TOXICOLOGICAL PROFILE FOR

VINYL ACETATE

Agency for Toxic Substances and Disease Registry

U.S. Public Health Service

July 1992
ii

DISCLAIMER

The use of company or product name(s) is for identification only and

does not imply endorsement by the Agency for Toxic Substances and Disease

Registry.
iii

FOREWORD

The Superfund Amendments and Reauthorization Act (SARA) of 1986

(Public Law 99-499) extended and amended the Comprehensive Environmental

Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).

This public law directed the Agency for Toxic Substances and Disease

Registry (ATSDR) to prepare toxicological profiles for hazardous

substances which are most commonly found at facilities on the CERCLA

National Priorities List and which pose the most significant potential

threat to human health, as determined by ATSDR and the Environmental

Protection Agency (EPA). The lists of the 250 most significant

hazardous substances were published in the Federal Register on April 17,

1987; on October 20, 1988; on October 26, 1989; and on October 171 1990.

A revised list of 275 substances was published on October 17, 1991.

Section 104(i)(3) of CERCLA, as amended, directs the Administrator

of ATSDR to prepare a toxicological profile for each substance on the

lists. Each profile must include the following content:

(A) An examination, summary, and interpretation of available

toxicological information and epidemiological evaluations on the

hazardous substance in order to ascertain the levels of ignificant

human exposure for the substance and the associated acute,

subacute, and chronic health effects.

(B) A determination of whether adequate information on the health

effects of each substance is available or in the process of

development to determine levels of exposure which present a

significant risk to human health of acute, subacute, and chronic

health effects.

(C) Where appropriate, an identification of toxicological testing

needed to identify the types or levels of exposure present

significant risk of adverse health effects in humans.

This toxicological profile is prepared in accordance with

guidelines developed by ATSDR and EPA. The original guidelines were

published in the Federal Register on April 17, 1987. Each profile will

be revised and republished as necessary.

The ATSDR toxicological profile is intended to characterize

succinctly the toxicological and adverse health effects information for

the hazardous substance being described. Each profile identifies and

reviews the key literature (that has been peer-reviewed) that describes

a hazardous substance's toxicological properties. Other pertinent

literature is also presented but described in less detail than the key

studies. The profile is not intended to be an exhaustive document;

however,. more comprehensive sources of specialty information are

referenced.









1

1. PUBLIC HEALTH STATEMENT

This Statement was prepared to give you information about vinyl acetate

and to emphasize the human health effects that may result from exposure to

it. The Environmental Protection Agency (EPA) has identified 1,177 sites on

its National Priorities List (NPL). Vinyl acetate has been found at 3 of

these sites. However, we do not know how many of the 1,177 NPL sites have

been evaluated for vinyl acetate. As EPA evaluates more sites, the number of

sites at which vinyl acetate is found may change. The information is

important for you because vinyl acetate may cause harmful health effects and

because these sites are potential or actual sources of human exposure to

vinyl acetate.

When a chemical is released from a large area, such as an industrial

plant, or from a container, such as a drum or bottle, it enters the

environment as a chemical emission. This emission, which is also called a

release, does not always lead to exposure. You can be exposed to a chemical

only when you come into contact with the chemical. You may be exposed to it

in the environment by breathing, eating, or drinking substances containing

the chemical or from skin contact with it.

If you are exposed to a hazardous substance such as vinyl acetate,

several factors will determine whether harmful health effects will occur and

what the type and severity of those health effects will be. These factor

include the dose (how much), the duration (how long), the route or pathway by

which you are exposed (breathing, eating, drinking, or skin contact), the

other chemicals to which you are exposed, and your individual characteristics

such as age, sex, nutritional status, family traits, life style, and state of

health.

1.1 WHAT IS VINYL ACETATE?

Vinyl acetate is a clear, colorless liquid. It has a sweet, pleasant,

fruity smell, but the odor may be sharp and irritating to some people. You

can easily smell vinyl acetate when it is in the air at levels around 0.5 ppm

(half a part of vinyl acetate in 1 million parts of air). It readily

evaporates into air and dissolves easily in water. Vinyl acetate is flammable

and may be ignited by heat, sparks, or flames. Vinyl acetate is used to make

other industrial chemicals (such as polyvinyl acetate polymers and

ethylenevinyl acetate copolymers). These other chemicals are used mostly to

make glues for the packaging and building industries. They are also used to

make paints, textiles, and paper. The Food and Drug Administration (FDA) has

determined that vinyl acetate may be safely used as a coating or a part of a

coating that is used in plastic films for food packaging, and as a modifier

of food starch. You can find more information on the production and uses of

vinyl acetate in Chapter 4.

Vinyl acetate does not occur naturally in the environment. It enters

the environment from factories and facilities that make, use, store, or

dispose of it. When vinyl acetate is disposed of at waste sites or elsewhere
2

1. PUBLIC HEALTH STATEMENT

in the environment, it can enter the soil, air, and water. Vinyl acetate will

break down in the environment. The half-life (time it takes for l/2 of the

chemical to break down) for vinyl acetate is about 6 hours in air and 7 days

in water. We have no information on how long vinyl acetate will stay in soil.

You can find more information on the chemical and physical properties of

vinyl acetate in Chapter 3. You can find more information on the occurrence

and fate of vinyl acetate in the environment in Chapter 5.

1.2 HOW MIGHT I BE EXPOSED TO VINYL ACETATE?

Industrial facilities, accidental spills, contact with products that

contain vinyl acetate, and hazardous waste disposal sites are possible

sources of exposure to vinyl acetate. The most important way that you can be

exposed to vinyl acetate if you live around factories that make, use, store,

and dispose of vinyl acetate on site or if you live near waste sites in which

vinyl acetate or products that contain vinyl acetate have been disposed, is

by breathing air or drinking water that contain it. You can also be exposed

to vinyl acetate by skin contact with products that were made with vinyl

acetate, such as glues and paints. Exposure can also occur through ingestion

of food items that were packaged in plastic films containing vinyl acetate or

food items that contain vinyl acetate as a starch modifier. However, exposure

to vinyl acetate occurs mostly in the workplace. Workers can breathe in the

chemical when they are making it or using it to make other chemicals. Workers

can also have skin contact with vinyl acetate solutions. It has been

estimated thatabout 50,000 workers employed at about 5,000 plants are exposed

to vinyl acetate in the United States.

Background levels of vinyl acetate in water, soil, or food have not

been reported. However, vinyl acetate has been detected in water and soil

from hazardous waste sites on the NPL. It has been measured in the air in

industrial areas of Houston, Texas at a level of about 0.5 ppm.

1.3 HOW CAN VINYL ACETATE ENTER AND LEAVE MY BODY?

Vinyl acetate can enter your body through your lungs when you breathe

air containing it, through your stomach and intestines when you eat food or

drink water containing it, or through your skin. Studies in animals show that

most of the vinyl acetate taken in through the nose or mouth enters the body

almost immediately. We have no information on how fast it will enter your

body tissues once it gets on your skin. Based on information obtained from

animal studies, once vinyl acetate is taken into your body through your nose

or mouth, vinyl acetate or its breakdown products may quickly be distributed

throughout the body and removed. Studies in animals indicate that vinyl

acetate is quickly broken down. Most of the vinyl acetate taken into your

body leaves in your breath within a few days in the form of carbon dioxide.

Small amounts of the vinyl acetate taken into your body also leave in your

urine and feces as break down products. Chapter 2 has more information on how

vinyl acetate enters and leaves your body.
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1. PUBLIC HEALTH STATEMENT

1.4 HOW CAN VINYL ACETATE AFFECT MY HEALTH?

People who were exposed to vinyl acetate in air for short periods

complained of irritation to their eyes, nose, and throat. One in nine

volunteers who breathed air containing 4 ppm of vinyl acetate for 2 minutes

had throat irritation. Several volunteers exposed to 72 ppm of vinyl acetate

in air for 30 minutes reported coughing and hoarseness and eye irritation. No

health effects were found in workers who were exposed to levels around 10 ppm

of vinyl acetate in work room air for an average of 15 years of employment.

However, we do not know if health effects would occur in people exposed to

low levels for longer periods.

Exposure to high levels (around 1,000 ppm) of vinyl acetate in air for

a couple of weeks caused irritation of the eyes, nose, throat, and lungs of

laboratory animals. Vinyl acetate at levels around 200 ppm caused irritation

to the respiratory tract and nose when it was breathed by rats and mice for

up to 2 years. In this same study, damage to the lungs (congestion and

increased lung weight) was seen in rats at 200 and 600 ppm and in mice at 600

ppm vinyl acetate. Studies with animals also suggest that breathing vinyl

acetate may affect the immune system and nervous system. The extent and way

in which vinyl acetate affects these systems is not well understood.

There is no evidence that vinyl acetate causes cancer in humans. Vinyl

acetate caused tumors in the noses of rats that breathed 600 ppm for 2 years.

The International Agency for Research on Cancer (IARC) has determined that

vinyl acetate is not classifiable as to its ability to cause cancer in

humans.

We have no information on health effects in humans exposed to vinyl

acetate in contaminated food or water. Information from animals exposed to

vinyl acetate in drinking water suggest that the immune system might be

affected at very high levels.

There is no information to show that birth defects or low birth weights

occur in humans exposed to vinyl acetate. No birth defects were seen in the

offspring of animals that were exposed to vinyl acetate during their

pregnancy. Pregnant animals exposed to high levels of vinyl acetate in

drinking water or air produced offspring which were smaller in size than

normal. These effects to the offspring were seen at the same level that

caused reduced weight gain in pregnant animals. This suggests that the

smaller size of the offspring may be due to the reduced weight gain in the

pregnant animals and may not be a direct effect of vinyl acetate on the

developing animal.

People who had a mild (2%) solution of vinyl acetate put on their skin

for 48-72 hours did not show signs of skin irritation. However, vinyl acetate

has caused skin irritation and blisters in workers who accidentally spilled

it on their skin. More concentrated solutions of vinyl acetate have caused

reddening, blisters, and corrosion to the skin of rabbits. The effects of
4

1. PUBLIC HEALTH STATEMENT

continual or repeated skin contact with vinyl acetate or products that

contain vinyl acetate over a long time are not known.

Exposure to vinyl acetate in air or direct contact with vinyl acetate

solutions has caused irritation to the eyes. Several volunteers exposed to 72

ppm of vinyl acetate in air for 30 minutes reported eye irritation that

lasted up to 60 minutes after exposure. Accidental contact of the eye with

concentrated solutions of vinyl acetate has caused reddening and irritation

to the eyes of workers. Symptoms were relieved after flushing the affected

eye with water. We know of no cases in which permanent eye damage resulted

after such contact. Rabbits that had very high concentrations of vinyl

acetate put in their eyes for a short period also showed irritation and

reddening to the eyes.

You can find out more information on the health effects of vinyl

acetate in Chapter 2.

1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO

 VINYL ACETATE?

No test is currently available to measure vinyl acetate in your blood,

urine, or body tissues. Because vinyl acetate breaks down very quickly to

substances that are normally found in your body, measurements of these

breakdown products are not useful for showing whether you have been exposed

to vinyl acetate. The symptoms caused by exposure to vinyl acetate can also

occur for many other reasons. Therefore, they can not be used as proof of

vinyl acetate exposure. You can find more information in Chapters 2 and 6

about tests to find vinyl acetate in the body.

1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

 PROTECT HUMAN HEALTH?

The federal government has set standards and guidelines to protect

people from the possible health effects of vinyl acetate. EPA requires that

any company that spills more than 5,000 pounds of vinyl acetate into the

environment report the spill to the National Response Center.

To protect workers, the Occupational Safety and Health Administration

(OSHA) has set a limit of 10 ppm vinyl acetate in workroom air during an 8-

hour shift and over a 40-hour work week. The American Council of Government

Industrial Hygienists (ACGIH) also recommends that workers should not be

exposed to more than 10 ppm vinyl acetate in workroom air during an 8-hour

shift and over a 40-hour work week. OSHA has also set a short-term exposure

limit (STEL) in work room air of 20 ppm for a 15-minute exposure period. The

National Institute for Occupational Safety and Health (NIOSH) recommends that

exposure to vinyl acetate should not exceed 4 ppm in workroom air for any

15-minute exposure period. For more information on the limits and standards

for vinyl acetate exposure, see Chapter 7.
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1. PUBLIC HEALTH STATEMENT

1.7 WHERE CAN I GET MORE INFORMATION?

If you have any more questions or concerns not covered here, please

contact your state health or environmental department or:

Agency for Toxic Substances and Disease Registry

Division of Toxicology

1600 Clifton Road, E-29

Atlanta, Georgia 30333

This agency can also provide you with information on the location of

thenearest occupational and environmental health clinic. Such clinics

specialize in recognizing, evaluating, and treating illnesses that result

from exposure to hazardous substances.

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2. HEALTH EFFECTS

2.1 INTRODUCTION

The primary purpose of this chapter is to provide public health

officials, physicians, toxicologists, and other interested individuals and

groups with an overall perspective of the toxicology of vinyl acetate and a

depiction of significant exposure levels associated with various adverse

health effects. It contains descriptions and evaluations of studies and

presents levels of significant exposure for vinyl acetate based on

toxicological studies and epidemiological investigations.

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals address the needs of persons living

or working near hazardous waste sites, the information in this section is

organized first by route of exposure--inhalation, oral, and dermal--and then

by health effect--death, systemic, immunological, neurological,

developmental, reproductive, genotoxic, and carcinogenic effects. These data

are discussed in terms of three exposure periods--acute (less than 15 days),

intermediate (15-364 days), and chronic (365 days or more).

Levels of significant exposure for each route and duration are

presented in tables and illustrated in figures. The points in the figures

showing noobserved-adverse-effect levels (NOAELs) or lowest-observed-adverseeffect levels (LOAELs) reflect the actual doses (levels of exposure) used in

the studies. LOAELs have been classified into "less serious" or "serious"

effects. These distinctions are intended to help the users of the document

identify the levels of exposure at which adverse health effects start to

appear. They should also help to determine whether or not the effects vary

with dose and/or duration, and place into perspective the possible

significance of these effects to human health.

The significance of the exposure levels shown in the tables and figures

may differ depending on the user's perspective. For example, physicians

concerned with the interpretation of clinical findings in exposed persons may

be interested in levels of exposure associated with "serious" effects. Public

health officials and project managers concerned with appropriate actions to

take at hazardous waste sites may want information on levels of exposure

associated with more subtle effects in humans or animals (LOAEL) or exposure

levels below which no adverse effects (NOAEL) have been observed. Estimates

of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of

interest to health professionals and citizens alike.

The level of exposure associated with the carcinogenic effects of vinyl

acetate is presented in Table 2-l and plotted in Figure 2-l.

Estimates of exposure levels pos‘ing minimal risk to humans (MRLs) have

been made, where data were believed reliable, for the most sensitive

noncancer
8

2. HEALTH EFFECTS

effect for each exposure duration. MRLs include adjustments to reflect human

variability from laboratory animal data to humans.

Although methods have been established to derive these levels (Barnes

etal. 1988; EPA 1989), uncertainties are associated with these techniques.

Furthermore, ATSDR acknowledges additional uncertainties inherent in the

application of the procedures to derive less than lifetime MRLs. As an

example, acute inhalation MRLs may not be protective for health effects that

are delayed in development or are acquired following repeated acute insults,

such as hypersensitivity reactions, asthma, or chronic bronchitis. As these

kinds of health effects data become available and methods to assess levels of

significant human exposure improve, these MRLs will be revised.

2.2.1 Inhalation Exposure

2.2.1.1 Death

No studies were located regarding death in humans after inhalation

exposure to vinyl acetate. The following data were available on experimental

animals. The 4-hour LC50 values for vinyl acetate have been reported to be

4,650 ppm (volume/volume [v/v]) (Weil and Carpenter 1969) and 3,680 ppm

(Smyth and Carpenter 1973) in rats, 1,460 ppm in mice, 5,210 ppm in guinea

pigs, and 2,760 ppm in rabbits (Smyth and Carpenter 1973). All of these

species exhibited labored breathing and clonic convulsions prior to death

(Smyth and Carpenter 1973). Lung damage was reported to be the cause of death

in all instances.

Vinyl acetate was not lethal to rats following intermediate- or

chronic-duration exposure (Hazleton 1979c, 1980c, 198813). Survival was not

apparently affected by treatment in either rats or mice following exposure to

1,000 ppm for 4 weeks (Hazleton 1979b, 1979c), in rats following exposure to

1,000 ppm for 3 months (Hazleton 1980c), or in rats or mice exposed to 600

ppm for 104 weeks (Hazleton 1988b). However, 9 out of 20 mice exposed to

1,000 ppm of vinyl acetate for 3 months died, while only 2 out of 20 control

mice died (Hazleton 1980b). All deaths occurred during the orbital sinus

blood sampling procedure. The author suggested that exposure to 1,000 ppm may

have increased animal susceptibility to the anesthesia used (Hazleton 1980b).

The highest NOAEL and lowest LOAEL values in which death was the

endpoint and all reliable LCsO values in each study for each species and

duration category are presented in Table 2-l and plotted in Figure 2-l.

2.2.1.2 Systemic Effects

The majority of the information available on the systemic effects of

inhaled vinyl acetate was obtained from unpublished 4-week, 3-month, and

104-week studies conducted by Hazleton Laboratories, Europe. These studies

contain a number of common limitations that are summarized as follows: A










19

2. HEALTH EFFECTS

variety of respiratory lesions, characteristic of those caused by pathogens

(e.g., inflammation of the nasal turbinates and bronchial and bronchiolar

epithelium), were common to these animals. The authors of the Hazleton

studies suggested that pathogens may have acted synergistically with vinyl

acetate to produce the lesions. In addition, food and water intake were not

monitored which makes interpretation of body weight changes difficult.

In the 4-week studies on rats and mice, the low-dose group animals were

initially exposed to 50 ppm vinyl acetate. When no toxic effects were

obsenred in the animals exposed to 1,000 ppm vinyl acetate (the highest

concentration tested), the concentration to which the low-dose groups were

exposed was increased to 1,500 ppm for the remainder of the 4 weeks,

resulting in a time-weighted average concentration of 1,034 ppm for rats and

1,138 ppm for mice. In many instances, histopathological examinations were

incomplete. In spite of these limitations, the available information from the

4-week study, 3-month, and 104-week studies indicates that the primary

systemic target of vinyl acetate toxicity following inhalation exposure in

animals is the respiratory system. Other organ systems, such as the immune

system andthe nervous system, may be adversely affected by inhalation

exposure to vinyl acetate in animals, as indicated by changes in organ

weights and clinical observations. No studies were located regarding

musculoskeletal effects in humans or animals after inhalation exposure to

vinyl acetate.

The highest NOAEL and all reliable LOAEL values for each systemic

effect in each study for each species and duration category are presented in

Table 2-1 and plotted in Figure 2-1.

Respiratory Effects. Acute inhalation exposure of humans to vinyl

acetate can cause irritation of the nose and throat (Smyth and Carpenter

1973). The responses of groups of 3 to 9 human volunteers exposed to varying

concentrations of vinyl acetate for 2 minutes to 4 hours were monitored.

Exposure to 1.3 ppm for 2 minutes was not irritating to the nose, throat, -or

eyes of any of the 9 volunteers. Irritation of the mucous membranes of the

throat was reported in one out of nine subjects exposed to 4 ppm for

2 minutes, four out of four subjects exposed to 72 ppm for 30 minutes, and

one out of three subjects exposed to 20 ppm for 4 hours. Partial to complete

olfactory fatigue was also noted in all subjects exposed to 20 ppm vinyl

acetate for 4 hours, 34 ppm vinyl acetate for 2 hours, and 72 ppm vinyl

acetate for 30 minutes (Smyth and Carpenter 1973). Ten minutes after exposure

all subjects were returned to the chamber and noted that the odor was as

strong as at the start of exposure, indicating that this effect was

transient. Twenty-one male chemical operators exposed to vinyl acetate for a

mean duration of 15.2 years were compared to unexposed workers by a thorough

multiphasic screening examination that included complete physical

examinations, chest X-rays, spirometry, electrocardiograms, and analyses of

blood and urine (Deese and Joyner 1969). Air samples obtained at several
20

2. HEALTH EFFECTS

locations over a period of 1 month showed that vinyl acetate concentrations

ranged from undetectable to 49.3 ppm with a mean of 8.6 ppm. Acute exposures

to much higher levels occurred. No major differences were found between the

exposed and control groups with respect to any of the respiration parameters

studied. However, acute exposure of three volunteers to 21.6 ppm resulted in

upper respiratory tract irritation, cough and/or hoarseness (Deese and Joyner

1969).

Respiratory tract damage is characteristic of vinyl acetate exposure in

laboratory animals following acute-, intermediate-, or chronic-duration

inhalation exposure. As reported in Section 2.2.1.1, respiratory tract damage

was reported to be the cause of death in rats, mice, guinea pigs, and rabbits

acutely exposed (4 hours) to vinyl acetate (Smyth and Carpenter 1973; Weil

and Carpenter 1969). Gasping and labored breathing were usually observed in

these animals prior to death, and necropsy revealed lung congestion and

hemorrhage, froth in the trachea, and excess pleural fluid.

Effects on the respiratory tract were also seen following intermittent

exposure of rats to 2,000 ppm vinyl acetate for 15 days as evidenced by nasal

irritation (i.e., sneezing progressing with increasing severity to a nasal

discharge and bloody exudate), respiratory difficulty (i.e., as rapid shallow

breathing progressing to labored and slow breathing), and the presence of

excess macrophages in the lungs (Gage 1970). Respiratory distress was

observed in rats and mice during an intermediate-duration inhalation exposure

to 500-1,034 ppm (rats) (Hazleton 1979c) and 500-1,138 ppm (mice) (Hazleton

1979b) for 4 weeks. When exposure durations were increased to 3 months, rats

and mice exhibited evidence of respiratory distress at vinyl acetate levels

of 1,000 ppm (rats) and 200 and 1,000 ppm (mice) (Hazleton 1980b, 1980c). The

NOAEL for the 3-month study was 50 ppm for mice and 200 ppm for rats. An

intermediate inhalation MRL of 0.01 ppm was calculated based on the NOAEL of

50 ppm for respiratory effects in mice exposed to vinyl acetate for 3 months,

as described in the footnote in Table 2-l. Evidence for adverse respiratory

effects included respiratory distress; an increase in relative lung weight at

1,000 ppm in both rats and mice, presumably due to lung congestion; and

histopathological differences between the exposed and control groups. Rats

exposed to 1,000 ppm vinyl acetate exhibited a mild increase in the incidence

of focal histiocytic alveolitis. Mice exposed to 200 ppm vinyl acetate

exhibited very mild to slight focal areas of inflammation of the nasal

turbinate epithelium and mild multifocal bronchitis. Microscopic examination

of mice exposed to 1,000 ppm vinyl acetate revealed focal and diffuse

rhinitis with associated exudation and transudation into the nasal passages,

metaplasia or hyperplasia of the trachea, multifocal bronchitis,

bronchiolitis, multifocal bronchiostania, bronchial epithelial metaplasia and

hyperplasia, and occasional bronchiolar or bronchial exudation (Hazleton

1980b). These results indicate that the extrathoracic region is more

susceptible to the irritant effects of inhaled vinyl acetate in the mouse

than the lower respiratory tract since the extrathoracic effects were

observed more commonly at lower exposure concentrations.
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2. HEALTH EFFECTS

Chronic inhalation exposure (104 weeks) of rats and mice to vinyl

acetate resulted in treatment-related effects on the respiratory tract

similar to those seen with shorter-duration exposures (Hazleton 1988b).

Significantly increased relative lung weights were seen in all exposed female

rats at terminal sacrifice and in both male and female mice exposed to 600

ppm at terminal sacrifice. Histopathological changes were seen in mice and

rats exposed to 200 and 600 ppm vinyl acetate. The histopathological changes

were considered by the authors to be characteristic of chronic irritation. In

rats, olfactory epithelial atrophy was observed at 200 and 600 ppm, whereas

lung lesions consisting of exfoliation of bronchial epithelium, presence of

fibroepithelial tags, and histiocyte accumulation were observed at 600 ppm.

