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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 2 Ethylene Oxide1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 min to 8 h. AEGL-2 and AEGL-3, and AEGL-1 levels, as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be susceptible. The three AEGLs have been defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could 1 This document was prepared by the AEGL Development Team composed of Kowetha Davidson (Oak Ridge National Laboratory) and Chemical Managers Susan Ripple and Kyle Blackman (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGLs represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Ethylene oxide is a highly flammable gas produced in very large quantities in the United States (5.3 to 6.3 billion pounds). It is very reactive with nucleophilic substances such as water, alcohols, halides, amines, and sulfhydryl compounds. Ethylene oxide is used as an intermediate in the production of ethylene glycol and nonionic surfactants; a small amount is used as a fumigant for sterilizing foods and heat-sensitive medical equipment. The database on the toxicity of ethylene oxide vapor in humans and experimental animals is extensive, including data on all aspects of toxicity except lethality in humans. Pharmacokinetics data show that ethylene oxide is readily absorbed from the respiratory tract in humans and other animals. Ethylene oxide alkylates proteins and DNA, and it is metabolized primarily by nonenzymatic hydrolysis, enzymatic hydrolysis, and glutathione conjugation. The odor detection threshold for ethylene oxide was reported to be 260 ppm by one investigator and 700 ppm by another. In humans, ethylene oxide vapors affect the eyes, respiratory tract, central and peripheral nervous systems, gastrointestinal tract (probably secondary effects to nervous system toxicity), hematopoietic system, and possibly the reproductive system and fetus. Acute exposure to ethylene oxide at the odor detection level (≥260 ppm) causes eye and upper respiratory tract irritation and signs and symptoms of effects on the central and peripheral nervous systems. Acute exposure to a calculated concen-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 tration of at least 500 ppm for 2 to 3 min caused hematologic effects and more severe effects on the central nervous system than those noted at the odor detection level. Most effects observed after acute exposure are reversible, including effects on the nervous system. Repeated exposures exacerbate peripheral nerve damage. Human studies have provided evidence suggestive of reproductive toxicity, some evidence of an association between exposure to ethylene oxide and genetic damage to somatic cells, and limited evidence of carcinogenicity. Acute lethality studies in experimental animals showed that mice are the most sensitive species (4-h LC50 [concentration with 50% lethality] = 660 to 835 ppm), followed by the dog (4-h LC50 = 960 ppm) and rat (4-h LC50 = 1,537 to 1,972 ppm; 1-h LC50 = 4,439 to 5,748 ppm). Immediate deaths were likely due to respiratory failure and delayed deaths were due to secondary respiratory infections. Experimental animals exposed to lethal and nonlethal concentrations of ethylene oxide showed evidence of eye and respiratory tract irritation and effects on the central and peripheral nervous systems. Additional studies in animals exposed to ethylene oxide for up to 6 h/day provided evidence of reproductive toxicity (subchronic exposure), developmental toxicity, neurotoxicity, genetic toxicity in germ cells, and carcinogenicity. Data were available for deriving AEGL-2 and -3 values. Values for AEGL-1 were not derived because concentrations causing mild sensory irritation are ≥260 ppm, which is above the AEGL-2 values and would not serve as a warning of potential exposure. Therefore, AEGL-1 values are not recommended. The absence of AEGL-1 values does not imply that exposure below the AEGL-2 is without adverse effects. The AEGL-2 values were based on an acute neurotoxicity study in rats exposed to 0, 100, 300, or 500 ppm for 6 h (Mandella 1997a) and a developmental toxicity study with pregnant rats exposed to ethylene oxide at 10, 33, or 100 ppm for 6 h/day during organogenesis (Snellings et al. 1982a). The point of departure is 100 ppm, the no-observed-adverse-effect level (NOAEL) for neurotoxicity and developmental toxicity. The decrease in fetal body weight and the increase in litter incidence of delayed ossification of the vertebrae at 100 ppm were not toxicologically significant, and 100 ppm is the NOAEL for the collective neurotoxicity end points (droopy, half-closed eyelids; impaired locomotion; low arousal; and no response to approach). A total uncertainty factor of 10 was applied to the point of departure: 3 for interspecies sensitivity and 3 for intraspecies variability. An uncertainty factor of 3 was selected for interspecies sensitivity because similar neurotoxicity effects (distal axonal degeneration) have been observed in rats and humans. Direct alkylation of DNA, proteins, and other macromolecules—one potential mechanism of toxicity—is not expected to differ across species. Physiologically based pharmacokinetic (PBPK) models have shown that the area under the curve, peak blood levels, internal dose in milligram per kilogram of body weight (mg/kg), and hemoglobin adduct levels (measure of internal exposure) in humans are similar to or lower than the corresponding values for rats. In addition, the hemoglobin adduct level in rats and humans is proportional to exposure concentration. A factor of 3 was selected for
