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7 Vinyl Acetate1 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 Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished 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 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Claudia Troxel (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Richard Thomas (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). 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 scientifi- cally valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 210

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Vinyl Acetate 211 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 sus- ceptible 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 sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory 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 AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Vinyl acetate is a colorless, flammable liquid with low solubility in water (Rhum 1970; O’Neil et al. 2006). It is manufactured by reacting ethylene with sodium acetate (Bisesi 2001). U.S. production of vinyl acetate in 1993 was reported to be 2.83 billion pounds (Reisch 1994). Vinyl acetate is mainly used as a monomer in the production of poly(vinyl acetate) and vinyl acetate copolymers, which in turn are used to produce water-based paints, adhesives, and other coatings and bindings (Rhum 1970). Poly(vinyl acetate) is also a precursor for the synthesis of poly(vinyl alcohol) and poly(vinyl acetate) resins, or is copolymerized with vinyl chloride or ethylene to form polymers or with acrylonitrile to form acrylic fibers. The odor of vinyl acetate has been described as immediately pleasant, but then quickly sharp and irritating (Rhum 1970). The odor detection threshold is 0.12 ppm, and the recognition threshold is 0.4 ppm (Hellman and Small 1974; AIHA 1989; EPA 1992). AEGL-1 values are based on a human study that reported throat irritation from inhalation of vinyl acetate. Irritation was minimal or slight after 2 min at 4- 20 ppm, slight and persistent after 4 h at 20 ppm, and persistent after 2 h at 34 ppm (Smyth and Carpenter 1973). A no-effect level for notable discomfort of 20 ppm was selected as the point of departure. 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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212 Acute Exposure Guideline Levels AEGL-2 values are based on a no-observed-effect level (200 ppm for 6 h) for serious, long-lasting histopathologic nasal lesions in rats (Bogdanffy et al. 1997). A total uncertainty factor of 10 was applied: 3 for interspecies differences and 3 for intraspecies variability. 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. 1998). Esterase distribution in the nasal respiratory tissue of humans is believed to be similar to that of rats (Andersen et al. 2002). An intraspecies uncertainty factor of 10 would normally be applied because of the variability in the olfactory nasal tissue of humans with respect to surface area, composition of epithelial tissue layers (respiratory-type tissue can be interspersed with more characteristic olfactory tissue), and age-related changes (Andersen et al. 2002). However, a total uncertainty factor of 30 would result in an 8-h AEGL-2 value (5 ppm) lower than the AEGL-1 value of 6.7 ppm. Reducing 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). Therefore, the intraspecies uncertainty factor was reduced to 3. Time scaling was performed by using the equation Cn × t = k, where C = concentration, t = time, k is a constant, and n generally ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data on vinyl acetate were insufficient for determining an empirical value of n; therefore, default values of n = 1 for extrapolating from shorter to longer durations and n = 3 for extrapolating from longer to shorter durations were used. The 10-min AEGL-2 value was set equal to the 30-min value because of the uncertainties associated with extrapolating a 6-h exposure to a 10-min AEGL value (NRC 2001). AEGL-3 values for vinyl acetate were based on the highest nonlethal concentration (1,000 ppm) after a single 6-h exposure (Bogdanffy et al. 1997) or after repeated 6-h exposures of rats and mice (Owen 1979a,b; 1980a,b). A total uncertainty factor of 10 was applied: 3 for interspecies differences and 3 for intraspecies variability. An interspecies uncertainty factor of 3 was applied be- cause nasal toxicity is expected to be similar between species (see rationale in discussion of AEGL-2 values above). An intraspecies uncertainty factor of 3 instead of 10 was applied because the higher value would have resulted an 8-h AEGL-3 value (25 ppm) that is lower than concentrations that, did not result in serious health effects in a human volunteer study. In that study, no life- threatening effects were observed in humans exposed to vinyl acetate at 34 ppm for 2 h or at 72 ppm for 30 min (Smyth and Carpenter 1973). 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). Therefore, the intraspecies factor was reduced to 3. Time scaling was performed in the same manner as for AEGL-2 values. The 10-min AEGL-3