Mice exhibited the same changes, and in addition, were found to have focal

epithelial hyperplasia and inflammatory changes in the nasal cavity and

hyperplasia of the tracheal epithelium. Slides of the respiratory tract of

the rats and mice from the Hazleton (1988b) study were reevaluated by Deems

(1988) (mice) and Dreef-van der Meulen (1988b) (rats). In mice the most

prominent nasal change was atrophy of the olfactory epithelium at 200 ppm and

600 ppm. Epithelial hyperplasia was also observed in the trachea at 200 and

600 ppm. Changes in the lung were more prominent at higher levels while the

larynx was unaffected. In rats, the most prominent lesion was thinning of the

nasal olfactory epithelium accompanied by basal cell hyperplasia. Pulmonary

changes observed in the higher exposure group were mainly in the bronchi and

bronchioli and consisted of fibrous plaques and buds protruding into the

lumen of the bronchi and bronchioles, covered by normal bronchial epithelium

and without obvious evidence of an associated inflammatory response. Thus,

this observation supports the original authors' conclusions that the changes

in the respiratory tract of rats and mice were a result of chronic

irritation and inflammation, Taken together, the results of the acute-,

intermediate-, and chronic-duration exposure experiments, indicate that mice

may be more susceptible to the toxic effects of vinyl acetate than rats. This

conclusion is supported by the higher susceptibility to the lethal effects of

vinyl acetate seen in mice (i.e., a lower LC50 value, as discussed in Section

2.2.1.1). Furthermore, the extrathoracic region appears to be the primary

site of vinyl acetate-induced lesions at lower levels, with the pulmonary

region being affected at higher levels.

Cardiovascular Effects. Twenty-one male chemical operators exposed to

vinyl acetate for a mean of 15.2 years were compared to unexposed workers by

thorough multiphasic screening examination, that included complete physical

examinations and electrocardiograms (Deese and Joyner 1969). Air samples

obtained at several locations over a period of 1 month showed that vinyl

acetate concentrations ranged from undetectable to 49.3 ppm with a mean of

8.6 ppm. Acute exposures to much higher levels were possible. No major

differences were found between the exposed and control groups with respect to

any of the parameters studied.
22

2. HEALTH EFFECTS

With the exception of a statistically significant decrease in absolute

(but not relative) heart weight that was observed in male and female rats

exposed to 1,000 ppm vinyl acetate for 3 months (Hazleton 1980c) and 600 ppm

for 104 weeks (Hazleton 1988b) no other changes in heart weight or the

histological or macroscopic appearance of the heart or blood vessels were

found in rats or mice exposed to vinyl acetate at concentrations of up to

1,000 ppm for up to 3 months (Hazleton 1979b, 1979c, 1980b, 1980c) or 600 ppm

for 104 weeks (Hazleton 1988b).

Gastrointestinal Effects. No studies were located regarding

gastrointestinal effects in humans after inhalation exposure to vinyl

acetate.

No histological evidence of treatment-related changes in the

gastrointestinal tract was found in rats or mice exposed to vinyl acetate at

concentrations of up to 1,000 ppm for up to 3 months (Hazleton 1979b, 1979c,

1980b, 1980c) or 600 ppm for 104 weeks (Hazleton 1988b). However, a

doserelated increase in dark material was reported in the intestine of the

mice exposed to up to 1,000 ppm of vinyl acetate for 3 months (Hazleton

1980b). This material was observed at an incidence of 0/20 (control), 2/20

(50 ppm), 6/20 (200 ppm), and 6/20 (1,000 ppm). This substance was never

identified in the study, and the biological significance of its occurrence

'is not known.

Hematological Effects. Twenty-one male chemical operators exposed to

vinyl acetate for a mean of 15.2 years were compared to unexposed workers by

thorough multiphasic screening examinations including complete physical

examinations, blood pressure, blood chemistry, and urinalysis (Deese and

Joyner 1969). Air samples obtained at several locations.over a period of 1

month showed that vinyl acetate concentrations ranged from undetectable to

49.3 ppm with a mean of 8.6 ppm. Acute exposures to much higher levels were

possible. No major differences were found between the exposed and control

groups with respect to any of the hematological parameters studied.

Rats exposed to 2,000 ppm vinyl acetate for 15 days exhibited no

treatment-related hematological changes (Gage et al. 1970). No changes in

hematological parameters were found in rats or mice exposed to vinyl acetate

at concentrations of up to 1,000 ppm for 3 months (Hazleton 1980b, 198Oc). A

decrease in red blood cell count and in packed cell volume, and an increase

in prothrombin time were noted in both the rats and mice in the chronic

study. However, these changes were not concentration-related, and did not

occur consistently across exposure groups, sampling times, or sexes.

Therefore, they are most likely not treatment-related.

Hepatic Effects. Twenty-one male chemical operators exposed to vinyl

acetate for a mean of 15.2 years were compared to unexposed workers by

thorough multiphasic screening examinations including complete physical

examinations, blood pressure, blood chemistry, and urinalysis (Deese and

Joyner 1969). Air samples obtained at several locations over a period of 1
23

2. HEALTH EFFECTS

month showed that vinyl acetate concentrations ranged from undetectable to

49.3 ppm with a mean of 8.6 ppm. Acute exposures to much higher levels were

possible. No major differences were found between the exposed and control

groups with respect to selected blood parameters of liver function (e.g.,

alkaline phosphatase, cholesterol, total protein, albumin, or globulin

levels).

A significant dose-related decrease in absolute but not relative liver

weight was noted in both male and female mice exposed to vinyl acetate at

concentrations of 1,000 ppm for 3 months (Hazleton 1980b) and male rats

exposed to 1,000 ppm for 3 months (Hazleton 1980c). Similarly, male mice

exposed to 600 ppm for 104 weeks exhibited a significant decrease in absolute

liver weight, but not liver weight relative to body weight (Hazleton 1988b).

Male rats exposed to 200 ppm and 600 ppm vinyl acetate for 104 weeks showed a

significant decrease in both absolute and relative liver weights. No

histopathological changes or changes in serum enzymes indicative of hepatic

dysfunction were noted in these studies. No liver weight changes or

alterations in the macroscopic appearance of the liver were found in rats or

mice of either sex exposed to 1,034 ppm (rats) or 1,138 ppm (mice) for 4

weeks (Hazleton 1979b, 1979c).

Renal Effects. Twenty-one male chemical operators exposed to vinyl

acetate for a mean of 15.2 years were compared to unexposed workers by

thorough multiphasic screening examination, including complete physical

examinations, blood pressure, blood chemistry, and urinalysis (Deese and

Joyner 1969). Air samples obtained at several locations over a period of 1

month showed that vinyl acetate concentrations ranged from undetectable to

49.3 ppm with a mean of 8.6 ppm. Acute exposures to much higher levels were

possible. No major differences were found between the exposed and control

groups with respect to any of the urinary parameters studied.

Urine from rats exposed to 1,000 ppm vinyl acetate for 3 months was

decreased in volume and more concentrated when compared to controls (Hazleton

1980c). Reduced urine volume was also observed in rats exposed to 600 ppm of

vinyl acetate for 104 weeks (Hazleton 1988b). The authors attributed this

effect to reduced food and water intake in these animals. No treatmentrelated

macroscopic or histopathologic changes were observed in the kidneys of

these animals or of mice similarly exposed (Hazleton 1980b, 1980c, 1988b).

Furthermore, no consistent exposure-related changes in blood urea nitrogen

were observed in rats or mice exposed to vinyl acetate at concentrations of

up to 1,000 ppm for 3 months (Hazleton 1980b, 1980c) or 600 ppm for 104 weeks

(Hazleton 1988b). Decreases in blood urea nitrogen were sporadically observed

in both rats and mice in these studies, but these changes were generally

within the range of historical controls, not dose-related, and not

consistently observed across all sampling times.
24

2. HEALTH EFFECTS

Demal/Ocular Effects. The responses of human volunteers exposed to

varying concentrations of vinyl acetate for an unspecified period (less than

8 hours) were monitored (Deese and Joyner 1969). One of 5 volunteers reported

slight eye irritation at 5.7 and 6.8 ppm and all 3 volunteers exposed to

21.6 ppm complained of eye irritation that "would be intolerable over an

extended period" (Deese and Joyner 1969). In another study, four volunteers

exposed to 72 ppm vinyl acetate in air for 30 minutes reported eye irritation

that persisted for up to 60 minutes after exposure (Smyth and Carpenter

1973). These ocular effects are due to direct contact of the eye with vinyl

acetate and thus not a true systemic effect. Prolonged occupational exposure

to vinyl acetate generally does not cause eye irritation at levels below 10

ppm (Deese and Joyner 1969).

Eye irritation was noted in animals exposed to 2,000 ppm vinyl acetate

for 15 days (Gage 1970). However, this effect can be attributed to direct

contact of the eye with vinyl acetate vapor. Other dermal/ocular effects

resulting from direct contact with vinyl acetate are discussed in

Section 2.2.3, Dermal Exposure.

Other Systemic Effects. Decreases in body weight gain have been

observed in rats and mice exposed to vinyl acetate for acute, intermediate,

and chronic durations (Gage 1970; Hazleton 1979b, 1980b, 1980c, 1980d,

1988b). These effects were statistically significant and occurred at or above

the levels that caused adverse respiratory effects, which suggests that

reduction in weight gain may be secondary to the poor health of the animals

as a result of exposure to vinyl acetate. These effects proved to be

transient in animals that were chronically exposed to vinyl acetate, as

evidenced by the reversal of the body weight gain reduction during the

recovery period (Hazleton 1988b).

2.2.1.3 Immunological Effects

No studies were located regarding immunological effects in humans after

inhalation exposure to vinyl acetate.

Reductions in relative thymus and/or spleen weight were consistently

noted in rats and mice exposed to vinyl acetate for 4 weeks and 3 months at

exposure concentrations of 1,000 ppm, but no gross or histopathological

effects were noted in these organs (Hazleton 1979b, 1979c, 1980b, 1980c). In

rats chronically exposed to vinyl acetate, only males exposed to 50 or 600

ppm exhibited a decrease in relative spleen weight (Hazleton 1988b). The

biological significance of these changes is not known. They may be suggestive

of an immunosuppressive action of vinyl acetate, but the appropriate

parameters were not investigated to delineate this possibility.

The LOAEL values for spleen and thymus weight changes for each species

and duration category are presented in Table 2-l and plotted in Figure 2-l.
25

2. HEALTH EFFECTS

2.2.1.4 Neurological Effects

No studies were located regarding neurological effects in humans after

inhalation exposure to vinyl acetate.

All rats and mice exposed to at least the highest concentration of

vinyl acetate for 4 weeks, 3 months, and 104 weeks exhibited hunched posture

and ruffled fur (Hazleton 1979b, 1979c, 1980b, 1980c, 1988b). These clinical

signs occurred intermittently in the 4-week studies (Hazleton 1979b, 1979c).

In the 3-month mouse study, hunched posture and ruffled fur were observed

from days 1 through 9 in mice exposed to 200 ppm and intermittently through

day 34 in mice exposed to 1,000 ppm (Hazleton 1980b). In the 3-month rat

study, these clinical signs were consistently observed for the first 13 days

of the study and intermittently thereafter in the animals exposed to 1,000

ppm only (Hazleton 1980c). A dose-related increase in the incidence of head

tilt was also noted in some rats and mice exposed to vinyl acetate for 104

weeks (Hazleton 198813). These neurological signs were noted only

intermittently throughout the chronic studies (Hazleton 1988b). It is

possible that these neurological signs were secondary to the poor health of

the animals and may not be indicative of a primary effect of vinyl acetate on

the nervous system. No other neurological effects have been noted in animals

exposed to vinyl acetate. However, no studies have been conducted that

investigated the potential neuropharmacologic or neuropathological effects of

vinyl acetate; no special histopathological techniques were used to examine

the neurological tissues obtained from the animals in the Hazleton studies.

The LOAELs for hunched posture and ruffled fur for each species and

duration category are presented in Table 2-l and plotted in Figure 2-l.

2.2.1.5 Developmental Effects

No studies were located regarding developmental effects in humans

following inhalation exposure to vinyl acetate.

One inhalation developmental toxicity study in rats was conducted in

which pregnant animals were exposed to vinyl acetate during gestation days

6-15, and sacrificed on gestation day 20 (Hazleton 1980d). Dams exposed to

1,000 ppm exhibited a significant reduction in body weight gain of 18% during

the exposure period. This effect was transient, as body weight gain returned

to normal during the post-exposure period. Several dams in each exposure

group were found to have lung congestion at necropsy, with the highest

incidence occurring in the animals exposed to 1,000 ppm vinyl acetate.

Fetuses of dams exposed to 1,000 ppm exhibited significant growth retardation

(e.g., mean litter weight, mean fetal weight, and mean fetal crown/rump

length were significantly lower as compared to the controls). This fetal

growth retardation may be due to the marked retardation in maternal weight

gain observed, and not to a direct developmental effect of vinyl acetate on

the fetus. No embryolethality or major teratogenic effects were seen in the
26

2. HEALTH EFFECTS

fetuses of the exposed rats. A significant increase in the incidence of minor

skeletal fetal defects/variants was observed in the fetuses of dams exposed

to 1,000 ppm vinyl acetate. This was mainly variant retarded sternebral

ossification, which can be a consequence of the small fetal size and not a

direct effect of vinyl acetate. Therefore, under the conditions of this

study, the only adverse developmental effect elicited by vinyl acetate was

marked growth retardation observed in the fetuses of dams exposed to 1,000

wm . This effect may have been secondary to the maternal toxicity observed.

The LOAEL for reduced fetal growth is presented in Table 2-1 and

plotted in Figure 2-1.

2.2.1.6 Reproductive Effects

No studies were located regarding reproductive effects in humans after

inhalation exposure to vinyl acetate.

No gross or histopathological changes in the reproductive organs were

observed in the dams or their offspring when rats were exposed to 1,000 ppm

vinyl acetate on gestation days 6-15 (Hazleton 1980d). Similarly, no gross or

histopathological changes in the reproductive organs were observed in male or

female mice exposed to 1,000 ppm vinyl acetate for 3 months (Hazleton 1980b).

The NOAEL for reproductive effects is presented in Table 2-1 and

plotted in Figure 2-1.

2.2.1.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans after

inhalation exposure to vinyl acetate. Vinyl acetate failed to produce

specific DNA adducts in the liver of rats exposed to 1,200-1,800 ppm for 90

minutes (Simon et al. 1985b). Micronuclei were evaluated in bone marrow

smears taken from all rats and mice exposed to up to 1,000 ppm vinyl acetate

6 hours/day, 5 days/week for 4 weeks and 3 months, and no exposure related

effects on the incidence of micronuclei were noted (Hazleton 197913, 1979c,

1980b, 1980c).

Other genotoxicity studies are discussed in Section 2.4.

2.2.1.8 Cancer

No studies were located regarding cancer in humans after inhalation

exposure to vinyl acetate.

Rats chronically exposed to 600 ppm vinyl acetate were found to have an

increased incidence of nasal cavity tumors as compared to control animals

(Hazleton 1988b). Slides of the respiratory tract of the rats from the
27

2. HEALTH EFFECTS

Hazleton (1988b) study were reevaluated by Dreef-van der Meulen (1988b). A

total of 12 nasal cavity tumors were found in the exposed rats; 5 were benign

and 7 were malignant (Dreef-van der Meulen 1988b). These 5 benign papillomas

were of various cell types and location in the nose and were seen in 1

200 ppm-exposed male and 4 600 ppm-exposed males. The 7 malignant tumors were

found in 3 males and 4 females exposed to 600 ppm vinyl acetate. The

malignant tumors were squamous carcinomas with one carcinoma in situ that

showed a widespread distribution from anterior to posterior nasal cavity. No

nasal cavity tumors were observed in control rats or those exposed to 50 ppm

vinyl acetate. The statistical significance of tumor incidence in the nasal

cavity was not reported. Effects to the larynx of rats was confined to a

single squamous carcinoma in a female rat exposed to 600 ppm. No tumors were

seen in the lungs of rats.

Slides of the respiratory tract of mice chronically exposed to vinyl

acetate from the Hazleton (1988b) study were reevaluated by Beems (1988b). No

tumors were observed in the nasal cavity, larynx, or trachea of the exposed

or control mice (Hazleton 1988b). Pathology of the lungs of male mice exposed

to 600 ppm vinyl acetate revealed one squamous carcinoma in the major

bronchus and one squamous nodule in a terminal airway. No squamous cell

carcinomas were seen in animals of either sex from the control group.

Bronchiolealveolar adenomas and carcinomas were found in the lungs of both

the exposed and control mice at comparable incidences, indicating that their

occurrence was not a result of exposure to vinyl acetate.

The cancer effect level for rats is presented in Table 2-l and plotted

in Figure 2-l.

2.2.2 Oral Exposure

2.2.2.1 Death

No studies were located regarding death in humans after oral exposure

to vinyl acetate. Lethality data are available from studies in animals (see

Table 2-2 and Figure 2-2). The oral LD50 for vinyl acetate has been reported

to be 2,920 mg/kg in rats (Smyth and Carpenter 1948) and 1,613 mg/kg in mice

(Goeva 1966). The cause of death was not specified for either species.

Vinyl acetate was not lethal to rats or mice administered drinking

water that contained up to 5,000 ppm (equivalent to 684-950 mg/kg/day) for up

to 3 months (Hazleton 1979d, 1980e, 1980f) or 235 mg/kg/day (rats) following

in utero exposure (Hazleton 1988a).

2.2.2.2 Systemic Effects

No studies were located regarding systemic effects in humans following

oral exposure to vinyl acetate.








36

2. HEALTH EFFECTS

The majority of the information available on the systemic effects of

oral exposure to vinyl acetate was obtained from unpublished 4-week, 3-month,

and 104-week studies conducted by Hazleton Laboratories, Europe. In these

studies Sprague-Dawley rats and CD-1 mice were exposed to vinyl acetate in

drinking water. The vinyl acetate used was 99.9% pure. Because of the

volatility and instability of vinyl acetate in water, the drinking water

solutions were made fresh daily and overformulated by 5% to allow for

decreases in drinking water concentration and to assure that the animals were

receiving the target dose. The levels of vinyl acetate in the air of the room

housing both control and exposed animals in the 104-week study was measured

and found to be less than 1 ppm. These studies contained some common

limitations that are summarized as follows: In many cases only a small number

of the control and treated animals were examined histologically. In addition,

several findings such as an increased incidence of lymphoid hyperplasia of

nasal turbinates, and chronic dacryoadenitis of the harderian glands were

dismissed as having resulted from the method of histologic sectioning.

However, it is likely that these effects, that were seen in both control and

treated animals, may indicate that these animals were in poor physical

condition. Reduced body weight gain was often observed in intermediate- and

chronic-duration drinking water studies in animals. However, these changes

are generally attributed to reduced water intake because of unpalatability.

No studies were located regarding musculoskeletal effects in animals

after oral exposure to vinyl acetate.

The highest NOAEL and all reliable LOAEL values for each systemic

effect in each study for each species and duration category are presented in

Table 2-2 and plotted in Figure 2-2.

Respiratory Effects. No changes in lung weight or histological or

macroscopic appearance of the lung were found in rats or mice administered

vinyl acetate in the drinking water that provided maximum doses ranging from

684 mg/kg/day to 950 mg/kg/day for up to 3 months (Hazleton 1979d, 1980e,

1980f), or 235 mg/kg/day (rats) for 104 weeks following in utero exposure

(Hazleton 1988a). Lymphoid hyperplasia of the submucosa of the paranasal

sinuses was reported for mice that received doses of 950 mg/kg/day via the

drinking water for 3-months. However, the authors attributed this to

variation in histologic sectioning. Since this effect was not observed in the

104 week in utero exposure study, it is not clear if it was treatmentrelated, and its toxicological significance is not known.

Cardiovascular Effects. No changes in heart weight or histological and

macroscopic appearance of the heart or blood vessels were found in rats or

mice administered vinyl acetate in the drinking water that provided doses

ranging from 684 mg/kg/day to 950 mg/kg/day for up to 3 months (Hazleton
37

2. HEALTH EFFECTS

1979d, 1980e, 1980f) or 235 mg/kg/day (rats) for 104 weeks following in utero

exposure (Hazleton 1988a).

Gastrointestinal Effects. No changes in histological and macroscopic

appearance of the gastrointestinal organs were found in rats or mice

administered vinyl acetate in the drinking water that provided doses ranging

from 684 mg/kg/day to 950 mg/kg/day for up to 3 months (Hazleton 1979d,

1980e, 1980f) or 235 mg/kg/day (rats) for 104 weeks following in utero

exposure (Hazleton 1988a). However, mice administered vinyl acetate for 4

weeks exhibited a dose-related increase in the incidence of dark-colored

gastrointestinal contents (Hazleton 1979d). This effect was observed in

control and exposed groups at an incidence of 1/10 (control), l/10

(9.5-mg/kg/day), 1/10 (28.5-mg/kg/day), 3/10 (190-mg/kg/day), and 4/10 (950-

mg/k/day). A similar effect was observed in mice exposed to 1,000 ppm of

vinyl acetate via inhalation for 3 months (Hazleton 1980b) (see Section

2.2.1.2). The identity of the dark-colored material was not determined in

either study. This effect was not accompanied by any histopathological

evidence of irritation, so the biological significance of this observation is

not known.

Hematological Effects. No changes in any of the hematological

parameters studied were found in rats administered vinyl acetate in the

drinking water that provided doses ranging from 684 mg/kg/day to 950

mg/kg/day for up to 3 months (Hazleton 1979d, 1980e, 1980f) or 235 mg/kg/day

(rats) for 104 weeks following in utero exposure (Hazleton 1988a).

Hepatic Effects. Although changes in absolute, and in some instances,

relative liver weight occurred in many animals exposed to vinyl acetate in

the drinking water, these changes were usually unaccompanied by

histopathological changes, (Hazleton 1979d, 1980f). Histopathological

evaluation of the rats that received 684-810 mg/kg/day vinyl acetate in the

drinking water for 3 months revealed pericholangitis and granulomatous

hepatitis, but no weight changes were evident (Hazleton 1980f). The

pericholangitis was observed at an incidence of 3/10 (control male), 10/10

(684-mg/kg/day male), 6/10 (control female), and 7/10 (810-mg/kg/day female).

The incidence of hepatitis was 0/10 (control male), 2/10 (684-mg/kg/day

male), 2/10 (control female), and 2/10 (810-mg/kg/day female). Although the

incidence of pericholangitis and granulomatous hepatitis appears to be

somewhat increased in treated rats, none of these lesions were observed in

the 104-week study, suggesting that the lesions may not be treatment related.

No changes in liver weight or histological and macroscopic appearance of the

liver were found in mice administered vinyl acetate in the drinking water at

doses of 950 mg/kg/day for 3 months (Hazleton 1980e) or in rats that received

235 mg/kg/day vinyl acetate in the drinking water for 104 weeks following in

utero exposure (Hazleton 1988a).
38

2. HEALTH EFFECTS

Renal Effects. No changes in the macroscopic appearance of the kidneys

or in urinalysis parameters were found in rats administered vinyl acetate in

the drinking water at doses of up to 700 mg/kg/day for 4 weeks (Hazleton

1979d). More concentrated and darker colored urine was observed in female

rats receiving a dose of 810 mg/kg/day vinyl acetate in the drinking water

for 3 months (Hazleton 1980f). This effect was attributed to reduced water

intake due to the unpalatability of the drinking water solution. An increase

in absolute kidney weight was found in male mice administered vinyl acetate

in the drinking water at dosages of 28.5 mg/kg/day for 4 weeks (Hazleton

1979d). A decrease in absolute, but not kidney weight relative to body weight

was found in male rats administered vinyl acetate in drinking water at

dosages of 684 mg/kg/day for 3 months (Hazleton 1980f). An increase in kidney

weight relative to body weight was observed in male rats administered dosages

of 235 mg/kg/day vinyl acetate in the drinking water for 104 weeks following

in utero exposure (Hazleton 1988a). Male mice that received 190 mg/kg/day of

vinyl acetate in drinking water for 3 months showed a statistically

significant increase in relative kidney weight, but this effect was not seen

in male mice that received higher doses of vinyl acetate or in any of the

treated female mice in this study (Hazleton 1980e). Furthermore, no

significant gross or histopathological changes were observed in the kidneys

in any of these studies. The biological significance of a change in organ

weight, especially when the change is not consistent in direction across

studies, does not occur consistently in the same species and/or sex, is not

always dose-dependent, and that occurs in the absence of histopathological

changes is difficult to ascertain.

Other Systemic Effects. Dose-related reductions in body weight gains

were observed in rats and mice administered vinyl acetate in drinking water

that provided doses up to 950 mg/kg/day (male mice) for 4 weeks (Hazleton

1979d) and 235 mg/kg/day (rats) for 104 weeks following in utero exposure

(Hazleton 1988a). These growth retardation effects were generally accompanied

by reduced water consumption and may therefore be due to unpalatability of

the drinking water.

Changes in the Harderian gland (chronic dacryoadenitis) were observed

in mice administered 950 mg/kg/day vinyl acetate in the drinking water for

3 months (Hazleton 1980e). The authors attributed this effect to variation in

histologic sectioning, however, the toxicological significance of this

finding is not known. In toxicokinetic studies, the Harderian gland was found

to have the highest concentration of radiolabel in the body following the

administration of radiolabeled vinyl acetate (see Section 2.3.2). This high

concentration of radiolabel may be associated with the chronic dacryoadenitis

seen in mice. Since Harderian glands are not present in humans, the relevance

of this finding to human health is not known.
39

2. HEALTH EFFECTS

2.2.2.3 Immunological Effects

No studies were located regarding immunological effects in humans after

oral exposure to vinyl acetate.