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 intraspecies variability because glutathione-S-transferase polymorphism in humans modulates systemic exposure as measured by hemoglobin adducts. Ethylene oxide exposure measured by hemoglobin adduct levels is within a factor of 3 in individuals with the GSTT1 genotype (conjugator) and the GSTT1-null genotype (nonconjugator). There is no evidence that individuals with respiratory diseases, including asthma, would respond differently to ethylene oxide concentrations far below odor detection or irritation levels. The time-scaling approach used ten Berge’s equation in which Cn × t = k (chemical concentration in air with a chemical-specific exponent applied to a specific end point × exposure time = response), where n = 1.2, based on analysis of rat lethality data. The AEGL value for a 10-min exposure is the same as the 30-min value because of the uncertainty of extrapolating from a 6-h exposure to 10 min. AEGL-3 values were derived from a lethality study with rats (Jacobson et al. 1956). An LC01 (concentration with 1% lethality) value (628 ppm), which is considered an approximation of the lethality threshold, was estimated from a 4-h acute inhalation study with rats. Uncertainty factors of 3 for interspecies sensitivity and 3 for intraspecies variability (total uncertainty factor of 10) were applied to the LC01. The rationale for the interspecies uncertainty factor was the same as that described for AEGL-2 as a rat study was used to derive the AEGL values and the exposure concentration was within range for the PBPK model simulations showing linearity of systemic uptake. An intraspecies uncertainty factor of 3 was selected because glutathione-S-transferase polymorphism can modulate systemic exposure as measured by hemoglobin adduct levels, and individuals with asthma are not expected to be affected differently by ethylene oxide exposure. An interspecies or intraspecies uncertainty factor of 10 would lower the 10- and 30-min AEGL values below the odor detection or irritation thresholds and exposure concentrations associated with life-threatening events. Scaling to the different timeframes was based on ten Berge’s equation (Cn × t = k), where n = 1.2. The AEGL value for a 10-min exposures is the same as the 30-min value because of the uncertainty of extrapolating from a 4-h exposure to 10 min. Assessment of carcinogenicity data (alveolar or bronchiolar adenomas or carcinomas in the lungs of female mice) showed that extrapolating the total cumulative exposure over 2 years to a single exposure and estimating a 10–4 risk resulted in AEGL-3 values of 1,300, 1,300, 640, 160, and 80 ppm for 10- and 30-min and 1-, 4-, and 8-h exposures, respectively. These values exceed those derived for AEGL-2 and AEGL-3. AEGL values derived for ethylene oxide are summarized in Table 2-1. 1. INTRODUCTION Ethylene oxide (a monoepoxide) is a gas at room temperature and normal atmospheric pressure; the vapor density is 1.49. The vapor is highly flammable at concentrations ranging from 3% to 100%, and it may undergo explosive de-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 composition (WHO 1985; Gardiner et al. 1993). Ethylene oxide is very reactive with nucleophiles such as water, alcohols, halides, amines, and sulfhydryl compounds (EPA 1985, WHO 1985). Physicochemical properties of ethylene oxide are presented in Table 2-2. TABLE 2-1 Summary of AEGL Values for Ethylene Oxide Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1a (Nondisabling) Not Recommended AEGL-2 (Disabling) 80 ppm (144 mg/m3) 80 ppm (144 mg/m3) 45 ppm (81 mg/m3) 14 ppm (25 mg/m3) 7.9 ppm (14 mg/m3) NOAEL for neurotoxicity and developmental toxicity (Snellings et al. 1982; Mandella 1997a) AEGL-3 (Lethal) 360 ppm (648 mg/m3) 360 ppm (648 mg/m3) 200 ppm (360 mg/m3) 63 ppm (113 mg/m3) 35 ppm (63 mg/m3) Lethality (Jacobson et al. 1956) aThe absence of AEGL-1 values does not imply that exposure below the AEGL-2 is without adverse effects. TABLE 2-2 Physical and Chemical Data for Ethylene Oxide Parameter Value Reference Chemical name Ethylene oxide Synonyms 1,2-epoxyethane, oxirane, dimethylene oxide, ethene oxide CAS registry no. 75-21-8 Chemical formula C2H4O Molecular weight 44.05 Budavari et al. 1996 Physical state Colorless, flammable gas Budavari et al. 1996 Boiling and freezing points 10.4ºC and –112.5ºC Gardiner et al. 1993 Specific gravity 0.8966 at 0/4ºC; 0.8711 at 20/20ºC Gardiner et al. 1993 Solubility Soluble in water, acetone, acetone, benzene, ethanol, and diethyl ether IARC 1994 Vapor pressurea 1.50 atm; 152 kPa, 1.52 bar at 21ºC Braker and Mossman 1980 Vapor density 1.49 at 40ºC Gardiner et al. 1993 Liquid density 0.8824 at 10/10ºC IARC 1994 Critical temperature 468.95 K, 195.8ºC, 384.4ºF Braker and Mossman 1980 Autoignition temperature 702 K, 429ºC, 804ºF Braker and Mossman 1980 Flammability limit 3.0-100% Braker and Mossman 1980 Conversion factor 1 ppm = 1.8 mg/m3 at 25ºC, 1 atm Gardiner et al. 1993 aatm, atmosphere; kPa, kilopascal.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 Ethylene oxide is produced in very large quantities in the United States and in other countries. Estimated U.S. production was 5.3 to 6.2 billion pounds in 1990 (Gardiner et al. 1993; IARC 1994) and 5.6 billion pounds in 1992 (IARC 1994). Worldwide production exceeded 12 billion pounds (IARC 1994) and may be as high as 16.5 billion pounds (Gardiner et al. 1993). Ethylene oxide is used as an intermediate in the production of ethylene glycol (antifreeze), which accounts for about 60% of its use; nonionic surfactants, which account for about 16%; ethanolamines, which account for about 8.5%; and glycol ethers, diethylene glycol, triethylene glycol, and other chemicals, which account for the remaining 16% (IARC 1994). A small amount of ethylene oxide is used as a fumigant for sterilizing heat-sensitive medical and dental equipment and foods, such as spices and nuts (Gardiner et al. 1993; IARC 1994). Ethylene oxide is not persistent in the environment; the estimated degradation rate in the atmosphere is 37% in 5.8 days. The half-life is 12 to 14 days in fresh water and 4 days in salt water (EPA 1985; IARC 1994). The database for ethylene oxide is very large; humans and experimental animal studies on acute toxicity, developmental and reproductive toxicity, genetic toxicity (somatic and germ cells), carcinogenicity, and pharmacokinetics and metabolism were available. These data were used to derive the AEGL values. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No studies were available on lethality attributed to ethylene oxide exposure in humans. Marchand et al. (1957) reported the accidental death of three workers involved in the manufacture of ethylene oxide. They experienced vomiting, abdominal pain, diarrhea, headache, and severe nervous system effects that progressed to coma, circulatory collapse, and respiratory failure. Pulmonary edema and congestion of the meninges and brain were observed at the postmortem examination of one of them. The workers were exposed to glycol chlorohydrin, dichloroethane, and ethylene oxide; the deaths were attributed to glycol chlorohydrin and dichloroethane exposure and not to ethylene oxide. 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold Several human studies on ethylene oxide exposure were available in the literature. In one study, human volunteers sniffed ethylene oxide from an osmoscope (an apparatus attached to the nose) to determine the detection level and description of the odor (Jacobson et al. 1956). The ethylene oxide atmospheres were generated in a 0.7-m3 chamber and drawn into the osmoscope. The concen-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 tration of ethylene oxide in the chamber was analyzed by collecting the chamber air into a solution of calcium chloride (CaCl2) and hydrochloric acid (HCl) or a 50% solution of magnesium bromide (MgBr2) containing 0.1 N sulfuric acid (H2SO4) and titrating with sodium hydroxide (NaOH). The subjects described the odor as pleasantly to sickeningly sweet, fruity, alcoholic, or acetone- or etherlike. The median detectable concentration was 700 ppm (1,260 mg/m3) with a 95% confidence interval of 317 to 1,540 ppm (571 to 2,772 mg/m3). Hellman and Small (1974) conducted a study in which a trained panel of subjects (“trained odor panel”) characterized the sensory odor properties of 101 petrochemicals, one of which was ethylene oxide. The properties were defined as (1) absolute odor threshold, the concentration at which 50% of the panel detected an odor; (2) 50% odor recognition threshold, the concentration at which 50% of the panel defined the odor as being representative of the odorant; (3) 100% odor recognition threshold, the concentration at which 100% of the panel defined the odor as being representative of the odorant; and (4) hedonic tone, the pleasure or displeasure associated with the odor quality as judged by the panel. They also derived an “odor index”, which is the vapor pressure (ppm)/100% odor recognition threshold (ppm). The absolute odor threshold for ethylene oxide was 260 ppm (468 mg/m3), and the 50% and 100% odor recognition thresholds were both 500 ppm (900 mg/m3). The odor index was 2,000 ppm, which placed ethylene oxide in a category of low odor potential. The odor was considered to be sweet or olefinic and was judged as neutral with respect to odor pleasantness or unpleasantness. Hellman and Small (1974) did not report the number of subjects involved in this study or provide additional information on the “training” the subjects received. Cawse et al. (1980) reported that olfactory fatigue occurs upon repeated exposure to ethylene oxide, thus rendering ineffective the warning properties of odor. The level of distinct odor awareness (LOA) for ethylene oxide calculated based on an odor threshold of 260 ppm and using the guidance provided by van Doorn et al. (2002) is 1,625 ppm. This value is similar to the 95% upper confidence limit on the median odor threshold reported by Jacobson et al. (1956). The derivation of the LOA is presented in Appendix C. 2.2.2. Case Reports and Anecdotal Data The following case studies describe signs and symptoms of ethylene oxide intoxication and the concentrations and exposure durations at which they occurred. Salinas et al. (1981) reported that a female nurse was exposed to ethylene oxide vapor while disposing of an ampule she accidentally dropped. Her exposure lasted 2 to 3 min and she showed immediate signs and symptoms of intoxication, including repeated episodes of nausea, stomach spasms, paleness, light-headedness, short periods of unconsciousness, convulsive movements of her arms and legs, and periods of apnea (cessation of breathing). Muscle twitching,
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 nausea, and malaise continued for 24 h after exposure; malaise and an inability to perform minor motor tasks continued for up to 1 week after exposure. Chest X-rays, laboratory studies, and arterial blood gases were normal. The patient was asymptomatic 2 months after exposure. The authors estimated maximum exposure as 500 ppm based on the release of 17 g of ethylene oxide into the sterilizer bag, resulting in a minimal peak concentration of 500 micrograms per milliliter (μg/mL) in the bag. Her exposure may have been considerably greater than the calculated concentration of 500 ppm. Five hospital workers were exposed for 30 min to ethylene oxide vapors emitted from a leaky sterilizer at concentrations high enough to be detected by odor (≥260 ppm) (Deleixhe et al. 1986; Laurent 1988). The sterilizing gas consisted of a mixture of ethylene oxide and carbon dioxide (15/85, v/v). The equipment was operated under 6 atmospheres of pressure, and the concentration of ethylene oxide in the equipment was 1,200 mg/L. The investigators did not specify the method for monitoring the air concentrations after this accident, but a colorimetric method and flame-ionization detection had been used previously. The sterilizer workers experienced ethylene oxide concentrations at the odor threshold of 260 ppm, but it could have been higher. Measured concentrations were 15 to 50 ppm 2.5 h after the accident and about 5 ppm the next day. Two workers