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Vinyl Acetate 213 value was set equal to the 30-min value because of the uncertainties associated with extrapolating a 6-h exposure to a 10-min AEGL value (NRC 2001). A level of distinct odor awareness (LOA) of 0.25 ppm was derived on the basis of the odor detection threshold for vinyl acetate reported by Hellman and Small (1974) (see Appendix C for the derivation). The LOA is the concentration above which more than half of the exposed population are predicted to perceive at least a distinct odor intensity; about 10% of the population will perceive a strong odor intensity. 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 ace- tate. Therefore, a one-time exposure even to high concentrations of vinyl acetate would not be expected to result in tumor development. AEGL values for vinyl acetate are presented in Table 7-1. 1. INTRODUCTION Vinyl acetate is a colorless, flammable liquid with low solubility in water (Rhum 1970; O’Neil et al. 2006). Its odor has been described as being immediately pleasant, but then quickly sharp and irritating (Rhum 1970). The odor detection threshold is reported to be 0.12 ppm, and the recognition threshold is 0.4 ppm (Hellman and Small 1974; AIHA 1989; EPA 1992). Other reported odor thresholds were rejected by EPA (1992) and AIHA (1989) because they were the minimum perceptible value or the result of a passive exposure. Vinyl acetate is manufactured by reacting ethylene with sodium acetate (Bisesi 2001). U.S. production of vinyl acetate in 1993 was reported to be 2.83 billion pounds (Reisch 1994). Vinyl acetate is primarily used as a monomer in the production of poly(vinyl acetate) and vinyl acetate copolymers, which in turn are used to produce water-based paints, adhesives, and other coating and binding applications (Rhum 1970). Poly(vinyl acetate) is also a precursor for the synthesis of poly(vinyl alcohol) and poly(vinyl acetate) resins, or is copolymerized with vinyl chloride or ethylene to form polymers or with acrylonitrile for acrylic fibers. The chemical and physical properties of vinyl acetate are presented in Table 7-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data on lethality in humans after acute exposure to vinyl acetate were found.

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214 Acute Exposure Guideline Levels TABLE 7-1 AEGL Values for Vinyl Acetate End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm No effect level for (nondisabling) (24 (24 (24 (24 (24 notable discomfort mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) in humans (Smyth and Carpenter 1973) AEGL-2 46 ppm 46 ppm 36 ppm 23 ppm 15 ppm No effect level for (disabling) (160 (160 (130 (81 (53 serious, long-lasting mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) histopathologic nasal lesions in rats (Bogdanffy et al. 1997) AEGL-3 230 ppm 230 ppm 180 ppm 110 ppm 75 ppm Highest nonlethal (lethal) (810 (810 (630 (390 (260 concentration mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (1,000 ppm) in rats or mice (Owen 1979a,b; 1980a,b; Bogdanffy et al. 1997) TABLE 7-2 Chemical and Physical Properties of Vinyl Acetate Parameter Value Reference Synonyms Acetic acid ethenyl ester; O’Neil et al. 2006; NIOSH acetic acid vinyl ester; 1- 2011 acetoxyethylene; ethynyl acetate; vinyl ethanoate CAS registry no. 108-05-4 O’Neil et al. 2006 Chemical formula C4H6O2 O’Neil et al. 2006 Molecular weight 86.09 O’Neil et al. 2006 Physical state Liquid O’Neil et al. 2006 Melting point -100°C, -93°C O’Neil et al. 2006 Boiling point 72.7°C O’Neil et al. 2006 Liquid density (water = 1) 0.9317 ACGIH 2001 Vapor density (air =1) 3.0 Bisesi 2001 Solubility in water 1 g/50 mL at 20°C O’Neil et al. 2006 Vapor pressure 115 mmHg at 25°C ACGIH 2001 Conversion factors 1 ppm = 3.52 mg/m3 NIOSH 2011 1 mg/m3 = 0.284 ppm