As was observed following inhalation exposure (see Section 2.2.1.3),

changes in thymus and/or spleen weight were consistently noted in rats and

mice exposed to vinyl acetate in the drinking water (Hazleton 1979d, 1980e,

1988a). However, these changes were not always dose-related. For example, in

the 4-week mouse study, a significant decrease in absolute and relative

thymus weight was observed in all mice that received only the highest dose of

vinyl acetate (950 mg/kg/day) (Hazleton 1979d). In the 3-month mouse study,

absolute and relative spleen weights were significantly reduced in the lowand

mid-dose females (38 mg/kg/day and 190 mg/kg/day) and absolute spleen

weight was reduced in the mid-dose males, but no changes in spleen weight

were observed in animals of either sex administered 950 mg/kg/day vinyl

acetate (Hazleton 1980e). However, thymus weights relative to body weights

were significantly decreased in male mice that received 950 "g/kg/day vinyl

acetate for 3 months. In the 104-week study, only a decrease in absolute

spleen weight was noted in the low- and high-dose males (Hazleton 1988a).

Extramedullary hematopoiesis was observed in both control mice and mice

receiving 950 mg/kg/day vinyl acetate in the 3-month study (Hazleton 1980e),

which is suggestive of poor physical condition in the animal colony rather

than an immunotoxic effect in the treated animals. In addition, the incidence

of grossly-detectable splenomegaly was not increased in the high-dose

animals. The decrease in spleen and thymus weight relative to body weight may

be suggestive of an immunosuppressive action of vinyl acetate, but the

appropriate parameters were not investigated to delineate this possibility.

No other studies have provided evidence that vinyl acetate is immunotoxic.

The highest NOAEL values and all reliable LOAEL values for

immunological effects in each study for rats and mice in each duration

category are presented in Table 2-2 and plotted in Figure 2-2.

2.2.2.4 Neurological Effects

No studies were located regarding neurological effects in humans after

oral exposure to vinyl acetate.

No treatment-related clinical signs of neurotoxicity were observed in

rats or mice administered vinyl acetate in the drinking water that provided

doses ranging from 684 mg/kg/day to 950 mg/kg/day for 3 months (Hazleton

1979d, 1980e, 1980f) and 235 mg/kg/day (rats) for 104 weeks following in

utero exposure (Hazleton 1988a). However, despite a decrease in relative

brain weight observed in males administered 60 mg/kg/day or 235 mg/kg/day

vinyl acetate in the drinking water for 104 weeks following in utero exposure

(Hazleton 1988a), no macroscopic or histopathological evidence of

neurotoxicity was found in any of the studies described above.
40

2. HEALTH EFFECTS

The highest NOAEL values for neurological effects in each study for

rats in each duration category are presented in Table 2-2 and plotted in

Figure 2-2.

2.2.2.5 Developmental Effects

No studies were located regarding developmental effects in humans after

oral exposure to vinyl acetate.

Administration of up to 5,000 ppm (equivalent to a mean of

477 mg/kg/day, based on authors' calculations of water intake) vinyl acetate

in the drinking water of pregnant rats on days 6-15 of gestation failed to

elicit any treatment-related effects on reproductive parameters, fetal

growth, or development (Hazleton 1980d). Slight reductions in body weight

gain were seen in the dams administered 477 mg/kg/day at initiation of

treatment, but mean body weight of this group was similar to the control

group for the remainder of the study. This initial growth retardation in dams

accompanied decreases in food and water consumption. No treatment-related

gross or histopathological changes were observed in the dams. No effects of

treatment were seen on any of the fetal parameters measured (e.g., weight,

crown/rump length, and incidence of visceral or skeletal defects). In this

study, vinyl acetate was not a developmental toxicant in rats. However, a

statistically significant reduction in F1 pup weight was observed in a twogeneration reproductive toxicity study in which rats received 5,000 ppm vinyl

acetate in the drinking water (equivalent to 431-763 mg/kg/day, based on the

authors' calculation of test article consumption) prior to mating, throughout

gestation and lactation, and into adulthood (Hazleton 1987). This effect may

be attributed to the slight growth retardation observed in the F0 dams

administered 431 mg/kg/day vinyl acetate, and thus is most likely not a

direct toxic effect of vinyl acetate on the fetus. The F, females exhibited

slight (nonsignificant) decreases in body weight gain during the gestation

period, but this growth reduction achieved statistical significance during

the lactation period. However, a significant reduction in water intake was

observed in the F0 females during the pre-mating period, gestation, and

lactation which could have also contributed to the reduced F1 pup weight. No

other developmental effects were observed in any treatment group.

The NOAEL values and one LOAEL value for developmental effects in rats

are presented in Table 2-2 and plotted in Figure 2-2.

2.2.2.6 Reproductive Effects

No studies were located regarding reproductive effects in humans after

oral exposure to vinyl acetate.

Although decreased relative testes weight was observed in male mice

administered 38 mg/kg/day vinyl acetate in the drinking water for 3 months,

this effect was not seen at higher doses and no gross or histopathological
41

2. HEALTH EFFECTS

changes were observed in the testes of these animals (Hazleton 1980e).

Furthermore, no organ weight, gross, or histopathological changes were

observed in male or female reproductive organs of rats or mice administered

vinyl acetate in the drinking water at dosages of up to 950 mg/kg/day for 3

months (Hazleton 1980e, 1980f) or in rats receiving 235 mg/kg/day vinyl

acetate in the drinking water for 104 weeks following in utero exposure

(Hazleton 1988a). A marginal reduction in the number of pregnancies was

observed in the F, female rats administered 5,000 ppm vinyl acetate in the

drinking water (equivalent to 431-763 mg/kg/day) in a two-generation study

(19/24 treated animals became pregnant as opposed to 24/25 of the controls)

(Hazleton 1987). However, this difference was not statistically significant

and the pregnancy incidence in the treated animals was within the reported

range of historical controls. No other effects on reproductive performance

were observed in this study.

The NOAEL values for reproductive effects in rats are presented in

Table 2-2 and plotted in Figure 2-2.

2.2.2.7 Genotoxic Effects

No studies were found regarding genotoxic effects in humans after oral

exposure to vinyl acetate.

Vinyl acetate administered by gavage to rats (concentration not

specified) did not result in DNA-adduct formation in the liver (Simon et al.

1985b). Micronuclei were evaluated in bone marrow smears taken from rats and

mice exposed to vinyl acetate in drinking water for 4 weeks (Hazleton 1979d).

The group mean incidence of erythrocytes containing micronuclei was increased

as compared to the controls in the mice receiving 950 mg/kg/day vinyl

acetate. However, all micronuclei counts were within the expected range of

spontaneous occurrence. No treatment-related effects on the incidence of

micronuclei were seen in the rats exposed to vinyl acetate.

Other genotoxicity studies are discussed in Section 2.4.

2.2.2.8 Cancer

No studies were located regarding cancer in humans after oral exposure

to vinyl acetate.

Oral administration of 400 mg/kg/day of vinyl acetate to rats for

3 weeks did not result in an increase in preneoplastic enzyme altered foci

(gamma-glutamyltranspeptidase-positive or adenosine 5'-triphosphatasenegative foci) in the liver (Laib and Bolt 1986b).

A statistically significant carcinogenic effect of vinyl acetate was

observed in a screening study in which this chemical was administered in the

drinking water of Fischer-344 rats at doses of 57 mg/kg/day and 143 mg/kg/day
42

2. HEALTH EFFECTS

(females) and 36 mg/kg/day and 89 mg/kg/day (males) 5 days/week for 100 weeks

(Lijinsky and Reuber 1983; NCI 1982a). Tumor incidences that were

significantly increased in the treated animals as compared to the controls

included neoplastic nodules of the liver in both sexes, adenocarcinomas of

the uterus in the females, and C-cell adenomas or carcinomas of the thyroid

in both sexes, but predominantly in the females. The uterine carcinomas were

large, malignant invasive neoplasms, that are extremely unusual, which

supports the evidence that vinyl acetate is carcinogenic. Limitations

associated with this study that may underestimate the carcinogenic risk of

vinyl acetate included the possibility that the maximum tolerated dose of

vinyl acetate was not achieved, the animals received less than the calculated

doses due ,to the instability of vinyl acetate in drinking water, and use of

a small sample size (20 animals/sex). Other limitations include the fact that

only two dose levels were used and the vinyl acetate used was commercial

grade of undetermined purity. Various inhibitors (i.e., p-hydroquinone,

benzoquinones, nitrobenzenes, diphenyl, toluenes, anthracene, phenanthrene,

naphthalene, see Section 4.1) are added to commercial formulations of vinyl

acetate at varying concentrations to prevent polymerization (Daniels 1983;

Mannsville 1988). It is not known what effects, if any, these inhibitors may

have had in this study. Drinking water solutions for 5 consecutive day

exposures were made up once a week. sufficient solutions for 3 days was

dispensed in feeding bottles, while the remainder was stored in the

refrigerator and dispensed on day 4. The authors calculated that the vinyl

acetate in solution decomposed at an average rate of 8.5% per day at room

temperature, thus resulting in a substantial loss over the 5 day exposure

period. Furthermore, because vinyl acetate hydrolyses to acetaldehyde, the

exposure in this experiment was not only to vinyl acetate, but to both vinyl

acetate and acetaldehyde. Another factor compromising the validity of this

study is that the animals were housed 4 per cage and given 80 mL of vinyl

acetate solution per day. The possibility exists that the more aggressive

animals received more test solution than their less aggressive cagemates. In

addition, the animals received tap water ad libitum on the weekends. The

stress imposed on the animals by restricting their water intake during the

week and providing water ad libitum on the weekends may be a confounding

factor in the study. Lijinsky and Reuber (1983) concluded that the study

needed to be repeated with larger numbers of animals per group, higher dose

levels, and vinyl acetate solutions that are prepared fresh daily before

definitive conclusions regarding the carcinogenicity of vinyl acetate

following oral exposure can be made.

In a later study, Sprague-Dawley rats that received up to 235 mg/kg/day

vinyl acetate (99.9% pure) in their drinking water for 104 weeks following in

utero exposure developed tumors, but they were not considered by the authors

to be treatment-related, since they occurred at a similar incidence in the

high-dose animals as in the controls, and were commonly occurring tumors in

aging Sprague-Dawley rats (Hazleton 1988a). Two squamous cell carcinomas of

the oral mucosa were observed in the treated animals, but the incidence was

not statistically significant, and the study authors considered them to be a
43

2. HEALTH EFFECTS

result of tooth-related problems (Hazleton 1988b). Therefore, this study

provides no evidence for the carcinogenicity of vinyl acetate following

exposure in the drinking water. The negative data obtained from this study

should be given more weight than the positive data obtained from the Lijinsky

and Reuber (1983; NCI 1982) screening study because many of the limitations

associated with the earlier study were remedied in the Hazleton (1988a)

study. For example, in the Hazleton (1988a) study, more animals per group

were used (90 vs. 20), and a higher dose was used (5,000 ppm vs. 2,500 ppm,

or 235 mg/kg/day vs. 89-143 mg/kg/day). Furthermore, the animals were exposed

beginning in utero, resulting in exposure for a greater period of their lives

as well as exposure to effectively higher doses (on a mg/kg basis) in the

young weanlings as compared to the adults. Finally, the drinking water

solutions were prepared daily in the Hazleton (1988b) study, eliminating the

problem of stability of the test formulation. Hydroquinone was present in the

vinyl acetate at a concentration of ≤1 ppm. However, two different strains

of rat were used in the Lijinsky and Reuber (1983) and Hazleton (1988b)

studies which may have contributed to the difference in results obtained.

2.2.3 Dermal Exposure

2.2.3.1 Death

No studies were located regarding death in humans after dermal exposure

to vinyl acetate. The dermal LDsO in rabbits for a 24-hour application of

vinyl acetate has been reported to be 8 mL/kg (undiluted vinyl acetate) (Weil

and Carpenter 1969) and 2.5 mL/kg (undiluted vinyl acetate) (Smyth and

Carpenter 1948). Death was preceded by convulsions, and necropsy revealed

congestion of the lungs and liver, mottled spleen and kidney, and prominent

liver acini (Weil and Carpenter 1969). The LD50 values for rabbits are

presented in Table 2-3.

2.2.3.2 Systemic Effects

No studies were located in humans or animals regarding respiratory,

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, or

renal effects in humans or animals after dermal exposure to vinyl acetate.

Dermal/Ocular Effects. No irritation was observed when 11 volunteer

paperhangers had a 2% vinyl acetate solution applied to their skin for 48 or

72 hours in a patch test (Tanaka and Lucas 1984). However, occupational

experience has shown that some workers may react to dermal contact with vinyl

acetate with blister formation, particularly on the thin skin of the finger

web and the underside of the wrist, and that continued contact, such as that

afforded by clothing wet with the chemical might result in severe irritation

or blistering of the skin (Union Carbide 1958).

45

2. HEALTH EFFECTS

The responses of human volunteers exposed to varying concentrations of

vinyl acetate in the air for an unspecified period (less than 8 hours) were

monitored (Deese and Joyner 1969). One of 5 volunteers reported slight eye

irritation at 5.7 and 6.8 ppm and all 3 volunteers exposed to 21.6 ppm

complained of eye irritation that "would be intolerable over an extended

period" (Deese and Joyner 1969). In another study, four volunteers exposed to

72 ppm vinyl acetate in air for 30 minutes reported eye irritation that

persisted for up to 60 minutes after exposure (Smyth and Carpenter 1973).

These ocular effects are due to direct contact of the eye with vinyl acetate.

Prolonged occupational exposure to vinyl acetate generally does not cause eye

irritation at levels below 10 ppm (Deese and Joyner 1969).

Undiluted vinyl acetate was reported to be nonirritating when 0.1 mL

was applied to the clipped intact skin of rabbits (Weil and Carpenter 1969).

However, erythema, edema, and necrosis of the skin was observed when near

lethal levels of vinyl acetate (8.0 mL/kg of undiluted chemical) were applied

to the skin of rabbits (Weil and Carpenter 1969). Slight edema of both intact

and abraded skin was observed in rabbits following application of 0.5 mL of

undiluted vinyl acetate (Industrial Biotest 1972). Based on these results,

the authors classified vinyl acetate as noncorrosive to the skin. Application

of vinyl acetate to the conjunctival sac of rabbits caused only a "trace" of

eye irritation (Weil and Carpenter 1969). Eye irritation was also noted in

animals exposed to 2,000 ppm vinyl acetate in air for 15 days (Gage 1970).

NOAEL and LOAEL values for skin and eye irritation are presented in

Table 2-3.

No studies were located regarding the following health effects in

humans

or animals after dermal exposure to vinyl acetate:

2.2.3.3 Immunological Effects

2.2.3.4 Neurological Effects

2.2.3.5 Developmenfal Effects

2.2.3.6 Reproductive Effects

2.2.3.7 Genotoxic Effects

Genotoxicity studies are discussed in Section 2.4.

2.2.3.8 Cancer

2.3 TOXICOKINETICS

2.3.1 Absorption

2.3.1.1 Inhalation Exposure

No studies were located regarding the absorption of vinyl acetate in

humans after inhalation exposure.
46

2. HEALTH EFFECTS

Studies in rats indicate that vinyl acetate is rapidly and effectively

absorbed via this route (Hazleton 1979a). Following administration of

radiolabeled vinyl acetate ([vinyl-1,2-14C]-VA, or 14C-VA) in the air at a

concentration of 1,000 ppm for 6 hours, almost half of the radioactivity was

eliminated via expired air within 6 hours after exposure. The exact dose of

vinyl acetate administered by inhalation, however, could not be determined

because some of the radioactivity was exhaled during the 6-hour exposure

period. A follow-up study using rats exposed to 750 ppm 14C-VA for 6 hours

supported these results and showed that the major portion of the

radioactivity was eliminated in expired air primarily as CO2 during the first

24 hours (Hazleton 1980a).

2.3.1.2 Oral Exposure

No studies were located regarding the absorption of vinyl acetate in

humans following oral exposure.

Animal studies indicate that vinyl acetate is quickly and effectively

absorbed via this route (Hazleton 1979a, 1980a). Following gavage

administration of 1 mL of a 5,000 ppm aqueous solution of 14C-VA, high

concentrations of the radiolabel were found to be distributed throughout the

body, and the majority was eliminated in expired air primarily as CO2 during

the first 6 hours after dosing (Hazleton 1979a). Similarly, 65% of the

radioactivity of six 1 mL doses of a 10,000 ppm solution orally administered

by gavage to rats in a follow-up study was eliminated during both the 6-hour

dosing period and 96-hour collection period (Hazleton 1980a). In mice, 1 mL

of a 5,000 ppm 14C-VA aqueous solution was quickly absorbed as shown by the

wide distribution of radiolabel in tissues throughout the body 1 hour after

oral administration (Hazleton 1980a).

2.3.1.3 Dermal Exposure

No studies were located regarding the absorption of vinyl acetate in

humans following dermal exposure.

Dermal penetration of vinyl acetate in rabbits was indirectly

demonstrated through the observation of mortality in animals that were

dermally treated with 2.5 mL/kg (Smyth and Carpenter 1948) and 8.0 mL/kg

(Weil and Carpenter 1969). No further details regarding absorption are

available.

2.3.2 Distribution

2.3.2.1 Inhalation Exposure

No studies were located regarding the distribution of vinyl acetate in

humans following inhalation exposure.
47

2. HEALTH EFFECTS

Studies in male and female rats show that radioactivity is immediately

and widely distributed throughout the body after inhalation exposure to

1,000 ppm 14C-VA (Hazleton 1979a). The salivary glands, lacrimal glands,

Harderian glands, gastrointestinal mucosa, nasoturbinates, kidneys, and

certain portions of the larynges had the highest concentrations of the

radiolabel. The brain, spinal cord, liver, fat, and bone marrow also had

readily detectable levels of radioactivity. Low levels in the heart, blood,

testes, and skeletal muscle were also observed. Whole-body autoradiographs

obtained at 1 and 6 hours after exposure show a general decrease in the

radioactivity with increased time, Seventy-two hours after exposure,

radioactivity was still found in the brain, spinal cord, Harderian glands,

maxillary sinuses, adrenal glands, and kidneys. Approximately 19% of the

total radioactivity recovered was found in the carcass 96 hours after

exposure.

In a follow-up study 16 rats were exposed to air containing 750 ppm 14C-VA for 6 hours (Hazleton 1980a). The tissue distribution of radioactivity

is given in Table 2-4. As can be seen in Table 2-4, the highest

concentrations were observed in the Harderian gland, followed by the ileum,

submaxillary salivary gland, and the contents of the gastrointestinal tract.

Radioactivity was also found at significant levels in the liver, kidney,

lung, brain, stomach, colon, and ovaries. Differences between the sexes in

the distribution of radioactivity was seen in the gonads; females had higher

concentrations in the ovaries than did males in the testes. Although the

total radioactivity decreased with time, no major differences in the pattern

were found at 1, 6, and 72 hours after exposure. Relative tissue

concentrations also tended to be higher in animals exposed via inhalation

compared with oral exposure. This was particularly true in the lung and

brain.

2.3.2.2 Oral Exposure

No studies were located regarding the distribution of vinyl acetate in

humans following oral exposure.

In animals, the distribution of radioactivity following oral exposure

to 14C-VA has been studied using male and female rats and mice (Hazleton

1979a, 1980a). Similar distribution patterns were observed in rats

administered either 6 hourly 1-mL doses of an aqueous solution containing

10,000 ppm vinyl acetate (equivalent to 237 mg/kg) by gavage (Hazleton 1980a)

or one dose containing 1 mL of a 5,000 ppm vinyl acetate solution (equivalent

to 23.4 mg/kg) (Hazleton 1979a). One hour following administration of either

dose, the radioactivity was found to be widely distributed with the highest

concentrations found in the Harderian gland and salivary glands. High levels

of radioactivity were also found in the liver, kidney, heart, and

gastrointestinal tract. As with inhalation exposure, the level of

radioactivity decreased with time, and there were no major differences in the

distribution pattern at 6 and 72 hours after oral exposure. A mean of 7.1% of

49

2. HEALTH EFFECTS

the administered radioactivity was present in the carcass 96 hours after

exposure. As with inhalation exposure, a sex difference in the distribution

of radioactivity was seen in the gonads; females had higher concentration in

the ovaries than did males in the testes. A similar distribution pattern was

seen in mice of both sexes administered a single oral dose of 5,000 ppm of

14C-VA as an aqueous solution (Hazleton 1980a). In this study, the highest

concentrations of radioactivity were found in Harderian glands, salivary and

lingual glands, gastrointestinal mucosa, liver, and brown fat. The high

concentration of 14C found in the Harderian gland may be associated with the

chronic dacryoadenitis seen in mice administered vinyl acetate in drinking

water for 3 months (Hazleton 1980e, see Section 2.2.2.2). Low levels were

found in blood muscle, fat, and testes. As with the rats, the distribution

pattern was unchanged 6 and 72 hours after dosing, although the levels were

reduced.

2.3.2.3 Dermal Exposure

No studies were located regarding the distribution of vinyl acetate in

humans or animals after dermal exposure.

2.3.3 Metabolism

No studies are available on the in vivo metabolism of vinyl acetate in

humans via any exposure route.

The metabolism of vinyl acetate has been studied in animals (Boyland

and Chasseaud 1967; Hazleton 1979a, 1980a; Holub 1983; Holub and Tarkowski

1982; Simon et al. 1985a; Tiunova and Rumyandsev 1975). A summary of the

proposed metabolic pathways for vinyl acetate is presented in Figure 2-3.

Vinyl acetate is rapidly hydrolyzed by esterases in the blood to acetate and

the unstable intermediate, vinyl alcohol. Vinyl alcohol is rapidly converted

to acetaldehyde, which in turn is metabolized to acetate in the liver. This

in turn is incorporated into the "2 carbon pool" of normal body metabolism

and eventually forms CO2 as the major breakdo-m product. Therefore, the

metabolism of vinyl acetate results in two acetate molecules that enter the 2

carbon pool. This has been confirmed in excretion studies that have

documented 14CO2 in exhaled air as the major metabolite and source of

radioactivity recovered following either inhalation or oral exposure to 14C-VA

(Hazleton 1979a, 1980a). A very small amount also appears to be excreted in

the urine as urea and several other unidentified metabolites. The metabolic

pattern was not influenced by the route of administration.

Similar results were found in rats exposed to concentrations of vinyl

acetate (200-2,000 ppm) in the air for 1.4 hours or less (Simon et al.

1985a). The results show that vinyl acetate is rapidly metabolized by blood

esterases and that hepatic monooxygenases have a minor role, if any, in the

metabolism of vinyl acetate. Zero-order kinetics were observed at higher

51

2. HEALTH EFFECTS

concentrations (800-1,400 ppm) and first-order kinetics at lower

concentrations. This indicates that the metabolic pathways of vinyl

acetate are saturable at high levels. Following 6 months of exposure to

10-500 mg/m3

 (2.8-142 ppm) of vinyl acetate in the air, a transient decrease

in cytochrome P-450 and microsomal protein content was found in the liver of

rats (Holub 1983). No further details were given.

The induction of preneoplastic enzyme altered foci is believed to be an

indication of DNA alkylation by epoxides and subsequent genotoxicity. If

vinyl acetate was metabolized by the microsomal P-450 system to its

corresponding epoxide, than it ha's been predicted that this epoxide would

produce the same products of DNA alkylation as vinyl chloride and vinyl

carbamate (Laib and Bolt 1986). Oral administration of 400 mg/kg/day of vinyl

acetate to rats for 3 weeks did not result in an increase in preneoplastic

enzyme altered foci (γ-glutamyltranspeptidase-positive or adenosine

5'-triphosphatase-negative foci) in the liver, whereas previous studies have

shown that vinyl chloride and vinyl carbamate do induce these foci (Laib and

Bolt 1986b). These results suggest that vinyl acetate is not likely

epoxidized by the microsomal P-450 system to an ultimate carcinogenic

metabolite in the liver. These results also support the observation that the

primary route of metabolism for vinyl acetate is hydrolysis by esterases to

acetaldehyde and acetate rather than via the P-450 microsomal mixed-function

oxygenase system to the corresponding epoxide.

In vitro tests in which vinyl acetate was added to blood, plasma, or

liver homogenate from rats and mice provided results that suggested that

enzyme-mediated hydrolysis of vinyl acetate occurred at all three sites,

resulting in the production of vinyl alcohol (which is unstable) and acetate

(Hazleton 1979a). The vinyl alcohol is quickly converted to acetaldehyde.

