Jnited States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-6067
September, 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
:OR VINYL ACETATE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document 1s a preliminary draft. It has not been formally released
the U.S. Environmental Protection Agency and should not at this stage be
u£onstrue
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act {RCRA; as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain tc potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the cates searched are Included In "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft datu listed on the front cover. Final draft document dates {front
cover) reflect the date the document Is sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure Durations of 30-90 days. The general methodology for estimating
subchronlc RfOs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In th(< case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980), Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and carclno-
gen1c1ty ere derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification Is required In the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodolocy for chronic toxlclty and cancer based RQs are defined In U.S.
EPA, 1984*and 1986d, respectively.
111
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EXECUTIVE SUMMARY
Vinyl acetate Is a colorless, flammable liquid with an odor that can be
pleasant Initially, but quickly becomes sharp and Irritating (Daniels,
1983). H is readily susceptible to Free radical polymerization (Daniels,
1983; IARC, 1985}. U.S. production of vinyl acetate 1n 1986 and 1987 was
1.710 and 1.813 billion pounds, respectively {USITC, 1987, 1988). Vinyl
acetate 1: produced domestically by four companies operating five manufac-
turing fa«11H1es 1n Texas (SRI, 1988). The only commercial use for vinyl
acetate 1: In polymerization (Daniels, 1983). The following use pattern for
vinyl acrtate has been reported (CMR, 1986): polyvlnyl acetate and
emulsions, 40%; polyvlnyl alcohol, 15%; ethylene-vlnyl acetate resins, 7%;
polyvlnyl butyral, 6%; polyvlnyl chloride copolymers, 4%; miscellaneous, 3%;
and exports, 26%.
Vinyl acetate appears to readily degrade 1n air, water and soil, and Is
therefore probably not a persistent environmental contaminant. In the
atmosphere, vinyl acetate Is expected to exist In the vapor phase where It
will degrade rapidly by reaction with sunlight-formed HO radical. The
half-life for this reaction In average air can be estimated to be 14.6 hours
(Atkinson, 1987). In water or soil, vinyl acetate may undergo hydrolysis
and blodngradatlon or be physically removed by volatilization. Using
reported lydrolysls rate constants (Habey and Mill, 1978), the hydrolysis
half-live; at pH 6, 7, 8 and 9 have been estimated to be 38.2 days, 7.3
days, 0.8 days and 1.9 hours, respectively, at 25°C. In alkaline water or
moist soil, hydrolysis Is probably the major fate process. The results of
several Modegradatlon screening studies Indicate that vinyl acetate Is
biodegradable (Takemoto et al., 1981; Ludzack and Ettlnger, 1960; Price et
1v
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al.t 1974; Pahren and Bloodgood, 1961; Chou et al., 1978). Blodegradatlon
may be more significant than hydrolysis In addle soil or water. Volatili-
zation half-lives of 4.3 and 49 hours can be estimated for a shallow model
river and environmental pond, respectively (Thomas, 1982; U.S. EPA, 1986a).
Although significant leaching Is possible, concurrent hydrolysis and
blodegradatlon should decrease the potential significance of leaching.
Occupational exposure to vinyl acetate occurs primarily among workers
engaged In monomer production and polymerization operations with primary
exposure occurring by Inhalation of the vapor and skin contact with both
vapor anc liquid (IARC, 1985}. According to the National Occupational
Exposure Survey, -13,230 U.S. workers are potentially exposed to vinyl
acetate (NIOSH, 1988). Vinyl acetate concentrations of 0-173 mg/m3 have
been detected In the breathable air In various production and use facilities
(IARC, 1935). Vinyl acetate can be released to the aquatic environment by
wastewate- emissions. Release to the atmosphere can occur from Industrial
sources aid from blomass combustion (Graedel et al., 1986}. Data regarding
detection of vinyl acetate In the ambient environment are very limited.
Ambient clr levels of 0.07-0.57 ppm (0.25-2.04 mg/m3) have been detected
In Houston, TX (Gordon and Meeks, 1977).
Exposure of fathead minnows, P. promelas. blueglll sunflsh, L. macro-
chlrus. coldflsh, C. auratus and gupples, U retlculatus. In hard and soft
water produced 96-hour TL values ranging from 18.0-42.3 mg/l (Pickering
and Henderson, 1966). The 48-hour LC™ of vinyl acetate In £. flesus was
>100 mg/l (Portmann, 1972). The 48-hour LC5Q of vinyl acetate In the
Golden Orfe, L.. Idus melanotus. was 26 mg/l (Juhnke and Luedemann, 1978).
The 48-hour LC,-0 of vinyl acetate In the European brown shrimp, £.
crangon. was between 10 and 100 mg/l (Portmann, 1972). The 24-hour TLm
of vinyl acetate In brine shrimp, A. sallna. was 45 mg/l (Price et al.,
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1974). The 24-hour LC&0 and EC5Q for vinyl acetate In D. magna was 330
and 52 mg/l, respectively (Brlngmann and KQhn, 1977b, 1982). The 48-hour
LC5Q for vinyl acetate In the marine polychaete worm, 0. djadema. was ~33
mg/l (Parker, 1984).
The tixlclty thresholds for exposure of a green alga, S. quadrlcauda,
and a blue-green alga, M. aeruglnosa. to vinyl acetate were 35 and 370
mg/l, respectively (Brlngmann and KQhn, 1976, 1977a, 1978a,b, 1979, 1980a).
The tjxldty thresholds for exposure of an aquatic bacterium, P_. putlda
and a flagellated protozoan, I. sulcatum. to vinyl acetate were 6 and 81
mg/l, respectively (Brlngmann and KQhn, 1976, 1977a, 1979, 1980a;
Brlngmann, 1978). The 48-hour toxlclty threshold values for the effects of
exposure of ciliated protozoans, £. parameclum Ehrenberg and U. parduczl
Chatton-Lvoff, to vinyl acetate were 9.5 and 91 mg/l, respectively
(Brlngmam and KQhn, 1980a, 1981). The 5-mlnute EC™ for the luminescent
bacteria, £. phosphoreum. exposed to vinyl acetate was 2081 mg/l. The
2-week 5DX Inhibition concentration for vinyl acetate 1n the anaerobic
toxlclty assay was 689 mg/l.
Experimental BCFs for vinyl acetate In fish were not available. A
calculated BCF of 2.1 suggests that bloconcentratlon In aquatic organisms Is
not significant.
Vinyl acetate 1s rapidly absorbed by either oral or Inhalation exposure
and quIcMy hydrolyzed In rodent and human blood to acetate and (by tauto-
merlzatlon from vinyl alcohol) acetaldehyde (Cresswell et al., 1979; Strong
et al., 1980). The acetaldehyde, which Is not acted on by blood, degrades
more slowly, largely In liver, to acetate (Strong et al., 1980; Simon et
al., 198fa). Both products are normal metabolites In most tissues, account-
Ing for .he widespread distribution of radioactivity after administration of
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14C-labeled vinyl acetate by either route (Strong et al., 1980). The
kinetics cf hydrolysis and subsequent metabolism, and failure of those
kinetics to be altered by monooxygenase affectors, Is not consistent with
the occurrence of appreciable quantities of carcinogenic epoxlde Interme-
diates (Simon et al., 1985a). While glutathlone conjugation may occur
following Intraperltoneal administration (NIOSH, 1978), this mechanism does
not const1tute a major route of elimination following oral or Inhalation
administration, since most of the vinyl acetate administered by these routes
1s eliminated as exhaled COp and most of what Uttle Is excreted 1n urine
appears as urea (Strong et al., 1980). Thus, nearly all vinyl acetate Is
metabolized to acetaldehyde and acetate and ultimately leaves the organism
as C02- Toxlclty probably results from the different rates of hydrolysis
and acetaldehyde metabolism with consequent overexposure of tissues to
acetaldehyde (F1lov, 1959; Strong et al., 1980).
Subchronlc Inhalation exposure of rats (Owen, 1980a) and mice (Owen,
1980b) to 1000 ppm (3521 mg/m3) vinyl acetate for 6 hours/day. 5 days/week
caused deceased weight gain and respiratory distress with lung congestion
and lesions In rat lungs and mouse nasal cavities, tracheae and bronchial
systems. The mice were more sensitive, showing respiratory distress
Intermittently at 200 ppm (704 mg/m3). Neither species was affected by
lower concentrations In these studies. Russian Investigators reported some
alterations 1n the activity of liver enzymes 1n rats or mice following
continuous subchronlc exposure to concentrations >2.4-68 mg/m3 (Tlunova
and Rumyintsev, 1975; Rumyantsev et al., 1979; Kolesnlkov et al., 1975);
Interpretation of these studies 1s problematical. Nearly half of rats
chronically exposed to 2500 ppm (8803 mg/m3) for 4 hours/day, 5 days/week
died (Maltonl and Lefemlne, 1974, 1975) and chronic exposure of rats
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(Dreef-van der Meulen, 1988; Hazleton Laboratories, 1987) and mice (Hazleton
Laboratories, 1986) to 600 ppm (2113 mg/m3) vinyl acetate 6 hours/day, 5
days/week produced respiratory tract lesions, with a NOEL for mice of 50 ppm
(176 mg/n3). U.S. workers chronically exposed to 5-10 ppm (1.8-3.5
mg/ma) v1 iy! acetate experienced no adverse health effects as compared
with workers exposed to other chemicals (Deese and Joyner, 1969). Russian
Investigators reported that vinyl acetate workers suffered Impaired cardiac
(Agaronyan and Amatunl, 1980; Amatunl and Agaronyan, 1979b) and pulmonary
(Amatunl md Agaronyan, 1979a; Oedrychowskl et a!., 1979; Agaronyan and
Amatunl, 1982) function, but neither the exposure levels nor the duration of
exposure were specified 1n the available accounts of these studies.
Subchronlc administration of 5000 ppm vinyl acetate In drinking water
slightly i educed terminal (3-month) weights In male rats, but the unpalat-
ablllty or this dose decreased water consumption In rats (Gale, 1980a) and
Increased water wastage In mice (Gale. 1980b); no adverse effects were
reported In either species. Chronic administration of 5000 ppm vinyl
acetate In drinking water to rats decreased water and food consumption and
weights and weight gains In both sexes, and Increased relative kidney
weights 1i males (Shaw, 1988). Low Incidences of thrombotlc lesions were
reported in rats chronically dosed with 2500 and 1000 ppm vinyl acetate In
drinking water (LlJInsky and Reuber, 1983).
In acjte Inhalation exposures, human males consistently found 21.6 ppm
(76 mg/m3) vinyl acetate vapor Irritating to the eyes and throat (Deese
and Joyner, 1969). Rabbits exposed 40 minutes to 250 ppm (880 mg/m3)
vinyl acetate vapor exhibited CNS Impairment (Barteney, 1957). All rats
Inhaling air saturated with vinyl acetate vapor died In minutes (Gage,
1970). In exposures for 6 hours/day, 5 days/week for 3 weeks, 2000 ppm
(7042 mg/m3) caused respiratory difficulty and depressed weight gain;
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250-630 ppm (880-2218 mg/m3) affected weight gain only. No effects were
seen at 1UO ppm (352 mg/m3) (Gage, 1970). In 28-day Inhalation studies (6
hours/day, 5 days/week), respiratory distress was exhibited by rats at
500-1500 |)pm (1761-5281 mg/m3) and mice at 150-1500 ppm (528-5281 mg/m3}
(Owen, 1979a,b). In the same studies, weights and weight gains were
affected n treated female rats and In rats and mice of both sexes at >1000
ppm; spleen weights were reduced at >1000 ppm In both species.
In 2f-day drinking water studies with vinyl acetate concentrations
ranging Irom 50-5000 ppm (Gale, 1979), weights and weight gains were
affected, especially In female rats and male mice. Decreases 1n food and
water consumption were also seen, but these did not parallel each other or
weight effects. Decreased weights were seen In liver and thymus. Lahdetle
(1988) reported 1ntraper1toneal administration of 125-1000 mg/kg/day vinyl
acetate t> male mice caused dose-dependent decreases 1n body, testlcular and
seminal vesicle weights. Doses >500 mg/kg resulted In abnormal sperm
counts, aid doses >750 mg/kg resulted 1n high mortality.
Inhalation IC,Q values for mice, rabbits and rats varied from 5.3 (4
hours foi mice) to 14.1 (4 hours for rats) g/m3 (NIOSH, 1989; Rumyantsev
et al., 979). Oral LD5Q values for rats and mice were 2.92 and 1.63 g/kg
respectively (NIOSH, 1989).
Data on carclnogenlclty are equivocal. Two Inhalation studies of vinyl
acetate, one In rats (Dreef-van der Meulen, 1988; Hazleton Laboratories,
1987) ard one 1n mice (Hazleton Laboratories, 1986), reported a few
malignant squamous cell carcinomas at 600 ppm (2113 mg/m3) vinyl acetate
(6 hours/day, 5 days/week) 1n both species, and benign tumors In rats at 200
ppm (704 mg/m3) (6 hours/day, 5 days/week) In the respiratory tracts.
Although none of these lesions appeared 1n controls, only the squamous cell
carcinomas 1n the nasal passages of female rats were marginally significant
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(p=0.06). A third Inhalation study (Maltonl and Lefemlne, 1974, 1975) In
rats was regatlve, but the exposure was so high (2500 ppm or 8802 mg/m3, 4
hours/day, 5 days/week) that there may have been Inadequate numbers of
survivors to generate positive data. The one human study (Lefflngwell et
al., 1983) reported an association between Industrial exposure and death by
glloma of the brain (see Table 6-2). However, vinyl acetate was one of many
chemicals reported with such an association, no correlation with length of
exposure was seen, confidence Intervals were large, and there were confound-
ing factors. In one oral (drinking water) study of rats (Lljlnsky and
Reuber, 1982, 1983; Lljlnsky, 1988; Busey and Hardlsty. 1982), statistically
significant Increases 1n neoplastlc liver nodules (p-0.05), uterine adeno-
cardnomas and adenomas (p=0.02) and thyroid C-cell neoplasms (p=0.02) were
seen In female animals given 1000 or 2500 ppm vinyl acetate; except for
thyroid neoplasms, these types of tumors were not seen In controls. In
contrast, Shaw (1988) also studied carclnogenesls In rats (albeit a
different strain) arising from vinyl acetate In drinking water, using 5
times as many animals/dose and a broader dose range. There were no tumors
found tha: could be attributed to vinyl acetate. Including tumors of the
types reported by Lljlnsky and colleagues.
All piokaryotlc assays for mutagenlclty of vinyl acetate were negative
(Lljlnsky and Andrews, 1980; Florin et al., 1980; McCann et al., 1975; Brams
et al., 1987; Bartsch, et al., 1979, 1980; Bartsch. 1976; Bartch and
Nontesano, 1980). In contrast, assays for chromosome breakage In mammalian
cells wer«' usually positive, both Vn vitro (He and Lambert, 1985; Norppa et
al., 1985, 1988; Jantunen et al., 1986; Lambert et al., 1985; Mak1-Paakkanen
and Norppi, 1987) and In vivo (Makl-Paakkanen and Norppa, 1987; Sh1r1n1an
and Arutyinyan, 1980; Takeshita et al., 1986).
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Irvine (1980) reported no teratogenU effects or effects on reproductive
parameters Induced by oral (drinking water) or Inhalation administration of
vinyl acetate to rats. Significant fetotoxldty (reduced mean litter
weight, fital weight, fetal crown/rump length or retarded sternebral ossifi-
cation) wis seen at 1000 ppm (3521 mg/m9) (6 hours/day on gestation days
6-15), an Inhalation level causing maternal toxldty (decreased weight gain
and lung congestion).
Vinyl acetate at 5000 ppm 1n drinking water, a level possibly toxic to
dams (transiently decreased weight gain and decreased food and water con-
sumption) had no effect on fetuses. In a two-generation study of rats given
vinyl acetate In drinking water, the only signs of toxldty were decreased
water consumption and weight gain (especially during lactation) at 5000 ppm
and a marginal effect of treatment on outcome of mating In first filial
generation males treated at 5000 ppm (Shaw, 1987).
Because of the limited evidence of cardnogenlclty by both the oral and
Inhalation routes, vinyl acetate Is categorized In EPA Group C (possible
human carcinogen). This classification does not require derivation of
quantitative cancer risk estimates (U.S. EPA. 1986d). Subchronlc and
chronic Inhalation RfDs of 1.3 and 0.1 mg/m3, respectively, were derived
for vinyl acetate using the NOAEL for respiratory distress In mice (Owen,
1980b). A chronic oral RfD of 1 mg/kg/day was derived using the NOAEL for
effects of body weight and relative kidney weight In rats (Shaw. 1988).
Because of low confidence 1n the available subchronlc oral toxldty data,
the chroilc oral RfD was adopted as the RfD for subchronlc oral exposure. A
chronic toxlclty-based RQ of 1000 was calculated for vinyl chloride based on
fetotox1:1ty In rats (Irvine, 1980). An RQ of 100 was assigned on the basis
of equlvDcal evidence of cardnogenlclty.
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TABLE Of CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 4
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Photolysis 5
2.2.3. Mlcroblal Degradation 6
2.2.4. Volatilization 6
2.2.5. Adsorption 7
2.2.6. Bloconcentratlon 7
2.3. SOIL 7
2.3.1. Mlcroblal Degradation 7
2.3.2. Chemical Degradation 7
2.3.3. Adsorption/Leaching 7
2.4. SUMMARY 8
3. EXPOSURE 9
3.1. WATER 9
3.2. FOOD 10
3.3. INHALATION 10
3.4. DERMAL 10
3.5. SUMMARY 11
4. ENVIRONMENTAL TOXICOLOGY 12
4.1. AQUATIC TOXICOLOGY 12
4.1.1. Acute Toxic Effects on Fauna 12
4.1.2. Chronic Effects on Fauna 13
4.1.3. Effects on Flora 13
4.1.4. Effects on Bacteria and Other Microorganisms. . . 14
4.2. TERRESTRIAL TOXICOLOGY 15
4.2.1. Effects on Fauna 15
4.2.2. Effects on Flora 15
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TABLE OF CONTENTS (cent.)
Page
4.3. FIELD STUDIES 15
4.4. AQUATIC RISK ASSESSMENT 16
4.5. SUMMARY 16
5. PHARMMIOKINETCS 19
5.1. ABSORPTION 19
5.2. DISTRIBUTION 20
5.3. METABOLISM 21
5.4. EXCRETION 23
5.5. SUMMARY 24
6. EFFECTS 25
6.1. SYSTEMIC TOXICITY 25
6.1.1. Inhalation Exposure 25
6.1.2. Oral Exposure 29
6.1.3. Other Relevant Information 31
6.2. CARCINOGENICITY 36
6.2.1. Inhalation 36
6.2.2. Oral 41
6.2.3. Other Relevant Information 43
6.3. MUTAGENICITY 44
6.4. TERATOGENICITY 48
6.5. OTHER REPRODUCTIVE EFFECTS 49
6.6. SUMMARY 52
7. EXISTING GUIDELINES AND STANDARDS 56
7.1. HUMAN 56
7.2. AQUATIC 56
8. RISK ASSESSMENT 57
8.1. CARCINOGENICITY 57
8.1.1. Inhalation 57
8.1.2. Oral 57
8.1.3. Other Routes 58
8.1.4. Weight of Evidence 58
8.1.5. Quantitative Risk Estimates 59
8.2. SYSTEMIC TOXICITY 59
8.2.1. Inhalation Exposure 59
8.2.2. Oral Exposure 62
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TABLE OF CONTENTS (cont.)
9. REPOPTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
9.2. BASED ON CARCINOGENICITY .
10. REFEFENCES.
APPENDIX /
APPENDIX I
APPENDIX (
LITERATURE SEARCHED
SUMMARY TABLE FOR VINYL ACETATE
DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
VINYL ACETATE
Page
65
65
69
72
90
93
94
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LIST OF TABLES
No. Title Page
1-1 Ccmmerclal Manufacturers of Vinyl Acetate 3
6-1 Acute LC5Q and LD50 Values for Vinyl Acetate 37
6-2 Cx1c1ty Summary for Vinyl Acetate 66
9-2 Composite Scores for Vinyl Acetate 68
9-3 Vinyl Acetate: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 70
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LIST OF ABBREVIATIONS
ACTH
ATP
BCF
BOOT
CAS
CNS
CS
DNA
F344
FEL
GGT
GI
GMAV
GHCV
NEC
ow
LOAEL
NED
NAD
NOAEL
ppm
Adrenocort1cotrop1c hormone
Adenoslne tMphosphate
B1oconcentrat1on factor
Biological oxygen demand, theoretical
Chemical Abstract Service
Central nervous system
Composite score
Oeoxyrlbonuclelc acid
Fischer 344
Frank effect level
Gamma-glutamyHranspeptldase
Gastrointestinal
Genus mean acute value
Genus mean chronic value
Human equivalent concentration
Soil sorptlon coefficient standardized
with respect to organic carbon
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effect level
Minimum effective dose
Nlcotlnamlde adenlne dlnucleotlde
No-observed-adverse-effect level
Parts per million
xv1
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ROD
RDDR
RF
RfD
RQ
RVd
RVe
SCE
STEL
TLC
TLm
TLV
TNA
UV
LIST OF ABBREVIATIONS (cont.)
Regional deposited dose
Regional deposited dose ratio
Radioactive fraction
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Sister chromatld exchange
Short-term exposed level
Thin layer chromatography
Median tolerance limit
Threshold limit value
Time-weighted average
Ultraviolet
xv11
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Vinyl acetate Is also known by the synonyms vinyl ethanoate, ethenyl
acetate, -acetoxyethylene, vinyl acetate monomer, vinyl A monomer and
acetic add, ethylene ester. Zeset T 1s a trade name for vinyl acetate
(IARC, 19t5). The structure, molecular weight, empirical formula and CAS
Registry njmber for vinyl acetate are as follows:
CH2=CH-0-C(=0)-CH3
Molecular weight: 86.09
Empirical formula: C^H^O-
CAS Registry number: 108-05-4
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Vinyl acetate Is a colorless, flammable liquid with an odor that can be
pleasant Initially, but quickly becomes sharp and Irritating {Daniels,
1983). It Is soluble In most organic solvents such as ether, acetone,
benzene, jthanol, chloroform and chlorinated solvents (IARC, 1985; Daniels,
1983). Selected physical properties are as follows:
Melting point:
Bolll ig point:
Sped Me gravity:
Vapor pressure
at ?0°C:
Mater solubility
at 20°:
-93 to -100°C
72.7°C
0.9338 (20/20°C)
90.16 mm Hg
2.0-2.4 wt %
Daniels, 1983
Daniels, 1983
Daniels, 1983
Daubert and
Danner, 1985
Daniels, 1983
0181d
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05/03/89
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Log K0,,:
Flash )o1nt, closed cup:
A1r od)r threshold:
Water Ddor threshold:
50% -ecognltlon
100% recognition
Conversion factor:
(air at 20°C)
0.73
-8°C
0.28 ppm
0.40 ppm
0.55 ppm
1 mg/m3 =0.28 ppm
1 ppm =3.58 mg/m3
Hansch and Leo,
1985
IARC, 1985
Verschueren, 1983
Verschueren, 1983
Verschueren, 1983
Vinyl acetate 1s readily susceptible to free radical polymerization
(Daniels, 1983; IARC, 1985). Commercial grades of vinyl acetate are
supplied with Inhibitors (3-300 ppm hydroqulnone or dlphenylamlne) to
prevent polymerization during transport or storage. Vinyl acetate Is also
susceptible to add- and base-catalyzed hydrolysis In water (Daniels, 1983).
1.3. PRCDUCTION DATA
Table 1-1 lists commercial manufacturers of vinyl acetate and their
annual capacities. U.S. production of vinyl acetate In 1986 and 1987 was
1.710 and 1.813 billion pounds, respectively (USITC, 1987. 1988). Exports
of vinyl acetate amount to -600-650 million pounds annually, while Imports
total <15 million pounds/year (C8.E News, 1987).
All o: the U.S. manufacturers listed In Table 1-1 produce vinyl acetate
by the vapor-phase ethylene process (SRI, 1988), which Involves the oxlda-
tlve addition of acetic acid to ethylene In the presence of a palladium
catalyst [Daniels, 1983). The major reaction products are vinyl acetate and
water.
OlBld
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05/03/89
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TABLE 1-1
Commercial Manufacturers of Vinyl Acetate*
Company
Location
Annual Capacity
(millions of pounds)
DuPont
Hoechst Celanese
Quantum Chem. Corp.
(US1 Chemicals)
Union Cartlde Corp.
LaPorte, TX
Bay City, TX
Clear Lake, TX
Deer Park, TX
Texas City, TX
>50
475
450
600
550
*Source: SRI, 1988
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1.4. USE DATA
The only commercial use for vinyl acetate Is In polymerization (Daniels,
1983). The following use pattern for vinyl acetate has been reported (CMR,
1986):
Polyvlnyl acetate and emulsions
Polyvlnyl alcohol
Ethylene-vlnyl acetate resins
Polyvlnyl butyral
Polyvlnyl chloride copolymers
Miscellaneous
Exports
40*
15%
7%
6%
4%
3%
26%
Use of vlryl acetate for polyvlnyl acetate emulsions and resins Is divided
about evenly between paints and adheslves (CMR, 1986). The major end uses
for all derivatives of vinyl acetate are: adheslves, 35%; paints, 30%; and
paper and textile coatings, 25% (C&E News, 1987).
1.5. SUMMARY
Vinyl acetate 1s a colorless, flammable liquid with an odor that can be
pleasant initially, but quickly becomes sharp and Irritating (Daniels,
1983). II Is readily susceptible to free radical polymerization (Daniels,
1983; IAR(, 1985). U.S. production of vinyl acetate 1n 1986 and 1987 was
1.710 and 1.813 billion pounds, respectively (USITC, 1987. 1988). Vinyl
acetate 1: produced domestically by four companies operating five manufac-
turing facilities 1n Texas (SRI, 1988). The only commercial use for vinyl
acetate Is 1n polymerization (Daniels, 1983). The following use pattern for
vinyl ace.ate has been reported (CMR, 1986): polyvlnyl acetate and emul-
sions, 405,; polyvlnyl alcohol, 15%; ethylene-vlnyl acetate resins, 7%; poly-
vlnyl butjral, 6%; polyvlnyl chloride copolymers, 4%; miscellaneous, 3%; and
exports, 26%.
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based upon Us relatively high vapor pressure of 90.16 mm Kg at 20°C
(Daubert fnd Danner, 1985), vinyl acetate Is expected to exist almost
entirely In the vapor phase 1n the ambient atmosphere (Elsenrelch et al.,
1981). Th» dominant degradation process In ambient air Is probably reaction
with sunlight-formed HO radical. Based upon an estimated rate constant of
26.3xlO~12 cm3/molecule-sec at 25°C (Atkinson, 1987) and an average
atmospherl: HO radical concentration of 5xl03 molecules/cm3, the
half-life for this reaction 1s estimated to be -14.6 hours.
Vinyl acetate has a relatively high water solubility of 20,000-24,000
pptn at 20'C (Daniels, 1983), which suggests that physical removal from air
by wet deposition (washout by rainfall, dissolution In clouds, etc.) Is
possible. However, the relatively rapid degradation rate by HO radical Is
probably IT ore significant than physical removal In the ambient atmosphere.
2.2. WATER
2.2.1. hydrolysis. Vinyl acetate 1s hydrolyzed 1n water by acidic and
basic catalysis forming acetic add (Daniels, 1983). Vinyl alcohol 1s also
formed by the hydrolysis; however, It 1s unstable In water and changes by
tautomerlc rearrangement to form acetaldehyde. The hydrolysis rate
constants for vinyl acetate at 25°C are 0.00014, 0.00000011 and 10.0/M-sec
for adds, neutrals and bases, respectively (Habey and Mill, 1978). Using
these rat? constants, the estimated hydrolysis half-lives at pH 6, 7, 8 and
9 are 38.;! days, 7.3 days, 0.8 days and 1.9 hours, respectively.
2.2.2. Photolysis. Vinyl acetate does not absorb UV light significantly
above 250 nm 1n ethanol solvent (Daniels, 1983); therefore, It should not be
susceptible to direct photolysis 1n sunlight.
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2.2.3. M croblal Degradation. The results of several blodegradatlon
screening studies Indicate that vinyl acetate Is biodegradable under aerobic
conditions (Takemoto et al., 1981; Ludzack and Ettlnger, 1960; Price et al.,
1974; Pahr?n and Bloodgood, 1961). Takemoto et al. (1981) found that 51.3%
of Initial vinyl acetate bio-oxidized during a standard dilution method test
(sewage se;d) over a 5-day Incubation period, while 42% b1o-ox1d1zed during
a seawater dilution method test. Using an acclimated sewage culture (19
days acclimation), a theoretical CO- evolution of 42% was measured over a
10-day 1ncjbat1on period (Ludzack and Ettlnger, 1960). Price et al. (1974)
measured -'Inyl acetate BODTs of 62-72% during 5- to 20-day Incubation
periods using a standard sewage Inocula, and 51-69% using seawater,
synthetic sewage and raw wastewater Inocula. Pahren and Bloodgood (1961)
measured '.heoretlcal CO- evolutions of 27-49% using unaccllmated sewage
Inocula ani 58% using acclimated (19 days acclimation) sewage Inocula. Chou
et al. (1*78) observed 100% degradation of vinyl acetate after a 3-day lag
period using the Hungate Serum Bottle technique (anaerobic conditions) and
enriched methane cultures.
2.2.4. V>lat1l1zat1on. Based upon a water solubility of 20,000 ppm and a
vapor pressure of 90.16 mm Hg at 20°C (see Section 1.2.). the Henry's Law
constant for vinyl acetate has been estimated to be 5.11x10"*
atm-mVmol. A Henry's Law constant of this magnitude Indicates that
volatilization from environmental waters may be significant (Thomas, 1982).
Using a model river estimation method (Thomas, 1982), the volatilization
half-life of vinyl acetate from a river 1 m deep flowing at a speed of 1
m/sec wit i a wind velocity of 3 m/sec Is ~4.3 hours. The estimated
volatilization half-life from a model environmental pond 1s ~49 hours (U.S.
EPA, 1986a).
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2.2.5. AcsorpUon. The relatively high water solubility of vinyl acetate
(20,000-24,000 ppm at 20°C) suggests that partitioning from the water column
to sediment and suspended material should not be significant.
2.2.6. B ^concentration. Experimental BCFs for vinyl acetate In fish
were not ocated; however, a BCF of 2.1 has been calculated using a log
K value of 0.73 (Hansch and Leo, 1985) and the following equation
(Bysshe, 1982): log BCF = 0.76 log KQW - 0.23. This BCF value Indicates
that blocoicentratlon In aquatic organisms Is not significant.
2.3. SOI.
2.3.1. Mlcroblal Degradation. Pertinent data regarding mUroblal degra-
dation of vinyl acetate In soil were not located In the available literature
cited In Appendix A. However, based upon the results of blodegradatlon
screening tests 1n aqueous media (see Section 2.2.3.), vinyl acetate may
readily blodegrade In soil.
2.3.2. Chemical Degradation. Aqueous hydrolysis may be a major process
by which /1nyl acetate Is degraded 1n soil. In moist soil at 25°C, vinyl
acetate cm be expected to hydrolyze at least as fast as the hydrolysis
rates discussed In Section 2.2.1. (38.2 days at pH 6, 1.9 hours at pH 9).
In moist alkaline soils, hydrolysis will probably be the major route by
which v1n;fl acetate Is removed from soil. In acidic soils, blodegradatlon
may be competitive or more significant than hydrolysis.
Vinyl acetate polymerizes readily (Daniels, 1983). If released to the
terrestrial environment In a spill situation, a significant fraction of the
spill may polymerize. Significant amounts may also evaporate because of the
high vapor pressure of vinyl acetate.
2.3.3. Adsorption/Leaching. Pertinent data regarding the leaching of
vinyl acetate In soil were not located 1n the available literature cited In
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Appendix A. A KQC of 19 was estimated using a water solubility of 20,000
ppm and the following equation (Lyman, 1982): log K = 3.64 - 0.55 log
water solu>111ty. This K value Indicates very high soil mobility (Swann
et al., '983). Although significant leaching Is possible, concurrent
hydrolysis and blodegradatlon should decrease the potential significance of
leaching.
2.4. SUMMARY
Vinyl icetate appears to readily degrade In air, water and soil, and 1s
therefore probably not a persistent environmental contaminant. In the
atmosphere, vinyl acetate Is expected to exist In the vapor phase where It
will degrade rapidly by reaction with sunlight-formed HO radical. The
half-life For this reaction 1n average air can be estimated to be 14.6 hours
(Atkinson, 1987). In water or soil, vinyl acetate may undergo hydrolysis
and blodegradatlon or be physically removed by volatilization. Using
reported hydrolysis rate constants (Mabey and Mill, 1978), the hydrolysis
half-lives at pH 6, 7, 8 and 9 have been estimated to be 38.2 days, 7.3
days. 0.8 days and 1.9 hours, respectively, at 25°C. In alkaline water or
moist soil, hydrolysis 1s probably the major fate process. The results of
several blodegradatlon screening studies Indicate that vinyl acetate 1s
blodegradaDle (Takemoto et al., 1981; Ludzack and Ettlnger, 1960; Price et
al., 1974; Pahren and Bloodgood, 1961; Chou et al., 1978). Blodegradatlon
may be more significant than hydrolysis In acidic soil or water. Volatili-
zation half-lives of 4.3 and 49 hours can be estimated for a shallow model
river and environmental pond, respectively (Thomas, 1982; U.S. EPA, 1986a).
Although significant leaching Is possible, concurrent hydrolysis and
blodegradatlon should decrease the potential significance of leaching.
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3. EXPOSURE
Occupational exposure to vinyl acetate occurs primarily among workers
engaged 1r monomer production and polymerization operations, with primary
exposure occurring by Inhalation of the vapor and skin contact with both the
vapor and liquid (IARC, 1985). According to the National Occupational
Exposure survey, -13,230 U.S. workers are potentially exposed to vinyl
acetate (NIOSH, 1988).
It Is not known whether vinyl acetate occurs as a natural product,
although It has been detected In trace amounts In one Isolated plant
monitor1n( study (IARC, 1985).
The only commercial use of vinyl acetate Is In polymerization. Residual
levels of vinyl acetate monomer as high as 5 g/kg can remain 1n the polymer
(Daniels, 1983). Although 1t has never been demonstrated experimentally, It
1s speculated that residual monomer (In polyvlnyl acetate containers used to
store fool products) may leach Into food products and result In exposure by
Ingestlon,
3.1. WATER
MonlUMng data regarding vinyl acetate In environmental waters are
limited. Vinyl acetate has been detected 1n a river water sample collected
1n Great Britain 1n Nay, 1979 (Fielding et al.. 1981). It also was quanta-
tlvely detected In wastewater effluents collected from an advanced waste
treatment facility In Lake Tahoe, CA, In October, 1974 (Lucas, 1984). A
concentration of 50 ppm vinyl acetate was found In a wastewater effluent
from a pclyvlnyl acetate plant (IARC, 1985).
Wastewater releases may be the major source of vinyl acetate emission to
the aqua:1c environment. In addition, drums containing vinyl acetate wastes
0181d
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have been round at dumping sites In the North Sea (Greve, 1971). Corrosion
of these drums will eventually lead to Us release to seawater.
3.2. FOOC
Pertlntnt monitoring data regarding exposure to vinyl acetate through
food were rot located In the available literature cited In Appendix A.
3.3. INHALATION
Amblen. vinyl acetate air levels of 0.07-0.57 ppm (0.25-2.04 mg/m3)
were detected In Houston, TX, air during monitoring conducted 1n June and
July, 1974 (Gordon and Weeks, 1977). Since all U.S. manufacturers of vinyl
acetate are located In Texas (see Section 1.3.), H 1s not surprising that
vinyl acetate has been detected In air near production sites. Samples of
ambient a'r collected In the vicinity of the Kln-Buc waste disposal site
(Edison, HJ) between June 29 and July 1, 1976 contained 0.5 yg/m3 vinyl
acetate (Pelllzzarl, 1982).
Vinyl acetate Is released to the atmosphere In emissions from Industrial
sources and from the combustion of blomass (Graedel et al., 1986). Waste
gases fron scrubbers (generated during the Industrial manufacture of vinyl
acetate) nay contain trace levels of vinyl acetate (Lleplns et al., 1977).
Air concentrations of 0-173 mg/ma (mean concentration of 30 mg/m3)
were dete:ted In occupational air samples from a vinyl acetate production
plant. Concentrations of 1.4-17 mg/m3 were reported In other vinyl
acetate production facilities. Occupational exposures of <0.4-126 mg/m3
have beer reported for various applications facilities such as adhesive,
latex paint and polymer plants (IARC, 1985).
3.4. DEINAL
Pertlient monitoring data regarding the dermal exposure of vinyl acetate
were not located In the available literature cited In Appendix A.
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3.5. SUMMARY
Occupa:1onal exposure to vinyl acetate occurs primarily among workers
engaged It monomer production and polymerization operations with primary
exposure recurring by Inhalation of the vapor and skin contact with both
vapor and liquid (IARC, 1985). According to the National Occupational
Exposure Jurvey, -13,230 U.S. workers are potentially exposed to vinyl
acetate (IIIOSH, 1988). Vinyl acetate concentrations of 0-173 mg/m3 have
been detected In the breathable air In various production and use facilities
(IARC, 19ii5). Vinyl acetate can be released to the aquatic environment by
wastewater emissions. Release to the atmosphere can occur from Industrial
sources and from blomass combustion (Graedel et al., 1986). Data regarding
detection of vinyl acetate In the ambient environment are very limited.
Ambient air levels of 0.07-0.57 ppm (0.25-2.04 mg/ma) have been detected
1n Houston, TX (Gordon and Meeks, 1977).
0181d
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUJTIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Pickering and Henderson {1966}
assessed the toxlclty of vinyl acetate to fathead minnows, Plmephales
promelas. In both soft and hard water and to blueglll sunflsh, Lepomls
macrochlru; . goldfish, Carasslus auratus and gupples, Leblstes retlculatus.
In soft water. Soft water was prepared by mixing 5 parts of natural lime-
stone water with 95 parts of distilled dem1neral1zed water to produce a
diluent with pH, alkalinity and hardness levels of 7.5, 18 mg/i, and 20
mg/it respectively. Chemical characteristics reported for hard water were
8.2, 300 mg/t and 360 mg/i, respectively. Vinyl acetate concentrations
In test solutions were not analytically verified during the static tests
conducted at 25°C. Exposure of minnows to vinyl acetate In soft water
resulted in 96-hour TL values (and 9554 confidence Intervals) of 24.0
(18.9-30.5) and 19.7 mg/l (16.3-25.1). Tests conducted with minnows In
hard water produced 96-hour TL values (and 95% confidence Intervals) of
39.2 (34,1-47.6) and 35.8 mg/l (31.4-41.7). Exposure of bluegllls,
goldfish and gupples to vinyl acetate In soft water produced 96-hour TL
values (and 95% confidence Intervals) of 18.0 (15.0-21.5), 42.3 (33.5-53.5)
and 31.1 ng/t (26.1-36.6), respectively.