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Vinyl Acetate 215 2.2. Nonlethal Toxicity Groups of three to nine volunteers were exposed to various concentrations of vinyl acetate for durations ranging from 2 min to 4 h (Smyth and Carpenter 1973). Vinyl acetate vapor was generated by feeding metered air through a spirally corrugated surface of a minimally heated Pyrex tube. Calculated concentration was corrected using a curve based on a gas chromatographic analysis of calculated concentrations ranging from 0.6 to 16,000 ppm. The concentrations were unknown to the volunteers, the concentrations were presented in random order, and symptoms were reported privately. No infor- mation was provided on the exposure chamber, whether the volunteers were previously exposed or naive, or how much time elapsed between exposures. The results of this study are presented in Table 7-3. TABLE 7-3 Human Sensory Response to Controlled Exposures to Vinyl Acetatea Exposure Concentration No. of Duration (ppm)a 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 (average 63 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 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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216 Acute Exposure Guideline Levels The medical division of Union Carbide Company undertook a study to evaluate three end points: the average environmental concentrations of vinyl acetate to which chemical workers are exposed; potential chronic health effects that might have resulted from exposure to vinyl acetate; and subjective descrip- tions of effects from short-term exposure to vinyl acetate (Deese and Joyner 1969). To determine average environmental concentrations of vinyl acetate, air samples were measured during normal operating conditions in three different production units. Forty samples (and two blanks) were taken from the three units during two sampling periods approximately one month apart. The total sampling time was more than 18 h. Samples were taken from three to six designated sites in each of the three production units. Sampling sites were determined by the amount of time the operator spent in each area, the investigator’s observation of probable exposure based on personal subjective responses, and the operator’s description of duties and exposures. Short-term and long-term air samples were taken. For short-term samples (10 min), a minimum of 15 L of air was collected by scrubbing air through a fritted glass midget impinger bubbler and a standard midget impinger in series. Long-term samples (2 h) of 180 L were collected using standard Greenburg-Smith impingers. 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. Concentrations ranged from 0 to 59.3 ppm; 83% of the samples were less than 10 ppm. The 8-h time-weighted averages (TWAs) for the three production facilities were 8.2, 5.2, and 7.7 ppm. Some operations, such as maintenance, resulted in brief exposures at higher concentrations. For example, concentrations measured in the breathing zone of workers as they opened the hopper door to unplug material flow were 123.3, 125.6, and 326.5 ppm. Exposures lasted for 3 min and occurred twice a day. The concentrations of vinyl acetate documented in this study were believed also represent exposures over the previous 5 years, because operating conditions, process methods, and physical equipment had not changed over that time period. To evaluate the potential health effects resulting from long-term exposure to vinyl acetate, company medical records were evaluated and compared with a control group (Deese and Joyner 1969). Twenty-one of 26 vinyl acetate operators participated in the study. Sixteen operators had worked with vinyl acetate for more than 15 years, and six for 20 years or more. Each participant was matched by taking the next operator listed alphabetically in the medical division files who had an age within 5 years of the operator’s and who had never worked in the vinyl acetate complex. The control group comprised individuals exposed to many chemicals commonly used in the petrochemical industry, but their exposures were not categorized for this study. Medical records of the participants were evaluated for the following: all sickness-related absences between January 1 and December 31 (classified according to etiology and duration); all initial visits to the medical division over the same interval; and all reported exposures to vinyl acetate. No exposure-related differences in blood

