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Committee on Acute Exposure Guideline Levels; Committee on Toxicology; Board on Environmental Studies and Toxicology; Division on Earth and Life Studies; National Research Council. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14. Washington (DC): National Academies Press (US); 2013 Apr 26.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14.

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7Vinyl 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 Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 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 distinguished 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.

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.

Airborne concentrations below the AEGL-1 represent exposure concentrations that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.

SUMMARY

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.

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 because 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 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 acetate. 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.

TABLE 7-1. AEGL Values for Vinyl Acetate.

TABLE 7-1

AEGL Values for Vinyl Acetate.

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.

TABLE 7-2. Chemical and Physical Properties of Vinyl Acetate.

TABLE 7-2

Chemical and Physical Properties of Vinyl Acetate.

2. HUMAN TOXICITY DATA

2.1. Acute Lethality

No data on lethality in humans after acute exposure to vinyl acetate were found.

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 information 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 Acetate.

TABLE 7-3

Human Sensory Response to Controlled Exposures to Vinyl Acetate.

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 descriptions 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 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 acetate 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 reported 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 concentrations 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 investigator 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 reported 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 irritation. 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.

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. Polyvinylacetate workers were divided into three groups on the basis of neurotoxicity: 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.

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).

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 concentration, 50% lethality) was calculated to be 3,680 (2,660–5,100) ppm using the moving average table of Weil (1952).

TABLE 7-4. Results of 4-Hour Inhalation Study of Rats Exposed to Vinyl Acetate.

TABLE 7-4

Results of 4-Hour Inhalation Study of Rats Exposed to Vinyl Acetate.

The following acute lethality studies in rats lacked adequate reporting of study details, so exposure concentrations were assumed to be nominal. Gage (1970) exposed four male and four female Alderley Park specific pathogen-free rats to air saturated with vinyl acetate for 5 min (Gage 1970). Exposure produced rapid anesthesia and death. Six Sherman rats (sex not specified) were exposed to vinyl acetate vapor at 4,000 ppm for 4 h (no details about exposure conditions were provided) and observed for 14 days for mortality (Smyth and Carpenter 1948). Three of the six rats died. Exposure concentration was not confirmed by analytical methods, and no controls were used. Rumiantsev et al. (1981) reported a 4-h LC50 value of 3,238 ppm in rats. Animals were observed for 30 days. No specifics were provided about the deaths other than they occurred during exposure or in the days following exposure.

3.1.2. Mice

Groups of six mice were exposed to vinyl acetate for 4 h at nominal concentrations of 500, 1,000, 2,000, 4,000, or 8,000 ppm (calculated concentrations of 410, 820, 1,640, 3,280, and 6,560 ppm as corrected using a curve based on a gas chromatographic analysis of concentrations ranging from 0.6 to 16,000 ppm) (Smyth and Carpenter 1973). No information was provided about the sex, strain, or age of the mice, the exposure chamber, or a control group. 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 7-5. Gross necropsy of the animals that died revealed pulmonary congestion and excess pleural fluid. The LC50 was calculated to be 1,460 (925 2,305) ppm using the moving average table of Weil (1952).

TABLE 7-5. Results of 4-Hour Inhalation Study of Mice Exposed to Vinyl Acetate.

TABLE 7-5

Results of 4-Hour Inhalation Study of Mice Exposed to Vinyl Acetate.

Rumiantsev et al. (1981) reported a 2-h LC50 of 3,010 ppm in mice. Animals were observed for 30 days. No specifics were provided about the deaths other than they occurred during exposure or in the days following exposure.

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) (Smyth and Carpenter 1973). No information was provided about the age of the guinea pigs, the exposure chamber, or a control group. 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 group of studies reported by Smyth and Carpenter (1973). Clinical signs, body weight changes, and mortality data are presented in Table 7-6. Gross necropsy of the animals that died revealed congestion, emphysema, and scattered hemorrhages in the lungs. The LC50 was calculated to be 5,210 (3,500–7,740) ppm using the moving average table of Weil (1952).

TABLE 7-6. Results of 4-Hour Inhalation Exposure Study of Vinyl Acetate in Guinea Pigs.

TABLE 7-6

Results of 4-Hour Inhalation Exposure Study of Vinyl Acetate in Guinea Pigs.

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) (Smyth and Carpenter 1973). No information was provided about the strain or age of the rabbits, the exposure chamber, or a control group. 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. The results of the study are presented in Table 7-7. Gross necropsy of the animals that died revealed bloody nostrils, froth in the trachea, excess pleural fluid, and pulmonary hemorrhage. The LC50 was calculated to be 2,760 (1,800–4,200) ppm using the moving average table of Weil (1952).

TABLE 7-7. Results of 4-Hour Inhalation Study of Vinyl Acetate in Rabbits.

TABLE 7-7

Results of 4-Hour Inhalation Study of Vinyl Acetate in Rabbits.

3.2. Nonlethal Toxicity

3.2.1. Dogs

One male beagle dog per group was exposed to vinyl acetate for 4 h at nominal concentrations of 62.5, 125, 250, 1,000, 2,000, or 4,000 ppm (calculated concentrations of 51.25, 102.5, 205, 820, 1,640, or 3,280 ppm as corrected by using a curve based on a gas chromatographic analysis of concentrations ranging from 0.6 to 16,000 ppm) (Smyth and Carpenter 1973). Vinyl acetate vapor was generated by feeding metered air through a spirally corrugated surface of a minimally heated Pyrex tube. No controls were used, and no details were provided about the exposure chamber. All animals survived. Results of the study are presented in Table 7-8; no further details were provided.

TABLE 7-8. Results of 4-Hour Inhalation Exposure in Dogs.

TABLE 7-8

Results of 4-Hour Inhalation Exposure in Dogs.

3.2.2. Rats

Gage (1970) conducted a series of experiments in which Alderley Park specific pathogen-free rats were exposed to vinyl acetate at 100, 250, 630, or 2,000 ppm for 6 h/day for a total of 15 exposures. Animals were exposed in a glass desiccator with wire mesh separating the animals. The purity of the chemical was not determined. Appropriate nominal concentrations were produced by injecting vinyl acetate at a known rate into a metered flow of air using a controlled fluid-feed atomizer, but analytic concentrations in the chamber were not determined during the exposures. No clinical signs or abnormal necropsy findings were observed at 100 ppm. 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. No further details were provided.

To investigate the effect of vinyl acetate on nasal epithelial cell proliferation, groups of five male Sprague-Dawley rats were exposed by whole body inhalation at target concentrations of 0, 50, 200, 600, or 1,000 ppm (actual exposure concentrations 0, 50.8, 199.6, 598.5, and 1,007.3 ppm) for 6 h once or for 6 h/day for a total of 5 or 20 consecutive exposures (Bogdanffy et al. 1997). Rats were exposed in a 150-L stainless steel and glass dynamic inhalation chamber with an air flow of approximately 35 L/min. Chamber atmospheres were analyzed directly using gas chromatography. Rats were weighed three times per week and were observed for clinical signs. Animals received intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) 16 h after the last exposure, and were killed 2 h later. The respiratory tract of the rats was examined for gross changes, and the nasal cavities were removed and prepared for histopathologic examination. Five cross Sections of the nose were examined, and Sections of the duodenum were used as a positive control for the BrdU procedure. 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). Histopathologic examination revealed concentration-related olfactory epithelial changes in the 600- and 1,000-ppm groups, but the incidence and severity of the lesions were low. Some rats developed degeneration, necrosis, and exfoliation after one exposure; the most affected regions were the dorsal one-third of the nasal septum and dorsolateral wall, Masera's organ, and the medial-most extent of the ethmoid turbinates (see Table 7-9 for incidence data). In a personal communication with one of the study authors, Frame (S.R. Frame, DuPont, Haskell Laboratory, Newark, DE, personal commun., December 1, 2004) concluded that the changes observed at 600 and 1,000 ppm were likely to be completely reversible both morphologically and functionally, on the basis of the focal and limited nature of the olfactory lesions and the known regenerative capacity of olfactory tissue. After 5 or 20 exposures, post-necrotic repair and adaptation were found; changes included regenerative hyperplasia of the olfactory epithelium and attenuation and disorganization of the olfactory mucosa and occasional areas of squamous metaplasia (Bogdanffy et al. 1997). Additionally, olfactory nerve bundles in the olfactory lumina exhibited degeneration and atrophy. Cell labeling of rats after one 6-h exposure revealed a concentration-related increase in cell proliferation in the respiratory and olfactory epithelium, generally confined to the basal cells of the epithelial cell layer. Increase in the labeling index was statistically significant in the 600- and 1,000-ppm groups. 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) was statistically significantly increased in the 600- and 1,000-ppm groups after 20 exposures. Such an increase was not evident in the respiratory epithelium. The investigators concluded that the cell proliferation response could be a two-phase reaction, the first involving chemical insult of the tissue followed by early regenerative repair (exposure days 1–5) and the second involving cellular and biochemical adaptation.

TABLE 7-9. Histopathologic Observations in Nasal Epithelium of Rats Exposed to Vinyl Acetate for 6 Hours.

TABLE 7-9

Histopathologic Observations in Nasal Epithelium of Rats Exposed to Vinyl Acetate for 6 Hours.

3.2.3. Mice

The RD50 (concentration that reduces respiratory rate by 50%) for vinyl acetate was 380 ppm in mice tested according to the ASTM E981 protocol (Dudek et al. 1996).

3.3. Developmental and Reproductive Toxicity

Vinyl acetate was administered to 24 confirmed-mated Sprague-Dawley rats by whole-body inhalation at concentrations of 0, 50, 200, or 1,000 ppm for 6 h/day on days 6 through 15 of gestation (Hurtt et al. 1995). Observations for clinical signs of maternal toxicity were made daily and body weight was recorded on gestation days (GDs) 0, 2, 4, 6, 10, 15, and 20; however, food and water consumption were not measured. On GD 20, dams were sacrificed, subjected to gross necropsy, and all fetuses were examined externally and viscerally (half by disSection and evisceration and the remaining half by Wilson's technique). The total numbers of fetuses examined (number of litters) were 322 (24), 320 (22), 345 (24), and 327 (22) for the 0-, 50-, 200-, and 1,000-ppm groups, respectively. Approximately half of the fetuses were examined for skeletal malformations and variations. Maternal toxicity was evident in the 1,000-ppm group; dams had significantly (p < 0.05) 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. 17.5 g for controls), GDs 10–15 (64% of controls), and GDs 6–15 (24% of controls). Weight gain in this group was comparable with controls over GDs 15–20 (96% of controls). Because food consumption was not measured, it is unknown whether the decreased body weight was an effect of decreased food consumption. Delays in fetal growth were present in the 1,000-ppm group and included significantly (p < 0.05) decreased mean fetal weight (72% of controls), decreased crown-to-rump length (88% of controls), and delays in ossification. Evidence of delayed ossification (number of fetuses [litter] in the 1,000-ppm group vs. controls) included incompletely ossified occipital bone (41 [12] vs. 1 [1]); unossified No. 2 sternebra (28 [10] vs. 0 [0]); unossified No. 5 sternebra (118 [22] vs. 17 [11]); unossified No. 6 sternebra (126 [22] vs. 16 [7]); and bipartite vertebra (52 [18] vs. 24 [13]). The delays in fetal growth correlate with maternal toxicity in the high-concentration group. The investigators concluded that vinyl acetate is not uniquely toxic to the fetus.

