Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 17 (2014) / Chapter Skim
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4 Epichlorohydrin Acute Exposure Guideline Levels
4 Epichlorohydrin Acute Exposure Guideline Levels
Pages 190-261
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From page 190... ...
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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concentrations have caused irritation to eyes, throat, and respiratory tract and gastrointestinal disturbances that may be delayed in onset. Irreversible respiratory and hepatic damage, but no renal damage, have been observed in humans.
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Before death, the animals showed signs of cyanosis, muscle relaxation of the extremities, gasping, labored breathing, depressed or increased respiration, lethargy, fine tremors, and clonic convulsions. In addition, animals showed degenerative lesions of the nasal epithelium and kidneys and damage to the lower respiratory tract.
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values of 90-238 mg/kg in rats, guinea pigs, and mice (Berdasco and Waechter 2012)
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194 Acute Exposure Guideline Levels The database that can be used to derive AEGL values for epichlorohydrin consists of acute and repeat-exposure inhalation studies in multiple species and a carcinogenicity study in rats. TABLE 4-1 AEGL Values for Epichlorohydrin End Point Classification 10 min 30 min 1h 4h 8h (Reference)
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In a toxicology book, a chapter stated that humans exposed to epichlorohydrin vapor at 20 ppm for 1 h experienced burning of the eyes and nasal mucosa, that exposure at 40 ppm caused ocular and throat irritation that lasted about 48 h, and that 100 ppm was intolerable to man, with potential for pulmonary edema and renal lesions (Lefaux 1968)
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. Clinical examination about 2 days after the accident showed inflammation of mucous membranes in the upper respiratory tract and a painfully enlarged liver, slight jaundice, increased serum bilirubin, and positive urine urobilinogen.
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2.2.3. Epidemiologic Studies Epidemiologic studies of epichlorohydrin have involved the analysis of mortality or morbidity data from two cohorts from the Shell Oil Company in its Texas and Louisiana facilities, both of which produced epichlorohydrin (Enterline et al.
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(1981) investigated the association between fertility, as measured by sperm count and hormone concentrations, and potential exposure to epichlorohydrin at the two Shell chemical plants that produced epichlorohydrin.
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(1994) reported an association between occupational exposure to epichlorohydrin, particularly acute exposure, and central nervous system neoplasms (in decedents and living)
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Picciano (1979) compared the frequency of chromosome aberrations in peripheral lymphocytes from 93 workers occupationally exposed to epichlorohydrin with the frequency in 75 preemployment individuals (control)
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2.7. Summary No lethality data in humans after acute exposure to epichlorohydrin were available, and data on acute nonlethal effects after acute exposure were limited.
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ANIMAL TOXICITY DATA 3.1. Acute Lethality The literature on the acute and short-term inhalation toxicity of epichlorohydrin is extensive, consisting of lethality data from studies of rats, mice, guinea pigs, rabbits, dogs, hamsters, and cats.
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No rats exposed for only 5 min died within the specified time; five of six rats exposed for 10 min died within 2 days, and all six exposed for 15 min died within 12 h. Gasping was observed during exposure in all groups, and poor condition (indicative of narcosis)
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Five of 10 rats exposed at 661 ppm died within 2-4 days and all 10 rats exposed at 2,646 ppm died within 1-2 days. Symptoms of toxicity (not otherwise described)
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The difference in the mortality response of rats exposed in the 9-L glass chamber and the 193-L hardboard chamber was attributed to the generation of heat by the rats and the smaller surface:volume ratio that prevented adequate heat loss in the smaller chamber. Slott et al.
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3.1.2. Mice In 1941, Freuder and Leake reported the effects of inhaled epichlorohydrin on groups of 20-30 white mice exposed to epichlorohydrin vapors in a dynamic glass chamber at calculated concentrations of 8,300 or 16,600 ppm (0.35 or 0.70 mmol/L)
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, or irritation of mucous membranes were observed at 132 and 331 ppm, but one death occurred at 661 ppm and 100% died after exposure at 2,646 ppm. Toxicity was observed in all mice exposed at 661 and 2,646 ppm, moderate irritation was observed at 661 ppm, and strong irritation occurred at 2,646 ppm.
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From page 208... ...
Moderate and strong irritation of mucous membranes was observed at 661 and 2,646 ppm, respectively, and symptoms of toxicity were observed at concentrations of 331 ppm and higher. Groups of five male Purlbright guinea pigs were exposed to epichlorohydrin aerosols at concentrations of 70, 204, 324, 500, and 3,350 mg/m3 for 1 h and at 171 and 498 mg/m3 for 4 h in a 2-m3 chamber containing multiple species as described for rats (see Section 3.1.1)
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No deaths occurred at 66 ppm, but four deaths occurred at 661 ppm. Symptoms of toxicity or irritation to mucous membranes were observed in all five guinea pigs exposed at 661 ppm, but not those exposed at 66 ppm.