experienced only headache and diarrhea, which disappeared within 70 h after exposure; the other three workers experienced more serious signs of toxicity, which included irritation of the upper respiratory tract, dry mouth and thirst, conjunctival irritation, severe headache, and intense generalized pruritus, along with muscular weakness in one worker and dizziness in another. Muscular weakness may have been a sign of toxicity to the peripheral nervous system. Nausea, vomiting, and diarrhea started 20 h after exposure, lasted for 14 days, and cleared up by 21 days. Hemolysis was noted on days 9 to 11 and persisted until day 16. Garry et al. (1979) described the symptoms experienced by 12 workers exposed to ethylene oxide in the instrument and materials sterilization area. Informed consent was obtained from this study population. Another group of 12 individuals represented an unexposed or incidentally exposed population. Freon gas was used as a carrier with the ethylene oxide to prevent an explosion. Ambient ethylene oxide concentrations were monitored over the entire sterilization cycle by infrared spectroscopy and gas chromatography. Gas chromatography identified the two constituents in the sterilizing gas but could not be used for measuring ethylene oxide because the humidified air resulted in poor absorption of ethylene oxide to the charcoal filter. The frequency of upper respiratory tract irritation indicated that exposure was intermittent, showing a bimonthly cycle over a 5-month period. During a 2-month period, 12 nurses experienced sore throat and dry mouth (most prominent symptoms), diarrhea, conjunctival irritation, headache, nausea, speech difficulty, recent memory loss, weakness, dizziness, and incoordination. The maximum ethylene oxide concentrations ranged from 36 ppm (64.8 mg/m3) in the room about 15 feet from the sterilizer (probably representing the breathing zone) to 1,500 ppm (2,700 mg/m3) in the open
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 drain leading from the sterilizing unit. Garry et al. (1979) also reported that an investigator was exposed to 1,500 ppm for 5 min; symptoms of intoxication were not described. The signs and symptoms Garry et al. (1979) described cannot be attributed to a single exposure. However, the investigators noted that illnesses were periodic and alleviated by time away from the workplace. Finelli et al. (1983) described the signs and symptoms experienced by three sterilizer operators accidentally exposed to ethylene oxide over 4-month to 12-year periods. Ambient ethylene oxide concentrations were not determined. Symptoms of intoxication included numbness, tingling, cramps, weakness, and incoordination in the lower extremities and cramps in the hands. In addition, frequent complaints reported by the sterilizer operators included eye irritation, headaches, smelling of fumes, sleeplessness, and nervousness. Neurologic examination showed distal abnormalities in the legs and feet (reflex, vibratory sensation, and flexion) but no abnormalities in cranial nerves. An abnormal gait was noted in one patient and bilateral footdrop was found in two patients. Nerve conduction studies showed abnormalities in motor and sensory conduction potential in the lower extremities in two patients and normal conduction potential in the third. Electromyograms showed abnormal potentials in the lower extremities. The resulting diagnosis was distal axonal neuropathy (peripheral neuropathy). Two patients were fully recovered within 7 months and one was almost fully recovered after 6 months. The National Institute for Occupational Safety and Health conducted a survey to assess the effects of exposure to ethylene oxide on 10 hospital workers (Zey et al. 1994). The workers complained of headache, dizziness, mucous membrane irritation, nasal bleeding, vomiting, diarrhea, facial flushing and swelling, fatigue, nervousness, and a “sweet”-like odor. The 8-h time-weighted average (TWA) concentration in the breathing zone of the workers ranged from 0.23 to 0.56 ppm, with short-term excursions reaching 77 ppm in one area of the breathing zone and 11 ppm in another. The authors believed the concentrations were higher than those measured in the present investigation, because the employers noticed the ethylene oxide odor, which has a detection threshold higher than the measured concentration. The clinical signs also suggest exposure to higher concentrations. Deschamps et al. (1992) described a case of persistent nonimmunologic asthma and slight peripheral neuropathy that developed in a worker exposed to ethylene oxide 4 h/day for 4 days. The worker was about 18 m from an ethylene oxide leak and he wore no protective equipment. The worker noticed an odor, suggesting that the concentration was ≥260 ppm. Signs and symptoms after the 4-day exposure included coughing, shortness of breath, and wheezing. Respiratory symptoms persisted and 1 year after the accident, pulmonary function tests showed bronchial obstruction and bronchial hyperreactivity. The forced vital capacity was 93% of the predicted value, forced expiratory volume in 1 s (FEV1) was 74% of the predicted value, midexpiratory flow rate (forced expiratory flow 25% to 75%) was 44% of the predicted value, and the FEV1 after 600 μg of acetylcholine showed a 20% decrease. The respiratory effects persisted for at least 3