Acetaldehyde added to rat and human whole blood or plasma was not degraded,

but when added to rat liver homogenate, it was converted to acetate (Hazleton

1980a). This provides evidence that the metabolism of acetaldehyde to acetate

occurs primarily in the liver. Subsequent reactions yield carbon dioxide, and

water. It is also known that vinyl acetate hydrolyses in water at 25° C at

the rate of 8.5% per day (Lijinsky and Reuber 1983). These in vitro studies

show that the half-lives for conversion of vinyl acetate to acetaldehyde in

rat plasma to be 57, 58, and 57 seconds at concentrations of 25, 50, or

100 ppm, respectively. Using rat whole blood, the half lives of vinyl acetate

were found to be 112, 121, and 141 seconds at the same conditions,

respectively. In rat liver homogenates, the half lives were 50, 97, and 167

seconds, again at the same concentrations, respectively. Similar half-lives

were seen in mouse plasma, whole blood, and liver homogenates. Furthermore,

even with diluted preparations of plasma, whole blood, and liver homogenates

the hydrolysis of vinyl acetate is very rapid (Hazleton 1979a). A later in

vitro study using human blood and plasma found that the hydrolysis of vinyl

acetate proceeded at a similar rate as reported for the rat and mouse

(Hazleton 1980a). However, different results were reported by Fedtke and

Wiegand (1990) using 200 μM vinyl acetate added to rat and human blood. They
52

2. HEALTH EFFECTS

reported that the half-life of vinyl acetate elimination in human whole blood

was 4.1 minutes as compared to <1 minute in rat whole blood (Fedtke and

Wiegand 1990). The majority of the hydrolysis was found to occur in the red

blood cells rather than the plasma of human blood. The half-life in plasma

was 62 minutes as compared to 5.5 minutes in red blood cells. However, in rat

plasma, the half-life of vinyl acetate elimination was 1.2 minutes as

compared to 5.6 minutes in rat red blood cells. While these results differ

from those reported above with regard to the location of the hydrolytic

enzymes in the blood across species, they do confirm that hydrolysis is the

predominant route of metabolism for vinyl acetate in both human and rat

blood.

Further in vitro metabolic studies show that vinyl acetate added to

preparations of rat liver supernatant did conjuwte (although not to a large

degree) with glutathione (Boyland and Chasseaud 1967). The reaction is

mediated by glutathione S-transferase and further metabolism produces

mercapturic acid derivatives that are eliminated in the urine (Boyland and

Chausseaud 1967, 1970). Rats exposed for 5 hours a day for 6 months to vinyl

acetate in the air (10, 100, or 500 mg/m3

) showed a significant depletion of

free nonprotein thiols in the liver but not in a dose-dependent pattern

(Hobub and Tarkowski 1982). According to the authors, the thiol depletion

indicates that conjugation with glutathione plays an important role in the

detoxification of this chemical. Similar results were seen in rats, guinea

pigs, and mice given single intraperitoneal doses of vinyl acetate (Holub and

Tarkowski 1982). The highest decrease (50%) in SH content was seen in guinea

pigs following a single intraperitoneal injection of 500 mg/kg vinyl acetate.

Glutathione conjugation may decrease the toxicity of potentially harmful

electrophiles by facilitating excretion into the bile (Chasseaud 1973).

These studies show that vinyl acetate quickly undergoes hydrolysis in

the body through several intermediate steps to form the principal end

products, carbon dioxide and water. The metabolic pattern was not influenced

by the route of vinyl acetate exposure, but did show nonlinear kinetic

patterns at high concentrations, indicating that the metabolic processes are

saturable. In vivo and in vitro tests indicate that vinyl acetate may bind to

various degrees with glutathione in different species, which may help to

detoxify vinyl acetate or its metabolites and enhance their elimination.

2.3.4 Excretion

2.3.4.1 Inhalation Exposure

No studies were located regarding the excretion of vinyl acetate in

humans following inhalation exposure.

Studies in animals indicate that vinyl acetate is rapidly eliminated

following inhalation exposure (Hazleton 1979a, 1980a). In one of these

studies, rats were exposed to 750 ppm 14C-VA for 6 hours (Hazleton 1980a).

Ninety-six hours following administration, the mean proportions of the
53

2. HEALTH EFFECTS

recovered radioactivity found in the urine, feces, and expired air were 4.8%,

3.6%, and 74.6%, respectively. Most of the radioactivity was eliminated in

the form of carbon dioxide during the first 24 hours after exposure. Also, a

substantial percentage (16.4%) of the total recovered radioactivity was

present in the carcasses at 96 hours. Similar results were obtained in an

earlier study conducted by Hazleton (1979a). In this study, rats were exposed

to 1,000 ppm vinyl-1,2-14C-VA for 6 hours. Ninety-six hours following

administration, the mean proportions of the recovered radioactivity in the

urine, feces, and expired air were 7.1%, 3.9%, and 70.3%, respectively. As

with the above study, much of the radioactivity was eliminated within 24

hours of exposure.

2.3.4.2 Oral Exposure

No studies were located regarding the excretion of vinyl acetate in

humans following inhalation exposure.

In animals, the excretion of vinyl acetate following oral exposure has

been studied in male and female rats (Hazleton 1979a, 1980a). The excretion

of radioactivity in rats following oral administration of 1 mL of a 5,000 ppm

[vinyl-1,2-14C]-VA solution (equivalent to 23.4 mg/kg) by gavage was rapid (as

in inhalation exposure) (Hazleton 1979a). Ninety-six hours after

administration, 3.1%, 1.1%, and 86.3% of the mean radioactivity was excreted

in the urine, feces, and expired air, respectively. After 96 hours, an

additional 7% was recovered in the carcasses, accounting for a total of 96%

of the administered radioactivity. Most of the radioactivity was eliminated

during the first 6 hours after exposure. In a later study, rats were given 6

hourly doses of a 10,000 ppm aqueous solution of [vinyl-1,2-14C]-VA by oral

gavage (Hazleton 1980a). During the six hours of exposure and the 96-hour

collection period, 1.8%, 1.4%, and 61.2% of the mean radioactivity was

excreted in the urine, feces, and expired air, respectively. After 96 hours,

an additional 5% was recovered from the carcasses, accounting for a total of

70% of the administered radioactivity. The authors attributed the unaccounted

30% to loss in expired air that escaped from the metabolic cages housing the

animals. The studies show that following oral exposure, vinyl acetate is

eliminated rapidly from the body, primarily through expired air as carbon

dioxide.

2.3.4.3 Dermal Exposure

No studies were located regarding the excretion of vinyl acetate in

humans or animals after dermal exposure.

2.4 RELEVANCE TO PUBLIC HEALTH

Since few monitoring data are available for vinyl acetate

concentrations in environmental media, physical/chemical property data can be

used to predict the partitioning of the compound to air, water, and soil and

subsequent human
54

2. HEALTH EFFECTS

exposure through contact with these media. Based on the high vapor pressure

of vinyl acetate, volatilization to the atmosphere will be an important

transport process for vinyl acetate released to surface water and soils. The

low Koc(soil adsorption coefficient) and high water solubility indicates that

vinyl acetate is highly mobile in soils and that when released to subsurface

soils it is likely to partition to groundwater. The low Kow (octanol/water

partition coefficient) for vinyl acetate, suggests that it is unlikely to

bioconcentrate/biomagnify in terrestrial or aquatic organisms/food chains,

hence, exposure to vinyl acetate through consumption of meat or fish is not

an important exposure pathway for this compound. In the atmosphere, vinyl

acetate is rapidly broken down by photochemical oxidation with a half-life on

the order of hours. In soils and surface and groundwater, the compound

undergoes hydrolysis and biotransformation,.with half-lives on the order of

days. The main products of these transformat,ion processes are acetic acid,

acetaldehyde, and acetate,

Populations living in areas surrounding hazardous waste sites may be

exposed to vinyl acetate through inhalation of contaminated air and ingestion

of or dermal contact with contaminated water; the latter route may be

particularly important for populations living near certain types of disposal

sites (e.g., underground injection sites). The relative importance of these

pathways in terms of human exposure potential is difficult to establish given

the limited monitoring data available for vinyl acetate. Most people,

however, are probably exposed to very small amounts of vinyl acetate through:

(1) inhalation of contaminated ambient air and cigarette smoke; (2) dermal

contact with products containing the compound (e.g., glues and paints); and

(3) ingestion of residual vinyl acetate monomers in food (i.e., that may have

migrated from plastic food wraps) or food items containing the compound as a

starch modifier. Occupational exposure to vinyl acetate occurs via inhalation

of contaminated workplace air and by dermal contact with vinyl acetate vapor

or liquids and products containing the compound.

Vinyl acetate is a water soluble volatile organic compound that acts

directly on the site of contact. The clinical signs common to both humans and

animals after acute exposure to high levels of vinyl acetate in air are

respiratory and ocular irritation. Other organ systems apparently affected in

animals following inhalation and/or oral exposure include the immune and

nervous systems. The mechanism by which vinyl acetate exerts its effects on

these systems has not been investigated. Death has been reported in animals

following acute inhalation, oral, or dermal exposure to high doses of'vinyl

acetate. Reduced body weight gain is often observed in intermediate- and

chronic-duration inhalation and drinking water studies in animals. In

drinking water studies, these changes have been attributed to reduced water

intake due to the unpalatability of the test solution containing vinyl

acetate. Similarly, growth retardation has been observed in pups born to rats

exposed to vinyl acetate via inhalation or oral administration. This effect

is most likely a result of reduced body weight gain in the maternal animals

during exposure to vinyl acetate. An increased incidence of some tumor types
55

2. HEALTH EFFECTS

has been observed in rats that were chronically exposed to vinyl acetate via

inhalation. In most cases, the tumor types observed'following exposure to

vinyl acetate (i.e., nasal) were not observed in the control animals. Studies

on the carcinogenic potential of vinyl acetate following oral exposure have

generally been inconclusive or negative. Very little information is available

on the toxicity of vinyl acetate following dermal exposure in humans or

animals. However, exposure to vinyl acetate has caused ocular irritation and

blistering of the skin of workers and laboratory animals.

An acute-duration inhalation MRL was not derived for vinyl acetate

because of the lack of information on target organ(s) of effect for this

compound. Clinical studies with human volunteers have shown that irritation

of the mucous membranes of the throat can occur at levels as low as 4 ppm for

exposure durations of 2 minutes (Smyth and Carpenter 1973). However, this was

based on effects reported in one out of nine exposed volunteers. Higher

levels and/or longer durations of exposure resulted in an increased incidence

of reported irritation.

An intermediate-duration inhalation MRL of 0.01 ppm was derived for

vinyl acetate based on the Hazleton 1980b study. This study used the species

that shows the greatest sensitivity to the respiratory effects of vinyl

acetate (i.e., the mouse). Ten CD-1 mice/sex/group were intermittently

exposed to vapor concentrations of 0, 50, 200, or 1,000 ppm for 6 hours/day,

5 days/week, for 3 months. Animals were observed daily for clinical signs of

toxicity, body weight was monitored, hematological and blood chemical

parameters were assayed, and a full necropsy was performed at terminal

sacrifice. There were no exposure-related deaths during the study; however,

11 animals died as a result of the blood sampling procedure (2 out of 20

controls and 9 out of 20 exposed to 1,000 ppm). No treatment-related adverse

effects were observed in the control or 50-ppm exposure group. Respiratory

distress, hunched posture, and ruffled fur were observed at exposure

concentrations of 200 ppm and above. A statistically significant decrease in

body weight gain was seen in the animals exposed to 1,000 ppm vinyl acetate.

No other clinical or macroscopic signs of exposure-related toxicity were

observed in these animals. Inflammation of the nasal turbinate epithelium and

mild multifocal bronchitis were observed in animals exposed to 200 ppm vinyl

acetate. Focal and diffuse rhinitis associated with exudation and

transudation into the nasal passages, metaplasia or hyperplasia of the

trachea, multifocal bronchitis, bronchiolitis, multifocal bronchiostania,

bronchial epithelial metaplasia and hyperplasia, and occasional bronchiolar

and bronchial exudation were observed in the animals exposed to 1,000 ppm

vinyl acetate. The 200-ppm vinyl acetate level was considered a LOAEL and the

50-ppm vinyl acetate level was considered a NOAEL for respiratory effects in

the extrathoracic region. The NOAEL was used as the basis for calculating the

MRL. The administered concentration (50 ppm) was corrected for intermittent

exposure and human equivalent concentration as follows:

57

2. HEALTH EFFECTS

congestion and histopathological lesions of the respiratory tract have also

been observed in 4-week and 2-year studies in rats and mice that support the

critical end point chosen for the calculation of the intermediate inhalation

MRL (Hazleton 1979b, 1979c, 1980c, 1988b).

A chronic-duration inhalation MRL was not calculated. In the chronic

inhalation studies conducted by Hazleton (1988b), neurological and

immunological effects were observed at the same exposure levels as the NOAEL

for respiratory effects. The neurological effects were reported to be

concentration-related, duration-related, and were consistently observed in

both intermediate- and chronic-duration studies. Decreases in spleen weight

consistently occurred in the intermediate-duration studies at the highest

concentration tested. In the chronic duration study, male rats exposed to 50

or 600 ppm exhibited a significant decrease in relative spleen weight and no

significant changes in spleen weight were observed in mice. Because studies

have not been conducted to further examine these organ systems or to

determine the mechanism by which vinyl acetate elicits its effect on these

systems, it was decided that neurological and immunological effects needed

further clarification before a chronic inhalation MRL could be derived.

No oral MRLs were derived for the following reasons:

(1) Although the LOAELs presented in Table 2-2 represent statistically

significant differences, they are either of questionable

biological significance (e.g., spleen and thymua weight changes

without accompanying gross or histopathological changes) or for

changes to the Harderian gland (e.g., chronic dacryoadenitis),

which are not relevant to humans. In the absence of further

definition, neither of these end points provide an appropriate

basis for an MRL.

(2) The developmental LOAELs reported are thought to be due to growth

retardation in the maternal animals, which is in turn thought to

be due to unpalatability of the drinking water. Therefore, these

effects are of questionable biological significance as well.

(3) All of the NOAELs reported are “free-standing”. and are thus not

an appropriate basis for the calculation of an MRL.

Death. Although no deaths have been reported in humans following

exposure to vinyl acetate, this chemical has caused lethality in animals

following inhalation, ingestion, or dermal application of high doses. Death

in animals is generally associated with adverse respiratory effects and

convulsions following inhalation and dermal exposure, but no cause of death

has been specified following ingestion of vinyl acetate. Mice appear to be

more sensitive to the toxic effects of vinyl acetate than rats, rabbits, or

guinea pigs (Goeva 1966; Smyth and Carpenter 1948, 1973). The doses required
58

2. HEALTH EFFECTS

to produce death are relatively high. Furthermore, no treatment-related

deaths have been observed in chronic inhalation or oral studies (Hazleton

1988a, 1988b). Therefore, it is likely that the risk of death is very small

under conditions of long-term, low-level exposure either from ingestion of

contaminated food or water or from inhalation of vinyl acetate.

Systemic Effects

Respiratory Effects. The primary systemic target of vinyl acetate

toxicity following inhalation exposure in humans and animals is the

respiratory system. Acute inhalation exposure of humans to vinyl acetate can

cause irritation of the nose and throat (Smyth and Carpenter 1973). Prolonged

occupational exposure to vinyl acetate is generally without adverse

respiratory effect at levels below 10 ppm (Deese and Joyner 1969).

Respiratory tract damage is characteristic of vinyl acetate exposure in

laboratory animals following acute-, intermediate-, or chronic-duration

inhalation exposure. Deaths following acute inhalation exposure to vinyl

acetate are generally accompanied by evidence of respiratory irritation.

Gasping and labored breathing were generally observed in animals prior to

death, and necropsy revealed lung congestion and hemorrhage, froth in the

trachea, and excess pleural fluid (Smyth and Carpenter 1973; Weil and

Carpenter 1969).

Evidence of respiratory irritation and distress was reported in rats

and mice during intermediate-duration inhalation exposure to vinyl acetate

(Gage 1970; Hazleton 1979b, 1979c, 1980b, 198oc). These clinical signs were

not accompanied by changes in lung weight or macroscopic evidence of

respiratory tract damage following 4-week exposures. However, an increase in

relative lung weight in both rats and mice, presumably due to treatmentrelated lung congestion, was observed in the high-exposure groups in the 3-

month studies (Hazleton 1980b, 1980c). Histopathological evidence of

treatment-related respiratory effects was seen in mice following exposure for

3 months (Hazleton 1980b). Mice exposed to 200 ppm vinyl acetate exhibited

very mild to slight focal areas of inflammation of the nasal turbinate

epithelium and mild multifocal bronchitis. Microscopic examination of mice

exposed to 1,000 ppm vinyl acetate revealed focal and diffuse rhinitis with

associated exudation and transudation into the nasal passages, metaplasia or

hyperplasia of the trachea, multifocal bronchitis, bronchiolitis, multifocal

bronchiostania, bronchial epithelial metaplasia and hyperplasia, and

occasional bronchiolar or bronchial exudation (Hazleton 1980b). These results

indicate that the extrathoracic region is more susceptible to the irritant

effects of inhaled vinyl acetate in the mouse than the lower respiratory

tract since the effects to the extrathoracic region were observed more

commonly at lower exposure concentrations.

Chronic inhalation exposure (104 weeks) of rats and mice to vinyl

acetate resulted in clinical and histopathological treatment-related effects
59

2. HEALTH EFFECTS

on the respiratory tract similar to those seen with shorter-duration

exposures (Hazleton 1988b). In mice the most prominent nasal change was

atrophy of the olfactory epithelium at 200 ppm and 600 ppm. Epithelial

hyperplasia was also observed in the trachea at 200 and 600 ppm. Changes in

the lung were more prominent at higher levels while the larynx was

unaffected. In rats, the most prominent lesion was thinning of the nasal

olfactory epithelium accompanied by basal cell hyperplasia. Pulmonary changes

observed in the higher dose group were mainly in the bronchi and bronchioli

and consisted of fibrous plaques and buds protruding into the lumen of the

bronchi and bronchioles, covered by normal bronchial epithelium and without

obvious evidence of an associated inflammatory response. Taken together, the

results of the acute-, intermediate-, and chronic-duration inhalation

exposure experiments, indicate that mice may be more susceptible to the toxic

effects of vinyl acetate than rats. This is supported, in part, by the higher

susceptibility of mice to the lethal effects of vinyl acetate (i.e., a lower

LC50 value), as discussed in Section 2.2.1.1.

The effects of vinyl acetate on the respiratory tract differ from those

seen after exposure to acetaldehyde. Acetaldehyde is a hydrolysis product of

vinyl acetate and is also a respiratory irritant. Acetaldehyde was present in

the mid- and high-exposure group inhalation chambers in the chronic rat and

mouse study at a concentration of 34 and 49 ppm, respectively (Hazleton

1988b). Dreef-van der Meulen (1988b) compared the non-neoplastic changes

observed following chronic inhalation exposure of rats to vinyl acetate with

those seen after chronic inhalation exposure to 750-3,000 ppm acetaldehyde.

Both compounds cause damage to the olfactory epithelium at lower

concentrations. However, exposure to higher concentrations of acetaldehyde

(1,500-3,000 ppm) also results in damage to the nasal respiratory epithelium,

whereas no damage to the nasal respiratory epithelium was found at levels up

to 600 ppm vinyl acetate. In addition, vinyl acetate adversely affects the

bronchi and lungs, but not the larynx, whereas acetaldehyde induces damage to

the laryngeal epithelium but has no effect on the bronchi and lungs. Based on

the differences in responses to the two compounds, and the fact that

acetaldehyde was not present in the inhalation chambers in the vinyl acetate

study at levels that would be expected to result in adverse respiratory

effects, it can be concluded that the effects of vinyl acetate on the

respiratory tract were most likely not due to the action of its metabolite,

acetaldehyde.

In vitro studies have shown that vinyl acetate is ciliatoxic at a total

exposure of 4 μg (Battista 1976). Isolated trachea were exposed to 40 mL

puffs of air containing vinyl acetate (0.5 μg/puff) for 12 seconds at 1

minute intervals for 8 puffs. Proper functioning of the respiratory tract

cilia is essential for mucociliary clearance, which in turn is essential for

the maintenance of a normal pulmonary environment. Impairment of ciliary

action can lead to accumulation and retention of noxious chemicals within the

respiratory tract.
60

2. HEALTH EFFECTS

Hepatic Effects. Prolonged occupational exposure to vinyl acetate did

not result in any adverse renal effects in humans at levels below 10 ppm

(Deese and Joyner 1969). Elevated serum ornithine carbamyl transferase (OCT)

levels, which are indicative of liver damage, were measured in one of four

guinea pigs administered 500 mg/kg vinyl acetate by intraperitoneal injection

(the remaining three died) (DiVincenzo and Krasavage 1974). Decreases in

liver weight have been observed in rats and mice exposed to vinyl acetate by

inhalation for 3 months and 104 weeks (Hazleton 1980b, 1980c, 1988a), and in

rats and mice administered vinyl acetate in the drinking water for 4 weeks

and 3 months (rats) (Hazleton 1979d, 1980f). These weight changes were not

accompanied by histopathological changes or biochemical evidence of liver

damage. The biological significance of a changes in organ weight in the

absence of histopathological or functional changes is difficult to ascertain.

Renal Effects. Prolonged occupational exposure to vinyl acetate did not

result in any adverse renal effects in humans at levels below 10 ppm (Deese

and Joyner 1969). No adverse renal effects were observed in animals exposed

to vinyl acetate by inhalation (Hazleton 1979b, 1979c, 1980b, 1980c, 1988b).

A decrease in absolute, but not kidney weight relative to body weight was

found in male rats administered vinyl acetate in drinking water for 3 months

(Hazleton 1980f). An increase in kidney weight relative to body weight was

observed in male rats administered vinyl acetate in the drinking water for

104 weeks following in utero exposure (Hazleton 1988a). Decreased and more

concentrated urine was observed in female rats administered vinyl acetate in

the drinking water for 3 months and in male and female rats exposed via

inhalation to vinyl acetate for 3 months or 104 weeks (Hazleton 1980c, 1980f,

1988b). However, no gross or histopathological changes were observed in the

kidneys of these animals. The decreased and more concentrated urine was most

likely a result of reduced water intake. Therefore, the toxicological

significance of the organ weight and urine changes is questionable. The

kidney weight changes observed in the chronically treated male rats may have

been due to age-related disease processes that normally occur in male rats

and were exacerbated by exposure to vinyl acetate. No other adverse renal

effects were observed in rats or mice in any other intermediate-or chronicduration study (Gage 1970; Hazleton 1979b, 1979c, 1979d, 1980b, 1980c, 1980e,

1980f, 1988a, 1988b).

Dermal/Ocular Effects. Acute exposure of humans or animals to vinyl

acetate in air can cause irritation of the eyes (Deese and Joyner 1969; Gage

1970; Smyth and Carpenter 1973). These effects are the result of direct

contact with vinyl acetate vapor or liquid. Prolonged occupational exposure

to vinyl acetate at levels below 10 ppm generally does not cause eye

irritation (Deese and Joyner 1969). Dermal application of diluted solutions

of vinyl acetate generally does not cause irritation in either humans or

animals (Tanaka and Lucas 1984; Weil and Carpenter 1969). However,

occupational experience has indicated that some persons might react to dermal

contact with vinyl acetate with blister formation, particularly on the thin

skin of the finger web and the underside of the wrist, and that continued
61

2. HEALTH EFFECTS

contact, such as that afforded by clothing wet with the chemical might result

in severe irritation or blistering of the skin (Union Carbide 1958). High

doses of vinyl acetate applied to the skin of rabbits has resulted in

erythema, edema, and necrosis of the skin (Weil and Carpenter 1969).

Immunological Effects. No studies were located regarding immunological

effects in humans after exposure to vinyl acetate. Decreases in thymus and/or

spleen weight were consistently noted in rats and mice exposed to vinyl

acetate orally or by inhalation for either 4 weeks or 3 months (Hazleton

1979b, 1979c, 1979d, 1980c, 1980b, 1980e). Extramedullary hematopoiesis was

observed at an increased incidence over controls in mice receiving vinyl

acetate in the drinking water for 3 months (Hazleton 1980e). However, in this

study, the incidence of grossly-detectable splenomegaly was not increased in

the high-dose animals, and hematopoietic activity was the same as that seen

in the control animals. No other histopathological changes were noted in

either the spleen or the thymus in any of these studies. These organ weight

changes may be suggestive of an immunosuppressive action of vinyl acetate,

but the appropriate parameters were not investigated to delineate this

possibility.