Portm«nn (1972) assessed the toxlclty of vinyl acetate to Pleuronectes
flesus at 15°C. The 48-hour LC5Q was >100 mg/i. Juhnke and Luedemann
(1978) assessed the acute toxlclty of vinyl acetate to the Golden Orfe,
Leuclscus 1dus melanotus. They reported a 48-hour LC5Q of 26 mg/i. The
LC0 and Li:,QO values were 9 and 93 mg/l, respectively.
Portmann (1972) assessed the toxlclty of vinyl acetate to the European
brown shrimp, Crangon crangon. at 15°C. The 48-hour LC50 was between 10
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and 100 m<;/l. Price et al. (1974) assessed the static acute toxlclty of
vinyl acetate to brine shrimp, Artemla sallna. In artificial seawater at
24.5°C. The Investigators reported a 24-hour TLm of 45 mg/1.
Br1ngm,inn and KQhn (1977b) reported an EC™ for Daphnla magna exposed
to vinyl acetate for 24 hours of 330 mg/l. The ECQ and EC100 values
1n this study were 16 and 1000 mg/i, respectively. Subsequently,
BMngmann and KQhn (1982) reassessed the toxldty of vinyl acetate to D.
magna. IT this second study, they reported a 24-hour EC5Q (and 95%
confidence limits) of 52 mg/t (44-62) with ECQ and EC1QO values of 17
and 128 mg/i, respectively.
Parker (1984) assessed the acute toxlclty of vinyl acetate to the marine
polychaete worm, Ophryotrocha dladema. The 48-hour exposure phase was
preceded hy a 48-hour starvation period and followed by a 1-week recovery
period. Each phase was conducted at 21"C. The LC™ was -33 mg/l.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY -- Pertinent data regarding the effects of chronic
exposure
-------
Cultures wore Incubated with a series of vinyl acetate solutions for 8 days
at 27°C to determine the toxlclty threshold. The toxlclty threshold was
defined as the concentration of vinyl acetate that Inhibited multiplication
of cells 1n suspension. Inhibition was measured turb1d1metr1cally and
defined as a >3% extinction of the primary light of monochromatic radiation
at 436 nm for a layer of cells 10 mm thick from cultures exposed to vinyl
acetate. Toxlclty threshold levels for exposure of H. aeruglnosa and £.
quadr 1 cauda to vinyl acetate were 35 and 370 mg/SL, respectively.
4.1.3.2. BIOCONCENTRATION -- Pertinent data regarding the bloconcen-
tratlon pctentlal of vinyl acetate 1n aquatic flora were not located In the
available literature cited 1n Appendix A.
4.1.4. Effects on Bacteria and Other Microorganisms. Brlngmann and Kuhn
(1976, 19^7a, 1979, 1980a; Brlngmann, 1978) assessed the effects of exposure
of an aqiatlc bacterium, Pseudomonas putlda, and a flagellated protozoan,
Entoslphor sulcatum. to vinyl acetate. Effects on bacterial suspensions
were determined turb1d1metr1cally by the extinction of primary light at 436
nm for a layer 10 mm thick. The toxlclty threshold was defined as the
concentration of toxicant having an extinction value of >3X below the mean
value of extinction for nontoxlc dilutions of the test cultures. Effects on
protozoa vere determined by cell counts on a Coulter counter. The toxlclty
threshold with protozoa was defined as a 554 reduction 1n cell counts,
obtained mathematically from regressions between vinyl acetate concentra-
tions and cell counts. Bacterial suspensions were exposed to vinyl acetate
for 16 haurs at 25°C, and protozoan cultures for 72 hours at 25°C. The
Investigators reported toxlclty thresholds of 6 and 81 mg/ft. for the
bacteria and protozoa, respectively. Subsequently, Brlngmann and Kuhn
(1980b)
-------
ciliated protozoans, ChUomonas paramedum Ehrenberg and Uronema parduczl
Chatton-Lwoff, to vinyl acetate. They reported 48-hour toxldty threshold
values of ').5 and 91 mg/l, respectively.
Atklnsjn and Swltzenbaum (1987) assessed the toxldty of vinyl acetate
to the luminescent bacteria, Photobacterlum phosphoreum, In the mlcrotox
assay and to a mixed culture of anaerobic bacteria In the anaerobic toxldty
assay. The mlcrotox assay was conducted In accordance with manufacturers'
recommendations. The anaerobic toxldty assay was conducted In 125 ml
serum bottles containing defined media, anaerobic seed Inoculum, vinyl
acetate and a methanogenlc substrate. The duration of the assay was 2
weeks. Tie 5-mlnute EC50 for £. phosphoreum. defined as the concentration
of vinyl acetate that resulted 1n a SOX reduction In light output, was 2081
mg/l. Th> 50% Inhibition concentration for vinyl acetate In the anaerobic
toxldty assay, defined as the concentration of toxicant causing a 50%
reduction In methane gas production rate, was 689 mg/l.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Pertinent data regarding the effects of
exposure of terrestrial fauna to vinyl acetate were not located In the
available literature cited In Appendix A.
4.2.2. Effects on Flora. Pertinent data regarding the effects of
exposure of terrestrial flora to vinyl acetate were not located 1n the
available literature cited 1n Appendix A.
4.3. FIELD STUDIES
Pert'nent data regarding the effects of vinyl acetate on flora and fauna
In the field were not located In the available literature cited In
Appendix A.
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4.4. AQU/JIC RISK ASSESSMENT
The 1a:k of pertinent data regarding the effects of exposure of aquatic
fauna and flora to vinyl acetate precluded the development of a freshwater
criterion (Figure 4-1). Development of a freshwater criterion requires the
results of acute assays with a salmon1d fish species, planktonlc and benthlc
crustaceans, an Insect, a nonarthropod and nonchordate species and an Insect
or specie* from a phylum not previously represented. The development of a
freshwater criterion also requires data from chronic toxlclty tests with two
species o: fauna and one species of algae or vascular plant, and at least
one blocorcentratlon study.
The lack of pertinent data regarding the effects of exposure of aquatic
fauna ant flora to vinyl acetate also precluded the development of a
saltwater criterion.
4.5. SUMMARY
Exposure of fathead minnows, P. promelas. blueglll sunflsh, L. macro-
chlrus. goldfish, C. auratus and gupples, L. retlculatus. In hard and soft
water produced 96-hour TLffl values ranging from 18.0-42.3 mg/l (Pickering
and Henderson, 1966). The 48-hour LC5Q of vinyl acetate In £. flesus was
>100 mg/i (Portmann, 1972). The 48-hour LC5Q of vinyl acetate In the
Golden Orfe, L,. Idus melanotus, was 26 mg/l (Juhnke and Luedemann, 1978).
The 18-hour LC5Q of vinyl acetate 1n the European brown shrimp, C.
crangon. was between 10 and 100 mg/l (Portmann, 1972). The 24-hour TL
of vinyl acetate 1n brine shrimp, A. sallna. was 45 mg/l (Price et al.,
1974). the 24-hour IC™ and EC5Q for vinyl acetate In D. magna was 330
and 52 ng/l, respectively (Brlngmann and Kuhn, 1977b, 1982). The 48-hour
LC50 for vinyl acetate 1n the marine polychaete worm, 0. dladema. was ~33
mg/i (Parker, 1984).
m
0181d
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Fa n i 1 y
411
Chordate (Salmoriid-f ish)
K£
Chord ate (warrnwater fish)
*3
Chordate (fish or amphibian)
K4
Crustacean (planktonic)
#5
Crustacean (bent hie)
*G
Insect an
#7
non-fir t hropod /-Chordat e
#a
New Insect an or phylum
repr esent at i ve
#3
al gae
«10
Vasci.lar plant
•NA=Not ftvailable » 96-hour TL.
minnows, Pi me oh ales Dronielas,
GMftV*
Nft
£8.5*
16.0*
Nfi
NA
NA
NA
NA
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
in mg/L for
conducted in
TEST TYPE
SMCV*
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
BCF-
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
tests with fathead
hard and soft water,
* 96-hour TL. in mg/L for bluegill sunfish, Leoomis macrochirus
FIGURE 4-1
Organization Chart for Listing GMAVs, GHVCs and BCFs Required to Derive
Numerical Water Quality Criteria by the Method of U.S. EPA/OHRS (1986)
to Frotect Freshwater Aquatic Life From Exposure to Vinyl Acetate.
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The todclty thresholds for exposure of a green alga, S. quadrlcauda,
and a blur-green alga, M. aeruglnosa. to vinyl acetate were 35 and 370
mg/l, respectively (Brlngmann and Kuhn, 1976, 1977a, 1978arb, 1979, 1980a).
The todclty thresholds for exposure of an aquatic bacterium, P. put Ida
and a flagellated protozoan, £. sulcatum, to vinyl acetate were 6 and 81
mg/i, respectively (Brlngmann and Kuhn, 1976, 1977a, 1979, 1980a;
Brlngmann, 1978). The 48-hour toxldty threshold values for the effects of
exposure
-------
5. PHARHACOKINETICS
5.1. ABSCRPTION
Vinyl icetate Is rapidly absorbed and metabolized whether given orally
or by Imalatlon. When [v1nyl-l,2-14C]-v1nyl acetate (24 mg/kg) was
administered orally by gavage to two male and two female Sprague-Dawley CD
rats, >9Q% of the administered radioactivity was excreted within 96 hours
(3.4% In irlne, 1.1% In feces and 86.3% expired CO-), and 7.1% remained In
the carcass (Cresswell et al., 1979). Host was excreted during the first 6
hours after dosing, and excretion was virtually complete by 24 hours after
dosing.
In ancther study from the same laboratory. Increasing the dose level to
297 mg/kg In six hourly doses resulted In 64% recovery of the administered
radioactivity 1n excreta within 96 hours (1.8% 1n urine, 1.4% In feces and
61.2% exp red CO.), with most of the excretion occurring during the 6-hour
dosing pe~1od and the next 6 hours (Strong et al., 1980). An additional
5.4% was found In the carcasses. The remaining 30% of the administered
radioactivity was presumed lost as expired C0? during removal of the rats
from the metabolism cages for repeat dosing. In the latter study, another
group of rats (same sexes, number and strain) was exposed to 750 ppm
[14C]-v1ny1 acetate for 6 hours by Inhalation. Over the 96 hours follow-
ing exposure, 4.8, 3.6, 74.6 and 16.4% of the total recovered radioactivity
was found In urine, feces, expired air and carcasses, respectively. Again,
most of the recovery occurred within the first 24 hours. The authors
adjusted dose levels in this study so that oral and Inhalation administra-
tion wou d cause animals to receive approximately the same quantities of
vinyl acetate. The rapid excretion of much of the administered radioactiv-
ity In e>p1red air and urine following oral dosing Indicates that absorption
0181d
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from the 6J tract was fairly rapid and complete. The excretion data follow-
ing 1nhala:1on exposure Indicate that absorption occurs by this route as
well.
Simon et al. (1985a) exposed two male Wlstar rats simultaneously to
vinyl acetite vapor concentrations of 200-2000 ppm 1n a closed chamber. The
decline of vinyl acetate concentration was blphaslc: zero order for concen-
trations >?00 ppm and first order for concentrations <50 ppm. This resulted
from a saturable process 1n the uptake or metabolism of vinyl acetate. The
Initial prase of rapid decline of vapor concentration In the chamber seen
with volatlles that equilibrate between chamber and organism was not
observed with vinyl acetate because of Us rapid hydrolysis by blood
esterases. This prevented distribution In the tissues of vinyl acetate per
se (no vliyl acetate was expired by rats Inoculated IntraperUoneally with
the compound). The rate of uptake by the rats In the first order part of
the curve was 30,000 mi/hour/kg, which Is close to the maximal ventilation
rate In rats of 32,000 ml/kg. Thus, pulmonary uptake and subsequent
metabollsn Is ventilation-limited.
5.2. DISTRIBUTION
Strong et al. (1980) found that tissue distribution of radioactivity
does not depend on route of administration of [l4C]-v1nyl acetate. For
each route, eight Sprague-Dawley rats/sex were administered the doses
described above and [14C}-t1ssue distribution was examined by whole-body
autoradlography. The pattern of distribution was not significantly depen-
dent on administration route, except that the lungs and brain had higher
concentretlons of radioactivity following Inhalation than oral exposure. In
both cases, high concentrations were noted 1 hour after exposure In the
harderlan gland, submaxlllary salivary gland and 1leum. Concentrations of
0181d
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radioactivity were also high In the stomach, GI tract, liver, kidney, colon
and ovarle: , but not In fat. By 6 hours, concentrations In most tissues,
especially the submaxlllary salivary gland, had declined. Retention was
greatest 1r the harderlan gland, adrenal gland and skin 6 and 72 hours after
exposure.
Strong et al. (1980) also used whole-body autoradlography to examine
three GDI albino mice/sex orally dosed with [v1nyl-l,2-l4C]-v1nyl acetate
at 1.17 mg/mouse. After 1 hour, the highest concentrations of radioactivity
were seen in the harderlan, salivary and lingual glands, GI mucosa, liver
and brown fat, with lower levels In blood, muscle, fat and testes. Radio-
activity cecllned at 6 and 72 hours, with the most retention In the GI
mucosa.
5.3. MET\BOLISM
Fllov (1959} found no vinyl acetate In blood drawn from rats (number,
strain anc sex unreported) that Inhaled unspecified concentrations of vinyl
acetate vapor for an unspecified duration. However, groups of 7 rats dosed
by Inhalctlon with vinyl acetate or acetaldehyde (concentrations and
durations not reported) had whole blood acetaldehyde concentrations of 45.8
and 30.4 jigX, respectively. When 380 yg vinyl acetate were Incubated 3
minutes with 2 mi whole blood, plasma, or washed erythrocytes, the human
samples yielded 175, 178 and 0 yg acetaldehyde, respectively, and the rat
samples gelded 158-165, 162-165 and 70 yg acetaldehyde, respectively.
The theorstlcal yield was calculated to be 194 yg. Incubation of plasma
from e1th?r species for 1 hour at 62°C destroyed this catalytic capacity.
The Implication was that Inhaled vinyl acetate was hydrolyzed by a heat-
labile plasma constituent to acetate, a normal metabolic Intermediate and
vinyl alcohol, which then Immediately tautomerlzed to acetaldehyde, another
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common metabolite. Cresswell et al. (1979) found that vinyl acetate 1n rat
plasma, wtnle blood and liver homogenate had half-lives of 58, 112-141 and
50-167 seonds, respectively, and that breakdown of vinyl acetate paralleled
formation of acetaldehyde. Strong et al. (1980) obtained half-lives for
vinyl ace.ate 1n human whole blood and plasma of 190-222 and 136-152
seconds, respectively. Simon et al. (1985a) Investigated vinyl acetate
hydrolysis In human and rat plasma and In rat liver and lung cytosollc,
mitochondria! and mlcrosomal fractions. Specific activities of these
tissues aid tissue fractions for hydrolysis of vinyl acetate at pH 8.0
exceeded those at 7.4, where they ranged from 0.12 (rat lung cytosol)
through 0.44 and 0.49 (human female and male plasma) to 12.5 (male rat liver
mlcrosomes) timol x mlnute/mg protein. Simon et al. (1985a) followed the
kinetics of the transient appearance of exhaled acetaldehyde as vinyl
acetate wis Inspired In a closed chamber (see Section 5.1.). Initially,
productlor of acetaldehyde mirrored linear consumption of vinyl acetate, but
after 0.1-0.6 hours, atmospheric acetaldehyde concentration declined,
reflecting further metabolism.
Acetaldehyde formed 1n the blood 1s further metabolized elsewhere.
Strong et al. (1980) found no degradation of acetaldehyde In the presence of
NAD by hjman or rat whole blood or plasma. In the cytoplasmlc (nonmlto-
chondMal) fraction of rat and mouse liver homogenates, acetaldehyde was
degraded at 1.27-2.27 and 1.53-2.73 Vmol/m1nute/g protein, respectively.
Since mcst of the radioactivity from absorbed 14C-v1nyl acetate 1s
eliminated as CO^ (see Section 5.I.), and the little excreted In urine 1s
primarily urea (Section 5.4.), Strong et al. (1980) concluded that vinyl
acetate is hydrolyzed In blood to acetate and vinyl alcohol. The latter
Immediately converts to acetaldehyde, which then forms acetate In hepatocyte
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cytosol. Ihe acetate from both sources Is widely distributed throughout the
body, when? most of It Is metabolized to CO- by the citric add cycle. A
small port'on 1s Incorporated Into the urea cycle to be excreted as urea.
Simon et al. (1985a) calculated that, 1n a simulated open exposure
system, tre rate of metabolic elimination of vinyl acetate Is linearly
dependent on atmospheric concentrations <650 ppm vinyl acetate. This rate
did not crange 1n rats prelnoculated with 200-600 mg/kg dlethyldlthlocarba-
mate, unlike volatlles blotransformed by monooxygenases. The Implication
that vinyl acetate 1s not appreciably metabolized through an epoxlde Inter-
mediate Is consistent with results reported by Simon et al. (1985b) and La1b
and Bolt (1986) (Section 6.2.3.).
Limited evidence for the formation of glutathlone conjugates In livers
of rats dcsed Intraperltoneally with vinyl acetate has been reviewed (NIOSH,
1978) and -111 not be detailed here.
5.4. EXCRETION
As noted In Section 5.1., 1.8-4.8% of the radioactivity from
[l4C]-v1njl acetate given to rats either orally or by Inhalation was
recovered In the urine, and most of the radioactivity was excreted as C02
In the expired air. Strong et al. (1980) subjected urine to TLC In three
solvent systems, finding one major and several minor bands In the auto-
radiogram; . The pattern of bands was not affected by route of administra-
tion. The RF for the major band In all solvents, as well as the color
elicited )y the sodium nltroprusslde-potasslum ferrlcyanlde reagent, matched
that of the reference compound, urea.
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5.5. SUMMARY
Vinyl acetate 1s rapidly absorbed by either oral or Inhalation exposure
and quickly hydrolyzed In rodent and human blood to acetate and (by tauto-
merlzatlon from vinyl alcohol) acetaldehyde (Cresswell et al., 1979; Strong
et al., 1*180). The acetaldehyde, which Is not acted on by blood, degrades
more slow y, largely 1n liver, to acetate (Strong et al., 1980; Simon et
al., 1985a). Both products are normal metabolites In most tissues, account-
Ing for the widespread distribution of radioactivity after administration of
14C-labeled vinyl acetate by either route (Strong et al., 1980). The
kinetics of hydrolysis and subsequent metabolism, and failure of those
kinetics 10 be altered by monooxygenase affectors, 1s not consistent with
the occurrence of appreciable quantities of carcinogenic epoxlde Interme-
diates (Simon et al., 1985a). While glutathlone conjugation may occur
following Intraperltoneal administration (NIOSH, 1976), this mechanism does
not constitute a major route of elimination following oral or Inhalation
administration, since most of the vinyl acetate administered by these routes
1s eliminated as exhaled CO^ and most of what little 1s excreted In urine
appears as urea (Strong et al., 1980). Thus, nearly all vinyl acetate 1s
metabolized to acetaldehyde and acetate and ultimately leaves the organism
as CO-.
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.. SUBCHRONIC ~ Groups of CD rats and CD-I mice (10/sex/
species) were exposed to 0, 50 (176 mg/m3), 200 (704 mg/m3) and 1000 ppm
(3521 mg/nr3) of vinyl acetate vapor generated with a nebulizer from 99.9%
pure 11qu1) for 6 hours/day, 5 days/week for 13 weeks (Owen, 1980a,b).