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 years after exposure. Immunologic tests showed no formation of immunoglobulin E antibodies to ethylene oxide. The investigators proposed that the time of onset of symptoms was too short to be explained by a sensitizing mechanism. They further suggested that the alkylating properties of ethylene oxide probably explained why the onset of symptoms occurred after the fourth day of exposure, because alkylating injuries take longer to appear than direct irritation or caustic injuries. A neurologic examination showed signs of proprioceptive axonal neuropathy. An additional five workers, including one with asthma, were exposed because of the leak; none of them experienced respiratory symptoms. Gross et al. (1979) reported on three workers accidentally exposed for 2 weeks to 2 months to ethylene oxide vapor from a leaky sterilizer. Symptoms they experienced included irritation of the conjunctiva and mucous membranes, decreased sense of smell and taste, headaches, nausea, vomiting, and lethargy. One patient had recurrent major motor seizures, but there was no evidence of peripheral neuropathy. A second worker experienced muscle weakness and increased fatigue and showed evidence of peripheral neuropathy. A third worker had problems with memory and thinking, difficulty swallowing, cramps, numbness, and weakness in the arms and legs, along with clinical signs that included slurred speech, confusion, weakness of facial and distal muscles, and muscular incoordination. A neurologic test also showed evidence of peripheral neuropathy. The exposure concentrations for these workers were not monitored; however, intermittent odor detection of ethylene oxide suggested excursions greater than 260 ppm during work shifts. 2.2.3. Epidemiologic Studies Bryant et al. (1989) surveyed sterilizer workers from 27 hospitals who were potentially exposed to ethylene oxide. Short-term symptoms were identified by means of a questionnaire sent to 241 workers; 182 responded, 165 of whom worked with ethylene oxide. The age of the cohort ranged from less than 20 years (1%) to greater than 60 years (9%). The sterilizers used in the hospitals included table top or portable sterilizers and built-in sterilizers with and without ventilation hoods. The portable sterilizers used cartridges containing 100% ethylene oxide, and the other sterilizers used a mixture containing ethylene oxide and an inert carrier gas. The investigators did not describe the analytic procedure for determining ethylene oxide concentrations. Ethylene oxide concentrations ranged from peaks of 11 to 23.5 ppm, decreasing to <1 ppm within 60 seconds (s) or from 8.5 ppm decreasing to 1 ppm within 160 s depending on the type of sterilizer used. The total exposure concentration per sterilizer cycle ranged from undetectable to 10.7 ppm with exposure durations per cycle ranging from 166 s (2.77 min) to 705 s (11.75 min). The mean concentration per cycle was 3.4 ppm. The detection of the ethylene oxide odor suggests that the concentrations exceeded 260 ppm, at least briefly. The most prevalent symptoms other than the odor of ethylene oxide included headaches, skin and eye irritation, dry mouth,
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 and sore throat. Other symptoms included skin rash, runny nose, loss of sense of smell, shortness of breath, nausea, numbness in fingers, and drowsiness. A larger number of workers exposed to concentrations above the mean concentration reported more symptoms than workers exposed to concentrations below the mean, suggesting a concentration effect. Some symptoms may have been due to daily peak exposures and some were likely due to repeated exposures over a prolonged period. 2.3. Developmental and Reproductive Toxicity Hemminki et al. (1982) conducted a cross-sectional study on the spontaneous abortion rate (number of spontaneous abortions per number of pregnancies) among the staff of 80 Finnish hospitals who used ethylene oxide to sterilize heat-sensitive equipment. Control groups exposed to ethylene oxide were identified by hospital nursing staff, who also distributed the questionnaires to the subjects. The return rate for the questionnaires was about 91% for both groups. Specific exposure data were not reported in this study, but the mean 8-h TWA ranged from 0.1 to 0.5 ppm, with the peak concentration reaching 250 ppm at Finnish hospitals. Data from about 24 hospitals showed that concentrations varied between 5 and 10 ppm for about 20 min when the sterilizer door was open (Hemminki et al. 1983). The data as summarized in Table 2-3 are presented as crude and adjusted rates (age, parity, decade of reported pregnancy, coffee and alcohol consumption, and smoking habits). Crude and adjusted spontaneous abortion rates were significantly elevated in female staff exposed to ethylene oxide compared with the unexposed control group. Data obtained from hospital discharge records produced similar results for the spontaneous abortion rates: 22.5% (p < 0.05, compared with controls) for the staff exposed to ethylene oxide and 9.2% for the controls. The abortion ratio (number of spontaneous abortions per number of births) based on hospital records was also higher in workers exposed to ethylene oxide (33.3% compared with 11.8% for controls, p < 0.05). The findings of this study are not conclusive; several weaknesses are evident. Both the exposed and control populations were identified by the nursing staff without corroborating exposure data. Hospital discharge records confirmed the results for only about one-third of the respondents. There are inherent recall biases when results are based on respondents’ memories. The number of sterilizing staff exposed only to ethylene oxide during pregnancy was very small compared with the other groups. Rowland et al. (1996) conducted a cross-sectional epidemiologic study on the reproductive outcome among California dental assistants potentially exposed to ethylene oxide and showed an increased risk of adverse reproductive outcome associated with exposure. The exposed population consisted of respondents who listed ethylene oxide as the method used to sterilize instruments at the last menstrual date of their last pregnancy. Adverse pregnancy outcomes included spontaneous abortion (<21 weeks), preterm delivery (21 to 36 weeks), and post-term