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Vinyl Acetate 217 chemistry results, pulmonary pathology, work days lost, or total number of initial visits for occupational injury or illness were found. Vinyl acetate workers had a higher number of total days lost due to respiratory illness and gastrointestinal conditions. Closer examination of the records revealed that these differences were primarily because of two individuals; one operator had a recurrent upper-respiratory-tract infection and one had cholecystitis. Vinyl ace- tate operators completed a questionnaire at the same time as their screening examination. When asked if vinyl acetate bothers them under normal working conditions, 13 (61%) responded no, two complained of odor, two reported nasal and throat irritation, three reported dermal irritation, and one replied that it “does bother”. When asked if vinyl acetate irritated their eyes, nose, or throat, 15 (71%) responded no, two responded “some”, three reported ocular irritation, and one described irritation that is noticeable but worse at certain times. When asked for other comments, one individual reported he liked the odor and another re- ported that breathing the fumes hurt his chest (Deese and Joyner 1969). In the third and final part of the study, individuals were asked to provide subjective descriptions about odor, ocular irritation, and upper respiratory irritation during 10-min air sampling of vinyl acetate. The individuals included one of the investigators, a laboratory analyst assisting in sampling, and one chemical operator from each of the production units. Vinyl acetate concentra- tions ranged from 0.4 to 21.6 ppm (exact concentrations reported at the three plant units were 0.4, 0.8, 2.7, 4.2, 4.2, 5.7, 6.8, 7.6, 7.6, 9.5, 9.9, or 21.6 ppm). Odor was generally described as slight at 0.4 to 9.9 ppm, although no odor was detected by a few subjects. At 21.6 ppm, odor was described as marked by all three individuals. Ocular irritation was not reported at concentrations of 9.9 ppm or lower, with the exception of slight ocular irritation reported by the investiga- tor at 5.7 and 6.8 ppm. At 21.6 ppm, all three individuals agreed that the ocular irritation would be “intolerable over an extended period of time”. Upper respiratory irritation (cough and hoarseness) was present at 21.6 ppm in all three subjects. Hoarseness was noted by the investigator at 4.2 and 5.7 ppm. Data from the study of Deese and Joyner (1969) conflict with those re- ported by Smyth and Carpenter (1973). 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 irrita- tion. Examination of the sampling data from Deese and Joyner (1969) indicates that 21.6 ppm was measured in the production area associated with the highest concentration of vinyl acetate (49.3 ppm in a 10-min sample) measured in any part of the facility. Thus, the subjects might have been briefly exposed to a much higher concentration of vinyl acetate during the sampling period. Furthermore, Deese and Joyner (1969) noted that the odor threshold of vinyl acetate was difficult to measure in the facility because of the “intermittent and unpredictable presence of odors of other assorted chemicals in the subject’s environment”; similarly, the ocular irritation reported at 21.6 ppm might have been confounded by concurrent exposure to other irritant compounds.

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218 Acute Exposure Guideline Levels Air emissions around Monsanto production facilities were evaluated to assess the potential for human health effects (Monsanto Company 1989). Emission of vinyl acetate was identified as a concern at the Decatur production plant because of its carcinogenicity. Ambient air sampling at four locations in the Texas City, Texas, area revealed concentrations ranging from 0.07 to 0.57 ppm (0.25-2.0 mg/m3). To conduct a safety assessment, the maximum annual- average concentration of vinyl acetate was estimated using a dispersion model developed by the U.S. Environmental Protection Agency. The modeled annual- average concentration for community exposure was estimated to be 1.8 × 10-3 ppb (5.52 × 10-3 µg/m3), with the highest exposure being 8.3 × 10-2 ppb (0.25 µg/m3). Several studies investigating the potential health effects of workers chronically exposed to vinyl acetate were published in the Russian literature. Agaronyan and Amatuni (1980) examined the prevalence of neurotoxicity and cardiovascular effects in workers exposed at a “polyvinylacetate” plant compared with workers in a mechanical department of a different factory. Poly- vinylacetate workers were divided into three groups on the basis of neurotoxici- ty: those that had no signs of central nervous system toxicity, those that had the beginning phase of neurotoxicity (as defined by neuroasthenia), and those with asthenovegetative syndrome with pronounced autonomic-dystonia and involvement of the hypothalamic regions. Incidence of cardiovascular effects increased with increasing neurotoxicity and included: piercing pain in the area of the heart, palpitations, muffled heart sounds, systolic murmur, hypertension, and electrocardiogram findings of tachycardia, bradycardia, decreased P wave, widened QRS complex, prolonged Q-T, and decreased T wave. Amatuni and Agaronyan (1979, 1980) 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) at 15 years and longer). Pulmonary effects included decreases in vital capacity, forced expired volume in one second (FEV1), maximal voluntary ventilation (MVV), and expiratory and inspiratory capacity (Cexp; Cinsp), and clinical manifestations of chronic bronchitis. In another study, Agaronyan and Amatuni (1982) evaluated the pulmonary ventilation function of workers at the beginning of the study and after 5 years of employment. They found statistically significant decreases in ventilation parameters primarily indicative of obstructive and mixed impairment of pulmonary ventilation function. Limitations of the Russian studies include occupational exposures to multiple chemicals and of documented concentrations of vinyl acetate. 2.3. Developmental and Reproductive Toxicity No studies of potential developmental or reproductive effects in humans after inhalation exposure to vinyl acetate were found.

