DRAFT RISK ASSESSMENT REPORT 

VINYL ACETATE 

CAS No: 108-05-4 

EINECS No: 203-545-4 

GENERAL NOTE 

Please note that this draft risk assessment report contains the following documents: 

- R059_0505_enV: ENV part, May 2005 (pages 2-83, version sent in October 2005 to 

SCHER for their opinion) 

- R059_0805_hh: HH part, July 2008 (pages 84-286, version sent in July 2008 to SCHER for 

their opinion) 

- the appendices 
RISK ASSESSMENT 

Vinyl acetate 

CAS-No.: 108-05-4 

EINECS-No.: 203-545-4 

Draft of 04.05.2005 
R059_0505_env 

Draft of 04.05.2005 

Information on the rapporteur 

Contact point: 

Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA) 

Anmeldestelle Chemikalien / Zulassungsstelle Biozide 

(Federal Institute for Occupational Safety and Health 

Division for Chemicals and Biocides Regulation) 

Friedrich-Henkel-Weg 1-25 

44149 Dortmund (Germany) 

fax: +49(231)9071-2679 

e-mail: chemg@baua.bund.de

This document is the 3rd draft of the Environment Section of the Comprehensive Risk 

Assessment Report of Vinyl acetate, a substance chosen from the EU 1st Priority List in 1994, 

which is distributed for the last visit written procedure. 

The Comprehensive Risk Assessment Report of Vinyl acetate was discussed preliminary 

(written procedure) at the TM II / 2001 (June 2001). 

The Human Health part was discussed first in depth at the TM I/2002 (March 2002), second 

in depth at the TM IV/2002 (December 2002) and last visit at the TM II/2003 (June 2003). 

The Environmental part was discussed in depth at the TM III/2002 (August 2002) and further 

in depth at the TC NES IV 04 (December 2004). 

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CONTENTS 

0 OVERALL CONCLUSIONS/RESULTS OF THE RISK ASSESSMENT 6

1 GENERAL SUBSTANCE INFORMATION 8

2 GENERAL INFORMATION ON EXPOSURE 12

2.1 Exposure sources 12

2.1.1 Production 13 

2.1.1.1 Global production figures 13

2.1.1.2 Production in Western Europe 13

2.1.2 Processing 14 

2.2 Uses 17 

3 ENVIRONMENT 20

3.1 Environmental exposure 20

3.1.1 General discussion 20 

3.1.1.1 Releases into the environment 20

3.1.1.1.1 Production of the monomer 20

3.1.1.1.2 Processing of vinyl acetate monomer 21

3.1.1.1.3 Compounding and use of materials containing vinyl acetate (co)polymers 25

3.1.1.1.4 Storage and Transport 25

3.1.1.2 Degradation in the environment 25

3.1.1.2.1 Degradation in the atmosphere 25

3.1.1.2.2 Degradation in the aquatic compartment 26

3.1.1.2.3 Degradation in soil and sediment 27

3.1.1.3 Distribution 28

3.1.1.3.1 Adsorption 28

3.1.1.3.2 Volatility 29

3.1.1.3.3 Modelling of distribution 29

3.1.1.3.4 Elimination in Sewage Treatment Plants (STP) 30

3.1.1.3.5 Accumulation 30

3.1.2 Exposure Assessment for the Aquatic Compartment 30 

3.1.2.1 Estimation of local environmental concentrations (Clocalwater ) 31

3.1.2.1.1 Production of the monomer 31

3.1.2.1.2 Processing of the monomer 32

3.1.2.1.3 Manufacture of synthetic fibres 35

3.1.2.1.4 Manufacture of coatings and printing inks 35

3.1.2.1.5 Manufacture of adhesives 37

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3.1.2.1.6 Paper recycling and use of printing inks and paintings 37

3.1.2.2 Measured data in aqueous environment 37

3.1.3 Exposure Assessment for the Atmosphere 37 

3.1.3.1 Estimation of local concentrations (Clocalair) 37

3.1.3.1.1 Production of the Monomer 38

3.1.3.1.2 Processing of the Monomer 39

3.1.3.1.3 Manufacture of synthetic fibres 40

3.1.3.1.4 Manufacture of coatings and printing inks 40

3.1.3.1.5 Manufacturing of adhesives 41

3.1.3.2 Measured data in the atmosphere 41

3.1.4 Exposure assessment for the terrestrial compartment 41 

3.1.5 Non compartment specific exposure relevant to the food chain 43 

3.1.6 Regional concentrations 43 

3.2 Effects assessment: Hazard identification and Dose (concentration) - response 

(effect) assessment 45

3.2.1 Effects assessment for the aquatic compartment (including sediment) 45 

3.2.1.1 Test results 45

3.2.1.1.1 Criteria for validation 45

3.2.1.1.2 Fish 48

3.2.1.1.3 Aquatic invertebrates 49

3.2.1.1.4 Aquatic algae 50

3.2.1.1.5 Microorganisms 52

3.2.1.2 Calculation of Predicted No Effect Concentration (PNEC) 52

3.2.1.2.1 Surface water (PNECaqua) 52

3.2.1.2.2 Sewage treatment plants (PNECSTP) 52

3.2.1.2.3 Sediment (PNECsed) 53

3.2.2 Effects assessment for the terrestrial compartment 53 

3.2.2.1 Terrestrial effect data 53

3.2.2.2 Calculation of PNECsoil 54

3.2.3 Effects assessment for the atmosphere 54 

3.2.3.1 Biotic effects 54

3.2.3.2 Abiotic effects 55

3.2.3.2.1 Global warming 55

3.2.3.2.2 Troposheric ozone 55

3.2.3.2.3 Stratospheric ozone (ODP) 55

3.2.3.2.4 Acidification 55

3.2.4 Non compartment specific effects relevant to the food chain 55

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3.3 Risk characterisation 56

3.3.1 Aquatic compartment (incl. sediment) 56 

3.3.2 Atmosphere 60 

3.3.3 Terrestrial compartment 61 

3.3.4 Non compartment specific effects relevant to the food chain 62 

3.3.5 Marine Assessment including PBT Assessment 62 

3.3.5.1 PBT Assessment 62

3.3.5.2 Marine Assessment 63 

4 HUMAN HEALTH 65

4.1 HUMAN HEALTH (TOXICITY) 65

4.1.1 Exposure assessment 65 

4.1.1.1 Indirect exposure via the environment 65

5 CONCLUSIONS / RESULTS 66

6 REFERENCES 68

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0 OVERALL CONCLUSIONS/RESULTS OF THE RISK ASSESSMENT 

CAS No. 108-05-4 

EINECS No. 203-545-4 

IUPAC Name Vinyl acetate 

 

Overall results of the risk assessment:

(x) i) There is need for further information and/or testing 

(x) ii) There is at present no need for further information and/or testing and for risk 

reduction measures beyond those which are being applied already 

() iii) There is a need for limiting the risks; risk reduction measures which are already 

being applied shall be taken into account 

Summary of conclusions: 

Environment

As a follow up to conclusion (i), which was drawn in the first draft of the Environment Section 

of the Comprehensive Risk Assessment Report of Vinyl acetate (August 2002), further acute 

and long-term toxicity tests were performed for the aquatic compartment and more data on a 

number of production and processing sites were obtained, leading to the following revised risk 

characterisation. 

conclusion i): 

Terrestrial compartment

A risk to the local terrestrial compartment was identified for the life cycle stages of vinyl 

acetate production and processing. This conclusion applies to one major production site (site 

number 26) due to aerial deposition of vinyl acetate in the vicinity of the site and for the 

generic processing scenario calculated for the local main source. 

There is a need for further information and/or testing to adequately characterize the potential 

risks to the terrestrial compartment by refining the PNECsoil. It is recommended to perform an 

earthworm acute toxicity test (OECD 207) and a terrestrial plants growth test (OECD 208). 

The need for further testing should be reconsidered in case that risk reduction measures are 

being applied at the site indicating a risk to the terrestrial compartment (site number 26). If no 

risk remains after risk reduction measures have been applied for the life cycle stage of vinyl 

acetate production, conclusion ii) should follow. 

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conclusion ii): 

Aquatic compartment

A risk to the local or regional aquatic compartment (surface water and sediments) was not 

identified for production and processing of vinyl acetate. This conclusion applies to all sites. 

Atmospheric compartment

Based on a qualitative risk characterisation, no unacceptable risk for the atmosphere is 

expected from vinyl acetate. The substance is rapidly removed from air by chemical 

breakdown, adsorption to airborne particles or aerosols, and wet deposition. Furthermore, air 

concentrations indicate a negligible risk with regard to ecotoxicity. 

Non-compartment specific effects

Non compartment specific effects (secondary poisoning) of vinyl acetate are not expected as 

there is no indication that the substance has potentially bioaccumulative properties. 

Marine Assessment including PBT assessment

VAM does not meet the PBT/vPvB criteria. A risk for the regional or local marine 

environment is not expected. 

Human Health

Workers 

Consumers 

Man exposed indirectly via the environment 

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1 GENERAL SUBSTANCE INFORMATION 

Identification of the substance 

CAS No.: 108-05-4 

EINECS No.: 203-545-4 

IUPAC Name: Vinyl acetate 

Synonyma: Acetic acid vinyl ester 

Empirical formula: C4H6O2

Structural formula: 

2CH

CH

O CH3

O

Molecular weight: 86 g/mol 

Purity/impurities, additives 

Purity: 99.8 % w/w 

Impurities: ≥ 0.03 - 0.1 % w/w water 

≥ 0.005 - 0.01 % w/w acetic acid 

≥ 0.005 - 0.02 % w/w acetaldehyde 

Additives: hydrochinone or hydrochinone mono methyl ether as stabilisator 

0.00015 - 0.002 % w/w 

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Table 1-1: Physico-chemical properties 

Physical state liquid at 20 °C 

Melting point - 93.2 °C Handbook of Chemistry and 

Physics, 1980 - 1981 

Boiling point + 72.7 °C Merck Index, 1996 

Relative density 0.932 at 20 °C Merck Index, 1996 

Vapour pressure 120 hPa at 20 °C Hoechst AG, 1994c 

Surface tension 24 mN/m at 20 °C 

(pure substance) 

Handbook of Chemistry and 

Physics, 1980 - 1981 

Water solubility 20 g/l at 20 °C Merck Index, 1996 

Partition coefficient logPow 0.7 Hoechst AG, 1992 

Flash point - 8 °C (DIN 51755) CHEMSAFE, 1994 

Auto-flammability, 

ignition temperature 

385 °C (DIN 51794) CHEMSAFE, 1994 

Explosive properties not explosive due to structural reasons 

Oxidizing properties not oxidizing due to structural properties 

Vapour pressure: 

Vapour pressure values were available from safety data sheets, product information and 

literature without any details about the used methods. All values correlate well with the 

boiling point of 72.7 °C (Clausius-Clapeyron). 

Water solubility: 

The water solubility is 20 g/l at 20 °C according to safety data sheets and product 

information. No further information about the determination method is available. 

Partition coefficient: 

According to literature data the partition coefficient was determined experimentally (HPLC 

method: logPow 0.21, shaking method: logPow 0.73). The calculation with CLOGP3-

Software resulted in a logPow of 0.7. Due to the agreement of experimentally and calculated 

values a logPow of 0.7 was used for the risk assessment. 

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Classification 

• (Classification according to Annex I) 

F R 11 Highly flammable 

• (Proposal of the rapporteur) 

The current classification included in Annex I to Directive 67/548/EEC is only due to human 

health effects and does not yet consider environmental effects of vinyl acetate. Based on the 

data presented in the environmental section of this risk assessment report and the criteria of 

Directive 93/21/EEC, the rapporteur proposes the substance not to be classified and labelled 

for environmental risks. 

The classification included in Annex I to Directive 67/548/EEC does not yet include toxic 

effects. According to the data presented below and the criteria of Directive 93/21/EEC, vinyl 

acetate should be classified as follows and assigned the risk phrases: 

Harmful R 20 Harmful by inhalation 

Irritant R 36/37/38 Irritating to eyes, respiratory system, and to skin 

Sensitizing R 43 May cause sensitization by skin contact 

Carcinogenic, cat. 2 R 45 May cause cancer 

Human data on irritation/corrosion caused by vinyl acetate are not available. Vinyl acetate has 

proven to cause irritation or corrosion to the skin of rabbits depending on the duration of the 

skin contact. According to EU regulations (basing on effects seen after a single 4-hours 

occlusive dermal exposure) the substance has to be classified as irritant. The eye irritation 

potential of the compound seems to be similar as judged on the basis of poorly documented 

eye irritation tests with rabbits. Acute inhalation tests with rats demonstrated severe irritation 

in the respiratory tract of the animals. Thus, vinyl acetate should be labelled “R 36/37/38, 

Irritating to eyes, to respiratory system and to skin“. 

It has to be noted that a positive Buehler Test with commercial grade vinyl acetate is 

available. Based on this evidence vinyl acetate (commercial grade) should be labelled as 

“R 43 - May cause sensitization by skin contact”. 

There is clear evidence for the carcinogenicity of vinyl acetate in two animal species and in 

both sexes. The carcinogenic potential was demonstrated for the inhalation and oral route of 

administration. Vinyl acetate was carcinogenic at the surface epithelium of multiple sites 

along the exposure routes. No species-specific mode of action for vinyl acetate carcinogenesis 

was identified. A reasonable threshold mechanism could not be identified for all tumors and 

tumor sites which finding does not allow to clarify whether vinyl acetate is rather genotoxic 

and cancerogenic and not a genotoxic cancerogen. The data from human experience are 

inadequate for the evaluation of the carcinogenicity of vinyl acetate in humans. 

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In Germany, vinyl acetate is assigned to the MAK-pregnancy category "D" denoting that the 

current data base is not sufficient for final evaluation of developmental toxicity. However it is 

outlined that vinyl acetate was evaluated for reproductive toxicity in one species (rat) already 

with negative results. If this latter outcome could be verified in additional species vinyl 

acetate could be assigned to category "C" denoting that no risk for adverse developmental 

effects have to be expected for female workers in compliance with the respective MAK value 

of 10 ppm. 

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2 GENERAL INFORMATION ON EXPOSURE 

2.1 EXPOSURE SOURCES 

Exposure of man and environment to vinyl acetate monomer (VAM) may result from releases 

during each of the consecutive steps downstream the supply chain. These are production of 

the substance, polymerisation of the monomer, compounding operations involving the 

polymers, and eventually use of the end products. 

 

 Production 

 synthesis of 

 the monomer 

 ▼

 Use 

processing 

= (co)polymerisation 

of the monomer 

(co)polymers are marketed as 

dispersions, solid resins or solutions 

 ▼

Compounding 

handling of the (co)polymers, e.g. manufacture 

of ready-to-use products like paints, adhesives, 

textile finishing agents, etc. 

 ▼

---------------------------------------------------------------------------- 

End user

 manual end-user: e.g. painter man, floor layer, carpenter, etc. 

 industrial end-user: e.g. printer, manufacturer of finished film

 ▼

Consumer

 e.g. painted walls, glued flooring, glued furniture, printed card, packed food, etc. 

The first three stages in the chain, i.e. manufacture of the monomer, polymerisation of 

(co)polymers, and compounding of (co)polymers are in most cases conducted by different 

companies and at separate locations. Notwithstanding, there is a small number of sites where 

both production of the monomer and further polymerizing is carried out, while there are other 

cases where VAM is (co)polymerized and subsequently also compounded. 

Only a few manufacturers of VAM exist in the EU, whereas the number of companies 

polymerising the monomer and in particular the number of downstream users of the polymers 

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is considerably higher. For example, there are no more than two VAM manufacturers in 

Germany that use parts of the produced VAM volume to manufacture vinyl acetate 

(co)polymers. Similarly, just six out of fifty-three European manufacturers of coating/printing 

inks manufacture the required polymer constituents from the monomer on-site. 

Production sites of VAM and facilities producing the (co)polymers, but also compounding 

operations are typical point sources of VAM emissions. Any VAM entering the environment 

from the latter type of operation results from releases of monomer residuals remaining with 

the processed (co)polymers. 

Finally, diffusive releases of residuals may occur during end-use of the finished products that 

contain vinyl acetate (co)polymer constituents. 

2.1.1 Production 

Vinyl acetate is produced by a catalytic vapour-phase reaction of ethylene and acetic acid in 

gas phase, liquid phase or a fluidised-bed process. 

2.1.1.1 Global production figures 

The worldwide demand for VAM reportedly amounted to 4.3 million t/a in 2003, representing 

an overall operating rate of about 86 % of a maximum global production capacity of 

5 million t/a. The main production capacities are located in Asia (43 %) and North America 

(34 %), followed by Western Europe on third rank (18 %) (Chemical Week, 2003). 

2.1.1.2 Production in Western Europe 

A questionnaire was launched by the European Chemical Industry Council (CEFIC) among 

member companies in 2000 and updated in 2002 to collect data on produced and processed 

volumes of vinyl acetate monomer in Europe. Five producers of VAM were identified with a 

nominal production capacity of 800,000 t/a (cf. Table 2-1). Fluctuating operating rates 

(additional capacities brought online, partly offset by shutting down other plants) make it 

difficult to provide a general figure for the annual production volume of VAM in the EU. 

For comparison, the production volume of VAM reported by the CEFIC Acetyls Sector 

Group (ASG) for Western Europe was about 715,000 tonnes in 2002. Additionally, total 

purchases1

 in 2002 accounted for almost 250,000 tonnes. Along with an opening stock2 of 

approximately 80,000 tonnes, the “total supply” for 2002 amounted to 1,045,000 tonnes. 

From the total supply of about 1,045,000 tonnes, some unquantified amounts were exported 

outside Western Europe again (figures were not given by industry for confidentiality reasons). 

 

1

 Purchase from outside Western Europe but also from co-producers in Western Europe 

2

 Includes all product produced or purchased but not yet invoiced or transferred to internal captive use, e.g. 

product in storage or in transit (should be equal to the closing stock of the previous period). 

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With an end stock3 of less than 50,000 tonnes in 2002, approximately 750,000 tonnes of 

VAM were marketed in Western Europe that year (all figures provided by CEFIC ASG). 

The outcome of the CEFIC survey was in poor consistency with data retrieved from the 

IUCLID database (as of May 1999). A number of the companies included in the CEFIC 

survey were not covered by the IUCLID data - and vice versa. Several of the enterprises had 

discontinued to exist as a business entity, owing to an intensive restructuring process of the 

market (mergers, acquisitions and divestitures of business segments). In some cases it turned 

out that some IUCLID-mentioned capacities had been only sales bureaus, whereas other 

facilities had meanwhile been shut down. IUCLID data were therefore left aside. 

2.1.2 Processing 

Unlike for production, no exact figure of the processed volume of vinyl acetate can be 

extracted from the statistics provided by the CEFIC Acetyls Sector Group (ASG). The 

provided data is difficult to balance for import/export and purchases/sales as ASG statistics 

comprise all Western European countries, which does not coincide with EU countries, and 

some parts of the statistics are confidential, thus were not disclosed to the rapporteur. 

According to the CEFIC Acetyls Sector Group, the total supply of VAM in Western Europe 

was approximately 1,045,000 tonnes in 2002, based on a production volume of about 

715,000 t, total purchases of about 250,000 t and an opening stock of about 80,000 t. When 

exports, sales, captive use and closing stock are deducted, approximately 750,000 t entered 

the open market in Western Europe in 2002. From this tonnage, an unknown amount is sold to 

non-EU countries in Western Europe (Switzerland, Turkey, Iceland, Norway), with the 

remaining tonnage of VAM being sold and processed in the EU. Some amounts of the total 

VAM supply of 1,045,000 tonnes is directed to captive use4

 and also processed in the EU, but 

figures on captive use are not provided. As sales to non-EU countries in Western Europe and 

captive use were not quantified, the exact processing volume in the EU cannot be determined. 

It is therefore assumed to be in the range of 750,000 – 800,000 tonnes per year. 

Responses to the CEFIC questionnaire came either from individual processors or industry 

associations of processing companies. One industry association (CEPE) did not provide 

information broken down to individual members or processing sites, but for reasons of 

confidentiality submitted aggregated, in part statistically evaluated data (max./min. values or 

average means) which were compiled from a questionnaire among member companies. In 

addition to the CEFIC data, other processing sites could be identified and consulted. Based on 

this data collection, the actual total processing volume of VAM may amount to 

474,900 tonnes per year in the EU (cf. Table 2-1). 

 

3

 Closing or end stock of the previous period. Includes all product produced or purchased but not yet invoiced or 

transferred to internal captive use, e.g. product in storage points or products in transit. 

4

 All product transferred internally in Western Europe whether from own production or purchased. 

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Figure 2-1 Market statistics of VAM for 2002, based on CEFIC Acetyls Sector Group. 

It has to be concluded that the data provided on production and processed volumes of VAM 

do not match very well: 

Based on single sites: Based on market statistics : 

Production 800,000 tonnes 715,000 tonnes 

Processing 474,900 tonnes 750,000 - 800,000 tonnes (estimate) 

This imbalance may be due to a number of reasons: 

 Figures on volumes were reported for different business years and reflect the 

dynamics of a market which is characterized by continuous restructuring activities 

 Some annual production data are based on nominal capacities, thus do not reflect 

actual figures which may change from year to year 

 Production figures are rounded to nearest 10,000 t/a 

 Downstream users did not reply to the questionnaire 

 Data are not corrected for import/export or sales/purchases 

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The maximal difference between reported production volume and specific processing data for 

individual sites is 325,000 t/a (= 800,000 t/a - 475,000 t/a). It is therefore assumed that a 

number of processing sites exist that were not covered by the CEFIC questionnaire. As no 

information on these sites is available, a generic risk characterization will be conducted. A 

fraction of main source of 0.15 and 300 emission days are assumed (Tab. B3.2 of the TDG) to 

estimate the fraction of the total emissions that is expected to be released through the main 

local point source (worst case scenario for the local environment). The estimated total 

emissions that are released during processing of the total volume of 325,000 t/a are included 

in the calculation of the regional and continental background concentrations.

Specific local risks were calculated for the production and processing sites that could be 

identified (cf. Table 2-1). In several cases it could not be clarified whether the term “use” in 

the questionnaire was interpreted by the responders as (co)polymerisation, or compounding of 

already polymerised material, or both. If not specified otherwise it was assumed that the data 

referred to (co)polymerisation, although this may overestimate emissions in some cases. For 

confidentiality reasons, sites were coded. Five producers of VAM were identified being 

located in four EU member states (France, Germany, Spain and UK). Identified processing 

plants are located in Belgium, Denmark, Finland, France, Italy, Germany, the Netherlands, 

Spain and UK. No information on geographical locations was disclosed by industry 

associations that provided only aggregated data.

Table 2-1: Production and/or processed volumes of VAM identified within the EU 

Site code Produced volumes Processed volumes Data source 

1 30,000 CEFIC 

2 10,000 CEFIC 

3a 6,000 CEFIC/CIRFS 

3b 10,000 CEFIC/CIRFS 

3c 8,000 CEFIC/CIRFS 

3d 4,000 CEFIC/CIRFS 

4/5 110,000 90,000 CEFIC 

6 25,000 CEFIC 

7* 10,810 CEPE 

8 15,000 CEFIC 

9 9,100 CEFIC 

10 15,000 CEFIC 

11 110,000 CEFIC 

12 36,000 CEFIC 

13 280 CEFIC 

14 2,000 CEFIC/FEICA 

15 2,200 CEFIC/FEICA 

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Site code Produced volumes Processed volumes Data source 

16 400 CEFIC/FEICA 

17 300 CEFIC/FEICA 

18 14,000 CEFIC/FEICA 

19 25,000 CEFIC/FEICA 

20** 0 0 CEFIC/FEICA 

21 200,000 CEFIC 

22 100,000 CEFIC 

23 17,000 CEFIC 

24 5,000 pers. communicated 

25 6,910 pers. communicated 

26 140,000 pers. communicated 

27 250,000 pers. communicated 

28 8,000 pers. communicated 

29 6,500 pers. communicated 

30 8,400 pers. communicated 

∑ 800,000 474,900

CEFIC: European Chemical Industry Council 

CEPE: Conseil Européen des Industries des Peintures, Encres d’Imprimerie et Couleurs d’Art 

CIRFS: Comité International de la Rayonne et des Fibres Synthetiques 

FEICA: Fédération Européenne des Industries de Colles et Adhésifs 

* As communicated by industry association CEPE, most manufacturers buy polymer emulsions (PVA) ready 

for use and do not polymerise VAM themselves: 52 companies reported in a questionnaire to use PVA at 116 

different sites for making printing inks, paintings and coatings. The total volume of VAM polymers was 

43,524 t in 2000. The processing volume in the table refers to the two companies still polymerising VAM. 

** confirmation of conducting merely compounding operations, i.e. handling of the (co)polymers.

2.2 USES 

Vinyl acetate monomer is solely used as an intermediate in chemical industry for 

manufacturing (polymerisation) of vinyl acetate (co)polymers (IC 3 / UC 33). Hence it is 

concluded that the entire production volume of VAM is used up for the manufacture of 

various (co)polymers, mainly polyvinyl acetate. 

Apart from manufacture of homopolymers the monomer is combined with other monomers 

like ethylene, vinyl chloride and acrylic acid esters to form various types of co-polymers. 

According to the Directory of Chemical Producers Western Europe (SRI International, 

1997/98) two types of co-polymers involving ethylene are produced: 

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(i) ethylene-vinyl acetate co-polymer resins (EVA) with a production capacity of 

approximately 1 million t/a, and 

(ii) vinyl acetate-ethylene co-polymer resins (VAE) with a production capacity of 

approximately 300,000 t/a. 

Polymers manufactured from VAM are used in a broad spectrum of products, including 

water-based paints, printing inks, lacquer, ceramic, adhesives for packaging and construction, 

paper finishing, and protective colloids for various materials. Other important products 

include textile fibres, paper coating and inks (Table 2-2). The content of residual VAM in 

homo- and co-polymers depends on the product, spanning a wide range of reported values of 

less than 5 ppm up to 6,000 ppm (Celanese, 2000). According to the CEFIC compilation of 

data from industry, the majority of polymers have an average content of around 1,000 - 2,000 

ppm or less. Ullmann (1998) provides a quantitatively weighted median value for the 

monomer content of roughly 3,000 ppm. The latter value will be used for estimating diffuse 

releases of VAM from (co)polymers and end-use products in this document. 

In addition, vinyl acetate (co)polymers are used as feedstock for manufacture of vinyl alcohol 

(co)polymers (e.g. polyvinyl alcohol). Polyvinyl alcohol is obtained by hydrolysing polyvinyl 

acetate. The production capacity within the EU is reported at > 100,000 t/a (SRI International, 

1997/98). Commercial grades of polyvinyl alcohol differ in the degree of polymerisation 

(molecular mass) and degree of hydrolysis (residual polyvinyl acetate content). Along with 

saponification (alkaline hydrolysis of fatty acid esters) of the acetyl moieties of polyvinyl 

acetate, monomer residuals are getting eliminated as well. A minor fraction of polyvinyl 

alcohol ends up in the manufacture of polyvinyl acetales, e.g. of polyvinyl butyral (PVB). 

A broad quantitative breakdown of the use pattern of vinyl acetate is available for Germany 

for 1990. In this year, approximately 68 % of the produced vinyl acetate was used mainly for 

the manufacturing of polyvinyl acetate and, to a less extent, for the manufacturing of 

copolymers. 32 % of the produced vinyl acetate was manufactured to polyvinyl alcohol 

(BUA, 1993). Vinyl acetate occurs as residual monomer in homo- and copolymers based on 

vinyl acetate and in products or formulations based on these polymers. As polyvinyl alcohol 

is produced by trans esterfication (saponification) of vinyl acetate (co)polymers, residual 

vinyl acetate monomer does not occur in polyvinyl alcohol and in polymers derived from 

polyvinyl alcohol (Celanese, 2000). Hence the manufacturing of polyvinyl alcohol is not 

relevant in the context of residual monomer content. 

Use pattern of vinyl acetate: 

Main category Industry category Use category 

Non dispersive use Chemical industry: 

used in synthesis 

(IC 3) 

Intermediate: monomer in the production 

of polyvinyl acetate (UC 33) 

18 CAS No.: 108-05-4 
Table 2-2: Vinyl acetate in the value chain: (co)polymers are used in a wide spectrum of products (Wacker-Special

material 

Building 

ink 

Printing 

Paint 

Film 

Lacquer 

Adhesive 

VAM + VAM Æ polyvinyl acetate x x x x x VAM + acrylate Æ vinyl acrylic co-polymer x x VAM + ethylene Æ EVA x x VAM + ethylene Æ VAE x x x VAM + vinyl chloride Æ VC copolymer x x x VAM + carbonic acid Æ VA carbonic acid copolymer VAM + vinyl ester Æ VA vinyl ester copolymer x x 

19 
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3 ENVIRONMENT 

3.1 ENVIRONMENTAL EXPOSURE 

3.1.1 General discussion 

3.1.1.1 Releases into the environment 

Vinyl acetate is used as an intermediate in the production of a range of polymeric materials. 

Releases of the monomer into the environment may be expected during various life cycle 

stages and from the final products and articles generated from VAM (cf. chapter 2.1). VAM is 

a comparatively volatile substance that is likely to evaporate into the atmospheric 

compartment, primarily via off-gas. Likewise, owing to the high water solubility of VAM, 

emissions may occur to the aqueous phase if the substance is getting into contact with water. 

Waste water may in turn be a relevant source for emissions to the atmosphere during 

treatment (e.g. stripping). 

3.1.1.1.1 Production of the monomer 

Vinyl acetate is produced by a catalytic reaction of ethylene and acetic acid. All commercial 

producers of vinyl acetate communicated closed system facilities in a largely continuous 

process. Nevertheless, start-up, shut-down and purification operations may result in some 

releases of VAM to waste products. Incineration of waste was reported by all but one 

producer, flue gas is commonly flared, and waste water typically undergoes a distillation 

procedure in order to regain the dissolved monomer. Measured values of VAM in waste water 

discharges from closed production systems show that losses can be significantly reduced by 

an adequate process design including pre-treatment of the waste water. 

The aggregated capacity of the five vinyl acetate production facilities identified across the EU 

amounts to approximately 800,000 tonnes per annum (chapter 2.1.1.2). Specific emission data 

for releases of VAM to water and air have been provided by all producers. The figures are set 

out in Table 3-1 below. 

From combined measured and estimated data it is concluded that emissions to surface water 

from production totalled approximately 0.486 t/a while emissions to air accounted for about 

218 t/a. 

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Table 3-1: VAM releases from production to the aquatic and atmospheric compartment 

Site Production 

(t/year) 

Release to 

surface water 

(kg/year) 

Comment Direct release 

to atmosphere 

(kg/year) 

Comment 

4 110,000 < 331 water treated within 

process (distillation) 

and then discharged to 

biological WWTP; 

concentration below 

d.l. of 50 μg/l 

367 below d.l., figure 

communicated by 

company 

21 200,000 < 155 emission to biological 

WWTP provided - incineration 

22 100,000 < 0.36 water treated within 

purifying unit and 

external WWTP; 

calculated from d.l. 

of 0.1 mg/l and 

site-specific data 

- incineration 

26 140,000 - water is treated within 

process (distillation, 

no STP); no VAM 

detected in waste 

water* 

217,500 figure 

communicated by 

company 

27 250,000 - plant designed to 

reduce emissions 

(no STP)** 

- waste gas from 

routine venting 

is flared 

Σ 800,000 

t/year 

 486.36

 kg/year 

217,867 

kg/year 

* The waste water is treated within the process by distillation (no STP) and sent to a collection basin where 

organic compounds are measured before release to a waste water discharge canal and then to a river. Organic 

compounds are mostly acetates and acetaldehyde. No VAM is detected in the discharge (detection limit of < 1 

ppm by ionic chromatography). Any residual VAM molecules are assumed to hydrolyse completely at a pH of 

12 in the waste stream. 

** The company operating the plant reported that new technology had been implemented in the recently 

commissioned facility in order to contain and recover VAM in the process (closed system process, distillation 

of wastewater for re-introduction of material in the process, incineration of remaining waste). 

3.1.1.1.2 Processing of vinyl acetate monomer 

Table 2-2 shows the most common (co)polymers generated from VAM. It could not be 

elucidated for all processing sites, which notified being "users" of VAM in the CEFIC 

questionnaire, what kind of operations they actually perform. If not indicated otherwise, the 

term “use” or “processing” of VAM was interpreted as polymerisation of the monomer. 

Roughly, three types of processors can be distinguished: 

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 a few large-scale facilities which manufacture (co)polymers from VAM for resale 

 some small- to medium-scale (SMC) facilities polymerising for captive use, e.g. 

manufacturers of paints, coatings or fibre 

 the majority of SMC facilities which do not perform polymerisation but purchase 

VAM (co)polymers for compounding, i.e. mixing of vinyl acetate (co)polymers with 

e.g. fillers, binders and other polymeric dispersions 

A default emission factor for waste water of 0.7 % of the annually processed volume is 

provided in the TGD for intermediates in chemical synthesis. The emission factor foreseen in 

the TGD is not considered representative for vinyl acetate and replaced by a more specific 

value of 0.02 %, which was communicated by industry representatives at a technical meeting5

in 2002. The factor of 0.02 % is backed by the available site-specific data. The majority of 

facilities emitted less than 0.01 %, many even less than 0.001 % of their tonnage to waste 

water. Three sites emitted between 0.01 and 0.02 % of their tonnage, while only two exceeded 

the latter value. The highest emission factors were 0.04 and 0.15 %. The value of 0.02 % 

provided by industry is therefore assumed to be a realistic factor for estimating emissions. 

Unlike for some of the SMC facilities, waste gas from routine venting is typically collected 

and flared in large operational sites. If no specific data were provided by the companies, it 

was assumed that 0.1 % of the polymerised material is being released to the atmosphere as 

VAM, which is the default emission factor for air provided in the TGD. The rapporteur 

considered to extrapolate information from the available site specific data in order to obtain a 

more representative fraction of release to air. The site specific emission factors ranged from 

less than 0.01 % to 0.5 %. Most facilities emitted between 0.01 and 0.1 % of their tonnage to 

air. The fraction of 0.1 % foreseen in the TGD is therefore considered a realistic and 

conservative value for estimating releases to air. 

Table 3-2: VAM releases from processing sites to the aquatic and atmospheric 

compartment 

Site Processing 

(t/year) 

Release to 

surface water 

(kg/year) 

Comment Direct release 

to atmosphere 

(kg/year) 

Comment 

1 30,000 15.8 calculated from 

d.l. of 50 μg/l, 

specific STP flow 

430 figure provided 

by company in 

CEFIC 

questionnaire 

2 10,000 1550 d.l. of 10 μg/l 

specific STP flow 

2,630 from CEFIC 

questionnaire 

3a 6,000 100.2 calculated from 

given effluent 

concentrations 

28,000 from CEFIC 

questionnaire 

 

5

 As agreed on TM III’02, a technical meeting with industry took place in Frankfurt, Germany, in October 2002 

to further the discussion on information and data to be included in the exposure scenario. 