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 Snellings, W.M., R.R. Maronpot, J.P. Zelenak, and C.P. Laffoon. 1982a. Teratology study in Fischer 344 rats exposed to ethylene oxide by inhalation. Toxicol. Appl. Pharmacol. 64(3):476-481. Snellings, W.M., J.P. Zelenak, and C.S. Weil. 1982b. Effects on reproduction in Fischer 344 rats exposed to ethylene oxide by inhalation for one generation. Toxicol. Appl. Pharmacol. 63(3):382-388. Snellings, W.M., C.S. Weil, and R.R. Maronpot. 1984a. A subchronic inhalation study on the toxicologic potential of ethylene oxide in B6C3F1 mice. Toxicol. Appl. Pharmacol. 76(3):510-518. Snellings, W.M., C.S. Weil, and R.R. Maronpot. 1984b. A two-year inhalation study of the carcinogenic potential of ethylene oxide in Fischer 344 rats. Toxicol. Appl. Pharmacol. 75(1):105-117. Steenland, K., L. Stayner, A. Greife, W. Halperin, R. Hayes, R. Hornung, and S. Nowlin. 1991. Mortality among workers exposed to ethylene oxide. N. Engl. J. Med. 324(20):1402-1407. Tardif, R., R. Goyal, J. Brodeur, and M. Gerin. 1987. Species differences in the urinary disposition of some metabolites of ethylene oxide. Fundam. Appl. Toxicol. 9(3):448-453. Tates, A.D., Boogaard, F. Darroudi, A.T. Natarajan, M.E. Caubo, and N.J. van Sittert. 1995. Biological effect monitoring in industrial workers following incidental exposure to high concentrations of ethylene oxide. Mutat. Res. 329(1):63-77. Tavares, R., P. Ramos, J. Palminha, M.A. Bispo, I. Paz, A. Bras, J. Rueff, P.B. Farmer, and E. Bailey. 1994. Transplacental exposure to genotoxins. Evaluation in haemoglobin of hydroxyethylvaline adduct levels in smoking and non-smoking mothers and their newborns. Carcinogenesis 15(6):1271-1274. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309. Teta, M.J., L.O. Benson, and J.N. Vitale. 1993. Mortality study of ethylene oxide workers in chemical manufacturing: A 10 year update. Br. J. Ind. Med. 50(8): 704-709. UCC (Union Carbide Corp.). 1993. Ethylene Oxide: An Assessment of Epidemiologic Evidence on Carcinogenicity with Attachment and Cover Letter Dated 07/22/93. Doc. No. 86-930000340. Office of Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. UCCPC (Union Carbide Chemical and Plastic Co.). 1991. A Cohort Mortality Study of Workers Potentially Exposed to Ethylene Oxide (Final) with Cover Letter Dated 07/25/91. Doc. ID No. 86-910000937. Office of Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. Van Doorn, R., M. Ruijten, and T. van Harreveld. 2002. Guidance for the Application of Odor in Chemical Emergency Response, Version 2.1. August 29, 2002 [Presented at the NAC/AEGL Meeting, September 2002, Washington, DC]. Vergnes, J.S., and I.M. Pritts. 1994. Effects of ethylene on micronucleus formation in the bone marrow of rats and mice following four weeks of inhalation exposure. Mutat. Res. 324(3):87-91. Waite, C.P., F.A. Patty, and W.P. Yang. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds. IV. Ethylene oxide. Public Health Rep. 45(32):1832-1844. Walker, V.E., T.R. Fennell, J.A. Boucheron, N. Fedtke, F. Ciroussel, and J.A. Swenberg. 1990. Macromolecular adducts of ethylene oxide: A literature review and a time-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 course study on the formation of 7-(2-hydroxyethyl)guanine following exposure of rats by inhalation. Mutat. Res. 233(1-2):151-164. Walker, V.E., T.R. Fennell, P.B. Upton, T.R. Skopek, V. Prevost, D.E. Shuker, and J.A. Swenberg. 1992a. Molecular dosimetry of ethylene oxide: Formation of persistence of 7-(2-hydroxyethyl)guanine in DNA following repeated exposure of rats and mice. Cancer Res. 52(16):4328-4334. Walker, V.E., J.P. MacNeela, J.A. Swenberg, M.J. Turner Jr., and T.R. Fennell. 1992b. Molecular dosimetry of ethylene oxide: Formation and persistence of N-(2-hydroxyethyl)valine in hemoglobin following repeated exposures of rats and mice. Cancer Res. 52(16):4320-4327. Walker, W.J.G., and C.E. Greeson. 1932. The toxicity of ethylene oxide. J. Hyg. 32(3):409-416. Weller, E., N. Long, A. Smith, P. Williams, S. Ravi, J. Gill, R. Henessey, W. Skornik, J. Brain, C. Kimmel, G. Kimmel, L. Holmes, and L. Ryan. 1999. Dose-rate effects of ethylene oxide exposure on developmental toxicity. Toxicol. Sci. 50(2):259-270. WHO (World Health Organization). 1985. Ethylene Oxide. Environmental Health Criteria 55. Geneva: World Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc55.htm [accessed Mar. 22, 2010]. Wong, O., and L.S. Trent. 1993. An epidemiological study of workers potentially exposed to ethylene oxide. Br. J. Ind. Med. 50(4):308-316. Woo, D.C., and R.M. Hoar. 1972. “Apparent hydronephrosis” as a normal aspect of renal development in late gestation of rats: The effect of methyl salicylate. Teratology 6(2):191-196. Yager, J.W. 1987. Effect of concentration-time parameters on sister-chromatid exchanges induced in rabbit lymphocytes by ethylene oxide inhalation. Mutat. Res. 182(6):343-352. Yong, L.C., P.A. Schulte, J.K. Wiencke, M.F. Boeniger, L.B. Connally, J.T. Walker, E.A. Whelan, and E.M. Ward. 2001. Hemaglobin adducts and sister chromatid exchanges in hospital workers exposed to ethylene oxide: Effects of glutathione-S-transferase T1 and M1 genotypes. Cancer Epidemiol. Biomarkers Prev. 10(5):539-550. Zey, J.N., V.D. Mortimer, and L.J. Elliott. 1994. Ethylene oxide exposures to hospital sterilization workers from poor ventilation design. Appl. Occup. Environ. Hyg. 9(9):633-641.