Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 9 (2010) / Chapter Skim
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2 Ethylene Oxide
2 Ethylene Oxide
Pages 46-135
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From page 46... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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From page 47... ...
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)
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From page 48... ...
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)
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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.
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TABLE 2-1 Summary of AEGL Values for Ethylene Oxide Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1a (Nondisabling)
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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)
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(1981) reported that a female nurse was exposed to ethylene oxide vapor while disposing of an ampule she accidentally dropped.
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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.
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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.
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(1979) reported on three workers accidentally exposed for 2 weeks to 2 months to ethylene oxide vapor from a leaky sterilizer.
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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.
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Sterilizing staffb 1,443 11.3 9.7 16.7c 15.1c Exposed during pregnancy 545 Not exposed during 605 6.0 4.6 pregnancy 123c 11.3c Uncertain 293 Ethylene oxide alone 20.7d 16.1c Exposed during pregnancy 82 Not exposed during 1,068 10.3 7.8 pregnancy Control 1,179 10.6 10.5 a Adjusted for age, parity, decade of reported pregnancy, coffee and alcohol consumption, and cigarette smoking. b Includes staff exposed to ethylene oxide, glutaraldehyde, and formaldehyde sterilants.
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. Ethylene oxide exposures varied over the years (Hogstedt et al.
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The risk of all cancers combined, stomach cancer, and blood and lymphatic cancer -- particularly the risk of stomach cancer and leukemia among male workers -- was increased. The risk of cerebrovascular diseases among male workers exposed to ethylene oxide was also increased (Hogstedt 1988)
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. Current estimates for single exposures to ethylene oxide are presented in Appendix B
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Laurent (1988) reported increased SCE frequencies in peripheral lymphocytes of three sterilizer workers accidentally exposed for 30 min to ethylene oxide concentrations exceeding the odor detection level (260 ppm or 1,260 mg/m3)
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Their assessment considered genetic end points in germ cells and somatic cells in animals, including humans. They estimated a risk of 4 × 10−4 above background from occupational exposure to ethylene oxide at 1 ppm for 1 year.
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The absolute odor detection level for ethylene oxide is 260 ppm as reported by one author, and the median odor threshold is 700 ppm as reported by another. The odor recognition level is 500 ppm.
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1981 twitching, malaise, incoordination for up to 1 wk Not reported Not reported 4 mon to 12 y Eye irritation, headaches, smelling of fumes, distal axonal Finelli et al. 1983 neuropathy 36-1,500 65-2,700 Cyclic for 2-5 mon Upper respiratory irritation, eye irritation, sore throat and Garry et al.
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Peak = 23.5 42.3 Up to 1 min Odor, headache, skin and eye irritation, dry mouth, sore Bryant et al. 1989 throat, runny nose, shortness of breath, nausea, and Total up to 10.7 19.3 Up to 11.75 min numbness in fingers Average 3.4 6.1 Not reported Drowsiness 0.1-0.5 (8-h 0.18-0.9 (8-h During pregnancy Increased risk of spontaneous abortion Hemminki et al.
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Nonimmunologic asthma was reported in one study; this effect has not been confirmed and may not be due to ethylene oxide exposure. One worker with asthma exposed to ethylene oxide at the odor detection level experienced no symptoms suggestive of effects on the respiratory tract.
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. Clinical signs immediately after exposure included tremors and an absence of tail and toe TABLE 2-7 Mortality in Male White Rats Exposed to Ethylene Oxide Vapor for 4 Hours Concentration Mortality (%)
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Other lesions included alveolar histiocytosis, pulmonary edema, interstitial pneumonitis, and emphysema. TABLE 2-8 Lethality and Clinical Signs in Male and Female Sprague-Dawley Rats Exposed to Ethylene Oxide Vapor for 4 Hours Concentration (ppm)
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was metered into a 120-L glass and stainless steel dynamic exposure chamber. The chamber atmospheres were analyzed with a gas chromatograph equipped with a flame ionization detector, and nominal concentrations were calculated based on the amount of ethylene oxide delivered to the chamber.