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Vinyl Acetate 219 2.4. Genotoxicity In vitro incubation of vinyl acetate with human lymphocytes or leukocytes has resulted in chromosome aberrations, increased sister chromatid exchanges (SCEs), and DNA cross-linking. Human whole-blood lymphocyte cultures incubated for 48 h with vinyl acetate at 0.125, 0.25, 0.5, 1, or 2 mM exhibited a peak in the frequency of micronucleated lymphocytes at 0.5 and 1 mM (3.2 ± 1% and 3.1 ± 0.7%, respectively, vs. 0.9 ± 0.1% for controls) (Mäki-Paakkanen and Norppa 1987). A concentration of 2 mM was considered a toxic, resulting in a decreased frequency of micronucleated lymphocytes due to inhibition of mitosis. Whole blood cultures and isolated lymphocytes incubated with vinyl acetate for 48 h at 0.25, 0.5, 1, or 2 mM showed a concentration-dependent increase in chromatid-type aberrations and a slight increase in chromosome-type breaks, but no effects at 0.125 mM (Jantunen et al. 1986). Concentration-related increases in SCEs and chromosome aberrations (in first division cells) were found in human whole-blood lymphocyte cultures and purified lymphocyte cultures incubated with vinyl acetate at 0.1-1 mM for 48 h (Mäki-Paakkanen et al. 1984; Norppa et al. 1985). The most common chromosome aberration was the chromatid-type break; at 1 mM, 84% of the cells were aberrant and 38% had a chromatid-type exchange. Purified lymphocyte cultures exhibited a more pronounced effect on both SCEs and the number of aberrant cells (Norppa et al. 1985). 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). A two-fold higher SCE frequency was observed in cells exposed in the late G1 phase compared with cells exposed during the early G1 phase. Cells treated during the first G1 phase had a statistically significant increase in SCEs in three subsequent cell cycles. Human leukocytes incubated with vinyl acetate at 10 or 20 mM for 4 h at 37°C did not have evidence of direct DNA strand breaks, but had concentration-dependent DNA cross-linking (Lambert et al. 1985). 2.5. Carcinogenicity A series of epidemiologic studies were conducted to investigate the potential link between employment at a Texas petrochemical plant and an increased incidence of mortality from brain cancer, specifically gliomas (Alexander et al. 1980; Austin and Schnatter 1983a,b; Leffingwell et al. 1983; Waxweiler et al. 1983). Although vinyl acetate was one of the chemicals with a greater apparent risk (Leffingwell et al. 1983), no statistically significant associations were found between exposure to specific chemicals and mortality from brain cancer (Austin and Schnatter 1983a; Leffingwell et al. 1983). Confounding factors include, but are not limited to, concurrent exposure to other chemicals, exposure to unknown concentrations of the chemicals of concern, and the use of in-plant controls (might have obscured a significant finding).