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Site Processing 

(t/year) 

Release to 

surface water 

(kg/year) 

Comment Direct release 

to atmosphere 

(kg/year) 

Comment 

3b 

3c 

3d 

10,000 

8,000 

4,000 

and STP default 

values 

5 90,000 331 see production 

site 4 (Table 3-1) 

367 from CEFIC 

questionnaire 

6 25,000 22.2 calculated from 

annual emission 

to waste water 

and STP flow 

11,100 from CEFIC 

questionnaire 

7* 10,810 3 generic 

calculation 

7,110 aggregated data 

provided by 

CEPE 

max. value given 

mean: 1126 kg/a 

8 15,000 230 annual emission 

to waste water, 

specific STP flow 

31,000 from CEFIC 

questionnaire 

9 9,100 5 annual emission 

to waste water, 

specific STP flow 

14,000 from CEFIC 

questionnaire 

10 15,000 1.13 annual emission 

to waste water, 

specific STP flow 

14,000 from CEFIC 

questionnaire 

11 110,000 84.5 d.l. of 5.7 μg/l 

and STP flow - incineration 

12 36,000 720 no specific data 

on emissions but 

on STP flow 

7,500 worst case 

scenario for 

diffuse releases, 

below d.l. at 

waste gas 

incinerator 

13 280 - no water 

involved in 

process 

280 estimate based on 

release of 1 kg/t 

14 2,000 40 generic 

calculation 

2,000 from CEFIC 

questionnaire 

15 2,200 6.5 annual emission 

to waste water, 

specific STP flow 

1,500 from CEFIC 

questionnaire 

16 400 - no water 

involved in 

process 

70 from CEFIC 

questionnaire 

17 300 6 generic 

calculation 

400 from CEFIC 

questionnaire 

18 14,000 10 annual emission 8,000 from CEFIC 

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Site Processing 

(t/year) 

Release to 

surface water 

(kg/year) 

Comment Direct release 

to atmosphere 

(kg/year) 

Comment 

to waste water, 

specific STP flow 

questionnaire 

19 25,000 249 annual emission 

to surface water, 

specific STP flow 

7,000 from CEFIC 

questionnaire 

20** 0 0.1 annual emission 

to waste water 

1 pers. commun. 

23 17,000 - pers. commun. < 1.05E-05 pers. commun. 

24 5,000 225 calculated from 

d.l. of 5 mg/l and 

effluent flow 

from process 

 24,925 pers. commun. 

25 6,910 138 generic 

calculation 

3,500 pers. commun. 

28 8,000 160 generic 

calculation 

8,000 estimate based on 

release of 1 kg/t 

29 6,500 7.5 annual emission 

to waste water, 

specific STP flow 

200 pers. commun. 

30 8,400 1.39 calculated from 

given effluent 

concentrations 

and STP flow 

- pers. commun. 

Σ 474,900 

t/year 

3,906

kg/year 

172,013 

kg/year 

* Aggregated data. The processing volume of 10,810 t/a in the table refers to the two companies still 

conducting polymerisation of VAM themselves. The total volume of ready to use VAM polymers in 

manufacture, however, added up to 43,524 tonnes in 2000. The magnitude of emissions in relation to total 

VAM use was specified as a maximum of 30 kg/year to waste water treatment plants, and a maximum of 7,110 

kg/year to air by industry association CEPE. 

** confirmation of conducting merely compounding operations, i.e. handling of the (co)polymersAs the 

difference of 325,000 t/a between nominal production volume (800,000 t/a) and verified 

processing capacities (total of 475,000 t/a) is rather high, a generic worst case scenario is 

included in the risk assessment to estimate the fraction of release at the local main source. The 

estimate is based on: 

 a fraction of main source of 0.15 (Tab. B3.2 of TDG) 

 a duration of emission of 300 d (Tab. B3.2 of TDG) 

 a waste water flow of 10,000 m3/s and a dilution of D = 40

 an emission factor to waste water of 0.02 % for processing 

(personal communication, technical meeting with industry representatives in 2002)

 a release fraction of 0.1 % of the polymerised material to air (as VAM)

For the local main source, a release of 9.75 t/a to waste water, of 975 kg/a to surface water, 

and of 48.75 t/a to the atmosphere is calculated. 

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For the whole processing volume of 325,000 t/a, a release of 65 t/a to waste water, of 6,5 t/a 

to surface water and of 325 t/a to the atmosphere is derived.

3.1.1.1.3 Compounding and use of materials containing vinyl acetate (co)polymers 

Finished (co)polymers contain various concentrations of VAM residuals. Owing to the high 

volatility of VAM, it is anticipated that these residuals are exhaustively released during 

further life-cycle stages down the supply chain such as compounding into ready-to-use 

products. 

Further diffusive releases from end-use products during service lifetime (e.g. adhesives, 

paints, fillers, coating materials, plasters and primers for porous building materials in the 

construction industry and in finishing agents; Ullmann, 1998) are expected to be low. 

Nevertheless, a contribution of these products to regional background concentrations was 

considered. Assuming that (co)polymers have on average a VAM content of 3,000 ppm (cf. 

section 2.2), the diffusive emissions may amount to 3,000 t/a based on a VAM market supply 

of roughly 1,000,000 t/a (cf. section 2.1.1.2). To estimate the fractional release to air and 

water, the fugacity of VAM was calculated (cf. Table 3-6): accordingly, 2,700 t/a (90 %) were 

assumed to be released to air while 300 t/a (10 %) would enter the aquatic compartment. 

Polyvinyl alcohol is produced by trans-esterfication (saponification) of vinyl acetate (co)polymers. After this additional processing step, residual VAM will not be present in the finished 

product. Therefore, releases of VAM from polyvinyl alcohol were not estimated. 

3.1.1.1.4 Storage and Transport 

Gaseous releases of VAM could occur during storage and transport of the substance due to its 

high vapour pressure. However, a contribution to air emissions of these operations was not 

assumed because the use of supposedly closed-system containers and storage systems was 

reported. Furthermore, no tool is currently available to estimate the fractions which might be 

released during storage and transport despite the taken precautionary measures. 

3.1.1.2 Degradation in the environment 

3.1.1.2.1 Degradation in the atmosphere 

Direct photolysis 

Vinyl acetate molecules do not absorb light at wavelengths longer than 250 nm (Daniels, 

1983). As solar irradiation wavelengths in the troposphere exceed 290 nm, no direct phototransformation of VAM is expected to occur in this layer of the atmosphere. 

Indirect photolysis 

VAM undergoes rapid photooxidative transformation in air. It predominantly reacts with 

hydroxyl radicals and to a minor extent also with ozone by addition to the olefinic moiety. 

Calculations were performed with the AOPWIN TM (v1.91) computer program based on 

experimentally determined rate constants both for OH-radicals and ozone (cf. Appendix). 

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Based on a mean atmospheric concentration of [OH] = 5 x 105 cm-3 and an overall OH rate 

constant of 26.3 x 10-12 cm3 molec-1 s-1 (Atkinson et al., 1982), an atmospheric half-life of 

14.6 hours is estimated for VAM. Assuming a rate constant of 25 x 10-12 as included in the 

AOPWIN TM Experimental Database (Saunders et al., 1993), an atmospheric half-life of 

15.4 hours results. The OH rate constant of 26.3 x 10-12 

cm3 molec-1 s

-1 and estimated 

atmospheric half-life of 14.6 hours were used in the risk assessment. 

From a mean ozone concentration of 7 x 1011 cm-3, a half-life of 6.55 days is derived. 

Table 3-3: Reactivities and half-lives for phototransformation of VAM in the troposphere 

Oxidative 

species 

Species 

concentration 

Rate constant 

(cm3 molec-1 s-1) 

Half-life 

(days) Source 

OH radicals 5.0E+05 cm-3 26.34E-12 0.608 (e) Atkinson et al. (1982)

OH radicals 5.0E+05 cm-3 25.00E-12 0.642 (e) Saunders et al. (1993) 

Ozone 7.0E+11 cm-3 17.50E-19 6.55 (e) Atkinson et al. (1982) 

Ozone 4 - 8 ppm 3.2 ± 0.47E-18 2 (m) Grosjean and Grosjean 

(1998) 

NOx 0.2 - 2.0 ppm 0.2 - 0.3 (m) Joshi et al. (1982) 

(e) = estimated (m) = measured value 

In smog chamber experiments with NOx concentrations simulating rural and urban 

atmospheres, photooxidative half-lives of VAM were determined to 4.1 ± 0.1 and 

6.5 ± 3.0 hours, respectively (Joshi et al., 1982). The initial VAM concentration was 4 ppm 

(v/v) while NOx levels were either 0.2 ppm (v/v) or 2 ppm. 

3.1.1.2.2 Degradation in the aquatic compartment 

Abiotic degradation 

VAM undergoes hydrolysis in surface and groundwater. A hydrolytic half-life of 7.3 days at 

pH 7 and 25 °C was estimated for the compound (Mabey and Mill, 1978). From this value, a 

half-life of 17 days can be derived for a generic environmental temperature of 12 °C, as 

foreseen in the TGD. As pH decreases, the hydrolysis rate decreases and half-life increases. 

Main hydrolysis products of VAM are acetic acid and acetic aldehyde (Daniels, 1983; 

Stuckey et al., 1980). 

Half-lifes of VAM in basic and acidic aquatic environments could not be obtained. However, 

hydrolysis rate constants were determined for VAM residuals in water-based dispersion 

paints, having typically an alkaline pH of 8 – 9. One paint was acidified to pH of 5.5 in order 

to determine the rate constant in an acidic solution. At pH 8.6, the half-life of VAM was 

found to be less than 4 days at room temperature, and a rate constant of 1.68 l mol-1

 s

-1

 was 

experimentally determined. At a pH of 5.5, hydrolysis was found to be distinctly slower with 

a rate constant of 0.002 l mol-1 s

-1 (kinetic data provided by industry, 2002). The observed 

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hydrolysis rates in water-based and dispersion paints give further indication that hydrolysis of 

VAM decreases with pH, but cannot be transferred to aquatic environments. 

The estimated half-life of 17 days at standard environmental parameters (pH 7 and 12 °C) is 

used in the risk assessment of VAM. 

Biodegradation 

In an initial degradation step, VAM is enzymatically hydrolysed to acetate and acetaldehyde, 

followed by either mineralization or biotranformation into biomass.

Based on a Ready Biodegradability Modified MITI Test I (OECD test guideline 301 C), 

measuring the mineralization of a test substance on the basis of oxygen consumption, vinyl 

acetate is classified as readily biodegradable (Chemicals Inspection and Testing Institute 

(Ed.), Japan, 1992). In the test, a biodegradation rate of 82-98 % was observed by BOD after 

a test period of 14 days and using non-adapted, activated sludge under aerobic conditions (pH 

7, temperature 25 ± 1 °C, concentration of test substance at test begin: 100 mg/l). 

The results of several other laboratory studies also demonstrate that VAM is readily 

biodegraded by domestic sewage effluent microorganisms both under aerobic (e.g. Pahren 

and Bloodgood, 1961; Price et al., 1974) and anaerobic conditions of sludge digesters (e.g. 

Chou et al., 1979; Stuckey et al., 1980). Although the tests were not conducted according to 

standardized test guidelines, they provide further evidence for the above classification as 

readily biodegradable. 

In a more recent study (Nieder et al., 1990) it was demonstrated that VAM is biotransformed 

in samples of soil sludge and sewage under aerobic and anaerobic conditions. Four yeasts and 

13 bacteria feeding aerobically on VAM were isolated. Rates of transformation were higher 

under aerobic conditions, but anaerobic and aerobic degradation pathways both yielded the 

same products, i.e. acetaldehyde as an intermediate and acetic acid as a final product. An 

aerobic transformation half-life of 12 hours was obtained with one of the bacterial isolates, 

whereas a half-life of 60 hours was found for the non-enzymatic hydrolysis in a sterile 

medium. 

No tests are available that simulate the biodegradation of VAM in surface waters. Therefore, 

the rate constant and half-life for biodegradation in surface waters has to be derived based on 

the results from the available screening tests. For readily biodegradable substances a rate 

constant of 0.047 d-1 that is equivalent to a half-life of 15 d is proposed in the TGD (Table 

3-4). 

3.1.1.2.3 Degradation in soil and sediment 

Vinyl acetate is also transformed by biotic and abiotic hydrolysis in soils and sediments. As 

described in the preceding section, microbial isolates from sludge and soil were found to be 

capable of utilizing VAM as a sole carbon source (Nieder et al., 1990). 

There is evidence that some soil organisms are also capable of decomposing polymers of 

vinyl acetate. In an aqueous test medium containing 4.5 g/l of polyvinyl acetate as the sole 

carbon source, the polymers were biotransformed by oil fungi during an incubation period of 

15 days at room temperature (Garcia Trejo, 1988). It should be noted, however, that de27 CAS No.: 108-05-4 
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polymerisation is assumed to be the limiting step. Further biodegradation is rapid so that 

relevant VAM concentration in environmental compartments are not to be expected. 

Biodegradation rate constants were derived for the different environmental compartments 

according to section 2.3.6.5 of the TGD, based on the ready biodegradability of VAM as 

shown in a number of studies and a Kpsoil < 100. The rate constants are compiled in Table 3-4

below. 

Table 3-4: Biodegradation rate constants of VAM in different environmental compartments 

Compartment Biodegradation rate 

activated sludge (STP) kSTP = 1 h

-1

surface water kSW = 0.047 d

-1

sediment ksed = 0.00231 d

-1

soil ksoil = 0.023 d

-1

3.1.1.3 Distribution 

No information on transport and partitioning of VAM between different environmental media 

was found in the available literature or was provided by industry. The distribution of the 

compound between air, water, sediment, and soil compartments following release to the 

environment was therefore assessed based on the physical and chemical properties of VAM. 

3.1.1.3.1 Adsorption 

Measured data on adsorption and desorption of VAM to soil or sediment could not be 

obtained. However, given an octanol - water partition coefficient of log Kow = 0.73, it is 

concluded that VAM has only a low potential to adsorb to soils or sediments. 

Using the QSAR regression equation given in the TGD for non-hydrophobic substances, an 

organic carbon - water partition coefficient of Koc = 24.2 l/kg was calculated from the 

log Kow. 

Further solid - water partition coefficients (Kp) were derived from this Koc for the various 

environmental compartments by using the generic values given in the TGD for organic carbon 

contents of soils and sediments (cf. Table 5, section 2.3.4 in the TGD). 

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Table 3-5: Partition coefficients of VAM for various compartments, derived 

according to the standard environmental characteristics of the TGD 

Compartments Partition coefficients (l/kg) 

soil – water Kpsoil = 0.484 

sediment – water Kpsed = 1.211 

suspended matter – water Kpsusp = 2.421 

activated sludge – water Kpsludge = 8.958 

raw sewage – water Kpsewage = 7.263 

3.1.1.3.2 Volatility 

Given the high vapour pressure of VAM and a Henry's law constant of H = 51.6 Pa m3

 mol-1

(at 20 °C), a relevant transfer from the aqueous to the atmospheric compartment is expected. 

This transfer is mainly caused by volatilisation and air stripping during treatment of waste 

water, and to a lower degree by volatilisation from surface waters. The transfer to the 

atmosphere is to some extent counterbalanced by the high water solubility of the compound. 

Based on the Henry's law constant, VAM can be regarded as a moderately volatile compound. 

3.1.1.3.3 Modelling of distribution 

The (steady state) distribution of VAM between various environmental compartments at 

12 °C was estimated by means of the Mackay level 1 six compartment fugacity model, 

employing the EQC Model v.1.0 and the physico-chemical data compiled in Table 1-1. The 

output, as shown in Table 3-6, indicates that the major environmental compartment for VAM 

is air, with a smaller proportion entering the aqueous compartment and just negligible 

quantities being predicted for other compartments. 

Table 3-6: Mackay level 1 environmental distribution of vinyl acetate calculated 

from the OECD EQC model v.1.0 at 12 °C 

Compartments Distribution (%) 

air 91.5 

water 8.4 

soil 0.037 

sediment < 0.001 

suspended sediment < 0.001 

fish < 0.001 

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3.1.1.3.4 Elimination in Sewage Treatment Plants (STP) 

The fraction of VAM degraded in a municipal standard STP as well as the distribution of the 

residual VAM leaving the STP was estimated from SIMPLETREAT 3.0. Calculations were 

performed using the partition coefficients Kpsludge = 8.958 l/kg, Kpsewage = 7.263 l/kg and a 

first order biodegradation rate constant for VAM in a STP of 1 h-1. 

Table 3-7: Modelled fate of vinyl acetate in a standard municipal STP, 

according to the provisions of section 2.3.7 of the TGD 

Fraction Percent 

directed to air 11.6 

directed to sludge 0.2 

degraded 78.2 

total removal from waste water 90.0 

directed to water 10.0 

3.1.1.3.5 Accumulation 

Bioaccumulation test results of VAM are not available. However, as a result of the high 

vapour pressure, ready degradability and low lipophilicity of the substance, it is neither 

expected to bioconcentrate in terrestrial or aquatic organisms, nor to biomagnify in food 

chains. This appraisal is further backed by results from QSAR calculations (BCFWIN v.2.14) 

which give a BCF of 3.16 (log BCF = 0.50) based on a log Kow = 0.73 of VAM. 

Geoaccumulation of VAM is not expected, based on a Koc value of 24.2 l/kg along with 

effective biotic and abiotic breakdown processes in soil, hydrolysis and ready 

biodegradability in water, and rapid photooxidative breakdown of VAM in the atmosphere. 

3.1.2 Exposure Assessment for the Aquatic Compartment 

Exposure of the aquatic compartment to VAM may result from the production of VAM, from 

the polymerisation of the monomer, from compounding of polymer-containing formulations 

and eventually during subsequent use of the products. Water is generally involved in the 

stages of VAM production and consecutively VAM polymerisation as well as cleaning of the 

systems. In polymeric material, the residual monomer concentration decreases rapidly due to 

“outgassing”. As the average VAM content in (co)polymers is assumed to be 3,000 ppm, it 

can be concluded that diffusive releases from end-use products will be a major exposure 

pathway. However, as the major amount of the residual monomer material will be released in 

the early stages of product lifetime, releases to the aquatic compartment after disposal to 

landfills is assumed to be relatively low compared to production and processing point sources. 

Local point emission sources of VAM for the aqueous compartment can be roughly grouped 

into three categories: 

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 large-scale production and/or polymerisation of the monomer 

 medium-scale sites which comprise polymerisation of VAM and compounding 

 compounding operations 

While there exist few large scale producers and/or polymerisers, the number of medium-scale 

polymerisers and notably compounders is considerably higher. An increasing lack of 

knowledge about VAM emissions down the supply chain has to be noticed. To this end the 

final destination of hundred thousands of tonnes of VAM produced or imported into Western 

Europe could not be elucidated within the scope of this report. 

3.1.2.1 Estimation of local environmental concentrations (Clocalwater ) 

In general the local concentrations in water were calculated using the approach outlined in the 

TGD (section 2.3.8.3) and the corresponding annexes (A- and B-tables). The calculations 

involved the following steps: 

(1) Emission per day: Derivation of the local daily emission rates (Elocalwater), based 

on emission data provided by industry or default values from the TGD. 

(2) Influent concentration: Conversion of the local emission rate to a concentration in 

untreated waste water (Clocalinfl) by the effluent volume (default of 2,000 m3

/day 

or 10,000 m3/day depending on tonnage, or site-specific data). 

(3) Effluent concentration: Calculation of the concentration in the STP effluent 

(Clocaleffl) assuming a remaining fraction of 0.1 (90 % removal rate according to 

SIMPLETREAT calculation) of the influent going to the STP effluent. 

(4) Concentration in surface water: Derivation of the local concentration in the 

aqueous compartment from the equation Clocalwater = Clocaleffl / D, with D = 10 or 

D = 40 depending on tonnage, or specific dilution factors supplied for the 

individual site. 

(5) Average annual concentration in surface water: The average annual concentration 

was derived by multiplication of Clocalwater by X/365, yielding Clocalwater_annual, 

with X being the specific number of operation days per annum or a generic value 

of Temission = 300 days. 

(6) PEClocal: The PEClocalwater was derived by adding the PECregionalwater to the 

calculated value of Clocalwater, with PECregionalwater being taken from Simplebox 

calculations (see Appendix 4). 

(7) Average annual PEClocalwater_ann: This parameter was derived by addition of 

PECregionalwater to the calculated value of Clocalwater_annual. 

3.1.2.1.1 Production of the monomer 

VAM is manufactured in closed systems at elevated temperature and pressure. Fractional 

distillation is applied to separate different constituents from the waste water and recuperate 

VAM to enhance reaction yields. Hence VAM concentration in waste water of production 

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facilities is generally low. Site-specific data were made available from all VAM producers by 

providing figures either on annual loads to waste water or surface water or measured 

concentrations in waste water (cf. Table 3-8). 

All producers of VAM are either located at large rivers, estuaries, or at the sea. Hence 

dilution of the waste water is high. Leaving aside shut-downs for reasons of maintenance 

work, continuous production was reported by all VAM manufacturers. 

Table 3-8: Emissions to water from production sites of VAM in the European Union 

Site Productio

n 

(t/year) 

Release 

to STP 

(kg/year) 

Release to 

surface water 

(kg/year) 

Clocalwater 

(μg/l) 

Specific 

information 

provided/used 

4 110,000 3.31E+03 < 3.31E+02 < 2.09E-01 effluent concentration below 

d.l. of 50 μg/l; STP effluent 

flow and dilution data 

21 200,000 1.55E+03 <1.55E+02 6.80E-02 emission load, STP effluent 

flow and dilution data 

22 100,000 3.60E+00 3.60E-01 4.00E-03 effluent concentration below 

d.l. of 0.1mg/l; STP effluent 

flow data 

26 140,000 no STP* - - effluent concentration below 

d.l. of 1mg/l; at pH 2 VAM 

hydrolyses completely in the 

waste stream 

27 250,000 no STP** - - TOC of waste water, 

dilution data 

Σ 800,000 

t/year 

4.86E+03 

kg/year 

4.86E+02 

kg/year 

* The waste water is treated within the process by distillation (no STP) and sent to a collection basin where 

organic compounds are measured before release to a waste water discharge canal and then to a river. No 

VAM is detected in the discharge (detection limit of < 1 ppm by ionic chromatography). Any residual VAM 

molecules are assumed to hydrolyse completely at a pH of 12 in the waste stream. ** The company operating 

the plant reported that new technology had been implemented in the recently commissioned facility in order to 

contain and recover VAM in the process (closed system process, distillation of wastewater for re-introduction 

of material in the process, incineration of remaining waste).

3.1.2.1.2 Processing of the monomer 

Release from point-sources: verified processing sites 

An emission factor for wastewater of 0.02 % was used in the calculations for the aquatic 

compartment if no site-specific emission data were provided (personal communication, 

technical meeting with industry representatives in 2002, cf. section 3.1.1.1.2). 

Where no site-specific information on the flow rate of the STP or the receiving water course 

was given, the generic scenario of the TGD was applied: For low production volume facilities 

(≤ 1000 t/a), a domestic treatment plant scenario with a flow rate of 2,000 m3/d and a dilution 

factor of 10 in surface water was assumed, whereas a flow rate of 10,000 m3

/d and a dilution 

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factor of 40 was assumed for high production volume facilities6. Most operators, however, 

provided specific data which were used in the calculations. 

Pretreatment of raw waste water is common practice, e.g. by adding special zeolites or by 

electroflotation. The solid phase is subsequently removed (e.g. with a filter press), while the 

pre-purified waste water is sent to a municipal STP for further treatment. It is expected that at 

least 50 % of the residual VAM in waste water is retained with the filter cake. A preliminary 

purification step can therefore substantially reduce the content of total organic carbon in the 

waste water. Regarding the reported site-specific emissions or concentrations in waste water 

that were used in the exposure calculations, it is assumed that any internal pre-treatment is 

already reflected in the figures provided, if not indicated otherwise. 

In few cases, VAM production and polymerisation were conducted at the same location, 

although not necessarily by one single company. If so, the individual emissions of both 

operations were added up to calculate one combined local concentration in the receiving 

surface water. 

Table 3-9: Emissions of VAM to surface water from processing (polymerisation) sites of 

VAM in the European Union (fibre industry and paint/coating industry 

excluded) 

Site Processing 

(t/year) 

Release 

to STP 

(kg/year) 

Release to 

surface water 

(kg/year) 

Clocalwater 

(μg/l) 

Specific 

information 

provided/used 

1 30,000 1.58E+02 1.58E+01 4.81E-04 calculated from d.l. of 50 μg/l, 

STP effluent flow, dilution 

2 10,000 1.55E+04 1.55E+03 6.60E-02 calculated from d.l. of 10 μg/l, 

STP effluent flow, dilution 

3a 6,000 6.00E+02 6.00E+01 1.00E+01 calculated from d.l. of 100 μg/l 

3b 10,000 3.00E+02 3.00E+01 5.00E-01 effluent concentr. of 50 μg/l 

3c 8,000 2.40E+01 2.40E+00 4.00E-01 effluent concentr. of 4 μg/l 

3d 4,000 7.80E+01 7.8E+00 1.3E+00 effluent concentr. of 13 μg/l 

5 90,000 3.31E+03 3.31E+02 2.09E-01 calculated from d.l. of 50 μg/l, 

STP effluent flow, dilution 

6 25,000 2.22E+02 2.22E+01 3.04E+00 calculated from emission to 

waste water, dilution 

7* 10,810 3.00E+01 3.00E+00 5.00E-01 generic calculation 

8 15,000 2.30E+03 2.30E+02 2.30E+00 emission to waste water, 

STP effluent flow 

9 9,100 5.00E+01 5.00E+00 9.81E-01 emission to waste water, 

STP effluent flow 

 

6

 default values according to emission scenario document for IC-3 (chemicals used in synthesis, TGD part IV) 

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Site Processing 

(t/year) 

Release 

to STP 

(kg/year) 

Release to 

surface water 

(kg/year) 

Clocalwater 

(μg/l) 

Specific 

information 

provided/used 

10 15,000 1.13E+01 1.13E+00 3.10E-03 emission to waste water, 

STP effluent flow 

11 110,000 8.45E+02 8.45E+01 1.32E-01 calculated from d.l. of 5.7 μg/l, 

STP effluent flow, dilution 

12 36,000 7.20E+03 7.20E+02 2.10E+00 STP effluent flow, dilution 

13 280 0.00E+00 0.00E+00 0.00E+00 no water used in process 

14 2,000 4.00E+02 4.00E+01 7.69E+00 generic calculation 

15 2,200 6.50E+01 6.50E+00 1.03E+01 emission to waste water, 

STP effluent flow, dilution 

16 400 0.00E+00 0.00E+00 0.00E+00 no water used in process 

17 300 6.00E+01 6.00E+00 1.16E-05 generic calculation 

18 14,000 1.00E+02 1.00E+01 1.27E+00 emission to waste water, 

STP effluent flow 

19 25,000 2.49E+03 2.49E+02 9.61E+00 emission to surface water, 

STP effluent flow 

20** 0 1.00E+00 1.00E-01 1.91E-07 emission to waste water 

23 17,000 0.00E+00 0.00E+00 0.00E+00 no emission to waste water 

24 5,000 2.25E+03 2.25E+02 7.23E-03 calculated from d.l. of 5 mg/l, 

STP effluent flow, dilution 

25 6,910 1.38E+03 1.38E+02 2.67E-05 generic calculation 

28 8,000 1.60E+03 1.60E+02 1.33E+00 generic calculation 

29 6,500 7.50E+01 7.50E+00 2.03E-03 emission to waste water, 

STP effluent flow, dilution 

30 8,400 1.39E+01 1.39E+00 1.78E-03 emission to waste water, 

STP effluent flow, dilution 

Σ 474,900 

t/year 

39,063 

kg/year 

3906 

kg/year 

* The processing volume of 10,810 t/a in the table refers to the two companies still conducting polymerisation 

of VAM themselves. The total volume of ready to use VAM polymers in manufacture, however, added up to 

43,524 tonnes in 2000. The magnitude of emissions in relation to total VAM use was specified as a maximum 

of 30 kg/year to waste water treatment plants by industry association CEPE. 

** confirmation of conducting merely compounding operations. i.e. handling of the (co)polymers 

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Release from point-sources: non-verified generic site 

Based on a difference of 325,000 t/a between nominal production volume (800,000 t/a) and 

verified processing capacities (total of 475,000 t/a), a generic scenario was calculated for the 

local main source (fraction of main source = 0.15, cf. section 3.1.1.1.2). 

A release of 9.75 t/a to waste water, of 975 kg/a to surface water and a Clocalwater of 

8.12 μg/l are derived. 

Release from diffuse sources 

A quantitative breakdown of the use pattern of VAM is a difficult task to perform since the 

notified annual production volume in Western Europe (800,000 t/a) considerably exceeds 

that of the verified industrial uses (475,000 t/a). For a conservative estimate of the diffusive 

releases from end-use products during service lifetime, a VAM total market supply of about 

1,000,000 t/a and an average VAM content of 3,000 ppm in (co)polymers is assumed, 

leading to an estimated total release of 3,000 t/a, with a fractional release of 300 t/a (10 %) 

directed to the aquatic compartment (cf. section 3.1.1.1.3). 

3.1.2.1.3 Manufacture of synthetic fibres 

According to information provided by the industry association of European Fibre Producers 

CIRFS (Comité International de la Rayonne et des Fibres Synthetiques) in the CEFIC 

questionnaire of 2000, seven sites in five different countries (including Turkey) were using 

VAM in the manufacture of acrylic fibres at approximately 60,000 t/a. With a share of around 

25 % accounting for Turkey, 45,000 t/a were processed at Western Europe sites. 

More recent data provided by CIRFS in 2004 reveals that acrylic fibre production in the EU 

takes place at four sites with a combined capacity of up to 28,000 t/a (sites 3a-3d, Table 3-9). 

VAM is used in the production of acrylic fibre strands in proportions of less than 10 % by 

weight in the finished product. The filaments are coagulated and subsequently stretched in 

wet processes, thereby leaving some VAM in the process water. Reportedly, the process 

water is circulated in closed loop systems and finally discharged. All following calculations 

are based on site-specific effluent concentrations and default values for STP effluent flow and 

dilution. 

Emissions from downstream manufacturing are "none or very low" according to the 

information provided by CIRFS in 2000. 

3.1.2.1.4 Manufacture of coatings and printing inks 

As communicated by industry association CEPE (Conseil Européen des Industries des 

Peintures, Encres d’Imprimerie et Couleurs d’Art), most of the manufacturers buy polymer 

emulsions (PVA) ready for use in paints and do not polymerise VAM by themselves. 

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According to a questionnaire launched by CEPE in the year 2000, 52 companies used vinyl 

acetate polymers (PVA) at 116 different sites in the EU for making printing inks, paintings 

and coatings. The total quantity of processed polymers added up to 43,524 tonnes, of which 

40,419 tonnes were used in water-born products. The largest volume of PVA used on one site 

was 8,900 tonnes (figure for 2002). 

According to information provided by CEPE in 2003, only two companies still conducted 

polymerisation of VAM in the EU in 2002, at one single site each. Reported annual volumes 

were about 7,120 tonnes and 3,690 tonnes, respectively (combined capacity of 10,810 

tonnes). 

For reasons of confidentiality only ranges of processed PVA volumes and arithmetic means of 

emission data have been provided by CEPE rather than specific values of individual sites. 

Absolute quantities of VAM emissions to water were reported by CEPE to be in a range of 

0 - 30 kg/a (mean of 2 kg/a). Related to the site-specific processed VAM volumes, the 

emissions to water were between 0 - 2 ppm, at a mean of 0.7 ppm. Employing the generic 

values tabled below, a local concentration of Clocalwater = 0.5 μg/l is predicted from a 

reported max. annual emission to waste water of 30 kg (site 7 in Table 3-9). 

Table 3-10: Parameters used in calculation of Clocalwater for a coatings and printing inks site 

Parameter Figure Source

Maximum annual emission to waste water 30 kg/a provided by CEPE in 2002 

Operation 300 days * TGD default, B 3.9 

STP effluent flow 2,000 m3/d TGD default 

Dilution factor 10 TGD default 

* Albeit the number of days where batches containing VAM polymers being manufactured were reported to 

cover a span of 4 to 365 days per year (mean 127 d/a) it could not be elucidated if continuous operation (= 365 

d/a) can be attributed to the highest volume. 

According to CEPE, waste water from the manufacturing plants handling the vinyl acetate 

monomer is typically treated on-site to remove solids (oligomers) prior to discharge to a 

municipal waste water treatment plant. Measured VAM concentrations after this pretreatment 

were reported in a range of 1 - 10 μg/l, at a mean of 6 μg/l. If the highest measured 

concentration of 10 μg/l is chosen for calculation (instead of a maximum annual emission of 

30 kg) and assuming a 90 % removal rate and a dilution factor of 10 in the receiving river, a 

local concentration of Clocalwater = 0.1 μg/l was calculated for surface waters. However, the 

above given Clocalwater of 0.5 μg/l was used as a worst case value for the risk characterization 

for coatings and printing inks manufacturers (no. 7). Typical contents of VA polymers in 

paints and inks span a broad range of 0.6 % up to 60 %, averaging 18 %. As notified by 53 

manufacturers of paints and inks, the VAM residuals in their products range from 0.0003 % to 

0.2 %, averaging 0.07 % (aggregated data, CEPE 2000). In the process of incorporating the 

polymer emulsions into the paint product, however, it can be expected that the residual VAM 

content is decreased due to evaporation or hydrolysis into acetic acid and acetaldehyde. At an 

alkaline pH of 8 – 9 which is typical for finished water-based paints, VAM residuals within 

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the formulated paints are rapidly hydrolysed at a rate constant of kHydro = 1.6 l mol-1 s

-1

(corresponding to a half-life of less than 4 days). Therefore, residual VAM levels in waterbased paints will be negligibly low once the product enters the market and is used. In contrast, 

hydrolysis is distinctively slower in acidified dispersion paints, with a rate constant of 

k = 0.002 l mol-1 s

-1 (kinetic data provided by industry in 2002). 

3.1.2.1.5 Manufacture of adhesives 

According to the European Adhesives Manufactures Association FEICA (Fédération 

Européenne des Industries de Colles et Adhésifs) the vast majority of manufacturers of 

adhesives and tackifiers undertake only compounding, thereby utilizing ready-made polymer 

formulations. Nonetheless, some sites were found out to conduct also VAM polymerisation 

for captive use. Unlike for other industry associations which submitted data in aggregated 

form, manufacturers of adhesives provided data on individual sites for the CEFIC 

questionnaire (sites 14-20, Table 3-9) 

3.1.2.1.6 Paper recycling and use of printing inks and paintings 

From the high vapour pressure of the monomer, it is concluded that paper and cardboard will 

have lost all VAM residuals during service lifetime. When finally arriving at the recycling 

plant no residuals are anticipated to be included in the material any more. Hence, recycling of 

paper and cardboard is not deemed to be a relevant source of VAM for the hydrosphere. The 

same applies to printing inks, coatings and paintings. No PEClocal for paper recycling was 

therefore derived. 

3.1.2.2 Measured data in aqueous environment 

Measured data of VAM in the aqueous compartment are either not available from the open 

literature or relate to emission levels several decades ago. The available data may therefore be 

representative for the historical but not for the present situation. 

In the CEFIC questionnaire, producers and users of VAM were asked to provide monitoring 

data on VAM concentrations in the surface water bodies receiving their discharges. The 

companies either stated that no data is available, or commented that VAM cannot be 

measured in surface water bodies as the concentration in the WWTP effluent is already below 

the analytical detection limit. The notified detection limits at the outlets ranged from 5 - 100 

μg/l. 

3.1.3 Exposure Assessment for the Atmosphere 

3.1.3.1 Estimation of local concentrations (Clocalair) 

Within the CEFIC questionnaire some responding companies (majority of the VAM 

producers and several sites undertaking polymerisation) provided data on the VAM quantities 

released to air on an annual basis, or provided figures on measured aerial concentrations. 

Some other companies indicated data on request. 

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3.1.3.1.1 Production of the Monomer 

Almost all of the producers of VAM confirmed that routine venting of the plant is carried out 

and that the exhaust gas is flared. However, there is no evidence that this can be assumed for 

all plants. Moreover, diffuse releases from flanges, pumps etc. cannot be totally excluded. 

Measured site-specific data was provided by all but one facility, and was used to override 

defaults in calculations. The producer communicating no data argued that no particular 

control data is available because of running a “closed circuit system” without emissions Due 

to the high volatility of vinyl acetate, the amount which is released via indirect emissions 

from STP cannot be ignored. In the tables below the amounts from production/processing and 

from STP are summed up under “total releases to air”. 