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TABLE 2-10 Clinical Signs in Male and Female Sprague-Dawley Rats Exposed to Ethylene Oxide for 1 Hour Concentration (ppm) Males Females Effects 6,161 5,546 4,827 4,827 4,202 4,064 3,966 3,609 Mortality (%)
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In another experiment, 10 male and 10 female rats were exposed to ethylene oxide vapor at 357 ppm for 33 to 59 exposures for 48 to 85 days. Growth was retarded, and by the 38th exposure 18 rats (90%)
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All males exposed to 800 ppm died 2 to 6 days after exposure and four females exposed to 800 ppm died 1 to 3 days after exposure. All male and female mice exposed to 1,600 ppm died within 4 h after exposure.
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All five male and four of five female mice exposed to 800 ppm died within 1 day of exposure; one female died within 2 days of exposure, thus confirming the lethality of 800 ppm in the single-exposure study. Clinical signs at 800 ppm included hunched posture and listlessness.
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(1956) exposed 30 female white mice to ethylene oxide vapor at 400 ppm (720 mg/m3)
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TABLE 2-14 Mortality in Male Beagle Dogs Exposed to Ethylene Oxide Vapor for 4 Hours Concentration Mortality (%)
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vapor. Groups of 30 male and 30 female mice were exposed to ethylene oxide vapor in a 4,350-L stainless steel and glass chamber at target concentrations of 0, 10, 50, 100, or 250 ppm, 6 h/day, 5 days/week for 10 weeks (males)
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All mice exposed to 400 or 600 ppm died within the first 4 weeks of the study. Clinical signs observed in mice exposed to ethylene oxide at 600 ppm included anorexia, dyspnea, decreased activity, bloatedness, and listlessness.
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Overall, this study showed exposurerelated acute neurotoxicity in male and female rats on day 1 after a single exposure to ethylene oxide at 300 or 500 ppm. The effects were reversible because no clear exposure-related effects were observed on day 8 or 15.
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In a subchronic neurotoxicity study, groups of 15 male and 15 female Sprague-Dawley rats were exposed by whole body inhalation to ethylene oxide vapor at concentrations of 0, 25, 50, 100, or 200 ppm for 14 weeks (Mandella 1997c)
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The remaining animals were maintained for an additional 7 years without ethylene oxide exposure, at which time two additional animals per group were subjected to neuropathologic examination. Mean body weight of monkeys exposed to 50 ppm was similar to that of controls, but the 100-ppm group weighed significantly less than controls from week 25 to the termination of exposure.
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No effects occurred at 10 or 33 ppm. In another developmental toxicity study, groups of 25 pregnant CD rats (Sprague-Dawley stock)
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(1996) conducted a developmental toxicity study with pregnant Sprague-Dawley rats exposed to ethylene oxide on GD 6 to 15 inclusive.
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The mean body weight of female rats exposed to ethylene oxide vapor before mating and throughout gestation (group 4) was significantly lower (4% to 6%)
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The control group consisted of 12 males rats exposed to clean air. The animals were exposed in a 0.2-m3 inhalation chamber; the chamber atmosphere was monitored with a gas chromatograph equipped with a flame ionization detector (Mori et al.
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(1987) exposed female mice to ethylene oxide at 0 or 1,200 ppm (2160 mg/m3)
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A marked reduction was observed in the number of live fetuses from female mice exposed to ethylene oxide vapor 1 h after mating (6 fetuses per dam versus 9.72 for controls) and 6 h after mating (1.81 fetuses per dam versus 10.11 for controls)
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The overall incidence of clinical signs at 24 h was lower than that observed 30 min after exposure and showed an increasing trend with exposure concentrations at 2,100 and 2,700 ppm-h. Developmental toxicity was exhibited by increased resorptions, decreased fetal body weight, decreased crown-to-rump length, and increased litter incidences of eye defects after exposure to ethylene oxide.
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88 TABLE 2-17 Developmental Toxicity in C57BL6 Mice Exposed Whole Body to Ethylene Oxide on GD 7 Maternal Effects Developmental Effects % with Eye Defects Number Number Number Number Clinical Signs with Resorptions Dead Fetal C-R Offspring (Offspring/ Weight Number Concentration Exposed Number Lost (%) Implants Weight (g)
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From page 89... ...
with B6C3F1 mice exposed to ethylene oxide vapor at 50 or 100 ppm for 102 weeks showed statistically significant increases in the incidences of alveolar and bronchiolar adenomas or carcinomas and Harderian gland tumors in male and female mice and increases in uterine tumors and malignant lymphomas in female mice. Snellings et al.