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220 Acute Exposure Guideline Levels 2.6. Summary Human data on acute exposure to vinyl acetate are limited. Odor detection and recognition threshold values for vinyl acetate are 0.12 and 0.4 ppm, respectively (Hellman and Small 1974; AIHA 1989; EPA 1992). A controlled- exposure study by Smyth and Carpenter (1973) 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. The study by Deese and Joyner (1969) did not have controlled exposure to vinyl acetate, but was simply a survey of subjective symptoms reported by three individuals during air sampling of the work environment. All three subjects reported that ocular irritation was intolerable at 21.6 ppm, and slight cough and hoarseness were noted in two individuals. Slight ocular irritation at 5.7 or 6.8 ppm was also reported by one individual. In vitro genotoxicty studies with human lymphocytes or leukocytes have reported that vinyl acetate increased the number of chromosome aberrations, sister chromatid exchanges, and DNA-crosslinking. Epidemiologic studies have not identified any clear relationship between vinyl acetate and brain cancer. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Groups of six male and six female rats were exposed to vinyl acetate for 4 h at nominal concentrations of 2,000, 4,000, or 8,000 ppm (Smyth and Carpenter 1973). The nominal concentrations were corrected using a curve based on a gas chromatographic analysis of calculated concentrations ranging from 0.6 to 16,000 ppm; the corrected concentrations were 1,640, 3,280, and 6,560 ppm. No information was provided regarding a control group, the strain or age of the rats, or the exposure chamber. Vinyl acetate vapor was generated by feeding liquid vinyl acetate at a constant rate through a spirally corrugated surface of a minimally heated Pyrex tube, through which metered air was passed. Although not specifically stated, an observation period of 14 days was inferred from the results of the group of studies reported by Smyth and Carpenter (1973). Clinical signs, body weight changes, and mortality data are presented in Table 7-4. Gross necropsy of the animals that died revealed pulmonary congestion and hemorrhage, froth in the trachea, and opaque corneas. The LC50 (lethal concen- tration, 50% lethality) was calculated to be 3,680 (2,660-5,100) ppm using the moving average table of Weil (1952).

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262 Acute Exposure Guideline Levels APPENDIX B CALCULATION OF LEVEL OF DISTINCT ODOR AWARENESS FOR VINYL ACETATE The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, and about 10% of the population will experience strong odor intensity. The LOA should help chemical emergency responders assess the public awareness of the exposure to vinyl acetate on the ba- sis of odor perception. The LOA for vinyl acetate was derived according to the guidance of van Doorn et al. (2002). For derivation of an odor detection threshold (OT50), a study by Hellman and Small (1974) was used. 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) ÷ 0.3 = 0.016 ppm The concentration (C) leading to an odor intensity (I) of distinct odor detection (I = 3) is derived using the Fechner function: I = kw × log (C ÷ OT50) + 0.5 For the Fechner coefficient, the default of kw = 2.33 will be used due to the lack of chemical-specific data: 3 = 2.33 × log (C ÷ 0.016) + 0.5 which can be rearranged to: log (C ÷ 0.016) = (3 - 0.5) ÷ 2.33 = 1.07 and results in: C = 101.07 × 0.016 = 11.8 × 0.016 = 0.1888 ppm The resulting concentration is multiplied by an empirical field correction factor. The factor takes into account that everyday life factors, such as sex, age, sleep, smoking, upper airway infections, allergies, and distractions, increase the odor detection threshold by a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 seconds), which leads to the perception of concentration peaks. On the basis of current knowledge, a factor of 1/3 is

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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). LOA = C × 1.33 = 0.189 ppm × 1.33 = 0.25 ppm The LOA for vinyl acetate is 0.25 ppm.

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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) 265

