Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 14 (2013) / Chapter Skim
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7 Vinyl Acetate Acute Exposure Guideline Levels
7 Vinyl Acetate Acute Exposure Guideline Levels
Pages 210-272
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From page 210... ...
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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An intraspecies uncertainty factor of 3 was applied because throat irritation is caused by a local effect of the chemical and the response is not expected to vary greatly among individuals. Because irritation is considered a threshold effect and should not vary over time, the same AEGL-1 value of 6.7 ppm was used for all exposure durations.
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A factor of 3 for interspecies differences was applied because nasal toxicity appears to depend on the metabolism of vinyl acetate to the metabolites acetic acid and acetaldehyde via carboxylesterase and aldehyde dehydrogenase. Metabolism studies found little difference in carboxylesterase-mediated metabolism of vinyl acetate in the nasal cavity of mice, rats, and humans, particularly in the olfactory epithelium (Bogdanffy and Taylor 1993; Bogdanffy et al.
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The LOA should help chemical emergency responders with assessing the public awareness of exposure to vinyl acetate by its odor. A carcinogenicity assessment for vinyl acetate was not appropriate for an acute exposure scenario because the proposed mechanism of carcinogenicity suggests a nonlinear mode of action requiring continuous exposure to vinyl acetate.
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2006; NIOSH acetic acid vinyl ester; 1- 2011 acetoxyethylene; ethynyl acetate; vinyl ethanoate CAS registry no.
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1 persistent slight throat irritation 34 3 120 1 complete, 2 partial olfactory fatigue; 1 transient, 1 persistent throat irritation 72 4 30 4 strong odor, partial olfactory fatigue; 4 slight throat irritation 20-60 min after exposure; ocular irritation until 60 min after exposure; subjects expressed unwillingness to work at this concentration for 8 h Source: Smyth and Carpenter 1973. a Corrected using calibration curve.
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Calibrated rotometers metered the collection at a rate of 1.5 L/min, and a vacuum was maintained using appropriate equipment. Vinyl aceate was measured by gas chromatography.
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. Three subjects in the first study reported upper respiratory irritation when exposed for 10 min at 21.6 ppm whereas three volunteers in the second study tolerated vinyl acetate at 20 ppm for 4 h with only one subject reporting olfactory fatigue and slight but persistent throat irritation.
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also investigated the same workers for potential pulmonary effects after chronic exposure to vinyl acetate. They reported a progressive and significant increase in the frequency of impaired pulmonary function in proportion to length employment (from 16.6 ± 8.7% at less than a year to 48.4 ± 5.1% (p < 0.001)
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. Cultured human lymphocytes exposed to vinyl acetate at 0.1-2.4 mM exhibited a linear increase in SCEs with increasing exposure duration up to 24 h (He and Lambert 1985)
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reported that a 2-min exposure to vinyl acetate at 4, 8, or 20 ppm resulted in minimal ocular, nasal, and throat irritation in one of two volunteers. One of three individuals complained of persistent throat irritation when the concentration was increased to 34 ppm for 2 h, and all four test subjects exposed at 72 ppm for 30 min reported ocular irritation and slight throat irritation for up to 60 min post-exposure.
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. Clinical signs, body weight changes, and mortality data are presented in Table 7-5.
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3.1.3. Guinea Pigs Groups of six male guinea pigs were exposed to vinyl acetate for 4 h at nominal concentrations of 2,000, 4,000, 8,000, or 16,000 ppm (calculated concentrations of 1,640, 3,280, 6,560, and 13,120 ppm as corrected using a curve based on a gas chromatographic analysis of concentrations ranging from 0.6 to 16,000 ppm)
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3.1.4. Rabbits Groups of four male rabbits were exposed to vinyl acetate for 4 h at nominal concentrations of 2,000, 4,000, or 8,000 ppm (calculated concentrations of 1,640, 3,280, or 6,560 ppm as corrected using a curve based on a gas chromatographic analysis of concentrations ranging from 0.6 to 16,000 ppm)
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Low body weight gain was noted in females exposed at 250 or 630 ppm, but gross necropsy and blood and urine analyses were normal. Exposure to vinyl acetate at 2,000 ppm produced clinical signs of ocular and nasal irritation, respiratory difficulty, poor condition, and low body weight gain, and histopathologic examination of the lungs revealed excess macrophages.