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90 TABLE 2-18 Inhalation Exposure to Ethylene Oxide: Summary of Carcinogenicity Studies Animal Description Response Species/ Number Tissue Exposure Protocol Reference Strain Sex in Group and Tumor Type Incidencea Mouse/A/J F 30 0, 70, or 200 ppm, 6 h/d, 5 Lung adenoma 28%, 56%, and 87%; 0.46, Adkins et al.
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M 80 0, 50, or 100 ppm 7 h/d, 5 Body cavity, peritoneal 3/78, 7/79, and 21/79* Lynch et al.
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(1977) showed that dominant lethality is induced in male Long-Evans rats exposed to ethylene oxide at 1,000 ppm (1,800 mg/m3)
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F1 600 ppm for 3 h/d, or 1,200 11%, 32%, and 64% dominant al. 1986 ppm for 1.5 h/d for 4 d lethality Dominant lethality Control, 165, 204, 250, or 47,025-85,500 ppm-h Positive: dose-related increase; Generoso et Mouse, (C3H × 101)
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F1 male mice exposed to ethylene oxide at 300, 400, or 500 ppm (540, 720, or 900 mg/m3) for 6 h/day for 4 days; the total concentrations were 7,200, 9,600, or 12,000 ppm-h.
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(1993) showed that SCEs are induced in spleen and bone marrow cells of male F344 rats exposed to ethylene oxide at 100 ppm for 6 h/day, 300 ppm for 2 h/day, or 600 ppm for 1 h/day, 5 days/week, for 3, 6, or 9 months.
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and compared the results with those of male F344 rats exposed to 300 ppm for 4 weeks. DNA adducts were measured in lungs, kidneys, liver, spleen, testes, and brain.
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Clinical signs observed in animals that survived a single exposure to ethylene oxide vapor were similar to those observed in animals that died. Eye and respiratory tract irritation and neurologic signs were the primary effects observed in animals surviving exposure to ethylene oxide.
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; no deaths at 4,827 ppm Rat, female 4,439 7,990 60 Lowest experimental concentration causing death was Nachreiner 1992 3,966 ppm (40%) ; no deaths at 3,609 ppm Rat, male and female 5,029 9,052 60 No comments Nachreiner 1992 Mouse, female 835 1,504 240 Lowest experimental concentration causing death was Jacobson et al.
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However, respiratory tract irritation progressed to secondary effects; neurologic effects progressed to hindlimb weakness, muscle atrophy, and paralysis, depending on the concentration. Growth retardation, mild anemia, and pathologic lesions in adrenal gland, thymus, nasal cavity, kidney, and spleen occurred after repeated exposures to ethylene oxide vapor.
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5 d/wk, premating, regardless of stage of exposure 1982 GD 7-16 or 1-16 Rat 0, 400, 800, No effects on fetus at any Saillenfait et al. 1,200 ppm, 0.5 h/d, concentration 1996 GD 6-15 Rat 0, 200, 400, 800, 800 ppm, fetal growth retardation Saillenfait et al.
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From page 101... ...
Physiologically-based pharmacokinetic (PBPK) model simulation of rats exposed to ethylene oxide at 100, 600, and 1,200 ppm for 4 h estimated glutathione depletion to be 10% to 15% in the liver, 60% to 70% in the lungs, and 60% to 80% in the testes (Krishnan et al.
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Maples and Dahl (1993) reported that blood uptake gradually increased during the first 15 min and reached a plateau at about 60 ng per g of blood in male F344 rats exposed to ethylene oxide vapor at 5 ppm for 60 min.
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(1996) reported t2 for ethylene oxide clearance from the blood as 13.8 ± 3.0 min for male rats and 10.8 ± 2.4 min for female rats exposed to 100 ppm; similar values were obtained for animals exposed to 330 ppm.
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(1992b) also showed that hemoglobin adduct formation exhibited a linear trend in mice and rats exposed to ethylene oxide at 3 to 33 ppm (6 h/day, 5 days/week, for 4 weeks)
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(1996) studied HEV hemoglobin adducts in maternal blood from smokers and nonsmokers along with the adduct levels in umbilical cord (fetal)
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The time of onset of symptoms indicated that direct irritation or caustic injury was not the mechanism causing respiratory tract irritation. The mechanisms by which ethylene oxide induces developmental and testicular toxicity (not including genetic damage to germ cells)
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Species Variability Acute lethality studies showed that mice are the most sensitive species, followed by dogs and rats. The LC50 value was about three times greater for male rats than for female mice exposed for 4 h.