3.4. Genotoxicity and Cytotoxicity

Vinyl acetate was not mutagenic to Salmonella typhimurium strains TA 1535, 1537, 1538, 98, or 100 with or without metabolic activation at a maximum, nontoxic concentration of 1,000 μg/plate (Lijinsky and Andrews 1980); to S. typhimurium strains TA 97, 98, or 100 at 100–500 μg/mL (Brams et al. 1987); or to S. typhimurium strain TA 102 (vinyl acetate concentrations not specified) (Jung et al. 1992; Müller et al. 1993). Vinyl acetate was not mutagenic in Escherichia coli strain PQ37 using the SOS chromotest (Brams et al. 1987).

A statistically significant and concentration-related increase in sister chromatid exchanges was found in both Chinese hamster ovary cells incubated with vinyl acetate at 0.125-1 mM without metabolic activation and after a 4-h pulse treatment with vinyl acetate at 0.3-5 mM with or without metabolic activation (Mäki-Paakkanen et al. 1984; Norppa et al. 1985). Male C57B1/6 mice exhibited a statistically significant increase in micronucleated polychromatic erythrocytes in the bone marrow 30 h after intraperitoneal injection of vinyl acetate at 1,000 or 2,000 mg/kg (1.33 ± 0.29% and 1.57 ± 0.19%, respectively, vs. 0.6 ± 0.10% for olive oil-treated controls), but no increase was seen after injection with 250 or 500 mg/kg (Mäki-Paakkanen and Norppa 1987). Injections of vinyl acetate at 1,000 and 2,000 mg/kg were fatal to 6/14 and 8/14 mice, respectively.

Hepatic DNA adducts were not formed in male or female F344 rats administered 14C-labeled vinyl acetate by oral gavage (1 mCi of radioactivity; rats killed 4 h after administration) or by inhalation (1,200 to 1,800 ppm in static exposure chamber for 4 h) (Simon et al. 1985b). Accumulation of DNA-protein crosslinks followed S-phase kinetics when pUC13 plasmid DNA, calf histones, and rat liver microsomes were incubated with vinyl acetate at 1-100 mM for 3 h at 37°C (Kuykendall and Bogdanffy 1992a,b). DNA-protein crosslink formation was inhibited by the addition of a carboxylesterase inhibitor (bis-[p-nitrophenyl]phosphate, or BNPP) and by the removal of the rat liver microsomes.

To evaluate cytotoxicity in nasal tissues, explants of the maxilloturbinate (lined with pure populations of respiratory epithelia) and endoturbinate-1 (lined with pure populations of olfactory epithelia) 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. 1993a). Vinyl acetate was cytotoxic at 100 and 200 mM after incubation for 20 min and at 50 mM after incubation for at least 1 h, but 25 mM was not cytotoxic after incubation for up to 2 h. Therefore, vinyl acetate at 50 mM for 1 h was chosen to study the effects of a carboxylesterase inhibitor (BNPP) or aldehyde scavenger (semicarbazide) on vinyl acetate -mediated cytotoxicity. To assess the effects of BNPP on vinyl acetate induced cytotoxicity, acetaldehyde production was measured in the nasal tissues first. Acetaldehyde production increased steadily for up to 60 min in respiratory turbinates and up to 40 min in olfactory turbinates, reaching a plateau when acetaldehyde concentrations reached approximately 16 mM. Therefore, BNPP pre-treatment was assessed using a 20-min incubation period with vinyl acetate at 50 mM. Treatment with BNPP for 3 days before tissue collection reduced the cytotoxic effect of vinyl acetate, resulting in only a two-fold increase in acid phosphatase production compared with a three- to four-fold increase without BNPP. BNPP also inhibited the metabolism of vinyl acetate; acetaldehyde release into the media was reduced by 59% or 37% in respiratory and olfactory turbinates, respectively. When turbinates were incubated with semicarbazide, no effect on cytotoxicity was noted. Further evaluations demonstrated that the vinyl-acetate-induced cytotoxicity was the result of acetic acid production, not acetaldehyde production.

Kuykendall et al. (1993a,b) also assessed the formation of DNA-protein crosslinks in rat nasal epithelial tissues by vinyl acetate and acetaldehyde. Isolated epithelial cells from both olfactory and respiratory turbinates incubated with vinyl aceatate at 0-75 mM generally exhibited a concentration-related increase in DNA-protein crosslink formation. Olfactory and respiratory cells had comparable DNA-protein crosslink formation, as assessed by the absolute difference in DNA accumulation in the protein-bound phases. Epithelial cells were then pre-incubated with increasing concentrations of BNPP for 30 min before the addition of vinyl acetate at 25 mM to assess whether carboxylesterase-dependent metabolism of vinyl acetate to acetaldehyde is necessary for DNA-protein crosslink formation. DNA-protein crosslink formation in respiratory and olfactory cells was 3.9- and 2.9-fold higher, respectively, in cells exposed to vinyl acetate alone compared with untreated cells. When cells were pretreated with BNPP at 1 mM, crosslink formation in respiratory and olfactory cells was reduced by 76% and 78%, respectively. Reduction in crosslink formation was dependent on BNPP concentration.

3.5. Repeated Exposure Data

A 4-week range finding study and a 3-month subchronic study in rats and mice were performed by the same laboratory and are described below. 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). The 50-ppm exposure was increased to 1,500 ppm on day 10 (rats) or day 8 (mouse) because marked clinical effects were not observed in the 1,000-ppm groups. Animals were exposed in a stainless steel and glass dynamic inhalation exposure chamber, and chamber concentrations were measured every 15 min by gas chromatography. Mean measured concentrations for the rat and mouse were 51.3, 150.5, 497.6, 1,000.2, and 1,488.5 (rats) or 1,488.7 (mouse) ppm. All animals survived treatment. Although similar effects were found in rats and mice, mice were more sensitive. A concentration-related increase in incidence and severity of respiratory distress and hunched posture was reported in rats exposed to vinyl acetate at 500 ppm or greater and in mice exposed at 150 ppm or greater, but incidence data were not provided. A concentration-related decrease in overall body weight gain was also noted. 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. No gross necropsy findings were reported, and no hematopoietic abnormalities were found in the analysis of bone marrow samples. Spleen weight relative to body weight was decreased at concentrations of 1,000 or 50/1,500 ppm in male rats (85 and 82% of controls, respectively), male mice (80 and 74% of controls, respectively), and female mice (74 and 72% of controls, respectively). The biologic relevance of this finding is unknown. A histopathology report of a 28-day study that appears to be from this study was included a 3-month study by Owen (1980a). Findings in the nasal turbinates, trachea, and bronchi of mice exposed at 50/1,500 ppm were similar to those reported in the 3-month study described below.

In a subchronic study, groups of 10 male and 10 female CD rats or CD-1 mice were exposed to vinyl aceatate at 0, 50, 200, or 1,000 ppm for 6 h/day, 5 days/week for 13 weeks (Owen 1980a,b). Animals were exposed in a stainless steel and glass dynamic inhalation exposure chamber, and chamber concentrations measured every 15 min by gas chromatography. Mean measured concentrations were 0.5, 51, 200, and 999 ppm. A number of effects were noted in rats exposed at 1,000 ppm, including: intermittent respiratory distress, hunched posture, and ruffled fur (incidence data were not provided); decreased overall body weight gain (62% and 56% of controls for males and females, respectively; p < 0.01); smaller volume and more concentrated urine compared with controls; and increased lung weight relative to body weight (126% and 130% of controls for males and females, respectively; p < 0.01) (Owen 1980b). No effects were noted during ophthalmoscopic examination, hematology or blood chemistry analysis, or gross or microscopic examination (nasal turbinate was included in the microscopic examination).

Mice appeared to be more sensitive to vinyl acetate (Owen 1980a). Intermittent respiratory distress, hunched posture, and ruffled fur were noted in the 200-ppm group over the first 9 days of exposure. The 1,000-ppm group exhibited respiratory distress throughout the exposure and hunched posture and ruffled fur intermittently (incidence data were not provided). Other effects were limited to the 1,000-ppm group. Nine animals in that group died as a consequence of routine blood sampling. It was postulated that vinyl acetate made mice more susceptible to the anesthesia used during the sampling period. Males and females had decreased overall body weight gain (40% and 50% of controls, respectively; p < 0.01) and increased lung weight relative to body weight (148% and 155% of controls, respectively; p < 0.01). Microscopic examination revealed exposure-related lesions in the upper and lower respiratory tissues of mice exposed at 1,000 ppm. Upper respiratory tract lesions were confined to the nasal cavity and included focal to diffuse rhinitis with associated exudation and transudation into the nasal passages and occasional mucosal metaplasia. Inflammation was chronic in nature and associated with hyperplasia of epithelial goblet cells. Findings in the laryngeal Sections were difficult to assess because of variation in the Section (mucosal epithelium undergoes changes from an oral to respiratory epithelium in this Section). Noninflammatory changes were noted in the trachea as well as several areas of suspected metaplasia or hyperplasia. Metaplasia was characterized by a loss of ciliated epithelium and reduction in epithelial size from a columnar to a cuboidal cell. Changes in the pulmonary parenchyma were confined to the bronchial system and manifested as multifocal bronchitis to bronchiolitis, multifocal bronchiectasis, bronchial epithelial metaplasia and hyperplasia, and occasional bronchiolar or bronchial exudation. The investigator commented that these lesions were consistent with changes often observed in mice experimentally or naturally infected with respiratory pathogens. However, the absence of similar changes in control mice precludes an interpretation of infectious pathogenesis. Exposure to vinyl acetate might be synergistic with the induction of microbial pathogens.

