, forehead, axillae, genitalia and periumbilical region were reported in workers after cleaning a storage tank containing traces of ethylene oxide (Fisher, 1984).
    3) CASE SERIES - Burns of the buttocks and back were seen in patients who wore improperly aerated sterilized gowns. The residual level of ETO in these gowns was 3,600 to 10,800 ppm.
    4) CASE SERIES - A 0.75- to 1.0-minute exposure to a 40 to 60 percent ethylene oxide solution caused second-degree burns in tests in which human volunteers permitted the aqueous solutions to be placed on small areas of their forearms.
    a) First-degree burns were the result of a 50- to 60-minute exposure to a 1 percent solution. A 75-minute (or more) exposure to this same concentration resulted in second-degree burns.
    b) The appearance of erythema and vesication, large bleb formation, marked desquamation, and residual pigment formation occurred after a latent period (Hayes & Laws, 1991).
    5) Very serious dermal burns were found on 19 hospital patients exposed to operating room gowns and sheets that had been sterilized with ethylene oxide. Residual ethylene oxide levels were 3,600 to 18,000 ppm (Baselt, 2000).
    6) Maximum residue allowed in clothing (standards set by Health Industries Association) is 200 ppm. Experiments show the lowest level that will produce skin irritation in non-sensitive patients is 1000 ppm (Fisher, 1984).
    C) CONTACT DERMATITIS
    1) Contact dermatitis has been reported in minor or chronic exposures (Fisher, 1984).
    2) A red, raised rash secondary to direct skin contact has been reported (Brashear et al, 1995).
    D) HYPERSENSITIVITY REACTION
    1) Allergic contact dermatitis has IgE, IgG antibody and hapten specificity. This condition occurs in patients exposed to plastic tubing, hemodialysis equipment, face mask, and gauze that contain traces of ETO (Fisher, 1984).
    2) Patients undergoing long-term dialysis with allergic reactions during dialysis have a significantly increased incidence of sensitivity to ethylene oxide as determined by RAST test (D'Ambrosio et al, 1997).
    3) Three of eight human volunteers used to assess the dermal irritancy of ethylene oxide in various concentrations developed dermal hypersensitivity (Hayes & Laws, 1991).
    E) FROSTBITE
    1) Evaporation may cause cooling rapid enough to produce burns similar to frostbite (Bingham et al, 2001). Ongoing contact with human skin, such as contaminated clothing, can cause severe chemical burns and blistering.
    2) Frostbite may result from contact with the pure liquid (Sittig, 1991).
    3) Immediate and painful frosting appeared when undiluted ethylene oxide was sprayed on the skin. The injured area developed an itching urticarial wheal, which disappeared after 4 hours (Hayes & Laws, 1991).
    F) ULCER
    1) Contact with an aqueous solution of ethylene oxide can result in erosion of the skin (Margan, 1993).
    G) EDEMA
    1) Edema and erythema occurred 1 to 5 hours after application of ethylene oxide solutions to human volunteers (Hathaway et al, 1996).
    H) GENERALIZED EXFOLIATIVE DERMATITIS
    1) Desquamation occurred after vesiculation and bleb formation when human volunteers were dermally exposed to ethylene oxide solutions (Hathaway et al, 1996).
    I) DISORDER OF SKIN
    1) Skin sensitization occurs from chronic, long-term exposures to ethylene oxide (ACGIH, 1991).