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No clinical signs or gross necropsy abnormalities were reported. Body weight gain in the 1,000-ppm group was decreased, with the maximum decrease occurring on exposure day 5 (86% of controls)
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No statistically significant increases in the labeling indexes were found in olfactory or respiratory epithelium of rats exposed five times. However, cell proliferation of the olfactory epithelium (primarily the basal cells)
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decreased mean absolute body weight on GDs 10, 15, and 20 (91, 88, and 89% of controls, respectively) and decreased body weight gain over GDs 6-10 (-10.3 g vs.
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from rat nasal cavities were incubated with vinyl acetate at 0, 20, 25, 50, 100, or 200 mM, followed by assaying for acid phosphatase release (Kuykendall et al.
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Although repeated-exposure studies are not relevant for derivation of acute exposure values, they do support the premise that exposure to "lower" concentrations of vinyl acetate is compensated for by nasal scrubbing, whereas exposure to concentrations exceeding the scrubbing capacity of the nasal cavity result in lower-respiratory-tract effects. Groups of five male and five female Sprague-Dawley rats or CD 1 mice were exposed to vinyl acetate at 0, 50, 150, 500, or 1,000 ppm for 6 h/day, 5 days/week for 4 weeks (Owen 1979a,b)
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Body weight gain in the 150-, 500-, 1,000-, and 50/1,500-ppm groups was 104, 102, 81, and 79% of controls, respectively, for male rats and 95, 92, 80, and 78% of controls, respectively for female rats. In mice, weights were 67, 44, 33, and 33% of controls for male mice, respectively, and 80, 80, 40, and 0% of controls, respectively, for female mice.
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From page 231... ...
Clinical signs of rough coat and hunched posture were noted at all concentrations and are believed to be an effect of inhalation exposure. In rats, exposure to vinyl acetate at 600 ppm resulted in statistically decreased body weight gain and decreased absolute body weight (approximately 10% less than controls at 104 week)
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Following the 15-week recovery period, 600-ppm male mice and all exposed female mice exhibited a statistically significant increase in body weight gain compared with controls. No significant differences were noted in hematology or clinical chemistry parameters.
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A single, 6-h exposure to vinyl acetate at 600 or 1,000 ppm resulted in increased cell proliferation in the respiratory and olfactory epithelium, with 200 ppm being a no-observed-adverse-effect level for all histologic effects. A developmental toxicity study of vinyl acetate in rats reported maternal toxicity at 1,000 ppm, as evidenced by decreased maternal body weight and
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. A carcinogenicity bioassay reported that rats exposed to vinyl acetate at 600 ppm developed nasal papillomas, squamous cell carcinomas, and carcinoma in situ, but that mice did not develop nasal tumors.
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olfactory and respiratory 1997 epithelium; increase in cell proliferation in nasal respiratory and olfactory epithelium. Mouse 410 4 No clinical signs; no effect l Smyth and evel for death (0/6)
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(1997) provided information on the deposition of inhaled vinyl acetate in the rat nasal cavity.
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1979 270 0.011 0.263 100 0 1.11 0.052 270 0.079 1.05 Rat whole blood 100 0 1.10 0.014 Cresswell et al. 1979 565 ND 1.06 Homogenized rat liver 100 0 0.924 0.064 Cresswell et al.
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. Histochemical staining of the rat nasal cavity revealed that a high-affinity carboxylesterase was bound to the luminal plasma membrane (Bogdanffy et al.
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are lined with olfactory epithelium. Source: Bogdanffy et al.
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; and rat nasal epithelial tissues (Kuyendall et al.
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Once metabolic saturation has occurred, vinyl acetate would be able to move further down into the respiratory tract. This is evidenced by the strong anterior to posterior gradient seen in the rat nasal cavity during histopathologic examination after acute exposure to inhaled vinyl acetate (Bogdanffy et al.
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DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 In a controlled-exposure study, a 2-min exposure of nine subjects to vinyl acetate at 4, 8, or 20 ppm resulted in minimal ocular, nasal, and throat irritation in one or two people (Smyth and Carpenter 1973)
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These findings conflict with those of the human volunteer study by Smyth and Carpenter (1973) , in which 20 ppm was tolerated by three subjects for 4 h and findings were limited to olfactory fatigue and slight throat irritation in one individual.
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reported that controlled exposure to vinyl acetate at 34 ppm for 2 h resulted in persistent throat irritation in one of three individuals, and exposure at 72 ppm for 30 min resulted in ocular irritation and slight throat irritation for up to 60 min after exposure ended in all four subjects. Irritation at 72 ppm was so severe that subjects expressed an unwillingness to work at this concentration for 8 h.