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TABLE C-1 Continued 266 Source Species Sex No. Exposures ppm Minutes Category Comments Human 1 20 240 1 Olfactory fatigue; throat irritation Human 1 34 120 1 Olfactory fatigue; throat irritation Human 1 72 30 1 Olfactory fatigue; throat irritation Deese and Joyner 1969 Human 1 21.6 10 1 Odor detection, upper respiratory irritation Smyth and Carpenter 1973 Rat Both 1 1,640 240 2 Congestion Rat Both 1 3,280 240 SL Mortality (4/12); gasping, convulsions Rat 1 6,560 240 3 Mortality (12/12) Smyth and Carpenter 1973 Mouse 1 410 240 2 Mouse 1 820 240 SL Mortality (1/6), labored breathing Mouse 1 1,640 240 SL Mortality (4/6), gasping, convulsions Mouse 1 3,280 240 SL Mortality (5/6), gasping, convulsions, ocular effects Mouse 1 6,560 240 3 Mortality (6/6) Smyth and Carpenter 1973 Guinea pig Male 1 1,640 240 1 Lacrimation Guinea pig Male 1 3,280 240 SL Mortality (1/6), 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), gasping, nose rubbing, lacrimation Rabbit Male 1 3,280 240 SL Mortality (3/4), red nose, cloudy eyes Rabbit Male 1 6,560 240 3 Mortality (4/4); labored breathing, convulsions, cloudy eyes, bloody nose

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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) For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality. 267

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268 Acute Exposure Guideline Levels APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR VINYL ACETATE Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm (24 mg/m3) (24 mg/m3) (24 mg/m3) (24 mg/m3) (24 mg/m3) Key reference: Smyth, H.F., and C.P. Carpenter. 1973. Initial Submission: Vinyl Acetate: Single Animal Inhalation and Human Sensory Response with Cover Letter Dated 08/27/92. Special Report 36-52. Carnegie-Mellon Institute, Pittsburgh, PA. Submitted to EPA by Union Carbide Corporation, Danbury, CT. EPA Document. No. 88-920010328. Microfiche No. OTS 0571724. Test species/Strain/Number: Human volunteers, 3-9 subjects (3 volunteers at concentration selected as point of departure) Exposure route/Concentrations/Durations: 0.6, 1.3, 4, 8, or 20 ppm for 2 min; 20 ppm for 4 h; 34 ppm for 2 h; 72 ppm for 30 min Effects: Concentration No. of Duration (ppm) 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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Vinyl Acetate 269 End point/Concentration/Rationale: Exposure to vinyl acetate at 4-20 ppm for 2 min and 20 ppm for 240 min produced slight throat irritation; exposure at 34 ppm for 2 h resulted in one of three individuals complaining of persistent throat irritation; and exposure at 72 ppm for 30 min resulted in irritation severe enough that the exposed subjects expressed unwillingness to work at that concentration for 8 h (Smyth and Carpenter 1973). Therefore, 20 ppm for 4 h represents a no-effect level for notable discomfort. Uncertainty factors/Rationale: Total uncertainty factor: 3 Intraspecies: 3, because irritation is caused by a local effect of the chemical and the response is not expected to vary greatly among individuals. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Because irritation is considered a threshold effect and should not vary over time, AEGL-1 values are not scaled across time. The threshold value was applied to all AEGL durations. Data adequacy: The key study lacked measured exposure concentrations, but provided adequate basis for AEGL-1 values and is supported to some extent by occupational health data. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 46 ppm 46 ppm 36 ppm 23 ppm 15 ppm (160 mg/m3) (160 mg/m3) (130 mg/m3) (81 mg/m3) (53 mg/m3) Key reference: Bogdanffy, M.S., N.L. Gladnick, T. Kegelman, and S.R. Frame. 1997. Four-week inhalation cell proliferation study of the effects of vinyl acetate on rat nasal epithelium. Inhal. Toxicol. 9(1):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. End point/Concentration/Rationale: 200 ppm for 6 h is a no-observed-effect level for serious, long-lasting histopathologic nasal lesions Uncertainty factors/Rationale: Total uncertainty factor: 10: (Continued)