Reproductive

    3.20.1) SUMMARY
    A) Ethylene oxide has been fetotoxic and teratogenic in experimental animals.
    3.20.2) TERATOGENICITY
    A) FETOTOXICITY
    1) ANIMAL STUDIES
    a) In rat studies, fetotoxicity, changes in the live birth index, and specific developmental abnormalities in the craniofacial area (including nose and tongue) and musculoskeletal system were observed. In mouse studies, fetal death, fetotoxicity, specific developmental abnormalities in the musculoskeletal system and changes in homeostasis and litter size were observed (RTECS , 2001).
    b) IP injection of 125 mg/kg ethylene oxide at various times up to 7 hours after mating increased loss of conceptuses, skeletal malformations, external defects and delayed ossification evident by day 17 of gestation in mice; cleft sternum was especially evident in the group exposed 3 hours after mating (Polifka et al, 1996).
    c) Ethylene oxide was teratogenic in rats exposed to a high dose of 150 mg/kg on days 6 to 15 of gestation, where maternal toxicity was present (Shepard, 1995). Early developmental stages appear to be more sensitive to ethylene oxide in mice (Generoso et al, 1987). A single exposure to a very high dose of 1200 ppm either 1 or 6 hours after mating induced CNS defects (hydrops and eye defects), cleft palate, and defects of the heart, abdominal wall, and extremities and/or tail in the offspring (Rutledge & Generoso, 1989). Exposures 9 to 25 hours after mating had little effect (Rutledge & Generoso, 1989). Brief daily exposure to 800 or 1200 ppm of ethylene oxide produced fetotoxicity as indicated by decreased fetal weight, but maternal toxicity was evident at the higher dose (Saillenfait et al, 1996).
    d) Ethylene oxide induced skeletal malformations in CD-1 mice at high IV doses up to 150 mg/kg on days 6 to 8 of gestation (Laborde & Kimmel, 1980; 21). It induced skeletal defects and CNS defects, including exencephaly (Schardein, 1994; Kimmel & LaBorde, 1979).
    e) Ethylene oxide was not teratogenic in rabbits when administered by inhalation at 150 ppm for 7 hours per day on days 1 to 16 or days 7 to 16 of gestation (Hayes & Laws, 1991). It was also not teratogenic in the rabbit by the IV route (Schardein, 1994; Kimmel et al, 1982).
    B) CNS CONGENITAL MALFORMATION
    1) ANIMAL STUDIES
    a) In mice, ethylene oxide is active as early as 1 to 6 hours after conception and induces eye and other defects (Schardein, 1993).
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) ABORTION
    a) A higher frequency of spontaneous abortions were found in hospital workers exposed to ethylene oxide in sterilizing operations during pregnancy. The adjusted rate was 16.1 percent in the exposed group versus 7.8 percent in the nonexposed group (Hathaway et al, 1996).
    b) An increase in abortions were reported in production plant workers exposed to ethylene oxide (Schardein, 1993).
    c) Compared with a control group, dental hygenists who used ethylene oxide gas to sterilize instruments while pregnant had an increase in spontaneous abortions (Bingham et al, 2001).
    d) Ethylene oxide is a suspected human reproductive hazard. Increased spontaneous abortions (16.7% versus 5.6% in controls) have been seen in pregnant hospital personnel who were exposed to ethylene oxide. These workers were also exposed to glutaraldehyde and formaldehyde, but spontaneous abortions correlated only with exposure to ethylene oxide (Hemminki, 1982). Among California dental assistants with occupational exposure to ethylene oxide, increased risks were found for spontaneous abortion (relative risk = 2.5), preterm birth (RR = 2.7), and postterm birth (RR = 2.1). Exposures were mixed with mercury and nitrous oxide, but these results provide some support for ethylene oxide as a human reproductive hazard (Rowland et al, 1996). In a survey of female veterinarians, no increased risk for spontaneous abortions was seen with self-reported exposure to ethylene oxide (Steele et al, 1989).
    2) RISK ASSESSMENT
    a) A risk assessment for reproductive effects from ethylene oxide has been performed. The reference dose for developmental toxicity was 0.1 to 0.3 ppm, based on the two studies by Snellings et al (Kimmel et al, 1990). This level is lower than most occupational exposure standards.
    B) ANIMAL STUDIES
    1) STILLBIRTH
    a) Changes in the live birth index were noted when both male and female rats were given ethylene oxide (RTECS , 2001).
    2) DEATH
    a) Pre-implantation mortality was noted in rats and post-implantation mortality was noted in mice and rabbits (RTECS , 2001).
    b) Several studies indicate that mid-gestational or late fetal deaths, as well as malformations in some survivors, occur when female mice are exposed to 600 to 1,200 ppm ethylene oxide at the time of fertilization or early zygote development (Bingham et al, 2001).
    3) FETOTOXICITY
    a) Ethylene oxide appears to be fetotoxic, but not teratogenic, in rats at doses insufficient to produce maternal toxicity. Decreased fetal weight was the only treatment-related effect seen in Fischer 344 rats exposed to concentrations of ethylene oxide as high as 100 ppm for 6 hours per day on days 6 to 15 of gestation (Carnegie-Mellon University, 1979; Snellings et al, 1979). Repeated short exposures to ethylene oxide at 800 or 1200 ppm for 0.5 hours, 3 times per day produced fetotoxicity in the form of reduced fetal weight gain in rats. Neither embryotoxicity nor teratogenicity occurred (Saillenfait et al, 1996).