Neurological Effects. No studies were located regarding neurological

effects in humans or animals after exposure to vinyl acetate. All rats and

mice exposed by inhalation to at least the highest concentration of vinyl

acetate for 4 weeks, 3 months, and 104 weeks exhibited hunched posture and

ruffled fur (Hazleton 1979b, 1979c, 1980b, 1980c, 1988b). A dose-related

increase in the incidence of head tilt was also noted in some rats and mice

exposed by inhalation to vinyl acetate for 104 weeks (Hazleton 1988b). It is

possible that these neurological signs were secondary to the poor health of

the animals following inhalation exposure, and may not be indicative of a

primary effect of vinyl acetate on the nervous system. These neurological

signs were not seen in animals that were orally administered vfnyl acetate,

and no other treatment-related clinical or histopathological signs of

neurotoxicity have been observed in rats or mice exposed to vinyl acetate

(Hazleton 1979b, 1979c, 1979d, 1980b, 198Oc, 1980e, 1980f, 1988a, 1988b).

However, neurobehavioral toxicity often occurs in the absence of other

clinical or histopathological signs of neurotoxicity, so it is not known if

exposure to vinyl acetate is likely to result in any adverse neurological

effects in humans.

Developmental Effects. No studies were located regarding developmental

effects in humans after exposure to vinyl acetate. Growth retardation and

delayed ossification have been observed in pups born to rats exposed to vinyl

acetate via inhalation during gestation days 6-15 (Hazleton 1980d). Growth

retardation was also observed in pups following oral exposure of rats to

vinyl acetate during the pre-mating, gestation, and lactation periods

(Hazleton 1987). These effects may be secondary to the reduced body weight

gain that occurred in the maternal animals. No other adverse developmental

effects have been observed in animals following inhalation or oral exposure

to vinyl
62

2. HEALTH EFFECTS

acetate. Based on the results obtained in animals, vinyl acetate is unlikely

to cause adverse developmental effects in humans at exposure concentrations

below those that would cause maternal toxicity.

Reproductive Effects. No studies were located regarding reproductive

effects in humans after exposure to vinyl acetate. A marginal reduction in

the number of pregnancies was observed in the F1 female rats administered

vinyl acetate in the drinking water in a two-generation study (Hazleton

1987). However, this difference was not statistically significant and the

pregnancy incidence in the treated animals was reported to be within the

range of historical controls. With the exception of a decrease in relative

testes weight which was not dose-related and not accompanied by any

histopathological changes in mice administered vinyl acetate in the drinking

water for 3 months (Hazleton 1980e), no other gross or histopathological

changes in either male or female reproductive organs were observed in rats or

mice administered vinyl acetate by inhalation or oral administration

(Hazleton 1980b, 1980c, 1980d, 1980e, 1980f, 1987, 1988a, 1988b). Reduced

testicular weight and increased sperm abnormalities were reported in male

mice given intraperitoneal injections of 125 mg/kg/day and 500 mg/kg/day,

respectively (Lahdetie 1988). The authors concluded that in mice, vinyl

acetate impaired sperm production in the testis, but did not appear to affect

its endocrine function. However, the adverse male reproductive effects may

have been a result of the decreased body weight also observed in these

animals. Some of the effects (i.e., reduced testicular weight) were not doserelated, and the route of administration is not relevant to human exposure.

Given the limitations associated with this study, and the fact that no

adverse effect on reproductive performance or histopathology of the

reproductive organs has been seen following inhalation or oral exposure of

animals to vinyl acetate, the relevance of the effects to human health is not

known,

Genotoxicity. Vinyl acetate has been evaluated for genotoxicity in a

variety of in vitro and in vivo assays. As summarized in Tables 2-5 and 2-6,

the results of these assays in microorganisms have been negative, but the

majority of mutagenicity tests in mammalian cells have been positive.

The mutagenicity of vinyl acetate has been demonstrated in several

in vitro studies. In cultured human lymphocytes and whole blood,

dosedependent increases in the induction of chromosomal aberrations (Jantunen

et al. 1986; Norppa et al. 1985), sister chromatid exchanges (He and Lambert

1985; Norppa et al. 1985), micronuclei (Maki-Paakkanen and Norppa 1987;

Norppa et al. 1988), and DNA cross-links (Lambert et al. 1985) have been

observed. Vinyl acetate also induced a dose-dependent increase in sister

chromatid exchanges in Chinese hamster ovary cells with and without metabolic

activation (Norppa et al. 1985), and has enhanced adenovirus transformation

of Syrian hamster fetal cells (Casto 1980, 1981). Thus, vinyl acetate has

demonstrated clastogenicity in mammalian cells, which was more pronounced in

isolated human lymphocytes than in lymphocytes in whole blood (Jantunen et

al. 1986; Norppa


65

2. HEALTH EFFECTS

et al. 1985). However, no mutagenic effects have been reported in bacterial

assays with the Salmonella typhimurium strains TA98, TA100, TA1530, TA1535,

TA1537, or TA1538 with or without metabolic activation (Barbin et al. 1978;

Bartsch et al. 1976; 1979, 1980; Florin et al. 1980; Lijinsky and Andrews

1980; McCann et al. 1975). These results indicate that vinyl acetate damage

to the genome occurs at the chromosome level, rather than at the gene level.

In vivo, vinyl acetate induced a dose-dependent increase in

micronucleated polychromatic erythrocytes in mouse bone marrow cells

following a single intraperitoneal injection (Maki-Paakkanen and Norppa 1987;

Norppa et al. 1988). However, no treatment-related effect on the incidence of

micronuclei was seen in erythrocytes taken from bone marrow smears of animals

exposed to vinyl acetate by either inhalation or ingestion (Hazleton 1979b,

1979c, 1979d, 1980b, 1980c). A small dose-related increase in sister

chromatid exchanges was observed in the bone marrow cells of hepatectomized

and non-hepatectomized mice injected intraperitoneally with vinyl acetate

(Takeshita et al. 1986). However, vinyl acetate failed to produce specific

DNA-adducts in rat liver following treatment by gavage or by inhalation

(Simon et al. 1985b) and did not induce an increase in the.occurrence of

micronuclei in the spermatogonial cells of mice following intraperitoneal

injection compared to positive controls (Lahdetie 1988). These discrepant

results may be due to the tissue distribution of vinyl acetate, route of

administration, species differences, the duration of the cell cycles and

recovery time of induced damage, and differences in sensitivity of the cell

types to

cytotoxicity.

Cancer. No reports of cancer in humans associated with exposure to

vinyl acetate have been found. The carcinogenicity of vinyl acetate has been

studied in chronic bioassays using Sprague-Dawley and Fischer-344 rats and

CD-1 mice (Hazleton 1988a, 1988b; NCI 1982a). Slides of the respiratory tract

of the rats and mice from the chronic Hazleton (1988b) inhalation study were

reevaluated by Beems (1988) (mice) and Dreef-van der Meulen (1988b) (rats).

Tumors were not observed in the lungs or trachea of the exposed rats, but one

squamous cell carcinoma of the larynx and twelve nasal tumors were found in

this species. Out of twelve, five benign papillomas were found in exposed

male rats while seven malignant carcinomas were found in rats of both sexes.

Bronchiolar-alveolar adenomas were found in the lungs of both the exposed and

control mice at comparable incidences, indicating that their occurrence was

not a result of exposure to vinyl acetate. No tumors were seen in the nose,

larynx, or trachea of either exposed or control mice. Therefore, either the

tumorigenic effect of vinyl acetate is species specific, or the mouse is not

as sensitive to the tumorigenic effects of vinyl acetate, and higher exposure

levels may be needed to see this effect in mice. It is not known if the

increased incidence of nasal cavity tumors seen in rats exposed to vinyl

acetate is the result of repeated cell proliferation, or whether a genotoxic

mechanism is involved. Respiratory tract tumors in rodents exposed to high

levels of irritating vapors that cause cell proliferation are common (Cohen
66

2. HEALTH EFFECTS

and Ellwein 1990). If the carcinogenic response to inhalation of vinyl

acetate vapor is a result of cell proliferation resulting from irritation and

not a genotoxic mechanism, then the risk of cancer to humans exposed to low,

nonirritating levels of vinyl acetate vapor should be minimal.

Vinyl acetate is metabolized to acetaldehyde, which is an animal

carcinogen following inhalation exposure. Dreef-van der Meulen (1988b)

compared the neoplastic changes observed following chronic inhalation

exposure of rats to vinyl acetate with those seen after chronic inhalation

exposure to acetaldehyde. In the vinyl acetate study, benign and malignant

nasal tumors (papillomas and squamous cell carcinomas) were seen with no

preferential site of origin (i.e., olfactory or respiratory epithelium).

Acetaldehyde induced squamous cell carcinomas of the nasal respiratory

epithelium and adenocarcinomas of the olfactory epithelium following

inhalation exposure. Both are believed to be the result of acetaldehyde's

cytotoxic effects on the epithelium. Therefore, the carcinogenic response to

the two compounds differs in, the type and site of origin of nasal tumors as

well as the fact that acetaldehyde-induced nasal tumors arose from severely

damaged epithelium whereas vinyl acetate-induced tumors arose from epithelium

that did not show any signs of damage. Vinyl acetate-damaged olfactory

epithelium did not give rise to adenocarcinomas, whereas adenocarcinomas from

severely damaged olfactory epithelium were the predominant response to

acetaldehyde. Furthermore, these carcinogenic responses to acetaldehyde were

not seen at exposure concentrations below 1,500 ppm, whereas the levels of

acetaldehyde present in the inhalation chambers in the vinyl acetate study

were only 34 and 49 ppm. These observations suggest that neither acetaldehyde

or cytotoxicity was involved in the induction of nasal tumors in rats exposed

to vinyl acetate in the Hazleton (1988b) study (Dreef-van der Meulen 1988b).

A statistically significant carcinogenic effect of vinyl acetate was

observed in a screening study in which this chemical was administered in the

drinking water of Fischer-344 rats for 100 weeks (Lijinsky and Reuber 1983;

NCI 1982a). Tumor incidences that were significantly increased in the treated

animals as compared to the controls included neoplastic nodules of the liver

in both sexes, adenocarcinomas of the uterus in the females, and C-cell

adenomas or carcinomas of the thyroid in both sexes, but predominantly in the

females. There were many limitations associated with this study, as discussed

in Section 2.2.2.8. Because of these limitations, Lijinsky and Reuber (1983)

concluded that the study needed to be repeated with larger numbers of animals

per group, higher dose levels, and vinyl acetate solutions that are prepared

fresh daily before definitive conclusions regarding the carcinogenicity of

vinyl acetate following oral exposure can be made.

In a later study, Sprague-Dawley rats that received higher doses of

vinyl acetate in their drinking water for 104 weeks following in utero

exposure than those used by Lijinsky and Reuber (1983) developed tumors, but

they were not considered by the authors to be treatment-related, since they

occurred at a similar incidence in the high-dose animals as in the controls,
67

2. HEALTH EFFECTS

and were commonly occurring tumors in aging Sprague-Dawley rats (Hazleton

1988a). Two squamous cell carcinomas of the oral mucosa were observed in the

treated animals, but the incidence was not statistically significant, and the

study authors considered them to be a result of tooth-related problems

(Hazleton 1988b). Therefore, this study provides no evidence for the

carcinogenicity of vinyl acetate following exposure in the drinking water.

The negative data obtained from this study should be given more weight than

the positive data obtained from the Lijinsky and Reuber (1983; NCI 1982)

screening study because many of the limitations associated with the earlier

study were remedied in the Hazleton (1988a) study, as discussed in

Section 2.2.2.8.

Prior to the Hazleton (1988a) study, IARC (1986) had concluded that

there is inadequate evidence for the carcinogenicity of vinyl acetate in

humans or animals.

Results of genotoxicity studies are mixed, but generally provide

evidence that vinyl acetate is clastogenic and indicate that vinyl acetate

damage to the genome occurs at the chromosome level, rather than at the gene

level. Therefore, based on the positive results summarized above for

inhalation exposure, and the generally positive genotoxicity results, vinyl

acetate may pose a carcinogenic risk to humans.

2.5 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in

biologic systems or samples. They have been classified as markers of

exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989).

A biomarker of exposure is a xenobiotic substance or its metabolite(s)

or the product of an interaction between a xenobiotic agent and some target

molecules or cells that is measured within a compartment of an organism

(NAS/NRC 1989). The preferred biomarkers of exposure are generally the

substance itself or substance-specific metabolites in readily obtainable body

fluids or excreta. However, several factors can confound the use and

interpretation of biomarkers of exposure. The body burden of a substance may

be the result of exposures from more than one source. The substance being

measured may be a metabolite of another xenobiotic substance (e.g., high

urinary levels of phenol can result from exposure to several different

aromatic compounds). Depending on the properties of the substance (e.g.,

biologic half-life) and environmental conditions (e.g., duration and route of

exposure), the substance and all of its metabolites may have left the body by

the time biologic samples can be taken. It may be difficult to identify

individuals exposed to hazardous substances, that are commonly found in body

tissues and fluids (e.g., essential mineral nutrients such as copper, zinc,

and selenium). Biomarkers of exposure to vinyl acetate are discussed in

Section 2.5.1.
68

2. HEALTH EFFECTS

Biomarkers of effect are defined as any measurable biochemical,

physiologic, or other alteration within an organism that, depending on

magnitude, can be recognized as an established or potential health impairment

or disease (NAS/NRC 1989). This definition encompasses biochemical or

cellular signals of tissue dysfunction (e.g., increased liver enzyme activity

or pathologic changes in female genital epithelial cells), as well as

physiologic signs of dysfunction such as increased blood pressure or

decreased lung capacity, Note that these markers are often not substance

specific. They also may not be directly adverse, but can indicate potential

health impairment (e.g., DNA adducts). Biomarkers of effects caused by vinyl

acetate are discussed in Section 2.5.2.

A biomarker of susceptibility is an indicator of an inherent or

acquired limitation of an organism's ability to respond to the challenge of

exposure to a specific xenobiotic substance. It can be an intrinsic genetic

or other characteristic or a preexisting disease that results in an increase

in absorbed dose, biologically effective dose, or target tissue response. If

biomarkers of susceptibility exist, they are discussed in Section 2.7,

"POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE."

2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to Vinyl Acetate

Metabolic studies demonstrate that vinyl acetate is effectively

hydrolyzed by esterases in the blood to vinyl alcohol and acetate. The vinyl

alcohol is subsequently converted to acetaldehyde (Hazleton 1979a; Hazleton

1980a; Simon et al. 1985a). Acetaldehyde is subsequently metabolized to

acetate in the liver. Acetate enters normal metabolic pathways and is broken

down to carbon dioxide which is eliminated in expired air. Because the

metabolism of vinyl acetate occurs rapidly (in vivo tests indicate that most

is eliminated within 24 hours after exposure), it would be difficult to

measure the presence of vinyl acetate or acetaldehyde for reasonable periods

following exposure to vinyl acetate. Likewise, other metabolites would not be

useful because these are incorporated into normal metabolic pathways, making

it impossible to determine which metabolites were due to vinyl acetate

exposure and which were present as a result of normal metabolic processes.

2.5.2 Biomarkers Used to Characterize Effects Caused by Vinyl Acetate

Numerous positive genotoxic end points in human lymphocytes (e.g.,

micronuclei,' chromosomal aberrations, sister chromatid exchange, and DNA

cross-links) have been associated with exposure to vinyl acetate. However,

because these results are from in vitro tests and because many other commonly

encountered chemicals and factors (e.g., smoking) may also cause these same

abnormalities, these changes cannot be considered specific biomarkers of

effects caused by vinyl acetate. Another possibility is to use protein or

hemoglobin adducts of acetaldehyde as a marker of effect for vinyl acetate.

Stable protein-acetaldehyde adducts (Izumi et al. 1988; Lin and Lumeng 1988)

and hemoglobin-acetaldehyde adducts (Peterson et al. 1988) have been shown to
69

2. HEALTH EFFECTS

be formed following chronic alcohol ingestion. Since vinyl acetate does not

form adducts with DNA, this type of marker is also not available to serve as

a marker for effect. No other biomarkers (specific or otherwise) have been

identified to indicate exposure to vinyl acetate.

2.6 INTERACTIONS WITH OTHER CHEMICALS

There are no chemicals known that influence the toxicity of vinyl

acetate in the body.

2.7 POPULATIONS THAT AEE UNUSUALLY SUSCEPTIBLE

Individuals with existing problems in the upper respiratory tract,

eyes, and, possibly, skin may be unusually susceptible to effects associated

with exposure to vinyl acetate, based on its irritant properties.

Preplacement medical examinations to identify such conditions have been

recommended for people who may be occupationally exposed to vinyl acetate

(NIOSH 1978). Smokers may represent another potentially susceptible

subpopulation because vinyl acetate is a respiratory irritant. In addition,

vinyl acetate has been shown to have an effect on mucociliary clearance

similar to that of nicotine, so the combined effects of vinyl acetate and

nicotine in smokers could result in enhanced impairment of respiratory

function (Battista 1976).

2.8 MITIGATION OF EFFECTS

This section will describe clinical practice and research concerning

methods for reducing toxic effects of exposure to vinyl acetate. However,

because some of the treatments discussed may be experimental and unproven,

this section should not be used as a guide for treatment of exposures to

vinyl acetate. When specific exposures have occurred, poison control centers

and medical toxicologists should be consulted for medical advice.

Methods for enhancing the elimination of vinyl acetate are not known;

however, the relatively short half-life of vinyl acetate in the body may

obviate the need to enhance elimination. Furthermore, the mechanism of action

by which vinyl acetate produces toxic effects is undetermined. Therefore, the

main objective of treating vinyl acetate exposure is to decrease absorption.

Human exposure to vinyl acetate may occur by inhalation, ingestion, or

by dermal contact. Vinyl acetate is a respiratory irritant and acute highdose inhalation exposure may result in respiratory distress requiring the

administration of oxygen and ventilation assistance. Treatment for pulmonary
70

2. HEALTH EFFECTS

edema may be necessary (Bronstein and Currance 1988; Stutz and Janusz 1988).

Administration of water or milk for dilution has been suggested; however, it

is not clear whether such treatment would reduce absorption (it may simply

reduce irritant effects on the stomach). Gastrointestinal absorption is

decreased by administration of activated charcoal (Stutz and Janusz 1988).

Cathartics such as magnesium sulfate are also used to accelerate the fecal

excretion of ingested vinyl acetate (Stutz and Janusz 1988). Some medical

toxicologists advise against the use of emetics to induce vomiting following

oral exposure to vinyl acetate (Bronstein and Currance 1988). Dermal exposure

to concentrated solutions of vinyl acetate has resulted in blister formation.

Procedures that have been employed to reduce the irritating effects and

dermal absorption of vinyl acetate following dermal exposure include removal

of contaminated clothing and promptly flushing the skin with copious amount

of water followed by thorough washing with soap and water (Stutz and Janusz

1988). If the eyes have been exposed, they should be thoroughly irrigated

with water (Stutz and Janusz 1988)

2.9 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of

ATSDR (in consultation with the Administrator of EPA and agencies and

programs of the Public Health Service) to assess whether adequate information

on the health effects of vinyl acetate is available. Where adequate

information is not available, ATSDR, in conjunction with the National

Toxicology Program (NTP), is required to assure the initiation of a program

of research designed to determine the health effects (and techniques for

developing methods to determine such health effects) of vinyl acetate.

The following categories of possible data needs have been identified by

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as

substance-specific informational needs that, if met, would reduce or

eliminate the uncertainties of human health assessment. In the future, the

identified data needs will be evaluated and prioritized, and a substancespecific research agenda will be proposed.
71

2. HEALTH EFFECTS

2.9.1 Existing Information on Health Effects of Vinyl Acetate

The existing data on health effects of inhalation, oral, and dermal

exposure of humans and animals to vinyl acetate are summarized in Figure 2-4.

The purpose of this figure is to illustrate the existing information

concerning the health effects of vinyl acetate. Each dot in the figure

indicates that one or more studies provide information associated with that

particular effect. The dot does not imply anything about the quality of the

study or studies. Gaps in this figure should not be interpreted as "data

needs" information.

The only literature available concerning the health effects of vinyl

acetate in humans described the results of a controlled study utilizing

volunteers and also one occupational study. The route of exposure in these

reports was inhalation, but the possibility of some degree of dermal or oral

exposure cannot be ruled out. The information on human exposure is limited

because of the small sample size employed in these studies.

The database for the health effects of vinyl acetate following

inhalation or ingestion in experimental animals consists almost entirely of

unpublished reports. Many of the oral studies failed to provide any doseresponse information, as the highest dose tested was often without

unequivocally treatment-related adverse effect. As can be seen in Figure 2-4,

very little information is available on the systemic effects of dermal

exposure to vinyl acetate in animals.

Populations living in areas surrounding hazardous waste sites may be

exposed to vinyl acetate through inhalation of contaminated air and ingestion

of or dermal contact with contaminated water; the latter route may be

particularly important for populations living near certain types of disposal

sites (e.g., underground injection sites). The relative importance of these

pathways in terms of human exposure potential is difficult to establish given

the limited monitoring data available for vinyl acetate. Most people,

however, are exposed to very small amounts of vinyl acetate through: (1)

inhalation of contaminated ambient air and cigarette smoke; (2) dermal

contact with products containing the compound (e.g., glues and paints); and

(3) ingestion of residual vinyl acetate monomers in food (i.e., that may have

migrated from plastic food wraps) or food items containing the compound as a

starch modifier. Occupational exposure to vinyl acetate occurs via inhalation

of contaminated workplace air and by dermal contact with vinyl acetate vapor

or liquids and products containing the compound.

73

2. HEALTH EFFECTS

2.9.2 Data Needs

Acute-Duration Exposure. Information is available regarding the effects

of acute-duration exposure in humans following inhalation and dermal exposure

and in animals following exposure by all routes. Vinyl acetate may be lethal

to animals by all routes of exposure studied, depending on the dose (Goeva

1966; Smyth and Carpenter 1948; Weil and Carpenter 1969). Only limited

information exists on the systemic effects of vinyl acetate following acute

exposure. Respiratory effects occur in humans and animals following acute

inhalation exposure (Deese and Joyner 1969; Hazleton 1980d; Smyth and

Carpenter 1973; Weil and Carpenter 1969). However, since few quantitative

human and animal data exist, an acute inhalation MRL was not derived.

Although vinyl acetate can be lethal following ingestion (Goeva 1966; Smyth

and Carpenter 1948), acute oral exposure studies failed to identify a

specific target system in animals. The data in animals are insufficient to

derive an acute oral MRL for vinyl acetate. Only dermal and ocular effects

have been investigated following dermal exposure (Industrial Biotest 1972;

Tanaka and Lucas 1984; Weil and Carpenter 1969). However, necropsy data from

rabbits dermally administered lethal levels of vinyl acetate revealed

congestion of the lung and liver, mottled spleen and kidney, and prominent

liver acini (Weil and Carpenter 1969). The available toxicokinetic data are

not adequate to predict whether the behavior of vinyl acetate following

dermal exposure would be similar to that seen following inhalation or oral

exposure. Since the data suggest that respiratory tract irritation and/or

damage is the most likely adverse effect following acute inhalation exposure

to vinyl acetate, and since inhalation is the most likely route of exposure

to vinyl acetate, additional studies on the acute effects of vinyl acetate

following exposure by any route may not be necessary.

Intermediate-Duration Exposure. No information is available on the

toxicity of vinyl acetate to humans following intermediate-duration exposure

by any route. The main target of toxicity in animals following intermediateduration inhalation exposure is the respiratory tract (Gage 1970; Hazleton

1979b, 1979c, 1980b, 1980c). With the possible exception of the immune and

nervous systems (Hazleton 1979d, 1980f), no other organ system appears to be

adversely affected by inhalation exposure to vinyl acetate. An intermediate

inhalation MRL of 0.01 ppm was calculated based on a NOAEL of 50 ppm for

respiratory effects in mice exposed to vinyl acetate for 3 months (Hazleton

1980b). Intermediate oral exposure studies failed to identify a specific

target system in animals. With the exception of organ weight changes that

were not accompanied by histopathological changes (Hazleton 1979d, 1980e,

1980f), no adverse health effects were observed in animals at the doses

tested. Therefore, the data are insufficient to calculate an intermediate

oral MRL. The available toxicokinetic data are not adequate to predict

whether the behavior of vinyl acetate following dermal exposure would be

similar to that seen following inhalation or oral exposure. Since it has been
74

2. HEALTH EFFECTS

consistently found that the major adverse effects seen after intermediateduration inhalation exposure to vinyl acetate in animals is respiratory tract

irritation and damage, and since this is the most likely route of exposure to

vinyl acetate, additional studies on the intermediate effects of vinyl

acetate following exposure by any route may not be necessary.