Table 3-11: Estimation of local VAM concentrations in air and soil for VAM production 

sites 

Site Clocalair

(μg/m3) 

DEPtotal_ann 

(mg/m2⋅d1) 

Comments Direct releases 

to air 

(t/year) 

Total releases 

to air 

(t/year) 

4 0.3 8.20E-04 maximum value 

calculated from 

limit of detection 

< 0.37 7.51E-01 

21 1.35E-01 1.95E-04 incineration and 

indirect release 

from STP 

0 1.78E-01 

22 3.87E-04 5.57E-07 incineration and 

indirect release 

from STP 

0 4.18E-04 

26 2.88E+02 2.38E-01 specific data 2.175E+02 2.175E+02 

27 0 0 air emissions do 

not occur due to 

closed system, 

distillation of waste 

water and waste 

incineration 

(no STP) 

 0 0 

Σ 2.18E+02 2.18E+02 

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3.1.3.1.2 Processing of the Monomer 

Release from point-sources: verified processing sites

The term “use” was interpreted by respondents to the CEFIC questionnaire in different ways: 

as synonym for any kind of activity downstream of production, i.e. polymerisation of VAM 

and/or handling and packing of the polymer solutions and resins (see steps 2 and 3 in section 

2.1). Consequently, it could not be clarified which kind of activities each “user” actually 

performed. 

Some of the respondents provided site-specific emission loads of VAM to the atmosphere. 

Releases were estimated for those sites that provided no data, with estimates ranging from as 

low as 0.4 x 10-3 % up to 0.2 % of the processed volume. The facilities which manufacture 

high volumes of the polymer(s) all reported low emissions of approximately 5 x 10-3 kg/t, due 

to incineration of off-gas. Small and medium-scale facilities typically emit around 1 kg/t to 

air, although some employ some sort of purification equipment. 

Table 3-12: Estimated local concentrations of VAM in air and deposition to soil 

Site Clocalair 

(μg/m3) 

DEPtotal_ann 

(mg/m2⋅d1) 

Comments Direct releases 

to air 

(t/year) 

Total releases 

to air 

(t/year) 

1 3.28E-01 4.91E-04 site-specific data 4.30E-01 4.48E-01 

2 2.00E+00 4.85E-03 site-specific data 2.63E+00 4.43E+00 

3a 5.56E+00 8.09E-03 based on estimates 6.0E+00 6.07E+00 

3b 9.27E+00 1.30E-02 based on estimates 1.0E+01 1.003E+01 

3c 7.41E+00 1.10E-02 based on estimates 8.0E+00 8.003E+00 

3d 3.71E+00 5.35E-03 based on estimates 4.00E+00 4.009E+00 

5 2.93E-01 8.23E-04 site-specific data 3.67E-01 7.51E-01 

6 8.45E+00 1.20E-02 site-specific data 1.11E+01 1.11E+01 

7 5.4 7.8E-03 based on estimates 7.11E+00 7.113E+00 

8 2.40E+01 3.40E-02 site-specific data 3.10E+01 3.13E+01 

9 1.10E+01 1.50E-02 site-specific data 1.40E+01 1.40E+01 

10 1.10E+01 1.50E-02 site-specific data 1.40E+01 1.40E+01 

11 1.58E-03 2.27E-06 site-specific data 0 2.08E-03 

12 5.71E+00 9.14E-03 site-specific data 7.50E+00 8.34E+00 

13 2.99E-01 4.31E-04 calculation based 

on default of 1 kg/t 

 2.80E-01 2.80E-01 

14 2.14E+00 5.58E-03 calculation based 

on default of 1 kg/t 

 2.00E+00 3.62E+00 

15 1.60E+00 2.32E-03 site-specific data 1.50E+00 1.51E+00 

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Site Clocalair 

(μg/m3) 

DEPtotal_ann 

(mg/m2⋅d1) 

Comments Direct releases 

to air 

(t/year) 

Total releases 

to air 

(t/year) 

16 9.7E+01 1.40E-01 site-specific data 7.00E-02 7.00E-02 

17 3.71E-01 5.43E-04 site-specific data 4.00E-01 4.07E-01 

18 7.41E-03 1.10E-02 site-specific data 8.00E+00 8.01E+00 

19 6.49E-03 9.72E-03 site-specific data 7.00E+00 7.29E+00 

20 9.27E-04 1.49E-06 site-specific data 1.00E-03 1.12E-03 

23 8.01E-06 1.15E-08 site-specific data 1.05E-05 1.10E-05 

24 1.90E+01 2.80E-02 site-specific data 2.49E+01 2.52E+01 

25 3.24E+00 4.88E-03 site-specific data 3.50E+00 3.66E+00 

28 7.41E+00 1.10E-02 site-specific data 8.00E+00 8.19E+00 

29 2.22E-01 3.34E-04 site-specific data 2.00E-01 2.09E-01 

30 1.48E-03 2.13E-06 site-specific data 0 1.60E-03 

Σ 1.72E+02 1.78E+02 

Release from point-sources: non-verified generic site 

Based on a difference of 325,000 t/a between nominal production volume (800,000 t/a) and 

verified processing capacities (total of 475,000 t/a), a generic scenario was calculated for the 

local main source (fraction of main source = 0.15, cf. section 3.1.1.1.2). 

A Clocalair of 45 μg/m3, a DEPtotal_ann of 5.5E-02 mg/m2⋅d1, a direct release of 48.75 t/a and a 

total release of 3.33 E+02 t/a to air are derived. 

Release from diffuse sources

For a conservative estimate of the diffusive releases from end-use products during service 

lifetime, a VAM total market supply of about 1,000,000 t/a and an average VAM content of 

3,000 ppm in (co)polymers is assumed, leading to an estimated total release of 3,000 t/a, with 

a fractional release of 2,700 t/a (90 %) directed to the atmosphere (cf. section 3.1.1.1.3). 

3.1.3.1.3 Manufacture of synthetic fibres 

As communicated by CIRFS (2002), approximately 1 per mill (1 kg/t) of VAM is released to 

air. For fibre strands production (sites 3a-3d, Table 3-12), local concentrations in air and 

corresponding deposition rates are therefore based on a fraction of emission of 0.001 (0.1 %). 

3.1.3.1.4 Manufacture of coatings and printing inks 

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According to aggregated data provided by industry association CEPE (Conseil Européen des 

Industries des Peintures, Encres d’Imprimerie et Couleurs d’Art), the air emissions of 

facilities manufacturing paints and printing inks range from zero to > 7 t/a, with a mean of 1.1 

t/a (based on 53 companies responding to a CEPE questionnaire in 2000). 

The maximum reported value of 7.11 t/a was used to calculate local air concentrations 

(Clocalair) and deposition rates (DEPtotal) for a printing ink / coating manufacturing site as a 

worst case scenario, following the provisions of the TGD (chapter 2.3.8.2). The results are 

provided in Table 3-12 (site 7). 

Annual release to air by this industry sector is approximately 0.1 % of the reported annual use 

volume of 43,524 t/a. An estimated release of 43.5 t/a by all facilities manufacturing paints 

and printing inks is used in the regional assessment. 

3.1.3.1.5 Manufacturing of adhesives 

The calculated local concentrations of VAM in air and soil adjacent to adhesive 

manufacturing sites are included in Table 3-12 (sites 14-20). 

3.1.3.2 Measured data in the atmosphere 

Only very few measured vinyl acetate concentrations in ambient air are available. Vinyl 

acetate was detected in the atmosphere of an industrial area in Texas (USA) in 1974 in 

concentrations up to 2 mg m-3. In the ambient air of a landfill in New Jersey (USA), 

concentrations of 0.5 μg m-3 were measured in 1976. In a more recent study of 1990/91, cited 

in the SIDS Dossier, vinyl acetate was not detected in ambient air in Texas (representing the 

background concentration) at a detection limit of 2 ppb. 

A monitoring campaign on non-methane volatile organic compounds (VOCs) was carried out 

in Italy, Spain and Germany, encompassing urban areas, suburban areas, forest-rural and 

remote areas. VAM was not detected in all samples but occurred in “traces” in 6 % of the 

samples from remote areas, with “traces” meaning “less than 0.5 % w/w of a total VOC 

concentration of 20-200 μg/m3

” (Ciccioli et al., 1994). The results were interpreted by the 

authors in a way that biogenic sources contribute substantial parts to the overall emissions of 

VOCs. In addition, VAM was formed under conditions simulating incineration of pine wood 

and wheat straw. Forest fires and agricultural practises were therefore deemed to be a further 

anthropogenic source of VAM, particularly in Mediterranean countries (Ciccioli et al., 2001). 

3.1.4 Exposure assessment for the terrestrial compartment 

VAM may enter the terrestrial compartment by aerial deposition or by spreading of 

contaminated sewage sludge on soils. Based on the water solubility and octanol-water 

partition coefficient of VAM, it is anticipated that VAM is relatively mobile in soil. This is 

backed by QSAR calculations on the Koc, suggesting only little affinity to organic material. 

Information provided by industry indicates that only small amounts of industrial sludge from 

VAM production and processing facilities is spread on soils. The majority of companies 

indicated that contaminated sludge is either incinerated or landfilled. 

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Sludge from production sites is either incinerated (2 sites), landfilled (1 site) or does not 

emerge at all since no WWTP is involved (2 sites). The same applies also for major 

polymerisation facilities. Several facilities indicated pre-treatment (e.g. electroflotation) of 

waste water on-site. Such treatment upstream of discharge to municipal sewer systems is to 

reduce TOC contents. The cakes from filter presses are usually incinerated or transported to a 

landfill. However, no data was provided for a few small-size facilities. 

Estimates on the fate of VAM in waste water treatment plants revealed that only 0.2 % of the 

VAM load entering the WWTP will remain within the sludge. Further reduction in sludge 

concentrations is anticipated from subsequent digestion. From these considerations it is 

concluded that the main source of release of VAM to soil will be deposition from the 

atmospheric compartment after local releases to air from point sources. Small quantities of 

VAM entering the soil will be swiftly degraded (section 3.1.1.2.3). 

As a worst case approach, soil concentrations were estimated for the two sites having the 

highest deposition rates of DEPtotalann = 238 μg m-2 d-1 (site 26) and DEPtotalann = 140 μg m-2

d-1 (16) according to the provisions of the TGD. Both facilities do not operate a STP so that 

sludge application is not included in the estimate. Soil concentrations were also calculated for 

several sites that had relatively high deposition rates and reported that sludge is being used on 

agricultural soils (Table 3-13). 

Table 3-13: Local concentrations of VAM in soil and in soil porewater 

Clocal for DEPtotal_an

n

(mg/m2

⋅d1) 

Csludge

(mg/kg) soil 

(mg/kg) 

agric. 

soil 

(mg/kg) 

grassland 

(mg/kg) 

soil 

porewater

(mg/l) 

agric. soil 

porewater 

(mg/l) 

grassland 

porewater

(mg/l) 

26 2.38E-01 No STP 8.77E-03 8.77E-03 1.00E-02 1.60E-02 1.60E-02 1.90E-02

16 1.40E-01 No STP 5.16E-03 5.16E-03 6.03E-03 9.42E-03 9.42E-03 1.10E-02

3a 8.09E-03 0.56 6.13E-04 3.56E-04 3.63E-04 1.12E-03 6.50E-04 6.62E-04

3b 1.30E-02 0.28 6.36E-04 5.08E-04 5.67E-04 1.17E-03 9.27E-04 1.04E-03

3c 1.10E-02 0.02 4.18E-04 4.08E-04 4.74E-04 7.63E-04 7.44E-04 8.66E-04

3d 5.35E-03 0.07 2.40E-04 2.05E-04 2.34E-04 4.38E-04 3.77E-04 4.28E-04

6 1.20E-02 1.71 1.40E-03 6.17E-04 5.58E-04 2.55E-03 1.13E-03 1.02E-03

Furthermore, a generic scenario was calculated for the local main source (fraction of main 

source = 0.15, cf. section 3.1.1.1.2), based on a difference of 325,000 t/a between nominal 

production volume (800,000 t/a) and verified processing capacities (total of 475,000 t/a). 

From a DEPtotal_ann of 5.5E-02 mg/m2⋅d1 and a Csludge of 20.9 mg/kg, a Clocalsoil of 0.014 mg/kg 

is calculated. 

42 CAS No.: 108-05-4 
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3.1.5 Non compartment specific exposure relevant to the food chain 

As the physical-chemical properties of VAM do not indicate any relevant bio-accumulation 

potential, the potential for secondary poisoning is considered to be low. 

3.1.6 Regional concentrations 

For the estimation of the regional background concentrations, the following releases from 

diffuse as well as point sources are taken into account. 

Point source releases to surface water 

For the production and processing sites included in the CEFIC survey (cf. Table 3-1 and 

Table 3-2), annual releases of vinyl acetate to waste water were calculated, either based on 

default estimations or site-specific data provided. The identified production and processing 

sites have a combined annual load of 40 tonnes VAM, which is expected to end up in waste 

waters. 

Not included in this estimated total release are the sites located at the sea (3b, 22, 27). The 

marine sites were exempted as they are not assumed to contribute to the PECregional for 

surface (fresh) water, that is used for risk characterisation of inland sites in section 3.3.1. A 

marine risk assessment is included in Section 3.3.5.2. 

Accounting for the difference between nominal production volume (800,000 t/a) and verified 

processing capacities (total of 475,000 t/a), a generic scenario was calculated for the 

remaining processing volume of 325,000 t/a. A release fraction of 0.02 % for waste water as 

communicated by industry was assumed to calculate a total release of 65 tonnes/year. 

Point source releases to air 

For the production and processing sites included in the CEFIC survey (cf. Table 3-1 and 

Table 3-2), annual releases of vinyl acetate to atmosphere were calculated, either based on 

default estimations or site-specific data provided. The identified production and processing 

sites have a combined annual release of 389 tonnes VAM, which is expected to be released to 

the atmosphere. SimpleBox calculations of the PECregional for air take these direct releases 

as well as indirect releases of VAM from STPs into account. 

Similar to surface water, a generic scenario was calculated. Applying a release fraction of 

0.1 % to air as communicated by industry to the remaining processing volume of 325,000 t/a, 

results in a total release of 325 t/a. 

Point source releases to soil 

No point sources were identified for the soil compartment. 

Diffuse releases 

Residual monomers of vinyl acetate are diffusively released from products containing vinyl 

acetate polymers to the environment. Due to the high vapour pressure of the substance, it is 

43 CAS No.: 108-05-4 
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assumed that around 90 % of the residual vinyl acetate contained in polymeric products enter 

the atmosphere, whilst 10 % are released into water during processing and formulation of the 

polymeric products. 

Based on a residual VAM content of 3,000 ppm and a processing volume of roughly 

1,000,000 tonnes, an annual release of 3,000 t/a can be estimated. It is assumed that 2,700 t/a 

(90 %) of the total annual release enter the atmosphere, whilst 300 t/a (10 %) are released into 

waste water. Contrary to TGD specifications it is assumed that 100 % of the waste water is 

treated in WWTP because all waste water is produced by industrial facilities. 

The following table summarizes the estimated emissions of vinyl acetate from different point 

and diffuse sources to water and atmosphere: 

Emission to waste 

water 

(tonnes/year) 

Direct release 

to air 

(tonnes/year) 

Release from point-sources: 

verified processing sites 40.31 389.52 

Release from point-sources: 

non-verified (based on 325,000 t/a) 65.00 325.00 

Diffuse release from end-use 

products containing VAM 300.00 2,700.00 

Total 405.31 3,414.52 

Regional (10 %) 40.53 341.45 

Continental (90 %) 364.78 3,073.06 

Continental and regional background concentrations of vinyl acetate were calculated. A share 

of 90 % of the total releases was allotted to the continental scale, while 10 % was allocated to 

the regional sector. The software tool SimpleBox 2.0a was used to predict the following 

continental and regional environmental concentrations (see Appendix 4): 

Table 3-14: Regional and continental concentrations (PECs) according to SimpleBox 2.0a 

Continental PECs Regional PECs 

PECcontsurfacewater 

9.26E-07 mg l-1

PECregsurfacewater

8.35E-06 mg l-1

PECcontair

1.99E-06 mg m-3

PECregair

1.03E-05 mg m-3

PECcontagr.soil

1.12E-07 mg kgwwt

-1

PECregagr.soil

9.18E-07 mg kgwwt

-1

PECcontagr.soil,porew

2.06E-07 mg l-1

PECregagr.soil,porew

1.68E-06 mg l-1

PECcontnat.soil

4.94E-08 mg kgwwt

-1

PECregnat.soil

2.56E-07 mg kgwwt

-1

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3.2 EFFECTS ASSESSMENT: HAZARD IDENTIFICATION AND 

DOSE (CONCENTRATION) - RESPONSE (EFFECT) ASSESSMENT 

3.2.1 Effects assessment for the aquatic compartment (including sediment) 

3.2.1.1 Test results 

3.2.1.1.1 Criteria for validation 

Despite being a HPVC with a market supply of more than 1 million tonnes per year, only a 

comparatively small data set is available on the ecotoxic effects of VAM. Toxicity studies can 

only be classified as valid if suitable precautions have been taken to prevent decreasing 

exposure concentrations of the test substance due to volatilisation during the test (e.g. flowthrough or sealed vessels). Furthermore, exposure concentrations should be measured in the 

course of the study. Test results which were obtained under static conditions without 

analytical determination of test substance concentrations can only give a rough estimate of the 

ecotoxic effects, since the possible decrease in test concentrations due to volatilisation is not 

considered. In these cases it has to be assumed that the effective concentrations are lower as 

relevant parts of the test substance might have evaporated during the course of the test. 

The most relevant test results for aquatic vertebrates, invertebrates and algae are summarized 

in Table 3-15 and are described in more detail below. 

45 CAS No.: 108-05-4 
Table 3-15: Summary of the most relevant results of toxicity tests with aquatic vertebrates, invertebrates and 

Species Duration Test design / remarks Endpoint Concentr

(mg/

Vertebrates Lepomis macrochirus

96 h static (open system) 

endpoint mortality

96 h-LC50 adult:

18 (n)

Pimephales promelas

96 h static (open system) 

endpoint mortality

96 h-LC50 adult:

19.7 (n) 1 d old juv

14-15 (n) 

2 d old juv

15 (n)

Pimephales promelas

34 d OECD 210 (Fish Early Life Stage) 

flow-through, analytical data 

34 d-NOEC 34 d-LOEC 

0.55 (m) 0.93 (m) 

Invertebrates Daphnia magna

48 h OECD 202, semi-static, 

sealed test vessels, analytical data, endpoint immobilisation

24 h EC5048 h-EC50 

24.0 (m) 12.6 (m)

Daphnia magna

24 h static (open system) 

endpoint immobilisation

24 h-LC50 52 (n) 

Artemia salina

24 h static (open system) 

endpoint mortality

24 h-LC50 45 (n) 

46 
Species Duration Test design / remarks Endpoint Concentr

(mg/

Ophryotrocha diadema(sediment dwelling, marine)

48 h determined one week after exposure, 

endpoint mortality

48 h-LC50 33 (n) 

Plants (algae) Pseudokirchneriella subcapitata(Selenastrum capricornutum)

96 h OECD 201, static, sealed test vessels with 

zero headspace, analytical data 

72 h-ERC50 

72 h-NOEC

12.7 (m) 5.96 (m)

Scenedesmus quadricauda

8 d cell multiplication inhibition test 8 d-EC3 370 (n) 

Microcystis aeruginosa

8 d cell multiplication inhibition test 8 d-EC3 35 (n) 

(n) nominal concentration (m) measured concentration 

47 
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48 CAS No.: 108-05-4 

3.2.1.1.2 Fish 

Acute toxicity 

Pickering and Henderson (1966) examined the effects of short term exposure of VAM in 

different species of fish. Tests were performed according to the methods recommended by the 

American Public Health Association (Standard Methods for the Examination of Water and 

Waste Water, 11th Ed., 1960). Fish were exposed in open, static systems for 96 hours. 

Different concentrations of test solution were prepared in a logarithmic series ranging 

nominally from 10 to 100 mg/l (temperature 25 °C, dissolved oxygen 7.8 mg/l, pH 7.5 - 8.2, 

water hardness as EDTA 20 - 172 mg/l, no aeration throughout the test period). The test 

results obtained for bluegill (Lepomis macrochirus) and fathead minnow (Pimephales 

promelas) are summarized in Table 3-15. As no chemical measurements were available the 

derived effect concentrations were related to nominal concentrations. The test results are 

therefore only of limited use for the effects assessment of VAM. 

Long-term toxicity 

The chronic toxicity of VAM to the early life-stages of fathead minnow (Pimephales

promelas) was examined under flow-through conditions by ASG/CEFIC (2003b) according to 

OECD-Guideline 210. One hundred embryos (< 30-hours post fertilization, 4 replicates of 25 

embryos) per dose level and control were exposed to nominal concentrations of 0.389, 0.648, 

1.08, 1.80, 3.00 and 5.00 mg vinyl acetate per litre. All test aquaria were sampled weekly 

throughout the duration of the study (days 0, 7, 14, 21, 28 and 34) and the collected samples 

were analysed for vinyl acetate using GC/EI-MS. The measured test solution concentrations 

were variable and did not remain within +/- 20 % of the mean measured concentrations over 

the course of the study. Study average percent of target values for vinyl acetate ranged from 

41.8 to 60.8 % and resulted in mean measured exposure concentrations of 0.163, 0.353, 0.551, 

0.930, 1.71 and 3.04 mg/l. 

The test system was maintained for 31 days post hatch of the control embryos (34 days total). 

Based on mean measured concentrations, the no-observed-effect concentration (NOEC) and 

lowest observed-effect concentration (LOEC) were statistically determined for the following 

endpoints: 

 percent of embryos that hatched (embryo survival) 

 time to hatch (day-to-mean hatch) 

 percent of normal larvae (larvae exhibiting no lethal or sublethal effects) at test 

termination 

 percent larvae survival 

 percent overall survival and growth (length and weight) 

If the raw data (or alternatively the transformed variables after logarithmic inverse or square 

root transformation) were found to be both normal (Shapiro-Wilk’s test) and homogeneous 

(Bartlett’s test), a parametric analysis was conducted with a Dunnett’s test. Data that was not 

normally and/or homogeneous were analysed parametrically with a Steels’ Many-one rank 

test or Kruskal-Wallis test. 
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49 CAS No.: 108-05-4 

The test results can be summarised as follows: 

 No statistically significant (α = 0.05) effects were observed for the percent of embryos 

hatched and the time to hatch endpoints up through the highest exposure level of 

3.04 mg/l tested for these endpoints. 

 No statistically significant (α = 0.05) effects were observed for the percent normal 

larvae at test termination, the percent larvae survival, and the percent overall survival 

up to the exposure concentration of 0.551 mg/l. Statistically significant effects for 

these endpoints were observed at exposure levels of 0.93 mg/l and above. These 

effects showed a clear concentration-dependency: While 93.9 ± 13.8 % of the larvae 

survived and showed normal development at a test concentration of 0.551 mg/l, this 

fraction was reduced to 78.0 ± 5.2 % at the next higher exposure level of 0.93 mg/l, to 

32.5 ± 11.0 % at 1.71 mg/l, and to zero at the highest exposure level of 3.04 mg/l. 

 No statistically significant (alpha = 0.05) differences in growth (lengths, weights) of 

surviving organisms at study termination were observed up through the highest 

exposure level tested for this endpoint (1.71 mg/l). 

Therefore, NOEC and LOEC were determined with 0.551 and 0.930 mg/l. 

Table 3-16: Chronic toxicity of VAM for early life stages of Pimephales promelas

Parameter NOEC (m) 

(mg/l) 

LOEC (m) 

(mg/l) 

Weight (mg) 1.71 > 1.71 

Length (mm) 1.71 > 1.71 

Percent embryos hatched 3.04 > 3.04 

Time to hatch 3.04 > 3.04 

Percent normal larvae 0.551 0.930 

Percent larvae survival 0.551 0.930 

Percent overall survival 0.551 0.930 

(m) measured concentration 

3.2.1.1.3 Aquatic invertebrates 

Acute toxicity 

An acute 48-hour Daphnia magna toxicity test with VAM was conducted under semi-static 

conditions according to the OECD-Guideline 202 by ASG/CEFIC (2003a). The study was 

performed with 20 daphnia (ten individuals per replicate with two replicates per dose level) 

exposed to nominal test concentrations of 4.28, 7.13, 11.9, 19.8, 33.0 and 55 mg vinyl acetate 

per litre. Due to the volatility of the test material serum bottles were filled to capacity and 

sealed. In order to maintain the exposure concentrations and dissolved oxygen levels test 

solutions were renewed after 24 hours. The concentration of vinyl acetate in the test solutions 

were confirmed in new and old test media via GC/EI-MS. The time-weighted mean (TWM) 
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50 CAS No.: 108-05-4 

measured values ranged from 66.9 to 110 % of target concentration resulting in TWM 

measured concentrations for the study of 2.91, 4.77, 9.77, 14.9, 31.0 and 60.5 mg vinyl 

acetate / l. A 24 h-EC50 of 24.0 mg/l (95 % confidence limits 20.2-29.0 mg/l) and a 48 hEC50 of 12.6 mg/l (95 % confidence limits 11.2-14.4 mg/l) were obtained from this study, 

indicating that toxicity is increasing with the duration of exposure. 

Additional static tests are available using Daphnia magna (Bringmann and Kühn 1982), the 

brine shrimp Artemia salina (Price et al., 1974) and the marine polychaete Ophryotrocha 

diadema (Parker, 1983). As only nominal concentrations are reported, these studies are 

regarded as invalid and not suitable for effects assessment purposes, but are nevertheless 

described in more detail below for completeness. 

In an acute immobilization study with Daphnia magna (Bringmann and Kühn 1982) a 24 hEC50 of 52 mg/l related to nominal concentrations was derived. The corresponding LC0 and 

LC100 value was 17 mg/l and 128 mg/l. The test was performed in an open, static system 

(local tap water free from chlorine, saturated with oxygen / content of at least 2 mg/l, 

temperature: 20 °C, pH at beginning of test: 7.8 - 8.2, water hardness: 16° dH.). 

Price et al. (1974) examined the toxicity of vinyl acetate to the brine shrimp Artemia salina. 

In a static test conducted with artificial sea water a 24 h-LC50 of 45 mg/l based on nominal 

concentrations was found. During the study bottles were loosely capped and incubated at 

ambient temperature (24.5 °C). After incubation the number of live and dead shrimp were 

noted by viewing the shrimp in the bottle aided by a colony counter. 

Another static toxicity test in filtered sea water (temperature: 21 °C) was carried out by Parker 

(1983) using the marine polychaete Ophryotrocha diadema as test organism. For the study a 

half-logarithmic series of concentrations was applied. After an 48 hours exposure period, 

surviving animals were transferred into pure sea water, where they were allowed to recover 

for one week. Any animals which died during this period were recorded along with the earlier 

mortalities in the test. A 48 h-LC50 of about 33 mg/l (nominal concentration) was derived 

from this study for vinyl acetate. 

Long-term toxicity 

Tests on long-term effects of vinyl acetate on aquatic invertebrates are not available. 

3.2.1.1.4 Aquatic algae 

The only reliable test result for aquatic algae was obtained from a growth inhibition test with 

the freshwater green alga Pseudokirchneriella subcapitata (ASG/CEFIC, 2003c). Due to the 

volatility of vinyl acetate several deviations of the standard algal bioassay were made in order 

to maximize the retention time of the substance in the test medium over the exposure period: 

 The study was performed under zero headspace conditions in sealed test vessels. 

 In order to avoid CO2-limitation the content of sodium carbonate in the growth 

medium was increased by a factor of five. 

 Test vessels were not shaken during the incubation period. 
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51 CAS No.: 108-05-4 

 For the daily cell density determinations test vessels were vigorously shaken 

prior to unsealing to suspend as much biomass as possible. 

 After sampling, additional test medium from a surrogate test vessel was added 

in order to maintain zero headspace conditions. 

The algae were exposed to six nominal test concentrations of 1.56, 3.13, 6.25, 12.5, 25.0, 50 

and 100 mg vinyl acetate / l over a 96-hour period. Since the concentration of vinyl acetate 

declined over time (after 72 hours between 75 and 30 % of the target concentrations were still 

present in the test solutions), time weighted means (TWM) were calculated leading to 72-hour 

TWMs of 0.331, 0.733, 1.58, 5.96, 6.57, 14.9 and 34.7 mg/l. Based on these TWMs the 

following test results were obtained: 

Table 3-17: Toxicity of vinyl acetate in algae (Pseudokirchneriella subcapitata)

Parameter Endpoint Concentration (mg/l) (m)

Growth rate 72 h-ERC50 12.70 (95 %-CI: 9.50-17.1) 

NOEC 5.96 

Biomass 72 h-EBC50 7.48 (95 %-CI: 1.60-34.9) 

NOEC 1.58 

(m) measured concentration 

For comparison purposes a second test using standard algal bioassay techniques was conducted by the same authors. Since the concentration of vinyl acetate declined very rapidly (after 

24 hours only 0.4 - 0.8 % of the target concentration was found in the highest tested 

concentrations of 50 - 200 mg/l) and the vinyl acetate concentrations tested were not set high 

enough to determine a concentration-response curve, the test results of the zero-headspace 

bioassay are regarded as more reliable. 

The green algae Scenedesmus quadricauda was investigated in a cell multiplication study by 

Bringmann and Kühn (1977a). Under this method, the onset of cell multiplication inhibition 

by different substances was determined. From this study an 8d-TGK value of 370 mg/l for 

vinyl acetate was obtained. Another cell multiplication inhibition test with the blue-green 

algae Microcystis aeruginosa as test organism found an 8d-TGK value of 35 mg/l (Bringmann 

and Kühn, 1976, 1978a, 1978b). 

In both tests, the substances were dissolved in distilled water (temperature 27 °C, pH 7 at 

beginning of test). As the effect concentrations were related to nominal concentrations and 

presumably the algae were not in the exponential growth phase during the whole test duration, 

both studies are classified as not valid. 
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52 CAS No.: 108-05-4 

3.2.1.1.5 Microorganisms 

The toxicity of vinyl acetate to different microorganisms was examined by Bringmann and 

coworkers using cell multiplication inhibition tests. The following test results based on 

nominal concentrations were obtained: 

Table 3-18: Toxicity of VAM to microorganisms

Species Effect Endpoint Concentration 

(mg/l) 

 pH / 

temp. 

 Reference 

Pseudomonas 

putida 

inhibtion of cell 

multiplication 

16 h-EC3 6 (n) 7.0 / 

25 °C 

Bringmann 

& Kühn 

(1976, 

1977a) 

Chilomonas 

paramaecium 

(Protozoa) 

inhibtion of cell 

multiplication 

48 h-EC5 9.5 (n) 6.9 / 

20 °C 

Bringmann 

et al. 

(1980) 

3.2.1.2 Calculation of Predicted No Effect Concentration (PNEC) 

3.2.1.2.1 Surface water (PNECaqua) 

Due to the volatility of vinyl acetate, only effect values based on analytically measured 

concentrations are suitable for derivation of the PNEC. Reliable acute test results are available 

for aquatic invertebrates and algae. For aquatic vertebrates a valid long-term test result is 

reported. As long-term NOECs from species representing two trophic levels are available 

(algae and fish), an assessment factor of 50 is proposed. Applying this factor to the long-term 

NOEC as determined in an ELS test using Pimephales promelas, the PNEC for aquatic 

ecosystems is calculated as follows: 

 PNECaqua = 0.55 mg/l / 50 = 0.011 mg/l

3.2.1.2.2 Sewage treatment plants (PNECSTP) 

According to the procedure described in the TGD for assessing the toxicity of a substance to 

microorganisms in order to identify adverse effects in WWTPs, an assessment factor in the 

range of 10 to 100 is applied for tests on microorganisms with different sensitivities and 

different endpoints. 

For vinyl acetate, an EC3-value of 6 mg/l is reported for Pseudomonas putida, which can be 

considered as a NOEC-value for microorganisms. For the determination of a PNECSTP, an 

assessment factor of 10 is proposed for this kind of test result, which leads to: 

 PNECSTP = 6 mg l / 10 = 0.6 mg/l 
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3.2.1.2.3 Sediment (PNECsed) 

Information on toxic effects of vinyl acetate on benthic organisms is not available. A 

provisional PNECsed can be calculated using the equilibrium partitioning method of the TGD: 

PNECsed = 

K susp_water

RHOsusp

 x PNECwater = 

1.51 m3 m 3 .

1300 kgwwt m 3

 x 0 .011 mg l 1 . x 1000 = 1.27 E-02 mg/kg

As measured data on concentrations of vinyl acetate in sediment is not available either, the 

PEC has to be derived with the same method. If both PEC and PNEC are calculated using the 

equilibrium partitioning method, the same risk ratios as for surface water are obtained. It is 

therefore referred to the risk characterisation for surfaces waters in section 3.3.1. 

The above equation only considers uptake via the water phase, but uptake may also occur via 

other exposure pathways like ingestion of sediment. However, these other exposure pathways 

are considered negligible due to the low adsorptive properties of vinyl acetate and the low 

affinity to organic material. In addition, VAM is degraded hydrolytically and biologically in 

sediments. A significant transfer of VAM into the sediment-phase is therefore not expected. 

As the equilibrium partitioning method will yield the same risk ratios as for surface water and 

as a significant transfer of VAM into the sediment-phase is not expected, a quantitative risk 

assessment for sediments is not considered necessary. 

3.2.2 Effects assessment for the terrestrial compartment 

3.2.2.1 Terrestrial effect data 

No terrestrial effect data based on standard soil test organisms (e.g. earthworms, collembolan, 

microorganisms) is available. 

Burditt et al. (1963) investigated the potential of using vinyl acetate as a fumigant to eggs and 

larvae of fruit flies Ceratitis capitata and Dacus dorsalis (both Diptera). Effect values were 

based on 2 h exposure followed by 48 h of observation.

A further fumigation test with terrestrial organisms was carried out at 25 °C for 3 h by Ittah 

and Zisman (1992) using Theba pisana (Mollusca: Helicidae) as test organism. In this study 

the fumigation was also followed by 48 h of observation. The derived effect values from both 

studies are summarized in the table below. 

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Table 3-19: Fumigation tests with fruit flies (Ceratitis capitata and Dacus dorsalis) and 

mollusc (Theba pisana) 

Species Age Effect Duration of 

fumigation 

 Effect Concentr. 

(g/m3) 

 Reference 

Ceratitis 

capitata 

24 h old 

eggs 

mortalit

y 

2 h 2 h-LC50

2 h-LC95 

53 

90 

Burditt et 

al. (1963) 

Ceratitis 

capitata 

mature 

larvae 

mortalit

y 

2 h 2 h-LC50 

2 h-LC95

43 

60 

Burditt et 

al. (1963) 

Dacus 

dorsalis 

24 h old 

eggs 

mortalit

y 

2 h 2 h-LC50 > 96 Burditt et 

al. (1963) 

Dacus 

dorsalis 

mature 

larvae 

mortalit

y 

2 h 2 h-LC50

2 h-LC95 

46 

70 

Burditt et 

al. (1963) 

Theba 

pisana 

differing 

ages 

mortalit

y 

3 h 3 h-LC31 2.3 Ittah & 

Zisman 

(1992) 

3.2.2.2 Calculation of PNECsoil

The available test results on terrestrial organisms (i.e. diptera and mollusca) are originated 

from fumigation studies. The PNECsoil cannot be deduced from these data. According to the 

TGD, the risk assessment is performed on the basis of the equilibrium partition method 

(EPM) if no standard test data with soil dwelling organisms is available (equation 72): 

PNECsoil = 

K soil_water

RHOsoil

 x PNECwater = 

0.931 m3 m 3 .

1700 kgwwt m 3 .

 x 0.011mg l 1 . x 1000 = 6.02E-03 mg/kg 

3.2.3 Effects assessment for the atmosphere 

3.2.3.1 Biotic effects 

Data on toxicity of airborne VAM are very scarce. 

For the mollusc Theba pisana, a 3 h-LC31 of 2.3 g/m3 is reported. This effect concentration is 

in the same order of magnitude as the results from the acute inhalation studies with mammals. 