    b) Increased gestational times, fewer pups per litter, reduced numbers of implantation sites, and fewer pups per implantation were seen in rats when both sexes were exposed to 100 ppm for 6 hours per day, 7 days per week, for 12 weeks prior to mating and through day 19 of gestation (Snellings et al, 1982).
    c) Ethylene oxide was not teratogenic in rats or rabbits exposed to 150 ppm for 7 hours per day on days 1 to 16 or days 7 to 16 of gestation (Hayes & Laws, 1991; Hardin et al, 1983). Embryotoxicity with increased resorptions and lower numbers of corpora lutea was seen in female rats exposed to 150 ppm for 3 weeks prior to breeding and throughout gestation (Hayes & Laws, 1991).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) A reduction in the fertility index and litter sizes was seen in a one-generation reproductive toxicity study in which F344 rats were exposed to ethylene oxide at a concentration of 100 ppm. These effects were not seen at 33 ppm. A later study found the No Observed Effect Level (NOEL) to be 10 ppm while the Lowest Observed Effect Level (LOEL) was measured at 33 ppm (Bingham et al, 2001).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS75-21-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Ethylene oxide
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.2) SUMMARY/HUMAN
    A) Ethylene oxide has been linked with leukemia, stomach, brain and pancreatic cancer, lymphatic cancer, hematopoietic cancer, non-Hodgkin lymphoma, and Hodgkin disease.
    B) The evidence for human and animal carcinogenicity and for genotoxicity has been extensively reviewed (Their & Bolt, 2000).
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) Ethylene oxide is regarded as a potential human carcinogen by NIOSH (NIOSH , 2002). It has been classified in Group 1 (human carcinogen) by the International Agency for Research on Cancer (IARC , 2001). In some studies, exposure to ethylene oxide has been associated with increased risk for various cancers, including leukemia, stomach, brain, and pancreatic cancer, hematopoietic cancer, non-Hodgkin lymphoma, and Hodgkin's disease (ACGIH, 1991; Hathaway et al, 1996; Hayes & Laws, 1991; IARC , 2001; ILO, 1998).
    B) LEUKEMIA
    1) Ethylene oxide has been shown to be mutagenic in various tests. Leukemia was reported at higher levels in a small group of Swedish workers exposed to a time-weighted eight hour average (TWA) of 20 +/- 10 ppm (Hogstedt et al, 1979; (IARC , 2001).
    2) Studies indicate that there may be a causal relationship between leukemia and ethylene oxide exposure. However, many of these studies lack certainty about actual ethylene oxide exposure, are small in size, and involve concurrent exposure to other suspected carcinogens (ACGIH, 1991; Hayes & Laws, 1991).
    3) A retrospective mortality study of 18,254 US workers exposed to ethylene oxide at 14 plants producing sterilized medical supplies and spices demonstrated a trend toward an increased risk of death from hematopoietic cancer with increasing lengths of time since the first exposure to ethylene oxide (Steenland et al, 1991).
    a) In a continuation of that study with follow up extended form 1987 to 1998, there was little evidence of excess cancer mortality with the exception of bone cancer, with 6 obseved deaths (SMR 2.82, 95% CI 1.23-5.56). There was also a tred toward an excess of lymphoid cancers in men (Steenland et al, 2004)
    4) Excess morbidity and mortality due to leukemia and stomach cancer were seen in workers exposed to high levels of ethylene oxide (Hogstedt et al, 1979a, 1979b, 1986). Several chemicals besides ethylene oxide were possibly involved, including ethylene, ethylene dichloride, and ethylene chlorohydrin (Hogstedt et al, 1979b; JEF Reynolds , 1995). Increased cancer morbidity due to malignant lymphoma/myelomatosis and bronchial cancer were seen in workers, with latent periods of 10 and 15 years, respectively (Hagmer et al, 1987).
    C) CARCINOMA
    1) In some studies, occupational exposure to ethylene oxide has been linked with spontaneous abortions and various cancers including leukemia, stomach, brain, breast, and pancreatic cancer, lymphatic cancer, hematopoietic cancer, non-Hodgkin lymphoma, and Hodgkin disease (CFR, 1988; (Steenland et al, 2003; ACGIH, 1991) Hathaway et al, 1995; (Hayes & Laws, 1991) Hogstedt et al, 1979; (IARC , 2001; ILO, 1998).
    2) An epidemiological study of 18,278 employees at 14 plants in the US producing sterilized medical supplies and spices found no significant increase in mortality in the cancer sites of interest based on previous studies, including stomach, leukemia, pancreas, and brain. Although there was an increase in non-Hodgkin lymphoma among men, there was no dose-response relationship, no specific job category association, and no increase in NHL among women. The authors concluded that the increase seen was not due to exposure to ethylene oxide (Wong & Trent, 1993).
    3) Excess deaths from pancreatic, brain and CNS cancers, and Hodgkin disease were seen in a group of 767 chemical workers with estimated exposures to ethylene oxide of less than 10 ppm (Hayes & Laws, 1991).
    4) Increased deaths from myeloid leukemia and stomach and brain cancers were seen in a group of 602 chemical workers with recent exposure of only 4 ppm; past exposures were thought to have been much higher, however (Hayes & Laws, 1991).