Chronic-Duration Exposure and Cancer. One occupational study

investigated limited parameters following chronic-duration inhalation

exposure (15.2 years) to vinyl acetate in humans (Deese and Joyner 1969). No

epidemiological studies examining carcinogenicity in humans have been

conducted. Information is available regarding the effects of chronic-duration

exposure in animals following inhalation and oral exposure. The most noted

adverse effect in rats and mice following chronic inhalation exposure was

respiratory tract damage (Beems 1988; Dreef-Van der Muelen 1988b; Hazleton

1988b). In the chronic inhalation studies conducted by Hazleton (1988b),

neurological and immunological effects were observed at the same exposure

levels as the NOAEL for respiratory effects. Because studies have not been

conducted to further examine these organ systems or to determine the

mechanism by which vinyl acetate elicits its effect on these systems, it was

decided that neurological and immunological effects needed further

clarification before a chronic inhalation MRL could be derived. No organ

system appears to be adversely affected by chronic-duration oral exposure to

vinyl acetate in animals. Reduced weight gains (in both adults and fetuses)

(Hazleton 1987) and kidney weight changes (Hazleton 1988a) have been observed

following chronic oral exposure, but the organ weight changes were not

accompanied by any functional or morphological changes, and the body weight

changes were most likely due to unpalatability of the drinking water solution

containing vinyl acetate. The marginal reduction in pregnancies observed in

the two-generation drinking water study was only apparent in one generation,

was within the range of historical control data, and was therefore of

questionable toxicological significance (Hazleton 1987). The data are

insufficient to calculate a chronic oral MRL because no specific target organ

could be identified at the doses of vinyl acetate tested. No studies were

located on health effects resulting from chronic dermal exposure. The

available toxicokinetic data are not adequate to predict whether the behavior

of vinyl acetate following dermal exposure would be similar to that seen

following inhalation or oral exposure. Since inhalation is the most likely

route of exposure to vinyl acetate, additional studies on the chronic effects

of vinyl acetate following oral and dermal exposure may not be necessary.

No reports of cancer in humans associated with exposure to vinyl

acetate by any route have been found. The carcinogenicity of vinyl acetate

has been studied in chronic bioassays using rats (inhalation and oral) and

mice (inhalation only) (Hazleton 1988a, 1988b; Lijinsky and Reuber 1983; NCI

1982a). The available data in experimental animals were positive for

inhalation exposure (in rats only) and negative or inconclusive for oral

exposure (Hazleton 1988a, 1988b; NCI 1982a). Although the NCI
75

2. HEALTH EFFECTS

(1982a)/Lijinsky and Reuber (1983) oral bioassay provided suggestive evidence

for carcinogenic effects of vinyl acetate, there were many limitations (refer

to Section 2.2.2.8) with the study that rendered it inadequate for drawing

definitive conclusions regarding the carcinogenicity of vinyl acetate

following oral exposure. No significant increase in tumor incidence was seen

in an oral study in which the animals were exposed to higher doses of vinyl

acetate (both in utero and for 104 weeks after birth in the drinking water)

than those in the NCI (1982a)/Lijinsky and Reuber (1983) bioassay (Hazleton

1988b). Therefore, this study provides no evidence for the carcinogenicity of

vinyl acetate following exposure in the drinking water (Hazleton 1988a). The

nasal cavity tumors seen in rats in the chronic inhalation bioassay (Hazleton

1988b) were-treatment related. It is impossible at this time to speculate on

the carcinogenic potential of vinyl acetate in humans by any route of

exposure. Since inhalation is the most likely route of exposure to vinyl

acetate, an additional well-conducted 2-year inhalation bioassay would

provide valuable information on whether vinyl acetate has the potential to be

carcinogenic in humans.

Genotoxicity. Vinyl acetate has been evaluated for genotoxicity in a

variety of in vitro and in vivo assays (Bartsch et al. 1976, 1979, 1980;

Lahdetie 1988; Maki-Paakkanen and Norppa 1987; Norppa et al. 1985, 1988;

Simon et al. 1985b; Takeshita et al. 1986). The results are mixed, but

generally provide evidence that this compound is clastogenic (Jantunen et al.

1986; Norppa et al. 1985) and indicate that vinyl acetate damage to the

genome occurs at the chromosome level, rather than at the gene level (Barbin

et al. 1978; Bartsch et al. 1976, 1979, 1980; Florin et al. 1980; Lijinsky

and Andrews 1980; McCann et al. 1975). Since conflicting results were

obtained in in vivo studies (Hazleton 1979b, 1979c, 1979d, 1980b, 198Oc;

Lahdetie et al. 1988; Maki-Paakkanen and Norppa 1987; Norppa et al. 1988;

Simon et al. 1985b; Takeshita et al. 1986), further animal testing may help

resolve whether vinyl acetate has the potential to be genotoxic in humans,

and the mechanism by which it may induce these effects.

Reproductive Toxicity. No information is available in humans to

indicate that vinyl acetate affects reproductive function. A marginal

reduction in the number of pregnancies was observed in F1 female rats

administered vinyl acetate in a two-generation study (Hazleton 1987).

However, this difference was not statistically significant, occurred in only

one generation, and the pregnancy incidence was reported to be within the

range of historical controls. No other effects on reproductive performance

were observed in this study. Decreased relative testes weight was observed in

male mice administered vinyl acetate in the drinking water for 3 months, this

effect was not seen at higher doses and no gross or histopathological changes

were observed in the testes of these animals (Hazleton 1980e). No

histopathological changes in either male or female reproductive organs were

observed in rats or mice following inhalation or oral exposure to vinyl

acetate (Hazleton 1987). However, a two-generation inhalation study has not
76

2. HEALTH EFFECTS

been conducted. No information is available on the reproductive effects of

dermally administered vinyl acetate. Therefore, although the available

reproductive studies indicate that vinyl acetate probably has no adverse

effects on reproductive performance in animals following oral exposure,

further investigation is warranted to clarify whether this chemical has the

potential to affect reproduction 'in humans. Any additional reproductive

toxicity testing should be by the inhalation route of exposure since limited

information exists on reproductive performance following exposure to vinyl

acetate by this route and because it is most relevant for humans living in

the vicinity of hazardous waste sites.

Developmental Toxicity. No information is available in humans to

indicate that vinyl acetate affects fetal development. Growth retardation and

delayed ossification have been observed in pups born to rats exposed to vinyl

acetate via inhalation for an acute duration, and growth retardation was also

observed in pups following oral exposure of rats to vinyl acetate in a two

generation study(Hazleton 1980d, 1987). These effects were observed at levels

causing decreased body weight gain in dams. No other adverse developmental

effects have been observed in animals following oral exposure to vinyl

acetate. Any additional developmental toxicity testing should be by the

inhalation route of exposure since limited information exists on

developmental toxicity following exposure to vinyl acetate by this route and

it is the most relevant route for humans living in the vicinity of hazardous

waste sites.

Immunotoxicity. No information is available on the immunological

effects of vinyl acetate in humans or animals by any route of exposure.

Reductions in thymus and/or spleen weight were consistently noted in rats and

mice exposed to vinyl acetate for either 4 weeks or 3 months (Hazleton 1979b,

1979c, 1979d, 1980b, 1980c, 1980e). Furthermore, an increased incidence of

extramedullary hematopoiesis was observed in mice receiving vinyl acetate in

the drinking water for 3 months (Hazleton 1980e). These changes may be

indicative of an immunosuppressive action of vinyl acetate, but the

appropriate parameters need to be investigated to delineate this possibility.

Therefore, additional studies that examine sensitive parameters of

immunological function following inhalation exposure, since this is the most

likely route of human exposure, would be useful to more fully assess the

immunotoxic potential of vinyl acetate.

Neurotoxicity. No studies were located regarding neurological effects

in humans or animals after exposure to vinyl acetate. Hunched posture,

ruffled fur, and head tilt were observed in animals exposed by inhalation to

vinyl acetate. No other treatment-related clinical or histopathological

evidence of neurotoxicity has been observed in rats or mice exposed to vinyl

acetate (Hazleton 1979b, 1979c, 1979d, 1980b, 1980c, 1980e, 1980f, 1988a,

1988b). Therefore, although it appears that the nervous system may be a

target of vinyl acetate toxicity following inhalation exposure, further

testing by the inhalation route employing more sensitive measurements of
77

2. HEALTH EFFECTS

functional neurotoxicity and neuropathology would be useful, given the

clinical signs noted in the inhalation studies.

Epidemiological and Human Dosimetry Studies. Only two studies were

found concerning the health effects of vinyl acetate in humans. Both assessed

the occurrence of respiratory and ocular irritation following either acute

(Smyth and Carpenter 1973) or long-term occupational exposure (Deese and

Joyner 1969), and are limited by the small sample size studied. The most

likely identifiable subpopulation exposed to vinyl acetate is chemical

workers involved in its production and use. Results of animal inhalation

studies indicate that the respiratory and nervous systems and possibly the

immune system are adversely affected by vinyl acetate (Beems 1988; Dreef-Van

der Meulen 1988b; Gage 1970; Hazleton 1979b, 1979c, 1980b, 1980c, 1988b),

well designed epidemiological studies of exposed workers that specifically

examine the effects of vinyl acetate on these systems would be especially

useful to further characterize the extent of possible injury to these systems

in humans. More definitive characterization of the adverse effects of vinyl

acetate in humans may be useful as a tool to monitor vinyl acetate exposure

in individuals living near hazardous waste sites.

Biomarkers of Exposure and Effect. Metabolic studies have shown that

vinyl acetate is quickly hydrolyzed to acetaldehyde and acetate, which then

enters normal metabolic cycles to produce primarily carbon dioxide and water

(Hazleton 1979a; Simon et al. 1985a). A small amount also has been shown to

be excreted in the urine as urea and other unidentified metabolites (Hazleton

1980a). Because of the relatively rapid hydrolysis and the fact that

metabolites are incorporated into normal metabolic pathways, it would be

difficult to use vinyl acetate metabolites as biomarkers of exposure to this

chemical (Hazleton 1979a; Simon et al. 1985a).

Exposure to vinyl acetate in vitro has been shown to result in various

positive genotoxic end points in human lymphocytes (e.g., micronuclei,

chromosomal aberrations, sister chromatid exchange, and DNA cross-links) (He

and Lambert 1985; Jantunen et al. 1986; Lambert et al. 1985; Maki-Paakkanen

and Norppa 1987; Norppa et al. 1985, 1988). Because these results are from in

vitro tests and because many other chemicals may induce such abnormalities,

these should not be considered specific biomarkers of the effects of vinyl

acetate. Another possibility is to use protein or hemoglobin adducts of

acetaldehyde as a marker of effect for vinyl acetate. Stable

proteinacetaldehyde adducts (Izumi et al. 1988; Lin and Lumeng 1988) and

hemoglobinacetaldehyde adducts (Peterson et al. 1988) have been shown to be

formed following chronic alcohol ingestion. Since vinyl acetate does not form

adducts with DNA, this type of marker is also not usable as a marker for

effect. No other biomarkers (specific or otherwise) have been identified

following exposure to vinyl acetate. Additional animal or epidemiological

studies that measure changes in body fluids or enzyme levels following vinyl
78

2. HEALTH EFFECTS

acetate exposure would be useful to determine if such biomarkers exist and to

devise sensitive and specific early biomarkers of effect.

Absorption, Distribution, Metabolism, and Excretion. No information is

available to assess the relative rates and extent of vinyl acetate absorption

following exposure by any route in humans. Quantitative and qualitative

evidence indicates that vinyl acetate is rapidly and efficiently absorbed by

laboratory animals following inhalation and oral exposures (Hazleton 1979a,

1980a). Qualitative evidence also indicates that vinyl acetate penetrates the

skin of rabbits (Smyth and Carpenter 1948; Weil and Carpenter 1969). Given

the clear evidence across different animal species, it may be assumed that

similar absorption would occur in humans. Studies designed to investigate the

extent of absorption following dermal exposure would be helpful.

No studies were available in humans describing the distribution of

vinyl acetate following exposure by any route. Animal studies indicate that

vinyl acetate is rapidly and widely distributed throughout the body following

inhalation and oral exposure (Hazleton 1979a, 1980a). In these studies, vinyl

acetate was primarily distributed to the Harderian glands, lacrimal glands,

salivary glands, gastrointestinal mucosa, kidney, and larynges. No data on

the distribution of vinyl acetate following dermal exposure were located.

Such information would be useful because absorption via this route has been

shown to occur and because dermal exposure is a probable route of exposure

for humans.

No in vivo studies were available in humans describing the metabolism

of vinyl acetate following exposure by any route. The metabolism of vinyl

acetate has been characterized in animals. Studies in animals have shown

nonlinear kinetic patterns at high concentrations, indicating that the

metabolic process is saturable (Simon et al. 1985a). The metabolic pattern

was not different following oral or inhalation exposure (Hazleton 1980a).

Information on the metabolism of vinyl acetate following dermal exposure

would be useful.

No studies were available in humans describing the excretion of vinyl

acetate following exposure by any route. Vinyl acetate has been shown to be

rapidly eliminated from the body following oral and inhalation exposure in

animals (Hazleton 1979a, 1980a). Most of the vinyl acetate is eliminated in

expired air as carbon dioxide but small amounts have also been excreted in

the urine and feces (Hazleton 1979a, 1980a). Differences in the amount of

radioactivity eliminated in exhaled air following oral and inhalation

exposure to radiolabeled vinyl acetate have been minor (Hazleton 1979a,

1980a). No data on the elimination of vinyl acetate following dermal exposure

were located.

Comparative Toxicokinetics. No data are available on the toxicokinetics

of vinyl acetate in humans. However, quantitative and qualitative information
79

2. HEALTH EFFECTS

on the absorption and metabolism of vinyl acetate in rats and mice following

oral and inhalation exposure indicates that little variation exists between

these two species (Hazleton 1979a, 1980a). However, there does appear to be

some variation across routes of exposure in the distribution and excretion

patterns of vinyl acetate (Hazleton 1979a, 1980a). There were some minor

differences in the distribution pattern between the sexes (Hazleton 1979a,

1980a). No studies are available that investigate the kinetics of vinyl

acetate following dermal exposure. Therefore, studies that investigate the

toxicokinetics of vinyl acetate in animals following dermal exposure would be

useful to better understand the disposition of this chemical.

Mitigation of Effects. All of the treatment methods currently available

for use in vinyl acetate exposure are supportive in nature (Bronstein and

Currance 1988; Stutz and Janusz 1988). Since the mechanism(s) of vinyl

acetate toxicity are not known, there are currently no methods geared towards

mitigating the effects of vinyl acetate by interfering with the mode of

action. Additional information on the ultimate mechanism of vinyl acetate

toxicity is needed before insights can be gained on how to treat exposure

victims.

2.9.3 On-going Studies

E.I. DuPont de Nemours and Company's Haskell Laboratory has initiated a

basic research program investigating the mechanisms of chronic toxicity and

carcinogenicity of vinyl acetate. The objective of the program is to develop

a biologically based model for assessing human health risk from exposure to

vinyl acetate vapor. Major phases of the program are to investigate the

biochemical mechanism of action of vinyl acetate in isolated rodent nasal

turbinates; to measure in vitro enzyme kinetics describing vinyl acetate

hydrolysis to acetaldehyde and acetic acid in rodent and human nasal tissue;

to measure in vivo cell proliferation responses following short-term (2-week)

inhalation exposure; and to develop a physiologically-based pharmacokinetic

risk assessment model for extrapolating human health risk from exposure to

vinyl acetate. Results of this work are not yet available.







87

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

4.1 PRODUCTION

It is not known whether vinyl acetate occurs naturally (IARC 1986).

Vinyl acetate is a man-made compound that was first produced in 1912 as a by

product in the synthesis of ethylidene diacetate (Matthews 1974). This

reaction involved bubbling acetylene through a mixture of mercurous sulfate

and anhydrous acetic acid (Leonard 1970). During the 1920s, the Germans

converted this liquid-phase process to a vapor phase process that allowed

Germany to achieve a production volume of 12 million kg per year by the 1940s

and which accounted for most of the world's production of vinyl acetate until

about 1970 (Leonard 1970; Rhum 1970). The vapor phase process involved

passing a 4:l acetylene-to-acetic acid mixture over a catalyst bed made of

zinc acetate-saturated activated carbon at 180°-200°C. (Daniels 1983;

Llewellyn and Williams 1972). Mercury salts can also be used as a catalyst in

this reaction when it is conducted at 40°-50°C (International Labour Office

1985). Originally, acetylene was generated from calcium carbide (Leonard

1970). More recently, acetylene has been produced by cracking petroleum

(Llewellyn and Williams 1972).

Currently, the manufacturing process most widely used to produce vinyl

acetate is the vapor phase ethylene process, an oxidative reaction in which

ethylene is bubbled through acetic acid at 120°C in the presence of palladium

chloride catalyst (Daniels 1983; IAKC 1986). Impurities found in the reaction

have been reported at less than 1% (for one manufacturer) and have included

the following: acetaldehyde, ethyl acetate, and methyl acetate. The vapor

phase ethylene process was developed in 1967 to take advantage of ethylene as

a cheaper feedstock than acetylene, and came into widespread use in the 1970s

(Daniels 1983; IARC 1986; Llewellyn and Williams 1972). By 1981, the vapor

phase ethylene process accounted for 92% of U.S. production and the vapor

phase acetylene process accounted for the remainder (Dylewski 1981). Various

firms in the United States, Japan, West Germany, and the United Kingdom have

independently and/or jointly modified the vapor phase ethylene process by

using different types of catalysts in the reaction. The catalyst is usually

palladium or its salt, although salts of rhodium, gold, platinum, ruthenium,

vanadium, and iridium have also been used (Daniels 1983; Leonard 1970;

Llewellyn and Willizms 1972). The advantage of these processes is that the

catalyst lasts longer and undergoes less corrosion (Mannsville 1982).

A less important commercial manufacturing process for vinyl acetate

involves the reaction between acetaldehyde and acetic anhydride. The

intermediate species, ethylidene diacetate, undergoes pyrolytic cleavage to

vinyl acetate and acetic acid (Daniels 1983; Leonard 1970; Mannsville 1988).

This process was used in the United States until the 1960s, and may still be

in use at small plants in China, India, and Mexico (Daniels 1983; Mannsville

1982, 1988). Vinyl. acetate can also be synthesized in high yields by

reacting vinyl chloride with sodium acetate in solution at 50°-75°C, using

palladium chloride as a catalyst (Daniels 1983). New methods for vinyl

acetate
88

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

manufacture were being developed in 1982 that were to utilize synthetic gas

as a feedstock. The gas would undergo a series of carbonylation reactions to

yield ethylidene diacetate, which can be pyrolytically converted to vinyl

acetate and acetic acid (Mannsville 1982). No information has been found that

would indicate whether or not such new methods have been perfected or adopted

for industrial production in the United States.

Vinyl acetate is normally produced in three grades that differ only in

their content of inhibitor, which is added to prevent spontaneous

polymerization (Daniels 1983; Mannsville 1988). To obtain these grades,

either 3-7 ppm, 12-17 ppm, or 200-300 ppm p-hydroquinone is added to freshly

produced vinyl acetate, depending upon how long the product is to be stored

prior to use. Longer storage times require higher concentrations of inhibitor

(Daniels .1983). Vinyl acetate is often stored and/or shipped with a variety

of other inhibitors including benzoquinones, nitrobenzenes, diphenyls,

toluenes, anthracene, phenanthrene, naphthalene, and others (Operations

Research Inc. 1974).

Commercial production of vinyl acetate in the United States was first

reported in 1928 (U.S. Tariff Commission 1930). From 1960 to 1979, U.S.

production rose from 250 million pounds to 2.0 billion pounds. Production

levels were approximately 1.9 billion pounds between 1980 and 1982, and then

rose from 1.96 billion pounds in 1983 to 2.1 billion pounds in 1985. Levels

dropped to 1.7 billion pounds in 1986 and then climbed to 1.8 billion pounds

in 1987 (Daniels 1983; USITC 1979, 1980, 1981, 1982, 1983, 1984, 1985, 1986,

1987, 1988).

In 1984, with an increasing demand for vinyl acetate derived copolymer

emulsions, due primarily to strong automobile and housing industries,

production (over 2 billion pounds) was rapidly approaching the "practical

effective capacity" of 2.2 billion pounds and supply was limited (Greek

1984). It was forecasted in 1984 that an increased demand for vinyl acetate

for making adhesives and coatings would result in a greater capacity in

production (Greek 1984). By 1989, the demand for vinyl acetate reached 2.6

billion pounds and is expected to reach 2.9 billion pounds by 1993 (Van et

al. 1989). In 1989, five U.S. production facilities had a combined annual

production capacity of 2.8 billion pounds (Van et al. 1989).

The following chemical companies currently produce vinyl acetate in the

United States: E.I. DuPont de Nemours and Company, Polymer Products Division

located in La Porte, Texas; Hoechst Celanese Corporation, Commodity Chemicals

located in both Bay City, Texas and Clear Lake, Texas; Quantum Chemical

Corporation, U.S.I. Division located in both La Porte, Texas and Clinton,

Iowa; Union Carbide Corporation, Solvents and Coatings Materials Division

located in Texas City, Texas; Monsanto Company located in Trenton, Michigan

(SRI 1989; TR187 1989). For further information on facilities in the United

States that manufacture or process vinyl acetate, refer to Table 4-1. Vinyl

acetate is also produced in Australia, Brazil, Canada, China, France, West


91

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

Germany, Great Britain, India, Italy, Japan, Mexico, South Africa, and Spain

(CIS 1988; IARC 1986; Mannsville 1988). In Japan alone there are eight

manufacturers of vinyl acetate (CIS 1988). Five Japanese companies reported a

combined production capacity of 1.3 billion pounds in 1981 (IARC 1986).

4.2 IMPORT / EXPORT

U.S. imports of vinyl acetate declined, with large fluctuations from 31

million pounds in 1970 to 1 million pounds in 1984 (Mannsville 1988). Imports

remained at 1 million pounds until 1986, when a sharp rise to 12 million

pounds was observed. Imports then decreased to 1 million pounds in 1987

(Mannsville 1988). Only a small fraction of the vinyl acetate consumed in the

U.S. is imported.

Exports of vinyl acetate increased rapidly from 15 million pounds in

1965 to 645 million pounds in 1980 (Mannsville 1988). In 1984, as the demand

for vinyl acetate increased and supply was limited, it was predicted that any

surplus demand that existed after anticipated increases in production

capacity would be satisfied by diversion of the chemical from exports (Greek

1984). Exports were down in 1984 at 515 million pounds, compared with 589.9

million pounds in 1983 (Anonymous 1984; Mannsville 1988). Exports increased

steadily after 1984 to a level of 736 million pounds in 1987 (Mannsville

1988). In 1987, U.S. exports of vinyl acetate accounted for approximately 40%

of the total production volume (1.8 billion pounds in 1987).

4.3 USE

The primary use for vinyl acetate is as a monomer in the production of

polyvinyl acetate and polyvinyl alcohol (IARC 1986). These products,

synthesized via polymerization of vinyl acetate, accounted for 75%-80% of

total U.S. consumption in 1982 (Mannsville 1982, 1988). Vinyl acetate is also

polymerized with vinyl chloride to produce copolymers. Polyvinyl butyral,

polyvinyl acetals, ethylene-vinyl acetate copolymers, and acrylonitrile

copolymers (for acrylic fibers) are also produced. It is also used in

polymeric lubrication oil additives (Daniels 1983; IARC 1986).

Polyvinyl acetate emulsions (homopolymer and copolymer), the major

derivatives of vinyl acetate, are widely used in adhesives for packaging and

construction (wood gluing) and in water-based paints (IARC 1986; Mannsville

1988). Other important uses include nonwoven textile fibers, textile sizings

and finishes, paper coatings, and inks. Polyvinyl alcohol is widely used in

textile finishing, adhesives, and as a raw material for polyvinyl butyral,

which is used as the adhesive interlayer in architectural and automobile

laminated safety glass (Cincera 1983; Mannsville 1,988). Uses of other

polymers made from vinyl acetate include barriers in packaging, paint and

coatings applications, plastic floor coverings, phonograph records, flexible

film and sheeting (including plastic films used for wrapping food), food

starch modifier, and moulding and extrusion compounds.
92

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

In 1987, the estimated end-use distribution pattern for vinyl acetate

was as follows: 55% was used to produce polyvinyl acetate emulsions

(homopolymer and copolymer), for use in adhesives (23%), paint emulsions

(20%) and textile and paper emulsions (12%); 20% was used to produce

polyvinyl alcohol; 10% to produce ethylene/vinyl acetate; 5% to produce

polyvinyl butyral; 5% to produce polyvinyl chloride copolymers; and 5% to

produce miscellaneous products (Mannsville 1988).