3.6. Chronic Toxicity and Carcinogenicity

In a chronic toxicity and oncogenicity study, groups of male and female Crl:CD(SD)BR (Sprague-Dawley) rats and Crl:CD-1(ICR)BR mice were exposed to vinyl acetate at concentrations of 0, 50, 200, or 600 ppm for 6 h/day, 5 days/week for 104 weeks via whole body inhalation (Bogdanffy et al. 1994). Chamber concentrations were measured every 15 min using a gas chromatograph. The main group consisted of groups of 60 mice or rats of each sex that were exposed for 104 weeks; clinical laboratory evaluations were conducted on 10 animals from each group during week 104. In addition, three satellite groups of 10 male and 10 female rats or mice had the following evaluations: clinical laboratory evaluations at week 51 and necropsy at weeks 52–53; clinical laboratory evaluations at week 81 and necropsy at weeks 82–83; and exposure to vinyl acetate for 70 weeks followed by a 15-week recovery period. 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) (Bogdanffy et al. 1994). Following the recovery period, male rats in the 600-ppm group exhibited a statistically significant increase in body weight gain compared with controls. No effects on body weight gain were observed at 50 or 200 ppm. Clinical pathology evaluation revealed a statistically significant decrease in blood glucose in 600-ppm females at weeks 51, 81, and 104, and a statistically significant decrease in urine volume in all 600-ppm rats at weeks 51 (males only), 81, and 104. Corresponding increases in specific gravity and decreased pH were observed but the differences were not always statistically significant. The investigators attributed effects on blood glucose and urinary parameters to decreased food and water consumption; however, food and water consumption were not measured. Gross necropsy revealed increases in relative lung weight in the 200- and 600-ppm groups at week 53, the 600-ppm group at week 83, and all treated groups at week 104. Following the 15-week recovery period, no statistically significant differences in terminal body weight or organ weights were observed in any groups of exposed females, whereas body weight gain in male rats remained slightly depressed. Histopathologic examination revealed nonneoplastic changes in the lungs and nose. Findings in the lungs of male and female rats exposed at 600 ppm included bronchial exfoliation, intraluminal fibrous projections, macrophage accumulation, and peribronchiolar/perivascular lymphoid aggregates. Nasal lesions were found in rats exposed at 200 and 600 ppm, and included olfactory epithelial atrophy, squamous metaplasia, regeneration, inflammatory cell infiltrate, and leukocytic exudate; epithelial nest-like folds; basal cell hyperplasia; turbinate leukocyte exudate; and submucosal inflammatory cell infiltrate. Neoplastic changes were confined primarily to the nasal cavity of rats exposed at 600 ppm. Findings in the control, 50-, 200-, and 600-ppm groups included squamous cell carcinoma (males: 0/59, 0/60, 0/59, and 2/59, respectively; females: 0/60, 0/60, 0/60, and 4/59, respectively), carcinoma in situ (males: 0/59, 0/60, 0/59, and 1/59, respectively), and benign lesion of inverted papilloma (males: 0/59, 0/60, 0/59, and 4/59, respectively). Additionally, one female rat exposed at 600 ppm had a squamous cell carcinoma in the larynx.

In mice, body weight gain was statistically decreased in the 200- and 600-ppm groups throughout the study, and in the 50-ppm group through week 52 (Bogdanffy et al. 1994). Absolute body weight in the 600-ppm group at week 104 was approximately 15% less than controls. 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. Gross necropsy revealed increases in absolute and relative lung weights in 600-ppm males at weeks 53, 83, and 104, in 600-ppm females at weeks 83 and 104, and 200-ppm males only at week 83. No statistically significant differences in final body weights or organ weights were found after a 15-week recovery period. Histopathologic examination revealed non-neoplastic changes in the lungs, nose, and trachea. Findings in the lungs were present primarily in mice exposed at 600 ppm, and included accumulation of alveolar and brown pigmented macrophages, intra-alveolar eosinophilic material, intraluminal fibroepithelial projections, bronchial gland dilation, bronchial/bronchiolar epithelial flattening and exfoliation, and bronchial/bronchiolar epithelial disorganization. Non-neoplastic nasal lesions were found in the 200- and 600-ppm groups, and included olfactory epithelial atrophy (mainly dorsal meatus or widespread), inflammatory exudate, mucosal inflammatory infiltrate, submucosal gland hyperplasia, squamous metaplasia at the naso/maxilloturbinate region, and replacement of olfactory epithelium by respiratory epithelium. Epithelial hyperplasia of the trachea and bronchi was also evident in 600-ppm group. Neoplastic changes were confined to a moderately invasive squamous cell carcinoma in a major bronchus of the lung of a 600-ppm male and a single adenocarcinoma in a control male.

The International Agency for Research on Cancer (IARC 1995) has concluded there is inadequate evidence in humans and limited evidence in experimental animals of the carcinogenicity of vinyl acetate. Therefore, IARC states that vinyl acetate is possibly carcinogenic to humans (Group 2B). The weight of the evidence was: (1) vinyl acetate is rapidly transformed into acetaldehyde; (2) sufficient evidence of carcinogenicity of acetaldehyde in experimental animals (both vinyl acetate and acetaldehyde induce nasal cancer in rats after administration by inhalation); and (3) vinyl acetate and acetaldehyde are genotoxic in human cells in vitro and in animals in vivo.

3.7. Summary

Acute toxicity studies of vinyl acetate included a series of studies in dogs, rats, mice, guinea pigs, ands rabbits performed by Smyth and Carpenter (1973); a study in rats by Gage (1970); an RD50 value reported in mice (Dudek et al. 1996); and a study investigating the histopathologic lesions in the rat nasal cavity (Bogdanffy et al. 1997). Tables 7-10 and 7-11 summarize the lethal and nonlethal effects of vinyl acetate.

TABLE 7-10. Summary of 4-Hour Lethal Inhalation Data in Laboratory Animals.

TABLE 7-10

Summary of 4-Hour Lethal Inhalation Data in Laboratory Animals.

TABLE 7-11. Summary of Nonlethal Inhalation Data in Laboratory Animals.

TABLE 7-11

Summary of Nonlethal Inhalation Data in Laboratory Animals.

The Smyth and Carpenter study provided the best general toxicity data. Nonlethal concentrations produced signs of congested extremities in rats and lacrimation in guinea pigs, but no signs were noted in mice or rabbits. Dogs exhibited lacrimation, nasal froth, and tremors. Lethal concentrations produced signs of irritation (gasping and lacrimation) and central nervous system effects (poor coordination, prostration, and clonic convulsions). Gross necropsy of animals that died indicated that mortality was due to pulmonary irritation (pulmonary congestion, hemorrhages, and excess pleural fluid). Limitations of the Smyth and Carpenter studies include incomplete reporting of study details (no details about exposure chamber, strain and age of animals not specified) and a lack of a control group. Chamber concentrations were not measured, but the nominal concentrations were corrected against a calibration curve.

The Gage (1970) study is of limited utility because the purity of the chemical is unknown, the exposure concentrations were nominal, and clinical signs were reported as a general statement, so it is not known when the clinical signs first occurred. The Dudek et al. (1996) data was published in an abstract, with the RD50 being the only toxicity end point investigated.

The Bogdanffy et al. (1997) study primarily focused on histopathologic lesions of the rat nasal epithelium. 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 body weight gain, and developmental toxicity in the form of delayed fetal growth (Hurtt et al. 1995). Results of genotoxicity testing indicate that vinyl acetate is clastogenic (proposed to result from the metabolite acetaldehdye) and cytotoxic (proposed to be caused by the metabolite acetic acid). 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.

4. SPECIAL CONSIDERATIONS

4.1. Metabolism and Disposition

Groups of male and female Sprague-Dawley rats were exposed for 6 h to 14C-vinyl acetate vapor at 750 ppm by nose-only inhalation to assess excretion, metabolism, and tissue distribution (Strong et al. 1980). The mean proportion of radioactivity recovered over a 96-h post-exposure period was 4.8% in urine, 3.6% in feces, 74.6% in expired air, and 16.4% in the carcass. The amount recovered in the expired air was almost exclusively 14CO2. No radiolabeled carbonates or bicarbonates were recovered in the urine or feces. Tissue distribution measurements of rats killed immediately after exposure revealed that the highest mean concentration of radioactivity (reported as μg equivalents of 14C-vinyl acetate/g) was found in the Harderian gland (2,045 μg equivalents/g), followed by the ileum (393 μg equivalents/g) and submaxillary salivary gland (341 μg equivalents/g). Radioactivity levels in the gastrointestinal tract contents, liver, kidneys, lung, brain, stomach, colon, and ovaries ranged from 150–300 μg equivalents/g. The pattern of distribution was essentially the same but at lower concentrations at 1-, 6-, or 72-h post-exposure, with the highest concentrations at 72 h found in the Harderian gland (193 μg equivalents/g), adrenal gland (112 μg equivalents/g), and ovaries (99 μg equivalents/g). No difference in the pattern of distribution was found between sexes (except for the gonads), or following oral administration. A separate study investigating the metabolic fate of 14C-vinyl acetate at 1,000 ppm administered for 6 h by nose-only inhalation to Sprague-Dawley rats resulted in similar results (Cresswell et al. 1979).

The study by Bogdanffy et al. (1997) provided information on the deposition of inhaled vinyl acetate in the rat nasal cavity. Histopathology results demonstrated a strong anterior to posterior gradient, with the response moving anterior to posterior with increasing concentrations. These findings are indicative of a material in which deposition is metabolically dependent. As vinyl acetate concentration increases, fractional deposition decreases due, in part, to saturation of the metabolism-dependent component of deposition.

The primary metabolic pathway of vinyl acetate is hydrolysis by carboxylesterases to acetic acid and vinyl alcohol, which rearranges to form acetaldehyde (see Figure 7-1 and Table 7-12) (Simon et al. 1985a; Fedtke and Wiegand 1990; Kuykendall et al. 1993a; Bogdanffy and Taylor 1993). Acetaldehyde can be further metabolized to acetate, which can be incorporated into the carbon pool via formation of acetyl coenzyme A and can ultimately result in the formation of CO2 (Strong et al. 1980). Acetaldehyde can also be oxidized to acetic acid by aldehyde dehydrogenase, a NADH-dependent reaction (Andersen et al. 2002). Monooxygenases do not play a significant role in the metabolism of vinyl acetate, and epoxide formation is not expected to be significant (Simon et al. 1985a; Bogdanffy et al. 1999a). A gas-uptake kinetic study in rats revealed a linear, concentration-dependent decay of vinyl acetate up to a concentration of 650 ppm, indicating the possibility of metabolic saturation (Simon et al. 1985a). At concentrations below saturation, the maximal clearance in rats was 30,000 mg/h/kg, similar to the maximal ventilation rate of 32,000 mg/h/kg. Therefore, the metabolic rate of vinyl acetate is determined by the ventilation rate when metabolic saturation has not been reached.