    5) A recent cohort study of 2658 ethylene oxide-exposed workers at 8 chemical plants in Germany found no significant elevations of either morbidity or mortality from cancers. Standardized mortality ratios were somewhat elevated for carcinomas of the stomach and esophagus but were not statistically significant, and no deaths from leukemia were seen (Kiesselbach et al, 1990).
    6) One study on 1132 employees in a medical sterilization plant found an increased incidence of breast cancer (Norman et al, 1995). Critics have pointed out that this increase may have been due to stepped up surveillance of this group, resulting in earlier detection of breast tumors (Lucas & Teta, 1996). Other studies have not found an association between occupational ethylene oxide exposure and breast cancer, and the cautious interpretation is to consider the matter still open (Norman et al, 1996).
    7) No excess deaths from any type of cancer were seen in a group of 2876 male and female workers in the manufacturing and use of ethylene oxide in England and Wales (Gardner et al, 1989).
    8) There were fewer than expected deaths from all causes and from all cancers in a group of 2174 ethylene oxide-exposed men. Elevations were seen in deaths from leukemia and pancreatic cancer, but these mostly involved exposure also to ethylene chlorohydrin and propylene chlorohydrin (Greenberg, 1990).
    9) Two separate mortality analyses, involving a total of 21,111 U.S. and British workers occupationally exposed to ethylene oxide, determined that the overall risk of mortality from human cancers was low (Steenland et al, 2004; Coggon et al, 2004).
    D) RISK ASSESSMENT
    1) Using the area under the plasma concentration-time curve as the basis for calculating the effective dose, one risk assessment gave the risk for brain cancer from daily exposures to 1.8 mcg/L as 90 to 142 per 10,000 workers (Beliles & Parker, 1987).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Various animal studies have shown increases in leukemia, subcutaneous fibroma, peritoneal mesothelioma, pancreatic adenoma, pituitary adenoma, brain neoplasm, lymphomas, gliomas, and cancer of the forestomach in rodents (Bingham et al, 2001; Sheikh, 1984). The lowest carcinogenic doses producing symptoms was 33 ppm for six hours a day, for five days per week for 18 or 19 months in females and two years in males (Bingham et al, 2001; Sheikh, 1984).
    2) In rats, ethylene oxide was found to be carcinogenic and an equivocal tumorigenic agent by RTECS criteria with the presence of leukemia, gastrointestinal tumors, liver tumors and brain and brain coverings tumors. In mice, ethylene oxide was found to be carcinogenic and neoplastic by RTECS criteria with the presence of lymphomas including Hodgkin disease, lungs, thorax, or respiration tumors and tumors at the site of ethylene oxide application (RTECS , 2001).
    3) In the NTP Carcinogenesis Studies (Inhalation) clear evidence for carcinogenicity (lung, thorax and respiratory tumors) was found in mice (RTECS , 2001).
    4) Mice of the A/J strain developed pulmonary adenomas after inhalation exposure to 70 and 200 ppm ethylene oxide for 6 hours per day, 5 days per week, for 6 months (Adkins et al, 1986). Dose-related increases in lung and harderian gland tumors were seen in male and female B6C3F(1) mice exposed to 50 or 100 ppm ethylene oxide for 6 hours per day, 5 days per week, for 102 weeks; additionally there were lymphomas and cancers of the uterus and mammary gland in the females (Anon, 1988).
    5) Ethylene oxide, applied dermally as 0.1 mL of a 10% solution in acetone for life, did not induce skin tumors in female ICR/HA Swiss mice (IARC, 1976). It was also inactive in rats when injected SC in arachis oil at a total dose of 1 g/kg over a period of 94 days (IARC, 1976).
    B) LEUKEMIA
    1) Male rats who were exposed to 50 ppm for 7 hours/day, five days per week for two years had a significant increase in the incidence of mononuclear cell leukemia (ACGIH, 1991).
    2) In a study on Fischer 344 rats exposed to 33 or 100 ppm for 6 hours per day, 5 days per week, for up to 104 weeks, brain tumors were induced in both sexes, mononuclear cell leukemias in the females, and peritoneal mesotheliomas in the males (Garman et al, 1985; Garman et al, 1986; Snellings et al, 1984; Bushy Run Research Center, 1981; Lynch et al, 1984a).
    C) GASTRIC CARCINOMA
    1) Increases in peritoneal, stomach, and pancreatic cancer, and leukemia and Hodgkin disease have been seen (NIOSH, 1999; (Anon, 1984).
    2) Ethylene oxide dissolved in salad oil and given orally at 7.5 or 30 mg/kg twice a week for 107 weeks increased the number of squamous cell carcinomas in rat forestomachs in a dose-related fashion (Hayes & Laws, 1991; Dunkelberg, 1982). Local tumors, mainly fibrosarcomas, were produced by SC injection of ethylene oxide dissolved in tricaprylin in female rats for 95 weeks (Hayes & Laws, 1991; Dunkelberg, 1981). Similar effects were seen in NMRT mice injected SC with ethylene oxide at doses up to 1 mg/animal (Dunkelberg, 1979).
    D) RISK FACTORS
    1) Ethylene oxide has been identified as a metabolite of ethene (Tornqvist et al, 1989). Although this may be a contributor to the carcinogenic risk of ethene, the significance of this is unknown.