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270 Acute Exposure Guideline Levels AEGL-2 VALUES Continued Interspecies: 3, 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 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. 1998). Esterase distribution in the nasal respiratory tissue of humans is believed to be similar to that of rats (Andersen et al. 2002). Intraspecies: 3, because the usual factor of 10 would result in an 8-h AEGL-2 value of 5 ppm, a concentration 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). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: The experimentally derived exposure values were scaled to AEGL durations using the equation Cn × t = k, where C = concentration, t = time, k is a constant, and n generally ranges from 0.8 to 3.5 (ten Berge et al. 1986). The value of n was not empirically derived because of insufficient data on vinyl acetate; therefore, the default values of n = 1 for extrapolating from shorter to longer durations and n = 3 for extrapolating from longer to shorter durations were used. The 10-min AEGL-2 value was set equal to the 30-min value of 46 ppm because of the uncertainty associated with extrapolating a 6-h exposure duration to a 10-min AEGL value (NRC 2001). Data adequacy: The database for nonlethal effects of vinyl acetate includes single exposure (Bogdanffy et al. 1997), 4-week (Owen 1979a,b), 13-week (Owen 1980a,b), and chronic (Bogdanffy et al. 1994) studies of mice and rats exposed via inhalation, and provides a robust basis for AEGL-2 values. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 230 ppm 230 ppm 180 ppm 110 ppm 75 ppm (810 mg/m3) (810 mg/m3) (630 mg/m3) (390 mg/m3) (260 mg/m3) Key references: Bogdanffy, M.S., N.L. Gladnick, T. Kegelman, and S.R. Frame. 1997. Four-week inhalation cell proliferation study of the effects of vinyl acetate on rat nasal epithelium. Inhal. Toxicol. 9(1):331-350. Owen, P.E. 1979a. Vinyl Acetate: 4 Week Inhalation Dose Range Study in the Mouse. Report No. 1884-51/3. Prepared for Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd., Harrogate, England, August 1979. EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278. Owen, P.E. 1979b. Vinyl Acetate: 4 Week Inhalation Dose Range Study in the Rat.

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Vinyl Acetate 271 Report No. 1835-51/3. Prepared for Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd., Harrogate, England, August 1979. EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278. Owen, P.E. 1980a. Vinyl Acetate: 3 Month Inhalation Toxicity Study in the Mouse. Report No. 2303-51/5. Prepared for The Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd., Harrogate, England, May 1980. EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278. Owen, P.E. 1980b. Vinyl Acetate: 3 Month Inhalation Toxicity Study in the Rat. Report No. 2286-51/5. Prepared for The Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd., Harrogate, England, May 1980. EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278. Test species/Strain/Number: Rat (Sprague-Dawley and CD) and mouse (CD-1), 5-20 males and females Exposure route/Concentrations/Durations: 0, 50, 150, 200, 500, 600, or 1,000 ppm for 6 h/day for 1-28 days Effects: No lethality at 1,000 ppm End point/Concentration/Rationale: 1,000 ppm for 6 h is considered a threshold for lethality Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, 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 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. 1998). Esterase distribution in the nasal respiratory tissue of humans is believed to be similar to that of rats (Andersen et al. 2002). Intraspecies: 3, because the usual factor of 10 would result in an 8-h AEGL-3 value of 25 ppm, a concentration lower than experimental concentrations that did not result in serious health effects in a human volunteer study. Reduction of an uncertainty factor is appropriate when the weight of the evidence indicates that a higher uncertainty factor would result in AEGL values at odds with human data (NRC 2001). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: The experimentally derived exposure values were scaled to AEGL durations using the equation Cn × t = k, where C = concentration, t = time, k is a constant, and n generally ranges from 0.8 to 3.5 (ten Berge et al. 1986). The value of n was not empirically derived because of insufficient data on vinyl acetate; therefore, the default values of n = 1 for extrapolating from shorter to longer durations and n = 3 for extrapolating from longer to shorter durations were used. (Continued)

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272 Acute Exposure Guideline Levels AEGL-3 VALUES Continued The 10-min AEGL-3 was set equal to the 30-min value of 230 ppm because of the uncertainty associated with extrapolating a 6-h exposure duration to a 10-min value (NRC 2001). Data adequacy: The animal database for nonlethal effects of vinyl acetate is robust, and includes single day, 4-week, 13-week, and chronic exposure studies (Owen 1979a,b, 1980a,b; Bogdanffy et al. 1994, 1997). These studies provide a strong basis for identifying a nonlethal point of departure. 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.