FIGURE 7-1. Pathways of vinyl acetate metabolism. Vinyl alcohol is an unstable intermediate that has not been isolated.

FIGURE 7-1

Pathways of vinyl acetate metabolism. Vinyl alcohol is an unstable intermediate that has not been isolated. Source: Bogdanffy et al. 2001. Permission needed to reprint- appears as Figure 2 in paper. Reprinted with permission; copyright 2001, Inhalation (more...)

TABLE 7-12. Degradation of Vinyl Acetate and Production of Acetaldehyde with Time.

TABLE 7-12

Degradation of Vinyl Acetate and Production of Acetaldehyde with Time.

Information on the kinetics of vinyl acetate hydrolysis is available for whole blood, plasma, erythrocytes, liver microsomes, and nasal tissue. The half-life of vinyl acetate in whole blood and liver homogenates was comparable in rats (60–125 and 50–167 seconds, respectively) and mice (114 and 66 seconds, respectively), with the most active compartment being plasma (57–72 and 36 seconds for rats and mice, respectively) (Creswell et al. 1979; Fedtke and Wiegand 1990). Hydrolysis of vinyl acetate in humans was generally slower than in rats and mice, with a half-life in human whole blood of 210–246 seconds and in human plasma of 150 or 3,720 seconds. However, the half-life of vinyl acetate in erythrocytes was similar in humans (330 seconds) and rats (336 seconds) (Fedtke and Wiegand 1990). Kinetic parameters of enzyme-mediated hydrolysis by rat liver and lung microsomes, rat and human plasma, and purified carboxylesterase are presented in Table 7-13.

TABLE 7-13. Kinetics of Vinyl Acetate from Various Sources.

TABLE 7-13

Kinetics of Vinyl Acetate from Various Sources.

Because the nasal cavity was the target organ of toxicity after chronic exposure to vinyl acetate, metabolism of vinyl acetate by nasal tissue was examined. Through the use of a carboxylesterase inhibitor (BNPP) and monooxygenase inhibitors (such as diallyl sulfide), metabolism of vinyl acetate by the nose was shown to be carboxylesterase dependent (Plowchalk et al. 1997; Bogdanffy et al. 1999a). Histochemical staining of the rat nasal cavity revealed that a high-affinity carboxylesterase was bound to the luminal plasma membrane (Bogdanffy et al. 1999a). To examine the kinetics of nasal carboxylesterase-mediated metabolism of vinyl acetate, homogenized samples of nasal respiratory and olfactory mucosa from male and female rats and mice were incubated with vinyl acetate (Bogdanffy and Taylor 1993). Few difference in kinetics between male or female rats or mice were observed; however, the olfactory mucosa had higher activity than the respiratory mucosa (see Table 7-13), a result also seen after histochemical staining of the nasal passages of Fischer 344 rats and B6C3F1 mice (Bogdanffy et al. 1987). An in vitro gas technique using whole-tissue samples and physiologically-based pharmacokinetic modeling were used to investigate differences in vinyl acetate metabolism in rat and human nasal tissues (Bogdanffy et al. 1998). Rat respiratory carboxylesterase and aldehyde dehydrogenase activities were approximately three and two times higher than those of humans, respectively, whereas rat olfactory enzyme activities were equivalent to humans (see Table 7-14). Km values did not differ between species.

TABLE 7-14. Kinetic Constants for Individual Tissue Specimens Derived from a Mini Vapor Uptake Technique.

TABLE 7-14

Kinetic Constants for Individual Tissue Specimens Derived from a Mini Vapor Uptake Technique.

As observed in the whole-body gas uptake study (Simon et al. 1985a), substrate inhibition of rat nasal carboxylesterase in vitro was found at high concentrations of vinyl acetate (Bogdanffy and Taylor 1993). This is also evident from studies that demonstrated that in vivo deposition of vinyl acetate in the upper respiratory tract of the rat is concentration dependent (Plowchalk et al. 1997). At low concentrations, removal of vinyl acetate from the airstream is highly efficient; more than 93% was extracted by the rat nose at concentrations of 76 ppm or less. At vinyl acetate concentrations of 76–550 ppm, extraction progressively decreased to about 40% and remained at that level until a vinyl acetate concentration of approximately 2,000 ppm. Acetaldehyde in expired air increased to an apparent maximum of 227 ppm, which corresponded to a vinyl acetate concentration of 1,000 ppm.

4.2. Mechanism of Toxicity

Several papers have been written about the mode of action of vinyl acetate (Bogdanffy et al. 1999b, 2001; Andersen et al. 2002; Bogdanffy 2002; Bolt 2003; Bogdanffy and Valentine 2003; Hengstler et al. 2003). Metabolism studies have demonstrated that vinyl acetate is metabolized to acetic acid and vinyl alcohol, which rearranges to form acetaldehyde (Simon et al. 1985a; Bogdanffy and Taylor 1993). Acetaldehyde can be further metabolized to acetic acid. Genotoxicity and cytotoxicity tests demonstrated that clastogenicity and cytotoxicity required the presence of carboxylesterases (Kuykendall and Bogdanffy 1992a,b; Kuykendall et al. 1993a). Production of of acetic acid was shown to be responsible for the observed cytotoxicity, and acetaldehyde was responsible for the DNA-protein crosslinking observed in test systems (Kuykendall et al. 1993a). The proposed mechanism of cytotoxicity is lowering of inter- and intra-cellular pH by the production of acetic acid (Kuykendall et al. 1993a; Plowchalk et al. 1997; Bogdanffy et al. 2001). An in vitro study measuring the pH of individual rat respiratory and olfactory nasal epithelial cells before and during exposure to vinyl acetate confirmed a concentration-related decrease in pH with increasing vinyl acetate concentration, with a maximum decrease in pH of 0.3 pH units (Lantz et al. 2003). The cytotoxic response leads to cellular degeneration followed by cellular proliferation (Kuykendall et al. 1993a; Plowchalk et al. 1997; Bogdanffy et al. 2001). Clastogenic effects include chromosomal aberrations, sister chromatid exchange, and DNA crosslinking in human lymphocytes (Mäki-Paakkanen et al. 1984; He and Lambert 1985; Lambert et al. 1985; Norppa et al. 1985; Jantunen et al. 1986; Mäki-Paakkanen and Norppa 1987); Chinese hamster ovary cells (Mäki-Paakkanen et al. 1984; Norppa et al. 1985); rat liver microsomes (Kuykendall and Bogdanffy 1992a,b); and rat nasal epithelial tissues (Kuyendall et al. 1993a,b). Clastogenic effects appear to be due to the production of acetaldehyde, a weak DNA protein crosslinking agent (Kuykendall et al. 1993a) in combination with a lowering of pH (Morita 1995). Acetaldehyde-induced DNA protein crosslinks are more stable at a pH lower than the physiologic pH (Kuyendall and Bogdanffy 1992a). Therefore, the following continuum of response has been proposed for vinyl acetate (Bogdanffy et al. 2001):

Image p240

Metabolic saturation of vinyl acetate occurs. Simon et al. (1985a) reported that metabolic saturation is reached around 650 ppm in rats. In the rat nose, removal of vinyl acetate from the airstream is highly efficient at low concentrations (more than 93% was extracted at concentrations of 76 ppm or less), but becomes less efficient with increasing concentrations (extraction progressively decreased to about 40% at 76–550 ppm and remained at that level up to a concentration of about 2,000 ppm) (Plowchalk et al. 1997). Therefore, olfactory degeneration would be the primary end point until metabolic saturation in the nasal cavity is reached. 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. 1997), by the histopathologic changes noted in the lungs of rats and mice exposed at 600 ppm in a 2-year bioassay (Bogdanffy et al. 1994), and by the pulmonary changes found in rats, mice, guinea pigs, and rabbits exposed to acute, lethal concentrations (Smyth and Carpenter 1973).

4.3. Structure-Activity Relationships

Structure-activity relationships were not used for deriving AEGL values for vinyl acetate.

4.4. Other Relevant Information

4.4.1. Species Variability

Four-hour LC50 data varied by a factor of 3.6; the most sensitive species was the mouse, followed by the rabbits, rat, and guinea pig (Smyth and Carpenter 1973). Regardless of species, the cause of death was attributed to pulmonary distress.

Olfactory degeneration is the proposed primary end point of inhaled vinyl acetate until metabolic saturation in the nasal cavity is reached (Bogdanffy et al. 1997). Therefore, much research is available regarding the metabolism of vinyl acetate by the nasal cavity. In general, little difference was observed between male and female mice and rats and humans in the carboxylesterase-mediated metabolism of vinyl acetate, particularly by 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). However, considerable variability in olfactory nasal tissue occurs in humans with regard 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). Children appear to have histologic organization similar to rodents, in that the olfactory epithelium is well-developed and delineated. Aging humans develop a very heterogenous mucosa with respiratory-like epithelial cells populating the olfactory region. Glandular structures become sparse and non-esterase-containing tissues fill the submucosa. However, esterase histochemistry of adult olfactory mucosa revealed that sustentacular cells and Bowman's glands do contain significant quantities of carboxylesterase.

4.4.2. Susceptible Populations

Data regarding populations susceptible to vinyl acetate were not available. Although older populations may not be as susceptible to olfactory degeneration as younger ones, they may have increased susceptibility of the respiratory epithelium or even greater pulmonary susceptibility because of decreased removal of vinyl acetate in the nose.

4.4.3. Concentration-Exposure Duration Relationship

The relationship between concentration and duration of exposure as related to lethality was examined by ten Berge et al. (1986) for approximately 20 irritant or systemically-acting vapors and gases. Individual animal data sets were analyzed by probit analysis, with exposure duration and exposure concentration as independent variables. An exponential equation Cn × t = k, where the value of n ranged from 0.8 to 3.5 for different chemicals, was found to be an accurate quantitative descriptor for the chemicals evaluated. Approximately 90% of the values of n range between n = 1 and n = 3. Consequently, these values were selected as the reasonable lower and upper bounds of n. A value of n = 1 is used when extrapolating from shorter to longer durations because the extrapolated values represent the most conservative approach in the absence of other data. Conversely, a value of n = 3 is used when extrapolating from longer to shorter durations because the extrapolated values are more conservative in the absence of other data.