Genotoxicity

    A) MUTAGENIC effects due to ethylene oxide exposure have been shown in non-mammalian animals. Many of the observed mutagenic effects are a result of high dose/short term exposure (Sheikh, 1984). Case studies indicate ethylene oxide is fetotoxic (Sheikh, 1984). In man, cytogenetic studies have shown increases in sister chromatid exchanges, ethylene oxide-hemoglobin adducts, micronuclei, chromosomal aberrations and DNA strand breaks in those exposed to ethylene oxide (ACGIH, 1991; Baselt, 2000; Mayer et al, 1991) Schulte, 1995; (Landrigan et al, 1984).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Chest film should be considered to evaluate the extent of pulmonary involvement after inhalation.
    4.1.2) SERUM/BLOOD
    A) Workers that are exposed to ethylene oxide at the TLV of 1 ppm should not have blood ethylene oxide concentrations of more than 10 mcg/L (Baselt, 1997).
    4.1.4) OTHER
    A) OTHER
    1) OTHER
    a) Monoclonal antibodies are available that detect the main DNA adduct produced by ethylene oxide. The greatest sensitivity was obtained with the immunoslot blot assay method (0.34 adducts per 10(6) nucleotides). Levels of adducts were not detectably increased in peripheral lymphocyte DNA from persons exposed to 2 to 5 ppm ethylene oxide, compared with unexposed controls, however (Vandelft et al, 1994).
    b) Enzyme polymorphism results in significant interindividual differences in ethylene oxide hemoglobin binding, making the utility of this test less suitable for biological monitoring than DNA adducts in lymphocytes (Fost et al, 1991).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) CHEST FILMS should be considered to evaluated the extent of pulmonary involvement after inhalation.