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 APPENDIX A DERIVATION OF AEGL VALUES FOR ETHYLENE OXIDE Derivation of AEGL-2 Key studies: Snellings et al. 1982a; Mandella 1997a Toxicity end point: NOAEL for neurotoxicity and developmental toxicity in rats, 100 ppm Time-scaling: ten Berge’s equation: Cn × t = k, where n = 1.2 derived from rat data Uncertainty factors: Total = 10 3 for interspecies sensitivity 3 for intraspecies variability Calculations: 6-h exposure (experimental) C = 100 ppm/10 (uncertainty factor) = 10 ppm Cn × t = k; n = 1.2 C = 10 ppm, t = 6 h, k = 95.09 ppm-h 10-min AEGL-2 80 ppm, same as the 0.5-h value 30-min AEGL-2 C = (k/t)1/1.2 = (95.09 ppm-h /0.5 h)1/1.2 = 80 ppm C = 80 ppm 1-h AEGL-2 C = (k/t)1/1.2 = (95.09 ppm-h /1 h)1/1.2 = 45 ppm C = 45 ppm 4-h, AEGL-2 C = (k/t)1/1.2 = (95.09 ppm-h /4 h)1/1.2 = 14 ppm C = 14 ppm 8-h AEGL-2 C = (k/t)1/1.2 = (95.09 ppm-h /8 h)1/1.2 = 7.9 ppm C = 7.9 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 Derivation of AEGL-3 Key study: Jacobson et al. 1956 Toxicity end point: Lethality; the LC50 for white male rats was 1,460 ppm for a 4-h exposure. The data were extrapolated to a LC01 (628 ppm) to approximate the lethality threshold. Time-scaling: ten Berge’s equation: Cn × t = k, where n = 1.2 derived from rat data Uncertainty factors: Total = 10 3 for interspecies sensitivity 3 for intraspecies variability Calculations: C = 628 ppm/10 (uncertainty factor) = 62.8 ppm Cn × t = k; c = 62.8 ppm, n= 1.2, t = 4 h, k = 574.93 ppm-h 10-min AEGL-3 360 ppm (same as the 0.5-h value) 30-min AEGL-3 C = (k/t)1/1.2 = (574.93 ppm-h /0.5 h)1/1.2 = 355 ppm C = 360 1-h AEGL-3 C = (k/t)1/1.2 = (574.93 ppm-h /1 h)1/1.2 = 199 ppm C = 200 ppm 4-h AEGL-3 C = (k/t)1/2 = (574.93 ppm-h /4 h)1/1.2 = 62.8 ppm C = 63 ppm 8-h AEGL-3 C = (k/t)1/1.2 = (574.93 ppm-h /8 h)1/1.2 = 35 ppm C = 35 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 APPENDIX B PRELIMINARY CANCER ASSESSMENT OF ETHYLENE OXIDE In 1985, EPA reported a unit risk or q1* for inhalation exposure to ethylene of 1 ×10-4 μg/m3 based on the combined incidences of leukemia and brain gliomas in F344 rats as reported by Snellings et al. (1981) (EPA 1985). A study by NTP (1987) was completed after EPA conducted its risk assessment of ethylene oxide. This study was summarized in Table 2-15 of the text and the data for lung tumors in female mice will be used to calculate another unit risk (q1*). The calculations of the unit risk and the AEGL values for carcinogenicity are presented below. Data summary (NTP 1987): Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 50, or 100 ppm for 6 h/day, 5 days/week, for 102 weeks. The incidence of lung adenomas and carcinomas in females was 2/49, 5.48, or 22/49 for 0, 50, or 100 ppm, respectively. Derivation of the unit risk for ethylene oxide: Convert exposure concentrations for 6 h/day and 5 days/week to continuous exposure: The unit risk (q1*) derived from the linearized multistage model is 8.82 × 10–3 (mg/m3)–1. The calculations for AEGL values following the method presented by NRC (1986a) are presented below. To calculate a “virtually safe dose” of d at a cancer risk of 10–4: To calculate the total cumulative dose for a total lifetime exposure of 70 years, which is equivalent to 25,600 days: In the adjustment to allow for uncertainties in assessing potential cancer risks under short-term exposures under the multistage model (Crump and Howe 1984), the total dose is divided by a factor of 6:
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 Therefore, a 24-h exposure concentration associated with a 10−4 risk is 26.7 ppm. The 10−4 cancer risk associated with exposures for 10, 30, 60, 240, and 480 min can be calculated from the following equation: The AEGL values associated with risks of 10−4, 10−5, and 10−6 are presented in Table B-1. TABLE B-1 AEGL Values Associated with Different Risks Exposure Time 10−4 10−5 10−6 10 min 1,300 ppm 130 ppm 13 ppm 30 min 1,300 ppm 130 ppm 13 ppm 1 h 640 ppm 64 ppm 6.4 ppm 4 h 160 ppm 16 ppm 1.6 ppm 8 h 80 ppm 8 ppm 0.8 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 APPENDIX C DERIVATION OF THE LEVEL OF DISTINCT ODOR AWARENESS (LOA) FOR ETHYLENE OXIDE The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than one-half of the exposed population will experience at least a distinct odor intensity and about 10% of the population will experience a strong odor intensity. The LOA should help chemical emergency responders in assessing the public awareness of the exposure due to odor perception. The LOA derivation follows the guidance given by van Doorn et al. (2002). The odor detection threshold (OT50) for ethylene oxide is calculated from the odor threshold of 260 ppm reported by Hellman and Small (1974) and adjusted by Van Doorn et al. (2002): The concentration (C) leading to an odor intensity (I) of distinct odor detection (I = 3) is derived by using the Fechner function: For the Fechner coefficient, the default kw = 2.33 is used because of the lack of chemical-specific data: The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in everyday life, factors, such as sex, age, sleep, smoking, upper airway infections, and allergy, as well as distraction, increase the odor detection threshold by up to a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 s), which leads to the perception of concentration peaks. Based on the current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustments for distraction and peak exposure lead to a correction factor of 4/3 = 1.33. Therefore, the LOA for ethylene oxide is 1,625 ppm.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR ETHYLENE OXIDE Derivation Summary for Ethylene Oxide AEGL-1 VALUES 10 min 30 min 1 h 4 h 8 h Not recommended Key reference: Not applicable Test species, strain, number: Not applicable Exposure route, concentration, durations: Not applicable Effects: Not applicable End point, concentration, rationale: Not applicable Uncertainty factors/rationale: Total uncertainty factor: Not applicable Interspecies: Not applicable Intraspecies: Not applicable Modifying Factor: Not applicable Animal to human dosimetric adjustment: Not applicable Time-scaling: Not applicable AEGL-2 VALUES 10 min 30 min 1 h 4 h 8 h 80 ppm 80 ppm 45 ppm 14 ppm 7.9 ppm Key references: Snellings, W.M., R.R. Maronpot, J.P. Zelenak, and C.P. Laffoon. 1982a. Teratology study in Fischer 344 rats exposed to ethylene oxide by inhalation. Toxicol. Appl. Pharmacol. 64(3):476-481. Mandella, R.C. 1997a. An Acute Inhalation Neurotoxicity Study of Ethylene Oxide (498-95-A) in the Rat Via Whole-Body Exposure. Final Report. Study No. 95-6097. Prepared by Huntingdon Life Sciences, East Millstone, NJ , for Allied Signal, Inc, Morristown, NJ, and ARC Chemical Division, Balchem Corporation, Slate Hill, NY. Test species, strain, number: Sprague-Dawley rats, 10/sex/group Exposure route, concentration, durations: Inhalation; 0, 100, 300, or 500 ppm for 6 h Effects: Developmental toxicity 10 ppm: no effect 33 ppm: no effect