Among rats, no compound-related mortality was observed at any exposure
level (Owei, 1980a). No treatment-related clinical signs were seen at 50 or
200 ppm v'nyl acetate, but rats exposed to 1000 ppm exhibited Intermittent
respirator/ distress, hunched posture, ruffled fur and significantly reduced
(35-55X) height gain (p<0.01). No treatment-related ophthalmic defects were
found. Hematology and blood chemistry were unremarkable. H1cronucle1 counts
and myelold/erythrold ratios were comparable with controls. Except for
smaller volumes of more concentrated urine In both sexes treated at 1000
ppm, no cibnormalltles were found In urlnalyses. The only significantly
(p<0.01) iltered relative organ weight 1n both sexes was Increased lung
weight at 1000 ppm, believed to result from congestion secondary to exposure
to the Ir-ltant test atmosphere. Macroscopic organ analyses were unremark-
able, as were the microscopic findings except for a slight Increase In
Incidence, but not severity, of focal hlstocytlc alveolltls, characterized
by Infiltration of alveolar macrophages Into lumlna of adjacent alveoli at
Junctions of alveolar ducts and alveoli, In both sexes of high-dose rats.
Durlnci blood sampling, nine high-dose mice died, probably from vinyl
acetate-Induced susceptibility to anesthesia (Owen, 1980b). No clinical
signs of loxldty were seen In low-dose animals, but mid-dose mice Intermit-
tently displayed hunched posture and respiratory distress during the first 9
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treatment days. High-dose mice had hunched posture and ruffled fur Inter-
mittently and respiratory distress continually during treatment. Decreased
weight gali In high-dose mice was similar In significance and extent to that
of rats atove, while mid- and low-dose mice gained normally. There were no
treatment-associated changes In ophthalmologlcal, hematologlcal or clinical
chemistry parameters and no effects on m1crolucle1 counts or mylold/
erythrold ratios. The only chemically Induced organ weight changes were
Increased absolute and relative weights for lungs In both sexes of high-dose
mice (p< 3.05 and p<0.01), believed to be associated with congestion. No
treatment-related changes were seen on macroscopic tissue and organ examina-
tions at
-------
desynchronlzed the two activities, especially at the high dose. The authors
proposed the use of correlated enzyme activity to distinguish adaptive and
pathological responses to chronic toxlcologlcal exposure. The toxicologlcal
significance of these effects Is unclear, and this report Is not considered
further.
Kolesnlkov et al. (1975) exposed white rats (sex, strain and number not
given) by Inhalation with 13.2 and 68 mg/m3 vinyl acetic acid vapor
continuously for 120 days, which caused decreased weight and ascorbic acid
content of the left adrenal. Ascorbate level fluctuated In adrenals of both
dose groups, as did the eoslnopenlc reaction to ACTH. Oxygen uptake
Increased In high-dose animals when dosing ceased. This study was Insuffi-
ciently reported to be considered further.
6.1.1.2. CHRONIC — Dreef-van der Meulen (1988) reported the hlsto-
pathology of respiratory tracts of rats used In a 104-week Inhalation study.
The prellnlnary report of the original study (Hazleton Laboratories, 1987)
Is not complete, giving only the strain (Sprague-Dawley) and exposure levels
[0 ppm, 50 ppm (176 mg/m3), 200 ppm (704 mg/m3) and 600 ppm (2113
mg/m3) of vinyl acetate 6 hours/day, 5 days/week for 2 years] and noting
that tumo*s had been observed In the nasal cavities of some high-dose rats.
The pathology report noted that 58/59 controls, 56/59 low-dose, 60 mid-dose
and 58/5< high-dose rats were examined per sex. Significantly Increased
Incidence; of lesions In the lungs (epithelial exhalation and Intralumlnal
flbrosls In high-dose rats) and nose (thinning of the olfactory epithelium
and basal cell hyperlasla In high- and mid-dose rats), but not In the
larynx, were reported (p<0.01). Similar lesions occurred In tissues from
Interim Hlls (duration of Interims not reported), although some types of
lung lesions were not seen In these rats.
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Another preliminary Hazleton Laboratories (1986) report described 2-year
exposures cf groups of 90 CD-I mice (sex not given) to 0, 50 (176 mg/m3),
200 (704 ng/m3) and 600 ppm (2113 mg/m3) of vinyl acetic acid 6 hours/
day, 5 days/week. The only adverse effects were In the respiratory tract.
High-dose nice had bronchlolar epithelial lesions In the lungs. Findings at
the 200 ppm exposure level were not presented. The 50 ppm exposure level
was a NOEL
Malton and Lefemlne (1974,1975) exposed 96 Sprague-Dawley rats (sex not
reported) by Inhalation to 2500 ppm (8802 mg/m3) vinyl acetate 4 hours/
day, 5 days/week for 52 weeks, observing them until 131 weeks. After 26
weeks, 49 survived; none were alive at 131 weeks. Of 68 untreated controls,
58 survived for 26 weeks, and 1 survived at 131 weeks. The difference In
mortality was significant (p<0.001; statistical analysis performed at SRC).
No neopla;tic effects were seen in the group exposed to vinyl acetate;
nonneoplastlc effects were not reported. Therefore, mortality was
attributed to vinyl acetate exposure.
Deese and Joyner (1969) studied 21 male vinyl acetate production workers
exposed t( TWA levels of 5-10 ppm (18-35 mg/m3) vinyl acetate for a mean
of 15.2 years. Controls were matched by age and consisted of male chemical
production workers who had never worked 1n vinyl acetate production, but who
had been exposed to other chemicals. The controls had never shown signs of
systemic chemical toxlclty. Results of multlphaslc screening physical exams
(which Included evaluation of pulmonory function and pathology by splro-
metry and x-ray) were compared, as were past medical records. No notable
differences were reported between controls and vinyl acetate workers.
RussUn Investigators reported Impaired cardiac (Agaronyan and Amatunl,
1980; Amatunl and Agaronyan, 1979b) and pulmonary (Amatunl and Agaronyan,
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1979a; Aga-onyan and Amatunl, 1982; Gedrychowskl et al., 1979) function In
vinyl acetite workers exposed to unspecified concentrations of the compound
for unknown periods of time.
6.1.2. 0-al Exposure.
6.1.2.1. SUBCHRONIC — Groups of 10 male and 10 female Sprague-Dawley
rats were given vinyl acetate In drinking water for 13 weeks at progres-
sively Increasing concentatlons to maintain constant dose: weight ratios
(Gale, 19iiOa). The Initial water concentrations (mean dose: weight ratios
for males and females, respectively) were 0 (0 mg/kg/day), 200 (31 and 36
mg/kg/day)t 1000 (163 and 193 mg/kg/day) and 5000 ppm (684 and 810
mg/kg/day]. No compound-related clinical signs of toxlclty were reported.
Male terminal weights were reduced 8% In the high-dose group only, and the
weights cf other groups and weight gains In all groups did not differ
significantly from controls. Water consumption throughout the study was
reduced for both sexes 1n the high-dose group and for males only In the
mid-dose group; In the first 9 weeks, It was reduced for males only. The
authors attributed the decreased drinking to unpalatabllUy. Food consump-
tion was reduced 7 and 4X for high-dose males and females, respectively.
Vinyl acetate did not affect ophthalmoscoplc, hematologlcal, blood chemistry
or mlcronucleus observations at any dose level. The only effect on
urlnalysls was darker, more concentrated urine In high-dose females than In
controls. Organ weights and macro- and microscopic organ and tissue
examinations were unremarkable.
Gale (1980b) dosed groups of 10 CD-I mice/sex In drinking water for 13
weeks w1 :h 0, 200, 1000 and 5000 ppm vinyl acetate, the last three concen-
trations overformulated by 10, 7.1 and 6.954 to compensate for evaporation of
the test article. No compound-related effects were seen In mortality.
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clinical signs, weights or weight gains, food consumption, hematology,
mlcronucleus counts, blood chemistry, organ weights or macro- and micro-
scopic tissue and organ hlstopathologlc examinations. The apparent water
consumption Increased 1n high-dose animals of both sexes and In mid-dose
males, reflecting Increased water wastage, which was believed to be the
result of jnpalatabUHy.
6.1.2.2. CHRONIC — Shaw (1988) administered vinyl acetate In
drinking water to groups of 90 male and 90 female Sprague-Dawley rats of the
Crl:CD(SD)8R strain at 0, 200, 1000 or 5000 ppm, equivalent to dose levels
of 0, 30, 150 and 670 mg/kg at week 1; and 0, 10, 60 and 235 mg/kg at week
104. An additional 30 satellite animals of each sex were assigned/group for
Interim k 11s of 10/sex/dose level at 52 and 78 weeks. The rats had been
prevlouslj exposed ^n utero by administration of the same concentrations 1n
the drinking water of the dams. There was no treatment-related mortality.
The mean body weight for high-dose animals of both sexes was reduced 5-6% at
the start of the study, believed to be due to the \r± utero exposure. In
high-dose animals, body weight gains were reduced for males (p<0.001) during
both yeais and for females (p<0.05) during the second year. Also In
high-dose animals, mean group body weights were reduced 11 and 6X at week 52
and 17, aid 11% at week 104 for males and females, respectively, In the main
study, with similar findings In satellite groups. The other dose groups
showed no consistent treatment-related weight effects. Food consumption was
reduced :J-15X In high-dose males and 3-1054 In high-dose females, with
significance (p<0.05-0.001) only In the males. Water consumption was
reduced In all groups In a dose-related fashion during the first year, and
In high-Jose groups during only the second year. There were no other
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treatment-related clinical signs and no treatment-related effects on hemato-
loglcal, clinical, chemical or urinalytic parameters. Relative kidney
weights were significantly elevated In high-dose males, but no other
treatment-related changes 1n organ weight or 1n macro- or microscopic
hlstopatho ogy were found that reflected target-organ toxldty.
Lljlnsl.y and Reuber (1983) administered vinyl acetate 1n drinking water
to groups of 20 male and 20 female F344 rats at Initial concentrations of
2500, 100C or 0 ppm 5 days/week for 100 weeks. Dosages of 89 and 143
mg/kg/day can be estimated for high-dose males and females, and 36 and 57
mg/kg/day can be estimated for low-dose males and females. Although vinyl
acetate concentrations decreased 5-8.5%/day, the drinking water was prepared
weekly; so, doses were actually less than those estimated above. There was
no effect on survival. Nonneoplastlc lesions Included atrlal thrombosis In
two high-dose males, one low-dose male and two low-dose females, thrombotlc
endocordlUs (sic) In one low-dose male and hepatic vein thrombosis In one
high-dose female. Nonneoplastlc lesions were not reported for the controls.
6.1.3. Cither Relevant Information. Deese and Ooyner (1969) studied 3-5
male humari subjects, Including Deese, a laboratory analyst and up to three
chemical cperators; the subjects were queried about odor, eye Irritation and
upper respiratory Irritation when they were exposed 10 minutes to 0.4-21.6
ppm (1.4-76 mg/m3) vinyl acetate. Odor was detected at >0.4 ppm by 3/3
subjects. Of five subjects exposed to 5.7 or 6.8 ppm (20 or 23.9 mg/ma),
one reported slight eye Irritation, but none of the others reported this
effect at <10 ppm. All three exposed to 21.6 ppm reported eye Irritation
that would have been Intolerable for >10 minutes. One subject reported
hoarseness at 4.2 and 5.7 ppm (14.8 and 20 mg/m3), but others did not
complain of hoarseness or coughing at <21.6 ppm.
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Owen (1979a,b) exposed groups of Sprague-Dawley CD rats and CD-I mice
(5/sex/specles) by Inhalation to 0, 150 (528), 500 (1761} or 1000 ppm (3521
mg/m3) vlryl acetate 6 hours/day, 5 days/week for 28 days. A group from
each spec'es was also exposed, using the same schedule, to 50 ppm (176
mg/m3) w1:h an Increase to 1500 ppm (5282 mg/m3) starting on exposure
day 10 (lor rats) or exposure day 8 (for mice) and continuing for the
remainder of the study. One group of five pregnant rats was exposed to 500
ppm; however, no pregnant controls were provided. There was no mortality.
For rats, no treatment-related clinical signs were seen at 0, 50 or 150 ppm,
but rats at all other exposure levels showed dose-related respiratory
distress ind hunched posture (Owen, 1979a). Decreased weights and weight
gains (nol significant) were dose-related In females of all treatment groups
and In Rules at 1000 and 1500 ppm. However, the pregnant females were
unaffected by treatment and gained steadily throughout pregnancy. Organ
weight analysis at necropsy yielded statistically significantly decreased
spleen weights 1n males at 1000, 50 and 1000 ppm. No other
treatment-related clinical signs, macroscopic abnormalities at necropsy or
hematopoetetlc effects were found.
No conpound-lnduced clinical signs were seen In mice at 0 or 50 ppm, but
>150 ppm vinyl acetate caused dose-related respiratory distress and hunched
posture. Both males and females had decreased weight gains and terminal
weights rfhlch were significant (p<0.01) at >1000 ppm. Both sexes had
significantly decreased spleen weights at 1000, 50 and 1500 ppm. No other
organ we ghts were affected. No abnormalities were found upon macroscopic
hlstopathologlc examination or analysis of bone marrow samples relative to
controls (Owen, 1979b).
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Gage 1970) exposed four Alderly Park rats/sex/group to 100 (352
mg/m3), 2'iO (880 mg/m3), 630 (2218 mg/m3} or 2000 ppm (7042 mg/rn3)
of vinyl ccetate 6 hours/day, 5 days/week for 3 weeks, or to air saturated
at 20°C with vinyl acetate vapor for 5 minutes. Both sexes exposed to 2000
ppm exhibited eye and nose Irritation, respiratory difficulty, poor condi-
tion and low weight gain; excess macrophages were found In lungs at termina-
tion. Females exposed to 250 or 630 ppm had decreased weight gain and
normal orcans on autopsy, with normal blood and urine tests at 250 ppm. No
effects w?re observed at 100 ppm. Saturated vapor exposure caused rapid
anesthesia, followed by 100X mortality.
Barterey (1957) exposed six male rabbits (strain not reported} to 125,
250 and 500 mg/m3 vinyl acetate vapor for 40 minutes and measured how long
target muscle tension took to develop and the maximum muscle tension
achieved by foot reflex. These parameters were unaffected In low-dose
animals, Dut 5/6 mid-dose rabbits showed decreased tension development times
In target muscle and decreased reflex strength. Of high-dose animals, 3/6
had Increased times and decreased reflex strength. CNS excitability and
functional Instability Increased 1n mid- and high-dose animals, more so In
the latter. The ability to distinguish by conditioned reflex among complex
auditory and visual stimuli was affected 1n a dose-dependent fashion.
Recovery of normal responsiveness was complete In 2-6 days. The author
concludec that the threshold concentration for these CNS effects was 250-500
mg/m3, aid that conditioned reflex activity was 3 times as sensitive as
uncondlt'oned reflex activity to vinyl acetate vapor exposure.
Gale (1979) administered drinking water with mean concentrations (for
males and females) of 0 (0 yl/kg/day), -50 (8.5 and 9.3 yl/kg/day), -200
(30.8 and 35.4 yl/kg/day), -1000 (149.5 and 156 yl/kg/day) and -5000 ppm
0181d
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(672.5 and 807.8 yl/kg/day) of vinyl acetate to groups of Sprague-Dawley
(CD) rats, or 0 (0 jjl/kg/day), -50 (10 and 11 vl/kg/day), -ISO ppm (30.2
and 33.2 jd/kg/day), -1000 ppm (191.5 and 230.5 pl/kg/day) and -5000 ppm
(1113 and 1095 iii/kg/day) of vinyl acetate to groups of five CD-I mice/
sex/spede; for 28 days. Animals originally dosed at 50 ppm were offered
water with 10,000 ppm (for male and female rats, 909 and 995, and mice, 1738
and 2264 jii/kg/day) of vinyl acetate for the last week. One group of two
pregnant rats was dosed at 1000 ppm on gestation days 6-15, but no pregnant
controls
-------
There were dose-related decreases \n absolute and relative liver weights In
all treated groups of rats and female mice, and low thymus weights In male
mice at 5)00 ppm. Gross necropsy In rats was unremarkable. Mice had a
dose-relatjd Incidence of dark 61 contents with no other signs of GI
Irritation. The toxlcologlcal significance of decreased liver weight and
altered myelold erythrold cell ratios Is uncertain. In this study, 5000 ppm
was considered a NOAEL In the rat and a LOAEL In the male mouse associated
with decreased body weights. The 1000 ppm level was considered a NOAEL 1n
the mice. Dosages estimated from the Intake data provided above are 690
mg/kg/day for rats at 5000 ppm, 1030 mg/kg/day for mice at 5000 ppm and 197
mg/kg/day for mice at 1000 ppm. Intake data were averaged for males and
females, «.nd a density of 0.932 was used (Mlndholz, 1983).
LahdeMe (1988) dosed male (C57Bl/6JxC3H/He)F1 hybrid mice Intraperl-
toneally rflth 0 (9 mice), 125 (5 mice), 250 (4 mice), 500 (7 mice), 750 (5
mice), ard 1000 (5 mice) mg/kg 1n physiological saline for 5 days and
observed them until 5 weeks after the first dose. In one study, 8/8 and 4/5
died at "000 and 750 mg/kg, respectively; 1n another, 8/9 and 1/4 died at
those dos;s, but In neither study were there mortalities at the lower doses.
During the week of administration, vinyl acetate caused a dose-dependent
decrease In body weight that was recovered In the last few days of observa-
tion. Mean relative testlcular and seminal vesicle weights were reduced 1n
dose-related fashion. For relative testlcular weights, the reductions were
significant (p<0.05) at 500 and 125 mg/kg/day. Decreases In sperm count,
while nol significant In palrwlse comparison with controls, were found to be
dose-releted by regression analysis (p<0.01). High frequencies of abnormal
sperm were seen In 2/7 and 3/7 at 3 and 5 weeks after dosing onset, respec-
tively, it 500 and 750 mg/kg, but not at the lower doses. There was no
Increase 1n melotlc mlcronuclel In early spermatlds.
0181d
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Acute LCcn and LDcrt values are listed 1n Table 6-1. The order of
bU DU
sensitivity to Inhaled vinyl acetate vapor Is mouse > rabbU > rat; avail-
able oral data support this relationship.
6.2. CAR! 1NOGENICITY
6.2.1. Inhalation. Dreef-van der Meulen (19B8) reported the hlstopathol-
ogy of res)1ratory tracts of rats 1n a 104-week Inhalation study at Hazleton
Laboratories. The preliminary report of the original study {Hazleton
Laboratories, 1987) Is Incomplete, giving only the strain (Sprague-Dawley)
and exposure levels [0, 50 (176), 200 (704) and 600 (2113 mg/m3) ppm vinyl
acetate 6 hours/day, 5 days/week for 2 years] and noting that tumors had
been observed In the nasal cavities of some of the high-dose rats. Report-
edly, 58/!9 controls, 56/59 low-dose, 59/60 mid-dose and 57/59 high-dose
rats were examined/sex. Twelve neoplastU changes were reported In treated
animals and one In the controls (a benign lung adenoma). In the high-dose
group, th?re were seven malignancies: four females and one male had
squamous-c;11 carcinomas, one male had a carcinoma ±i\ situ In the nose, and
one femalt had a squamous-cell carcinoma of the larynx. All five benign
growths were nasal: four Inverted papHlomas 1n high-dose males and one
papllloma In a mid-dose male. No tracheal or lung tumors were found In
treated animals. A summary of neoplastlc changes 1s listed 1n Table 6-2.
A preliminary and Incomplete report (Hazleton Laboratories, 1986)
described 2-year exposures of groups of 90 CD-I mice (sex not reported) to
0, 50, 200 and 600 ppm vinyl acetate 6 hours/day, 5 days/week. A squamous
cell nodu'e was found on a terminal bronchial airway of one animal, and a
squamous cell carcinoma was found In a major lung airway of another In the
high-dose group. No similar tumors were found In any other treated or
control group.