Methods

    A) CHROMATOGRAPHY
    1) In the atmosphere - current monitoring involves adsorption on activated charcoal that has been treated with hydrobromic acid. If present, ethylene oxide forms bromoethanol, which is desorbed with dimethyl formamide. After derivatization to a hepatafluorobutynate ester, it is analyzed by gas chromatography (Bingham et al, 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) If significant levels of ethylene oxide have been inhaled, immediate hospitalization and observation for 72 hours are recommended. There may be delayed onset of severe pulmonary edema (Proctor et al, 1988).

Monitoring

    A) Chest film should be considered to evaluate the extent of pulmonary involvement after inhalation.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY -
    1) EMESIS - Oral exposure to ethylene oxide is unusual. Because of the volatility of the liquid, and the extreme reactivity of ethylene oxide, it is questionable whether emesis would be of value. Activated charcoal may be of more benefit.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS
    1) Oral exposure to ethylene oxide is unusual. Because of the volatility of the liquid, and the extreme reactivity of ethylene oxide, it is questionable whether emesis would be of value. Activated charcoal may be of more benefit.
    B) ACTIVATED CHARCOAL
    1) Activated charcoal is used to adsorb ethylene oxide in vitro (Clayton & Clayton, 1981). It may be of some use in adsorbing unreacted ethylene oxide. Ethylene oxide is irritating and usually serves as its own cathartic.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) CATHARTIC
    1) Ethylene oxide is irritating and usually serves as its own cathartic.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatments following acute exposure should be concerned with managing gastrointestinal, pulmonary, and ocular irritation. Coma and respiratory failure may lead to cardiovascular collapse. Aggressive, supportive care is necessary. Chronically, peripheral neuropathies appear to be the largest problem.
    B) SUPPORT
    1) Coma and respiratory failure: good supportive care for maintenance of respiratory function and CNS activity is paramount.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    D) Contaminated clothing should be removed and washed thoroughly.
    6.7.2) TREATMENT
    A) OBSERVATION REGIMES
    1) If significant levels of ethylene oxide have been inhaled, immediate hospitalization and observation for 72 hours are recommended. There may be delayed onset of severe pulmonary edema (Proctor et al, 1988).
    B) OXYGEN
    1) Maintain PO2 above 60 mmHg by one of these methods:
    a) Administration of 60 to 100 percent oxygen by mask or cannula.
    b) Intubation and mechanical ventilation.
    c) Positive end-expiratory pressure (PEEP) breathing.
    C) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    D) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    B) Immediate flushing with water or saline may reduce the effects of exposure (Bingham et al, 2001).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) If liquid is spilled on the skin, allow the ethylene oxide to vaporize before washing with water (Fisher, 1984).
    2) Dermal exposure should be treated with high pressure water such as a hose or strong shower, not just gently washed (Fisher, 1984).
    3) Garments should be cleaned thoroughly with large amounts of water.
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) A physician should examine the exposed area if irritation or pain persists after the area is washed.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) 30 mg/kg caused nausea, vomiting, and diarrhea for 2 hours in animals. The permissible exposure limit in air is 1 ppm as an eight hour TWA. The OSHA action level is 0.5 ppm.

Minimum Lethal Exposure

    A) Ethylene oxide is fatal within a few minutes at a concentration of 50,000 to 100,000 ppm (OHM/TADS , 2002).