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Irritation of mucous membranes, increased respiration, lethargy, and labored breathing were observed in animals that died (580 and 1,160 ppm) and mucous membrane irritation was observed in surviving animals (290 ppm and higher)
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580 ppm. Rats/Carworth Farm-Wistar/males 4h 580 ppm Deaths at both concentrations; irritation of mucous membranes Kobernick et al.
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Guinea pigs/ Purlbright/males 4h 275 ppm Deaths and symptoms of toxicity at ≥331 ppm; moderate to Kimmerle 1967 (132-2,646 ppm) strong irritation at ≥661 ppm.
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of rats exposed to epichlorohydrin vapor; the study also was reported by Haskell Laboratory (1980)
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(1995) found no histopathologic evidence of hepatic or renal damage in rats exposed to epichlorohydrin vapor at a concentration of 100 ppm for 4 h.
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Clinical signs at 50 ppm and higher involved primarily the eyes and respiratory tract. The number of different clinical signs increased as the exposure concentration increased from 50 ppm to 200 ppm.
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Gross and histopathologic evidence of leucocytosis and toxicity were observed in the lung, kidneys, and liver of rats exposed at 120 ppm and evidence of toxicity was found in the lungs at 27 ppm but not at 56 ppm. No rats died after only one exposure, but one rat died after 11 exposures at 120 ppm.
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All nasal and renal damage was reversed during the 10-week postexposure period. The study was a reproduction study that showed marked transient decreases in fertility in male rats exposed at 25 and 50 ppm.
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No clinical signs attributed to epichlorohydrin were observed in the 10- and 25-ppm groups. The number of different clinical signs increased as the exposure concentration increased from 50 ppm to 200 ppm.
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The number of different clinical signs observed in each group increased as the exposure concentration increased from 50 ppm to 400 ppm. Salivation was observed before exposure was initiated.
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2/10 (3-6 d) + clinical signs observed; – no clinical signs observed Source: Data from Industrial Bio-Test Laboratories 1977c.
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(1983b) examined the effects of inhaled epichlorohydrin on fertility in groups of 30 male and 30 female Sprague-Dawley rats exposed to epichlorohydrin at 0, 5, 25, or 50 ppm for 6 h/day, 5 days/week for 10 weeks (about one spermatogenic cycle)
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Rats exposed at 10 or 30 ppm over a lifetime developed pulmonary congestion, bronchiectasis, pneumonia, a very low incidence of mucosal metaplasia of the nasal cavity, and tubular degenerative changes in the kidney. These studies showed that: (1)
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3.6. Summary Inhalation exposure to epichlorohydrin causes varying degrees of irritation of the mucous membranes of contact organs and effects on the central nervous system, kidneys, and liver.
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Clinical signs indicative of nasal irritation and sometimes ocular irritation have been observed in rats, mice, guinea pigs, hamsters, and rabbits exposed at nonlethal concentrations of epichlorohydrin. The nasal epithelium shows signs of degeneration similar to that described for lethal concentrations.
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1995 BUN in adult rats; no microscopic evidence of hepatic or renal damage. Rats 1.9, 5.3, or 93 ppm × 4 h Increased hepatic and renal weight; decreased pulmonary and Shumskaya et al.
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; nasal epithelial and renal degeneration after repeated exposures. Mouse/B6C3F1/males 100 ppm ×7 h/day for 5 days/week Signs of nasal irritation after each exposure (discharge, Quast et al.
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Stott and McKenna (1984) studied the absorption of epichlorohydrin in the isolated upper and isolated lower respiratory tract and the intact animal (male Fischer 344 rats)
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Air flow through the isolated upper respiratory was unidirectional, which circumvented the loss of absorbed chemical due to significant back pressure during exhalation; the lower relative humidity may have altered blood flow and consequently chemical absorption by the isolated organ; and stimulation of the trigeminal nerve may have altered uptake by the lower respiratory tract. The authors further noted that absorption by the intact animal may have been underestimated because of unavoidable rebreathing of exhaled air, the effective deadspace in the upper respiratory tract causing less effective uptake, and fluctuating airflow during normal breathing patterns in the intact animals.
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All three compounds are direct alkylating agents; however, the toxicity of epichlorohydrin is more like that of propylene oxide than ETO. Both epichlorohydrin and propylene oxide caused lesions in the upper respiratory tract after a single exposure and nasal tumors after repeated exposures.
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230 Accute Exposure Guideline Levels detectaable by its odorr. Epichlorohyydrin and ETO have similar sstructures.
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Studies of animals exposed under static conditions are considered inferior to studies in which exposures were under dynamic conditions, and were not used as basis for AEGL values. As discussed in Section 4.5, AEGL values were
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, rats, mice, and hamsters showed clinical signs, such as squinting, hypoactivity, and salivation, after a single exposure to epichlorohydrin at 50 ppm for 66-217 min. Squinting of the eyes was considered separately from ocular irritation, which occurred in rats exposed at 200 ppm for 136 min.
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From page 233... ...