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Mouse/NR/hR
Mouse/NR/hR
Rabblt/NR/NR
Rat/NR/NR
House/NR/fiR
TABLE 6-1
Acute LC5Q and 1050 Values for Vinyl Acetate
Species/
Strain/Sex
Rat/NR/NR
Rat/NR/NR
Route of
Administration
4 hour Inhalation
4 hour Inhalation
LCso or 1050 Value
4000 ppm (14.1 g/m3)
11.4 mg/l (or g/m3)
Reference
NIOSH, 1989
Rumyantsev
2 hour Inhalation
4 hour Inhalation
4 hour Inhalation
oral
oral
10.6 mg/l
1550 ppm (5.5 g/m3)
2500 ppm (8.8 g/m3)
2920 mg/kg
1613 mg/kg
et al., 1979
Rumyantsev
et al., 1979
NIOSH. 1989
NIOSH, 1989
NIOSH, 1989
NIOSH, 1989
NR = Not leported
01810
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05/03/89
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Maltonl and Lefemlne (1974, 1975} exposed 96 Sprague-Dawley rats (sex
not reported) by Inhalation to 2500 ppm vinyl acetate 4 hours/day, 5 days/
week for ?2 weeks, observing them until 131 weeks. After 26 weeks, 49 rats
survived, and none were alive after 131 weeks. No tumors were found, but It
1s unclear how many rats, 1f any, survived this exposure level long enough
for carclnogenesls to become apparent.
LefMngwell et al. (1983) reported a case-control study for factors
associated with an elevated Incidence of gllomas of the brain among workers
at a chenlcal and plastics plant In Texas CUy (Table 6-3). Possible
assoclatlcns explored Included job title, departmental employment history,
chemical jxposure history, location within the plant, employment dates and
residence. The list of chemicals for which an association was found
Included '*1nyl acetate. However, the absence of correlation with length of
exposure to any chemical, the Inclusion of carbon dioxide on the list of
chemicals the large confidence Intervals and confounding factors such as
employment date and residence association mitigate the Impact of correlation
with respoct to vinyl acetate.
6.2.2. Oral. Lljlnsky and Reuber (1982) administered vinyl acetate In
drinking water to groups of 20 male and 20 female F344 rats at Initial
concentra :1ons of 2500, 1000 or 0 ppm 5 days/week for 100 weeks and observed
the animals until death. Although vinyl acetate concentrations decreased
5-8.5X/da/, drinking water was prepared weekly; thus, doses received were
less than Intended. Also, the dose administered Is probably less than the
maximum tolerated dose for rats. Tumors In high frequency for this strain
of rats were reported In livers, uteri and parafolllcular cells of the
females' thyroids. Neoplastlc liver nodules (cellular origin not assigned)
were noted In two high-dose males, six high-dose females and four low-dose
0181d
-41-
10/16/89
-------
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-42-
10/04/89
-------
males. Aienocarclnomas were found In the uteri of one low-dose and four
high-dose females, and an adenoma was found In the uterus of another
high-dose female. These Incidences are reportedly unusual for F344 rats
(Busey anc Hardlsty, 1982; L1j1nsky, 1988). However, sarcomas and polyps of
the endormtrial stroma (five total 1n each treatment group) are typical of
the stralr. ProllferatWe lesions of thyroid C-cells were high In treated
females, >ut not treated males. C-cell carcinomas, adenomas and hyper-
plasla, rsspectlvely, were noted 1n one, five and three high-dose females,
In zero, :wo and eight low-dose females and In one, zero and two control
females. This work was later published (L1J1nsky and Reuber, 1983;
Lljlnsky, 1988} and Is summarized In Table 6-2.
Shaw (1988) administered vinyl acetate In drinking water to groups of 90
male and 93 female Sprague-Dawley rats of the Crl:CO(SO)BR strain at concen-
trations of 0, 200, 1000 or 5000 ppm, equlvalant to dose levels 0, 30, 150
and 670 nvj/kg at week 1, and 0, 10, 60 and 235 mg/kg at week 104. The
drinking w.iter was prepared dally, overformulated 5% to allow for decomposi-
tion 1n aqieous solution on standing. An additional 30 satellite animals of
each sex fcere assigned/group for Interim kills of 10/sex/dose at 52 and 78
weeks. Thu rats had been previously exposed In utero to the same concentra-
tions In .he drinking water of the dams. No neoplasms atypical of the
strain and attributable to the test article were noted In the main group or
satellite terminal kills.
6.2.3. Other Relevant Information. Lalb and Bolt (1986) orally dosed
four or five Wlstar rats/sex/dose with 0, 100 and 200 mg/kg vinyl acetate
dissolved !n commercial coffee cream twice dally, 5 days/week for 3 weeks.
No ATPase- and GGTase-deflclent preneoplastlc foci were detected, with or
without subsequent promotion by phenobarbltal. However, such foci had
0181d -43- 10/16/89
-------
previously been elicited by vinyl chloride and vinyl carbamate, both of
which gavu rise to hepatic nucleic add etheno-adducts (the promutagenldty
of such alducts was reviewed by Bolt (1988). Earlier, Simon et al. (1985b)
dosed malif and female F344 rats and male Wlstar rats by gavage (1 mC1} or
Inhalatlor (2.9-4.9 mC1) with [v1nyl-U-14C]v1nyl acetate, sacrificed the
animals after 4 hours and examined liver DNA. All radioactivity was
Incorporated Into normal bases; no etheno-adducts were formed. Lalb and
Bolt (198lt) concluded that vinyl acetate, unlike vinyl chloride and vinyl
carbamate, Is not appreciably metabolized through a carcinogenic epoxlde
Intermediate.
Vinyl acetate In all concentrations from 125-1000 yg/mi enhanced
transformation of hamster embryo cells by adenovlrus (Casto, 1980).
6.3. MITRGENICITY
Vinyl acetate has been assayed for mutagenklty In both prokaryotes
(primarily for reversion of hVs" mutants 1n Salmonella typhlmurlum) and
eukaryotes (Table 6-4). All reports of prokaryotlc assays have been
negative (.Ijlnsky and Andrews, 1980; Florin et al.. 1980; Me Cann et al.,
1975; Bram; et al., 1987; Bartsch, et al., 1979, 1980; Bartsch, 1976; Bartch
and Moniesino, 1980). In contrast, vinyl acetate has repeatedly shown the
ability to damage mammalian chromosomes, both _^n vitro (He and Lambert,
1985; Norpja et al., 1985, 1988; Jantunen et al., 1986; Lambert et al.,
1985; Ma*k1-Paakkanen and Norppa, 1987) and \t\ vivo (M3k1-Paakkanen and
Norppa, 1987; Shlrlnlan and Arutyunyan, 1980; Takeshlta et al., 1986).
Vinyl acetcte did not Induce single strand breaks 1n human lymphocyte DNA as
measured by alkaline elutlon. However, when cells were also treated with
X-1rrad1at1on, the elutlon rate of vinyl acetate + X-rays was Intermediate
between cortrols and X-rays alone, suggesting that vinyl acetate caused DNA
0181d -44- 10/16/89
-------
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10/04/89
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cross-links. Similar alterations were also reported with acetaldehyde
(Lambert »t al., 1985). Several Investigators believe that these effects
are due to the metabolite acetaldehyde (He and Lambert, 1985; Norppa et al.,
1985; Jan.unen et al., 1986; Lambert et al., 1985; TakeshUa et al.. 1986;
Hakl-Paakkanen and Norppa, 1987).
6.4. TEFATOGENICITY
Irvine (1980) studied the developmental toxldty of vinyl acetate by
both oral and Inhalation routes. In the oral study, groups of 23 mated
female Sprague-Dawley (CD) rats were given 0, 200, 1000 and 5000 ppm vinyl
acetate 1n drinking water, mean dosage equivalent to 28, 124 and 477
mg/kg/day, respectively, for gestation days 6-15. In the Inhalation study,
groups of 24 mated female Sprague-Dawley (CD) rats were exposed for 6 hours
dally on gestation days 6-15 to 50 (176), 200 (704) and 1000 ppm (3521
mg/rn3) atnospherlc vinyl acetate vapor. The dams were observed during and
subsequent to dosing for weight gain, food and water Intake (oral only) and
signs of toxldty. On gestation day 20, they were sacrificed and necrop-
sled; the pups were delivered by Cesarean section; the Investigators noted
number of corpora lutea, number and position of fetuses, early and late
1ntrauter1ne deaths and fetal weights, crown-rump lengths and sex.
Neither route of exposure produced any changes 1n maternal mortality nor
any grosi treatment-related signs of maternal toxldty. Weight gain
decreased In the high-dose group for each exposure route, slightly and
transiently for orally treated dams and significantly (p<0.01) during the
exposure period for dams dosed by Inhalation. Food consumption was margin-
ally reduced, and water consumption was significantly lower (p<0.01) for
high-dose oral dams. At necropsy, no treatment-related effects were seen on
the orally exposed dams, but those exposed by Inhalation to 1000 ppm had
0181d -48- 10/16/89
-------
Increased lung congestion. There was no effect on mean numbers of corpora
lutea/dam or fetal sex ratio caused by vinyl acetate given by either route.
There was no treatment-related effect on postlmplantatlon losses. Oral
exposure did not affect mean litter weight, fetal weight or crown/rump
length. However, Inhalation of 1000 ppm vinyl acetate significantly
(p<0.01) decreased these parameters; this was believed to be a consequence
of maternal growth retardation. Oral exposure did not Increase the Inci-
dence of external, visceral or skeletal defects, but Inhalation of 1000 ppm
vinyl ace;ate resulted 1n significantly higher Incidence of retarded sterne-
bral ossification (p<0.05). Minor skeletal defects also Increased slightly
1n the low- and mid-dose Inhalation groups. No other treatment-related
adverse fetal effects were Induced by either route.
6.5. OTHER REPRODUCTIVE EFFECTS
Shaw (1987) dosed groups of 18 male and 36 female (FQ) Sprague-Dawley
(Crl:CD(SI))BR) rats with 200, 1000 or 5000 ppm vinyl acetate In their
drinking *ater for 10 weeks and then mated them. Treatment of males ended
after another 4 weeks, while females were treated during mating, gestation
and lacUtlon. After weaning, FQ rats were sacrificed and necropsled.
Litters F,) were culled to 5/sex/l, and 25 pups/sex from each group
were selected to parent the F_ generation. The F, rats were treated
with the same dose as their parents for 10 weeks and then mated. Low- and
mid-dose nales continued on vinyl acetate 6 weeks; high-dose males, 11 weeks
more. Females continued treatment during mating, gestation and lactation.
For the Mrst mating, each F, female was paired with one nonslbllng male
of the Seme group and allowed to litter and rear the F~ pups to weaning.
Then, sone control and high-dose F, males, all low- and mid-dose F,
males am selected F« pups were necropsled. One week after weaning of
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the offspring, remaining parental control males were paired with all
high-dose females, and the remaining high-dose males were paired with all
control f;males (two females/male) for <10 days. When a mating was not
successful, nonproductive females were remated with males of known fertil-
ity. Halts were necropsled. Mated females were necropsled on gestation day
13, and ncnmated females, 13 days after the mating period ended.
In th'? parental generation, there were no treatment-related deaths or
clinical ;1gns of toxlclty. Body weight gains decreased slightly 1n the
high-dose group, significantly only during lactation. Water consumption
decreased 1n mid- and high-dose groups, significantly In the latter. No
slgnlflcart effects were reported on reproductive performance of FQ rats,
nor were there apparent effects on pup numbers, treatment-related clinical
signs or lecropsy abnormalities other than a significant reduction 1n body
weight gain of high-dose F. pups.
In the F, generation, there were no treatment-related deaths or
clinical ;1gns other than decreased body weight gain of mid- and high-dose
females djrlng lactation. Water consumption was significantly reduced In
high-dose rats of both sexes and mid-dose females before mating, and for
high- and mid-dose females during pregnancy and lactation. The mating Index
was unaffected, but the number of high-dose pregnancies was slightly but not
slgnlflcartly reduced. Pregnancy durations and Indlcles were unaffected.
Pup number/Utter, pup weights, development parameters, functional tests,
clinical ;1gns and necropsies were all comparable to controls.
In th» cross-mating, no deaths or clinical signs were reported. Body
weight gain was unaffected. High-dose water consumption was decreased. All
control and high-dose males sired at least one litter, but high-dose F,
males mated with control F, females Initiated fewer pregnancies than the
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reciprocal cross, although the difference In numbers mated and subsequently
pregnant rfas not significant. The number of corpora lutea and pre- and
postlmplartatlon losses resulting from the one cross was unaffected,
relative :o the reciprocal cross. If matings of F, animals to produce the
F_ generation 1s considered together with the cross-mating experiment,
there was a marginal but not statistically significant effect of treatment
on the outcome of mating 1n the high-dose males. There were no treatment-
related iiacroscoplc or microscopic abnormalities In high-dose F, male
reproductive organs.
Effects observed In this study Include significantly decreased body
weight gain 1n lactatlng females at 5000 ppm 1n both generations and at 1000
ppm In tie second generation. In addition, the body weight gain of F.
pups was significantly reduced. In both generations, however, the decrease
In body weight gain of the lactatlng rats was accompanied by a significant
reduction 1n water consumption. Although It seems that the effect on the
growth of pups may reflect Impaired nutrition resulting from decreased water
consumption by the dams possibly resulting 1n reduced milk production, the
Investigators offered no explanation and provided no milk production data.
The Investigators also reported slight but not statistically significant
decreases 1n male fertility at 5000 ppm. Taken together, these two effects
are considered to constitute sufficient evidence that exposure to 5000 ppm
may have potentially adverse effects on reproduction; this level Is
considered a LOAEL. The 1000 ppm level 1s considered a NOAEL In this study.
By aDplylng the assumptions that rats drink 0.049 8. water/day and
weigh 0.:!5 kg (U.S. EPA, 1986b), dosages of 700 and 140 mg/kg/day can be
estimated for 5000 and 1000 ppm, respectively.
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6.6. SUMMARY
Subchronlc Inhalation exposure of rats (Owen, 1980a) and mice (Owen,
1980b) to 1000 ppm (3521 mg/m3) vinyl acetate for 6 hours/day, 5 days/week
caused decreased weight gain and respiratory distress with lung congestion
and leslois In rat lungs and mouse nasal cavities, tracheae and bronchial
systems. The mice were more sensitive, showing respiratory distress Inter-
mittently at 200 ppm (704 mg/m3). Neither species was affected by lower
concentrations In these studies. Russian Investigators reported some
alterations In the activity of liver enzymes In rats or mice following
continuous subchronlc exposure to concentrations >2.4-68 mg/m3 (Tlunova
and Rumyantsev, 1975; Rumyantsev et a!., 1979; Kolesnlkov et a!., 1975);
Interpretation of these studies 1s problematical. Nearly half of rats
chronically exposed to 2500 ppm (8803 mg/m3), 4 hours/day, 5 days/week
died (Maitonl and Lefemlne, 1974, 1975) and chronic exposure of rats
(Dreef-vai der Meulen, 1988; Hazleton Laboratories, 1987) and mice (Hazleton
Laboratories, 1986) to 600 ppm (2113 mg/m3) vinyl acetate 6 hours/day, 5
days/week produced respiratory tract lesions, with a NOEL for mice of 50 ppm
(176 mg/u3). U.S. workers chronically exposed to 5-10 ppm (1.8-3.5
mg/m3} vinyl acetate experienced no adverse health effects as compared
with workers exposed to other chemicals (Deese and Joyner, 1969). Russian
Investigators reported that vinyl acetate workers suffered Impaired cardiac
(Agaronyai and Amatunl, 1980; Amatunl and Agaronyan, 19795) and pulmonary
(Amatunl and Agaronyan, 1979a; Jedrychowskl et al., 1979; Agaronyan and
Amatunl, 1982) function, but neither the exposure levels nor the duration of
exposure Mere specified In the available accounts of these studies.
Subchronlc administration of 5000 ppm vinyl acetate In drinking water
slightly reduced terminal (3-month) weights 1n male rats, but the unpalat-
ablllty cf this dose decreased water consumption In rats (Gale, 1980a) and
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Increased water wastage \n mice (Gale, 1980b); no adverse effects were
reported In either species. Chronic administration of 5000 ppm vinyl
acetate 1n drinking water to rats decreased water and food consumption and
weights and weight gains In both sexes, and Increased relative kidney
weights 11 males (Shaw, 1988). Low Incidences of thrombotlc lesions were
reported in rats chronically dosed with 2500 and 1000 ppm vinyl acetate In
drinking water (Lejlnsky and Reuber, 1983).
In acjte Inhalation exposures, human males consistently found 21.6 ppm
(76 mg/m3) vinyl acetate vapor Irritating to the eyes and throat (Deese
and Joyner, 1969). Rabbits exposed 40 minutes to 250 ppm (880 mg/m3)
vinyl acetate vapor exhibited CNS Impairment (Barteney, 1957). All rats
Inhaling air saturated with vinyl acetate vapor died In minutes (Gage,
1970). In exposures for 6 hours/day, 5 days/week for 3 weeks, 2000 ppm
(7042 mg/m3) caused respiratory difficulty and depressed weight gain;
250-630 ppm (880-2218 mg/m3} affected weight gain only. No effects were
seen at 100 ppm (352 mg/m3) (Gage, 1970). In 28-day Inhalation studies (6
hours/day, 5 days/week), respiratory distress was exhibited by rats at
500-1500 ppm (1761-5281 mg/m3) and mice at 150-1500 ppm (528-5281 mg/m3)
(Owen, l')79a,b). In the same studies, weights and weight gains were
affected 1n treated female rats and In rats and mice of both sexes at >1000
ppm; splesn weights were reduced at >1000 ppm In both species.
In 28-day drinking water studies with vinyl acetate concentrations rang-
ing from 50-5000 ppm (Gale, 1979), weights and weight gains were affected,
especially In female rats and male mice. Decreases 1n food and water
consumption were also seen, but these did not parallel each other or weight
effects. Decreased weights were seen In liver and thymus. La"hdet1e (1988)
reported 1ntraper1toneal administration of 125-1000 mg/kg/day vinyl acetate
to male nice caused dose-dependent decreases In body, testlcular and seminal
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vesicle we'ghts. Doses >500 mg/kg resulted In abnormal sperm counts, and
doses >750 mg/kg resulted 1n high mortality.
Inhalation LC5Q values for mice, rabbits and rats varied from 5.3 (4
hours for mice) to 14.1 (4 hours for rats) g/m3 (NIOSH, 1989; Rumyantsev
et al., 1979). Oral LD5Q values for rats and mice were 2.92 and 1.63 g/kg
respectlve'y (NIOSH, 1989).