No experimental data on toxicity of VAM to terrestrial plants is available. Therefore no 

PNECair can be calculated for terrestrial vegetation. 

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55 CAS No.: 108-05-4 

3.2.3.2 Abiotic effects 

3.2.3.2.1 Global warming 

Vinyl acetate absorbs solar irradiation wavelengths in the infrared region of 1,000 - 1,200 nm. 

Compared to the global warming effects caused by other substances (e.g. carbon dioxide) 

emitted from anthropogenic sources, the contribution of vinyl acetate to the overall man-made 

global warming potential (GWP) plays only an insignificant role, taking into account the 

released amounts and the short half-life of VAM in air. 

3.2.3.2.2 Troposheric ozone 

Ground-level ozone is formed by the reaction of VOCs and NOx in the presence of heat and 

sunlight. To this end vinyl acetate enhances formation of ground level ozone. The reactions 

that form ozone do not take place instantaneously, but can take hours or days. Nevertheless it 

cannot be excluded that for specific meteorologic conditions and intensive solar irradiation 

the contribution to ozone peaks may be substantial in the immediate vicinity of emission 

sources. On the regional scale, however, there are sources of (biogenic) volatile substances 

being of much more significance. Notwithstanding any feasible measure should be undertaken 

to abate releases of vinyl acetate to air in order to curb formation of ground level ozone. As 

compared to other volatile organics ozone-forming ability of vinyl acetate was found to be 

moderate (Joshi et al., 1982). 

3.2.3.2.3 Stratospheric ozone (ODP) 

The atmospheric lifetime of VAM is too short to allow for transport of relevant shares up to 

the stratospheric layer. In addition, the substance does no include any halogen atoms which 

could be split off and thereby form any free radicals that are capable of decomposing 

stratospheric ozone. 

3.2.3.2.4 Acidification 

Vinyl acetate is easily decomposed in the atmosphere, forming acetaldehyde and subsequently 

acetic acid. Following wet and dry deposition the substance may enter surface water bodies. 

However, acetic acid is not a strong acid (pKa = 4.76). Compared to atmospheric loads of 

other substances that form stronger acids such as NOx and SO2, the acidification potential of 

vinyl acetate is relatively low and the overall impact on surface water bodies negligible. 

3.2.4 Non compartment specific effects relevant to the food chain 

As vinyl acetate does not present indications of a bioaccumulation potential, an effect 

assessment for secondary poisoning is not required. 
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3.3 RISK CHARACTERISATION 

As a follow up to conclusion (i), which was drawn in the first draft of the Environment Section 

of the Comprehensive Risk Assessment Report of vinyl acetate (August 2002), further acute 

and long-term toxicity tests with aquatic organisms were performed and more data on a number 

of production and processing sites could be obtained, leading to the following refined and 

revised risk characterisation. 

3.3.1 Aquatic compartment (incl. sediment) 

Sewage treatment plants 

Based on a PNECSTP of 600 μg/l (cf. section 3.2.1.2.2) and PECSTP values derived for the 

different production, processing and manufacturing sites (= Clocaleff values, equation 38 of 

the TGD), the following PEC : PNEC ratios for waste water treatment plants were calculated. 

Table 3-20: Local risk characterisations for STPs 

Site Exposure source PECSTP (μg/l) PECSTP : PNECSTP

1 processing 5.00E+01 0.08 

2 processing 1.00E+01 0.02 

3a processing 1.00E+02 0.17 

3b processing 5.00E+01 0.08 

3c processing 4.00E+00 0.01 

3d processing 1.30E+01 0.02 

4/5 production/processing 5.00E+01 0.08 

6 processing 3.04E+01 0.05 

7 processing 5.00E+00 0.01 

8 processing 2.30+01 0.04 

9 processing 9.81E+01 0.16 

10 processing 3.10E-02 0.00 

11 processing 5.70E+00 0.01 

12 processing 2.57E+01 0.04 

13 processing 0.00E+00 - 

14 processing 7.69E+01 0.13 

15 processing 1.04E+01 0.02 

16 processing 0.00E+00 - 

17 processing 1.16E-04 0.00 

18 processing 1.27E+01 0.02 
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Site Exposure source PECSTP (μg/l) PECSTP : PNECSTP

19 processing 9.61E+01 0.16 

20 processing 1.91E-06 0.00 

21 production 1.03E+01 0.02 

22 production 4.00E-01 0.00 

23 processing 0.00E+00 - 

24 processing 1.21E+02 0.20 

25 processing 2.67E-04 0.00 

28 processing 5.33E+01 0.09 

29 processing 8.11E-01 0.00 

30 processing 7.70E-01 0.00 

An evaluation of the inhibition of microbial activity in STPs seems reasonable only for those 

sites where vinyl acetate-containing waste water is released to biological treatment plants. 

The production sites which are not connected to a biological WWTP, as their waste water is 

treated within the process (site 26 and 27), were thus excluded from the risk characterisation. 

As VAM is typically produced in closed systems and dissolved vinyl acetate monomers are 

often recovered from waste water streams, i.e. by fractional distillation to increase reaction 

yields, residual levels in the waste water are generally low (cf. section 3.1.2.1.1). For the 

remaining production sites (4, 21 and 22) discharging to waste water treatment plant, no risk 

was therefore identified. 

Based on a difference of 325,000 t/a between nominal production volume (800,000 t/a) and 

verified processing capacities (total of 475,000 t/a), a generic scenario was calculated for the 

local main source (fraction of main source = 0.15). A PECSTP of 325 μg/l was derived, 

resulting in a PEC : PNEC ratio of 0.54. 

Conclusion (ii) There is at present no need for further information and/or testing and for 

risk reduction measures beyond those which are being applied already. 

This conclusion applies to all production, processing and manufacturing sites. 
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Surface water 

A PNECaqua of 11 μg/l for surface water has been determined (cf. section 3.2.1.2.1). 

Using the PNECaqua and a PECregsurfacewater of 8.35E-03 μg/l (cf. section 3.1.6), the risk ratio 

for the regional environment is calculated as follows: 

 PECregsurfacewater : PNECaqua = 8.35E-03 μg/l : 11 μg/l = 7.59E-04 

From the PNECaqua and the estimated PEClocalwater ( = Clocalwater + PECregsurfacewater) for the 

different production and processing sites, the risk ratios for the local environments are 

calculated as follows: 

Table 3-21: Local risk characterisations for surface water (freshwater) 

 Site Exposure source PEClocalwater (μg/l) PEClocalwater : PNECaqua

1 processing 8.83E-03 0.00 

2 processing 7.44E-02 0.01 

3a processing 1.00E+01 0.91 

3b processing see marine risk assessment 

3c processing 4.08E-01 0.04 

3d processing 1.31E+00 0.12 

4/5 production/ processing 2.17E-01 0.02 

6 processing 3.05E+00 0.28 

7 processing 5.08E-01 0.05 

8 processing 2.31E+00 0.21 

9 processing 9.89E-01 0.09 

10 processing 1.14E-02 0.00 

11 processing 1.40E-01 0.01 

12 processing 2.11E+00 0.19 

13 processing 8.35E-03 0.00 

14 processing 7.70E+00 0.70 

15 processing 1.03E+01 0.94 

16 processing 8.35E-03 0.00 

17 processing 8.36E-03 0.00 

18 processing 1.28E+00 0.12 

19 processing 9.62E+00 0.87 

20 processing 8.35E-03 0.00 
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 Site Exposure source PEClocalwater (μg/l) PEClocalwater : PNECaqua

21 production 7.64E-02 0.01 

22 production see marine risk assessment 

23 processing 8.35E-03 0.00 

24 processing 1.56E-02 0.00 

25 processing 8.38E-03 0.00 

26 production 8.35E-03 0.00 

27 production see marine risk assessment 

28 processing 1.34E+00 0.12 

29 processing 1.04E-02 0.00 

30 processing 1.01E-02 0.00 

For the difference of 325,000 t/a between nominal production volume (800,000 t/a) and 

verified processing capacities (total of 475,000 t/a), a generic scenario was calculated based 

on a fraction of main source of 0.15. A PEClocalwater of 8.13 μg/l was derived, resulting in a 

PEC : PNEC ratio of 0.74. 

A risk to the local or regional aquatic compartment was not identified for production and 

processing of vinyl acetate. This conclusion applies to all sites and the generic scenario. 

-

Conclusion (ii) There is at present no need for further information and/or testing and for 

risk reduction measures beyond those which are being applied already. 
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Sediment 

Information on toxic effects of vinyl acetate on benthic organisms is not available, neither are 

measured data on concentrations of vinyl acetate in sediment. Both PEC and PNEC can be 

calculated using the equilibrium partitioning method, which will result in the same risk ratios 

as were obtained for surface water. 

This approach only considers uptake of vinyl acetate via the water phase, but uptake may also 

occur via other exposure pathways like ingestion of sediment. These other exposure pathways 

are considered negligible due to the low adsorptive properties of vinyl acetate and the low 

affinity to organic material. In addition, VAM is degraded hydrolytically and biologically in 

sediments. A significant transfer of VAM into the sediment-phase is therefore not expected. 

On the basis of the available information, it is concluded that an unacceptable risk for 

sediments and sediment dwelling organisms is generally not to be expected from vinyl 

acetate. 

Conclusion (ii) There is at present no need for further information and/or testing and for 

risk reduction measures beyond those which are being applied already. 

3.3.2 Atmosphere 

Due to the high volatility of VAM it is expected that – once released into the environment – 

the main compartment for environmental exposure is air. This finding is supported by the 

results of environmental distribution models based on the physico-chemical data of VAM. 

VAM beaks down rapidly in the atmosphere with a globally and seasonally averaged half-life 

of approximately 0.6 days (cf. section 3.1.1.2.1.) Hence transport from points of release over 

long distances can be excluded. 

Although no breakdown products have been identified it seems likely that even more polar 

fragments are generated through addition to the olefinic bonds. Among the expected reaction 

products is formaldehyde (Atkinson, 1995). Besides photooxidation, wet deposition of VAM 

and its breakdown products is expected to be an important physical removal process from the 

atmosphere. Concurrently, cloud droplets further contribute to hydrolytic degradation of 

VAM in moist air. Since acetaldehyde and its oxidation product acetic acid show some 

acidification potential, their wet deposition adds to acidification of weakly buffered surface 

waters. From the results of this risk assessment it is however concluded that the specific 

contribution of VAM degradation products will not be of any relevance as compared with 

other substances. 

From its high vapour pressure and low Kow value it is concluded that either adsorption to 

airborne particles and aerosols is of relevance. In addition there is no indication that VAM 

significantly adds to adverse effects on other parameters of atmospheric quality like global 

warming or ozone depletion. 

At air concentrations of approximately 2 g/m3 significant biotic effects were observed. 

However, the data basis is far too scarce to derive a PNEC from this test result. As the highest 
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61 CAS No.: 108-05-4 

calculated local concentration of approx. 0.3 μg/m3 is several orders of magnitude lower, 

further tests on this endpoint seem not to be of high priority. 

It is concluded that an unacceptable risk for the environment via the atmosphere is not 

expected from vinyl acetate. 

Conclusion (ii) There is at present no need for further information and/or testing and for 

risk reduction measures beyond those which are being applied already. 

3.3.3 Terrestrial compartment 

No terrestrial effect data based on standard soil test organisms (e.g. earthworms, collembolan, 

microorganisms) is available. A PNECsoil = 6.02E-03 mg/kg was therefore derived using the 

equilibrium partition method of the TGD. 

It is expected that the main pathway of VAM immission into soil is aerial deposition after 

local releases to air from point sources, rather than sludge application: Only 0.2 % of the 

VAM load entering a STP is expected to adsorb to sludge, and most companies producing or 

processing VAM reported either incineration or landfill of STP sludge. 

As a worst case approach, soil concentrations were estimated for the two facilities with 

highest aerial deposition rates. Both facilities do not operate a STP so that sludge application 

is not included in the estimate (site 26 and 16). Furthermore, soil concentrations were 

calculated for several sites that had relatively high aerial deposition rates and reported sludge 

application on agricultural soils. 

From the PNECsoil and the PEClocalsoil (= Clocalsoil + PECregnat.soil) for the selected production 

and processing sites, the risk ratios for the local environment are calculated as follows: 

Table 3-29 Local risk characterisations for terrestrial soil 

Site Exposure source PEClocalsoil PEClocalsoil : PNECsoil

26 production (no STP) 8.77E-03 1.46 

16 processing (no STP) 5.16E-03 0.86 

3a processing 6.13E-04 0.10 

3b processing 6.36E-04 0.11 

3c processing 4.18E-04 0.07 

3d processing 2.40E-04 0.04 

6 processing 1.40E-03 0.23 

A potential risk was identified for production site number 26, based on a deposition rate that 

was derived from site specific data provided by the company operating the plant. 

A potential risk was also identified for the generic scenario calculated for the local main 

source (fraction of main source = 0.15), based on a difference of 325,000 t/a between nominal 

production volume (800,000 t/a) and verified processing capacities (total of 475,000 t/a). A 

PEClocalsoil of 0.014 mg/kg was derived, resulting in a PEC : PNEC ratio of 2.33. 
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Conclusion (i): There is need for further information and/or testing

A risk to the local terrestrial compartment was identified for the life cycle stages of vinyl 

acetate production and processing. This conclusion applies to one major production site (site 

number 26) and for the generic processing scenario calculated for the local main source. 

There is a need for further information and/or testing to adequately characterize the potential 

risks to the terrestrial compartment by refining the PNECsoil. It is recommended to perform 

an earthworm acute toxicity test (OECD 207) and a terrestrial plants growth test (OECD 208). 

The need for further testing should be reconsidered in case that risk reduction measures are 

being applied at the site indicating a risk to the terrestrial compartment (site number 26). If no 

risk remains after risk reduction measures have been applied for the life cycle stage of vinyl 

acetate production, conclusion ii) should follow. 

3.3.4 Non compartment specific effects relevant to the food chain 

As there is no indication for vinyl acetate to be a potentially bioaccumulative substance, it 

was abstained from assessing effects for secondary poisoning. 

3.3.5 Marine Assessment including PBT Assessment 

3.3.5.1 PBT Assessment 

The following table shows the PBT/vPvB criteria as defined in the TGD and the respective 

values of vinyl acetate as derived in chapter 3 of this risk assessment. 

Table 3-28 PBT/vPvB criteria according to TGD and data for vinyl acetate 

PBT-criteria vPvB-criteria VAM 

P half-life 

> 60 d in marine water or 

> 40 d in freshwater 

or half-life 

> 180 d in marine sediment or 

> 120 d in freshwater sediment 

half-life 

> 60 d in marine water 

or freshwater 

or half-life 

> 180 d in marine or 

freshwater sediment 

readily biodegradable 

in surface water, 

half-life: 15d 

(section 3.1.1.2.2) 

B BCF > 2,000 BCF > 5,000 BCF of 3.16 

(section 3.1.1.3.5)

T chronic NOEC < 0.01 mg/l 

or CMR or endocrine 

disrupting effects 

not applicable 34 d NOEC (fish): 

0.551 mg/l 

(section 3.2.1.1.2)

Vinyl acetate was found to be readily biodegradable in sewage treatment plants and is also 

considered as readily biodegradable in surface water. No standard tests on degradation of 
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63 CAS No.: 108-05-4 

vinyl acetate in soil or sediment are available, but different studies indicate that the substance 

is biotransformed and abiotically degraded in soil and sediment. 

A BCF of 3.16 was derived from log Kow of 0.73. Measured BCF are not available. 

A 34 d NOEC of 0.551 mg/l was found for fathead minnow (Pimephales promelas). 

It can be concluded that vinyl acetate does not meet any of the PBT/vPvB criteria. 

Conclusion (ii) There is at present no need for further information and/or testing and for 

risk reduction measures beyond those which are being applied already. 

VAM does not meet the PBT/vPvB criteria. 

3.3.5.2 Marine Assessment 

There is no indication that VAM persists or accumulates in the environment. However, it is 

known that two production sites (site 22 and 27) and one processing site (site 3b) discharge to 

the marine or estuarine environment. PEClocal for these sites are based on site-specific data 

in combination with default values from the TGD. Two facilities operate a WWTP (site 22 

and 3b). The company operating the other production plant (site 27) reported that new 

technology had been implemented in the recently commissioned facility in order to contain 

and recover VAM in the process (i.e. closed system process, distillation of wastewater for reintroduction of material in the process, incineration of remaining waste). Thus VAM in the 

waste water is either recycled or remaining material is incinerated. 

As a first approach, the marine regional background concentration was derived from the fresh 

water regional background concentration by division by 10: 

 PECregional_seawater = 8.35E-03 μg/l / 10 = 8.35E-04 μg/l 

The PECregional_seawater was added to the Clocalwater to obtain the respective PEClocal water for 

the marine sites. The PNECmarine was derived by dividing the PNECaqua by 10: 

 PNECmarine = PNECaqua / 10 = 11 μg/l / 10 = 1.1 μg/l 

Based on these values, the following PEC : PNEC ratios < 1 for all sites are derived. 

Table 3.22 PEC : PNECseawater ratios for marine sites 

Site 

Clocalsseawater 

(μg/l)

PEClocalseawater 

(μg/l)

PEClocalseawater : 

PNECmarine

3b processing 5.00E-01 5.01E-01 0.46 

22 production 4.00E-03 4.84E-03 0.00 

27 production 0.00E+00 8.35E-04 0.00 

 
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Conclusion (ii) There is at present no need for further information and/or testing and for 

risk reduction measures beyond those which are being applied already. 

Conclusion (ii) applies to all identified marine sites. 
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4 HUMAN HEALTH 

4.1 HUMAN HEALTH (TOXICITY) 

4.1.1 Exposure assessment 

4.1.1.1 Indirect exposure via the environment 

According to Appendix VII of chapter 2 of the TGD, the indirect exposure to humans via the 

environment, i.e. through food, drinking water and air is estimated. 

As a worst case scenario, the maximum intake due to exposure in the vicinity of a vinyl 

acetate production facility is calculated (site 26). This is compared to an average intake due to 

exposure via the regional background concentration. 

The resulting total daily dose is: DOSEtot_local = 36 μg / kg bw d 

 DOSEtot_regional = 2.47 E-03 μg / kg bw d 

The calculated total doses comprise the following routes: 

Route Percent of total dose 

local regional 

Drinking water 1.26 9.64 

Fish 2.97E-05 0.44 

Stem 0.36 0.33 

Root 0.24 0.37 

Meat 2.04E-04 2.41E-04 

Milk 3.80E-03 4.50E-03 

Air 98.13 89.22 

The main route of indirect exposure of both scenarios is the intake via inhalation of air. 
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5 CONCLUSIONS / RESULTS 

Overall results of the risk assessment: 

(x) i) There is need for further information and/or testing 

(x) ii) There is at present no need for further information and/or testing and for risk 

reduction measures beyond those which are being applied already 

() iii) There is a need for limiting the risks; risk reduction measures which are already 

being applied shall be taken into account 

Summary of conclusions: 

Environment

As a follow up to conclusion (i), which was drawn in the first draft of the Environment Section 

of the Comprehensive Risk Assessment Report of Vinyl acetate (August 2002), further acute 

and long-term toxicity tests were performed for the aquatic compartment and more data on a 

number of production and processing sites were obtained, leading to the following revised risk 

characterisation. 

conclusion i): 

Terrestrial compartment

A risk to the local terrestrial compartment was identified for the life cycle stages of vinyl 

acetate production and processing. This conclusion applies to one major production site (site 

number 26) due to aerial deposition of vinyl acetate in the vicinity of the site and for the 

generic processing scenario calculated for the local main source. 

There is a need for further information and/or testing to adequately characterize the potential 

risks to the terrestrial compartment by refining the PNECsoil. It is recommended to perform an 

earthworm acute toxicity test (OECD 207) and a terrestrial plants growth test (OECD 208). 

The need for further testing should be reconsidered in case that risk reduction measures are 

being applied at the site indicating a risk to the terrestrial compartment (site number 26). If no 

risk remains after risk reduction measures have been applied for the life cycle stage of vinyl 

acetate production, conclusion ii) should follow. 

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conclusion ii): 

Aquatic compartment

A risk to the local or regional aquatic compartment (surface water and sediments) was not 

identified for production and processing of vinyl acetate. This conclusion applies to all sites. 

Atmospheric compartment

Based on a qualitative risk characterisation, no unacceptable risk for the atmosphere is 

expected from vinyl acetate. The substance is rapidly removed from air by chemical 

breakdown, adsorption to airborne particles or aerosols, and wet deposition. Furthermore, air 

concentrations indicate a negligible risk with regard to ecotoxicity. 

Non-compartment specific effects

Non compartment specific effects (secondary poisoning) of vinyl acetate are not expected as 

there is no indication that the substance has potentially bioaccumulative properties. 

Marine Assessment including PBT assessment

VAM does not meet the PBT/vPvB criteria. A risk for the regional or local marine 

environment is not expected. 

 

Human Health

Workers 

Consumers 

Man exposed indirectly via the environment 

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80 CAS No.: 108-05-4 
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81 CAS No.: 108-05-4 
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82 CAS No.: 108-05-4 
RISK ASSESSMENT 

Vinyl acetate 

CAS-No.: 108-05-4 

EINECS-No.: 203-545-4 

Draft of 29.05.2008 
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2 CAS No.: 108-05-4 

Information on the rapporteur 

Contact point: 

Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA) 

Anmeldestelle Chemikalien / Zulassungsstelle Biozide 

(Federal Institute for Occupational Safety and Health 

Division for Chemicals and Biocides Regulation) 

Friedrich-Henkel-Weg 1-25 

44149 Dortmund (Germany) 

fax: +49(231)9071-2679 

e-mail: chemg@baua.bund.de

The first draft of the Comprehensive Risk Assessment Report of Vinyl acetate, a substance 

chosen from the EU 1st Priority List in 1994, was discussed preliminary (written procedure) at 

the TM II / 2001 (June 2001). 

The Environmental part was discussed in depth at the TM III/2002 (August 2002) and further 

in depth at the TC NES IV 04 (December 2004). It was distributed for the last visit written 

procedure in May 2005 and for the final written approval in May 2006. 

The Human Health part was discussed first in depth at the TM I/2002 (March 2002), second 

in depth at the TM IV/2002 (December 2002), last visit at the TM II/2003 (June 2003), 2nd

last visit (effects assessment only) at TC NES I/2007 and 2nd last visit (Risk characterisation) 

at TC NES II/2007. It was distributed for the final written procedure in December 2007 and 

for a further written approval in May 2008. 
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CONTENTS 

0 OVERALL CONCLUSIONS/RESULTS OF THE RISK ASSESSMENT 5

1 GENERAL SUBSTANCE INFORMATION 8

2 GENERAL INFORMATION ON EXPOSURE 12

2.1 Exposure sources 12

2.1.1 Production 13 

2.1.2 Processing 14 

2.2 Uses 17

3 ENVIRONMENT 20

3.1 Environmental exposure Error! Bookmark not defined. 

3.1.1 General discussion Error! Bookmark not defined.

3.1.2 Exposure Assessment for the Aquatic CompartmentError! Bookmark not defined.

3.1.3 Exposure Assessment for the Atmosphere Error! Bookmark not defined.

3.1.4 Exposure assessment for the terrestrial compartmentError! Bookmark not defined.

3.1.5 Non compartment specific exposure relevant to the food chainError! Bookmark not defined

3.1.6 Regional concentrations Error! Bookmark not defined.

3.2 Effects assessment: Hazard identification and Dose (concentration) - response 

(effect) assessment Error! Bookmark not defined. 

3.2.1 Effects assessment for the aquatic compartment (including sediment)Error! Bookmark not d

3.2.2 Effects assessment for the terrestrial compartmentError! Bookmark not defined.

3.2.3 Effects assessment for the atmosphere Error! Bookmark not defined.

3.2.4 Non compartment specific effects relevant to the food chainError! Bookmark not defined.
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3.3 Risk characterisation Error! Bookmark not defined. 

3.3.1 Aquatic compartment (incl. sediment) Error! Bookmark not defined.

3.3.2 Atmosphere Error! Bookmark not defined.

3.3.3 Terrestrial compartment Error! Bookmark not defined.

3.3.4 Non compartment specific effects relevant to the food chainError! Bookmark not defined.

3.3.5 Marine Assessment including PBT AssessmentError! Bookmark not defined.

4 HUMAN HEALTH 21

4.1 HUMAN HEALTH (TOXICITY) 21

4.1.1 Exposure assessment 21 

4.1.2 Effects assessment: Hazard identification and Dose (concentration) - response 

(effect) assessment 42 

4.1.3 Risk characterisation 150 

4.2 HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES) 180

4.2.1 Exposure assessment 180 

4.2.2 Effects assessment: Hazard identification and Dose (concentration) - response 

(effect) assessment 180 

4.2.3 Risk characterisation 180 

5 CONCLUSIONS / RESULTS 182

6 REFERENCES 185
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0 OVERALL CONCLUSIONS/RESULTS OF THE RISK ASSESSMENT 

CAS No. 108-05-4 

EINECS No. 203-545-4 

IUPAC Name Vinyl acetate 

 

Overall results of the risk assessment: 

( ) i) There is need for further information and/or testing 

(x) ii) There is at present no need for further information and/or testing and for risk 

reduction measures beyond those which are being applied already 

(x) iii) There is a need for limiting the risks; risk reduction measures which are already 

being applied shall be taken into account 

Summary of conclusions: 

Environment

As a follow up to conclusion (i), which was drawn in the first draft of the Environment Section 

of the Comprehensive Risk Assessment Report of Vinyl acetate (August 2002), further acute 

and long-term toxicity tests were performed for the aquatic compartment and more data on a 

number of production and processing sites were obtained, leading to the following revised risk 

characterisation. 

conclusion iii): 

Terrestrial compartment

A risk to the local terrestrial compartment can be identified for the life cycle stage of vinyl 

acetate processing. This conclusion applies to the generic processing scenario for the local 

main source. The unknown processing sites account for a missing tonnage of 325,000 t/a (or 

41 % of the total production volume of 800,000 t/a), compared to a verified processing 

tonnage of 475,000 t/a. 
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The risk characterisations for selected (worst case) production and processing sites with site 

specific data indicate no actual risk to the terrestrial compartment. However, the highest 

PEC/PNEC ratio calculated with site specific data (0.86) is not very far from the PEC/PNEC 

ratio calculated for the generic processing scenario (2.33), and there was also a risk at one of 

the production sites (which has been eliminated during the time of the preparation of this 

RAR). Consequently, it is not completely implausible that unknown processing sites pose a 

risk to the terrestrial environment. 

The risk characterisation for the terrestrial compartment could still be revised by requesting 

further testing (i.e. OECD 207 Earthworm acute toxicity test and OECD 208 Terrestrial plants 

growth test). However, a further data improvement by means of testing is not considered a 

reasonable next step by the rapporteur for the following reasons. 

Further information on the toxicity of vinyl acetate to terrestrial organisms allows for a reevaluation of the potential risk that emanates from the unknown processing sites, but delays 

risk reduction measures in case that a risk still remains with the new data. The rapporteur 

therefore proposes to enter directly into the risk reduction phase, which would be more 

effective than further data improvement at this stage of the risk assessment. 

Risk reduction measures should be considered for all facilities with a vinyl acetate processing 

capacity exceeding 20,000 t/a. This threshold is derived from the generic processing scenario, 

assuming that vinyl acetate is released to soils via sludge application and aerial deposition. 

Sites already applying advanced techniques would not require further consideration of risk 

reduction measures. It is known from some processing/production sites that techniques such 

as waste water distillation, sludge incineration or deposition in a landfill, waste gas 

incineration or vapour recovery systems can avoid significant releases of vinyl acetate to 

soils. 

In principle, the rapporteur agrees with the proposal of SCHER that considering the volatility 

of the substance, terrestrial plants might be exposed via air. However, no guidance is 

available how to derive a PNEC for the air compartment. In addition, the available guidelines 

for terrestrial plants (OECD 208 / 227) are designed to include exposure through soil or by 

wet residues (e.g. spray drift of plant production products). To determine effects of volatile 

compounds, testing needs to be conducted in closed greenhouses or chambers under 

continuous exposure conditions. We feel this kind of testing is not appropriate for vinyl 

acetate, because no indications for high toxicity for plants exist. For other soil organisms, a 

continuous exposure to volatile compounds like vinyl acetate is negligible since the substance 

is expected to evaporate from the soil. 

conclusion ii): 

Aquatic compartment

A risk to the local or regional aquatic compartment (surface water and sediments) was not 

identified for production and processing of vinyl acetate. This conclusion applies to all sites. 

Atmospheric compartment

Based on a qualitative risk characterisation, no unacceptable risk for the atmosphere is 

expected from vinyl acetate. The substance is rapidly removed from air by chemical 
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7 CAS No.: 108-05-4 

breakdown, adsorption to airborne particles or aerosols, and wet deposition. Furthermore, air 

concentrations indicate a negligible risk with regard to ecotoxicity. 

Non-compartment specific effects

Non compartment specific effects (secondary poisoning) of vinyl acetate are not expected as 

there is no indication that the substance has potentially bioaccumulative properties. 

Marine Assessment including PBT assessment

VAM does not meet the PBT/vPvB criteria. A risk for the regional or local marine 

environment is not expected. 

Human Health

Workers 

conclusion iii) 

Conclusion iii is expressed for the endpoint of carcinogenicity after dermal contact. Skin 

contact of vinyl acetate should be reduced at scenario 2a (manufacturing of formulations and 

products, vinyl acetate monomer), even if evaporation of the substance reduces the 

contribution of dermal exposure. 

On the background of cancer risks and repeated dose toxicity, air concentrations of vinyl 

acetate at the workplace should be controlled to a level in the range of 17.6 mg/m3 (critical 

exposure level). Conclusion iii is derived for repeated dose toxicity after inhalation for 

scenario 2 (manufacturing of formulations and products). This scenario with an exposure 

value of 14.6 mg/m3

 is a borderline case. Since there is the uncertainty concerning the 

reduction of the intraspecies factor and the mode of action for carcinogenesis for this 

borderline scenario conclusion iii is drawn. 

Consumers 

conclusion ii) 

There is at present no need for further information and/or testing and for risk reduction 

measures beyond those which are being applied already 

Man exposed indirectly via the environment 

conclusion ii) 

There is at present no need for further information and/or testing and for risk reduction 

measures beyond those which are being applied already 
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1 GENERAL SUBSTANCE INFORMATION 

Identification of the substance 

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EINECS No.: 203-545-4 

IUPAC Name: Vinyl acetate 

Synonyma: Acetic acid vinyl ester 

Empirical formula: C4H6O2

Structural formula: 

H2C

CH

O CH3

O

Molecular weight: 86 g/mol 

Purity/impurities, additives 

Purity: 99.8 % w/w 

Impurities: ≥ 0.03 - 0.1 % w/w water 

≥ 0.005 - 0.01 % w/w acetic acid 

≥ 0.005 - 0.02 % w/w acetaldehyde 

Additives: hydrochinone or hydrochinone mono methyl ether as stabilisator 

 0.00015 - 0.002 % w/w 
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Table 1-1: Physico-chemical properties 

Physical state liquid at 20 °C 

Melting point - 93.2 °C Handbook of Chemistry and 

Physics, 1980 - 1981 

Boiling point + 72.7 °C Merck Index, 1996 

Relative density 0.932 at 20 °C Merck Index, 1996 

Vapour pressure 120 hPa at 20 °C Hoechst AG, 1994c 

Surface tension 24 mN/m at 20 °C 

(pure substance) 

Handbook of Chemistry and 

Physics, 1980 - 1981 

Water solubility 20 g/l at 20 °C Merck Index, 1996 

Partition coefficient logPow 0.7 Hoechst AG, 1992 

Flash point - 8 °C (DIN 51755) CHEMSAFE, 1994 

Auto-flammability, 

ignition temperature 

385 °C (DIN 51794) CHEMSAFE, 1994 

Explosive properties not explosive due to structural reasons 

Oxidizing properties not oxidizing due to structural properties 

Vapour pressure: 

Vapour pressure values were available from safety data sheets, product information and 

literature without any details about the used methods. All values correlate well with the 

boiling point of 72.7 °C (Clausius-Clapeyron). 

Water solubility: 

The water solubility is 20 g/l at 20 °C according to safety data sheets and product 

information. No further information about the determination method is available. 

Partition coefficient: 

According to literature data the partition coefficient was determined experimentally (HPLC 

method: logPow 0.21, shaking method: logPow 0.73). The calculation with CLOGP3-

Software resulted in a logPow of 0.7. Due to the agreement of experimentally and calculated 

values a logPow of 0.7 was used for the risk assessment. 
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Classification 

• (Classification according to Annex I) 

F R 11 Highly flammable 

• (Proposal of the rapporteur) 

The current classification included in Annex I to Directive 67/548/EEC is only due to human 

health effects and does not yet consider environmental effects of vinyl acetate. Based on the 

data presented in the environmental section of this risk assessment report and the criteria of 

Directive 93/21/EEC, the rapporteur proposes the substance not to be classified and labelled 

for environmental risks. 

The classification included in Annex I to Directive 67/548/EEC does not yet include toxic 

effects. According to the data presented below and the criteria of Directive 93/21/EEC, vinyl 

acetate should be classified as follows and assigned the risk phrases: 

Harmful R 20 Harmful by inhalation 

Irritant R 37 Irritating to respiratory system 

Carcinogenic, Cat. 3 R 40 Limited evidence of a carcinogenic effect 

Human data on irritation/corrosion caused by vinyl acetate are not available. In the only valid 

test (RCC, 2003) mild irritative effects on the skin of rabbits was observed that do not need 

classification. The eye irritation potential of the compound seems to be mild as judged on the 

basis of poorly documented eye irritation tests with rabbits. Hence, no classification for eye 

irritative effects is needed. 

Acute inhalation tests with rats demonstrated severe irritation in the respiratory tract of the 

animals. Thus, vinyl acetate should be labelled “R 37 Irritating to respiratory system”. 

Results from an animal skin sensitization study (Buehler Test) showed a moderate skin 

sensitising potential of vinyl acetate (commercial grade). With the use of the Local Lymph 

Nodes Assay (LLNA) no significantly positive stimulation responses were detected at 

concentrations of 5% - 100%. Overall, the outcome of both studies may indicate that vinyl 

acetate is not devoid of a skin sensitising potential. The results of the LLNA do confirm the 

weak-moderate effects seen in the Buehler test. However, since the positive threshold level 

was not exceeded in the LLNA, classification and labelling with R 43 is not warranted. 

There is clear evidence for the carcinogenicity of vinyl acetate in two animal species and in 

both sexes. The carcinogenic potential was demonstrated for the inhalation and oral route of 

administration. Vinyl acetate exposure produced tumors at the site of first contact along the 

exposure routes. A thresholded mode of carcinogenic action is thought to be active. The 

observed tumor responses are reflecting the target site-specific enzyme activities: 
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Following inhalation and oral exposure vinyl acetate is rapidly hydrolysed by 

carboxylesterases leading to the formation of acetic acid and acetaldehyde which is further 

converted into acetic acid in the presence of aldehyde dehydrogenases. Intracellular aldehyde 

dehydrogenase activity is limited, at higher concentrations of vinyl acetate it will not be 

sufficient for the oxidation of generated acetadehyde. Thus, at high vinyl acetate 

concentrations non-physiological concentrations of acetaldehyde are produced. Acetaldehyde 

is a physiological intermediate with low background concentrations. Its adverse effects 

(genotoxicity and mutagenicity) are limited to non-physiologically high concentrations. 

Therefore, a threshold mode of action is assumed for vinyl acetate. 

Above threshold concentrations, cytotoxicity (only at the olfactory mucosa), mitogenic 

actions and genotoxic actions occurred. 

Data on vinyl acetate are in line with the idea that vinyl acetate genotoxicity is mediated by 

acetaldehyde. Increasing concentrations of acetaldehyde produce genotoxic actions at the site 

of contact. It has to be taken into consideration that acetaldehyde occurs naturally in 

mammalians cells and is part of the physiological cellular metabolism. 