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An interspecies uncertainty factor of 3 was applied because the mechanism of nasal toxicity appears to depend on the metabolism of vinyl acetate to the metabolites acetic acid and acetaldehyde via carboxylesterase and aldehyde dehydrogenase. Studies of the metabolism of vinyl acetate by the nasal cavity reported little difference among male and female mice and rats and humans in the carboxylesterase-mediated metabolism of vinyl acetate, particularly by olfactory epithelium (Bogdanffy and Taylor 1993; Bogdanffy et al.
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lower than the AEGL-1 value of 6.7 ppm. Reduction of an uncertainty factor is appropriate when the weight of evidence indicates that a higher uncertainty factor would result in AEGL values at odds with human data (NRC 2001)
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(53 mg/m3) As discussed in the context of AEGL-2 values, no histopathologic effects or cell proliferation were noted in the olfactory or respiratory epithelium of rats exposed to vinyl acetate for 6 h at 0, 50, or 200 ppm, but concentration-related olfactory epithelium changes (degeneration, necrosis, and exfoliation)
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An interspecies uncertainty factor of 3 is applied because the mechanism of nasal toxicity appears to depend on the metabolism of vinyl acetate to the metabolites acetic acid and acetaldehyde via carboxylesterase and aldehyde dehydrogenase. Studies investigating the metabolism of vinyl acetate by the nasal cavity reported little difference among male and female mice, rats, and humans in the carboxylesterase-mediated metabolism of vinyl acetate, particularly by olfactory epithelium (Bogdanffy and Taylor 1993; Bogdanffy et al.
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(260 mg/m3) TABLE 7-18 AEGL Values for Vinyl Acetate Exposure Duration Classification 10 min 30 min 1h 4h 8h AEGL-1 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm (nondisabling)
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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. 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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, which lacked analytic confirmation of exposure concentrations and had results that appear to conflict with those from repeated exposure studies. Thus, well-conducted animal lethality studies would enhance the toxicologic database, as would more rigorous occupational health studies or controlled-exposure experiments in humans.
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1980. Chronic bronchitis and pulmonary function in the shop workers of "Polyvinyl Acetate" [in Russian]
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1997. Four-week inhala tion cell proliferation study of the effects of vinyl acetate on rat nasal epithelium.
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1993b. DNA-protein crosslink for mation in isolated rat nasal epithelial cells exposed to vinyl acetate and acetalde hyde .84th Annual Meeting of the American Association for Cancer Research, May 19-22, 1993, Orlando, FL.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1997. Physiologically based modeling of vinyl acetate uptake, metabolism, and intracellular pH changes in the rat nasal cavity.
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OTS 0571724. Toxicity end point: Human exposure to vinyl acetate at 20 ppm for 4 h resulted in one of three individuals complaining of persistent, slight throat irritation, and exposure at 34 ppm for 2 h resulted in one of three individuals complaining of persistent throat irritation (no longer slight)
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Studies investigating the metabolism of vinyl acetate by the nasal cavity found little difference among mice, rats, and humans in the carboxylesterase-mediated metabolism of vinyl acetate, particularly by olfactory epithelium (Bogdanffy and Taylor 1993; Bogdanffy et al.
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1997. Four week inhalation cell proliferation study of the effects of vinyl acetate on rat nasal epithelium.
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From page 260... ...
Studies investigating the metabolism of vinyl acetate by the nasal cavity found little difference among mice, rats, and humans in the carboxylesterase-mediated metabolism of vinyl acetate, particularly by olfactory epithelium (Bogdanffy and Taylor 1993; Bogdanffy et al.
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Vinyl Acetate 261 4-h AEGL-3: C3 × 4 h = 6.0 × 109 ppm-h C3 = 1.5 × 108 ppm C = 1,144 ppm ÷ 10 = 110 ppm 8-h AEGL-3: C1 × 8 h = 6,000 ppm-h C1 = 750 ppm C = 750 ppm ÷ 10 = 75 ppm
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The study also determined an odor threshold for the reference chemical n-butanol (odor detection threshold 0.04 ppm) : Odor detection threshold for vinyl acetate : 0.12 ppm Odor detection threshold for n-butanol: 0.3 ppm Corrected OT50 for vinyl acetate : (0.12 ppm × 0.04)
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Vinyl Acetate 263 applied to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a correction factor of 1.33 (4 ÷ 3)
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264 Acute Exposure Guideline Levels APPENDIX C CATEGORY PLOT FOR VINYL ACETATE FIGURE C-1 Categoray plot of animal and human toxicity data on vinyl acetate compared with AEGL values.