1990; Berdasco and Waechter 2012) has suggested that exposure to epichlorohydrin at 20 ppm for 1 h caused burning to the eyes and nose, 40 ppm caused throat irritation lasting for about 48 h, and 100 ppm could not be tolerated and may be associated with pulmonary edema and renal damage.
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(1995) reported no histopathologic evidence of hepatic or renal damage in F344 rats exposed to epichlorohydrin at 100 ppm for 4 h; the result appears to conflict with information reported by Ito et al.
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Although the information is anecdotal, support for the effects comes from a study of rats exposed to epichlorohydrin at 150 ppm for 1 h that exhibited evidence of severe renal damage (Ito et al.
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Microscopic examination of the respiratory tract showed exfoliation, erosion, ulceration, and necrosis of the nasal epithelium and hemorrhage, congestion, edema, or pneumonia in the lower respiratory tract. Systemic effects may include severe renal or hepatic damage.
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A factor of 3 is also supported by human data. Use of higher total uncertainty factor of 30 would result in an 8-h AEGL-3 value of 6.6 ppm; however, occupational exposures as high as 15-54 ppm have occurred (Pet'ko et al.
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. As noted in Section 2.2.2, data supporting these anecdotal statements were not found in the available literature, so this information was not considered adequate to serve as the basis for AEGL values.
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The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversible or other serious health effects or symptoms that could impair an individual's ability to take protective action. The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing lifethreatening health effects.
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. That value is based on a NOAEL of 5 ppm for fertility in male rats exposed for 10 weeks (John et al.
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Therefore, additional animal studies in which clinical signs and gross and histopathologic changes in the respiratory tract and systemic organs are evaluated in the same animals would provide helpful information to determine the most sensitive end point.
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Submitted to EPA, Washington, DC, by Du Pont de Nemours & Co., Wilmington, DE with Cover Letter Dated December 3, 1982. EPA Document No.
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Sub mitted to EPA, Washington, DC, by Mobay Chemical Corporation, Stilwell, KS with Cover Letter Dated January 28, 1983. EPA Document No.
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Pp. 46-135 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol.
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1995. Hepatic and renal assessment of acute exposure to inhaled epichlorohydrin: Toxicological evaluation and exposure modeling.
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1983. Effect of occupational exposure to epichlo rohydrin on the frequency of chromosome aberrations in peripheral lymphocytes.
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Epichlorohydrin 247 WHO (World Health Organization)
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Anecdotal information provided by Lefaux (1968) suggested that concentrations greater than 100 ppm for short intervals might result in pulmonary edema and renal damage.
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Lake Jackson Research Center, Health & Environmental Sciences - Texas, Dow Chemical, Freeport, TX.
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:751-757. Toxicity end point: 6-h rat LC01 of 274 ppm Time scaling: Cn × k = t; n = 0.87; C = 274 ppm ÷ 10 = 27.4 ppm; t = 360 min k = 27.40.87 ppm × 360 min = 6,414.2 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability 4-h AEGL-3: C = (k/t)
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-1. The calculations for AEGL values following the method presented by NRC (1986)
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252 Acute Exposure Guideline Levels Risk 10 min 30 min 1h 4h 8h AEGL values (ppm) AEGL-1 1.7 1.7 1.7 1.7 1.7 AEGL-2 53 53 24 14 6.7 AEGL-3 570 160 72 44 20 Cancer risk-based values (ppm)
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for epichlorohydrin is calculated from the odor threshold of 10 ppm (50% of unconditioned personnel) reported by Shell Oil Co.
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Submitted to EPA, Washington, DC, by Union Carbide Corporation, Danbury, CT with Cover Letter Dated December 9, 1983 EPA Document No. 878212138, Microfiche No.
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The 10-min value was set equal to the 30-min AEGL-2 value because human and animal data suggested that pulmonary edema and renal damage could occur at concentrations greater than 100 ppm for short intervals.
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From page 256... ...
Use of higher total uncertainty factor of 30 would result in an 8-h AEGL-3 value of 6.6 ppm; however, occupational exposures as high as 15-54 ppm have occurred (Pet'ko et al. 1966 [cited in NIOSH 1976]
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Epichlo orohydrin 2257 AP PPENDIX E GORY PLOT FOR EPICH CATEG HLOROHYDR RIN FIGUR RE E-1 Category y plot of toxicity data and AEGL L values for epichhlorohydrin.
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1983 Human 1 17 2 0 Human 1 68 2 1 Throat irritation. Human 1 136 2 1 Ocular, throat and nasal irritation.
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Rat Males 1 369 360 SL Mortality (15/20) , acute respiratory irritation with hemorrhage and severe edema.
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1983 Mouse Males 1 1,160 240 3 Irritation of mucous membranes, increased respiration, lethargy, and labored breathing. Kimmerle 1967 Mouse Males 1 132 240 0 Mouse Males 1 331 240 0 Mouse Males 1 661 240 SL Mortality (1/20)
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1983 Rabbit Males 1 290 240 1 Irritation of mucous membranes. Rabbit Males 1 580 240 SL Mortality (2/3)
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