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 10 min 30 min 1 h 4 h 8 h 80 ppm 80 ppm 45 ppm 14 ppm 7.9 ppm Effects: 100 ppm: statistically significant decrease in fetal body weight and non-statistically significant increase in the litter incidence of delayed ossification (not considered toxicologically significant) Neurotoxicity: 0 ppm: droopy, half-closed eyelids (10%) and no response to approach (10%); other end points (0%) 100 ppm: droopy, half-closed eyelids (10%); low arousal (15%); and no response to approach (15%) 300 and 500 ppm: droopy, half-closed eyelids (25%, 40%**); impaired locomotion (10%, 15%); low arousal (30%,** 75%**); and no response to approach (35%,* 50%**) *p < 0.05; **p < 0.01 End point, concentration, rationale: NOAEL for neurotoxicity at 100 ppm; low arousal was observed at 100 ppm, but the incidence did not reach statistical significance (p = 0.12, Fisher’s exact test); the next higher concentration of 300 ppm caused significant increases in the incidences of low arousal and no reaction to approach response. Uncertainty factors and rationale: Total uncertainty factor:10 Interspecies: 3, one potential mechanism of toxicity, direct alkylation of DNA and proteins, is not expected to differ across species. Neurotoxicity similar in rats and humans (distal axonal degeneration, neuropathy); PBPK models have shown that the AUC, peak blood levels, internal dose in mg/kg of body weight, and hemoglobin adduct level (measure of internal exposure) for humans are similar to or lower than the corresponding values for rats. Intraspecies: 3, An uncertainty factor of 3 was selected for intraspecies variability because glutathione-S-transferase polymorphism can modulate systemic exposure as measured by hemoglobin adducts but appears to be within a factor of 3 within the population. Individuals with asthma are not expected to respond differently to ethylene oxide concentrations below the odor detection and irritation thresholds. Modifying factor: 1 Animal to human dosimetric adjustment: 1 Time-scaling: Cn × t = k, where n = 1.2 as determined from empirical LC50 data for the rat for 1 and 4 h. Data quality and support for the AEGL values: Human studies to evaluate adverse effects of ethylene oxide on reproduction and development have not been conclusive. However, multiple animal studies showed that ethylene oxide is a developmental toxicant in rats and mice. Humans and rats show similar manifestations of peripheral neurotoxicity; legs and hindlimbs are primary targets, with distal axonal degeneration and peripheral neuropathy developing in humans and rats. The AEGL-2 values are below the concentrations that cause respiratory tract irritation and are below the odor detection threshold.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 AEGL-3 VALUES 10 min 30 min 1 h 4 h 8 h 360 ppm 360 ppm 200 ppm 63 ppm 35 ppm Key reference: Jacobson, K.H., E.B. Hackley, and l. Feinsliver. 1956. The toxicity of inhaled ethylene oxide and propylene oxide vapors. AMA Arch. Ind. Health 13(3): 237-244. Test species, strain, number: White male rats, 10 per group Exposure route, concentration, durations: Inhalation, 882, 1,343, 1,648, 1,843, 1,992, 2,298 ppm for 4 h. Effects: Clinical signs: Frequent movement and preening, clear nasal discharge, lacrimation, salivation, diarrhea, gasping, and death. Gross observations: Signs of upper respiratory tract irritation, tracheal congestion, and petechial hemorrhages and mild edema in the lungs and peribronchial region. Mortality: 882 ppm (2/10), 1,343 ppm (2/10), 1,648 ppm (4/10), 1,843 ppm (9/10), 1,992 ppm (10/10), and 2,298 ppm (10/10); LC50 = 1460 ppm. End point, concentration, rationale: Lethality; LC01 = 628 ppm for 4 h, the estimated threshold for lethality derived by probit analysis of the data. Uncertainty factors and rationale: Total uncertainty factor: 10 Interspecies: 3, one potential mechanism of toxicity, direct alkylation of DNA and proteins, is not expected to differ across species. PBPK models have shown that the AUC, peak blood levels, internal dose in mg/kg of body weight, and hemoglobin adduct level (measure of internal exposure) for humans are similar to or lower than the corresponding values for rats. Intraspecies: 3, An uncertainty factor of 3 was selected for intraspecies variability because glutathione-S-transferase polymorphism can modulate systemic exposure as measured by hemoglobin adducts but appears to be within a factor of 3 within the population. Individuals with asthma are not expected be respond differently to ethylene oxide concentrations below or slightly above the odor detection and irritation thresholds. An interspecies or an intraspecies uncertainty factor of 10 would place AEGL-3 values below concentrations likely to be associated with life-threatening events. Modifying factor: 1 Animal to human dosimetric adjustment: 1 Time-scaling: Cn × t = k, where n = 1.2 as determined from empirical LC50 data for the rat for 1 and 4 h. Data quality and support of AEGL values: AEGL-3 values for ethylene oxide were derived from one of several well-conducted studies. AEGL-3 values are below the estimated 10–4 risk associated with the lifetime risk of developing cancer after a single exposure. The 10- and 30-min values exceed the lower limit on the odor detection threshold. Respiratory tract irritation may occur at these concentrations and reversible neurologic effects may occur at the AEGL-3 concentrations, but life-threatening events are unlikely to occur.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9 APPENDIX E CATEGORY PLOT FOR ETHYLENE OXIDE FIGURE D-1 Category plot for ethylene oxide.