From animal data it is concluded that vinyl acetate might pose a cancer risk for humans 

exposed to the substance via the inhalation or oral route. Carcinogenicity is thought to act via 

a secondary mechanism and the concern may only be relevant above threshold concentrations. 

The observed effects are thought to be relevant for the human. For the respiratory tract 

humans may be less sensitive than the rat due to a lower carboxylesterase activity in the nasal 

mucosa. 

In Germany, vinyl acetate is assigned to the MAK-pregnancy category "D" denoting that the 

current data base is not sufficient for final evaluation of developmental toxicity. However it is 

outlined that vinyl acetate was evaluated for reproductive toxicity in one species (rat) already 

with negative results. If this latter outcome could be verified in additional species vinyl 

acetate could be assigned to category "C" denoting that no risk for adverse developmental 

effects have to be expected for female workers in compliance with the respective MAK value 

of 10 ppm. 
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2 GENERAL INFORMATION ON EXPOSURE 

2.1 EXPOSURE SOURCES 

Exposure of man and environment to vinyl acetate monomer (VAM) may result from releases 

during each of the consecutive steps downstream the supply chain. These are production of 

the substance, polymerisation of the monomer, compounding operations involving the 

polymers, and eventually use of the end products. 

 

 Production 

 synthesis of 

 the monomer 

 ▼

 Use 

processing 

= (co)polymerisation 

of the monomer 

(co)polymers are marketed as 

dispersions, solid resins or solutions 

 ▼

Compounding 

handling of the (co)polymers, e.g. manufacture 

of ready-to-use products like paints, adhesives, 

textile finishing agents, etc. 

 ▼

---------------------------------------------------------------------------- 

End user

 manual end-user: e.g. painter man, floor layer, carpenter, etc. 

 industrial end-user: e.g. printer, manufacturer of finished film 

 ▼

Consumer

 e.g. painted walls, glued flooring, glued furniture, printed card, packed food, etc. 

The first three stages in the chain, i.e. manufacture of the monomer, polymerisation of 

(co)polymers, and compounding of (co)polymers are in most cases conducted by different 

companies and at separate locations. Notwithstanding, there is a small number of sites where 

both production of the monomer and further polymerizing is carried out, while there are other 

cases where VAM is (co)polymerized and subsequently also compounded. 
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Only a few manufacturers of VAM exist in the EU, whereas the number of companies 

polymerising the monomer and in particular the number of downstream users of the polymers 

is considerably higher. For example, there are no more than two VAM manufacturers in 

Germany that use parts of the produced VAM volume to manufacture vinyl acetate 

(co)polymers. Similarly, just six out of fifty-three European manufacturers of coating/printing 

inks manufacture the required polymer constituents from the monomer on-site. 

Production sites of VAM and facilities producing the (co)polymers, but also compounding 

operations are typical point sources of VAM emissions. Any VAM entering the environment 

from the latter type of operation results from releases of monomer residuals remaining with 

the processed (co)polymers. 

Finally, diffusive releases of residuals may occur during end-use of the finished products that 

contain vinyl acetate (co)polymer constituents. 

2.1.1 Production 

Vinyl acetate is produced by a catalytic vapour-phase reaction of ethylene and acetic acid in 

gas phase, liquid phase or a fluidised-bed process. 

2.1.1.1 Global production figures 

The worldwide demand for VAM reportedly amounted to 4.3 million t/a in 2003, representing 

an overall operating rate of about 86 % of a maximum global production capacity of 

5 million t/a. The main production capacities are located in Asia (43 %) and North America 

(34 %), followed by Western Europe on third rank (18 %) (Chemical Week, 2003). 

2.1.1.2 Production in Western Europe 

A questionnaire was launched by the European Chemical Industry Council (CEFIC) among 

member companies in 2000 and updated in 2002 to collect data on produced and processed 

volumes of vinyl acetate monomer in Europe. Five producers of VAM were identified with a 

nominal production capacity of 800,000 t/a (cf. Table 2-1). Fluctuating operating rates 

(additional capacities brought online, partly offset by shutting down other plants) make it 

difficult to provide a general figure for the annual production volume of VAM in the EU. 

For comparison, the production volume of VAM reported by the CEFIC Acetyls Sector 

Group (ASG) for Western Europe was about 715,000 tonnes in 2002. Additionally, total 

purchases1

 in 2002 accounted for almost 250,000 tonnes. Along with an opening stock2 of 

approximately 80,000 tonnes, the “total supply” for 2002 amounted to 1,045,000 tonnes. 

 

1

 Purchase from outside Western Europe but also from co-producers in Western Europe 

2

 Includes all product produced or purchased but not yet invoiced or transferred to internal captive use, e.g. 

product in storage or in transit (should be equal to the closing stock of the previous period). 
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14 CAS No.: 108-05-4 

From the total supply of about 1,045,000 tonnes, some unquantified amounts were exported 

outside Western Europe again (figures were not given by industry for confidentiality reasons). 

With an end stock3

 of less than 50,000 tonnes in 2002, approximately 750,000 tonnes of 

VAM were marketed in Western Europe that year (all figures provided by CEFIC ASG). 

The outcome of the CEFIC survey was in poor consistency with data retrieved from the 

IUCLID database (as of May 1999). A number of the companies included in the CEFIC 

survey were not covered by the IUCLID data - and vice versa. Several of the enterprises had 

discontinued to exist as a business entity, owing to an intensive restructuring process of the 

market (mergers, acquisitions and divestitures of business segments). In some cases it turned 

out that some IUCLID-mentioned capacities had been only sales bureaus, whereas other 

facilities had meanwhile been shut down. IUCLID data were therefore left aside. 

2.1.2 Processing 

Unlike for production, no exact figure of the processed volume of vinyl acetate can be 

extracted from the statistics provided by the CEFIC Acetyls Sector Group (ASG). The 

provided data is difficult to balance for import/export and purchases/sales as ASG statistics 

comprise all Western European countries, which does not coincide with EU countries, and 

some parts of the statistics are confidential, thus were not disclosed to the rapporteur. 

According to the CEFIC Acetyls Sector Group, the total supply of VAM in Western Europe 

was approximately 1,045,000 tonnes in 2002, based on a production volume of about 

715,000 t, total purchases of about 250,000 t and an opening stock of about 80,000 t. When 

exports, sales, captive use and closing stock are deducted, approximately 750,000 t entered 

the open market in Western Europe in 2002. From this tonnage, an unknown amount is sold to 

non-EU countries in Western Europe (Switzerland, Turkey, Iceland, Norway), with the 

remaining tonnage of VAM being sold and processed in the EU. Some amounts of the total 

VAM supply of 1,045,000 tonnes is directed to captive use4 and also processed in the EU, but 

figures on captive use are not provided. As sales to non-EU countries in Western Europe and 

captive use were not quantified, the exact processing volume in the EU cannot be determined. 

It is therefore assumed to be in the range of 750,000 – 800,000 tonnes per year. 

Responses to the CEFIC questionnaire came either from individual processors or industry 

associations of processing companies. One industry association (CEPE) did not provide 

information broken down to individual members or processing sites, but for reasons of 

confidentiality submitted aggregated, in part statistically evaluated data (max./min. values or 

average means) which were compiled from a questionnaire among member companies. In 

addition to the CEFIC data, other processing sites could be identified and consulted. Based on 

this data collection, the actual total processing volume of VAM may amount to 

474,900 tonnes per year in the EU (cf. Table 2-1). 

 

3

 Closing or end stock of the previous period. Includes all product produced or purchased but not yet invoiced or 

transferred to internal captive use, e.g. product in storage points or products in transit. 

4

 All product transferred internally in Western Europe whether from own production or purchased. 
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15 CAS No.: 108-05-4 

Figure 2-1 Market statistics of VAM for 2002, based on CEFIC Acetyls Sector Group. 

It has to be concluded that the data provided on production and processed volumes of VAM 

do not match very well: 

Based on single sites: Based on market statistics : 

Production 800,000 tonnes 715,000 tonnes 

Processing 474,900 tonnes 750,000 - 800,000 tonnes (estimate) 

This imbalance may be due to a number of reasons: 

 Figures on volumes were reported for different business years and reflect the 

dynamics of a market which is characterized by continuous restructuring activities 

 Some annual production data are based on nominal capacities, thus do not reflect 

actual figures which may change from year to year 

 Production figures are rounded to nearest 10,000 t/a 

 Downstream users did not reply to the questionnaire 

 Data are not corrected for import/export or sales/purchases 
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The maximal difference between reported production volume and specific processing data for 

individual sites is 325,000 t/a (= 800,000 t/a - 475,000 t/a). It is therefore assumed that a 

number of processing sites exist that were not covered by the CEFIC questionnaire. As no 

information on these sites is available, a generic risk characterization will be conducted. A 

fraction of main source of 0.15 and 300 emission days are assumed (Tab. B3.2 of the TDG) to 

estimate the fraction of the total emissions that is expected to be released through the main 

local point source (worst case scenario for the local environment). The estimated total 

emissions that are released during processing of the total volume of 325,000 t/a are included 

in the calculation of the regional and continental background concentrations.

Specific local risks were calculated for the production and processing sites that could be 

identified (cf. Table 2-1). In several cases it could not be clarified whether the term “use” in 

the questionnaire was interpreted by the responders as (co)polymerisation, or compounding of 

already polymerised material, or both. If not specified otherwise it was assumed that the data 

referred to (co)polymerisation, although this may overestimate emissions in some cases. For 

confidentiality reasons, sites were coded. Five producers of VAM were identified being 

located in four EU member states (France, Germany, Spain and UK). Identified processing 

plants are located in Belgium, Denmark, Finland, France, Italy, Germany, the Netherlands, 

Spain and UK. No information on geographical locations was disclosed by industry 

associations that provided only aggregated data.

Table 2-1: Production and/or processed volumes of VAM identified within the EU 

Site code Produced volumes Processed volumes Data source 

1 30,000 CEFIC 

2 10,000 CEFIC 

3a 6,000 CEFIC/CIRFS 

3b 10,000 CEFIC/CIRFS 

3c 8,000 CEFIC/CIRFS 

3d 4,000 CEFIC/CIRFS 

4 110,000 CEFIC 

5 90,000 CEFIC 

6 25,000 CEFIC 

7* 10,810 CEPE 

8 15,000 CEFIC 

9 9,100 CEFIC 

10 15,000 CEFIC 

11 110,000 CEFIC 

12 36,000 CEFIC 

13 280 CEFIC 

14 2,000 CEFIC/FEICA 
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Site code Produced volumes Processed volumes Data source 

15 2,200 CEFIC/FEICA 

16 400 CEFIC/FEICA 

17 300 CEFIC/FEICA 

18 14,000 CEFIC/FEICA 

19 25,000 CEFIC/FEICA 

20** 0 0 CEFIC/FEICA 

21 200,000 CEFIC 

22 100,000 CEFIC 

23 17,000 CEFIC 

24 5,000 pers. communicated 

25 6,910 pers. communicated 

26 140,000 pers. communicated 

27 250,000 pers. communicated 

28 8,000 pers. communicated 

29 6,500 pers. communicated 

30 8,400 pers. communicated 

∑ 800,000 474,900

CEFIC: European Chemical Industry Council 

CEPE: Conseil Européen des Industries des Peintures, Encres d’Imprimerie et Couleurs d’Art 

CIRFS: Comité International de la Rayonne et des Fibres Synthetiques 

FEICA: Fédération Européenne des Industries de Colles et Adhésifs 

* As communicated by industry association CEPE, most manufacturers buy polymer emulsions (PVA) ready 

for use and do not polymerise VAM themselves: 52 companies reported in a questionnaire to use PVA at 116 

different sites for making printing inks, paintings and coatings. The total volume of VAM polymers was 

43,524 t in 2000. The processing volume in the table refers to the two companies still polymerising VAM. 

** confirmation of conducting merely compounding operations, i.e. handling of the (co)polymers.

2.2 USES 

Vinyl acetate monomer is solely used as an intermediate in chemical industry for 

manufacturing (polymerisation) of vinyl acetate (co)polymers (IC 3 / UC 33). Hence it is 

concluded that the entire production volume of VAM is used up for the manufacture of 

various (co)polymers, mainly polyvinyl acetate. 

Apart from manufacture of homopolymers the monomer is combined with other monomers 

like ethylene, vinyl chloride and acrylic acid esters to form various types of co-polymers. 

According to the Directory of Chemical Producers Western Europe (SRI International, 

1997/98) two types of co-polymers involving ethylene are produced: 
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18 CAS No.: 108-05-4 

A. ethylene-vinyl acetate co-polymer resins (EVA) with a production capacity of 

approximately 1 million t/a, and 

B. vinyl acetate-ethylene co-polymer resins (VAE) with a production capacity of 

approximately 300,000 t/a. 

Polymers manufactured from VAM are used in a broad spectrum of products, including 

water-based paints, printing inks, lacquer, ceramic, adhesives for packaging and construction, 

paper finishing, and protective colloids for various materials. Other important products 

include textile fibres, paper coating and inks (Table 2-2). The content of residual VAM in 

homo- and co-polymers depends on the product, spanning a wide range of reported values of 

less than 5 ppm up to 6,000 ppm (Celanese, 2000). According to the CEFIC compilation of 

data from industry, the majority of polymers have an average content of around 1,000 - 2,000 

ppm or less. Ullmann (1998) provides a quantitatively weighted median value for the 

monomer content of roughly 3,000 ppm. The latter value will be used for estimating diffuse 

releases of VAM from (co)polymers and end-use products in this document. 

In addition, vinyl acetate (co)polymers are used as feedstock for manufacture of vinyl alcohol 

(co)polymers (e.g. polyvinyl alcohol). Polyvinyl alcohol is obtained by hydrolysing polyvinyl 

acetate. The production capacity within the EU is reported at > 100,000 t/a (SRI International, 

1997/98). Commercial grades of polyvinyl alcohol differ in the degree of polymerisation 

(molecular mass) and degree of hydrolysis (residual polyvinyl acetate content). Along with 

saponification (alkaline hydrolysis of fatty acid esters) of the acetyl moieties of polyvinyl 

acetate, monomer residuals are getting eliminated as well. A minor fraction of polyvinyl 

alcohol ends up in the manufacture of polyvinyl acetales, e.g. of polyvinyl butyral (PVB). 

A broad quantitative breakdown of the use pattern of vinyl acetate is available for Germany 

for 1990. In this year, approximately 68 % of the produced vinyl acetate was used mainly for 

the manufacturing of polyvinyl acetate and, to a less extent, for the manufacturing of 

copolymers. 32 % of the produced vinyl acetate was manufactured to polyvinyl alcohol 

(BUA, 1993). Vinyl acetate occurs as residual monomer in homo- and copolymers based on 

vinyl acetate and in products or formulations based on these polymers. As polyvinyl alcohol 

is produced by trans esterfication (saponification) of vinyl acetate (co)polymers, residual 

vinyl acetate monomer does not occur in polyvinyl alcohol and in polymers derived from 

polyvinyl alcohol (Celanese, 2000). Hence the manufacturing of polyvinyl alcohol is not 

relevant in the context of residual monomer content. 

Use pattern of vinyl acetate: 

Main category Industry category Use category 

Non dispersive use Chemical industry: 

used in synthesis 

(IC 3) 

Intermediate: monomer in the production 

of polyvinyl acetate (UC 33) 
19 

Table 2-2: Vinyl acetate in the value chain: (co)polymers are used in a wide spectrum of products (Wacker Chemie

material 

Building 

ink 

Printing 

Paint 

Film 

Lacquer 

Adhesive 

VAM + VAM Æ polyvinyl acetate x x x x x VAM + acrylate Æ vinyl acrylic co-polymer x x VAM + ethylene Æ EVA x x VAM + ethylene Æ VAE x x x VAM + vinyl chloride Æ VC copolymer x x x VAM + carbonic acid Æ VA carbonic acid copolymer VAM + vinyl ester Æ VA vinyl ester copolymer x x 
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3 ENVIRONMENT 

See separate rar. 
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4 HUMAN HEALTH 

4.1 HUMAN HEALTH (TOXICITY) 

4.1.1 Exposure assessment 

4.1.1.1 General discussion 

Vinyl acetate is a monomer, solely used to manufacture vinyl acetate (co)polymers. For 

production volumes see section 2. 

A quantitative breakdown of the use pattern is available for Germany, where in 1990 app. 

68 % of the produced vinyl acetate was mainly used for the production of polyvinyl acetate 

and, to a less extent, for the production of copolymers. 32 % of the produced vinyl acetate 

was manufactured to polyvinyl alcohol (BUA, 1993). 

Vinyl acetate occurs as residual monomer in homo- and copolymers based on vinyl acetate 

and in products / formulations based on these polymers. As polyvinyl alcohol is produced by 

trans-esterfication (saponification) of vinyl acetate (co)polymers, residual vinyl acetate 

monomer does not occur in polyvinyl alcohol and in polymers derived from polyvinyl alcohol 

(Celanese, 2000). 

The content of residual vinyl acetate monomer in homo- and copolymers depends on the 

product and the field of application (< 2 - 3000 ppm, Celanese, 2008). The quantitatively 

weighted median value of this content amounts to 3000 ppm (Ullmann, 1998). 

Polymers based on vinyl acetate are ingredients of a variety of products, which are applied in 

e.g. adhesives, paints, fillers, coating materials, plasters and primers for porous building 

materials in the construction industry and in finishing agents (Ullmann, 1998). 

For workers exposure to vinyl acetate occurs primarily via inhalation of the vapour and by 

immediate dermal contact with the substance. 

There is no direct consumer use of vinyl acetate monomer. However, consumer exposure may 

result from the use of polymerized vinyl acetate products containing very small amounts of 

residual monomer such as binders and additives for paints and plasters, glues (e.g. for carpets 

or structural members), and coatings. 

Among 42 products listed in the Swedish product register which contain vinyl acetate, 6 

products were found to be used by consumers. In the Norwegian product register, 15 products 

which contain vinyl acetate have been listed for use in the consumer field. 

In the Federal Republic of Germany, products containing polyvinyl acetate in which vinyl 

acetate may be present as a residual monomer are used in the consumer field. Thus, the 

consumer may be exposed to vinyl acetate; the exposure may take place via the inhalation, 

dermal and oral routes. 
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Vinyl acetate may be released to the environment, principally to the atmosphere, as a result of 

emissions from manufacturing, processing, and storage facilities. The short atmospheric halflife, the rapid hydrolysis in water, the low n-octanol/water partition coefficient, and the ability 

of biological fluids of mammals and other organisms to degrade vinyl acetate will lead to 

rapid removal. Little or no vinyl acetate is detected in environmental samples, including those 

from hazardous waste sites (VATG, 1994). 

4.1.1.2 Occupational exposure 

The exposure assessment generally aims at assessing exposure levels representing the 

reasonable worst case situation. The reasonable worst case is regarded as the level of 

exposure which is exceeded in a small percentage of cases over the whole spectrum of likely 

circumstances of use for a specific scenario. For scenarios with the reasonable worst case 

estimates leading to a risk, in addition, typical values are assessed, if the necessary 

information is available. The typical exposure is an estimate of the approximate location of 

the median levels of exposure over the whole spectrum of likely circumstance. The 

combination of both levels gives an impression on the distribution of the exposure levels for a 

specific scenario and might serve as an extended basis for a comprehensive risk 

characterisation and for the discussion of risk reduction measures. 

The assessment of inhalation exposure is mainly based on measured exposure levels from 

which – if possible – 90th percentiles are derived as representing reasonable worst case 

situations. For the purpose of exposure assessment only data measured later than 1990, if 

available, are taken. Scenarios are clustered as far as possible to make the description 

transparent. 

Beside inhalation exposure, dermal exposure is assessed for each scenario. Two terms can be 

used to describe dermal exposure: 

Potential dermal exposure is an estimate of the amount of a substance landing on the outside 

of work wear and on the exposed skin. 

Actual dermal exposure is an estimate of the amount of a substance actually reaching the skin. 

There is an agreement between the EU-memberstates, within the framework of existing 

substance, to assess - as a rule - dermal exposure as exposure to hands and parts of the 

forearms. In this, the main difference between both terms – potential and actual - is the 

protection of hands and forearms by work wear and – more important – the protection by 

gloves. Within this exposure assessment, the exposure reducing effect achievable by gloves is 

only considered if information is provided, that for a certain scenario gloves are a widely 

accepted protective measure and that the gloves are fundamentally suitable for protection 

against the substance under consideration. As a measure for the latter, tests according to DIN 

EN 374 are taken as a criteria. For most down stream uses it is commonly known, that gloves 

are not generally worn. In these cases, dermal exposure is assessed as actual dermal exposure 

for the unprotected worker. Since often quantitative information on dermal exposure is 

available, the EASE model is used for assessing dermal exposure, at the most. 

Industrial activities involving monomeric vinyl acetate present opportunities for exposure. 

Exposure ranges depend on the particular operation and the risk reduction measures in use. 

The following occupational exposure limits (OEL) and short term limits (STEL) apply in the 

EU and the USA: 
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Table 4.1.1.2.: Occupational exposure levels (EU, USA) 

Country OEL STEL Source 

Finland 36 mg/m3 (10 ml/m3) 71 mg/m3 (20 ml/m3) FIN, 2007 

Austria, Greece 36 mg/m3 (10 ml/m3) 70 mg/m3 (20 ml/m3) A, 2007, GR 2001 

Belgium, Spain 36 mg/m3 (10 ml/m3) 54 mg/m3 (15 ml/m3) B 2007, SP 2008 

USA: ACGIH, 

Italy, Portugal 

35 mg/m3 (10 ml/m3) 53 mg/m3 (10 ml/m3) USA, 2008, I, 

2008, POR, 2004 

Ireland 30 mg/m3 (10 ml/m3) 60 mg/m3 (20 ml/m3) IRL, 2007 

Denmark, France, 

Norway 

30 mg/m3 (10 ml/m3) - DK, 2007, F, 

2008, NO, 2007 

Sweden 18 mg/m3 (5 ml/m3) 35 mg/m3 (10 ml/m3) S, 2007 

Germany, The 

Netherlands 

18 mg/m3 (5 ml/m3) - GER, 2007, NL, 

2007 

Occupational exposure to vinyl acetate may occur in the following areas: 

- production of vinyl acetate and polymerisation in the chemical industry (scenario 1), 

- manufacturing of formulations and products (scenario 2), 

- use of formulations and products containing residual vinyl acetate (scenario 3). 

For the manifold uses of vinyl acetate (co)polymers with residual vinyl acetate monomer 

content < 2 – 3000 ppm, low levels of exposure are to be expected. In spite of this, on account 

of the carcinogenic effect of vinyl acetate, these scenarios are included in the occupational 

exposure assessment. Due to hydrolysis of vinyl acetate monomer, a further decrease of the 

residual monomer content occurs. 

Exposure during the skilled trade use of hair care products (3 w/w vinyl acetate copolymer) 

and car polishing products (1.5 w/w vinyl acetate copolymer) are regarded to be of minor 

relevance since the monomer concentration is approx. 100 times below the polymer 

concentration. Therefore these scenarios are not included in this occupational exposure 

assessment. 

4.1.1.2.1 Production of vinyl acetate and polymerisation in the chemical industry 

 (scenario 1) 

Vinyl acetate is produced by a vapour phase reaction between ethylene and acetic acid in the 

presence of a palladium catalyst or between acetylene and acetic acid in the presence of a zinc 

acetate catalyst (Zenz and Cordaso, 1994). The substance is manufactured continuously in 

closed systems at increased temperature and high pressure. It is to be assumed that the 

substance is processed daily. Consequently the duration and frequency of exposure are 

assumed to be daily and for the entire length of the shift. According to information provided 
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24 CAS No.: 108-05-4 

by one producer, filling devices are equipped with local exhaust systems and, for the purpose 

of dispatch, vinyl acetate is filled into tank cars by means of a gas displacement device. 

Vinyl acetate is used primarily to produce polymers like polyvinyl acetate, polyvinyl alcohol 

(via transesterification (saponification) of polyvinyl acetate), and a variety of copolymers. 

According to information provided by the producers, the polymerisation process takes place 

discontinuously or continuously in a closed system (Celanese, 2000). These polymers, usually 

formed as emulsions, suspensions, solutions, or resins are used to prepare different products e. 

g. adhesives, paints, paper coatings and textile finishing agents (Zenz and Cordaso, 1994). In 

part, the further processing is performed immediately after production, so that transfer or 

filling activities are avoided to a large extent. 

The other main use of vinyl acetate is the production of polyvinyl alcohol being also 

performed in closed systems. Residual vinyl acetate monomer does not occur in polyvinyl 

alcohol and in polymers derived from polyvinyl alcohol (Celanese, 2000). 

Since vinyl acetate is highly flammable it is to be expected, that high exposure levels at the 

workplace are avoided. For the large-scale chemical industry high standards of control at the 

workplaces are assumed to be practised even if the containment is breached. According the 

information provided by the companies, exposure is possible during sampling, maintenance, 

transfer, charging of catalysts, filter changing, drumming and cleaning. Inhalation exposure in 

other areas is normally minimised by technical equipment (e.g. special designed filling 

stations, local exhaust ventilation). 

Workers normally use PPE (gloves, eye glasses) and, during cleaning activities, respiratory 

protection in addition (Celanese, 2000). 
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Inhalation Exposure 

Workplace measurements 

Table 4.1.1.2.1: Vinyl acetate exposures at workplaces in the chemical industry during 

production and polymerisation 

Job category / 

activities 

Year of 

measurement 

Number 

of samples

Range of 

measurement 

data [mg/m3] 

Geometric 

mean 

[mg/m3] 

95thpercentile 

[mg/m3] 

Duration 

and 

frequency 

8-h time weighted average

Production 

maintenance 

sampling, loading 

production 

1992 

- 

since 1978 

2 

6/year 

(p) 

3/year 

< 1.8 – 3.5 

0.2 – 1.4 

< 17.8 

- 

- 

- 

- 

- 

- 

- 

- 

- 

Polymerisation since 1994 

1997 –1999 

1994 – 1999 

1994 – 1999 

1995 – 2000 

427 

20 (s) 

265 (p) 

38 (p) 

5 

0 – 22.9 

0.007 – 4.5 

<0.006 – 11 

<0.004 – 2.4 

2.6 

0.2 

0.1 

<0.03 

<0.03 

- 

2.6 

2.9 

0.4 

2 

- 

- 

- 

- 

- 

- 

Polyvinyl alcohol 

production

- 2/year 

(p) 

0.2 – 1.4 - - 

 

Short term values

Production 

Maintenance 1997 2 < 2 – 3.9 - - -

p: personal sampling; s: stationary sampling

For the purpose of measuring vinyl acetate in the air at the workplace, the substance is 

adsorbed to activated charcoal and then desorbed using carbon disulphide and determinated 

gas-chromatographically. The detection limit of the method amounts to 0.09 mg/m3 

(sampling volume: 25 l) (BASF AG, 1999). 

Due to the measurement method and the sampling strategy which were applied, the currently 

available measurement results (Table 4.1.1.2.1.) are regarded as valid. 

Three producers provide information on the collective of exposed workers: 35 – 40 workers. 

From the descriptions it is concluded that the exposure scenarios relating to the production 

and the polymerisation of vinyl acetate can be clustered. The collectives of measurement 

results comprise exposure levels from 0 – 22.9 mg/m3 with four 95th percentiles up to 

2.9 mg/m3. From the data given in table 4.1.1.2.1 regarding production and polymerisation, 
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26 CAS No.: 108-05-4 

3.0 mg/m3 (based on 95th percentile of 2.9, round off) is derived as the reasonable worst case 

of inhalation exposure in the chemical industry. 

Conclusions 

For the assessment of risks of inhalation exposure to vinyl acetate during the production and 

polymerisation in areas with high levels of protection belonging to the chemical industry an 

8-h time weighed average concentration (8-h TWA) of 3.0 mg/m3 (95th percentile, round off) 

should be taken to represent a reasonable worst case situation. 

 

Dermal exposure 

When producing and polymerising vinyl acetate dermal exposure could occur during 

activities like drumming, sampling, cleaning, maintenance and repair work. For the 

unprotected worker, according to the EASE model, potential dermal exposure is assessed as 

follows: 

 Input parameters: Non dispersive use, direct handling, intermittent 

 Level of exposure: 0.1 – 1 mg/cm2

/day. 

Considering an exposed area of 420 cm2 (palms of hands) the model yields an exposure level 

of 42 - 420 mg/person/day. 

For assessing actual dermal exposure levels, it has to be considered that the substance is 

manufactured and further processed primarily in closed systems and that the use of PPE (here 

gloves and eye protection) during exposure relevant activities is highly accepted in the largescale chemical industry. The extent of protection by PPE (here gloves) depends inter alia on 

the suitability of the recommended material with regard to the permeation properties of 

substance. 

According to information provided by the manufacturers, in case of vinyl acetate, suitable 

gloves (tested according EN 374) are worn. Further information shows that the permeation 

time of the recommended gloves is longer than normal operation activities length (vinyl 

acetate handling is less then 30 minutes per shift). Apart from this the gloves ought to be 

changed immediately by extensive contamination with vinyl acetate. 

The exposure assessment is made based on the assumption, that a vast majority of workers 

belonging to scenario 1 are protected by suitable gloves. However, in spite of this, dermal 

exposure may occur due to e. g. 

- unintended contamination during the handling of used gloves, 

- limited protection of suitable gloves at real working conditions (e. g. mechanical stress). 

As a rule, for the use of suitable gloves, low levels of daily dermal exposure are to be 

expected. Since no measurement results are available, a protection efficiency of 90 % is taken 

as a default value leading to an exposure level of 42 mg/person/day. 
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Besides in the case of vinyl acetate, the predominant effect reducing potential dermal 

exposure is the very high volatility of the substance (vapour pressure 12 kPa) which leads to 

considerable low retention times of the substance on the skin or on the protective gloves. This 

exposure reducing effect cannot be considered if workers have continuous direct contact with 

the substance, e.g. dipping hands into the substance. For using vinyl acetate as a chemical 

intermediate, this situation (occlusive exposure) is regarded to be rather non-probable. 

Furthermore, it is assumed, that non-occlusive exposure is the predominant exposure 

situation. In annex 1, the calculation of the evaporation time of the pure substance is 

described. For vinyl acetate with the EASE estimate of 1 mg/cm2, an evaporation time of 10 

second (T = 30°C) is calculated. For vinyl acetate on the gloves, an assumed temperature of 

20°C leads to a similar evaporation time. This values should be regarded to represent the 

order of magnitude, since it is not known in how far the interaction of the skin with the 

substance influences the evaporation time. 

In conclusion, the short retention time of vinyl acetate on the skin leads to considerably lower 

dermal exposures than predicted by the EASE model which considers dermal exposure during 

the whole shift (0 – 42 mg/person/day). 

Conclusions 

For assessing the health risks from daily dermal exposure in the area of production and 

polymerisation (scenario 1), an exposure level of 0 – 42 mg/person/day should be taken. The 

higher level is regarded to represent the reasonable worst case situation. This exposure 

assessment is based on the information provided by the producers, that suitable gloves are 

worn and takes into account the possible dermal exposure under actual workplace conditions. 

On account of the high vapour pressure of vinyl acetate, the resulting retention time of the 

substance on the gloves or the skin is shortened and lower levels of dermal exposure than the 

estimated one are to be expected. 

Exposure to the eyes is largely avoided by using eye protection. 

4.1.1.2.2 Manufacturing of formulations and products (scenario 2) 

According to information provided by industry there is normally no direct use of vinyl acetate 

monomer in formulating facilities and exposure is limited to the use of vinyl acetate 

(co)polymers containing small amounts of residual monomer. Vinyl acetate monomer itself is 

not used in formulations. However, some adhesive producing facilities use vinyl acetate 

monomer for (co)polymerisation and perform the adhesive formulation subsequently. 

Therefore, this exposure scenario comprises the polymerisation step (use of vinyl acetate 

monomer) and the formulation step (residual vinyl acetate in (co)polymers). 

The content of residual vinyl acetate monomer is < 2 - 3000 ppm in the different 

(co)polymers. It depends on the further application of the (co)polymer. During the further 

processing of the (co)polymers, residual monomer may be released. The content of residual 

vinyl acetate monomer in water-based systems decreases by hydrolysis (BUA, 1993). 
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Formulations and products based on vinyl acetate (co)polymers like adhesives and paints 

contain < 2 - 3000 ppm residual vinyl acetate monomer, which normally evaporates when 

applied by the end user. 

The processing to various products (formulation e.g. adhesives, paints) may not be limited to 

the large-scale chemical industry but occurs in small and medium-sized chemical companies, 

too. For this case, in principle, it cannot be excluded that, in addition to the level of technical 

protection described for the large scale industry, open systems without local exhaust 

ventilation are used (Voullaire and Kliemt, 1995). According to this scenario, higher 

inhalative and, as a result of the non regular use of gloves, higher dermal exposures are 

expected if vinyl acetate (co)polymers and compounds are handled, e.g. during filling, 

sampling, charging, cleaning, maintenance and repair works. Vinyl acetate monomer is 

normally handled in closed systems, but some tasks, e.g. pumping and filling, are performed 

using the monomer. 

Inhalation exposure 

Workplace measurements 

Measurement data is only available from the adhesive production. 
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Table 4.1.1.2.2: Vinyl acetate exposures at workplaces for adhesives production 

Job category / activities Years of 

measurement 

Number of 

samples 

Range of 

measurement 

data [mg/m3]

50th

percentile 

[mg/m3] 

90th

percentile 

[mg/m3] 

Adhesives production 

Formulation 

(FEICA, 2001) 

(no information on sampling 

and duration of sampling) 

1997 – 2000 

1995 – 2000 

1996, 2000 

1998, 1999 

1995 

60 

100 

2 

- 

1 

0.07 – 32 

10.3 – 14.6 

1.8 - 3.9 

3.2 – 46 

3.1 

3.9 

12.5 

- 

- 

- 

- 

- 

- 

Pumping of monomer vinyl 

acetate into tank 

Preparation of pre-emulsion 

Pumping of pre-emulsion 

into reactor 

1998, 1999 

1998, 1999 

1998, 1999 

- 

- 

- 

39 – 46.8 

(30 min) 

< 3.6 

(90 min) 

18 

(60 min) 

- 

- 

- 

- 

- 

- 

8 h time weighed averages 

Filling, cleaning, opening of 

reaction vessels 

(BGAA, 1996 and BG 

Chemie 2002) 

1990 – 1995 

1996 – 2002 

10 (p) 

23 

< 64 

- 

6 

3.1 

56 

14.6 

p: personal sampling

According to information provided by the adhesive producers 2 – 70 workers are exposed. 

Most of the data given in table 4.1.1.2.2 cannot be regarded as shift averages but - with some 

restrictions as exposure during activities, which do not last the whole shift. 

The data regarding adhesives production (table 4.1.1.2.2) shows one measurement collective 

with results from 10.3 - 14.6 mg/m3 and a 50th percentile of 12.5 mg/m3. But there are also 

measurement collectives with wide ranges from 3.2 mg/m3 to 47 mg/m3

. The sampling 

durations are in part given as 30 min – 60 min. Calculated shift averages thus amount to 2 – 

3 mg/m3. The highest measured result was obtained during pumping vinyl acetate monomer 

into a monomer tank. 
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Measurement results from workplaces in the adhesives industry with partly lower level of 

protection obtained during filling, cleaning and opening of reaction vessels were provided by 

the German Employer’s Accident Liability Insurance Association (BGAA, 1996 and BG 

Chemie 2002,, c.f. table 4.1.1.2.2). It can be seen, that measurement data obtained 1996 – 

2002 are considerably lower than those obtained 1990 – 1995. The 90th percentile of 

56 mg/m3 is reduced to 14.6 mg/m3. It is described that the two highest results (56 mg/m3 and 

64 mg/m3, 1990-1995) were obtained during polymerisation of monomer vinyl acetate, in 

part with not sufficient control measures in place. If necessary, the situation has been changed 

by the companies. BGAA states, that the old data were in part worst case measurements. 