Maximum Tolerated Exposure

    A) INHALATION EXPOSURE
    1) Brief exposure to concentrated vapors will cause significant symptoms (Salinas et al, 1981). Maximum tolerated concentration is 100 ppm. At 3000 ppm, ethylene oxide may be tolerated for 60 minutes (OHM/TADS , 2002).
    2) Chronic exposure to eight-hour time-weighted average of 2.4 ppm for 10 years resulted in cognitive impairment and subclinical sensory neuropathy (Crystal et al, 1988).
    3) Chronic exposure to ethylene oxide can result in headache, numbness of the extremities, muscular weakness, impaired gait, skin sensitization, numbing of the sense of smell and taste, staggering, increased fatigability, and an increased susceptibility for respiratory infection; these symptoms usually clear within months after exposure to ethylene oxide has ended. Long-term exposure has also been linked to increased rates of leukemia (ACGIH, 1991; Baselt, 1997; Baselt, 2000; Bingham et al, 2001; Hathaway et al, 1996; Hayes & Laws, 1991).
    4) Factory workers who were reported to have chronic ethylene oxide poisoning suffered from symptoms of multiple neuropathy, which consisted of sensory disturbance of the legs and feet, a diminished sense of vibration in the feet and irregular gait; this gradually spread to other parts of the body. When the workers were moved away from all exposure to ethylene oxide, the symptoms cleared (ACGIH, 1991; Hathaway et al, 1996).
    5) In humans, exposure to 500 to 700 ppm for 2 to 3 minutes resulted in nausea, vomiting, headache, disorientation and fluid in the lungs, followed by seizures. Volunteers breathing a concentration of 2,500 ppm experienced slight irritation and at 12,500 ppm, experienced definite irritation of the respiratory tract within 10 seconds (Pohanish, 2002). Symptoms may not occur for hours after inhalation.
    B) DERMAL EXPOSURE
    1) In human volunteers, a 40- to 60-percent solution produced second-degree burns in as little as 0.75 to 1.0 minutes. A 1-percent solution produced no effects after 20 to 25 minutes, and second degree burns after 75 minutes or more. Undiluted ethylene oxide evaporated rapidly and resulted in thermal injury. Three of eight volunteers developed skin sensitization (Hayes & Laws, 1991).