5. 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). For longer durations, one of three individuals reported persistent slight irritation of the throat after being exposed for 4 h at 20 ppm and two of three individuals complained of throat irritation (transient in one and persistent in the other) after being exposed for 2 h at 34 ppm. 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 test subjects; irritation was so severe that subjects expressed unwillingness to work at that concentration for 8 h.

In an occupational health report, Deese and Joyner (1969) reported that ocular irritation from exposure to vinyl acetate at 21.6 ppm would be “intolerable over an extended period”; a slight cough and hoarseness were also reported by three subjects exposed at this concentration. In addition, slight ocular irritation in one of three individuals was reported at 5.7 or 6.8 ppm, and hoarseness in one of three was reported at 4.2 and 5.7 ppm. 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. The Deese and Joyner (1969) study is of limited use for deriving AEGL values because it was not a controlled-exposure study. As noted earlier, the subjects might have been briefly exposed at a concentration higher than 21.6 ppm. Furthermore, coexposure to other chemicals used in the production facility might have exacerbated or contributed to the ocular irritation. Therefore, this study was not used for deriving AEGL-1 values.

5.2. Animal Data Relevant to AEGL-1

Irritation was noted in a dog exposed to vinyl acetate at 205 ppm for 4 h (blinking was observed after 1 min and the sclera were red after 1 h) (Smyth and Carpenter 1973). In the Bogdanffy et al. (1997) study, no histopathologic effects was found in the olfactory or respiratory epithelium of rats exposed to vinyl acetate at 0, 50, or 200 ppm for 6 h/day, 5 days/week for 1, 5, or 20 days. Thus, 200 ppm is a no-observed-effect level for these end points.

5.3. Derivation of AEGL-1 Values

AEGL-1 values are based on the no-effect level for notable discomfort found in a study of human volunteers (Smyth and Carpenter 1973). This study was selected over the occupational health report (Deese and Joyner 1969) or the rat study (Bogdanffy et al. 1997) because it was a controlled-exposure study in humans. Slight throat irritation was reported by one of three individuals exposed to vinyl acetate at 20 ppm for 4 h; therefore, effects at 20 ppm are considered to be mild and below a notable discomfort threshold. An intraspecies uncertainty factor of 3 was applied because the 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, AEGL-1 values were not scaled across time; instead, the same threshold value was adopted for all the exposure durations. The importance of concentration over exposure duration in the irritant response to vinyl acetate is supported by other findings in the Smyth and Carpenter (1973) study. Similar slight irritation was reported in one individual exposed to vinyl acetate at 20 ppm after 2 min and 4 h. More subjects reported irritation of greater severity when exposed at higher concentrations for shorter durations (e.g., 34 ppm for 2 h or 72 ppm for 30 min). However, the data are limited because of the small number of subjects and varying exposure concentrations. AEGL-1 values for vinyl acetate are presented in Table 7-15.

TABLE 7-15. AEGL-1 Values for Vinyl Acetate.

TABLE 7-15

AEGL-1 Values for Vinyl Acetate.

The AEGL-1 value of 6.7 ppm is similar to the range of concentrations that caused hoarseness and slight ocular irritation in one of three people exposed at 4.2 and 5.7 ppm in a vinyl acetate production facility (Deese and Joyner 1969); however, the data are potentially confounded by variable exposure conditions and concurrent exposure to other chemicals.

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 is 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 in assessing the public awareness of exposure to vinyl acetate from its odor.

6. DATA ANALYSIS FOR AEGL-2

6.1. Human Data Relevant to AEGL-2

A study by Smyth and Carpenter (1973) 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.

6.2. Animal Data Relevant to AEGL-2

No histopathologic changes or cell proliferation were found in the olfactory or respiratory epithelium of rats exposed to vinyl acteate for 6 h at 0, 50, or 200 ppm. However, concentration-related olfactory epithelium changes (degeneration, necrosis, and exfoliation) and a concentration-related increase in cell proliferation in both the respiratory and olfactory epithelium were found in rats exposed at 600 and 1,000 ppm (Bogdanffy et al. 1997). Whether the lesions were reversible could not be determined because a recovery phase was not included in the study. However, the effects should be completely reversible from both a morphologic and functional standpoint, based on the focal and limited nature of the olfactory lesions, as well as the known regenerative capacity of the olfactory tissue (S.R. Frame, DuPont, Haskell Laboratory, Newark, DE, personal commun., December 1, 2004).

6.3. Derivation of AEGL-2 Values

Although human data are preferred over animal data to derive AEGL values, the human study by Smyth and Carpenter was not used because its findings of notable discomfort are not relevant AEGL-2 effects. Therefore, the rat data reported by Bogdanffy et al. (1997) are the basis for the AEGL-2 values. In that study, rats exposed for 6 h to vinyl acetate at 600 and 1,000 ppm had histopathologic changes in the olfactory epithelium; no lesions were observed at 200 or 50 ppm. At 600 ppm, minimal or mild olfactory degeneration and necrosis was observed in 5/5 male rats and moderately severe lesion(s) were found in one nasal segment of 1/5 rats. At 1,000 ppm, 1/5 rats exhibited minimal degeneration and necrosis of the respiratory epithelium, and 2/5 rats had moderately severe lesions of the olfactory epithelium (Bogdanffy et al. 1997). The olfactory lesions are predicted to be reversible (S.R. Frame, DuPont, Haskell Laboratory, Newark, DE, personal commun., December 1, 2004). However, because the study did not include a recovery group, there are no data with which to empirically demonstrate that the effects were reversed. It is plausible that the effects at 600 and 1,000 ppm could be relevant AEGL-2 effects of “other serious, long-lasting adverse health effects” (NRC 2001). In a review of the toxicologic pathology of the nasal epithelium, Harkema et al. (2006) noted that olfactory epithelium damaged by exposure to toxic irritants may recover to near normal morphology, but that recovery may take weeks or months. In addition, some modification of the mucosa may occur during recovery, leading to olfactory epithelium cells that resemble respiratory epithelium. Because the reversibility of the lesions is uncertain, 200 ppm was selected as the point of departure for deriving AEGL-2 values. This concentration is considered a no-effect level for serious, long-lasting histopathologic nasal lesions in rats exposed for 6 h.

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 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. 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 considerable variability in olfactory nasal tissue occurs in humans with regard 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. 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 uncertainty factor was reduced to 3.

The experimentally derived exposure values were scaled to AEGL time frames 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, 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 AEGL-2 of 46 ppm because of the uncertainty in extrapolating a 6-h exposure to a 10-min value (NRC 2001).

AEGL-2 values for vinyl acetate are presented in Table 7-16.

TABLE 7-16. AEGL-2 Values for Vinyl Acetate.

TABLE 7-16

AEGL-2 Values for Vinyl Acetate.

7. DATA ANALYSIS FOR AEGL-3

7.1. Summary of Human Data Relevant to AEGL-3

No human data relevant to AEGL-3 values were available.

7.2. Summary of Animal Data Relevant to AEGL-3

Mortality data on vinyl acetate were available for rats, mice, guinea pigs, and rabbits (Smyth and Carpenter 1973). Chamber concentrations were not measured, but nominal concentrations were corrected against a calibration curve. Lethal concentrations produced signs of irritation (gasping and lacrimation) and central nervous system effects (poor coordination, prostration, and clonic convulsions), and death was attributed to pulmonary irritation (pulmonary congestion, hemorrhages, and excess pleural fluid).

Nonlethal concentrations of vinyl acetate produced signs of congested extremities in rats, lacrimation in guinea pigs, and no signs in mice or rabbits (Smyth and Carpenter 1973). Dogs exhibited lacrimation, nasal froth, and tremors when exposed for 4 h at 3,280 ppm, and irritation but no central nervous system effects at 1,640 ppm (Smyth and Carpenter 1973). Exposure to vinyl acetate at 1,000 ppm for 6 h/day, 5 days/week for 4 weeks was not lethal to male and female rats or mice (Owen 1979a,b; 1980a,b).

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) and a concentration-related increase in cell proliferation in both the respiratory and olfactory epithelium were present in animals exposed at 600 and 1,000 ppm (Bogdanffy et al. 1997).

A carcinogenicity assessment was not appropriate for an acute exposure scenario because the proposed mechanism of carcinogenicity suggests a nonlinear mode of action requiring continued exposure to vinyl acetate. Therefore, a one-time exposure at even high concentrations of vinyl acetate would not be expected to result in tumor development.

7.3. Derivation of AEGL-3 Values

The 4-h mortality data for vinyl acetate in five species reported by Smyth and Carpenter (1973) were not suitable for modeling. In studies with rats, mice, and guinea pigs, deaths occurred during exposure at all but the lowest concentration of vinyl acetate. In rabbits, deaths occurred at only the highest concentration. The time of death for each of the rats and mice were not specified, so the data could not be modeled. Times of death for guinea pigs and rabbits were reported, but efforts to model the data were unsuccessful. Only one dog per exposure was tested by Smyth and Carpenter (1973), so those data were also unsuitable for modeling.

In the absence of modeling results to determine a lethality threshold for vinyl acetate, the highest nonlethal concentrations found in different species were considered. Vinyl acetate at 1,640 ppm was nonlethal in rats, guinea pigs, and rabbits exposed for 4 h. In mice, no death occurred in six mice exposed at 410 ppm, and one of six mice died after exposure at 820 ppm (Smyth and Carpenter 1973). In other studies, 1,000 ppm was nonlethal to rats exposed for 6 h (Bogdanffy et al. 1997) or to rats and mice exposed for 6 h/day, 5 days/week for 4 or 13 weeks (Owen 1979a,b; 1980a,b).

Data from the Smyth and Carpenter (1973) study of mice exposed once to vinyl acetate appear to conflict with the results of repeated exposure studies. Smyth and Carpenter (1973) observed one death among six mice exposed for 4 h at 820 ppm; the exposure concentration was calculated as 1,000 ppm and then corrected to 820 ppm on the basis of gas chromatography measurements of calculated concentrations. In contrast, 10 mice (5/sex) survived exposure to vinyl acetate at 1,000 ppm (measured by gas chromatography at 15-min intervals) for 6 h/day, 5/days/week for 4 weeks, and a separate group of 10 mice survived 1,500 ppm for 20 days (initial concentration of 50 ppm was increased to 1,500 ppm on day 8 of the study and continued to the end of the study at 28 days) (Owen 1979a). In a subchronic study, a group of 20 mice (10/sex) survived exposure to vinyl acetate at 1,000 ppm for 6 h/day, 5 days/week for at least 4 weeks (9/20 mice died as a result of routine blood sampling during week 5, 6, or 12) (Owen 1980a). Finally, 104/120 mice survived exposure to vinyl acetate at 600 ppm for 6 h/day, 5 days/week for 104 weeks (Bogdanffy et al. 1994). Among the acute and subchronic studies, the Owen (1979a, 1980a) studies are considered more reliable than those of Smyth and Carpenter (1973) because group sizes were larger, sex and strain of the animals were reported, exposure concentrations were measured by gas chromatography at 15-min intervals, and the study design and findings were reported in more detail.