Data 01 cardnogenldty are equivocal. Two Inhalation studies of vinyl
acetate, oie using rats (Dreef-van der Meulen, 1988; Hazleton Laboratories,
1987} and one using mice (Hazleton Laboratories, 1986), reported malignant
squamous cell carcinomas at 600 ppm (2113 mg/m3) vinyl acetate (6 hours/
day, 5 days/week) 1n both species, and benign tumors 1n rats at 200 ppm (704
mg/m3) (6 hours/day, 5 days/week) 1n the respiratory tracts. Although
none of these lesions appeared In controls, only the squamous cell
carcinomas 1n the nasal passages of female rats were marginally significant
(p=0.06). A third Inhalation study (Maltonl and Lefemlne, 1974. 1975) In
rats was regatlve, but the exposure was so high (2500 ppm or 8802 mg/m3, 4
hours/day, 5 days/week) that there may have been Inadequate numbers of
survivors to generate positive data. The one human study (Lefflngwell et
al., 1983) reported an association between Industrial exposure and death by
glloma of the brain (see Table 6-3). However, vinyl acetate was one of many
chemicals reported with such an association, no correlation with length of
exposure was seen, confidence Intervals were large, and there were
uncontrolled confounding factors. In one oral (drinking water) study of
rats (Lljlnsky and Reuber, 1982, 1983; L1j1nsky, 1988; Busey and Hardlsty,
1982), statistically significant Increases In neoplastlc liver nodules
(p=0.05), uterine adenocardnomas and adenomas (p=0.02) and thyroid C-cell
neoplasms (p=0.05) were seen 1n female animals given 1000 or 2500 ppm vinyl
acetate; these types of tumors were not seen In controls. In contrast, Shaw
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(1988} al>o studied carclnogenesls 1n rats (albeit a different strain)
arising from vinyl acetate In drinking water, using 5 times as many
animals/dose and a broader dose range. There were no tumors found that
could be cttrlbuted to vinyl acetate, Including tumors of the types reported
by Ujlnsky and colleagues.
All pi okaryotlc assays for inutagenlclty of vinyl acetate were negative
(Ujlnsky and Andrews, 1980; Florin et al.t 1980; Me Cann et a!., 1975;
Brams et il., 1987; Bartsch, et al., 1979, 1980; Bartsch, 1976; Bartch and
Montesano, 1980). In contrast, assays for chromosome breakage 1n mammalian
cells were usually positive, both in vitro (He and Lambert, 1985; Norppa et
al., 1985, 1988; Jantunen et al., 1986; Lambert et al., 1985; Hakl-Paakkanen
and Norppi, 1987} and in vivo (Makl-Paakkanen and Norppa, 1987; Shlrlnlan
and Arut^unyan, 1980; Takeshlta et al., 1986). Hutagenlclty data are
presented In tabulated form 1n Table 6-4.
Irvine (1980) reported no teratogenlc effects or effects on reproductive
parameter; Induced by oral (drinking water) or Inhalation administration of
vinyl acetate to rats. Significant fetotoxldty (reduced mean Utter
weight, f ;tal weight, fetal crown/rump length or retarded sternebral ossifi-
cation) was seen at 1000 ppm (3521 mg/m3} (6 hours/day on gestation days
6-15), an Inhalation level causing maternal toxlclty (decreased weight gain
and lung congestion).
Vinyl acetate at 5000 ppm In drinking water, a level possibly toxic to
dams (transiently decreased weight gain and decreased food and water con-
sumption) had no effect on fetuses. In a two-generation study of rats given
vinyl acetate 1n drinking water, the only signs of toxlclty were decreased
water consumption and weight gain (especially during lactation) at 5000 ppm
and a marginal effect of treatment on outcome of mating In first filial
generatloi males treated at 5000 ppm (Shaw, 1987).
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7. EXISTING GUIDELINES AND STANDARDS
7,1. HUMN
AC3IH (1988) has adopted TLV-TWA and STEL values of 30 and 60 mg/ma,
respectively, for vinyl acetate. OSHA (1989) also recently adopted these
values, rather than the NIOSH (1978) 15-mlnute celling of 4 ppm (14.1
mg/m3). The STEL and the NIOSH REL are based on avoidance of Irritant
effects (OSHA, 1988; ACGIH, 1986).
U.S. EPA (1985, 1986c, 1987) listed an RQ for vinyl acetate of 5000
pounds based on aquatic toxlclty.
7.2. AQUATIC
Guide ines and standards for the protection of aquatic life from
exposure :o vinyl acetate were not located In the available literature cited
In Appendix A.
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8. RISK ASSESSMENT
8.1. CAFCINOGENICITY
8.1.1. Inhalation. Data on the cardnogenldty of Inhaled vinyl acetate
are equivocal. Two Inhalation studies, one \n rats (Dreef-van der Meulen,
1988; Hazleton Laboratories, 1987) and one 1n mice (Hazleton Laboratories,
1986) reported a few squamous cell carcinomas at 600 ppm (2113 mg/m3)
vinyl ace.ate (administered 6 hours/day, 5 days/week) In both species, and
benign tumors 1n rats at 200 ppm (704 mg/m3) (administered 6 hours/day, 5
days/week] In the respiratory tracts. None of these lesions appeared In
controls ar In the low-dose group. However, the sample sizes were very
small and limit the capacity to calculate a robust summary statistic. A
third Inhalation study (Maltonl and Lefemlne, 1974, 1975) of rats was
negative, but the exposure was so high (2500 ppm or 8802 mg/m3, 4 hours/
day, 5 da/s/week) that there may have been Inadequate numbers of survivors
to generale positive data. The one human study (Lefflngwell et al., 1983)
reported
-------
Busey and Hardlsty, 1982). In contrast, Shaw (1988) studied cardnogenesU
In rats (albeit a different strain) from vinyl acetate In drinking water,
using 5 times as many animals/dose and a broader dose range. No tumors were
found that could be attributed to vinyl acetate. Including tumors of the
types reported by Lljlnsky and colleagues.
8.1.3. Other Routes. Pertinent data regarding the carclnogenldty of
vinyl ace.ate following other routes of exposure could not be located 1n the
available literature cited In Appendix A.
8.1.4. Height of the Evidence. The carclnogenldty of vinyl acetate
would be expected to be similar to that of acetaldehyde, Us metabolite (see
Section E.2.). However, recent observations suggest such assumptions be
viewed w'th caution. In a comparison of the effects of Inhaled vinyl
acetate and acetaldehyde on rat respiratory tracts, Oreef-van der Meulen
(1988) points out a number of remarkable differences In the damage arising
from the two chemicals. Unlike acetaldehyde, vinyl acetate did not cause
nasal adenocarclnomas, and the nasal epithelial tumors engendered did not
arise fron the cytotoxlc damage to nasal epithelial tissue associated with
acetaldehyde. Also, vinyl acetate did not affect the larynx and did affect
bronchi aid lungs, whereas acetaldehyde damaged laryngeal epithelium but did
not affect bronchi and lungs. However, this may be related to differences
In the dynamics of the Inhaled dose.
Resul :s obtained from experiments that used oral exposures are In
conflict. Despite small sample sizes and a limited dose range, Lljlnsky
(1988) reported data that demonstrated a statistically Increased Incidence
for some sites In exposed rats. However, these results were not corrobo-
rated by Shaw (1988) who used a broader dose range and larger sample sizes,
but a d1f:erent strain of rats.
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Given that the only data on the carclnogenUHy of vinyl acetate In
humans ha:; unresolvable confounding factors affecting the Interpretation of
the results (Leflngwell et al., 1983) and that the animal studies lack
consistency and are limited by a number of problems, this compound 1s placed
In EPA (roup C: possible human carcinogen (U.S. EPA, 1986d). Ihls
designaten 1s supported by the fact that the Incidence of tumors was found
to be Increased 1n some experiments. Also, vinyl acetate 1s structurally
similar to other compounds that are recognized as carcinogens In humans and
animals -• vinyl chloride, vinyl cyanide and vinyl carbamate. Additionally,
1t appears that acetaldehyde, a group B2 carcinogen, Is a metabolite of
vinyl acetate. While the \n vivo behavior 1s different, some of the 1_n
vitro experiments Indicate that the activity of vinyl acetate 1s modulated
by acetalcehyde.
8.1.5. (luantHatlve Risk Estimates. The lack of adequate positive
studies on the cardnogenlclty of vinyl acetate following exposure either by
the oral or Inhalation route precludes the derivation of quantitative risk
estimates (U.S. EPA, 1986d).
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) — Subchronlc
Inhalatlor exposures (6 hours/day, 5 days/week) of rats (Recs. *4. 5), by
Owen (198Da) and of mice (Recs. #1-3) by Owen (1980b) to 1000 ppm (3521
mg/m3) vinyl acetate vapor caused decreased weight gain and respiratory
distress with lung congestion and lesions 1n rat lungs and mouse nasal
cavities, tracheae and bronchial systems. The mice showed respiratory
distress Intermittently at the next lower exposure level, 200 ppm (704
mg/m3), but only for the first 9 days of the study. The 200 ppm level 1s
01 Bid
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considered a NOAEL In mice. Neither species was affected by the lowest
concentration, 50 ppm (176 mg/m3), In these studies. In the absence of
more detailed data, the changes reported by Russian Investigators (Recs. #6,
7) In rats and mice subchronlcally exposed continuously to >2.4-68 mg/m3
vinyl acetate (Rumyantsev et al., 1979; Kolesnlkov et al., 1975; Tlunova and
Rumyantsev, 1975} are not readily classifiable as adverse. An Inhalation
teratogenUUy study In rats by Irvine (1980) Indicated fetotoxlc and
maternotoxlc effects at 1000 ppm but not at 200 ppm (6 hours/day on gesta-
tion days 6-15) (Recs. #30, 31). Thus, 704 (Owen, 1980a) and 176 mg/m3 (6
hours/day, 5 days/week) (Owen, 1980b), the highest exposures causing no
adverse e:fects 1n rats and mice, are the subchronlc NOAELs for rats and
mice, respectively. Using the Interim methodology of U.S. EPA (1989),
subchronlc HECs may be calculated for each species.
From :he distribution of respiratory lesions, It Is assumed that the
respiratory distress arose from the whole respiratory system, probably
mostly f-om the lower tract. For the rat, an ROD of 0.0000642
m3/day/cm5 can be obtained by dividing the rat ventilation rate of 0.223
m3/day b> Us total respiratory tract surface area of 3473 cm2 (U.S.
EPA, 1989 . The human ROD for the total respiratory tract area Is obtained
similarly (20/640,758 = 0.0000312). The rat human RDDR for the whole
respiratory tract Is then found from RODrat/RODnuman to be 2.057. A NEC
for the -at NOAEL (or rat NOA£Lu,r) of 258.6 mg/m3 can then be calcu-
Ht L
lated by expanding the rat NOAEL of 704 mg/m3 by a factor of 6 hours/24
hours x * days/7 days to continuous exposure at 125.7 mg/m3 and multiply-
ing by the RDDR.
The computation for the HEC of the mouse NOAEL Is altered, since a value
for the surface area of the murlne nasal cavity Is not available. There-
fore, surface areas of 294.8 and 640,581 cm* (U.S. EPA, 1989) for CO-1
0181d -60- 10/11/89
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mouse and human (respectively) tracheo-bronchlal plus pulmonary regions are
used with a mouse ventilation rate of 0.039 mVday to obtain a mouse:
human ROD* for the lower respiratory tract of 4.237. Expanding the mouse
NOAEL to continuous exposure as above from 176-31.4 mg/m3 and multiplying
by the RD3R yields a mouse NOAELHE_ of 133.2, which 1s lower than the rat
NOAELucr, and, therefore, a more appropriate basis for an RfD computation.
Htl
The sibchronlc Inhalation RfD 1s then derived by applying an uncertainty
factor of 100 (10 for Interspedes extrapolation and 10 to protect the most
sensitive Individuals). The resulting RfD, expressed to two significant
figures, is 1.3 mg/m3. Confidence In the key study (Owen, 1980b) Is low,
since there were only 10 rats/sex In each group (Recs. #1, 2). Confidence
In the da;a base Is also low, since there were only two toxlclty studies In
the subch-onlc range (one In rats and one In mice), only one Inhalation
teratogenlclty study (In rats) and no Inhalation reproductive toxlclty
studies. Therefore, confidence 1n this subchronlc RfO Is low.
8.2.1.2. CHRONIC EXPOSURE — U.S. workers chronically exposed to 5-10
ppm (1.8-}.5 mg/m3) vinyl acetate, well below the suchronlc RfD derived
above, dU not differ significantly from workers exposed to other chemicals
(Rec. #14) with regard to results of a screening physical exam or past
medical history (Deese and Joyner, 1969). Chronic exposure for 6 hours/day,
5 days/we?k of rats (Dreef-van der Meulen, 1988; Hazleton Laboratories,
1987) and mice (Hazleton Laboratories, 1986), to 600 ppm (2113 mg/m3)
vinyl aceiate produced respiratory tract lesions 1n both species; 200 ppm
(704 mg/m3} produced nasal lesions In rats (results In mice were not
presented); and 50 ppm (176 mg/m3} did not affect either species (Recs.
#8-12). However, the data presented In the Hazleton reports were too
lacking 1r detail to be used for an RfD derivation. Therefore, a chronic
0181d -61- 10/04/89
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RfD of C.I mg/m3 Is derived from the subchronlc RfD by applying an
additional uncertainty factor of 10 to extrapolate from a subchronlc study.
The confkence In the RfD Is low, as discussed above.
8.2.2. Cral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) -- Subchronlc
administration of 0, 200, 1000 and 5000 ppm vinyl acetate 1n drinking water
to mice
-------
The RfD f>r chronic oral exposure, however, 1s derived from a longer-term
study uslig rats exposed to 1000 ppm (Section 8.2.2.2.}. Because the
authors o the longer-term study performed a more thorough Investigation,
and greater confidence can be placed 1n the longer-term study, the RfD of 1
mg/kg/day for chronic oral exposure 1s adopted as the RfD for subchronlc
oral exposure. Confidence In the key study, data base and RfD are medium,
as discussed below.
8.2.2.2. CHRONIC EXPOSURE — The data base from which a chronic RfD
can be derived Includes three drinking water studies with rats: two 2-year
toxlclty itudles and one two-generation study. In the first, groups of 90
rats/sex/ciose were used In the main study with three additional Interim
kills of 10 rats each. Administration of 5000 ppm vinyl acetate for 104
weeks by Shaw (1988) resulted In decreased water and food consumption,
weights end weight gains In both sexes, and Increased relative kidney
weights \-( males (Recs. #1, 3). No effects were seen at 1000 ppm, which Is
considered a NOEL. From the data provided, It can be estimated that the two
concentrations are equivalent to mean doses of -450 and 100 mg/kg/day,
averaged :or both sexes. In the other chronic study, groups of 20 rats/sex/
dose were provided drinking water containing vinyl acetate at 0, 1000 or
2500 ppm for 100 weeks (L1J1nsky and Reuber, 1983). The authors reported
thrombotl: lesions at both dose levels, but the Incidences were low. Inci-
dence data for controls were not reported, and the protocol did not permit
reasonably accurate estimation of Ingested dosages. Shaw (1988) reported no
thrombotl: lesions In a very comprehensive hlstopathologlc evaluation of
rats exposed to higher levels for 104 weeks. This study, therefore. Is not
considered further for risk assessment. In the 2-generat1on study by Shaw
(1987) of 18-36 rats/sex/dose given vinyl acetate In drinking water (Recs.
0181d
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#12, 13), the only signs of toxlclty were decreased water consumption and
weight gam of dams and pups during lactation and a marginal effect of
treatment on outcome of mating In first filial generation males treated at
5000 ppm. The 1000 ppm level was a NOAEL for these effects. These concen-
trations, based on default assumptions, are equivalent to doses of 140 and
700 mg/kg/day. The key study Is Shaw [(1988) (Recs. #1, 3)]. It uses the
most an1m
-------
9. REPORTABLE QUANTITIES
9.1. BASiD ON SYSTEHIC TOXICITY
The systemic toxlclty of vinyl acetate was discussed In Chapter 6, and
dose/respoise data suitable for use In the determination of an RQ are summa-
rized In Table 9-1. The chronic Inhalation study selected was Dreef-van der
Heulen (1938). The Inhalation developmental toxldty study by Irvine (1980)
and the respiratory distress reported 1n rats and mice exposed for 13 weeks
was also Included. The 2-year Hazleton Laboratories {1986, 1987) study
using mice 1s not Included because the data were Insufficiently reported for
evaluation for risk assessment. The mortality reported at 26 weeks by
Maltonl ard Lefemlne (1974. 1975), although statistically significant and
not related to cancer, Is not Included because 1t Is considered an acute
response .0 an unusually high concentration. Furthermore, the exposure
protocol (4 hours/day) may be considered a repeated acute, rather than a
truly subchronlc or chronic, exposure. The human occupational study by
Deese and Joyner (1969) was not Included because adverse effects were not
reported In humans exposed to 5-10 ppm. Oral studies that were considered
Included the drinking water studies by Shaw (1987, 1988). The 100-week
study by .IJInsky and Reuber (1983) was not Included because the dosages
Ingested could not be accurately estimated and because nonneoplastlc effects
were InsufMclently reported.
Inspec:1on of the responses listed In Table 9-1 reveals that they may be
sorted Inta categories listed In descending severity as follows: potentially
Impaired reproductive ability (RV =8), fetotoxldty (RV =8), respiratory
6 C
distress i RV =7), respiratory tract lesions (RV =6), and organ or body
C C
weight changes {RV =4). The lowest equivalent human dose associated with
each of these effects was selected to construct Table 9-2, In which CSs and
RQs were computed. An uncertainty factor was not applied to expand from
0181d -65- 10/11/89
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subchronlc to chronic exposure for the respiratory tract Irritation and
distress reported In mice (Owen, 1980b), because It was considered an acute
response.
RQ values of 1000 were derived for potential Impairment of reproductive
performance (Shaw, 1987), fetotoxldty (Irvine, 1980), respiratory distress
(Owen. 19ltOb) and respiratory tract lesions (Dreef-van der Meulen, 1988).
An RQ val le of 5000 was derived for changes In organ weight reported In a
chronic oral study. These data suggest that vinyl acetate Is more toxic by
Inhalation than by oral exposure. The CS of 8 corresponding to an RQ of
1000, associated with fetotoxldty. Is chosen to represent the chronic
toxlclty of vinyl acetate (Table 9-3).
9.2. BASED ON CARCINOGENICITY
Data >n carclnogenlclty were equivocal. Two Inhalation studies with
experimental animals, one In rats (Dreef-van der Meulen, 1988; Hazleton
Laboratories, 1987) and one In mice (Hazleton Laboratories, 1986), reported
malignant squamous cell carcinomas at 600 ppm (2113 mg/m3) vinyl acetate
vapor In hoth species and benign tumors In rats at 200 ppm (704 mg/m3) 1n
respiratory tracts. However, although none of these lesions appeared In
controls, the Incidence In treated animals was only marginally statistically
significant. A third Inhalation study using rats was negative, but the dose
was so h1i[h (2500 ppm or 8802 mg/m3) that there were Inadequate numbers of
survivors to generate positive data. The one human study (Lefflngwell et
al., 1983) reported an association between Industrial exposure and death by
glloma of the brain (see Table 6-3). However, vinyl acetate was one of many
chemicals reported with such an association, and there were confounding
factors. In one oral (drinking water) study of rats (LlJInsky and Reuber,
1982, 198^; LlJInsky, 1988; Busey and Hardisty, 1982), 1000 and 2500 ppm
OlSld -69- 10/11/89
-------
TABLE 9-3
Vinyl Acetate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Species/Sex:
Dose*:
Duration:
Effect:
RVe:
CS:
RQ:
Reference:
Inhalation
rats/F
6623 nog/day
10 days (organogenesls)
fetotox1c1ty
1
8
8
1000
Irvine, 1980
*Chron1c himan MED
0181d
-70-
10/04/89
-------
vinyl acelate resulted In neoplastlc liver nodules, uterine adenocardnomas
and adenonas and thyroid C-cell neoplasms (females only), none of which were
seen In controls. However, Shaw (1988) also studied carclnogenesls 1n rats
(albeit a different strain) arising from vinyl acetate 1n drinking water,
using 5 times as many animals/dose and a broader dose range. There were no
tumors found that could be attributed to vinyl acetate, Including tumors of
the type reported by LlJInsky and colleagues.