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. The odor threshold and sensory irritation occur at ethylene oxide concentrations higher than those causing systemic effects.
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for 4 h/day for 4 days. Respiratory tract irritation could be attributed to each daily exposure, whereas peripheral neuropathy could have been caused by a single exposure and exacerbated upon repeated exposures.
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in the developmental toxicity studies in rats exposed repeatedly also was observed in mice after a single exposure. Therefore, a cumulative effect due to exposure is not necessary to explain growth retardation in rat fetuses.
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PBPK models have shown that the AUC, peak blood levels, dose in mg/kg of body weight, and hemoglobin adduct levels (measure of internal exposure) in humans are similar to or lower than those of rats (Fennell and Brown 2001)
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The resulting AEGL-2 values are summarized in Table 2-23. AEGL-2 values were derived from acute neurotoxicity and developmental toxicity studies.
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The LC01 is an estimate of the lethality threshold and is below the lowest concentration causing death. The uncertainty factors are 3 for interspecies sensitivity and 3 for intraspecies variability (total = 10)
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1986) was used to derive a unit risk for ethylene oxide from incidence data on alveolar and bronchiolar adenomas and carcinomas in female mice exposed to ethylene oxide vapor for 2 years.
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The calculations showed that the AEGL-3 values based on the excess lifetime cancer risk from a single exposure to ethylene oxide is greater than the concentration associated with the lethality threshold. Therefore, the AEGL-3 values were derived from an estimate of the lethality threshold (LC01)
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The ERPG-2 value was based on reproductive and developmental toxicity studies.
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d REL-TWA (recommended exposure limits–time-weighted average of the National Institute for Occupational Safety and Health)
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The database of animal studies is robust, containing acute inhalation studies in several species, an acute neurotoxicity, developmental and reproductive toxicity studies in several species, in vivo germ cell studies, and carcinogenicity studies in two species. However, a single-day developmental toxicity study would clear up some of the concerns about fetal growth retardation as a singleexposure or repeat-exposure event.
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1993. Ethylene Oxide: Developmental Toxicity Study of Maternally Inhaled Vapor in CD Rats With Cover Letter Dated 06/01/93.
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2000. Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: Effects of glutathione-S-transferase T1-null and M1-null genotypes.
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1956. The toxicity of inhaled ethylene oxide and propylene oxide vapors.
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1997a. An Acute Inhalation Neurotoxicity Study of Ethylene Oxide (498 95-A)
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1996. Developmental toxicity of inhaled ethylene oxide in rats following short-duration exposure.
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1982a. Teratology study in Fischer 344 rats exposed to ethylene oxide by inhalation.
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1999. Dose-rate effects of ethylene oxide exposure on developmental toxicity.
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127 Ethylene Oxide 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 ten Berge's equation: Cn × t = k, where n = 1.2 Time-scaling: derived from rat data Uncertainty factors: Total = 10 3 for interspecies sensitivity 3 for intraspecies variability Calculations: 6-h exposure (experimental)
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ten Berge's equation: Cn × t = k, where n = 1.2 Time-scaling: 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)
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From page 129... ...
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*
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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 10–4 10–5 10–6 Exposure Time 10 min 1,300 ppm 130 ppm 13 ppm 30 min 1,300 ppm 130 ppm 13 ppm 1h 640 ppm 64 ppm 6.4 ppm 4h 160 ppm 16 ppm 1.6 ppm 8h 80 ppm 8 ppm 0.8 ppm
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. The odor detection threshold (OT50)
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From page 132... ...
1982a. Teratology study in Fischer 344 rats exposed to ethylene oxide by inhalation.
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From page 133... ...
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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From page 134... ...
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)
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From page 135... ...
135 Ethylene Oxide APPENDIX E CATEGORY PLOT FOR ETHYLENE OXIDE Chemical Toxicity - TSD All Data Ethylene Oxide 100000.0 Human - No Effect Human - Discomfort 10000.0 Human - Disabling 1000.0 Animal - No Effect ppm Animal - Discomfort 100.0 Animal - Disabling AEGL3 AEGL-2 Animal - Some Lethality 10.0 Animal - Lethal 1.0 AEGL 0 60 120 180 240 300 360 420 480 Minutes FIGURE D-1 Category plot for ethylene oxide.
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