Taking into accpunt, that the new data were obtained in 10 companies, they can be regarded 

as representative for the exposure situation. 

Workplace measurements obtained during the manufacture of polymer dispersions in 

adhesive production facilities have been submitted by the Federal Monitoring Authorities in 

Germany for the period 1990 – 1993. Air measurements revealed concentrations between 

< 0.1 – 40mg/m3 (n = 10, personal sampling) with a mean value of 22 mg/m3. A higher value 

of 70 mg/m3

 was obtained with stationary sampling. The second highest value amounts to 

40 mg/m3. The workplaces were only partially equipped with local exhaust ventilation. Since 

only limited information is available on the results, the measurement results are not included 

in table 4.1.1.2.2. 

Taking into account the short term exposures of up to 46.8 mg/m3, the shift averaged given by 

BGAA seems to be quite plausible. Based on the available measurement results, 14.6 mg/m3 

(90th percentile of a collective of measured results) is regarded to represent a reasonable worst 

case situation in the adhesive production industry. In addition, a short term exposure level of 

47 mg/m3 should be taken for assessing the risks of daily inhalation exposure. 

Conclusions 

At present, the information on exposure levels in the formulation industry is limited. 

Measurement results are available from the adhesive production only. This fact might indicate 

that exposure levels are at highest in this industrial sector and possibly lower in the 

formulation of paints. However, the available information cannot be seen as a proof for this 

assumption. 

The available exposure levels indicate that exposure up to 46 mg/m3 (see table 4.1.1.2.2) 

(maximum value 70 mg/m3, see text on data from the Federal Monitoring Authorities) occurs. 

The high exposure level indicates that monomeric vinyl acetate is handled in the adhesive 

producing companies (polymerisation step). 

For assessment of the health risks from daily inhalation exposure to vinyl acetate during the 

formulation of products (here: adhesives), an 8-h time weighed average concentration (8-h 

TWA) of 14.6 mg/m3 (90th percentile of a measurement collective) should be taken to 

represent a reasonable worst case situation. It should be noted that considerably lower 

exposure levels are to be expected if only the formulating step is performed (no handling of 

monomer vinyl acetate). 
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Short term exposures up to 47 mg/m3 (duration 30 min) obtained during the handling of vinyl 

acetate monomer, e.g. pumping into storage tanks, should be taken into account. 

 

Dermal exposure 

According to the description given above, the use of vinyl acetate monomer (polymerisation 

step) is regarded to represent the reasonable worst case situation. The exposure level 

estimated for handling (co)polymers with residual monomer (formulation step) is appropriate 

for the typical exposure. 

For the handling of vinyl acetate monomer as well as (co)polymer (residual monomer: < 3000 

ppm) during the compounding of formulations and products (e.g. adhesives) in small and 

medium-sized chemical enterprises it cannot be excluded that gloves and eye protection are 

not regularly worn and that both, immediate dermal contact and exposure to eyes caused by 

hand-eye-contacts occur. Dermal exposure is assessed for the unprotected worker using the 

EASE model: 

 Input parameters: non-dispersive use, direct handling, intermittent 

 Exposure levels: 0.1 – 1 mg/cm2

/day 

If vinyl acetate monomer is used (polymerisation step), dermal exposure amounts to 42 – 420 

mg/person/day. The upper value is regarded to represent the reasonable worst case situation. 

For vinyl acetate with the EASE estimate of 1 mg/cm2, an evaporation time of 10 second (T = 

30°C) is calculated. For vinyl acetate on the gloves, an assumed temperature of 20°C leads to 

a similar evaporation time. 

Taking into account the content of residual vinyl acetate monomer of < 3000 ppm in the vinyl 

acetate (co)polymer, the estimated level of dermal exposure reduces to < 0.0003 - < 0.003 

mg/cm2/day (formulation step). Considering an exposed area of 420 cm2 (palms of two 

hands), dermal exposure amounts to 0.13 – 1.3 mg/person/day. For the assessment of the 

health risks, the upper value should be taken. On account of the high vapour pressure of vinyl 

acetate (12 kPa) and the resulting short retention time on the skin, lower levels of dermal 

exposure than the estimated ones are to be excepted. 

4.1.1.2.3 Use of formulations and products containing residual monomeric vinyl 

 acetate (scenario 3) 

There is no direct use of vinyl acetate monomer. However, exposure may result from the use 

of formulations and products like paints and plasters, glues (e.g. for carpets or structural 

members), and coatings, which are based on vinyl acetate (co)polymers containing small 

amounts of residual monomer. Formulations and products based on vinyl acetate 

(co)polymers like adhesives and paints contain < 2 - 3000 ppm residual vinyl acetate, which 

normally evaporates when applied by the end user. Due to hydrolysis of the residual 

monomer, its content might be reduced. 
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The main uses of polyvinyl acetate and vinyl acetate copolymers are applications in polymer 

dispersions. Homopolymer and copolymer dispersions are important binders for indoor and 

outdoor paints, special coatings, and textile finishing agents. Dispersions are used for plasters 

and water-thinable adhesives. Special types are applied in wood paints as well as in coatings 

for paper and cardboard, in adhesives and textile finishing agents (Ullmann, 1998). 

Quantitatively less important than polyvinyl acetate dispersions are solid resins which are 

used as binders in paints for paper, cardboard, wood, leather, certain plastics and in 

impregnation coatings. Vinyl acetate (co)polymers are an extremely important raw material in 

the adhesives industry. Copolymerisation of vinyl acetate with other monomers allows 

specific improvement of certain properties. These copolymers are used in heat-sealable 

finishes on paper, cardboard and aluminium foil, as a raw material for wash-off adhesives, 

textile finishing agents and marking inks (Ullmann, 1998). 

Inhalation and dermal exposure to traces of residual monomer is possible during a variety of 

activities depending on the product in use, e. g. charging, mixing and coating work as well as 

cleaning work. As a worst case it is assumed that these works are performed daily during the 

whole shift. 

Inhalation exposure 

Workplace measurements 

Workplace measurements obtained during the use of vinyl acetate products have been 

submitted by German Employer’s Accident Liability Insurance Association for the period 

1990 - 1995 (BGAA 1996). 

Table 4.1.1.2.3: Vinyl acetate exposures at different workplaces (BGAA 1996) 

Job category / 

activities 

Years of 

measurement 

Number of 

samples 

Range of 

measurement 

data [mg/m3] 

Geometric 

mean 

[mg/m3] 

95th

percentile 

[mg/m3] 

Duration 

and 

frequency 

8-h time weighted average

Wood working 

industry (hot melting 

glues) 

1990 - 1995 162 - 1 2 - 

Coating works 

(painting) 

1990 - 1995 28 - 1 1 - 

Air emission of residual vinyl acetate monomer during gluing of a carpet in a closed room 

with a glue containing 20-30 w/w polymer dispersion has been detected as 2.6 mg/m3 (0.7 

ml/m3

) (Hoechst AG, 1993a). Based on the conditions of exposure (closed room, limited 

ventilation) this value is regarded to represent a worst case situation. 
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FIN provided data from silk screen printing (0.18 mg/m3) and paper cardboard coating, paste 

mixing and coating (6 ± 7.7 mg/m3). Since no further information is available, this data 

cannot be considered in exposure assessment. 

 

Conclusions 

Because of the low residual monomer content in formulations, on the average 3000 ppm, low 

inhalation exposure levels are to be expected. This is confirmed by the available measurement 

results. For the area of the application of products (e.g. adhesives, paints) on the basis of 

polymeric vinyl acetate 2.6 mg/m3 (determined during air emission monitoring) should be 

taken as a worst case for assessing the risk of inhalation exposure. 

Dermal exposure 

For the handling of various polyvinyl acetate products in industrial and skilled trade areas it 

cannot be excluded that gloves are not regularly worn and that immediate dermal contact 

occurs (Voullaire and Kliemt 1995). Since detailed information on the possible activities are 

missing, for a rough estimation, dermal exposure is assessed with the EASE model using the 

category “wide dispersive use“: 

 Input parameters: wide dispersive use, direct handling, intermittent 

 Exposure level: 1 - 5 mg/cm2

/day. 

Taking into account the content of residual vinyl acetate monomer of < 2 – 3000 ppm in the 

different products, the estimated level of dermal exposure reduces to < 0.003 - < 0.015 

mg/cm2

/day. Considering an exposed area of 840 cm2 (both hands, worst case), dermal 

exposure amounts to 2.5 – 12.6 mg/person/day. The higher value is regarded to represent the 

reasonable worst case. It is to be assumed, that the content of residual monomer in the 

dispersions is decreased by chemical reactions of vinyl acetate, e.g. further polymerisation or 

hydrolysis. In addition, dermal exposure may be lowered by the evaporation of the substances 

(vapour pressure: 12 kPa). 

4.1.1.2.4 Summary 

Based on the available information, the exposure assessment reveals that handling the 

monomeric substance in the areas of production and polymerisation, the formulation of 

adhesives as well as the use of formulations, especially of adhesives, are the main source for 

occupational exposure. Direct uses of the substance other than polymerisation are not known. 

Applications of the manifold products containing vinyl acetate in traces as residual monomer, 

e.g. adhesives, coating materials and paints, are regarded to be of minor relevance. 

The relevant inhalation and dermal exposure levels are given in tables 4.1.1.2.4 A and 

4.1.1.2.4 B, respectively. 
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For the large-scale chemical industry, it is assumed that the production and polymerisation of 

vinyl acetate is mainly performed in closed systems with high levels of protection. Exposure 

occurs if the closed systems are breached for certain activities e. g. filling, cleaning and 

sampling in the area of manufacturing and polymerising of vinyl acetate monomer (scenario 

1). Dermal exposure is assessed using the EASE model (scenario 1). In addition, the high 

vapour pressure of vinyl acetate is taken into account as an exposure reducing effect. 

According to information provided by industry, there is normally no use of vinyl acetate 

monomer in formulating facilities and exposure is limited to the use of vinyl acetate 

(co)polymers containing < 2 – 3000 ppm residual monomer. However, some adhesive 

producing facilities use vinyl acetate monomer for (co)polymerisation and perform the 

formulation subsequently. Therefore, this exposure scenario comprises the polymerisation 

step (vinyl acetate monomer) and the formulation step (use of residual vinyl acetate in 

(co)polymers). Generally, in formulating facilities different levels of protection are realised. 

In part, processes like filling and mixing are performed in open systems. 

Measurement results are available from formulating adhesives only (scenario 2). This fact 

might indicate, that exposure to vinyl acetate at other formulating processes. e.g. of paints, is 

lower. The available exposure levels reveal that exposure of 47 mg/m3 vinyl acetate occurs. 

On the background of the information that normally only vinyl acetate (co)polymer is used, 

these high levels are non-plausible. At present it is assumed, that the high levels relate to the 

use of vinyl acetate monomer (polymerisation step). If no monomer is handled and a company 

uses only vinyl acetate (co)polymers (formulation step), exposure is expected to be 

considerably lower. 

The widespread industrial and skilled-trade applications of polymeric dispersions and solid 

resins containing residual vinyl acetate monomer (< 2 – 3000 ppm) comprise uses in paints, 

lacquers, adhesives, plasters and coating materials (see chapter 4.1.1.2.3). In scenario 3 a 

worst case situation is described assuming 3000 ppm residual monomer and daily exposure 

during the whole shift. 
35 

Table 4.1.1.2.4 A: Summary of inhalation exposure data of vinyl acetate which are relevant for occupational r

Inhalation exposure 

Area of production and 

use 

Form of 

exposure 

Activity Duration 

[hs/day] 

Frequency 

[days/year] 

Shift average 

[mg/m3] 

M

1. Production and 

polymerisation in the chemical industry 

vapour (liquid) 

filling, sampling, cleaning, repair, maintenance 

8 h / day daily 3.0

(reasonable worst 

case) 

pe

2. Manufacturing of 

formulations and products (e.g. adhesive production) 

vapour (liquid) 

filling, sampling, cleaning, repair, maintenance 

8 h / day 

(assumed) 

daily 14.6

(reasonable worst 

case) 

pe

3. Use of formulations 

and products containing residual vinyl acetate monomer (< 2 – 3000 ppm) 

vapour (liquid) 

different activities, e.g. coating, painting 

8 h / daily 

(assumed) 

daily 2.6

(worst case) 

la

ex

 w

co
36 

Table 4.1.1.2.4 B: Summary of dermal exposure data of vinyl acetate which are relevant for occupational risk 

Dermal exposure 

Area of production and use Form of 

exposure 

Activity Frequency 

[days/year]

Contact 

level (1)

Level of exposure

[mg/cm2/day] 

Exposed 

area [cm2] 

1. Production and 

polymerisation in the chemical industry 

liquid filling, sampling,

cleaning, repair, maintenance 

daily intermittent 0.1 (2) 420 

(palms of 

hands) 

2. Manufacturing of 

formulations and products (e.g. adhesive production) a) polymerisation step (vinyl acetate monomer) b) formulation step (vinyl acetate (co)polymer) 

liquid filling, sampling,

cleaning, repair, maintenance 

daily intermittent 1 (2)

1 (3) 

420 

(palms of 

hands) 

420 

(palms of 

hands) 

3. Use of formulations and 

products containing residual vinyl acetate monomer (< 2 – 3000 ppm) 

liquid different 

activities, e.g. coating, painting 

daily intermittent 5 (3) 840 

(hands) 

(1) Contact level according to the EASE model (2) The EASE estimate is largely reduced because of the short duration time of dermal exposure. The retention time of pure vinyl a

 0.1 mg/cm2 and to 10 seconds for 1 mg/cm2 (order of magnitude) independent on the use of gloves (non-occlusive exposure).

(3) Worst case estimation assuming 3000 ppm residual monomer. Due to the high vapour pressure of the substance shortened reten

 leading to considerable lower dermal exposure levels than estimated with the EASE model. For vinyl acetate in mixture the rete

 because of the complex composition of the mixtures and their specific drying behaviour. 
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4.1.1.3 Consumer exposure 

According to the Swedish product register, products containing vinyl acetate are used by 

consumers in Sweden. Such products are e.g. moisture barrier paints and other paints and 

lacquers/varnishes on a solvent basis, adhesives, glues, dispersion adhesives, hotmelt 

adhesives and sealing compounds. The consumer products are offered in wholesale and retail 

trade, e.g. in repair shops for motor vehicles and motorcycles as well as for personal and 

household goods (as per February 1995). 

In the Norwegian product register, 15 products for use in the consumer field have been listed 

in which vinyl acetate is used as a component of paints for the exterior and interior 

application to houses (as per 16 December 1994). No information is available for the amount 

of vinyl acetate in the formulations. 

In the Federal Republic of Germany, polyvinyl acetate is known to be used e.g. as a 

component of adhesives (vinyl acetate polymer content up to 36%), car polishing products 

(primers, polyvinyl acetate copolymer content up to 1.5%), hair care products (hair setting 

lotions, vinyl acetate copolymer content up to 3%, hair care products) and in plastics for toys 

and those coming into contact with foods. These products contain traces of vinyl acetate as a 

residual monomer; in adhesives (e.g. film and surface adhesives), the residual monomer 

content is 0.1 - 0.2% (voluntary reporting by the manufacturers/distributors etc. to the BgVV 

(as per 01.04.1996); Umbach, 1995; Ellenhorn and Barceloux, 1988). This content would be 

similar to 1000 - 2000 ppm. 

In case reports from the Swiss Toxicological Information Centre, polyvinyl acetate is stated as 

a component of paints and lacquers/varnishes (binding materials) for households (Velvart, 

1993). According to the data provided by the manufacturers, the concentration of polyvinyl 

acetate is up to 13%, and that of vinyl acetate as a residual monomer up to a maximum of 

0.3% in the (co)polymer. In water-based paints residual vinyl acetate monomer hydrolyses 

rapidly. 

According to information provided by the industry, poly vinyl acetate is used in printing inks. 

The maximum polymer concentration is 60%, the maximum concentration of the residual 

monomer is 0.2%; this results in a maximum content of vinyl acetate monomer of 0.12%. 

Inhalation exposure 

Measured exposure data from paints

At present, „solvent- and emission-free“ paints and plasters are available based on binders and 

additives with a content of volatile organic components (VOC; sum of vinyl acetate, 

acetaldehyde, and formaldehyde) below 100 ppm (Zeh et al., 1994). 

In an exposure study monitoring volatile components of polyvinyl acetate (PVA) based paints 

all fixed-station area air samples collected during application and drying of the painting 

process and analyzed for vinyl acetate showed concentrations below the analytical limit of 

detection (Kominsky and Freyberg 1992). The average environmental limit for detection with 

regard to fixed-station area air samples (measurement during application and drying up to 6 
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38 CAS No.: 108-05-4 

hours after application) was 10 ppb (= 36 μg/m3). The average environmental limit of 

detection for personal breathing zone concentrations during paint application was 220 ppb. 

The content of vinyl acetate monomers (VAM) in the samples of paint used during the study 

were <1 to 8.2 ppm (Kominsky and Freyberg, 1992). Shortly after production of paints 

relatively high amounts of residual monomers of ≈ 3200 ppm can be found. In the process of 

incorporating the resin into the paint product, the residual VAM content of the resin is lost or 

converted to hydrolysis products (acetic acid and acetaldehyde). This conclusion is supported 

by the results of the air monitoring for vinyl acetate during and after paint application. 

Surfaces coated with products containing polymer dispersions of vinyl acetate are generally 

free of vinyl acetate before drying since due to the difference in vapour pressure vinyl acetate 

evaporates more quickly than water (Wacker-Chemie, 1993). In addition, vinyl acetate 

hydrolyses at pH 8 to 9 (usual pH in paints) with a half-life of less than 4 days. With respect 

to potential vinyl acetate evaporation from glues of building material, due to the high vapour 

pressure of vinyl acetate building material might be free of vinyl acetate after a short time and 

not lead to a long-term vinyl acetate burden in the rooms (Wacker-Chemie, 1993). 

From this point of view it can be expected that vinyl acetate emission is very low from paints. 

In an experimental study, where paints have been spiked with vinal acetate, Zeh et al. (1994, 

2000) have evaluated VOC emissions from paints and, as a constituent of VOC’s, vinyl 

acetate. The experiments showed excellent correlation between measured and modelled data. 

With a paint spiked with 1200 ppm, room air levels were found of 10 mg/m3. Extrapolating 

these findings to paints containig concentrations in the range < 10 ppm, the room 

concentrations of vinyl acetate after use of paints shound not exceed levels in the range of 0.1 

mg/m3. 

Adhesives for carpets and other film and surface adhesives

Polyvinyl acetate is used as a component of film and surface adhesives, e.g. for carpets and 

floor sealings; 0.1 - 0.3% of vinyl acetate are contained in the products as residual monomer. 

The monitored air emission of vinyl acetate during gluing of a carpet with a VAM containing 

glue in a closed room has been detected at 2.6 mg/m3

 (glue formulation: 20-35% dispersion; 

the maximum VAM content of the dispersion is typically 0.1-0.3%) (Hoechst, 1993). 

This information can be used to estimate an acute exposure to the person who is gluing the 

carpet (normally workplace exposure). From other studies (Zeh, 1994, 2000) it is known that 

vinyl acetate concentrations will decline quickly and remaining long-term exposure may be 

low. There is no further information on room air levels although gluing carpets may serve as a 

considerable source of exposure to vinyl acetate. 

Emission of vinyl acetate from carpets

Vinyl acetate had been found after 16 hours of equilibration in a concentration of less than 2 

μg/m3

 (limit of detection) in air over three different carpets (two with and one without a finish 

containing up to 2000 ppm vinyl acetate; carpet size 0.2 m2

, test chamber size 0.5 m3, air 

exchange rate 0.5 h-1 (Deutsches Teppichforschungsinstitut e.V., 1992)). 

In an US study the air emissions of four new carpets (typically installed in residences, 

schools, and offices; the carpet samples were collected at the manufacturers’ mills 
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39 CAS No.: 108-05-4 

immediately following production) were measured in room air under simulated indoor 

conditions in a 20 m3 environmental test chamber over a period of one week following 

installation. After 3 hours the initial concentration amounted about 290 ppb (1.04 mg/m3

) and 

after 168 hours about 10 ppb (0.036 mg/m3

). The emission rate was estimated to be 853 μg/m2

per hour after 24 hours and 103 μg/m2 per hour after 168 hours. Altogether the carpets 

emitted 85 mg/m2

 of vinyl acetate over the period of 168 hours (Hodgson et al., 1992a, 

1992b). The room air ventilation rate was 1 h-1. 

The results of these studies obviously show, that the emission of vinyl acetate varies greatly. 

For risk assessment therefore the highest amounts that have been measured should be taken 

into consideration. As a realistic worst case estimate, the concentrations of vinyl acetate from 

carpet emissions would then amount to about 1000 μg/m3 (~ 300 ppb). For chronic exposure, 

the concentration measured by Hodgson et al. (1992a, 1992b) after 168 h equilibrium of 36 

μg/m3 (≈ 10 ppb) should be taken. 

Chronic exposure results in ≈ 0.2 μg/kg/h for women (activity level: resting) and ≈ 0.4 

μg/kg/h for men (activity level: resting) accounting for 4.6 and 9.2 μg/kg bw per day, 

respectively. For 3 year-old children, the result of estimation of chronic exposure by 

inhalation is 0.78 μg/kg/h (18 μg/kg bw per day). 

For calculating exposures the following data have been used (AIHC, 1994; AUH, 1995): 

 3-year-old children Adult (women) Adult (men) 

Body weight (TGD defaults) 11 kg 60 kg 70 kg 

Breathing volume (resting) 0.24 m3/h5 0.3 m3/h 0.7 m3/h 

Time of residential stay 23 h 23 h 23 h 

The inhalation exposure (Expinh) has been calculated by the equation 

BW

c r Exp air inh

inh

* = , where cair is the room air concentration obtained by measurements and rinh

the breathing volume (see table). 

Exposure to car polishing products (primers) 

In car polishing products (primers), polyvinyl acetate copolymer is used in a concentration up 

to 1.5%. The residual monomer content of vinyl acetate is very low so that the consumer 

exposure to vinyl acetate in this field of use may be neglected. 

Exposure from printing inks

 

5

 conservative unfavorable assumption for breathing rates considering chronic exposure over whole day 

(Finley, et al. 1994) 
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The use of printing inks containing vinyl acetate may lead to an exposure of consumers. 

Printing inks are used for example in computer ink-printers. For this purpose, the ink-solvents 

must volatilize very quickly. The content of a cartridge is 50 ml, the vinyl acetate residual 

monomer content is then 0.06 g. If the cartridge is used for 1 month, the daily release of ink 

will amount to 0.002 g. The liberation of this amount in a room of 40 m3 results in a 

concentration of 0.05 mg/m3. 

Dermal exposure

Exposure to hair setting lotions

The Scientific Committee (Scientific Committee, 1994; Colipa 1989) has stated a consumer 

exposure to hair setting lotion up to 1 g/day. Hair setting lotions contain up to 3% vinyl 

acetate copolymer which corresponds to a daily consumer exposure of 30 mg vinyl acetate 

copolymer. Assuming a residual monomer content of 0.2% vinyl acetate, the consumer 

exposure to vinyl acetate will be 60 μg vinyl acetate daily or 1 μg/kg bw and day. 

Oral exposure

Exposure to plastics coming into contact with food etc.

Substances that will come in contact with food as monomers for the manufacture of plastics 

are regulated under the "Regulations to amend the Regulations on Specific Commodities 

under the Foods Act, 1994". In this regulation, a maximum value of 12 mg/kg migrating from 

articles is allowed. This means, that an amount of 12 mg of the vinyl acetate residual 

monomer may migrate from one kg of food. Taking into consideration, that the real migration 

rate of vinyl acetate from plastic material is not known, and according to the proposed 

classification of vinyl acetate migration from articles must be held as low as possible. 

A tolerable daily intake (TDI) value of 0.2 mg/kg bw has been established6

. 

Conclusion 

 

6

 A tolerable daily intake (TDI) value of 0.2 mg/kg bw has been established. This rather high 

value was derived by taking the NOAEL and application of safety factors. The amount of the 

daily intake from migration can be roughly estimated assuming the following parameters: A 

can with a weight of 500 g containing 0.1% of vinyl acetate residual monomer contains a 

volume of one liter liquid. Assuming that 0.1% of the residual monomer will migrate every 

day, then an amount of 0.5 mg will migrate per day, which would result in an oral exposure of 

about 0.01 mg/kg bw if one person will drink the total content of the can. Therefore, it seems 

unlikely that the regulatory limits will be reached. 
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Following the exposure assessment there is no direct exposure of the consumer to vinyl 

acetate besides of the release of monomers from polymers. Overall exposure of consumers to 

vinyl acetate results mainly from inhalation due to emissions from carpets, paints and 

adhesives. However, there is a lack of sufficient data on other uses. For comparison with 

acute effects, the estimate for short-term exposure from carpets will be used (concentrations 

of 1 mg/m3). With regard to chronic effects, the concentration of 0.036 mg/m3 for long-term 

exposure will be used resulting in an exposure of 9.2 μg/kg bw/d for men, 4.6 μg/kg bw/d 

for women, and 18 μg/kg bw/d for children. For the risk characterisation a value of about 10 

μg/kg bw/d for adults will be used. 

The dermal exposure to vinyl acetate is estimated to be about 1 μg/kg bw/d. 

The sum of all types of exposure resulting from residual monomeric vinyl acetate (reasonable 

worst case) is estimated to be in the range of 5 to about 20 μg/kg bw/d. 

4.1.1.4 Indirect exposure via the environment 

According to Appendix VII of chapter 2 of the TGD, the indirect exposure to humans via the 

environment, i.e. through food, drinking water and air is estimated. 

As a worst case scenario, the maximum intake due to exposure in the vicinity of a vinyl 

acetate production facility is calculated (site 26). This is compared to an average intake due to 

exposure via the regional background concentration. 

The resulting total daily dose is: DOSEtot_local = 36 μg / kg bw d 

 DOSEtot_regional = 2.47 E-03 μg / kg bw d 

The calculated total doses comprise the following routes: 

Route Percent of total dose 

local regional 

Drinking water 1.26 9.64 

Fish 2.97E-05 0.44 

Stem 0.36 0.33 

Root 0.24 0.37 

Meat 2.04E-04 2.41E-04 

Milk 3.80E-03 4.50E-03 

Air 98.13 89.22 

The main route of indirect exposure of both scenarios is the intake via inhalation of air. 
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4.1.2 Effects assessment: Hazard identification and Dose (concentration) - 

 response (effect) assessment 

4.1.2.1 Toxico-kinetics, metabolism and distribution 

Vinyl acetate is hydrolysed by carboxylesterases to acetic acid and acetaldehyde which is 

subsequently oxidized to acetic acid by aldehyde dehydrogenases. Acetate enters the citric 

cycle in an activated form as acetyl coenzyme A. Vinyl acetate metabolism not only takes 

place in the liver but also in several tissues which might be of relevance for the toxicological 

effects elicited by vinyl acetate. 

The main pathway for the metabolism of vinyl acetate is shown in Fig. 1. 

Fig. 1: 

Biotransformation Pathways for Vinyl Acetate 

(Modified from Bogdanffy et al., 1998) 

Acetyl-CoA

CE

AldDH

ACS

Acetaldehyde Acetic Acid

CE

AldDH

ACS

+
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Animal data – in vivo 

Inhalative exposure 

Four CD rats (Sprague-Dawley-derived), 2 males and 2 females, were exposed nose only to 

an atmosphere of nominal 750 ppm of 14C-vinyl acetate (labelled at the vinyl moiety) for 6 h 

(2.68 mg/l x 0.8 l/min/kg x 360 min ≈ 772 mg/kg bw). The authors presented the results 

(radioactivity in urine, faeces, expired air, cage washing and carcasses) as percentage of the 

total radioactivity recovered because the precise amount of (14C)-vinyl acetate given to the 

animals was not known. The tables and appendices were not available to the rapporteur, 

therefore data are given as described by the authors. During a 96 h period the mean 

proportions of the recovered (not the administered!) radioactivity found in urine, faeces and 

expired air were 4.8, 3.6, and 74.6%, respectively. The major portion of radioactivity was 

eliminated in the first 24 h. A mean of 16.4% of the total recovered radioactivity was present 

in the carcass after 96 h. In case of nose-only inhalation of 750 ppm (772 mg/kg bw) about 

83% of the recovered radioactivity were found in the expired air (as CO2), urine and faeces. 

Based on the fact, that the percentages of radioactivity presented were based on the recovered 

amount of radioactivity and taking into consideration that presystemic metabolism in the nasal 

cavity occurs, no conclusions about the amounts of systemically available vinyl acetate can be 

drawn from this investigation. For investigation of tissue distribution (number of animals not 

available) radioactivity was investigated immediately, 1, 6 and 72 h after a 6 h exposure to a 

nominal dose of 750 ppm 14C-vinyl acetate. Immediately after exposure, the highest mean 

concentrations of radioactivity were found in harderian gland, ileum, submaxillary salivary 

gland and the contents of the gastrointestinal tract. Radioactivity was widely distributed with 

relatively high levels present in liver, kidneys, lung, brain, stomach, colon and ovaries. 1, 6 

and 72 h after exposure, the pattern of distribution was approximately the same although 

concentrations had declined. 72 h after exposure, the harderian gland, adrenal gland and 

ovaries contained the highest mean levels of radioactivity (Strong et al., 1980; the appendices 

and tables of the study were not available to the rapporteur). 

Two male Wistar Rats exposed to vinyl acetate (stabilised with 0.01% hydroquinone) 

concentrations varying between 200 and 2000 ppm in closed chambers with an exposure time 

of 1.4 h or less demonstrated dose dependent elimination kinetics. The authors concluded that 

the metabolic pathways became saturated when vinyl acetate exposure levels exceeded 

650 ppm (2320 mg/m3

) (Simon et al., 1985a). 

Vinyl acetate deposition was measured in the isolated upper respiratory tract (URT) of 

anaesthetised adult male CrlCD:BR rats at exposure concentrations ranging from 73 to 2190 

ppm during 1h inhalation under unidirectional flow conditions (flow rate 100 ml/min) 

(Plowchalk et al., 1997). The URT was isolated by inserting a polyethylene tube into the 

trachea to the level of the nasopharynx of sodium pentobarbital anaesthetised (70 mg/kg bw, 

ip) rats (250 to 350 g). A separate cannula was inserted into the trachea, toward the lungs, to 

maintain a patent airway. A valve system allowed alternative switching between two 

impingers to enable the continuous collection of expired air. Each animal was then placed into 

a holder in a supine position and the nose was inserted with Batelle-style nose-only restrainers 

into an exposure chamber. Chamber atmosphere (Cin, 73 to 2190 ppm vinyl acetate in 

nitrogen, 34 °C, humidity 88%) was drawn through the URT under constant velocity (nominal 

100 ml/min) and unidirectional flow conditions. The air exiting the nasal cavity (Cexp) was 

trapped in an impinger. Preliminary experiments showed that approximately 8 min of 
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exposure was required for vinyl acetate to achieve a steady state in nasal tissues. After 8 min 

of equilibration, impinger samples were collected, approximately every 4 min, for up to 40 

min and analysed for vinyl acetate and acetaldehyde by gas chromatography. Fractional 

deposition (equivalent to extraction) of vinyl acetate in the URT was calculated as (Cin - 

Cexp)/Cin. Fractional deposition of vinyl acetate from the nasal cavity was non-linear with 

reference to exposure concentration and ranged from 36 to 94%, with greatest uptake at 

lowest vinyl acetate concentrations. While the exposure concentration was increased from 76 

to 550 ppm, uptake decreased progressively to about 40% and remained at this level up to 

approximately 2000 ppm. When simulations were performed without carboxylesterase 

activity in nasal mucosa, it could be calculated, that vinyl acetate deposition due to bloodflow extraction is minimal and accounts for less that 15 % of total deposition (Plowchalk et 

al., 1997; Bogdanffy et al, Bericht 1998). Acetaldehyde was found in expired air at all vinyl 

acetate exposure concentrations. With increasing the vinyl acetate exposure, concentration of 

acetaldehyde in expired air increased. At vinyl acetate exposure of approximately 1000 ppm 

the concentration of acetaldehyde in the expired air was 277 ppm (499 mg/m3). To study the 

effect of carboxylesterase inhibition on vinyl acetate deposition, rats (n = 10) were pre-treated 

for 3 days with one ip injection per day (0.2 ml/100g bw) of a 5% BNPP (bis(pnitrophenyl)phosphate, an inhibitor of carboxylesterase) suspension in saline. Pre-treatment of 

rats with BNPP significantly decreased fractional deposition of vinyl acetate. At exposure 

concentrations ranging from 76 to 663 ppm, BNPP pre-treatment reduced fractional 

deposition by at least 55% compared to that seen in naive rats. The appearance of 

acetaldehyde in the expired air and the inhibition of its formation by the inhibitor BNPP are 

indicative for a carboxylesterase-mediated metabolism of vinyl acetate.

Oral exposure 

Rats were administered oral doses of 14C-vinyl acetate (labelled at the vinyl moiety, 1 ml of a 

10000 ppm (v/v) aqueous solution, overall dose level 297 mg/kg bw) by gastric intubation. 

The dosing regimen was 6 times 1 hour apart. During the dosing regime and subsequent 96 h 

collection period, a mean of 64.4% of the administered radioactivity was excreted (1.4% in 

faeces, 1.8% in urine and 61.2% in exhaled air). In addition a mean of 5.4% was found in the 

carcass at 96 h. The major portion of the urinary radioactivity was excreted within the first 24 

h. Most of the radioactivity eliminated by the expired air was recovered during the 6 h dosing 

regime and the first 6 h after dosing. This portion of radioactivity was recovered from the 

traps designed for collecting carbon dioxide. The authors of the study suppose, that the 

unaccounted 30.1% of the dose were most likely lost in the expired air, which escaped from 

the metabolism cages when the animals were removed for dosing. There was a wide tissue 

distribution of radioactivity following administration of 14C-vinyl acetate by the oral route. 

One hour after the sixth dose the highest mean concentrations of radioactivity were found in 

the harderian gland and the submaxillary salivary gland. High levels were also found in the 

liver, kidney, stomach, ileum, colon and gastrointestinal tract contents. Low concentrations of 

radioactivity were found in fat. Attempts have been undertaken to determine vinyl acetate 

metabolites in urine and faeces. No radiolabelled carbonates or bicarbonates were found in 

urine or feces. Thin layer chromatography of urine indicated that there was one major 

radioactive fraction and several minor fractions (Strong et al., 1980). Exhaled radioactivity 

was entirely present as 14C carbon dioxide. Therefore it can be concluded, that 63 % of orally 

applied 14C vinyl acetate is excreted as metabolites. 

A single oral dose of nominal 1.17 mg of 14C-vinyl acetate (labelled at the vinyl moiety) was 

orally administered to albino mice of the CDI strain (3 male, 3 female). Animals were taken 
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for analysis 1, 6 and 72 h after administration. Whole-body autoradiograms indicated a wide 

distribution of radioactivity. High concentrations were observed in harderian and salivary 

glands, gastrointestinal mucosa, liver and brown fat (Strong et al., 1980). 

Solutions of 0.9 % saline containing various concentrations of vinyl acetate were placed in the 

mouth of anesthetized male F344 rats for 10 min and then analyzed for acetaldehyde by 

HPLC (Morris et al., 2002). Acetaldehyde was detected in these solutions providing evidence 

that metabolism of vinyl acetate occurs in vivo in oral tissues. 

Dermal exposure 

There are no studies on absorption, metabolism, distribution and excretion of vinyl acetate 

after dermal exposure. A study has been undertaken to determine acute dermal toxicity 

(Mellon Institute, 1969), see also section “Acute toxicity”. In brief, all animals died after 

occlusive application of 16 ml vinyl acetate per kg bw on to the skin of rabbits. After 

occlusive application of 4 ml/kg, gross pathology revealed congestion of the lungs and liver, 

mottled spleen and kidney and prominent liver acini. The results indicated that vinyl acetate 

might be systemically bioavailable after dermal application. 