Becau; e the only data on the cardnogenldty of vinyl acetate In humans
(Lefflngwoll et al., 1983} and the animal studies by oral and Inhalation
routes are equivocal, this compound was placed In EPA Group C: potential
human carcinogen (U.S. EPA, 1986d). This classification does not require
the derivation of a quantitative risk estimate. Hence, the substance Is
assigned to a medium potency factor range, placed In Potency Group 2, and
assigned in RQ (based on cardnogenldty) of 100 (U.S. EPA, 1986d).
0181d
-71-
10/11/89
-------
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-------
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0181d
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0181d
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0181d
-79-
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Hak1-Paak
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NIOSH (Na;1onal Institute for Occupational Safety and Health). 1989. RTECS
(Registry of Toxic Effects of Chemical Substances). CAS No. 108-05-4.
Online: H.rch, 1989.
Norppa, K, F. Tursl, P. Pfaffll, J. Mak1-Paakkanen and H. Jarventaus.
1985. Ch •omosome damage Induced by vinyl acetate through In vitro formation
of aceta dehyde In human lymphocytes and Chinese hamster ovary cells.
Cancer Re;. 45: 4816-4821.
018 Id
-83-
10/04/89
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Norppa, H., J. Makl-Paakkanen, K. Oantunen, P. Elnlsto and R. Raty. 1988.
Nutagenlc'ty studies on styrene and vinyl acetate. Ann. NY. Acad. Scl.;
Liver Chen. World. 534: 671-678.
OSHA (Occupational Safety and Health Administration). 1988. Federal
Register. 53(109): 21103-21299.
OSHA (Occupational Safety and Health Administration). 1989. A1r Contami-
nants; F1ial Rule. Federal Register. 54(12): 2956.
Owen, P.E. 1979a. Vinyl acetate: 4-Week Inhalation dose ranging study In
the rat. Hazleton Laboratory Europe LTD. Report No. 2286-51/5. EPA
Document Mo. FYI-OTS-184-0278. Flche No. OTS0000278-0.
Owen, P.Ci. 1979b. Vinyl acetate: 4-Week Inhalation dose ranging study In
the mouse (1979). Hazleton Laboratories Europe, LTD. Report No. 1884-51/3.
EPA Doc. No. FYI-OTS-184-027850. Flche No. OTS0000278-0.
Owen, P.d. 1980a. Vinyl acetate: 3-Month Inhalation toxldty study 1n the
rat. H.izelton Labs Europe LTD. Report #2286-51/5. EPA Doc. No.
FYI-OTS-C184-0278. Flche No. OTS000278-0.
Owen, P.ii. 1980b. Vinyl Acetate: 3-Month Inhalation toxldty study In the
mouse. Hazleton Labs Europe LTD. Report No. 2303-51/5. EPA Doc. No.
FYI~OTS-(H84-0278. Flche No. OTS0060278-0.
018 Id
-84-
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Pahren, H.R. and D.E. Bloodgood. 1961. Biological oxidation of several
vinyl compounds. Water Pollut. Control Fed. J. 33: 233-238.
Parker, J.G. 1984. The effects of selected chemicals and water quality on
the marine polychaete Ophryotrocha diadema. Water Res. 18(7): 865-868.
PellzzaM, E.O. 1982. Analaysls for organic vapor emissions near
Industrial and chemical waste disposal sites. Environ. Scl. Technol. 16:
781-785.
Pickering, Q.H. and C. Henderson. 1966. Acute tox1c1ty of some Important
petrochemicals to fish. 0. Water Pollut. Control Fed. 38(9): 1419-1429.
Portmann, 3.E. 1972. Results of Acute Toxldty Tests with Marine Organ-
Isms, Being a Standard Method. Marine Pollution and Sea Life, Fishing News.
(Books)/Ltd., London, England (author communication used), p. 212-217.
Price, K.S., G.T. Waggy and R.A. Conway. 1974. Brine shrimp bloassay and
seawater BOD of petrochemicals. J. Water Pollut. Control Fed. 46: 63-77.
Qulllardet, P. and M. Hofnung. 1985. The SOS chromotest, a colorlmetrlc
bacterial assay for genotoxlns: Procedures. Mutat. Res. 147: 65-78.
Rumyantsev, A.P., S.A. Astapova, Z.R. Kustova, et al. 1979. Parameters of
acute tox'dty and chronic effect of Inhaled vinyl acetate. (Taken from
CA/092/175335Q). (Russ.)
0181d
-85-
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Shaw, D.C 1987. Vinyl acetate: Oral (drinking water) 2-generatlon repro-
duction study 1n the rat. Hazleton Laboratories of Europe, LTD. Report No.
466-51/17J. EPA Doc. No. 8EHQ-0588-0642. F1che No. 0750510582-2.
Shaw, D.C. 1988. Vinyl Acetate: 104-Week oral (drinking water) combined
chronic t5x1c1ty and carclnogenldty study 1n the rat following !£ vitro
exposure. Volume I. Hazleton Laboratories, UK. Report No. 5531-5/16. EPA
Doc. No. 86-0000265. Flche No. OTS0514156.
Shlrlnlan, G.S. and R.M. Arutyunyan. 1980. Study of cytogenlc change
levels under PVA production. Blol. Zh. Arm. 33: 748-752. (Cited 1n
Norppa, el al., 1988)
Simon, P., G.G. FUser and H.M. Bolt. 1985a. Metabolism and pharmaco-
klnetlcs c-f vinyl acetate. Arch. Toxlcol. 57: 191-195.
Simon, P. H. Ottenwalder and H.M. Bolt. 1985b. Vinyl acetate: DNA-blndlng
assay in \jWp_. Toxlcol. Lett. 27: 115-120.
SRI (Stafford Research Institute). 1988. 1988 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
p. 1048.
Strong, HA., D.G. Crosswell and R. Hopkins. 1980. Investigations Into the
metabolic fate of vinyl acetate In the rat and mouse, part 2. Hazleton
Laborator'es. Report No. 2511/51/11-14. EPA Document No. FY1-OTS-0184-
0178. Flche No. OTS0000278-0.
01 Bid -86- 10/04/89
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Swarm, R.I.., D.A. laskowskl, P.3. McCall, K. Vanderduy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Takemoto, S., Y. Kuge and H. Nakamoto. 1981. The measurement of BOO In sea
Mater. SilshUsu Odaku Kenkyu. 4: 80-90. (Jap.)
TakeshUa, T., S. Hjlma and H. Hlgurashl. 1986. Vinyl acetate-Induced
sister crromatld exchange 1n murlne bone marrow cells. Proc. Jap. Acad.
Ser. B. C2(7): 239-242.
Thomas, R.G. 1982. Volatilization from water. In: Handbook of Chemical
Property Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed.
McGraw-Hill Book Co., New York, NY. p. 15-1 to 15-34.
Tlunova, L.V. and A.P. Rumyantsev. 1975. Changes In rhythm of liver enzyme
activity in albino rats during chronic exposure to vinyl acetate. Bull.
Exp. Blol. Hed. (USSR). 79(4): 101-103. (Cited In NIOSH, 1978). (Russ.)
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Tcxlclty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
0181d -87- 10/04/89
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U.S. EPA. 1985. Notification Requirements; Reportable Quantity Adjust-
ments; Final Rule and Proposed Rule. Federal Register. 50(65): 13500.
U.S. EPA. 1986a. Exams II Computer Simulation Model. Athens, GA.
U.S. EPA. 1986b. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1986c. Superfund Programs Reportable Quantity Adjustments.
Final Rule. Federal Register. 51(188): 34549.
U.S. EPA 1986d. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003
U.S. EPA 1987. Hazardous Substances, Reportable Quantity Adjustments,
Proposed *ule. Federal Register. 52(50): 8171.
U.S. EPA, 1989. Interim Methods for Development of Inhalation Reference
Doses. E?A/600/8-88-066F. April.
U.S. EPA/OWRS (Environmental Protection Agency/Office of Water Regulations
and Staniards). 1986. Guidelines for Deriving Numerical Water Quality
Criteria for the Protection of Aquatic Organisms and Their Uses. U.S.
EPA/OWRS, Washington, DC. NTIS PB85-2270049.
OlBld
-88-
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US1TC (U.S. International Trade Commission). 1987. Synthetic Organic
Chemicals. U.S. Production and Sales, 1986. USITC Publ. 2009, Washington,
DC. p. 211.
USITC (U.S. International Trade Commission). 1988. Synthetic Organic
Chemicals. U.S. Production and Sales, 1987. USITC Publ. 2118, Washington,
DC. p. 1!,-16.
Verschueron, K. 1983. Handbook of Environmental Data on Organic Chemicals,
2nd ed. 'Fan Nostrand Relnhold Co., New York, NY. p. 1184-1185.
Wlndholz, M., Ed. 1983. Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, N). p. 1429.
0181d
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APPENDIX A
LITERATURE SEARCHED
This ttED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted 1n Hay, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0181d
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Clayton, 6.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, M. and 0. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graph! on the Evaluation of Carcinogenic Risk of Chemicals to
Human:. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey. A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA ('00/6-84-010. NTIS PB84-243906. SRI International, Nenlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Statu;..
Ouellotte, R.P. and J.A. King. 1977. Chemical Week Pesticide
Regis er. McGraw-Hill Book Co., NY.
Sax, LN. 1984. Dangerous Properties of Industrial Materials, 6th
ed. 'fan Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Offlcj of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington. DC.
Verselueren, K. 1983. Handbook of Environmental Data on Organic
Chem1:als, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndtnlz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0181d
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In addtlon, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnscn, W.W. and H.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
HcKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmenlal, D. 1971. Ecological Effects of Pesticides on Non-Target
Speeds. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schne'der, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
QlBld
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APPENDIX C
DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO VINYL ACETATE
C.I. DISCUSSION
Dose/duratlon-response graphs for Inhalation and oral exposure to vinyl
acetate generated by the method of Crockett et al. (1985) using the computer
software ty Durkin and Heylan (1988) are presented In Figures C-l to C-6.
Data used to generate these graphs are presented In Section C.2. In the
generation of these figures, all responses are classified as adverse (PEL,
AEL or I^EL) or nonadverse (NOEL or NOAEL) for plotting. For oral expo-
sure, the ordlnate expresses dosage as human equivalent dose. The animal
dosage expressed as mg/kg/day Is multiplied by the cube root of the ratio of
the animal:human body weight to adjust for species differences In basal
metabolic rate (Mantel and Schnelderman, 1975). The result Is then multi-
plied by 70 kg, the reference human body weight, to express the human
equivalent dose as mg/day for a 70 kg human. For Inhalation exposure, the
ordlnate expresses concentration In either of two ways. In Figure C-l, the
experimental concentration expressed as mg/m3 was multiplied by the time
parameters of the exposure protocol (e.g., hours/day and days/week) and Is
presented as expanded experimental concentration [expanded exp cone
(mg/m3)]. In Figure C-2, the expanded experimental concentration was
multiplied by the cube root of the ratio of the animal:human body weight to
adjust f
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HUNAN EQUIU MIMT10N
EHVtLOP NETHOP
Key:
F
A
I
N
N
FEL
AEL
LOAEL
NOAEL
NOEL
SolU line . Adverse Effects Boundary
Dashed line - No adverse Effects Boundary
FIGURE C-l
Dose^Ouratlon Response Graph for Inhalation Exposure to Vinyl Acetate,
Envelope Method
01 Bid
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im MM
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CEHSOXE» MTft MTMOB
N14
Key:
L
N
N
FEL
AEL
LOAEL
NOAEL
NOEL
Solid line - Adverse Effects Boundary
Dashed line • No adverse Effects Boundary
FIGURE C-2
Dose/Duration Response Graph for Inhalation Exposure to Vinyl Acetate,
Censored Data Method
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ill
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Key:
F
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L
N
N
PEL
AEL
LOAEL
NOAEL
NOEL
Solid line « Adverse Effects Boundary
Dashei line • No adverse Effects Boundary
FIGURE C-3
Dose/Duration Response Graph for Inhalation Exposure to Vinyl Acetate,
Envelope Method
0181d
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•.M01
•.MI •.•! a.i
HUMAN IQUIV MIMT10N
CDBOREB MTU
Key:
F
•A
L
N
N
FEL
AEL
LOAEL
NOAEL
NOEL
Solid line - Adverse Effects Boundary
Dashet line « No adverse Effects Boundary
FIGURE C-4
Dose/Duration Response Graph for Inhalation Exposure to Vinyl Acetate,
Censored Data Method
OlBld
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ENVELOP METHOD
Key:
F
L
N
N
PEL
LOAEL
NOAEL
NOEL
Solid line « Adverse Effects Boundary
Dashed line - No adverse Effects Boundary
FIGURE C-5
Dsse/Duratlon Response Graph for Oral Exposure to Vinyl Acetate,
Envelope Method
0181d
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\
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i
X
9
1MO
a.aai
*l
8.01 8.1
HUNAN IQUIV MIRATION *Cti«A lif**pan>
CINSOREP MIA NITHOD
Key:
F
L
N
N
PEL
LOAEL
NOAEL
NOEL
Solid line
Dashec line
Adverse Effects Boundary
No adverse Effects Boundary
FIGURE C-6
D(se/0urat1on Response Graph for Oral Exposure to Vinyl Acetate,
Censored Data Method
0181d
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line Is extended upward, parallel to the dose axis. The starting point 1s
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process 1s continued
to the lowest adverse effect dose or concentration. From this point, a line
1s extended to the right, parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
Using the envelope method, the boundary for no-adverse effects (dashed
line) 1s drawn by Identifying the highest no-adverse effects dose or concen-
tration. From this point, a line parallel to the duration axis Is extended
to the do>e or concentration axis. The starting point Is then connected to
the next lower or equal no-adverse effect dose or concentration at a longer
duration )f exposure. When this process can no longer be continued, a line
1s droppel parallel to the dose or concentration axis to the duration axis.
The regloi of no-adverse effects Hes below the no-adverse effects boundary.
At either ends of the graph between the adverse effects and no-adverse
effects boundaries are regions of ambiguity. The area (1f any) resulting
from Intersection of the adverse effects and no-adverse effects boundaries
Is defined as the region of contradiction.
In the censored data method, all no-adverse effect points located In the
region of contradiction are dropped from consideration, and the no-adverse
effect bcundary is redrawn so that 1t does not Intersect the adverse effects
boundary, and no region of contradiction 1s generated. This method results
1n the mcst conservative definition of the no-adverse effects region.
Figure C-l represents the dose/duration response graph of Inhalation
data expressed as expanded concentration and generated by the envelope
method. The adverse effects boundary Is defined by two LD,-n values (Rec.
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#29. 26), a LOAEL for decreased rat maternal weight gains and minor feto-
toxlclty (Rec. #30), a LOAEL for decreased weight gain 1n female rats (Rec.
#22) and a LOAEL for respiratory distress In mice (Rec. #19}. The
no-adverse effects boundary 1s defined by a NOEL for respiratory distress In
rats (Rec. #5), NOAELS for rat nonadverse liver and adrenal biochemical
effects (Fee. #6, 7), and two NOELs for respiratory tract lesions (Rec. #10,
12). A region of contradiction Is enclosed In which the only datum not a
part of tiie boundary lines Is a LOEL for respiratory distress In mice (Rec.
#3). The data are replotted In Figure C-2 by the censored data method to
eliminate the region of contradiction.
In Figure C-3 the no-adverse effects boundary Is defined by the same
data as before, but the scaling has removed the data of Rec. #30 from the
adverse effects boundary, thus enlarging the region of contradiction to
Include a NOEL for weight loss and respiratory distress In rats (Rec. #17).
Scaling h.is made H clearer that the region derives from the greater sensi-
tivity of the mouse respiratory tract to vinyl acetate, relative to that of
the rat. The region of contradiction Is eliminated using the censored
method In Figure C-4 (of scaled Inhalation data). The no-adverse effects
boundary las been shifted downward from Recs. #5-7 to pass through a NOAEL
for material lung congestion and fetotoxlclty In rats (Rec. #31) and a NOEL
for respiratory distress, eye and nose Irritation and decreased weight gain
In rats (Rec. #23). The NOEL on which the Inhalation RfD Is based Is that
for respiratory distress and mortality from susceptlbllty to anesthesia for
mice (Owen, 1980b), well outside of the adverse effects region In all four
figures.
F1gur» C-5 presents the dose/duration response graph of oral data
generated by the envelope method. The adverse effects line Is defined by
018 Id
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two LD50 ralues for rats and mice (Recs. #9, 10, respectively), a LOAEL
for effects on bone marrow cells and decreases 1n whole body and thymus
weights In mice (Rec. #9), and a LOAEL for decreased body weight and
Increased relative kidney weight In rats exposed for 2 years {Rec. #3). The
no-adverse effects line passes through NOAELs for decreased weight 1n rats
(Recs. #5, 2), a NOAEL for reproductive effects (Rec. #13) and a NOEL for
decreases In body and kidney weights 1n rats {Rec. #1). Rec. #1 1s the
basis for the subchronlc and chronic oral RfD values. The small Region of
Contradiction stems, 1n part, from the greater sensitivity of the mouse
compared tilth the rat when actual dosages are converted to equivalent human
dosages and. In part, from the difficulty of reliably administering an
unpalatable toxin In drinking water, and defining the adverse nature of a
decreased weight gain In animals with reduced water Intake. The data are
replotted by the censored data method In Figure C-6 to eliminate the region
of contradiction.
C.2. DA'A USED TO GENERATE DOSE/OURATION-RESPONSE GRAPHS
Inhalation Exposure
Chemical I lame: Vinyl Acetate
CAS Number: 108-05-4
Document "Hie: Health and Environmental Effects Document on Vinyl Acetate
Document Uumber: Pending
Document Date: Pending
Document Type: HEED
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RECORD #1
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Both
NOEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
31.400
13.0 weeks
13.0 weeks
Number Exposed: 20
Number Responses: NR
Type of Effect: FUND
Site of Effect: LUNG
Severity Effect: 7
50 ppm 6 hours/day, 5 days/week,doses 50, 200, 1000 ppm.
Lowest dose not showing respiratory distress or hunched
posture. NOEL of study Is NOAEL 1n database. Basis of
subchronlc and chronic RfDs.
Owen, 1980b
RECORD #2
Species: Mice
Sex: Both
Effect: FEL
Dose: 629.000
Duration Exposure: 13.0 weeks
Duration Observation: 13.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
NR
FUND
LUNG
7
Comment:
Comment:
Citation:
1000 ppm 6 hours/day, 5 days/week (see rec #1). Death due to
vinyl acetate-Induce susceptibility to anesthesia. Hunched
posture, continuous respiratory distress, lung congestion,
decreased weight gain, respiratory tract lesions.
Citation:
RECORD #3
Owen, 1980b
Species:
Sex:
Effect:
Route:
Mice
Both
LOAEL
Inhalation
Dose:
Duration
Duration
Exposure:
Observation:
125.700
13.0 weeks
13.0 weeks
Number Exposed: 20
Number Responses: NR
Type of Effect: FUND
Site of Effect: LUNG
Severity Effect: 7
200 ppm, 6 hours/day, 5 days/week (see Rec. #1)
hunched posture, respiratory distress.
Owen, 1980b
Intermittent
01 Bid
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RECORD #4:
Comment:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
629.000
13.0 weeks
13.0 weeks
20
NR
FUND
LUNG
7
20
NR
WGTDC
BODY
4
20
NR
WGTIN
LUNG
4
Citation:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1000 ppm, 6 hours/day, 5 days/week, doses 50, 200, 1000 ppm
Intermittent respiratory distress, hunched posture, ruffled
fur, reduced weight gain, lung congestion, Increased lung
weight.
Owen, 1980a
RECORD #5
Comment:
Citation:
RECORD #6:
Species: Rats Dose:
Sex: Both Duration Exposure:
Effect: NOEL Duration Observation:
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
200 ppm, 6 hours/day
Owen. 1980a
20
0
FUND
LUNG
7
, 5 days/week (see Rec. #4).