A point of departure of 1,000 ppm for 6 h was used to derive AEGL-3 values. That concentration was nonlethal in rats exposed for a single 6-h duration (Bogdanffy et al. 1997), as well as in both rats and mice exposed repeatedly for 6 h/day, 5 days/week for 4 weeks (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 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. 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 3 was applied instead of 10. Application of a higher total uncertainty factor of 30 would result in an 8-h AEGL-3 value (25 ppm) lower than concentrations that did not result in serious health effects in a human volunteer study, albeit at shorter exposure durations. No life-threatening effects were found in human volunteers 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, an intraspecies uncertainty factor of 3 was used.

Time scaling was performed in the same manner described for AEGL-2 values (see Section 6.3). Similarly, the 10-min AEGL-3 value was set equal to the 30-min AEGL-3 of 230 ppm because of the uncertainty in extrapolating a 6-h exposure to a 10-min value (NRC 2001).

AEGL-3 values for vinyl acetate are presented in Table 7-17.

TABLE 7-17. AEGL-3 Values for Vinyl Acetate.

TABLE 7-17

AEGL-3 Values for Vinyl Acetate.

8. SUMMARY OF AEGL VALUES

8.1. AEGL Values and Toxicity End Points

The Smyth and Carpenter (1973) study was used to derive AEGL-1 values for vinyl acetate on the basis of irritation in humans, but there were inadequate data from other human studies of AEGL-1 effects to verify consistency. AEGL-2 values are based on a no-effect level for serious, long-lasting nasal histopathologic lesions in rats. AEGL-3 values are based on the highest nonlethal concentration in rats and mice exposed for 6 h per day for up to 28 days (Owen 1979a,b, 1980a,b; Bogdanffy et al. 1997). AEGL values for vinyl acetate are presented in Table 7-18.

TABLE 7-18. AEGL Values for Vinyl Acetate.

TABLE 7-18

AEGL Values for Vinyl Acetate.

8.2. Comparison with Other Standards and Guidelines

Standards and guidance levels for workplace and community exposures to vinyl acetate are presented in Table 7-19. The emergency response planning guideline 1 (ERPG-1) for vinyl acetate of 5 ppm is similar to the AEGL-1 value of 6.7 ppm. The ERPG-2 of 75 ppm is based on evidence that healthy humans can tolerate irritant effects at 72 ppm for 30 min (Smyth and Carpenter 1973) and that no effects were observed in subchronic studies in animals at concentrations up to 200 ppm (Owen 1980a,b; Bogdanffy et al. 1997). The difference between the ERPG-2 and AEGL-2 values appears to be due to the use of an uncertainty factor for intraspecies differences in deriving the AEGL-2 value, which was not used in determining the ERPG-2 value.

TABLE 7-19. Standards and Guidelines for Vinyl Acetate.

TABLE 7-19

Standards and Guidelines for Vinyl Acetate.

AIHA (2004) selected an ERPG-3 of 500 ppm for vinyl acetate on the basis of a study reporting the death of one of six mice exposed at 1,000 ppm (810 ppm after adjustment based on gas chromotograpic calibration) (Smyth and Carpenter 1973) and chronic studies in which rats and mice survived exposure to vinyl acetate at 600 ppm (Bogdanffy et al. 1994). AIHA (2004) reported that mice were the most sensitive species, and that all species exhibited signs consistent with respiratory tract irritation. The organization concluded that “It is believed that nearly all individuals could be exposed to 500 ppm vinyl acetate for up to 1 h without experiencing or developing life-threatening health effects”. Thus, the primary difference between the ERPG-3 and AEGL-3 derivations appears to be that the AEGL-3 values incorporate uncertainty factors for interspecies differences and intraspecies variability.

Occupational standards for repeated 8-h exposures to vinyl acetate are 5 ppm (MSZW 2004) and 10 ppm (ACGIH 2012), and 15-min occupational exposure limits are 4 ppm (NIOSH 2011) and 15 ppm (ACGIH 2012). These standards are in the same range as the AEGL-1 of 6.7 ppm for protection against notable irritation.

8.3. Data Adequacy and Research Needs

Although data were considered adequate for derivation of all three AEGL levels, the overall database on vinyl acetate was limited. The volunteer study with controlled exposure to vinyl acetate (Smyth and Carpenter 1973) had inadequate documentation of the study design and findings, and exposure concentrations were calculated rather than measured. In the occupational health study, exposures were variable and subjects were likely exposed to other airborne contaminants concurrently (Deese and Joyner 1969). The animal database for nonlethal effects of vinyl acetate is more robust, and includes single-day, 4-week, 13-week, and chronic exposure studies (Owen 1979a,b, 1980a,b; Bogdanffy et al. 1994, 1997). However, lethality data were only available from the studies by Smyth and Carpenter (1973), 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.