4.4 DISPOSAL

The disposal method for vinyl acetate recommended in Japan, as reported

in 1982 by its International Technical Information Institute, was to

incinerate the compound by mixing it with a more flammable solvent and

spraying it into a furnace (ITII 1982). Information on disposal methods for

vinyl acetate that have been accepted or commonly used in the United States

is limited. Since underground injection accounts for 2.1 million pounds of

vinyl acetate releases, it is a probable method of disposal (TRI87 1989);

however, additional information on this method of disposal for vinyl acetate

is not available.
93

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Vinyl acetate is released to the environment, principally to the

atmosphere, as a result of emissions from manufacturing, processing, and

storage facilities. Vinyl acetate partitions to the atmosphere and to surface

water and groundwater. The compound is transformed by photochemical oxidation

in the atmosphere, and by hydrolysis and biodegradation in surface waters,

groundwater, and soils. As a result of its high vapor pressure and water

solubility/hydrolysis, vinyl acetate should not bioconcentrate in terrestrial

or aquatic organisms or biomagnify in food chains.

Workplace exposure via inhalation or dermal contact appears to be the

most important source of human exposure to vinyl acetate. Populations living

in areas surrounding hazardous waste sites may be exposed to vinyl acetate

through inhalation of contaminated air and ingestion of or dermal contact

with contaminated water; the latter route may be particularly important for

populations living near certain types of disposal sites (e.g., underground

injection sites). The relative importance of these pathways in terms of human

exposure potential is difficult to establish given the limited monitoring

data available for vinyl acetate. Most people, however, are probably exposed

to very small, amounts of vinyl acetate through: (1) inhalation of

contaminated ambient air and cigarette smoke; (2) dermal contact with

products containing the compound (e.g., glues and paints); and (3) ingestion

of residual vinyl acetate monomers in food (i.e., that may have migrated from

plastic food wraps) or food items containing the compound as a starch

modifier.

EPA had identified 1,177 NPL sites in 1989. We do not know how many of

the 1,177 NPL sites have been evaluated for vinyl acetate. Vinyl acetate has

been found at 3 of the total number of sites evaluated for that compound. As

more sites are evaluated by EPA, this number may change (View 1989). The

frequency of these sites within the United States can be seen in Figure 5-l.

5.2 RELEASES TO THE ENVIRONMENT

Vinyl acetate is released to the environment as a result of its

commercial production, use, storage, and disposal. According to the SARA

Section 313 Toxics Release Inventory (TRI), an estimated total of at least

8.8 million pounds of vinyl acetate was released to the environment from

manufacturing and processing facilities in the United States in 1987 (see

Table 5-l) (TR187 1989). The quality of the TRI data must be viewed with

caution since the 1987 data represent first-time reporting of estimated

releases by these facilities. Only certain types of facilities were required

to report. This is not an exhaustive list.

5.2.1 Air

Releases to the atmosphere accounted for about 75%, or 6.6 million

pounds, of the estimated total environmental releases from domestic



97

5. POTENTIAL FOR HUMAN EXPOSURE

manufacturing and processing facilities in 1987, according to TRI (TR187

1989).

The industrial organic chemicals, plastic materials and resins, paints

and allied products, and commercial printing industries have been identified

as potential sources of atmospheric releases of vinyl acetate (EPA 1987d).

Emission factors for volatile organic compounds (VOCs) and nonmethane

hydrocarbons (NMHCs) have been developed for vinyl acetate production via the

ethylene vapor-phase process. Emissions of VOCs from uncontrolled sources

(excluding fugitive emission sources) in a typical vinyl acetate production

plant have been estimated to total about 176 kg/hour; this estimate includes

about 36 kg/hour from vinyl acetate storage facilities (Dylewski 1980).

Fugitive emissions from valves and pump seals contribute an estimated

additional 0.0021 kg NMHC/hour and 0.0020 kg NMHC/hour, respectively (Langley

et al. 1981).

5.2.2 Water

Vinyl acetate has been detected in groundwater samples taken at an

estimated 0.71% of the NPL hazardous waste sites that have had samples

analyzed in the Contract Laboratory Program (CLP) at a geometric mean

concentration of 10 ppb for the positive samples (CLPSD 1989). The compound

was not detected in surface water samples at NPL sites participating in the

CLP. Note that these data from the CLP Statistical Database represent

frequency of occurrence and concentration information for NPL sites only.

According to TRI (TR187 1989), an estimated total of at least

10,000 pounds of vinyl acetate were released to surface waters in 1987 from

domestic manufacturing and processing facilities; an additional 147,219

pounds were released in effluents to publicly owned treatment works (POTWs).

Vinyl acetate has been detected in waste water from a polyvinyl acetate

production facility at a concentration of 50 mg/L (Stepanyan et al. 1970)

5.2.3 Soil

Vinyl acetate has been detected in soil samples taken at an estimated

2.13% of the NPL hazardous waste sites included in the CLP at a geometric

mean concentration of 19.5 ppb for the positive samples (CLPSD 1989). Note

that these data from the CLP Statistical Database represent frequency of

occurrence and concentration information for NPL sites only.

According to the TRI, an estimated total of at least 33 thousand pounds

of vinyl acetate were released to soils in 1987 from domestic manufacturing

and processing facilities; an additional 2.1 million pounds were released by

underground injection (TR187 1989).
98

5. POTENTIAL FOR HUMAN EXPOSURE

5.3 ENVIRONMENTAL FATE

5.3.1 Transport and Partitioning

No information was found in the available literature regarding the

transport and partitioning of vinyl acetate in environmental media. However,

estimates of the movement of the compound between the air, water, and soil

compartments following release to the environment can be made on the basis of

available physical and chemical property data.

Vinyl acetate is a volatile compound that is released mainly to the

atmosphere. Vinyl acetate is also highly soluble in water. Therefore,

dissolution of vinyl acetate released to the atmosphere in rainwater and

transport of the compound back to surface waters and soils in wet deposition

can be expected.

Using the vapor pressure and water solubility data presented in

Table 3-2, a Henry's law constant value of 4.8x10-4

 atm-m3 mol-1 can be

calculated. The magnitude of this value indicates that volatilization to the

atmosphere will be an important transport process for vinyl acetate released

to surface waters. Using this value and the methods reviewed by Thomas

(1982), a volatilization half-life of about 4 hours at 20°C can be estimated

for a river 1 meter deep flowing at a current of 1 m/second, with a wind

velocity of 3 m/second.

Vinyl acetate released to surface soils is also expected to volatilize

to the atmosphere. Releases of vinyl acetate to subsurface soils may leach to

and be transported in groundwater, depending upon site-specific

hydrogeological conditions, if the compound is not transformed or degraded

(Section 5.3.2.2). Sorption of the compound to soils and sediments is not

expected, given its high water solubility and low Koc value.

The log octanol/water partition coefficient for vinyl acetate has been

reported to be 0.21 (Fujisawa and Masuhara 1981) and 0.73 (Howard 1989). The

magnitude of these values indicates that bioconcentration and food chain

biomagnification will not be important processes for vinyl acetate.

5.3.2 Transfozmation and Degradation

5.3.2.1 Air

Vinyl acetate does not absorb ultraviolet light at wavelengths longer

than 250 nm (Daniels 1983), therefore, direct photolytic degradation of the

compound in the troposphere is not expected to occur. However, vinyl acetate

has been found to undergo rapid photochemical oxidation and polymerization in

laboratory studies in the absence of inhibitor (HSDB 1989). The average

second order rate constant for reaction with singlet molecular oxygen has

been reported to be 0.82 L mole-1

 sec-l (Datta and Rao 1979). In smog chamber
99

5. POTENTIAL FOR HUMAN EXPOSURE

studies with NOx concentrations representative of rural and urban

atmospheres, the photooxidation half-life of vinyl acetate was determined to

be 4.1-6.5 hours (Joshi et al. 1982).

5.3.2.2 Water

Vinyl acetate undergoes hydrolysis in surface water and groundwater.

The hydrolytic half-life of the compound at 25°C and pH 7.0 has been

estimated to be 7.3 days (Mabey and Mill 1978). Decreasing pH decreases the

hydrolysis rate; for example, the rate is minimal at pH 4.4 (Daniels 1983).

Acetic acid and acetaldehyde are the main products of vinyl acetate

hydrolysis (Daniels 1983; Stuckey et al. 1980).

Vinyl acetate also undergoes biologically-mediated transformation. The

results of several older laboratory studies with aqueous solutions of the

compound suggest the occurrence of biodegradation by domestic sewage effluent

microorganisms both under aerobic (Pahren and Bloodgood 1961; Price et 'al.

1974) and anaerobic (Chou et al. 1979; Stuckey et al. 1980) conditions. In a

more recent laboratory study, 17 isolates of bacteria and yeasts, capable of

utilizing vinyl acetate as a sole carbon source under aerobic conditions,

were obtained from samples of domestic sewage and loamy soil. Microorganisms

contained in a sludge inoculum were also found to be capable of

biotransforming vinyl acetate under anaerobic conditions. Under both aerobic

and anaerobic conditions, enzymatic hydrolysis of vinyl acetate yielded

acetaldehyde as a metabolic intermediate and acetate as an end product,

although the reaction was more rapid under aerobic conditions. A half-life of

12 hours was obtained for the enzymatic hydrolysis utilizing one of the

bacterial isolates under aerobic conditions, whereas, the half-life for the

nonenzymatic hydrolysis of the compound in a sterile medium was found to be

60 hours (Nieder et al. 1990).

5.3.2.3 Soil

In soils, vinyl acetate is also expected to be transformed by

hydrolysis and biotransformation. The rate of hydrolysis should increase as

soil moisture content and pH increase. As described in Section 5.3.2.2,

microbial isolates obtained from a loamy soil were found to be capable of

utilizing vinyl acetate as a sole carbon source under aerobic conditions

(Nieder et al. 1990). Metabolism studies utilizing one of the bacterial

isolates indicated that vinyl acetate was transformed via enzymatic

hydrolysis to acetaldehyde and acetate. The half-life for this biologicallymediated hydrolysis was found to be about one-fifth that of the nonenzymatic

hydrolysis of the compound (12 versus 60 hours).

Aqueous solutions containing 4.5 g/L of polyvinyl acetate have been

reported to undergo biotransformation by the soil fungi Aspergillis niger and

Penicillium following incubation for 15 days at 22°-25° C (Garcia 1988).

Polyvinyl acetate was the sole carbon source in the test media. Evidence of
100

5. POTENTIAL FOR HUMAN EXPOSURE

biotransformation included increased biomass of the fungi and increased

esterase levels in the media.

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

5.4.1 Air

Despite large releases of vinyl acetate to the atmosphere, data on

ambient air levels are limited to a single report from Texas City, Texas

(Houston/Gulf Coast area), of concentrations of 0.07-0.57 ppm (Gordon and

Meeks 1975). Note that these values should not be considered to represent

typical ambient air concentrations, since a number of the manufacturers of

vinyl acetate are located in Texas City (see Section 4.1). The compound has

also been detected in air samples taken at the Kin-Buc waste disposal site

located near Edison, New Jersey at a concentration of 0.5 μg/m3

 (0.00014 ppm)

(Pellizzari 1982).

5.4.2 Water

No information was found in the available literature regarding

concentrations of vinyl acetate in domestic surface waters or groundwaters.

Available groundwater monitoring data for NPL sites are reported in

Section 5.2.2.

5.4.3 Soil

No information was found in the available literature regarding

concentrations of vinyl acetate in domestic soils. Available soil monitoring

data for NPL sites are reported in Section 5.2.3.

5.4.4 Other Environmental Media

Available monitoring data for other environmental media are limited to

reports of vinyl acetate as a constituent of the vapor phase of cigarette

smoke at concentrations of 400 ng/cigarette (Guerin 1980) and 0.5 μg/puff

(Battista 1976).

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Human exposure to vinyl acetate is most well defined for workplace

populations. The National Occupational Exposure Survey (NOES), conducted by

NIOSH from 1980-1983, estimated that 50,282 workers employed at 5,046 plant

sites were potentially exposed to vinyl acetate in the United States in 1980

(NIOSH 1990b). The NOES database does not contain information on the

frequency, concentration, or duration of exposure; the survey provides only

estimates of workers potentially exposed to chemicals in the workplace.
101

5. POTENTIAL FOR HUMAN EXPOSURE

Workers involved in the production, storage, processing, and transport

of vinyl acetate are exposed primarily via inhalation-of vapors and skin and

eye contact with the liquid or vapor forms of the compound (NIOSH 1978).

Workplace air concentration levels reviewed by NIOSH (1978) were generally

within the recommended 15-minute ceiling limit of 4 ppm. In another survey of

vinyl acetate production facilities in Texas, the following workplace

airborne concentrations were reported: average TWA concentrations--5.2-8.2

ppm; average breathing zone concentrations--8.6 ppm; intermittent exposure

concentrations --about 50 ppm; and potential short-term exposures--up to

300 ppm (Deese and Joyner 1969).

Monitoring data are insufficient to establish ambient levels of vinyl

acetate in environmental media. However, the compound has fairly limited

residence times in environmental media as a result of its reactivity (see

Section 5.3.2). Contaminated environmental media may be important sources for

populations living in the vicinity of continuous emission point sources, such

as industrial manufacturing, processing, storage, or disposal sites (e.g.,

underground injection sites), or hazardous waste sites.

Although few monitoring data exist, given the high production volume

and extensive use of vinyl acetate, most people are probably exposed to very

small amounts of vinyl acetate through: (1) inhalation of contaminated

ambient air and cigarette smoke; (2) inhalation, dermal contact, or ingestion

of residual monomers in consumer products containing polyvinyl acetate (e.g.,

paints, adhesives, chewing gum); and (3) ingestion of food items packaged in

plastic films containing vinyl acetate.

Inhalation is expected to be the main route of human exposure to the

hydrolysis product of vinyl acetate, acetaldehyde. Acetaldehyde has a high

vapor pressure and is miscible with water. It rapidly volatilizes (e.g.,

half-life in river water = 1.9 hours) from surface waters or soils to the

atmosphere, where it is transformed via photolysis and reaction with hydroxyl

radicals, with a half-life on the order of hours. The high water solubility

of the compound suggests that releases to subsurface soil, or to surface soil

that do not volatilize, will partition to soil water and possibly groundwater

unless degraded by aerobic and anaerobic microorganisms. Acetaldehyde does

not sorb to soils or sediments, or bioconcentrate/biomagnify in terrestrial

or aquatic organisms/food chains. Acetaldehyde is a natural constituent of

foods (HSDB 1991).

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Workers involved in the production, processing, storage, and transport

of vinyl acetate are potentially exposed to high concentrations of the

compound. Members of the general population living in the vicinity of

industrial point emission sources, and individuals living near waste sites

that are contaminated with vinyl acetate may also be exposed to potentially

high concentrations of the compound. The sizes of these populations and the
102

5. POTENTIAL FOR HUMAN EXPOSURE

concentrations of vinyl acetate in the contaminated media to which these

people may be exposed have not been adequately characterized.

5.7 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of

ATSDR (in consultation with the Administrator of EPA and agencies and

programs of the Public Health Service) to assess whether adequate information

on the health effects of vinyl acetate is available. Where adequate

information is not available, ATSDR, in conjunction with the NTP, is required

to assure the initiation of a program of research designed to determine the

health effects (and techniques for developing methods to determine such

health effects) of vinyl acetate.

The following categories of possible data needs have been identified by

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as

substance-specific informational needs that, if met, would reduce or

eliminate the uncertainties of human health assessment. In the future, the

identified data needs will be evaluated and prioritized, and a substancespecific research agenda will be proposed.

5.7.1 Data Needs

Physical and Chemical Properties. The physical/chemical properties of

vinyl acetate are sufficiently well defined to enable assessment of the

environmental fate of this compound (Tables 3-l and 3-2).

Production, Import/Export, Use, and Disposal. Vinyl acetate is released

to the environment as a result of its commercial production, use, storage,

transport, and disposal. Human exposure occurs mainly in the workplace

through inhalation of vinyl acetate vapors.

Domestic production of vinyl acetate in 1986 and 1987 totaled

1.7 billion pounds and 1.8 billion pounds, respectively (Daniels 1983; USITC

1986, 1987). These levels are slightly lower than the recent high of 2.1

billion pounds reported in 1985 (Daniels 1983; USITC 1985). In 1987, imports

and exports of the compound totaled 1 million and 736 million pounds,

respectively (Mannsville 1988). Vinyl acetate is used primarily as a chemical

intermediate in the production of polymeric materials (Daniels 1983; IARC

1986; Mannsville 1982, 1988). Vinyl acetate is contained in polymeric

consumer products only as residual monomer (Cincera 1983; IARC 1986;

Mannsville 1988). Releases of the compound from industrial processes are

mainly to the atmosphere. Underground injection is also an important source

of release for certain facilities. No information was found on current

disposal methods or the regulations governing disposal of vinyl acetate.
103

5. POTENTIAL FOR HUMAN EXPOSURE

Additional information on disposal methods and pertinent regulations

would be useful in evaluating the potential for release of and exposure to

vinyl acetate.

According to the Emergency Planning and Community Right-to-Know Act of

1986, 42 U.S.C. Section 11023, industries are required to submit chemical

release and off-site transfer information to the EPA (EPA 1987c). The Toxics

Release Inventory (TRI), which contains this information for 1987, became

available in May of 1989 (TR187 1989). This database will be updated yearly

and should provide a list of industrial production facilities and emissions.

Environmental Fate. Little information is available regarding the

transport and partitioning or transformation and degradation of vinyl

acetate. Based on its physical/chemical properties, vinyl acetate is expected

to partition to the atmosphere and surface water and groundwater (Fujisawa

and Masuhara 1981; Hansch and Leo 1979). Vinyl acetate is not expected to

persist, bioconcentrate, or biomagnify (Fujisawa and Masuhara 1981; Hansch

and Leo 1979). The most important transformation processes for vinyl acetate

are photooxidation and hydrolysis (Joshi et al. 1982; Mabey and Mill 1978);

the relative importance of biodegradation is unknown (Chou et al. 1979;

Pahren and Bloodgood 1961; Price et al. 1974; Stuckey et al. 1980).

Additional information is needed on the transport/partitioning and

transformation/degradation of vinyl acetate in all media in order to confirm

the predicted behavior described above and establish the relative importance

of the various transformation processes. This information will be helpful in

defining the relative importance of various routes of exposure to the

compound in environmental media.

Bioavailability from Environmental Media. No information was found

regarding human absorption of vinyl acetate following inhalation, oral, or

dermal exposures from environmental media. Limited data available for

laboratory animals suggest that absorption may occur following exposure by

all of these routes (Hazleton 1979a, 1980a; Smyth and Carpenter 1948; Weil

and Carpenter 1969). Additional information is needed on the uptake of vinyl

acetate following inhalation of workplace and ambient air, dermal contact

with or ingestion of contaminated soils, and ingestion of contaminated

drinking water. This information would be useful in determining the

bioavailability of the compound from environmental media.

Food Chain Bioaccumulation. No information was found regarding the

bioconcentration of vinyl acetate by plants, aquatic organisms, or animals,

or the biomagnification of the compound in terrestrial or aquatic food

chains. On the basis of the reactivity, volatility, and water solubility of

the compound, bioconcentration and biomagnification are not expected to be

important environmental fate processes (Fujisawa and Masuhara 1981; Hansch

and Leo 1979). Additional information is needed to confirm this predicted
104

5. POTENTIAL FOR HUMAN EXPOSURE

behavior. This information will be useful in establishing the importance of

food chain bioaccumulation as a source of human exposure to vinyl acetate.

Exposure Levels in Environmental Media. Very limited data are available

concerning ambient concentrations of vinyl acetate in the atmosphere (Gordon

and Meeks 1975). No data are available for surface waters, groundwater, or

soils. Additional information is needed on ambient levels in these media,

including media concentration levels at hazardous waste sites, and on human

intake through contact with these media and ingestion of contaminated foods.

This information would be useful in estimating human exposure to vinyl

acetate.

Exposure Levels in Humans. Vinyl acetate is rapidly hydrolyzed by

esterases in the blood to acetate and vinyl alcohol. Vinyl alcohol is rapidly

converted to acetaldehyde, which in turn is metabolized to acetate (Hazleton

1979a, 1980a; Simon et al. 1985). Vinyl acetate metabolism is rapid; in vivo

tests with laboratory animals indicate that most of the compound is

eliminated within 24 hours after exposure (Hazleton 1979a, 1980a). Therefore,

it would be difficult to measure the presence of vinyl acetate or

acetaldehyde after reasonable periods following exposure to vinyl acetate.

Acetaldehyde and acetate may also not be useful as indicators of vinyl

acetate exposure. Because these compounds are incorporated into normal

metabolic pathways, it would be difficult to determine which metabolites were

due to vinyl acetate exposure and which were endogenous in biological tissues

and fluids. Additional investigation of the utility of biomarkers of exposure

in characterizing human exposure to vinyl acetate would be useful.

Exposure Registries. No exposure registries for vinyl acetate were

located. This compound is currently not one of the compounds for which a

subregistry has been established in the National Exposure Registry. The

compound will be considered in the future when chemical selection is made for

subregistries to be established. The information that is amassed in the

National Exposure Registry facilitates the epidemiological research needed to

assess adverse health outcomes that may be related to the exposure to this

compound.

5.7.2 On-going Studies

On-going remedial investigations and feasibility studies conducted at

NPL sites will add to the available database on exposure levels in

environmental media and exposure registries.

No other long-term on-going research pertaining to environmental fate

or human exposure potential of vinyl acetate was identified or located.
105

6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that

are available for detecting and/or measuring and monitoring vinyl acetate in

environmental media and in biological samples. The intent is not to provide

an exhaustive list of analytical methods that could be used to detect and

quantify vinyl acetate. Rather, the intention is to identify well-established

methods that are used as the standard methods of analysis. Many of the

analytical methods used to detect vinyl acetate in environmental samples are

the methods approved by federal agencies such as EPA and the National

Institute for Occupational Safety and Health (NIOSH). Other methods presented

in this chapter are those that are approved by groups such as the Association

of Official Analytical Chemists (AOAC) and the American Public Health

Association (APHA). Additionally, analytical methods are included that refine

previously used methods to obtain lower detection limits, and/or to improve

accuracy and precision.

6.1 BIOLOGICAL MATERIALS

The only method of analysis described in the literature for detecting

vinyl acetate and metabolites in biological media is by administration of

radioactive vinyl acetate (Hazleton 1979a, 1980a). Vinyl acetate is a

volatile organic compound that is very rapidly hydrolyzed to acetaldehyde

(via the unstable intermediate, vinyl alcohol) and acetate in the bodies of

humans and animals (Simon et al. 1985a; Vinegar 1983). The acetaldehyde is

converted to acetate and incorporated into the normal biochemical pathways

and primarily excreted as carbon dioxide in expired air (Vinegar 1983).

Section 2.3 contains more detailed information on the toxicokinetics of vinyl

acetate.

6.2 ENVIRONMENTAL SAMPLES

Most analysis of vinyl acetate has been done on workplace air,

especially in factories that make or use vinyl acetate. The primary method of

analysis for vinyl acetate in air is gas chromatography with flame ionization

detection (GC/FID). Infrared spectroscopy and gas chromatography/mass

spectrometry (GC/MS) are also frequently used. Problems encountered when

analyzing for vinyl acetate include volatility of the sample, interference

from other organic chemicals, degradation of vinyl acetate by hydrolysis and

polymerization, and desorption (extraction) of the sample. Most of the

variation in methodology occurs with sample collection and desorption.

Samples have been collected by grab-sampling, by midget impingers, and on

solid sorbent tubes.

Grab-sampling of air in Houston followed by analysis by GC/FID or

Fourier transform infrared spectroscopy (FTIR), showed that vinyl acetate

could be detected in the samples in the presence of a large number of other

organic compounds when analyzed by FTIR (Gordon and Meeks 1977).

Disadvantages of this method are possible loss of sample through leakage from

or decomposition in the collection bags and contamination of the sample by

bag
106

6. ANALYTICAL METHODS

components. Problems encountered with the FTIR hardware under field

conditions led the authors to conclude the technique was better suited for

laboratory use.

Midget impingers, as well as large-scale impingers, containing toluene

have been used to sample the air in a vinyl acetate production plant (Deese

and Joyner 1969). Analysis of samples was conducted by GC/FID. Several

evaluations indicated that the method was accurate (mean recovery of 99.2%)

and reliable for concentrations in the low ppm range. The main problems with

this method are that the liquid used in the impingers is subject to spillage

(however, unspillable impingers are now available) and it is difficult to

scale the impingers down to a suitable size for personal use.

Solid sorbents are the usual collection media for personal sampling

tubes used in occupational exposure situations because they are efficient,

simple to use, and can be easily be scaled down to a convenient size. Solid

sorbents are also the most frequently used for concentrations of organics

from air. One of the most commonly used solid sorbents is activated carbon

(Foerst and Teass 1980; Kollar et al. 1988; Krajewski et al. 1980; Sidhu

1981). Recoveries on this sorbent can be low due to hydrolysis or

polymerization, depending on humidity conditions. Recoveries have ranged from

40% to 101% depending on desorption technique, humidity level, sample storage

time, and how the sample was introduced to the sampler (Foerst and Teass

1980; Kollar et al. 1988; Krajewski et al. 1980; Sidhu 1981). Modifications

to the activated carbon sampler were made to alleviate some of the problems

associated with them (Kimble et.al. 1982). Recoveries approaching 100% were

reported with activated charcoal sorbent treated with a polymerization

inhibitor (hydroquinone) and preceded by a drying agent (calcium sulfate).