Species: Rats Dose:
Sex: Male Duration Exposure:
Effect: NOAEL Duration Observation:
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
10
NR
ENZYM
LIVER
1
251.600
13.0 weeks
13.0 weeks
68.000
4.0 months
5.0 months
Comment:
Citation
Continuous dose, experimental doses 2.5, 13.2, 68 mg/ma.
Disturbed rhythm of enzyme fluctuation and synchrony of liver
alanlne-amlnotransferase activity with activity of aspartate
amlno transferase.
Tlunova and Rumyantsev, 1975
01810
-105-
10/16/89
-------
RECORD #7:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
NOAEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
68.000
120.0 days
120.0 days
Number Exposed: NR
Number Responses: 0
Type of Effect: WGTDC
Site of Effect: ADRNL
Severity Effect: 4
Continuous dosage, other dose 1n study 13.2 mg/m3.
Decreased adrenal weight, decreased ascorb acid content,
decreased eoslnopen. rctn to ACTH, oxygen uptake Increased.
Kolesnlkof et al., 1975
RECORD #8 Species: Rats
Sex: Both
Effect: AEL
Dose:
Duration Exposure:
Duration Observation:
377.300
104.0 weeks
104.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
118
NR
IRRIT
LUNG
6
120
NR
IRRIT
NASAL
6
Comment: 600 ppm, 6 hours/day, 5 days/week, experimental doses 50, 200,
600 ppm. Lesions In nose and lungs. Pathological report;
original study details not available except as a letter.
Citation: Dreef-van der Meulen, 1988; Hazleton Laboratories, 1987
RECORD #9:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Inhalation
Dose:
Duration
Duration
Exposure:
Observation:
125.700
104.0 weeks
104.0 weeks
Comment:
Citation:
Number Exposed: 118 120
Number Responses: NR NR
Type of Effect: IRRIT IRRIT
Site of Effect: LUNG NASAL
Severity Effect: 6 6
200 ppm, 6 hours/day, 6 days/week (see Rec. #8). Lesions In
nose only.
Dreef-van der Heulen, 1988; Hazleton Laboratories, 1987
0181d
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RECORD #10;
Comment:
Citation:
RECORD #11:
Species: Rats
Sex: Both
Effect: NOEL
Route: Inhalation
Number Exposed: 118
Number Responses: 0
Type of Effect: IRRIT
SHe of Effect: LUNG
Severity Effect: 6
Dose:
Duration Exposure:
Duration Observation:
120
0
IRRIT
NASAL
6
31.400
104.0 weeks
104.0 weeks
50 ppm, 6 hours/day, 5 days/week (see Rec. #8).
Dreef-van der Meulen, 1988;
Species: Mice
Sex: NR
Effect: AEL
Route: Inhalation
Number Exposed: 90
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: LUNG
Severity Effect: 6
Hazleton Laboratories,
Dose:
Duration Exposure:
Duration Observation:
1987
377.300
2.0 years
2.0 years
Comment: 600 ppm, 6 hours/day, 5 days/week (studied 50, 200, 600 ppm}.
Bronchlolar epithelial lesions 1n lungs. Only report of study
Is letter with little detail.
Citation: Hazleton Laboratories, 1986
RECORD #i;i:
Comment:
Citation:
Species: Mice Dose:
Sex: NR Duration Exposure:
Effect: NOEL Duration Observation:
Route: Inhalation
Number Exposed: 90
Number Responses: 0
Type of Effect: IRRIT
Site of Effect: LUNG
Severity Effect: 6
50 ppm, 6 hours/day, 5 days/week (see Rec. #11).
Hazleton Laboratories, 1986
31.400
2.0 years
2.0 years
OlBld
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-------
RECORD
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
PEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
1048.000
26.0 weeks
131.0 weeks
Number Exposed: 96
Number Responses: NR
Type of Effect: DEATH
SHe of Effect: NR
Severity Effect: 10
2500 ppm, 4 hours/day, 5 days/week, 49 survived at 26 weeks;
none survived at 131 weeks.
Maltonl and Lefemlne, 1974, 1975
RECORD #H: Species: Humans
Sex: Male
Effect: NOEL
Dose: 4.190
Duration Exposure: 15.2 years
Duration Observation: 15.2 years
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
21
NR
NOS
NR
Comment: 5-10 ppm, factory workers, assumed exposure 8 hours/day, 5
days/week, no unequivocally chemically-Induced health problems
found.
Citation: Deese and Joyner, 1969
RECORD #1!.: Species: Rats
Sex: Both
Effect: AEL
Dose:
Duration Exposure:
Duration Observation:
629.000
28.0 days
28.0 days
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
5
NR
FUND
PULHN
7
5
NR
WGTDC
SPLEN
4
Comment:
Citation:
1000 ppm, 6 hours/day, 5 days/week. 50, 150, 500, 1000 ppm.
Group at 50 ppm also exposed at 1500 ppm. Last 18 days.
Respiratory distress 1n both sexes, decreased spleen weight
males.
Owen, 1979a
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RECORD #16:
Comment:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Inhalation
Number Exposed: 5
Number Responses: NR
Type of Effect: FUND
SHe of Effect: PULMN
Severity Effect: 7
Dose: 314.500
Duration Exposure: 28.0 days
Duration Observation: 28.0 days
5 5
NR NR
WGTDC WGTDC
BODY SPLEN
4 4
Citation:
500 ppm, 6 hours/day, 5 days/week. Hunched posture,
respiratory distress. No weight loss In males. Dose-related
weight loss 1n females not significant, no effect spleen
weight. See Rec. #15.
Owen, 1979a
RECORD #1 ':
Comment:
Citation:
RECORD #13:
Species: Rats
Sex: Both
Effect: NOEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
150 ppm (see Rec.
Owen, 1979a
5
NR
FUND
PULHN
7
#15).
Species: Mice
Sex: Both
Effect: AEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
5
NR
FUND
PULHN
7
Dose:
Duration
Duration
5
NR
WGTDC
BODY
4
Dose:
Duration
Duration
5
NR
WGTDC
BODY
4
94.300
Exposure: 28.0 days
.Observation: 28.0 days
5
NR
WGTDC
SPLEN
4
629.000
Exposure: 28.0 days
Observation: 28.0 days
5
NR
WGTDC
SPLEN
4
Comment: 1000 ppm, 6 hours/day, 5 days/week. Same doses as rat study
(see Rec. #15). Decreased weight gains, term, weights, spleen
weights, respiratory distress, hunched posture.
Citation: Owen, 1979b
01 Bid
-109-
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RECORD
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Both
LOAEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
5
NR
FUND
PUIMN
7
5
NR
WGTDC
BODY
4
5
NR
WGTOC
SPLEN
4
94.200
28.0 days
28.0 days
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
150 ppm (see Rec. #18). Hunched posture, respiratory
distress. No effect on spleen weight.
Owen, 1979b
RECORD #2C:
Comment:
Citation:
RECORD #21:
Species: Mice
Sex: Both
Effect: NOEL
Route: Inhalation
Number Exposed:
Number Responses
Type of Effect:
SHe of Effect:
Severity Effect:
50 ppm (see Rec.
Owen, 1979b
5
: NR
FUND
PULMN
7
#18).
Species: Rats
Sex: Both
Effect: AEL
Route: Inhalation
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
8
: NR
FUND
PULMN
7
Dose:
Duration
Duration
5
NR
WGTOC
BODY
4
Dose:
Duration
Duration
8
NR
IRRIT
EYE
7
31.400
Exposure: 9.0 days
Observation: 9.0 days
5
NR
WGTDC
SPLEN
4
1257.500
Exposure: 3.0 weeks
Observation: 3.0 weeks
8 8
NR NR
IRRIT UG1DC
NASAL BODY
7 4
Comment: 2000 ppm. Doses 100, 250, 630, 2000 ppm, 6 hours/day, 5 days/
week. Respiratory difficulty, poor condition, low weight
gain, excess macrophages In lungs.
Citation: Gage, 1970
0181d
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RECORD #22:
Comment:
Citation:
RECORD #23:
Comment:
Citation:
RECORD #24:
Species: Rats
Sex: Female
Effect: LOAEL
Route: Inhalation
Number Exposed: 8
Number Responses: NR
Type of Effect: FUND
Site of Effect: PULMN
Severity Effect: 7
250 ppm (see Rec. #21).
Gage, 1970
Species: Rats
Sex: Both
Effect: NOEL
Route: Inhalation
Number Exposed: 8
Number Responses: NR
Type of Effect: FUND
SHe of Effect: PULMN
Severity Effect: 7
100 ppm (see Rec. #21).
Gage, 1970
Species: Rabbits
Sex: Hale
Effect: NOAEL
Route: Inhalation
Number Exposed: 6
Number Responses: 3
Type of Effect: BEHAV
Site of Effect: CNS
Severity Effect: 1
Dose:
Duration
Duration
8
NR
IRRIT
EYE
7
157.200
Exposure: 3.0 weeks
Observation: 3.0 weeks
8 8
NR NR
IRRIT WGTOC
NASAL BODY
7 4
Decreased weight gain only.
Dose:
Duration
Duration
8
NR
IRRIT
EYE
7
Dose:
Duration
Duration
62.900
Exposure: 3.0 weeks
Observation: 3.0 weeks
8 8
NR NR
IRRIT WGTDC
NASAL BODY
7 4
13.900
Exposure: 1.0 days
Observation: 6.0 days
Comment:
Citation:
Exposed 40 minutes to 500 mg/m3. Nonadverse behavioral
changes In timing and Intensity of conditioned and
unconditioned reflexes; other concentrations tested: 125, 250
ppm.
Barteney, 1957
Q181d
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RECORD #25:
Comment:
Citation:
RECORD #26:
Comment:
Citation:
RECORD #27 :
Comment:
Citation:
Species: Rats Dose:
Sex: NR Duration Exposure:
Effect: PEL Duration Observation:
Route: Inhalation
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 10
2347.000
1 .0 days
1.0 days
4000 ppm or 14,084 mg/m3 expanded from 4 hours. LCjg study.
NIOSH, 1989
Species: Mice Dose:
Sex: NR Duration Exposure:
Effect: PEL Duration Observation:
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10.6 nig/ 1, expanded
Rumyantsev et al. ,
NR
NR
DEATH
NR
10
from 2 hours. LC$Q study.
1979
Species: Rats Dose:
Sex: NR Duration Exposure:
Effect: PEL Duration Observation:
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
11.4 mg/l, expanded
Rumyantsev et al. ,
NR
NR
DEATH
NR
10
from 4 hours. LCso study.
1979
883.300
1.0 days
1.0 days
1900.000
1.0 days
1.0 days
0181d
-112-
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RECORD #21):
Comment:
Citation:
RECORD #2*1:
Comment:
Citation:
RECORD #31:
Species: Mice Dose:
Sex: NR Duration
Effect: PEL Duration
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1500 ppm or 5.5 g/m3
NIOSH, 1989
NR
NR
DEATH
NR
10
expanded from 4
Species: Rabbits Dose:
Sex: NR Duration
Effect: PEL Duration
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
2500 ppm or 8.8 g/m3
NIOSH, 1989
NR
NR
DEATH
NR
10
. Expanded from
Species: Rats Dose:
Sex: Female Duration
Effect: LOAEL Duration
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
24 24
NR NR
UGTDC IRRIT
BODY LUNG
4 5
910.000
Exposure: 1 .0 days
Observation: 1.0 days
hours. LC5Q study.
1467.000
Exposure: 1.0 days
Observation: 1.0 days
4 hours. LCjg study.
880.000
Exposure: 10.0 days
Observation: 15.0 days
24
NR
HGTDC
FETUS
4
Comment:
Citation;
1000 ppm 6 hours/day, gestation days 6-15. Decreased weight
gains, lung congestion; 1n dams, decreased mean Utter weight,
fetal weight, crown/rump length. Increased retard, sternebral
ossification.
Irvine, 1980
0181d
-113-
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RECORD #31
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
NOAEL
Inhalation
Dose: 176.000
Duration Exposure: 10.0 days
Duration Observation: 15.0 days
24
0
WGTOC
BODY
4
24
0
IRRIT
LUNG
5
24
0
WGTDC
FETUS
4
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
200 ppm (see previous record for experimental details). No
effect on dams, slight, not significant, Increased minor
skeletal effects on fetus.
Irvine, 1980
Oral Exposure
Chemical Name:
CAS Number:
Document Title:
Document Number:
Document Date:
Document Type:
Vinyl Acetate
108-05-4
Health and Environmental Effects Document on Vinyl Acetate
Pending
Pending
HEED
RECORD #1:
weeks
weeks
Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Water
Dose:
Duration
Duration
Exposure:
Observation:
100.000
104.0
104.0
Comment:
Citation:
Number Exposed: 180 90
Number Responses: 0 0
Type of Effect: WGTDC WGTIN
Site of Effect: BODY KIDNY
Severity Effect: 4 4
1000 ppm, range 200, 1000, 5000 ppm, dosage conversions
estimated from data provided. Sprague-Dawley rats. Key study
on which chronic oral RfD Is based.
Shaw. 1988
0181d
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RECORD #2
Comment:
Citation:
Comment:
Citation:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
NOAEL
Water
Dose:
Duration Exposure:
Duration Observation:
684.000
13.0 weeks
13.0 weeks
Number Exposed: 10
Number Responses: NR
Type of Effect: WGTDC
Site of Effect: BODY
Severity Effect: 4
5000 ppm, range concentrations 0, 200, 1000, 5000 ppm given at
start and Increased progressively to keep constant dose/weight
ratio. Male terminal weights decreased 0.8%, food consumption
decreased 7%. Basis of subchronlc RfD.
Gale. 1980a
RECORD #3:
weeks
weeks
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Water
Dose:
Duration
Duration
Exposure:
Observation:
450.000
104.0
104.0
Number Exposed: 180 90
Number Responses: NR NR
Type Of Effect: WGTDC WGTIN
SHe of Effect: BODY KIDNY
Severity Effect: 4 4
5000 ppm (for experimental details, see Rec. #1). Weight
decrease = or <11% for both sexes. Increased relative kidney
weights of males only.
Shaw, 1988
RECORD #4:
Species:
Sex:
Effect:
Route:
Mice
Both
NOEL
Water
Dose:
Duration
Duration
Exposure:
Observation:
950.000
13.0 weeks
13.0 weeks
Number Exposed: 20
Number Responses: 0
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 4
5000 ppm. Studied 200, 1000, 5000 ppm, over formulated 7-10%
to compensate for loss on standing. No effects seen other
than water wastage due to unpalatablllty.
Gale, 1980b
0181d
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RECORD #5
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Water
Number Exposed: 5
Number Responses: NR
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 4
Dose:
Duration Exposure:
Duration Observation:
10
NR
WGTDC
LIVER
4
690.000
28.0 days
28.0 days
5000 ppm, range: 0, 50, 200, 5000, 10,000 ppm. Dose conver-
sion estimated from experimental data. Transient decreased
body weight not associated with decreased food consumption.
Gale, 1979
RECORD #6:
Species: Mice
Sex: Male
Effect: LOAEL
Route: Mater
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
5
NR
WGTDC
BODY
4
Dose:
Duration Exposure:
Duration Observation:
5 5
NR NR
HEMAT WGTDC
BONE THYMS
3 4
1030.000
28.0 days
28.0 days
Comment: 5000 ppm. Studied concentrations 0, 50, 150, 1000, 5000.
Decreased weight gains not associated with decreased food.
water consumption. Decreased mylold/erythrold ratios.
Citation: Gale, 1979
RECORD #7:
Species:
Sex:
Effect:
Route:
Mice
Male
NOAEL
Water
Dose:
Duration
Duration
Exposure:
Observation:
197.000
28.0 days
28.0 days
Comment:
Citation;
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1000 ppm (see previous record). No effects on bone marrow.
Gale, 1979
5
NR
WGTDC
BODY
4
5
NR
HEMAT
BONE
3
5
NR
WGTDC
THYMS
4
018 Id
-116-
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RECORD #8:
Species:
Sex:
Effect:
Route:
H1ce
Female
NOAEL
Water
Dose: 1030.000
Duration Exposure: 28.0 days
Duration Observation: 28.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: HGTDC
Site of Effect: LIVER
Severity Effect: 4
RECORD #9:
Comment:
Citation:
RECORD #10:
Comment:
Citation:
Species: Rats
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
SHe of Effect:
Severity Effect:
LD5Q value.
NIOSH, 1989
Species: Mice
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
1050 value.
NIOSH, 1989
(NOS)
NR
: NR
DEATH
NR
10
(NOS)
NR
: NR
DEATH
NR
10
Dose: 2920.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Dose: 1613.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Q181d
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RECORD
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
NOAEL
Water
Number Exposed: 23
Number Responses: NR
Type of Effect: WGTDC
Site of Effect: BODY
Severity Effect: 4
Dose:
Duration Exposure:
Duration Observation:
23
NR
TERAS
FETUS
9
477.000
10.0 days
15.0 days
5000 ppm. Concentrations 0, 200. 1000, 5000 ppm gestation
days 6-15. Decreased weight gain marginal and associated with
decreased food, water Intake.
Irvine, 1980
RECORD #1;!:
Species: Rats
Sex: Both
Effect: LOAEL
Route: Mater
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
25
NR
WGTDC
BODY
4
Dose:
Duration Exposure:
Duration Observation:
25
NR
REPRO
NR
7
700.000
24.0 weeks
24.0 weeks
Comment: 5000 ppm, reproductive study (range 200, 1000, 5000 ppm, doses
estimated from reference values); marginal decreased male
reproductive function, decreased growth In offspring.
Citation: Shaw, 1987
RECORD #13: Species: Rats
Sex: Both
Effect: NOAEL
Route: Water
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
25
NR
WGTDC
BODY
4
Dose:
Duration Exposure:
Duration Observation:
25
NR
REPRO
NR
7
140.000
24.0 weeks
24.0 weeks
Comment: 1000 ppm. Experimental details previous record. No effect on
reproduction. Decreased weight gains 1n lactatlng females.
Citation: Shaw, 1987
NR = Not reported
018 Id
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-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
CINCINNATI. OHIO 45268
MOV 20 1989
SUBJECT: Health and Environmental Effects Document
FROM: Chris DeRosa, Ph.D
Chief
Chemical Mixtures
TO: Matthew Straus
Chief, Waste Characterization Branch
Office of Solid Haste (OS-'
THRU: L Steven D. Lutkenhoff/") A"
Acting Director (J. "
Environmental Criteria and Assessment Off1ce-C1n
Farland, Ph.D.
Director
Office of Health and Environmental
Assessment (RD-689)
Attacied please find two unbound copies of the Health and Environmental
Effects DDCument (HEED) for:
iHnyl Acetate (ECAO-C1n-G067)
This Jocument represents a scientific summary of the pertinent available
data on tie environmental fate and mammalian and aquatic toxlclty of each
chemical it an extramural effort of about 10K. This document received
Internal )HEA, OPP and OTS reviews as well as review by two external
scientist;. Any part of this document's files (e.g., drafts, references,
reviews) ire available to you upon request.
Attachments
cc: K. Brmeske (OS-305) (w/enclosures)
M. Callahan (RD-689)
P. Ou'kln, Syracuse Research Corporation {w/enclosures)
R. Ha-desty (RD-689)
B. Hostage (OS-210) (w/enclosures)
S. Ir?ne (OS-330) (w/enclosures)
E. NcHamara (PM-211A) (w/enclosures)
J. Moore (RD-689)
M. Pfaff (RD-689) (w/enclosures)
C. R1 ; (RD-689)
R. Ruliensteln (OS-330)
R. Sc.irberry (OS-330)
C. Zanuda (OS-240)
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