9. REFERENCES

  • ACGIH (American Conference of Government and Industrial Hygienists). Vinyl Acetate (CAS Reg. No. 108-05-4); Documentation of the Threshold Limit Values and Biological Exposure Indices; Cincinnati, OH. 2001.
  • ACGIH (American Conference of Governmental Industrial Hygienists). Vinyl Acetate (CAS Reg. No. 108-05-4); TLVs and BEIs: Based on the Documentation of Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices; Cincinnati, OH. 2012.
  • Agaronyan ZP, Amatuni VG. The electrical activity of the heart in persons working in the production of vinyl acetate and its derivatives [in Russian] Krovoobrashchenie. 1980;13(4):31–36.
  • Agaronyan ZP, Amatuni VG. The significance of the working risk factor in the onset and progression of chronic bronchitis and pulmonary functional impairment in persons subjected to the effects of vinyl acetate and its derivatives [in Russian] Zh. Eksp. Klin. Med. 1982;22:151–155.
  • AIHA (American Industrial Hygiene Association). Odor Thresholds for Chemicals with Established Occupational Health Standards. Akron, OH: American Industrial Hygiene Association; 1989.
  • AIHA (American Industrial Hygiene Association). The AIHA 2004 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guidelines Handbook. American Industrial Hygiene Association; Fairfax VA: 2004. Vinyl Acetate (CAS Reg. No. 108-05-4).
  • Alexander V, Leffingwell SS, Lloyd JW, Waxweiler RJ, Miller RL. Brain cancers in petrochemical workers: A case series report. Am. J. Ind. Med. 1980;1(1):115–123. [PubMed: 7342751]
  • Amatuni VG, Agaronyan ZP. State of external respiratory function in persons engaged in the production of vinyl acetate and its derivatives [in Russian] Zh. Eksp. Klin. Med. 1979;19(4):72–78. [PubMed: 159592]
  • Amatuni VG, Agaronyan ZP. Chronic bronchitis and pulmonary function in the shop workers of “Polyvinyl Acetate” [in Russian] Gig. Tr. Prof. Zabol. 1980;2:14–16. [PubMed: 6445309]
  • Andersen ME, Green T, Frederick CB, Bogdanffy MS. Physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry of organic esters: Assessing the state-of-knowledge and risk assessment applications with methyl methacrylate and vinyl acetate. Regul. Toxicol. Pharmacol. 2002;36(3):234–245. [PubMed: 12473408]
  • Austin SG, Schnatter AR. A case-control study of chemical exposures and brain tumors in petrochemical workers. J. Occup. Med. 1983a;25(4):313–320. [PubMed: 6854420]
  • Austin SG, Schnatter AR. A cohort mortality study of petrochemical workers. J. Occup. Med. 1983b;25(4):304–312. [PubMed: 6304270]
  • Bisesi MS. Ketones/Alcohols/Esters/Epohy Compounds/Organic Peroxides. Acetates. In: Bingham E, Cohrssen B, Powell CH, editors. Patty's Industrial Hygiene and Toxicology. 5th. Vol. 6. New York: John Wiley and Sons; 2001. pp. 558–628.
  • Bogdanffy MS. Vinyl acetate-induced intracellular acidification: Implications for risk assessment. Toxicol. Sci. 2002;66(2):320–326. [PubMed: 11896299]
  • Bogdanffy MS, Taylor ML. Kinetics of nasal carboxylesterase-mediated metabolism of vinyl acetate. Drug Metab. Dispos. 1993;21(6):1107–1111. [PubMed: 7905391]
  • Bogdanffy MS, Valentine R. Differentiating between local cytotoxicity, mitogenesis, and genotoxicity in carcinogen risk assessments: The case of vinyl acetate. Toxicol. Lett. 2003;140–141:83–98. [PubMed: 12676454]
  • Bogdanffy MS, Randall HW, Morgan KT. Biochemical quantitation and histochemical localization of carboxylesterase in the nasal passages of the Fischer-344 rat and B6C3F1 mouse. Toxicol. Appl. Pharmacol. 1987;88(2):183–194. [PubMed: 3564037]
  • Bogdanffy MS, Dreff-van der Meulen HC, Beems RB, Feron VJ, Cascieri TC, Tyler TR, Vinegar MB, Rickard RW. Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse. Fundam. Appl. Toxicol. 1994;23(2):215–229. [PubMed: 7982530]
  • Bogdanffy MS, Gladnick NL, Kegelman T, Frame SR. Four-week inhalation cell proliferation study of the effects of vinyl acetate on rat nasal epithelium. Inhal. Toxicol. 1997;9(1):331–350.
  • Bogdanffy MS, Sarangapani R, Kimbell JS, Frame SR, Plowchalk DR. Analysis of vinyl acetate metabolism in rat and human nasal tissues by an in vitro gas uptake technique. Toxicol. Sci. 1998;46(2):235–246. [PubMed: 10048126]
  • Bogdanffy MS, Manning LA, Sarangapani R. High-affinity nasal extraction of vinyl acetate vapor is carboxylesterase dependent. Inhal. Toxicol. 1999a;11(10):927–941. [PubMed: 10509027]
  • Bogdanffy MS, Sarangapani R, Plowchalk DR, Jarabek A, Andersen ME. A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity. Toxicol. Sci. 1999b;51(1):19–35. [PubMed: 10496674]
  • Bogdanffy MS, Plowchalk DR, Sarangapani R, Starr TB, Andersen ME. Mode-of-action-based dosimeters for interspecies extrapolation of vinyl acetate inhalation risk. Inhal. Toxicol. 2001;13(5):377–396. [PubMed: 11295869]
  • Bolt HM. Genotoxicity - threshold or not? Introduction of cases of industrial chemicals. Toxicol. Let. 2003;140–141:43–51. [PubMed: 12676450]
  • Brams A, Buchet JP, Crutzen-Fayt MC, De Meester C, Lauwerys R, Leonard A. A comparative study, with 40 chemicals, of the efficiency of theSalmonella assay and the SOS chromotest (kit procedure). Toxicol. Lett. 1987;38(1–2):123–133. [PubMed: 3307023]
  • Cresswell DG, Strong HA, Hopkins R. Investigations into the Metabolic Fate of Vinyl Acetate in the Rat and Mouse: Part 1; Harrogate, England. October 1979; 1979. EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. 0278.
  • Deese DE, Joyner RE. Vinyl acetate: A study of chronic human exposure. Am. Ind. Hyg. Assoc. J. 1969;30(5):449–457. [PubMed: 5823425]
  • Dudek BR, Kaempfe TA, Bechtel CL, Mueller JE, Orth RG. Sensory irritation of 12 carpet-associated chemicals and their potential for causing irritation at ambient conditions. (Abstract No. 112).Toxicologist. 1996;30(1 Pt 2):21–22.
  • EPA (U.S. Environmental Protection Agency). Reference Guide to Odor Thresholds for Hazardous Pollutants Listed in the Clean Air Act Amendments of 1990. Office of Research and Development, U.S. Environmental Protection Agency; Washington, DC: 1992. [Mar. 1, 2013]. (EPA/600/R-92/047). [online]. Available: http://cfpub​.epa.gov​/ncea/cfm/recordisplay.cfm?deid=40610.
  • Fedtke N, Wiegand HJ. Hydrolysis of vinyl acetate in human blood. Arch. Toxicol. 1990;64(5):428–429. [PubMed: 2403294]
  • Gage JC. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 1970;27(1):1–18. [PMC free article: PMC1009036] [PubMed: 5418916]
  • Harkema JR, Carey SA, Wagner JG. The nose revisited: A brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Toxicol. Pathol. 2006;34(3):252–269. [PubMed: 16698724]
  • He SM, Lambert B. Induction and persistence of SCE-inducing damage in human lymphocytes exposed to vinyl acetate and acetaldehyde in vitro. Mutat. Res. 1985;158(3):201–208. [PubMed: 4079951]
  • Hellman TM, Small FH. Characterization of the odor properties of 101 petrochemicals using sensory methods. J. Air Pollut. Control Assoc. 1974;24(10):979–982. [PubMed: 4412400]
  • Hengstler JG, Bogdanffy MS, Bolt HM, Oesch E. Challenging dogma: Thresholds for genotoxic carcinogens? The case of vinyl acetate. Annu. Rev. Pharmacol. Toxicol. 2003;43:485–520. [PubMed: 12415124]
  • HSDB (Hazardous Substances Data Bank). Vinyl acetate (CAS Reg. No. 108-05-4). TOXNET, Specialized Information Services, U.S. National Library of Medicine; Bethesda, MD: 2009. [Feb. 27, 2013]. [online]. Available: http://toxnet​.nlm.nih​.gov/cgi-bin/sis/htmlgen?HSDB.
  • Hurtt ME, Vinegar MB, Rickard RW, Cascieri TC, Tyler TR. Developmental toxicity of oral and inhaled vinyl acetate in the rat. Fundam. Appl. Toxicol. 1995;24(2):198–205. [PubMed: 7737431]
  • IARC (International Agency for Research on Cancer); Dry Cleaning, Some Chlorinated Solvents, and Other Industrial Chemicals. Vinyl acetate. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 63. Lyon, France: International Agency for Research on Cancer; 1995. [Feb. 27, 2013]. pp. 443–465. [online]. Available: http://monographs​.iarc​.fr/ENG/Monographs/vol63/mono63-19.pdf.
  • Jantunen K, Mäki-Paakkanen J, Norppa H. Induction of chromosome aberrations by styrene and vinyl acetate in cultured human lymphocytes: Dependence on erythrocytes. Mutat. Res. 1986;159(1–2):109–116. [PubMed: 3941660]
  • Jung R, Engelhart G, Herbolt B, Jäckh R, Müller W. Collaborative study of mutagenicity with Salmonella typhimurium TA102. Mutat. Res. 1992;278(4):265–270. [PubMed: 1373863]
  • Kuykendall JR, Bogdanffy MS. Reaction kinetics of DNA-histone cross-linking by vinyl acetate and acetaldehyde. Carcinogenesis. 1992a;13(11):2095–2100. [PubMed: 1423881]
  • Kuykendall JR, Bogdanffy MS. Reaction kinetics of DNA-protein crosslink formation by acetaldehyde and vinyl acetate; P. Am. Assoc. Canc. Res; May 20–23; San Diego, CA: 1992b. p. 145. [Abstract No. 870]
  • Kuykendall JR, Taylor ML, Bogdanffy MS. Cytotoxicity and DNA-protein crosslink formation in rat nasal tissues exposed to vinyl acetate are carboxylesterase-mediated. Toxicol. Appl. Pharmacol. 1993a;123(2):283–292. [PubMed: 8248935]
  • Kuykendall JR, Taylor ML, Bogdanffy MS. 84th Annual Meeting of the American Association for Cancer Research, May 19–22, 1993, Orlando, FL. DNA-protein crosslink formation in isolated rat nasal epithelial cells exposed to vinyl acetate and acetaldehyde. P. Am. Assoc. Canc. Res. 1993b;34:156. [Abstract No. 929]
  • Lambert B, Chen Y, He SM, Sten M. DNA cross-links in human leucocytes treated with vinyl acetate and acetaldehyde in vitro. Mutat. Res. 1985;146(3):301–303. [PubMed: 4058447]
  • Lantz RC, Orozco J, Bogdanffy MS. Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol. Sci. 2003;75(2):423–431. [PubMed: 12883081]
  • Leffingwell SS, Waxweiler R, Alexander V, Ludwig HR, Halperin W. Case-control study of gliomas of the brain among workers employed by a Texas City, Texas chemical plant. Neuroepidemiology. 1983;2:179–195.
  • Lijinsky W, Andrews AW. Mutagenicity of vinyl compounds inSalmonella typhimurium. Teratog. Carcinog. Mutagen. 1980;1(3):259–267. [PubMed: 6119816]
  • Mäki-Paakkanen J, Norppa H. Induction of micronuclei by vinyl acetate in mouse bone marrow cells and cultured human lymphocytes. Mutat. Res. 1987;190(1):41–45. [PubMed: 3796670]
  • Mäki-Paakkanen J, Tursi F, Norppa H, Jarventaus H, Sorsa M. Vinyl acetate is a potent inducer of chromosome damage in cultured mammalian cells. Mu-tat. Res. 1984;130(3):249.
  • Monsanto Company. Health Effects Assessment for Vinyl Acetate at the Decatur Plant (Final Report) with Attachment and Cover Letter Dated 12/28/89. 1989. EPA Document No. 86-900000050. Microfiche No. OTS0521599.
  • Morita T. Low pH leads to sister-chromatid exchanges and chromosomal aberrations, and its clastogenicity is S-dependent. Mutat. Res. 1995;334(3):301–308. [PubMed: 7753094]
  • MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). Nationale MAC-lijst 2004: Vinylacetaat. Den Haag: SDU Uitgevers; 2004. [Mar.1, 2013]. [online]. Available: http://www​.lasrook.net​/lasrookNL/maclijst2004.htm.
  • Müller W, Engelhart G, Herbold B, Jäckh R, Jung R. Evaluation of mutagenicity testing withSalmonella typhimurium TA102 in three different laboratories. Environ. Health Perspect. 1993;101(suppl 3):33–36. [PMC free article: PMC1521147] [PubMed: 8143640]
  • NIOSH (National Institute for Occupational Safety and Health). NIOSH Pocket Guide to Chemical Hazards: Vinyl acetate. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health; Cincinnati, OH: 2011. [Mar. 1, 2013]. [online]. Available: http://www​.cdc.gov/niosh/npg/npgd0656​.html.
  • Norppa H, Tursi F, Pfaffli P, Mäki-Paakkanen J, Jarventaus H. Chromosome damage induced by vinyl acetate through in vitro formation of acetaldehyde in human lymphocytes and Chinese hamster ovary cells. Cancer Res. 1985;45(10):4816–4821. [PubMed: 4027971]
  • NRC (National Research Council). Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press; 1993.
  • NRC (National Research Council). Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press; 2001.
  • O'Neil MJ, Heckelman PE, Koch CB, Roman KJ, editors. Vinyl acetate. 14th. Whitehouse Station, NJ; Merck; 2006. p. 1719.The Merck Index;
  • Owen PE. Prepared for Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd. Harrogate, England: Aug, 1979a. 1979. Vinyl Acetate: 4 Week Inhalation Dose Range Study in the Mouse. (Report No. 1884-51/3). EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278.
  • Owen PE. Prepared for Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd. Harrogate, England: Aug, 1979b. 1979. Vinyl Acetate: 4 Week Inhalation Dose Range Study in the Rat. (Report No. 1835-51/3). EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278.
  • Owen PE. Prepared for Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd. Harrogate, England: May, 1980a. 1980. Vinyl Acetate: 3 Month Inhalation Toxicity Study in the Mouse. (Report No. 2303-51/5). EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278.
  • Owen PE. Prepared for Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe, Ltd. Harrogate, England: May, 1980b. 1980. Vinyl Acetate: 3 Month Inhalation Toxicity Study in the Rat. (Report No. 2286-51/5). EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS0278.
  • Plowchalk DR, Andersen ME, Bogdanffy MS. Physiologically based modeling of vinyl acetate uptake, metabolism, and intracellular pH changes in the rat nasal cavity. Toxicol. Appl. Pharmacol. 1997;142(2):386–400. [PubMed: 9070362]
  • Reisch MS. Top 50 chemical production rose modestly last year. HSDB; Chem. Eng. News. 1994;2009;72(15):13.
  • Rhum D. Kirk-Othmer Encyclopedia of Chemical Technology. Vol. 21. New York: John Wiley and Sons; 1970. Vinyl polymers (acetate) pp. 317–353.
  • Rumiantsev AP, Tiunova LV, Astapova CA, Kustova ZR, Lobanova IA, Ostroumova NA, Petushkov NM, Chernikova VV. Information from the Soviet Toxicology Center. Toxicometric parameters of vinyl acetate. Gig. Tr. Prof. Zabol. 1981;11:57–60.
  • Simon P, Filser JG, Bolt HM. Metabolism and pharmacokinetics of vinyl acetate. Arch. Toxicol. 1985a;57(3):191–195. [PubMed: 4062553]
  • Simon P, Ottenwalder H, Bolt HM. Vinyl acetate: DNA-binding assay in vivo. Toxicol. Lett. 1985b;27(1–3):115–120. [PubMed: 4060182]
  • Smyth HF, Carpenter CP. Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 1948;30(1):63–68. [PubMed: 18895731]
  • Smyth HF, Carpenter CP. Initial Submission: Vinyl Acetate: Single Animal Inhalation and Human Sensory Response with Cover Letter Dated 08/27/92. Carnegie-Mellon Institute; Pittsburgh, PA: 1973. [Mar. 1, 2013]. (Special Report 36–52). Submitted to EPA by Union Carbide Corporation, Danbury. CT. [online]. Available: http://yosemite​.epa.gov/oppts/epatscat8​.nsf​/ALLIDS/43FCF80E100FD26D85257084005A11D7​/$FILE/88920010238.pdf?OpenElement. EPA Document No. 88-920010328. Microfiche No. OTS 0571724.
  • Strong HA, Cresswell DG, Hopkins R. Prepared for Society of the Plastics Industry Inc., New York, by Hazleton Laboratories Europe Ltd. Harrogate, England: Nov, 1980. 1980. Investigations into the Metabolic Fate of Vinyl Acetate in the Rat and Mouse: Part 2. (Report No. 2511-51/11-14). EPA Document No. FYI-OTS-0184-0278SU. Microfiche No. OTS278.
  • ten Berge WF, Zwart A, Appelman LM. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 1986;13(3):301–309.
  • van Doorn R, Ruijten M, Van Harreveld T. Guidance for the application of odor in chemical emergency response. Version 2.1; Washington DC: Aug 29, 2002. 2002.
  • Waxweiler RJ, Alexander V, Leffingwell SS, Haring M, Lloyd JW. Mortality from brain tumor and other causes in a cohort of petrochemical workers. J. Natl. Cancer. Inst. 1983;70(1):75–81. [PubMed: 6571925]
  • Weil CS. Tables for convenient calculation of median-effective dose (LD50 or ED50) and instructions for their use. Biometrics. 1952;8:249–263.