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TABLE C-1 Data Used in Category Plot for Vinyl Acetate Source Species Sex No. Exposures ppm Minutes Category Comments NAC/AEGL-1 6.7 10 AEGL NAC/AEGL-1 6.7 30 AEGL NAC/AEGL-1 6.7 60 AEGL NAC/AEGL-1 6.7 240 AEGL NAC/AEGL-1 6.7 480 AEGL NAC/AEGL-2 46 10 AEGL NAC/AEGL-2 46 30 AEGL NAC/AEGL-2 36 60 AEGL NAC/AEGL-2 23 240 AEGL NAC/AEGL-2 15 480 AEGL NAC/AEGL-3 230 10 AEGL NAC/AEGL-3 230 30 AEGL NAC/AEGL-3 180 60 AEGL NAC/AEGL-3 110 240 AEGL NAC/AEGL-3 75 480 AEGL Smyth and Carpenter 1973 Human 1 0.6 2 0 No effects Human 1 1.3 2 0 Odor detection Human 1 4 2 1 Odor detection; minimal ocular, nasal, throat irritation Human 1 8 2 1 Odor detection; minimal ocular, nasal, throat irritation Human 1 20 2 1 Odor detection; minimal ocular, nasal, throat irritation (Continued)
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, labored breathing, lacrimation Guinea pig Male 1 6,560 240 SL Mortality (4/6) , gasping, convulsions Guinea pig Male 1 13,120 240 3 Mortality (4/6)
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Dog Male 1 51.25 240 0 No effects Dog Male 1 102.5 240 0 No effects Dog Male 1 205 240 1 Blinking, red sclera Dog Male 1 820 240 2 Lacrimation, red sclera Dog Male 1 1,640 240 1 Blinking, sneezing, lacrimation, inflamed eyelids, nasal froth Dog Male 1 3,280 240 2 Ocular and nasal irritation, tremors, froth from nostrils Dog 1 820 2 1 Lacrimation Gage 1970 Rat 1 630 360 1 Low body weight Bogdanffy et al. 1997 Rat 1 50.8 360 0 No effects Rat 1 199.6 360 0 No effects Rat 1 1,007.3 360 2 Histopathologic changes (nasal epithelium)
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subjects (min) Response 0.6 9 2 None 1.3 9 2 9 immediate odor; 5 no odor at 2 min 4 9 2 9 immediate odor, 3 no odor at 2 min; 1 minimal ocular, nasal, and throat irritation 8 9 2 9 immediate odor; 1 no odor at 2 min; 2 minimal ocular, nasal, and throat irritation 20 9 2 9 immediate odor;1 minimal ocular, nasal, and throat irritation 20 3 240 3 complete olfactory fatigue in 3-116 min; 1 persistent slight throat irritation 34 3 120 1 complete, 2 partial olfactory fatigue; 1 transient, 1 persistent throat irritation 72 4 30 4 strong odor, partial olfactory fatigue; 4 slight throat irritation 20-60 min after exposure; ocular irritation up to 60 min after exposure; subjects expressed unwillingness to work at this concentration for 8 h.
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:331-350. Test species/Strain/Number: Rat, Sprague-Dawley, 5 males/group Exposure route/Concentrations/Durations: Inhalation, 0, 50, 200, 600, or 1,000 ppm for 6 h Effects: 0, 50, 200 ppm: No effects 600 ppm: Degenerative lesions and increased cell proliferation in olfactory epithelium 1,000 ppm: Increased incidence and severity of lesions in olfactory epithelium; some minimal lesions in respiratory epithelium; increased cell proliferation in olfactory epithelium.
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From page 270... ...
1997. Four-week inhalation cell proliferation study of the effects of vinyl acetate on rat nasal epithelium.
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From page 271... ...
Studies investigating the metabolism of vinyl acetate by the nasal cavity found little difference among mice, rats and humans in the carboxylesterase-mediated metabolism of vinyl acetate, particularly by olfactory epithelium (Bogdanffy and Taylor 1993; Bogdanffy et al.
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From page 272... ...
Lethality data are only available from the poorly documented studies by Smyth and Carpenter (1973) , which lacked analytic confirmation of exposure concentrations and provided data that conflict with the results of repeated exposure studies.
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