When desorbed with carbon disulfide-acetone and analyzed by GC/FID, good

sensitivity and precision were obtained (see Table 6-l). Advantages of this

technique are apparent sample stability, high breakthrough volume, and

readily available desorption and detection techniques. When this approach was

repeated by others (Andersson and Andersson 1988), however, both recovery and

precision were poor at humidities below 50%. A more recent GC/FID method

using collection on the solid sorbent, Ambersorb XE-347, followed by

desorption with dichloromethane containing 5% methanol, yielded excellent

recovery and precision over humidities ranging from 20 to 85% (Andersson and

Andersson 1990).

The NIOSH-recommended procedure for determining vinyl acetate in air

calls for collection on Chromosorb 107, followed by thermal desorption and

analysis by GC/FID (NIOSH 1990a). The lowest quantifiable level with this

method is in the low ppb range with an average precision of 8.1% relative

standard deviation (RSD) at humidity levels greater than 80%. The NIOSH

method was developed and compared to activated charcoal by Foerst and Teass

(1979). Although activated charcoal had a higher affinity for vinyl acetate,

as demonstrated by its higher breakthrough volume (about 167 L compared to 

4L for Chromosorb 107), vinyl acetate was considerably less stable on the


109

6. ANALYTICAL METHODS

activated charcoal. Advantages of the Chromosorb 107 collection technique

are improved sample stability, better recovery, and improved precision

through a wider humidity range. Disadvantages are a lower breakthrough volume

and limited access of most field sites to the thermal desorption technique.

Vinyl acetate has also been determined in air at industrialized areas

and near waste disposal sites using Tenax GC sorbent with thermal

desorption. Separation and detection was on a high resolution GC/MS coupled

to a computer containing a mass spectra database. Recoveries for this method

were greater than 75%. Advantages of this method are its specificity in the

presence of large numbers of potentially interfering chemicals and ability to

quantify results (Pellizzari 1982). A disadvantage is the requirement for

sophisticated and expensive equipment and the expertise to use the method. In

addition, the effect of humidity is not known.

A more recently developed technique for use in industrial hygiene

situations depends on detection of vinyl acetate by coated surface acoustic

wave sensor. The special trans-PtCL2(ethylene)(pyridine) coating makes the

technique selective for vinyl acetate, and the apparatus can easily be scaled

down for personal use. In addition, the coating is regenerative, increasing

the cost/benefit ratio (Zellers 1989). More information is needed to compare

this method to those currently in use.

Very little information was found concerning analysis of vinyl acetate

in water and soil and no information was found for other media. The EPA

recommended method for water (Method 624) specifies sampling on a total

organics concentrator (Tenax -silica gel) used as a purge-trap device (EPA

1979). The sample is thermally desorbed and analyzed by GC/MS. This method

was used to detect vinyl acetate in secondary effluent from a publicly owned

treatment works (Spingarn et al. 1982). It proved to be sensitive, accurate,

and fairly precise. This method was also used to measure vinyl acetate in

coal combustion leachate with a detection limit of 10 μg/L (Sorini and

Jackson 1988).

6.3 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of

ATSDR (in consultation with the Administrator of EPA and agencies and

programs of the Public Health Service) to assess whether adequate information

on the health effects of vinyl acetate is available. Where adequate

information is not available, ATSDR, in conjunction with the NTP, is required

to assure the initiation of a program of research designed to determine the

health effects (and techniques for developing methods to determine such

health effects) of vinyl acetate.

The following categories of possible data needs have been identified by

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as

substance-specific informational needs that, if met, would reduce or

eliminate
110

6. ANALYTICAL METHODS

the uncertainties of human health assessment. In the future, the identified

data needs will be evaluated and prioritized, and a substance-specific

research agenda will be proposed.

6.3.1 Data Needs

Methods for Determining Biomarkers of Exposure and Effect. There are no

reliable biomarkers of exposure for vinyl acetate (see Sections 2.5.1 and

2.9.2). Vinyl acetate is rapidly absorbed and metabolized in the body

(Hazleton 1979a, 1980a; Simon et al. 1985a). The metabolites formed,

acetaldehyde and acetate, are commonly found in humans and animals, and thus

are not specific for exposure to vinyl acetate. Acetaldehyde and acetate are

incorporated into the biochemical cycles and converted primarily to carbon

dioxide and water. There are no tests currently available for measuring vinyl

acetate or its metabolites in biological tissues.

There are no established biomarkers of effect for vinyl acetate; thus,

there are no methods for determining biomarkers of effect for this compound.

No changes in enzyme levels or body fluids have been documented following

exposure to this compound. Genotoxic effects have been found in in vitro

tests, but these are not specific for vinyl acetate and there is no

established method for monitoring such effects in vivo.

Methods for Determining Parent Compounds and Degradation Products in

Environmental Media. Given vinyl acetate's high volatility, the media of most

concern for human exposure is most likely air, with exposure also occurring

by both oral and dermal routes (Deese and Joyner 1969; NIOSH 1978; Smyth and

Carpenter 1973). Sensitive, reliable, and accurate methods exist for

determining vinyl acetate in air (Deese and Joyner 1969; Foerst and Teass

1979; Gordon and Meeks 1977; Kimble et al. 1982; Kollar et al. 1988; NIOSH

1990a). The detection limits of these methods are probably too high for

monitoring ambient air, but are sufficient for measuring levels present in

occupational settings. At least one sensitive and accurate method exists for

detecting vinyl acetate in water (Springarn et al. 1982). Routine methods of

analysis for other environmental media were not located. Further studies on

measurement of vinyl acetate in air, water and soil would be useful in

determining the potential for exposure to this chemical at hazardous waste

sites.

6.3.2 On-going Studies

No on-going studies concerning methods for measuring and determining

vinyl acetate in biological and environmental samples were located.
111

7. REGULATIONS AND ADVISORIES

Vinyl acetate is on the list of chemicals appearing in "Toxic Chemicals

Subject to Section 313 of the Emergency Planning and Community Right-to-Know

Act of 1986" (EPA 1987c). ATSDR has derived an intermediate inhalation MRL of

0.01 ppm based on respiratory effects seen in mice (Hazleton 1980b).

The international, national, and state regulations and guidelines

regarding vinyl acetate in air, water, and other media are summarized in

Table 7-l.



115

8. REFERENCES

*ACGIH. 1986. Documentation of the threshold limit values and biological

exposure indices. 5th ed. American Conference of Governmental Industrial

Hygienists. Cincinnati, OH, 621.

*ACGIH. 1992. Written communication (April 23) to Lynne R. Harris, Society

of the Plastics Industry, Inc., regarding proposed changes in the ACGIH

recomendations for the Short Term Exposure Limit and Carcinogen

Classification of vinyl acetate. American Conference of Governmental

Industrial Hygienists. Cincinnati, OH.

Adkins JE Jr. 1982. Industrial hygiene monitoring for vinyl acetate. U.S.

EPA/OTS public files. Document no. 878221634. (Unpublished report submitted

August 30, 1982).

Adkins JE Jr. 1983a. Industrial hygiene monitoring: Vinyl acetate. U.S.

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137

9. GLOSSARY

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less,

as specified in the Toxicological Profiles.

Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical adsorbed

per unit weight of organic carbon in the soil or sediment to the

concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or

soil (i.e., the solid phase) divided by the amount of chemical in the

solution phase, which is in equilibrium with the solid phase, at a fixed

solid/solution ratio. It is generally expressed in micrograms of chemical

sorbed per gram of soil or sediment.

Bioconcentration Factor (BCF) -- The quotient of the concentration of a

chemical in aquatic organisms at a specific time or during a discrete time

period of exposure divided by the concentration in the surrounding water at

the same time or during the same period.

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group

of studies, that produces significant increases in the incidence of cancer

(or tumors) between the exposed population and its appropriate control.

Carcinogen -- A chemical capable of inducing cancer.

Ceiling Value -- A concentration of a substance that should not be exceeded,

even instantaneously.

Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified

in the Toxicological Profiles.

Developmental Toxicity -- The occurrence of adverse effects on the developing

organism that may result from exposure to a chemical prior to conception

(either parent), during prenatal development, or postnatally to the time of

sexual maturation. Adverse developmental effects may be detected at any point

in the life span of the organism.

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a

result of prenatal exposure to a chemical; the distinguishing feature between

the two terms is the stage of development during which the insult occurred.

The terms, as used here, include malformations and variations, altered

growth, and in utero death.

EPA Health Advisory -- An estimate of acceptable drinking water levels for a

chemical substance based on health effects information. A health advisory is

not a legally enforceable federal standard, but serves as technical guidance

to assist federal, state, and local officials.
138

9. GLOSSARY

Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental

concentration of a contaminant from which one could escape within 30 min

without any escape-impairing symptoms or irreversible health effects.

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days

as specified in the Toxicological Profiles.

Immunologic Toxicity -- The occurrence of adverse effects on the immune

system that may result from exposure to environmental agents such as

chemicals.

In Vitro -- Isolated from the living organism and artificially maintained, as

in a test tube.

In Vivo -- Occurring within the living organism.

Lethal Concentration (Lo) (LCLo) -- The lowest concentration of a chemical in

air which has been reported to have caused death in humans or animals.

Lethal Concentration (50) (LC50) -- A calculated concentration of a chemical in

air to which exposure for a specific length of time is expected to cause

death in 50% of a defined experimental animal population.

Lethal Dose (Lo) (LDLo) -- The lowest dose of a chemical introduced by a route

other than inhalation that is expected to have caused death in humans or

animals.

Lethal Dose (50) (LD50) -- The dose of a chemical which has been calculated to

cause death in 50% of a defined experimental animal population.

Lethal Time (50) (LT50) -- A calculated period of time within which a specific

concentration of a chemical is expected to cause death in 50% of a defined

experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical

in a study, or group of studies, that produces statistically or biologically

significant increases in frequency or severity of adverse effects between the

exposed population and its appropriate control.

Malformations -- Permanent structural changes that may adversely affect

development, or function.

Minimal Risk Level -- An estimate of daily human exposure to a chemical that

is likely to be without an appreciable risk of deleterious effects

(noncancerous) over a specified duration of exposure.
139

9. GLOSSARY

Mutagen -- A substance that causes mutations. A mutation is a change in the

genetic material in a body cell. Mutations can lead to birth defects,

miscarriages, or cancer.

Neurotoxicity - - The occurrence of adverse effects on the nervous system

following exposure to chemical.

No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which

there were no statistically or biologically significant increases in

frequency or severity of adverse effects seen between the exposed population

and its appropriate control. Effects may be produced at this dose, but they

are not considered to be adverse.

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the

concentrations of a chemical in n-octanol and water, in dilute solution.

Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace

air averaged over an 8-hour shift.

q1* -- The upper-bound estimate of the low-dose slope of the dose-response

curve as determined by the multistage procedure. The ql* can be used to

calculate an estimate of carcinogenic potency, the incremental excess cancer

risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and

μg/m3

 for air).

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an

order of magnitude) of the daily exposure of the human population to a

potential hazard that is likely to be without risk of deleterious effects

during a lifetime. The RfD is operationally derived from the NOAEL (from

animal and human studies) by a consistent application of uncertainty factors

that reflect various types of data used to estimate RfDs and anadditional

modifying factor, which is based on a professional judgment of the entire

database on the chemical. The RfDs are not applicable to nonthreshold effects

such as cancer.

Reportable Quantity (RQ) -- The quantity of a hazardous substance that is

considered reportable under CERCLA. Reportable quantities are (1) 1 lb or

greater or (2) for selected substances, an amount established by regulation

either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are

measured over a 24-hour period.

Reproductive Toxicity -- The occurrence of adverse effects on the

reproductive system that may result from exposure to a chemical. The toxicity

may be directed to the reproductive organs and/or the related endocrine

system. The manifestation of such toxicity may be noted as alterations in

sexual behavior, fertility, pregnancy outcomes, or modifications in other

functions that are dependent on the integrity of this system.
140

9. GLOSSARY

Short-Term Exposure Limit (STEL) -- The maximum concentration to which

workers can be exposed for up to 15 min continually. No more than four

excursions are allowed per day, and there must be at least 60 min between

exposure periods. The daily TLV-TWA may not be exceeded.

Target Organ Toxicity -- This term covers a broad range of adverse effects on

target organs or physiological systems (e.g., renal, cardiovascular)

extending from those arising through a single limited exposure to those

assumed over a lifetime of exposure to a chemical.

Teratogen -- A chemical that causes structural defects that affect the

development of an organism.

Threshold Limit Value (TLV) -- A concentration of a substance to which most

workers can be exposed without adverse effect. The TLV may be expressed as a

TWA, as a STEL, or as a CL.

Time-Weighted Average (TWA) -- An allowable exposure concentration averaged

over a normal S-hour workday or 40-hour workweek.

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route

other than inhalation, which is expected to cause a specific toxic effect in

50% of a defined experimental animal population.

Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD

from experimental data. UFs are intended to account for (1) the variation in

sensitivity among the members of the human population, (2) the uncertainty in

extrapolating animal data to the case of human, (3) the uncertainty in

extrapolating from data obtained in a study that is of less than lifetime

exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data.

Usually each of these factors is set equal to 10.
A-l

APPENDIX A

USER'S GUIDE

Chapter 1

Public Health Statement

This chapter of the profile is a health effects summary written in

nontechnical language. Its intended audience is the general public especially

people living in the vicinity of a hazardous waste site or substance release.

If the Public Health Statement were removed from the rest of the document, it

would still communicate to the lay public essential information about the

substance. The major headings in the Public Health Statement are useful to

find specific topics of concern. The topics are written in a question and

answer format. The answer to each question includes a sentence that will

direct the reader to chapters in the profile that will provide more

information on the given topic.

Chapter 2

Tables and Figures for Levels of Significant Exposure (LSE)

Tables (2-1, 2-2, and 2-3) and figures (2-l and 2-2) are used to summarize

health effects by duration of exposure and endpoint and to illustrate

graphically levels of exposure associated with those effects. All entries in

these tables and figures represent studies that provide reliable,

quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), LowestObserved- Adverse-Effect Levels (LOAELS) for Less Serious and Serious health

effects, or Cancer Effect Levels (CELs). In addition, these tables and

figures illustrate differences in response by species, Minimal Risk Levels

(MRLs) to humans for noncancer end points, and EPA's estimated range

associated with an upper-bound individual lifetime cancer risk of 1 in 10,000

to 1 in 10,000,000. The LSE tables and figures can be used for a quick review

of the health effects and to locate data for a specific exposure scenario.

The LSE tables and figures should always be used in conjunction with the

text.

The legends presented below demonstrate the application of these tables and

figures. A representative example of LSE Table 2-l and Figure 2-l are shown.

The numbers in the left column of the legends correspond to the numbers in

the example table and figure.

LEGEND

See LSE Table 2-l

(1). Route of Exposure One of the first considerations when reviewing the

toxicity of a substance using these tables and figures should be the

relevant and appropriate route of exposure. When sufficient data exist,
A-2

APPENDIX A

three LSE tables and two LSE figures are presented in the document. The

three LSE tables present data on the three principal routes of

exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and

2-3, respectively). LSE figures are limited to the inhalation (LSE

Figure 2-l) and oral (LSE Figure 2-2) routes.

(2). Exposure Duration Three exposure periods: acute (14 days or less);

intermediate (15 to 364 days); and chronic (365 days or more) are

presented within each route of exposure. In this example, an inhalation

study of intermediate duration exposure is reported.

(3). Health Effect The major categories of health effects included in

LSE tables and figures are death, systemic, immunological,

neurological, developmental, reproductive, and cancer. NOAELs and

LOAELs can be reported in the tables and figures for all effects but

cancer. Systemic effects are further defined in the "System" column of

the LSE table.

(4). Key to Figure Each key number in the LSE table links study information

to one or more data points using the same key number in the

corresponding LSE figure. In this example, the study represented by key

number 18 has been used to define a NOAEL and a Less Serious LOAEL

(also see the two "18r" data points in Figure 2-l).

(5). Species The test species, whether animal or human, are identified in

this column.

(6). Exposure Frequency /Duration The duration of the study and the weekly

and daily exposure regimen are provided in this column. This permits

comparison of NOAELs and LOAELs from different studies. In this case

(key number 18), rats were exposed to [substance x] via inhalation for

13 weeks, 5 days per week, for 6 hours per day.

(7). System This column further defines the systemic effects. These systems

include: respiratory, cardiovascular, gastrointestinal, hematological,

musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to

any systemic effect (e.g., a decrease in body weight) not covered in

these systems. In the example of key number 18, one systemic effect

(respiratory) was investigated in this study.

(8). NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest

exposure level at which no harmful effects were seen in the organ

system studied. Key number 18 reports a NOAEL of 3 ppm for the

respiratory system which was used to derive an intermediate exposure,

inhalation MRL of 0.005 ppm (see footnote “c”).

(9). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest

exposure level used in the study that caused a harmful health effect.

LOAELs have been classified into "Less Serious" and "Serious" effects.

These distinctions help readers identify the levels of exposure at

which adverse health effects first appear and the gradation of effects

with increasing dose. A brief description of the specific end point

used to
A-3

APPENDIX A

quantify the adverse effect accompanies the LOAEL. The "Less Serious"

respiratory effect reported in key number 18 (hyperplasia) occurred at

a LOAEL of 10 ppm.

(10). Reference The complete reference citation is given in Chapter 8 of the

profile.

(11). CEL A Cancer Effect Level (CEL) is the lowest exposure level associated

with the onset of carcinogenesis in experimental or epidemiological

studies. CELs are always considered serious effects. The LSE tables and

figures do not contain NOAELs for cancer, but the text may report doses

which did not cause a measurable increase in cancer.

(12). Footnotes Explanations of abbreviations or reference notes for data in

the LSE tables are found in the footnotes. Footnote "c" indicates the

NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm.

LEGEND

See LSE Figure 2-l

LSE figures graphically illustrate the data presented in the corresponding

LSE tables. Figures help the reader quickly compare health effects according

to exposure levels for particular exposure duration,

(13). Exposure Duration The same exposure periods appear as in the LSE table.

In this example, health effects observed within the intermediate and

chronic exposure periods are illustrated.

(14). Health Effect These are the categories of health effects for which

reliable quantitative data exist. The same health effects appear in the

LSE table.

(15). Levels of Exposure Exposure levels for each health effect in the LSE

tables are graphically displayed in the LSE figures. Exposure levels

are reported on the log scale "y" axis. Inhalation exposure is reported

in mg/m3

 or ppm and oral exposure is reported in mg/kg/day.

(16). NOAEL In this example, 18r NOAEL is the critical end point for which an

intermediate inhalation exposure MRL is based. As you can see from the

LSE figure key, the open-circle symbol indicates a NOAEL for the test

species (rat). The key number 18 corresponds to the entry in the LSE

table. The dashed descending arrow indicates the extrapolation from the

exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005

ppm (see footnote "b" in the LSE table).

(17). CEL Key number 38r is one of three studies for which Cancer Effect

Levels (CELs) were derived. The diamond symbol refers to a CEL for the

test species (rat). The number 38 corresponds to the entry in the LSE

table.
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APPENDIX A

(18). Estimated UDDer-Bound Human Cancer Risk Levels This is the range

associated with the upper-bound for lifetime cancer risk of 1 in 10,000

to 1 in 10,000,000. These risk levels are derived from EPA's Human

Health Assessment Group's upper-bound estimates of the slope of the

cancer dose response curve at low dose levels (q1*).

(19). Key to LSE Figure The Key explains the abbreviations and symbols used

in the figure.


A-7

APPENDIX A

Chapter 2 (Section 2.4)

Relevance to Public Health

The Relevance to Public Health section provides a health effects summary

based on evaluations of existing toxicological, epidemiological, and

toxicokinetic information. This summary is designed to present interpretive,

weight-of-evidence discussions for human health end points by addressing the

following questions.

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern to

humans?

3. What exposure conditions are likely to be of concern to humans,

especially around hazardous waste sites?

The section discusses health effects by end point. Human data are presented

first, then animal data. Both are organized by route of exposure (inhalation,

oral, and dermal) and by duration (acute, intermediate, and chronic). In

vitro data and data from parenteral routes (intramuscular, intravenous,

subcutaneous, etc.) are also considered in this section. If data are located

in the scientific literature, a table of genotoxicity information is

included.

The carcinogenic potential of the profiled substance is qualitatively

evaluated, when appropriate, using existing toxicokinetic, genotoxic, and

carcinogenic data. ATSDR does not currently assess cancer potency or perform

cancer risk assessments. MRLs for noncancer end points if derived, and the

end points from which they were derived are indicated and discussed in the

appropriate section(s).

Limitations to existing scientific literature that prevent a satisfactory

evaluation of the relevance to public health are identified in the

Identification of Data Needs section.

Interpretation of Minimal Risk Levels

Where sufficient toxicologic information was available, MRLs were derived.

MRLs are specific for route (inhalation or oral) and duration (acute,

intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all

six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic;

Oral - acute, - intermediate, - chronic). These MRLs are not meant to support

regulatory action, but to aquaint health professionals with exposure levels

at which adverse health effects are not expected to occur in humans. They

should help physicians and public health officials determine the safety of a

community living near a substance emission, given the concentration of a

contaminant in air or the estimated daily dose received via food or water.

MRLs are based largely on toxicological studies in animals and on reports of

human occupational exposure.
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APPENDIX A

MRL users should be familiar with the toxicological information on which the

number is based. Section 2.4, "Relevance to Public Health," contains basic

information known about the substance. Other sections such as 2.6,

"Interactions with Other Chemicals" and 2.7, "Populations that are Unusually

Susceptible" provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are

derived using a modified version of the risk assessment methodology used by

the Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA

1989a) to derive reference doses (RfDs) for lifetime exposure.

To derive an MRL, ATSDR generally selects the end point which, in its best

judgement, represents the most sensitive humanhealth effect for a given

exposure route and duration. ATSDR cannot make this judgement or derive an

MRL unless information (quantitative or qualitative) is available for all

potential effects (e.g., systemic, neurological, and developmental). In order

to compare NOAELs and LOAELs for specific end points, all inhalation exposure

levels are adjusted for 24hr exposures and all intermittent exposures for

inhalation and oral routes of intermediate and chronic duration are adjusted

for continous exposure (i.e., 7 days/week). If the information and reliable

quantitative data on the chosen end point are available, ATSDR derives an MRL

using the most sensitive species (when information frommultiple species is

available) with the highest NOAEL that does not exceed any adverse effect

levels. The NOAEL is the most suitable end point for deriving an MRL. When a

NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL,

and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from

Serious LOAELs. Additional uncertainty factors of 10 each are used for human

variability to protect sensitive subpopulations (people who are most

susceptible to the health effects caused by the substance) and for

interspecies variability (extrapolation from animals to humans). In deriving

an MRL, these individual uncertainty factors are multiplied together. The

product is then divided into the adjusted inhalation concentration or oral

dosage selected from the study. Uncertainty factors used in developing a

substance-specific MRL are provided in the footnotes of the LSE Tables.





C-l

APPENDIX C

PEER REVIEW

A peer review panel was assembled for vinyl acetate. The panel

consisted of the following members: Dr. Ghulam Ansari, Associate Professor of

Biochemistry and Pathology, University of Texas, Galveston, Texas; Dr. Arthur

Gregory, Private Consultant, Sterling, Virginia; and Dr. Shane Que Hee,

Associate Professor of Environmental Health, University of California at Los

Angeles School of Public Health, Los Angeles, California. These experts

collectively have knowledge of vinyl acetate's physical and chemical

properties, toxicokinetics, key health end points, mechanisms of action,

human and animal exposure, and quantification of risk to humans. All

reviewers were selected in conformity with the conditions for peer review

specified in the Comprehensive Environmental Response, Compensation, and

Liability Act of 1986, Section 104.

Scientists from the Agency for Toxic Substances and Disease Registry

(ATSDR) have reviewed the peer reviewers' comments and determined which

comments will be included in the profile. A listing of the peer reviewers'

comments not incorporated in the profile, with a brief explanation of the

rationale for their exclusion, exists as part of the administrative record

for this compound. A list of databases reviewed and a list of unpublished

documents cited are also included in the administrative record.

The citation of the peer review panel should not be understood to imply

its approval of the profile's final content. The responsibility for the

content of this profile lies with the ATSDR.

2U.S. GOVERNMENT PRINTING OFFICE: 1992- 638-281