APPENDIX A. DERIVATION OF AEGL VALUES FOR VINYL ACETATE

Derivation of AEGL-1 Values

Key study: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.
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). Therefore, 20 ppm represents a no-effect level for notable discomfort.
Time scaling:None; because irritation is considered a threshold effect and should not vary over time, the AEGL-1 value is not scaled across time. The threshold is used at the point of departure for all AEGL-1 durations.
Uncertainty factors:3 for intraspecies variability
Calculations: 
10- and 30-min, 1-, 4-, and 8-h AEGL-120 ppm ÷ 3 = 6.7 ppm

Derivation of AEGL-2 Values

Key study: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.
Toxicity end points:No-observed-effect level of 200 ppm for 6 h for serious, long-lasting histopathologic nasal lesions in rats.
Time scalingCn × t = k (defaults of n = 1 for extrapolating from shorter to longer durations and n = 3 for extrapolating from longer to shorter durations) (200 ppm)1 × 6 h = 1,200 ppm-h (200 ppm)3 × 6 h = 4.8 × 107 ppm-h
Uncertainty factors:3 for interspecies differences; 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).
3 for intraspecies variability; 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
Calculations: 
10-min AEGL-2:Set equal to the 30-min AEGL-2 value of 46 ppm, because of uncertainty in extrapolating a 6-h exposure to 10-min value (NRC 2001).
30-min AEGL-2:C3 × 0.5 h = 4.8 × 107 ppm-h
C3 = 9.6 × 107 ppm
C = 460 ppm ÷ 10 = 46 ppm
1-h AEGL-2:C3 × 1 h = 4.8 × 107 ppm-h
C3 = 4.8 × 107 ppm
C = 360 ppm ÷ 10 = 36 ppm
4-h AEGL-2:C3 × 4 h = 4.8 × 107 ppm-h
C3 = 1.2 × 107 ppm
C = 230 ppm ÷ 10 = 23 ppm
8-h AEGL-2:C1 × 8 h = 1,200 ppm-h
C1 = 150 ppm
C = 150 ppm ÷ 10 = 15 ppm

Derivation of AEGL-3 Values

Key studies: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. 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.
Toxicity end points:1,000 ppm for 6 h was nonlethal in rats and mice.
Time scaling:Cn × t = k (defaults of n = 1 for extrapolating from shorter to longer durations and n = 3 for extrapolating from longer to shorter durations) (1,000 ppm)1 × 6 h = 6,000 ppm-h (1,000 ppm)3 × 6 h = 6.0 × 109 ppm-h
Uncertainty factors:3 for interspecies differences; 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).

3 for intraspecies variability; the usual factor of 10 would result in an 8-h AEGL-3 value of 25 ppm, a concentration lower than 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
Calculations: 
10-min AEGL-3:Set equal to the 30-min AEGL-3 value of 230 ppm, because of uncertainty in extrapolating a 6-h exposure to 10-min value (NRC 2001).
30-min AEGL-3:C3 × 0.5 h = 6.0 × 109 ppm-h
C3 = 1.2 × 1010 ppm
C = 2,289 ppm ÷ 10 = 230 ppm
1-h AEGL-3:C3 × 1 h = 6.0 × 109 ppm-h
C3 = 6.0 × 109 ppm
C = 1,817 ppm ÷ 10 = 180 ppm
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

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 basis 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 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.

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.

FIGURE C-1Categoray plot of animal and human toxicity data on vinyl acetate compared with AEGL values

TABLE C-1Data Used in Category Plot for Vinyl Acetate

SourceSpeciesSexNo. ExposuresppmMinutesCategoiyComments
NAC/AEGL-1   6.710AEGL 
NAC/AEGL-1   6.730AEGL 
NAC/AEGL-1   6.760AEGL 
NAC/AEGL-1   6.7240AEGL 
NAC/AEGL-1   6.7480AEGL 
NAC/AEGL-2   4610AEGL 
NAC/AEGL-2   4630AEGL 
NAC/AEGL-2   3660AEGL 
NAC/AEGL-2   23240AEGL 
NAC/AEGL-2   15480AEGL 
NAC/AEGL-3   23010AEGL 
NAC/AEGL-3   23030AEGL 
NAC/AEGL-3   18060AEGL 
NAC/AEGL-3   110240AEGL 
NAC/AEGL-3   75480AEGL 
Smyth and Carpenter 1973Human 10.620No effects
 Human 11.320Odor detection
 Human 1421Odor detection; minimal ocular, nasal, throat irritation
 Human 1821Odor detection; minimal ocular, nasal, throat irritation
 Human 12021Odor detection; minimal ocular, nasal, throat irritation
 Human 1202401Olfactory fatigue; throat irritation
 Human 1341201Olfactory fatigue; throat irritation
 Human 172301Olfactory fatigue; throat irritation
Deese and Joyuer 1969Human 121.6101Odor detection, upper respiratory irritation
Smyth and Carpenter 1973RatBoth11,6402402Congestion
 RatBoth13,280240SLMortality (4/12); gasping. convulsions
 Rat 16,5602403Mortality (12/12)
Smyth and Carpenter 1973Mouse 14102402 
 Mouse 1820240SLMortality (1/6), labored breathing
 Mouse 11,640240SLMortality (4/6), gasping, convulsions
 Mouse 13,280240SLMortality (5/6), gasping, convulsions, ocular effects
 Mouse 16,5602403Mortality (6/6)
Smyth and Carpenter 1973Guinea pigMale11,6402401Lacrimation
 Guinea pigMale13,280240SLMortality (1/6), labored breathing, lacrimation
 Guinea pigMale16,560240SLMortality (4/6), gasping, convulsions
 Guinea pigMale113,1202403Mortality (4/6), gasping, nose nibbing, lacmnation
 RabbitMale13,280240SLMortality (3/4), red nose, cloudy eyes
 RabbitMale16,5602403Mortality (4/4); labored breathing, convulsions, cloudy eyes, bloody nose
 DogMale151.252400No effects
 DogMale1102.52400No effects
 DogMale12052401Blinking, red sclera
 DogMale18202402Lacriniation, red sclera
 DogMale11,6402401Blinking, sneezing, lacriniation, inflamed eyelids, nasal froth
 DogMale13,2802402Ocular and nasal irritation, tremors, froth from nostrils
 Dog 182021Lacriniation
Gage 1970Rat 16303601Low body weight
Bogdanffy et al. 1997Rat 150.83600No effects
 Rat 1199.63600No effects
 Rat 11,007.33602Histopathologic changes (nasal epithelium)

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

APPENDIX D. ACUTE EXPOSURE GUIDELINE LEVELS FOR VINYL ACETATE

Derivation Summary

AEGL-1. VALUES

10 min30 min1 h4 h8 h
6.7 ppm (24 mg/m3)6.7 ppm (24 mg/m3)6.7 ppm (24 mg/m3)6.7 ppm (24 mg/m3)6.7 ppm (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 (ppm)No. of subjectsDuration (min)Response None
0.692None
1.3929 immediate odor; 5 no odor at 2 min
4929 immediate odor, 3 no odor at 2 min; 1 minimal ocular, nasal, and throat irritation
8929 immediate odor; 1 no odor at 2 min; 2 minimal ocular, nasal, and throat irritation
20929 immediate odor;1 minimal ocular, nasal, and throat irritation
2032403 complete olfactory fatigue in 3–116 min;
1 persistent slight throat irritation
3431201 complete, 2 partial olfactory fatigue;
1 transient, 1 persistent throat irritation
724304 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.
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 min30 min1 h4 h8 h
46 ppm (160 mg/m3)46 ppm (160 mg/m3)36 ppm (130 mg/m3)23 ppm (81 mg/m3)15 ppm (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:
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 min30 min1 h4 h8 h
230 ppm (810 mg/m3)230 ppm (810 mg/m3)180 ppm (630 mg/m3)110 ppm (390 mg/m3)75 ppm (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.
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.
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.

Footnotes

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 scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).

Copyright 2013 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK201474

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