Other routes 

Injection of vinyl acetate (i.p.) to female Chester-Beatty rats (0.8 ml/kg bw) resulted in a 

decrease of hepatic glutathione level to 77% of the normal value 30 min after application 

(Boyland and Chasseaud, 1970). Similar decreases of hepatic non-protein sulfhydryls were 

reported after i.p. vinyl acetate injection to mice (300 mg/kg bw), Wistar rats (300 or 450 

mg/kg bw) and guinea pigs (500 mg/kg bw) (Holub and Tarkowski, 1982). It is assumed that 

these findings may indicate conjugation with glutathione. However due to the limited data the 

relevance of this pathway cannot be assessed. 

Human data – in vivo 

Inhalative exposure 

To provide validation data for the application of the PBPK model developed by Bogdanffy et 

al. (1999b; see also section PBPK modelling) in humans, controlled human exposures to 

inhaled vinyl acetate were conducted (Hinderliter et al., 2005). Air was sampled by a probe 

inserted into the nasopharyngeal cavity of five volunteers (two women, three men). 

Volunteers were instructed to inhale and exhale through the nose. Sampling was carried out 

during exposure to labelled 13C1, 13C2-vinyl acetate during resting and light exercise at three 

exposure levels (1, 5 and 10 ppm nominally). Both, labelled vinyl acetate and the major 

metabolite acetaldehyde from the nasopharyngeal region were sampled at a calibrated flow 

rate of 12 l/h and analysed in real time utilising ion trap mass spectrometry (MS/MS). 

Measurements were taken every 0.8 sec in an exposure period of 2 to 5 min resulting in data 

during all phases of the breathing. The rate of sampling was rapid enough to capture much of 

the behaviour of vinyl acetate in the human nasal cavity including inhalation and exhalation. 

However, the sampling was not frequent enough to accurately capture the peak concentration 
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in every breath. The method is free of interference from endogenous compounds and its 

detection limit is in the single digit ppb level. An acoustic rhinometry system was used to 

measure the cross-sectional area and volume of the nasal cavity. The complete set of human 

exposures resulted in a data set with over 22000 data points of vinyl acetate and acetaldehyde.

Oral exposure 

There are no toxicokinetic data on human oral vinyl acetate exposure. 

Dermal exposure 

There are no toxicokinetic data on human dermal vinyl acetate exposure. 

In vitro data (both animals and humans)

Carboxylesterase activity 

Carboxyl esterase activity in the nose 

Vinyl acetate hydrolysis has been studied in vitro in the nasal tissues of F344 rats and 

B6C3F1 mice. Homogenates of nasal respiratory and olfactory mucosa, adjusted to pH 7.4, 

were incubated with vinyl acetate at 37°C for 10 min (respiratory mucosa) or 2 min (olfactory 

mucosa). It was shown that nasal esterases catalyse formation of acetaldehyde and acetic acid 

with high efficiency. Vmax values for rat and mouse respiratory tissue ranged from 22 to 46 

μmoles/min/mg protein (22 to 24 for rat; 30 to 46 for mouse) which is in the same range as 

the data obtained in rat liver microsomes (23 μmoles/min/mg protein, Simon et al., 1985a). 

Vmax for rat and mouse olfactory tissue ranged from 89 to 165 μmoles/min/mg protein (88 to 

92 for rat, 95 to 165 for mouse). Km values obtained for rat and mouse nasal tissues ranged 

from 0.30 to 1.07 mM and were similar among olfactory and respiratory epithelium 

(Bogdanffy and Taylor, 1993). The enzyme kinetic data for carboxylesterase mediated 

hydrolysis of vinyl acetate do not account for the species differences in susceptibility to the 

carcinogenic effects of vinyl acetate. Values are listed in Table 1. 

Carboxylesterase activities have also been investigated in nasal (respiratory, olfactory) tissue 

from different species using p-nitrophenolbutyrate (Bogdanffy et al., 1987) or 

methylmethacrylate (Mainwaring et al., 2001) as substrates for carboxylesterase (see Table 2). 

Higher carboxylesterase activities could be determined in olfactory tissue of rats and mice 

compared to respiratory tissue. However, it is difficult to draw firm conclusions concerning 

carboxylesterase activities in nasal tissues of humans and rodents, because vmax values in 

human samples were obtained when analyzing just one substrate concentration. In the case of 

human olfactory tissue, only S9, but not microsomes have been analyzed (Mainwaring et al., 

2001) which makes species comparison difficult. 
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Since the nasal cavity epithelium is composed of a heterogeneous cell population, 

measurement of xenobiotic metabolizing enzymes using homogenates could yield artificial 

results. Therefore, an in vitro gas uptake technique has been established in order to enable 

more accurate measurement of kinetic constants (Bogdanffy et al., 1998). By applying this 

method, whole rat turbinates from CrlCD:BR rats covered with either respiratory or olfactory 

epithelium or sections of human nasal tissue (middle turbinate or dorsal meatus) were placed 

in a sealed scintillation vial. Vinyl acetate vapour was injected into the headspace over the 

tissue and its loss from the vial headspace and the appearance of acetaldehyde were 

determined and modeled using a distributed parameter model that reflects tissue 

histochemistry. In this model the individual compartments are said to represent epithelial 

cells, basal cells, or submucosal tissue in the respiratory and olfactory mucosa. Rat turbinate 

surface areas were estimated using a three-dimensional, anatomically “accurate” computer 

model of the nasal passages from one F344 rat. Human turbinate surface areas were estimated 

from the tissue samples. Vapour is transported to the air: tissue interface by diffusion. The 

diffusivity of the vapour in the tissue is approximated by its diffusivity in water. The vapour 

diffusivity in all the tissue subcompartments is assumed to be equal. Metabolic activity is 

assumed to be located in the tissue compartments according the observations from enzyme 

histochemical and immunohistochemical studies. The kinetic parameter estimates were 

compared to those derived from homogenate experiments using two normalization 

procedures. When the normalization took into account tissue architecture (epithelial cell 

volume vs. tissue wet weight), a good agreement between homogenization technique and gas 

uptake technique could be observed in animal tissues. No clear conclusions on species 

differences could be drawn from these investigations, because dependent on the scaling 

technique, different results were obtained for respiratory and olfactory carboxylesterase 

activities in rats and humans. An overview about carboxyl esterase activities in different rat 

and human tissues is given in Table 1. Major drawbacks of this technique were that mucosal 

and blood flow and cofactor loss were not taken into account by the in vitro gas uptake 

methodology and that only one rat has been used to create a computer model. 

Carboxyl esterase activity in the oral cavity 

Vinyl acetate hydrolysis has been investigated in homogenates from oral cavity mucosa which 

has been obtained from different regions of the oral cavity of male F344 rats and male BDF 

mice. Homogenates were incubated for 30 min with various concentrations (0.05 – 10 mM) of 

vinyl acetate and the production of acetaldehyde was quantified by HPLC. All tissue regions 

possessed vinyl acetate hydrolysis activity. In both species thy hydrolysis activity was 

greatest in the the dorsal interior regions. Activity in the other oral regions was 2-15-fold 

lower (Morris et al., 2002). Values are given in table 1. 

Carboxyl esterase activity in the skin 

Carboxyl esterase activities have been determined using different ester substrates (but not 

vinyl acetate itself) in rat and human skin microsomes but also in viable skin using flowthrough diffusion cells. Clark et al. (1993) investigated enzyme mediated hydrolysis of 

fluazifop butyl in human and rat skin post-mitochondrial fraction (with and without the 

esterase inhibitor BNPP). McCracken et al. (1993) investigated hydrolysis of four different 

ester substrates in rat skin microsomes and cytosol. Lobmeier et al. (1996) investigated the 
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hydrolysis of different 4-hydroxybenzoic acid esters in homogenates from different human 

skin compartments. Frederick et al. (1992) investigated the enzyme-mediated hydrolysis of 

ethylacetate in rat skin homogenates in comparison to other tissues. It could be demonstrated 

that rat and human skin both possess carboxyl esterase activities. Results are presented in 

Table 2. From the investigations by Frederick et al. (1992) it can be demonstrated, that 

carboxyl esterase activity in skin homogenate was lower compared to lung or liver, but higher 

compared to blood. 

Carboxyl esterase activity in the blood, liver and lung 

Vinyl acetate was rapidly degraded in the presence of human plasma and whole blood. Half 

lives for the breakdown of vinyl acetate, using initial concentrations of 30-130 ppm (0.33-

1.41 mM) were approximately 150 sec (2.5 min) with plasma and 210 sec (3.5 min) with 

whole blood (0.1 M phosphate buffer, pH 7.4, at 37o C). The reaction was shown to be an 

enzyme-mediated hydrolysis, which was characterised by a stoichiometric formation of 

acetaldehyde (Strong et al., 1980). 

The enzyme-mediated hydrolysis of vinyl acetate has been studied in vitro with microsomes 

from rat liver and lung, rat and human plasma and three different purified esterases 

(acetylcholine esterase, butyrylcholine esterase and carboxyl esterase). The incubation was 

carried out at 37°C and pH 8.0. Concentrations of vinyl acetate varied between 1.2 mM and 

30 mM in the experiments designed for determination of Km and Vmax. Kinetic data show that 

microsomes (rat liver: Vmax = 23 μmol/min/mg protein, rat lung: Vmax = 6 μmol/min/mg 

protein) as well as purified carboxyl esterase (from porcine liver) are capable to form acetic 

acid from vinyl acetate (Vmax = 238 μmol/min/mg protein), enzyme activity in rat plasma 

(Vmax = 0.6 μmol/min/mg protein) and human plasma (Vmax= 0.7 μmol/min/mg protein) is 

lower (Simon et al., 1985a). 

Degradation of 200 μM vinyl acetate from in vitro systems containing 1 ml blood or 0.5 ml 

plasma, or 0.5 ml red blood cells from rats or volunteers, diluted in 0.1 M sodium phosphate 

buffer pH 7.4, was measured at 37°C. Vinyl acetate disappeared with a half-life of 4.1 min in 

human blood, and below 1 min in rat blood. In rat plasma vinyl acetate was hydrolysed with a 

half life of 1.2 min. Preincubation of rat plasma with BNPP lowered the rate of disappearance, 

suggesting that the reaction was catalysed by carboxylesterases (Fedtke and Wiegand, 1990). 

Frederick et al. (1992) compared ethyl acrylate hydrolysis in tissue homogenates from 

different rat tissues. Results are presented in Table 2: Carboxylesterase activities (based on 

substrates other than vinylacetate). 
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Table 1: summary of vinyl acetate hydroxylase activities (carboxyl esterase activities) in 

human and animal tissues 

Tissue Km Vmax Literature 

rat respiratory tissue 

(determined in 

homogenates from 

respiratory mucosa) 

0.43 mM in males 

0.30 (0.34)* mM in females 

22.03 [μmol/mg prot/min] 

in males 

23.86 (25.14)* [μmol/mg 

prot/min] in females 

Bogdanffy and Taylor, 

1993 

mouse respiratory 

(determined in 

homogenates from 

respiratory mucosa) 

0.42 mM in males 

0.76 (0.93)* mM in females 

29.6 [μmol/mg prot/min] in 

males 

46.3 (51.78)* [μmol/mg 

prot/min] in females 

Bogdanffy and Taylor, 

1993 

rat respiratory tissue 

(determined in 

homogenates from 

respiratory mucosa, scaled 

to whole tissue based on 

wet weight) 

0.037 mg/ml 35.7 mg/h Bogdanffy et al., 1998 

rat respiratory tissue 

(determined in 

homogenates from 

respiratory mucosa, scaled 

to whole tissue based on 

epithelial volume) 

0.037 mg/ml 64.9 mg/h Bogdanffy et al., 1998 

rat respiratory tissue 

(determined by the gas 

uptake technique, scaled to 

whole tissue based on wet 

weight) 

0.04 mg/ml 10.8 mg/h Bogdanffy et al., 1998 

rat respiratory tissue 

(determined by the gas 

uptake technique, scaled to 

whole tissue based on 

epithelial volume) 

0.04 mg/ml 63.0 mg/h Bogdanffy et al., 1998 

Human respiratory tissue 

(determined by the gas 

uptake technique, scaled to 

whole tissue based on 

epithelial volume) 

0.05 mg/l 441 mg/h Bogdanffy et al., 1998 

Human respiratory tissue 

(determined by the gas 

uptake technique, activity 

per specimen (middle 

turbinate) 

0.05 1.5 mg/h Bogdanffy et al., 1998 

Human respiratory tissue 

(determined by the gas 

uptake technique, based on 

epithelial cell volume) 

0.05 0.57 mg/h/mm3

 Bogdanffy et al., 1998 
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Tissue Km Vmax Literature 

rat olfactory 

(determined in 

homogenates from 

respiratory mucosa) 

0.33 (0.55)* mM in males 

0.2 (0.51)* mM in females 

88.8 (113.5)* ([μmol/mg 

prot/min] in males 

91.52 (135.52)* ([μmol/mg 

prot/min] in females 

Bogdanffy and Taylor, 

1993 

mouse olfactory 

(determined in 

homogenates from 

respiratory mucosa) 

0.52 (1.07)* mM in males 

0.31 (0.41)* mM in females 

164.6 (253.8)* [μmol/mg 

prot/min] in males 

95.5 (107.56)* [μmol/mg 

prot/min] in females 

Bogdanffy and Taylor, 

1993 

rat olfactory tissue 

(determined in 

homogenates from olfactory 

mucosa scaled to whole 

tissue based on wet weight) 

0.028 mg/ml 133.1 mg/h Bogdanffy et al., 1998 

rat olfactory tissue 

(determined in 

homogenates from olfactory 

mucosa scaled to whole 

tissue based on epithelial 

volume) 

0.028 mg/ml 39.9 mg/h Bogdanffy et al., 1998 

rat olfactory tissue 

(determined by the gas 

uptake technique, scaled to 

whole tissue based on wet 

weight) 

0.05 mg/ml 5.8 mg/h Bogdanffy et al., 1998 

rat olfactory tissue 

(determined by the gas 

uptake technique, scaled to 

whole tissue based on 

epithelial volume) 

0.05 mg/ml 45.4 mg/h Bogdanffy et al., 1998 

Human olfactory tissue 

(determined by the gas 

uptake technique, scaled to 

whole tissue based on 

epithelial volume) 

0.05 mg/ml 45.0 mg/h Bogdanffy et al., 1998 

Human olfactory tissue 

(determined by the gas 

uptake technique, activity 

per specimen (dorsal 

meatus)) 

0.05 mg/ml 0.9 mg/h Bogdanffy et al., 1998 

Human olfactory tissue 

(determined by the gas 

uptake technique, scaled to 

epithelial cell volume) 

0.05 mg/ml 1.94mg/h/mm3

 Bogdanffy et al., 1998 

Rat oral cavity mucosa 0.49 mM (dorsal interior 

mucosa) 

0.41 mM (dorsal exterior 

mucosa) 

90 nmol/min (dorsal interior 

mucosa) 

50 nmol/min (dorsal 

exterior mucosa) 

Morris et al., 2002 
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Tissue Km Vmax Literature 

Mouse oral cavity mucosa 0.97 mM (dorsal interior 

mucosa) 

0.91 mM (dorsal exterior 

mucosa) 

24 nmol/min (dorsal interior 

mucosa) 

2.6 nmol/min (dorsal 

exterior mucosa) 

Morris et al., 2002 

rat liver microsomes 0.73 mM 23 μmol/mg prot/min Simon et al., 1985 

rat lung microsomes 6.1 mM 6.2 μmol/mg prot/min Simon et al., 1985 

rat plasma 4 mM 0.56 μmol/mg prot/min Simon et al., 1985 

human plasma 7.1 mM 0.69 μmol/mg prot/min Simon et al., 1985 

Rat liver homogenates Not given in the report 133.3 μmol/min/g liver 

(homogenate) 

Strong et al., 1980 

Mouse liver homogenates Not given in the report 140.0 μmol/min/g liver 

(homogenate) 

Strong et al., 1980 

*values in brackets: different equations have been used for calculation; see Bogdanffy and 

Taylor, 1993. 

Table 2: carboxylesterase activities (based on substrates other than vinylacetate) 

Tissue Substrate Km Vmax Literature 

rat respiratory 

mucosa 

p-nitrophenylbutyrate 20.8 mM (males) 

20.9 mM (females) 

0.099 μmol/mg 

prot/min (males) 

0.106 μmol/mg 

prot/min (females) 

Bogdanffy et al., 

1987 

rat olfactory mucosa p-nitrophenylbutyrate 34.1 mM (males) 

31.2 mM (females) 

0.605 μmol/mg 

prot/min (males) 

0.593 μmol/mg 

protein/min (females) 

Bogdanffy et al., 

1987 

mouse respiratory 

mucosa 

p-nitrophenylbutyrate 40.4 mM (males) 

25.6 mM (females) 

0.174 μmol/mg 

prot/min (males) 

0.124 μmol/mg 

protein/min (females) 

Bogdanffy et al., 

1987 

mouse olfactory 

mucosa 

p-nitrophenylbutyrate 23.1 mM (females) 

21.8 mM (females) 

0.467 μmol/mg 

prot/min (males) 

0.444 μmol/mg 

pro/min (females) 

Bogdanffy et al., 

1987 

Rat respiratory tissue Methylmetacrylate 0.15 mM (microsomes) 14.3 nmol/mg 

protein/min 

(microsomes) 

Mainwaring et al., 

2001 
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Tissue Substrate Km Vmax Literature 

3.5 nmol/mg 

protein/min) (S9)* 

Human respiratory 

tissue 

Methylmethacrylate Not determined 2.7 nmol/mg 

protein/min 

(microsomes)* 

0.15 nmol/mg 

protein/min 

(S9)* 

Mainwaring et al., 

2001 

Rat olfactory tissue Methylmethacrylate 0.14 mM 

(microsomes) 

38.6 nmol/mg 

protein/min 

(microsomes) 

12 nmol/mg 

protein/min (S9)* 

Mainwaring et al., 

2001 

Human olfactory 

tissue 

Methylmethacrylate Not determined 0.46 nmol/mg 

protein/min (S9)* 

Mainwaring et al., 

2001 

Rat liver microsomes Methylmethacrylate 0.1 mM 46.5 nmol/mg 

protein/min 

Mainwaring et al., 

2001 

Human liver 

microsomes 

Methylmethacrylate Not determined 494 nmol/mg 

protein/min* 

Mainwaring et al., 

2001 

Human skin postmitochondrial 

fraction 

Fluazifop butyl 420 μM 

(median from skin 

samples from different 

areas; n = 7) 

61 nmol/min/g 

(median from skin 

samples from different 

areas; n = 7)

Clark et al., 1993 

Rat skin postmitochondrial 

fraction 

Fluazifop butyl 248 μM ± 30.6 

(mean, n=7) 

740 nmol/min/g ± 90 

(mean, n=7) 

Clark et al., 1993 

Rat skin microsomes Fluazifop-butyl 

Carbaryl 

Paraoxon 

Phenylacetate 

14 ± 2.8 μM 

32 ± 4.2 μM 

950 ± 100 μM 

0.02 μmol/min/g 

0.2 nmol/min/g 

ND 

1.13 μmol/min/g 

McCracken et al., 

1993 

Rat skin cytosol Fluazifop-butyl 

Carbaryl 

Paraoxon 

Phenylacetate 

42 ± 2.8 μM 

36 ± 3.8 μM 

340 ± 50 μM 

0.4 μmol/min/g 

0.5 nmol/min/g 

ND 

3.44 μmol/min/g 

McCracken et al., 

1993 

Rat liver homogenate Ethyl acrylate 1.9 μmol/ml tissue 31.7 μmol/min/ml 

tissue 

Frederick et al., 1992 
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Tissue Substrate Km Vmax Literature 

Rat lung homogenate Ethyl acrylate 1.88 μmol/ml tissue 5.3 μmol/min/ml 

tissue 

Frederick et al., 1992 

Rat skin homogenate Ethyl acrylate 5.45 μmol/ml tissue 0.86 μmol/min/ml 

tissue 

Frederick et al., 1992 

Rat Arterial blood Ethyl acrylate 4.6 μmol/ml tissue 0.18 μmol/min/ml 

tissue 

Frederick et al., 1992 

* the values for rat S9 fractions and for all human tissues are for a single rate measured at a 

single substrate concentration of 1.0 mM. 

Aldehyde dehydrogenase 

Aldehyde dehydrogenase in the nose

Aldehyde dehydrogenase (ALDH) activities have been investigated in nasal homogenates 

(prepared from respiratory and olfactory mucosa) from male F344 rats (Casanova-Schmitz et 

al., 1984). Activities were quantified by measuring acetaldehyde-dependent formation of 

NADH at 340 nm during the first 1-5 min after addition of acetaldehyde. It could be 

demonstrated that in both respiratory and olfactory mucosa two isozymes were present. The 

higher Km isozeyme of ALDH was five to eight times greater in respiratory than in olfactory 

tissue, whereas the low Km ALDH was comparable in respiratory and olfactory homogenates. 

Exposure to acetaldehyde vapor does not significantly alter the enzyme activities in the nasal 

homogenates. Results are presented in table 3. 

Aldehyde dehydrogenase activities in whole nasal tissue homogenates (epithelia type not 

specified) from male B6C3F1 mice, Sprague-Dawley rats, Syrian golden hamsters and 

Hartley guinea pigs were determined according to the method described by Casanova-Schmitz 

et al. (1984) (Morris, 1997). The estimated Vmax values for each species were normalised to 

the predicted minute ventilation of that species. In mouse, rat, and hamster the data were 

compatible with the assumption of two isozymes with an apparent high affinity and an 

apparent low affinity. In contrast, only a single form (high affinity) was detected in guinea pig 

nose homogenates. Total metabolic capacity (when normalised to predicted minute ventilation 

of the respective species defined as the sum of Vmax for both high- and low-affinity isozymes, 

averaged 0.04, 0.16, 0.56, and 0.14 μmol/min/whole nose for nasal tissue of mouse, hamster, 

rat and guinea pig, respectively. The ratio Vmax/Km was significantly different between the 

species, the lowest activity observed in mouse (0.035 μmol/min/l/min) whereas hamster (0.13 

μmol/min/l/min) and rat (0.22 μmol/min/l/min) showed findings in the same range (Morris, 

1997). For comparison, the data are also presented in table 3. The data may indicate the 

existence of quantitative species differences. 

Since the nasal cavity epithelium is composed of a heterogeneous cell population, 

measurement of xenobiotic metabolizing enzymes using homogenates could yield artificial 

results. Therefore, a similar approach as has been used to comparatively evaluate kinetic 

constants of carboxyl esterase , the gas uptake technique (see carboxylesterase activity in the 

nose), has been applied for acetaldehyde dehydrogenase (Bogdanffy et al., 1998). Data from 

Casanova-Schmitz et al. (1984) were used for homogenate-derived values. Km and vmax values 

for aldehyde dehydrogenase activity in rats obtained by the gas uptake technique differed 
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from the values obtained using tissue homogenates. However, when data obtained from 

homogenates were scaled to whole nose based on epithelial volumes, comparable Km and vmax

values were obtained by the two different methodologies, which is illustrated in table 3. 

Table 3: summary of acetaldehyde hydroxylase activities in human and animal tissues 

Tissue Km Vmax Literatur 

rat respiratory tissue 

(determined in 

homogenates from 

respiratory mucosa) 

20 mM (high Km) 

3 x 10 exp-4 mM (low Km) 

128 nmol/mg prot/min 

(high Km) 

0.8 nmol/mg prot/min (low 

Km) 

Casanova-Schmitz et al., 

1984 

rat olfactory tissue 

(determined in 

homogenates from olfactory 

mucosa) 

22 mM (high Km) 

1 x 10 exp-1 mM (low Km) 

28 nmol/mg prot/min (high 

Km) 

2.2 nmol/mg prot/min (low 

Km) 

Casanova-Schmitz et al., 

1984 

rat whole nose homogenates 17 μmol/ml (high Km) 

0.03 μmol/ml (low Km) 

3.5 μmol/min/l/min (high 

Km) 

0.27 μmol/min/l/min (low 

Km) 

Morris, 1997 

mouse respiratory tissue 41 μmol/ml (high Km) 

0.07 μmol/ml (low Km) 

1.35 μmol/min/l/min (high 

Km) 

0.27 μmol/min/l/min (low 

Km) 

Morris, 1997 

hamster respiratory tissue 12 μmol/ml (high Km) 

0.02 μmol/ml (low Km) 

1.47 μmol/min/l/min (high 

Km) 

0.31 μmol/min/l/min (low 

Km) 

Morris, 1997 

guinea pig respiratory tissue ND (high Km) 

0.1 μmol/ml (low Km) 

ND (high Km) 

0.64 μmol/min/l/min (low 

Km) 

Morris, 1997 

rat respiratory tissue 

(homogenate data from 

Casanova-Schmitz et al., 

1984) 

0.8 mg/ml 3.38 mg/h Bogdanffy et al., 1998 

rat olfactory tissue 

(homogenate data from 

Casanova-Schmitz et al., 

1984) 

0.8 mg/ml 0.94 mg/h Bogdanffy et al., 1998 

rat respiratory tissue 

(determined by the gas 

uptake technique, 

normalized to tissue 

0.8 mg/ml 4.58 mg/h Bogdanffy et al., 1998 
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volume) 

rat olfactory tissue 

(determined by the gas 

uptake technique, 

normalized to tissue 

volume) 

0.8 mg/l 1.48 mg/h Bogdanffy et al., 1998 

human respiratory tissue 

(determined by the gas 

uptake technique, 

normalized to tissue 

volume) 

1.1 mg/ml 88.2 mg/h Bogdanffy et al., 1998 

human olfactory tissue 

(determined by the gas 

uptake technique, 

normalized to tissue 

volume) 

1.1 mg/ml 2.31 mg/h Bogdanffy et al., 1998 

Human oral cavity tissue 

(Acetaldehyde as substrate) 

75 – 83 mM (high Km) 

0.2 – 33 μM (low Km) 

 Dong et al., 1996; Yin et 

al., 1997 

Human oral cavity 170 nmol/min/ml tissue 

53 μmol/hr/ml tissue 

Dong et al., 1996 

Human esophagus and 

stomach 

75 – 85 mM Yin et al., 1997 

Human saliva 

(benzaldehyde as substrate) 

85 mM 9 nmol/min/ml saliva 

11.75 μmol/hr/ml saliva 

Aldehyde dehydrogenase in the gastrointestinal tract

ALDH activity has been demonstrated in oral cavity tissue in humans (Dong et al., 1996; Yin 

et al., 1997). Human ALDH can be divided into two groups based on their affinity for 

acetaldehyde metabolism, those having a low affinity (i.e. high Km of 75-83 mM) and those 

with a high affinity (i.e. low Km of 0.2 – 33 μM). Dong et al. (1996) report a low affinity 

ALDH in the human oral cavity with a specific activity of 170 nmol/min/ml tissue in the 

gingival at a substrate concentration of 20 mM acetaldehyde, which is approximately equal to 

a human oral cavity ALDH activity of 53 μmol/hr/ml tissue. The human esophagus and 

stomach also contains low affinity (Km: 75 – 85 mM) ALDH activity (Yin, 1997). ALDH 

activity has also been demonstrated in human saliva. Sreerama and coworkers identified a low 

affinity ALDH (Km = 85 mM) in the human saliva with a specific activity of 9 nmol/min/ml 

saliva at a substrate concentration of 4 mM benzaldehyde, which is equal to a ALDH activity 

of 11.57 μmol/hr/ml in human saliva (Sreerama et al., 1995). 

Aldehyde dehydrogenase in tissues different from nose and oral cavity
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In mammalians and humans, multiple forms of ALDH exist. Important to mention are the 

cytosolic aldehyde dehydrogenase of class 1 (ALDH1) and the mitochondrial aldehyde 

dehydrogenase of class 2 (ALDH2). ALDH1 and ALDH2 have been determined in a variety 

of human and animal tissues (Uotila and Koivusalo, 1997). However, Acetaldehyde was not 

degraded in the presence of diluted human (and also rat and mouse) plasma or whole blood, 

even when these systems were fortified with NAD (Strong et al., 1980). 

In an assay which detects both formaldehyde dehydrogenase (FAD) and ALDH activity 

simultaneously, formation of formate as a marker of enzyme activities could be determined in 

normal human bronchial epithelial cells and in normal human bronchial explants (Ovrebo et 

al., 2002). Nevertheless, expression of ALDH enzymes alone has not been determined so far 

in tissues of the upper respiratory tract of humans. Both ALDH1 and ALDH2 enzymes 

display Km values in the range of 0.5 mM for free formaldehyde (Mukerjee et al., 1992). 

Cytochrome P450 2E1 (CYP2E1)

It has been investigated whether CYP2E1 is involved in vinyl acetate metabolism. Rats were 

pretreated with the CYP2E1 inhibitor diallyl sulphide. Nasal tissues were removed and 

assayed for CYP2E1 dependent p-nitrophenol hydroxylase activity. Nasal respiratory and 

olfactory microsomal CYP2E1 activity was inhibited. However, CYP2E1 inhibition had no 

significant effect on nasal vinyl acetate extraction. Therefore it was concluded that CYP2E1 

does not contribute to local metabolism of vinyl acetate (Bogdanffy et al., 1999a). These 

investigations confirm previous results by Simon et al. (1985): after pre-treatment of rats with 

the CYP2E1 inhibitor diethyldithiocarbamate, the pharmacokinetics of vinyl acetate was not 

affected. 

Glutathione transferases/glutathione conjugation

Based on the facts that i.p. injection of vinyl acetate to female Chester-Beatty rats resulted in 

a decrease of hepatic glutathione level to 77% of the normal value 30 min after application 

(Boyland and Chasseaud, 1970) and that similar decreases of hepatic non-protein sulfhydryls 

were reported after i.p. vinyl acetate injection to mice (300 mg/kg bw), Wistar rats (300 or 

450 mg/kg bw) and guinea pigs (500 mg/kg bw) (Holub and Tarkowski, 1982), it has been 

assumed that these findings may indicate conjugation with glutathione. Unpublished results 

from DuPont Haskell Laboratories, however, did not confirm this assumption: no depletion of 

glutathione was noted in isolated nasal turbinates incubated in nutritive medium supplemented 

with vinyl acetate. Direct incubation of vinyl acetate with glutathione-containing solutions 

resulted in no loss of vinyl acetate from the headspace indicating that vinyl acetate does not 

readiliy react with glutathione. However, it could not be ruled out, that glutathione 

conjugation might occur at extremely high doses of vinyl acetate. 

Physiologically based modelling - inhalation

A physiologically based pharmacokinetic (PBPK) model was developed to describe the 

deposition of vinyl acetate in the nasal cavity of the rat. The model estimates tissue exposure 

to vinyl acetate, acetaldehyde, and acetic acid in respiratory and olfactory mucosa with a 

submodel estimating potential intracellular pHi change associated with vinyl acetate exposure 
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(Plowchalk et al., 1997). The model takes into account the known data on vinyl acetate 

metabolism (see fig.1). 

In this model nasal cavity is described by three separate tissue compartments which are in 

contact with two airstreams flowing through the nose (Morris et al., 1993; Kimbell et al., 

1993). Fractional airflows were set 12% for the dorsal medial airstream (olfactory and 

respiratory mucosa) and 88% for the lateral/ventral airstream (respiratory mucosa). In the 

model airflow is assumed to be unidirectional. Each tissue compartment was subdivided into 

layers representing mucus, epithelial cells, basal cells, and submucosal tissue. Mucus depth 

for both olfactory and respiratory mucosa was assumed to be 10 μm, based on morphometric 

analysis. Depth of the respiratory mucosa was estimated to be approximately 40 μm 

(epithelial cell layer 30 μm, basal cell layer 10 μm). The epithelial layer in the olfactory 

mucosa consisted of sustentacular cells (40 μm), sensory cell bodies (not included since these 

cells do not contain vinyl acetate metabolising enzymes), and basal cells (10 μm). 

It was assumed that all enzymatic activity located in the submucosa was in the cell layers of 

the first 20 μm. Enzymes involved in vinyl acetate metabolism are assumed not to be 

uniformly distributed throughout the nasal cavity. Histochemical studies (Bogdanffy et al., 

1987) indicate that carboxylesterase activity is located primarily in the cytoplasma of 

epithelium cells (strong), basal cells (moderate), and weak to negligible in goblet cells and the 

overlying mucus of the respiratory mucosa. Distribution of carboxylesterase activity in the 

olfactory tissue is primarily in sustentacular cells of the epithelia and Bowman’s glands. 

Overlying mucus, basal cells and neuronal (sensory) cells were negative. 

Aldehyde dehydrogenase is demonstrated by immunohistochemical staining primarily in the 

epithelial and basal cells of respiratory mucosa, was weak to negligible in basal cells and 

Bowman’s glands and was absent in the sustentacular and sensory cells of the olfactory 

mucosa (Bogdanffy et al., 1986). Kinetic constants for carboxylesterase catalysed hydrolysis 

of vinyl acetate were estimated from in vitro determinations by Bogdanffy et al., 1993 (nasal 

tissue homogenates, converted from nmol/min/g protein basis to mg/h for the whole nose). 

Rates of aldehyde dehydrogenase activity in respiratory and olfactory mucosa were estimated 

from literature (Casanova-Schmitz et al., 1984) by scaling the reported values 

(nmoles/min/mg protein from homogenates) to a whole nose basis, assuming a tissue protein 

content of 90 mg protein/g and tissue weights of 111 mg respiratory mucosa/nose and 141 mg 

of olfactory mucosal tissue/nose. 

Data for the kinetic constants and distribution of acetyl-CoA synthetase within the nasal tissue 

are not available. The Km and Vmax for acetyl-CoA synthetases were estimated from values 

reported for muscle tissue in Wistar rat (Knowles et al., 1974). It was assumed that the 

enzyme was equally distributed in each tissue compartment. 

Vapour is transported to the air: tissue interface by diffusion. The molecular diffusivities were 

extrapolated from the diffusivity of ethanol in water (Morris et al., 1993). 

Perfusion of blood through the nasal cavity was modelled as blood flowing only through the 

two submucosal compartments in the respiratory and olfactory tissues at a total nasal 

perfusion rate of 13.2 ml/h (Morris et al., 1993). Symmetrical perfusion was assumed (6.6 

ml/h). 

In the pharmacodynamic submodel reduction of intracellular proton concentration was 

described to depend on intracellular buffering and transport to the extracellular compartment 
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by the pH-dependent Na+

/H+ antiport. Na+/H+ antiport activities are not available for rat nasal 

tissues and were estimated from proton efflux rate versus pH data for human leukocytes 

(Goldsmith and Hilton, 1992). 

The dosimetry model was applied to data from a series of experiments in vivo (see above, 

Plowchalk et al., 1997) designed to measure uptake and metabolism of vinyl acetate in the 

isolated upper respiratory tract of anaesthetised rats at exposure concentrations ranging from 

73 to 2190 ppm during 1-h inhalation (unidirectional flow, 100 ml/min). The best model fit 

for the experimental data on vinyl acetate extraction was achieved when a second 

carboxylesterase ‘high affinity pathway’ was included into the model. The high-affinity 

carboxylesterase was placed in the mucus compartment of the model. Histochemical studies 

support this assignment (Bogdanffy et al., 1986). The kinetic constants derived for the high 

affinity pathway are similar to those that would be expected for many low molecular-weight 

substrates for cytochrome P-450 2E1. However, as the presence of P-450s in mucus is 

improbable the authors assume that the proposed high-affinity pathway is represented by an 

isoenzyme of carboxylesterase (see Bogdanffy et al. 1999a). 