Workplace Standards

    A) ACGIH TLV Values for CAS75-21-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Ethylene oxide
    a) TLV:
    1) TLV-TWA: 1 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A2
    2) Codes: Not Listed
    3) Definitions:
    a) A2: Suspected Human Carcinogen: Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as a confirmed human carcinogen; OR, the agent is carcinogenic in experimental animals at dose(s), by route(s) of exposure, at site(s), of histologic type(s), or by mechanism(s) considered relevant to worker exposure. The A2 is used primarily when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals with relevance to humans.
    c) TLV Basis - Critical Effect(s): Cancer; CNS impair
    d) Molecular Weight: 44.05
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:
    b) Under Study
    1) Ethylene oxide
    a) TLV:
    1) TLV-TWA:
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Not Listed
    3) Definitions: Not Listed
    c) TLV Basis - Critical Effect(s):
    d) Molecular Weight:
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS75-21-8 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Ethylene oxide
    2) REL:
    a) TWA: <0.1 ppm (0.18 mg/m(3))
    b) STEL:
    c) Ceiling: 5 ppm (9 mg/m(3)) [10-min/day]
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH:
    a) IDLH: 800 ppm
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS75-21-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A2 ; Listed as: Ethylene oxide
    a) A2 :Suspected Human Carcinogen: Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as a confirmed human carcinogen; OR, the agent is carcinogenic in experimental animals at dose(s), by route(s) of exposure, at site(s), of histologic type(s), or by mechanism(s) considered relevant to worker exposure. The A2 is used primarily when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals with relevance to humans.
    2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Ethylene oxide
    3) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Ethylene oxide
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    5) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Ethylene oxide
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    6) MAK (DFG, 2002): Category 2 ; Listed as: Ethylene oxide
    a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.
    7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS75-21-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Ethylene oxide; see 29 CFR 1910.1047
    2) Table Z-1 for Ethylene oxide; see 29 CFR 1910.1047:
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3:
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ACGIH, 1991 Bingham et al, 2001 Hayes & Laws, 1991 Hathaway et al, 1996 ITI, 1995 OHM/TADS, 2002 RTECS, 2002
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 175 mg/kg
    2) LD50- (ORAL)RAT:
    a) 72 mg/kg
    b) 330 mg/kg for 14D (OHM/TADS, 2002)
    c) 330 mg/kg -- administered as a 1% aqueous solution (Hayes & Laws, 1991)
    d) male, 330 mg/kg (ACGIH, 1991)
    3) LD50- (SUBCUTANEOUS)RAT:
    a) 187 mg/kg
    4) TCLo- (INHALATION)HUMAN:
    a) 12,500 ppm for 10S -- changes in sense organs
    b) Female, 500 ppm for 2M -- convulsion/seizure threshold, gastrointestinal, and pulmonary effects
    5) TCLo- (INHALATION)MOUSE:
    a) 50 ppm for 6H/2Y -- tumors in lung, thorax, or respiratory system
    b) 400 ppm for 6H/13W-intermittent -- changes in bladder weight; normocytic anemia; hepatic microsomal mixed oxidase
    c) 450 mg/m(3) for 6H/10W-intermittent -- changes in liver, spleen, and testicular weights
    d) 600 ppm for 6H/14W-intermittent -- changes in sense organs; changes in endocrine system; death
    e) 800 ppm for 6H/14D-intermittent -- death
    f) Female, 1200 ppm for 90M at 1D prior to mating -- post-implantation mortality, fetal death and other effects to embryo
    g) Female, 1200 ppm for 90M at 1D of pregnancy -- post-implantation mortality, fetal death, abnormal homeostasis
    h) Female, 2700 ppm for 6H at 7D of pregnancy -- effects to embryo
    i) Male, 255 ppm for 6H at 10D prior to mating -- fetal death
    6) TCLo- (INHALATION)RAT:
    a) 33 ppm for 6H/2Y-intermittent -- tumors in brain and coverings, leukemia
    b) 406 ppm for 6H/6W-intermittent -- weight loss/decreased weight gain; death
    c) 500 ppm for 6H/13W-intermittent -- behavioral changes; changes in liver
    d) 300 mcg/m(3) for 24H/83D-continuous -- muscle contraction/spasticity, changes in blood; nutritional and gross metabolic changes
    e) Female, 100 ppm for 6H at 6-15D of pregnancy -- fetotoxicity
    f) Female, 100 ppm for 6H at 12W prior to mating-21D of pregnancy -- pre-implantation mortality, altered live birth index
    g) Female, 150 ppm for 7H at 7-16D of pregnancy -- fetotoxicity, craniofacial and musculoskeletal effects
    h) Male, 50 ppm for 6H at 91D prior to mating -- spermatogenesis
    i) Male, 100 ppm for 6H at 12W and 9W prior to mating-3W of pregnancy prior to mating -- altered live birth index
    j) Male, 3600 mcg/m(3) for 24H at 60D prior to mating -- effects on testes, epididymis, sperm duct; pre-implantation mortality

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ethylene oxide acts as an alkylating agent and reacts directly and irreversibly with most organic substances such as: amino acids, proteins and nucleoproteins, DNA, and histidine found in hemoglobin (Sheikh, 1984).

Physicochemical

Physical Characteristics

    A) Ethylene oxide is an extremely flammable, highly reactive, colorless gas at room temperature and normal pressure. It becomes a stable, clear liquid at 10.4 degrees C (50.7 degrees F) and 101 kPa (14.7 psia), and it may polymerize violently. Liquid ethylene oxide is lighter than water. Vapors of ethylene oxide are heavier than air. Ethylene oxide has an ether-like odor that has also been described as a characteristic, sweet, olefinic odor (ACGIH, 1991; Ashford, 1994; Budavari, 1996; CGA, 1999; Bingham et al, 2001; Hathaway et al, 1996; HSDB , 2002; ILO, 1998; Verschueren, 2000).

Molecular Weight

    A) 44.05

Other

    A) ODOR THRESHOLD
    1) 260-261 ppm (perception) (ACGIH, 1991; Bingham et al, 2001)
    2) 500-700 ppm (recognition) (ACGIH, 1991; Bingham et al, 2001)
    3) 50 ppm (CHRIS , 2002)
    4) 1.5 mg/m(3) in air (OHM/TADS , 2002)
    5) 300 ppm in air (HSDB , 2002)
    6) Low: 520 mg/m(3); High: 1400 mg/m(3) (HSDB , 2002)

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