Model simulations (unidirectional flow, 188 ml/min, data at the end of 6 h-exposure of vinyl 

acetate for the first epithelial compartment in the tissue stack) predicted an exposure 

concentration-dependent increase in tissue concentrations of vinyl acetate, acetaldehyde and 

acetic acid in respiratory mucosa and also in olfactory epithelial mucosa (dosimeters given at 

vinyl acetate exposure concentrations of 50, 200, 600 and 1000 ppm). Steady-state 

concentrations of vinyl acetate in olfactory tissue are predicted to be much lower than in 

respiratory tissue at all exposure concentrations. Concentrations of acetaldehyde and acetic 

acid are expected to be approximately 1-2 orders of magnitude greater than vinyl acetate 

concentrations in all tissue compartments. 

At vinyl acetate expositions of ≤ 600 ppm the concentrations of acetaldehyde in nasal 

olfactory and respiratory epithelium were predicted to be less than 5 mM. The greatest 

reduction in intracellular pHi was predicted for respiratory mucosa . 

A sensitivity analysis was conducted for four concentrations (5, 50, 200, and 600 ppm vinyl 

acetate) of vinyl acetate during 4-h exposures. The air flow and high-affinity metabolic 

parameters are the most important model parameters in relation to uptake of vinyl acetate by 

the rat nose (Plowchalk et al., 1997). 

Bogdanffy et al. (1999b) have extended the model of Plowchalk et al. (1997) by 

(1) constructing a 5-compartment model of the rat nasal cavity 

(2) a 4-compartment model of the human nasal cavity and 

(3) air phase resistance to mass transfer from the lumen to the air: mucus interface. 

This model is modified to account specifically for the dorsal anterior patch of olfactory 

epithelium for the human and the rat nasal cavity. To better characterise the vinyl acetate flux 

to the apical regions of the olfactory compartments, the 5-compartment rat model divides the 

olfactory region into 2 compartments, a small dorsal anterior compartment (olfactory-1) and a 

larger posterior compartment (olfactory-2). The respiratory mucosa on the ventral side is also 

divided. This model incorporates air phase resistance to mass transfer. In the model of 

Plowchalk et al. (1997) equilibrium between the air and the mucus phase was assumed. A 

detailed quantitative estimate of the various cell layer thicknesses comprising the olfactory 
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and the respiratory mucosa of the rat and the human is provided by Bogdanffy et al. (1998).

Distribution of enzymes to specific compartments was based on histochemical localisation 

and is described in detail by Plowchalk et al. (1997). Enzyme kinetic constants for 

carboxylesterase and aldehyde dehydrogenase were obtained from a whole tissue, in vitro, gas 

uptake technique (Bogdanffy et al., 1998). For rats a high affinity carboxylesterase pathway 

was optimised from vinyl acetate deposition data (rat nasal air stream 100 ml/min; exposure 

concentration ranged from 75 to 1500 ppm) in vivo. These values were adopted for humans 

and were scaled to account for differences in tissue amount between rats and humans. The Km

and Vmax for acetyl-CoA synthetase were estimated from values reported for muscle tissue in 

Wistar rat (Knowles et al., 1974), scaled to humans based on surface area. Mass transfer 

coefficients are results from hybrid computational fluid dynamics simulations on rat and 

human nasal cavity (Frederick et al., 1998). Blood perfusion was scaled to species based on 

cardiac output and nasal region based on surface area. Total nasal perfusion estimated to be 

0.3% cardiac output compares favourably with measured values (Stott, 1983). The 

pharmacodynamic submodel for estimating intracellular acidification was described by 

Plowchalk et al., 1997. The PBPK model was used to examine the intracellular accumulation 

of acetic acid, acetaldehyde and protons produced during the metabolism of vinyl acetate at 

vinyl acetate expositions of 50, 200 and 600 ppm. At vinyl acetate exposure concentrations 

<600 ppm the concentrations of acetaldehyde in the olfactory-1-compartment of rats and the 

single olfactory compartment of humans were predicted to be <2 mM. Predictions of olfactory 

acidification for both rat and humans are presented. The change of intracellular pH is 

predicted to be slightly greater for human olfactory epithelium, than that of rats, per ppm 

inhaled vinyl acetate. Results for respiratory compartments are not shown. 

To provide validation data for the application of the model in humans (Bogdanffy et al., 

1999b), controlled human exposures to inhaled vinyl acetate were conducted (Hinderliter et 

al., 2005). Air was sampled by a probe inserted into the nasopharyngeal cavity of five 

volunteers (two women, three men). Volunteers were administered a nasal aerosol spray 

consisting of 2 % lidocaine and 0.25 % oxymetazoline hydrochloride and were instructed to 

inhale and exhale through the nose. Sampling was carried out during exposure to labelled 

13C1, 13C2-vinyl acetate during resting and light exercise at three exposure levels (1, 5 and 

10 ppm nominally). Both labelled vinyl acetate and the major metabolite acetaldehyde from 

the nasopharyngeal region were sampled at a calibrated flow rate of 12 l/h and analysed in 

real time utilising ion trap mass spectrometry (MS/MS). Measurements were taken every 0.8 

sec in an exposure period of 2 to 5 min resulting in data during all phases of the breathing. 

The rate of sampling is rapid enough to capture many of the behaviours of vinyl acetate in the 

human nasal cavity including inhalation and exhalation. The sampling frequency is not short 

enough, however, to accurately capture the peak concentration in every breath. The method is 

free of interference from endogenous compounds and its detection limit is in the single digit 

ppb level. An acoustic rhinometry system was used to measure the cross-sectional area and 

volume of the nasal cavity. The complete set of human exposures resulted in a data set with 

over 22000 vinyl acetate and acetaldehyde data points. Data treatment was needed to identify 

the relevant experimental data, i. e. the peak concentrations for comparison of experimental 

data from bidirectional air flow (breathing cycle) with model data from unidirectional flow. 

After treatment, the experimentally determined concentrations of both vinyl acetate and 

acetaldehyde were then compared to the predicted concentrations calculated by applying the 

previously published human model (Bogdanffy et al., 1999b). The PBPK-model was 

exercised at the actual exposure concentrations. Other parameters were the same as presented 

in the human nasal model. Sensitivity analysis indicates that the air phase concentrations are 

most sensitive to the tissue:air partition coefficients, nasal airflow and the metabolic capacity 

of mucus layer . For each individual volunteer, the data from each exposure (i.e. three resting 
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and three light exercise periods) were characterised by a mean standard deviation, along with 

the model simulations. The concentrations of both compounds in airway appear to be linear as 

the model predicts. For vinyl acetate deposition data sets, the experimental measured 

concentrations are close to the model predicted peak concentrations (r = 0.9). Acetaldehyde 

data are fitted with somewhat lower precision (r=0.6). The authors give the explanation that 

increase in breathing rate resulted in difficulties of the analytical set up which resulted in less 

accurate measurements of peak concentrations. We are of the opinion, that the precision of the 

prediction is fair. Given the variations in the experimental data there is no significant interindividual variation and no significant difference in nasopharyngeal concentrations of vinyl 

acetate and acetaldehyde based on exercise state. These results show that the human nasal 

model (Bogdanffy et al., 1999) predicts the experimental observations with regard to vinyl 

acetate concentrations and acetaldehyde wash-out in the airstream of human nasopharyngeal 

cavity in a concentration range from 1 to 10 ppm. 

Physiologically based modelling - upper gastrointestinal tract 

A physiologically based pharmacokinetic (PBPK) model was developed to describe the 

uptake and metabolism of vinyl acetate in the upper gastrointestinal (GI) tract following 

ingestion of vinyl acetate via drinking water in mice, rats and humans (Sarangapani, 2001). 

The model describes the upper GI tract using three compartments, one each for the oral 

cavity, esophagus and forestomach, respectively. Each compartment is divided into a threelayered substructure. A top lumen layer provides passage of the ingested vinyl acetate, a 

middle epithelial layer forms the target tissue for vinyl acetate toxicity, and a lower 

submucosal layer with blood perfusion clears the parent chemical and its metabolites. This 

model takes into account the known course on vinyl acetate metabolism (see Fig. 1). A 

pharmacodynamic submodel (PD model) was developed to describe the intracellular pHi 

change associated with vinyl acetate exposure (see also "physiologically based modellinginhalation"). The steady state pH of epithelial cells is determined by the balance between the 

rate of acid loading due to cellular metabolism, the cellular buffer strength, and the rate of 

proton transport due to special mechanisms. The PD model assumes the intracellular buffer to 

be a closed system containing bicarbonate and phosphate as buffers. 

The upper GI tract epithelial and submucosal tissue thickness in rats and mice were measured 

from histological sectioning. The tissue thickness in humans was assumed to be same as in 

rats. Morris et al. (2002) measured carboxylesterase activity in the oral cavity tissue of rats 

and mice in homogenates of several tissue samples (see "in vitro data"). The composite 

activity values were scaled for tissue volume. Carboxylesterase activity in the esophagus and 

the forestomach was not measured. Human activity was obtained by allometrically scaling the 

mouse value to man. Aldehyde dehydrogenase (ALDH) activity has been demonstrated in oral 

cavity tissue in humans (Dong et al., 1996; Yin et al., 1997). Rates of ALDH activity in rats 

and mice oral cavity were assumed to be equal to that of humans. The acetyl-CoA synthetase 

activity was taken from values reported for muscle tissue in Wistar rats (Knowles et al., 

1974). Other model parameters were either obtained from the available literature (diffusivity, 

cardiac output, surface area) or were estimated from experimental studies (water intake). The 

antiport parameter for the PD-submodel was estimated from values of cultured vascular 

muscle cells of rat or human lymphocytes. 

The PBPK model was used to estimate steady state concentrations (24-h exposure) of acetic 

acid, acetaldehyde and intracellular proton concentration in the epithelial cell layer of the 

three tissue compartments for a range of vinyl acetate exposure concentrations from 400 to 

10000 ppm in drinking water. The anterior tissue compartment along the GI tract (oral cavity) 
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is the tissue with the highest uptake of vinyl acetate both in rats and mice (rat data are not 

shown) when compared to oesophagus and forestomach (anterior-posterior gradient). The 

concentrations of vinyl acetate, acetaldehyde and acetic acid show a decline across the tissue 

layers in the mouse oral cavity for the three exposure concentrations used in the study. The 

amount of acetaldehyde, formed intermediately in the epithelial tissue of the mouse oral 

cavity is predicted to be about 0.16 and 0.63 mM at an exposure of 400 ppm and 2000 ppm 

vinyl acetate, respectively. Although this PBPK model focuses on the upper gastrointestinal 

tract and does not include systemic components, it could be concluded from the model, that 

the clearance of vinyl acetate and its metabolites from the submucosal tissue into systemic 

circulation will be negligible. The model-derived exposure-dose relationship for intracellular 

proton concentration is sigmoidal. The reduction in pH from the resting-phase proton 

concentration is about 0.4 and 0.7 pH units at a vinyl acetate exposure of 400 and 2000 ppm, 

respectively. Bogdanffy (2001) demonstrated this effect of intracellular acidification by 

exposing freshly isolated rat hepatocytes to vinyl acetate and observing transient alterations in 

intracellular pH by use of a pH sensitive fluorescent marker that was located within the 

cytoplasm of isolated hepatocytes. 

Sensitivity analysis reveals that the model-estimated internal dose-metrics are sensitive to oral 

esterase activity, tissue thickness and antiport characteristics. Values for oral esterase activity 

and oral tissue thickness are available for the rat and mouse, but not for humans. Similarly, 

antiport characteristics for rats cultured vascular muscle cells and human lymphocyte are 

available, but antiport data specific to the oral cavity epithelial cells are not available. Due to 

these missing data the exact variability in the internal dose-metric in humans cannot be 

accurately predicted from the mouse-PBPK model. 

Conclusion:

Following inhalation and oral exposure of rats vinyl acetate is rapidly and effectively 

hydrolysed by carboxylesterases leading to the formation of acetic acid and acetaldehyde 

which is further converted into acetic acid in the presence of aldehyde dehydrogenases. 

Further information on acetaldehyde and acetic acid can be obtained from separate reports 

(e.g. reports prepared by the German MAK Commission). 

The in vivo uptake of vinyl acetate was measured in the isolated upper respiratory tract of rats 

(anaesthetised rat, unidirectional flow, and 1 h-exposure). Disappearance of vinyl acetate 

from the airstream was highest at the lowest exposure concentrations. Greater than 94% 

extraction was observed at vinyl acetate exposure concentrations of 76 ppm or below. With 

increasing exposure concentration (76 to 550 ppm), extraction decreased progressively to 

about 40% and remained at this level up to concentration of approximately 2000 ppm. The 

impact on blood-flow extraction on vinyl acetate deposition has been calculated by simulating 

vinyl acetate exposure in the absence of carboxylesterase activity. It could be demonstrated, 

that blood flow extraction accounts for less than 15 % of total vinyl acetate deposition. Hence, 

15 % inhalative uptake can be taken as a worst case scenario for risk characterisation of 

systemic effects. However, it should be kept in mind, that vinyl acetate can be degraded in the 

blood with half lives between < 1 min and 4.1 min. 

After oral administration of 297 mg/kg/bw 14C vinyl acetate, 63 % of the applied radioactivity 

was excreted as metabolites in exhaled air, urine and faeces. Based on the fact that vinyl 

acetate can be metabolized in the upper GI tract epithelium it can be assumed, that a 

considerable extent of metabolism takes place presystemically which is supported by an oral 
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PBPK model (see below). This model led to the conclusion, that clearance of vinyl acetate 

and its metabolites into the systemic circulation would be negligible. Hence, 63 % absorption 

would represent an overestimation of systemically available amounts of vinyl acetate. 

However, the PBPK model developed for oral vinyl acetate exposure did not include systemic 

components and furthermore, the model was developed in the absence of valid data for 

carboxylesterases in animal and human tissues. Based on the fact, that carboxylesterases in 

the GI tract are lower compared to carboxylesterase activities in nasal tissues, 50 % 

absorption can be assumed as a worst case for systemically available amounts of vinyl acetate 

after oral uptake. However, no clear assumptions can be made for systemically available 

metabolites of vinyl acetate (acetaldehyde, acetic acid). 

There are no valid quantitative data on the systemic bioavailability of vinyl acetate and its 

metabolites following dermal exposure. However, based on an acute dermal study in rabbits 

and based on the fact that carboxylesterase activities are lower in skin compared to nose or 

oral cavity, it can be assumed that systemic bioavailablility of vinyl acetate and/or vinyl 

acetate-derived metabolites is higher after dermal exposure when compared to oral or 

inhalative exposure. Therefore 90 % dermal absorption should be taken forward to the risk 

characterisation. 

Local metabolism was studied in human and rat nasal respiratory and olfactory tissue with 

whole turbinates in vitro. The studies indicated species differences of nasal respiratory 

carboxylesterase activities between rats and humans. The differences varied depending on the 

mode of data presentation (activity per specimen/activity per epithelial cell volume/activity 

scaled to whole nose). Therefore, no clear conclusions on the magnitude of species 

differences of nasal respiratory carboxylesterase activities can be drawn from these 

investigations. Rat aldehyde dehydrogenase activity in respiratory epithelium was about twice 

that of humans. Activities of the rat olfactory enzymes (carboxylesterase and aldehyde 

dehydrogenase) were about equivalent to those of humans. The Km values for both enzymes 

are not different between the two species. Aldehyde dehydrogenase activities determined in 

whole nasal tissue homogenates from mouse, rat, hamster and guinea pig showed significantly 

different ratios Vmax/Km for the various species indicating the existence of species differences. 

Vinyl acetate hydrolysis has been studied in vitro in the oral mucosal tissues from the oral 

cavity of rats and mice. The hydrolysis activity of the oral tissues is at least 100-fold lower 

than that of the nasal tissues. 

A physiologically based pharmacokinetic model was developed which describes the 

deposition of vinyl acetate in the nasal cavity of the rat. This model predicts steady state 

concentrations of the metabolite acetic acid after continuing 6 h-exposure in respiratory tissue 

which are approximately 13 times greater and in olfactory tissue which are approximately 2 

times greater than those of acetaldehyde, the second metabolite. As the concentration of acids 

is indicative for the concentration of protons the model predicts the greatest reduction in 

intracellular pHi for respiratory mucosa. Hence, pH effects should be more pronounced in this 

tissue as compared to other tissues. This physiologically based toxicokinetic/toxicodynamic 

model for rat was modified for the olfactory epithelium of the both human and rat nasal 

cavity. The change in intracellular pH is predicted to be slightly greater for human olfactory 

epithelium, than that of rats. To provide validation data for this model, controlled human 

exposures at exposure levels of 1, 5 and 10 ppm to inhaled vinyl acetate were conducted. Air 

was sampled by a probe inserted into the nasopharyngeal cavity of five volunteers at 

bidirectional breathing through the nose. Data from ion trap mass spectrometry measurements 

of labelled vinyl acetate and acetaldehyde were compared with data from the human nasal 
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model simulation. For the vinyl acetate data a good fit was demonstrated (r = 0.9). 

Acetaldehyde data are fitted with a somewhat lower precision. The results show that the 

human nasal model predicts the experimental observations with regard to vinyl acetate 

concentrations and the acetaldehyde washout in the airstream of human nasopharyngeal cavity 

in a concentration range from 1 to 10 ppm. However, uncertainties of the model consist in the 

enzyme kinetic data used to establish the model. Therefore, data on PK and PD outcome 

derived from the model should be taken with caution. 

A similar PBPK model with a pharmacodynamic submodel for the upper GI tract of mouse, 

rat and man was developed to estimate oral vinyl acetate uptake, metabolism and the 

reduction in the intracellular pH. The model was used to estimate steady state concentrations 

(24 h exposure) of acetic acid, acetaldehyde and intracellular proton concentration in the 

epithelial cell layer for a range of vinyl acetate exposure from 400 to 10000 ppm in drinking 

water. Details of model simulations are given for mouse. The intracellular pH reduction from 

the resting-phase proton concentration is about 0.4 and 0.7 pH units at a vinyl acetate 

exposure of 400 and 2000 ppm, respectively. Due to missing human data (carboxylesterase 

activity and tissue thickness) the exact variability in the internal dose-metric in humans 

cannot be accurately predicted from the PBPK model. 
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4.1.2.2 Acute toxicity 

Animal data:

Vinyl acetate exhibits low acute toxicity by the oral and the dermal way of exposure but 

significant acute inhalation toxicity: 

Oral 

An oral LD50 value of 3.73 ml/kg (= 3470 mg/kg) was determined in a range finding study in 

rats, using vinyl acetate (no data on purity): Doses of 8, 4 and 2 ml/kg body weight were 

administered by stomach intubation to 5 rats per dose. After application of 8 ml/kg all rats 

died within 24 hours, whereas after application of 4 ml/kg 3/5 rats died within 24 hours, and 

after application of 2 ml/kg no mortalities were observed. Clinical signs included 

sluggishness, gross pathology detected congestion throughout the lungs and the abdominal 

viscera, the liver was mottled (no more data given) (Mellon Institute, 1969). 

The same oral LD50 value of 3.76 ml/kg (approximately 3500 mg/kg) for rats resulted from a 

study using 2% and 20% vinyl acetate emulsions with traganth. dyspnoe, tremors, apathy and 

diarrhoea were observed. At necropsy, no gross changes were detected (no further data given) 

(BASF AG, 1967). 

Dermal 

A range finding study with rabbits demonstrated a dermal LD50 value of 8.0 ml/kg (= 7440 

mg/kg) for vinyl acetate (no data on purity): Four rabbits per dose (doses: 4, 8 and 16 ml/kg 

body weight) were immobilised during a 24-hours contact period with the compound retained 

under impervious sheeting on the clipped intact skin of the trunk. The animals were placed in 

a hood with their heads protruding into the room to prevent the inhalation of the vapour. After 

occluded application of 16 ml/kg all animals died (clinical signs: convulsions within 15-30 

minutes, crying, pupils turned upward, deaths within 25-70 minutes). After occluded 

application of 8 ml/kg 2/4 animals died within 2 days (skin condition: erythema, oedema, 

necrosis). After occluded application of 4 ml/kg no mortalities and no clinical signs were 

observed. However, gross pathology revealed congestion of the lungs and liver, mottled 

spleen and kidney and prominent liver acini (Mellon Institute, 1969). 

Inhalation 

An acute inhalation range finding study with rats resulted in an LC50 value of 4490 ppm (= 

15.8 mg/l/4 hours): Vinyl acetate vapour at metered concentration, not checked analytically, 

was generated by feeding the liquid at a constant rate down the inside of a spirally corrugated 

surface of a minimally heated tube, through which metered air was passed. This vapour was 

delivered in a glass exposure chamber to 6 male and 6 female rats per dose (doses: 8000, 4000 

and 2000 ppm). While inhaling 8000 ppm all male and all female rats died during the 

exposure time (clinical signs: gasping at 10, prostration at 25, convulsions and death at 50 

minutes to 1.5 hours). While inhaling 4000 ppm 2/6 male and 2/6 female rats died during the 
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exposure time (clinical signs: laboured breathing at 20 minutes, convulsions at 2.5 hours, 

death at 3 hours). After inhalation of 2000 ppm no rat died (clinical signs: extremities red and 

irritated). Gross pathology detected haemorrhages in lungs and tracheae of victims, but no 

remarkable effects after inhalation of 2000 ppm (Mellon Institute 1969). In another study 

4000 ppm vinyl acetate (= 14.1 mg/l) killed 2-4/6 rats within an exposure time of 4 hours. No 

further data are submitted (Carpenter et al., 1949). 

In a study on toxicity caused by inhalation of saturated vinyl acetate vapours (temperature 

used was 20o

C) 10/12 rats died within 3 minutes of exposure. Saturated vapours were 

produced by blowing air through a 5 cm layer of vinyl acetate and inhalation resulted in death 

of 0/12 rats after 1 minute, 10/12 rats after 3 minutes and 6/6 rats after 10 minutes of 

exposure. Clinical signs prior to death included severe irritation of mucous membranes, 

laboured breathing and narcosis. At necropsy, no gross changes were detected (BASF AG, 

1967). 

Human data:

No human data available. 

Conclusion: 

Human data on the acute toxicity of vinyl acetate are not available. In tests with rats LD50

values were in two studies 3470 mg/kg and 3500 mg/kg, respectively. A dermal LD50 value of 

7440 mg/kg was determined from a range finding study with rabbits. Thus, vinyl acetate 

needs no labelling according to EU criteria with respect to acute oral and acute dermal 

toxicity. Inhalation toxicity testing, however, resulted in LC50 values of 15.8 mg/l/4 hours and 

14.1 mg/l/4 hours in rats; thus requiring classification as harmful and labelling with „R 20, 

harmful by inhalation“. 

4.1.2.3 Irritation 

4.1.2.4 Corrosivity 

Animal data:

Vinyl acetate has proven to cause irritation or corrosion to the skin of rabbits depending on 

the duration of the skin contact. 

The primary skin irritation potential of vinyl acetate (stab., 99.9% purity) was investigated 

according to international test guidelines by semi-occlusive application of 0.5 ml of the 

substance to the intact skins of one male and two female New Zealand White rabbits. Oedema 

was not observed, mean scores for erythema (observation 24, 48 and 72 hours after 

application) were calculated to be 0.7/0.3/0; erythema disappeared in all animals after 3 days. 

No corrosive effects were noted on the treated skin of any animal at any of the measuring 

intervals and no other clinical signs of substance related effects were observed (RCC 2003a). 
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In a Draize skin test with rabbits similar to current EU guidelines vinyl acetate caused skin 

irritation: Six rabbits were exposed by occlusion to 0.5 ml of undiluted liquid vinyl acetate 

each. Effects on intact skin included erythema (scores 1/1/1.5 for 4, 24, 72 h) and oedema 

(scores 2.7/2.2/0.3 for 4, 24, 72 h). Erythema observation at 4 and 24 h was difficult due to 

red staining of the application site. Subdermal haemorrhage was observed in one animal after 

72 hours (Industrial BIO-Test Labs. Inc., 1972). 

Mild irritation after 5-15 minutes of exposure and necrosis after 20 hours of exposure was 

demonstrated in a further skin irritation study: An unknown number of rabbits were dermally 

exposed to unknown amounts of undiluted vinyl acetate for 1, 5 and 15 minutes and for 20 

hours (no information on the kind of exposure). No signs of irritation were observed after 24 

hours following 1-minute exposure; slight erythema occurred 24 hours after the 5- and the 15-

minutes exposures. Mild erythema and mild oedema were observed at 24 h after the 20-hours 

exposure. Necrosis was observed 8 days after 20 hour-exposure to the compound (BASF AG, 

1967). 

Long time occlusive dermal application of 8 ml/kg killed 2/4 rabbits within 2 days; these 

animals showed necrosis at the application site (Mellon Institute, 1969, see chapter on acute 

toxicity). 

Application of 1-2 drops of the undiluted substance (stabilised with 3-5 ppm hydroquinone) to 

the eyes of rabbits after 1 hour mild (+) erythema, pronounced (++) oedema and after 24 

hours mild (+) erythema and mild (+) opacity. No signs were observed after 8 days. The 

number of test animals was not given, scores were mild (+), pronounced (++), very strong 

(+++) (BASF AG, 1967). 

Vinyl acetate caused mild irritation in the eyes of rabbits which was reversible within 48 h 

after application. The test was performed according to the current guidelines on acute eye 

irritation (OECD 405, B.5 92/69 EEC). The amount of 0.1 ml of undiluted vinyl acetate 

(purity of 99.9 %) was placed in the left conjuctival sacs of one male and two female New 

Zealand White rabbits. One hour after application mild redness and chemosis of conjunctivae 

were observed, which were fully reversible in all animals after 48 and 24 h, respectively. No 

changes of corneal opacity and iris were observed. The mean scores determined after 24, 48 

and 72 h and relevant for classification were 1/0/0 for redness and 0/0/0 for chemosis, corneal 

opacity and iris (RCC, 2003c). 

Five rabbits that received 0.1 ml undiluted vinyl acetate (clear liquid, purity not given) 

showed mild reddening 24 to 48 hours after application. In three animals chemosis was 

observed after 24-48 hours (without any scores). Overall, mild eye irritation was concluded 

(Hoechst, 1970). 

Vinyl acetate has proven to cause severe irritation in the respiratory tract of rats (see chapters 

on acute toxicity, 4.1.2.2 and repeated dose toxicity, 4.1.2.6).
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Human data:

Exposed workers are principally exhibiting local irritant reactions of the skin, eyes and 

respiratory tract (information by the vinyl acetate industry, without further details). Other, 

more substantiated information on irritating effects on humans is not available. 

Conclusion:

Except a general notice from occupational use no substantiated human data on 

irritation/corrosion caused by vinyl acetate are available. 

Due to the only valid tests (RCC, 2003a and c) mild irritative effects on the skin and eyes of 

rabbits were observed that do not warrant classification. Earlier studies of limited reliability 

indicated pronounced irritation or corrosion of skin after extended exposure periods. 

Acute inhalation tests with rats demonstrated severe irritation in the respiratory tract of the 

animals. Thus, vinyl acetate should be labelled „R 37 Irritating to respiratory system 

according to the Annex I rules. In September 2007 the TC C&L agreed on R37. 

 

4.1.2.5 Sensitisation 

Animal data:

The potential of undiluted vinyl acetate (commercial grade) to produce delayed contact 

hypersensitivity in guinea pigs was evaluated with the Buehler method (adoption of method of 

Ritz and Buehler). The study was performed with 20 animals in the test group and 10 animals 

in the control group. 

Animals were induced 3 days per week with undiluted commercial grade vinyl acetate 

(usually containing 1.5-20 ppm hydroquinone as a stabiliser) under an occluded patch (6 

hours per exposure) placed in a restrainer. After a rest period of 2 weeks the animals were 

challenged with 25% vinyl acetate in acetone. The incidence and severity of skin responses in 

the test group (grade 1 responses: slight but confluent, or moderate patchy erythema; grade +

responses: slight patchy erythema) were greater than those produced by the naive control: 

Twenty four hours after removal of the test 6/20 test animals demonstrated effects grade 1 and 

14/20 effects grade +, 48 hours after removal 3/20 test animals showed grade 1 and 17/20 

grade + effects; in the control group no grade 1 and 7/10 grade + effects were observed. Thus, 

the testing laboratory concluded that vinyl acetate was a skin sensitiser in guinea pigs. 

Since the vinyl acetate stabiliser hydroquinone (commercial grade vinyl acetate usually 

contains 1.5 to 20 ppm hydroquinone) has been reported to cause skin sensitization in 

concentrated form, 5 ppm hydroquinone in acetone was also tested (Buehler test). Following 

primary challenge no grade 1 responses occurred. The incidence of grade + responses (slight, 

patchy erythema) in the hydroquinone-treated group (7 of 10) was compared to that of the 

naive control group (7 of 10). Since incidence and severity of the responses were essentially 

comparable between these 2 groups, the testing laboratory concluded that sensitization had 

not been induced by hydroquinone (Hill Top Biolabs Inc., 1995). 
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Vinyl acetate (purity > 99.9%) was tested in a Local Lymph Node Assay (LLNA). A total of 

seven groups each of five female mice (CBA strain) were used. Five groups were treated with 

Vinyl acetate at concentrations of 5%, 10%, 25%, 50% (w/v) in acetone: olive oil, 4:1 (v/v) 

and 100% (undiluted) by topical application to the dorsum of each ear lobe (left and right) on 

three consecutive days. A negative control group was treated only with the vehicle. A positive 

control group was treated with Alpha-Hexylcinnamaldehyde at a 25% concentration. The 

application area of both ears of each mouse was measured for ear thickness prior to the first 

application, daily 24 hours after each dosing and prior to necropsy. Five days after the first 

topical application the mice were intravenously injected into the tail vein with 3

H-methyl 

thymidine (equal to 19.8 μC/mouse). Approximately five hours after the intravenous injection 

the mice were killed, auricular lymph nodes were excised and pooled per animal. Single cell 

suspension were prepared, washed and incubated with trichloroacetic acid overnight. 3

Hthymidine incorporation was measured in a scintillation counter. All animals had survived and 

systemic clinical were not noted. Local inflammatory reactions (increased ear thickness) were 

noted in all groups with the exception of the vehicle control group and the 5%-group. The 

Stimulation Index (SI) was below a 3-fold increase in all groups with the exception of the 

positive control group. Mean SI values were 2.0, 2.4, 1.9, 1.7, 1.3, 16.6 for the 5%, 10%, 25% 

50%, 100% test solution and the positive control (25% HCA) (5%)(RCC, 2003b). 

Data on respiratory sensitization are not available. 

Human data:

No allergic reactions were observed in twenty-one chemical operators who worked in vinyl 

acetate production for a mean period of more than 15 years: These operators, evaluated for 

overall health, were presumably exposed to levels of vinyl acetate in the air in concentrations 

of approximately 5-10 ppm for the duration of their service. In workers which came into 

contact with vinyl acetate (average exposure to 17.6-65 mg/m3

 over 15.2 years, with 

intermittent exposures near 180 mg/m3

) no allergic reactions were observed. However, no 

patch test was performed (Deese and Joyner, 1969). 

In workers with frequent and intensive dermal exposure to vinyl acetate, no allergic skin 

reactions could be detected. However, no patch test was performed (Wacker-Chemie, 1995a, 

Klaschka and Vossmann, 1994). 

Vinyl acetate is not included in standard patch test kits and this may be the reason that data on 

patch testing with this substance are not available. Thus, the inconclusive or negative data as 

cited above cannot be used as evidence that vinyl acetate may not cause sensitization by skin 

contact. 

There is no information available on the potential for vinyl acetate to produce respiratory 

sensitization in humans. 

Conclusion:

No cases of skin sensitization from the handling of vinyl acetate in the workplace have been 

reported in the last years. However, the data obtained for humans at the workplace are of 

limited value for assessing skin sensitising potential of vinyl acetate. There are no data on 
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negative patch tests to substantiate the conclusion that the substance has no skin sensitising 

potential. The absence of positive findings and the absence of adequate data do not allow the 

conclusion that vinyl acetate has no skin sensitising potential. 

Results from an animal skin sensitization study (Buehler Test) showed a moderate skin 

sensitising potential of vinyl acetate (commercial grade). With the use of the Local Lymph 

Nodes Assay (LLNA) no positive stimulation responses were detected at concentrations of 

5% - 100%. Increased ear thickness after treatment with concentrations >5% support the skin 

irritative properties seen after prolonged dermal exposure. However, the results obtained with 

this LLNA may not fully reflect the potential of concentrations >10%, since higher 

concentrations of vinyl acetate show increasing volatility, due to decreased proportions of 

acetone/olive oil. As a result, samples applied to the skin of the ear may have been quickly 

evaporated. SI values support this assumption, since a constant decrease was obtained for 

concentrations > 10%. 

Overall, the outcome of both studies may indicate that vinyl acetate is not devoid of a skin 

sensitising potential. The results of the LLNA do confirm the weak-moderate effects seen in 

the Buehler test. However, since the positive threshold level was not exceeded in the LLNA, 

classification and labelling with R 43 is not warranted. The LLNA was given a higher 

reliability since pure vinyl acetate was used for testing whereas a commercial grade test 

substance was applied in the Buehler test. In addition, the Buehler test was not fully compliant 

to the EU testing guideline due to some deviations of the test protocol. 

No direct information is available from studies in humans on respiratory sensitization. In view 

of the widespread use, the absence of any reports suggests that vinyl acetate may not be a 

respiratory sensitiser. 

4.1.2.6 Repeated dose toxicity 

Animal data:

Inhalation exposure 

- In a less well documented study (Gage, 1970, no details on parameters of laboratory 

investigations, no data on food consumption, no list of organs for microscopic 

examination or results) groups of 4 male and 4 female Alderly Park rats were exposed to 

vinyl acetate (no data on purity and details on exposure chamber) at 100, 250, 630 or 2000 

ppm (calculated as 360, 890, 2200 or 7100 mg/m3) 6 hours/day, 15 days in about 3 weeks. 

Animals exposed to 2000 ppm showed signs of eye and nose irritation, respiratory 

difficulties, and reduced body weight gain (no quantitative data). At the concentration of 

2000 ppm, increased numbers of macrophages in the lungs were observed. Females of the 

630 ppm- and 250 ppm-groups also had lower body weight gain. Autopsy revealed normal 

organs up to 630 ppm, at 250 ppm blood and urine tests were reported to be normal. There 

were no data on these tests for other dose groups. Based on this short note, the NOAEC 

for systemic effects was 100 ppm (360 mg/m3) in female rats and at 630 ppm (2200 

mg/m3) in male rats. The NOAEC for local effects on the respiratory tract was 630 ppm 

(2200 mg/m3). 

- In a 4-week range-finding study (Owen, 1979a,b) groups of 5 male and 5 female SpragueDawley rats and CD-1 mice were exposed to 0, 50, 150, 500 or 1000 ppm (calculated as 0, 
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180, 540, 1800 and 3600 mg/m3) of vinyl acetate vapour, 6 hours/day, 5 days/week (no 

data on the purity of the test substance, acetaldehyde concentration in the exposure 

chamber 8 ppm). The dose level of the 50 ppm group was increased to 1500 ppm (5360 

mg/m3) on exposure day 8 (in mice) and on exposure day 10 (in rats) as marked clinical 

effects had not been observed at 1000 ppm. The studies did not incorporate examinations 

on haematology, clinical chemistry or urinalysis. Multiple samples from tissues/organs 

were preserved, but were not processed for histopathology. The reports available did not 

contain figures and tables. Mice exposed to 150 ppm and rats exposed to 500 ppm or 

higher intermittently showed hunched posture and respiratory distress with dose-related 

frequencies and severity grades. A dose-related (non significant) decrease in body weight 

gain was noted in female rats of all treatment groups and in male rats of 50/1500 ppm- and 

1000 ppm groups. Mean body weight gain was decreased in all treated mice, however it 

gained significance only in males and females of the 1000 ppm group and in females of 

the 50/1500 ppm group. No treatment-related macroscopic abnormalities were observed at 

necropsy, the absolute and relative weights of spleen were decreased in male mice 

exposed to 1500 ppm and in male rats exposed to ≥1000 ppm. Histopathological 

examinations of respiratory tissues from mice of all concentration groups were performed 

subsequently and revealed hyperplastic and metaplastic changes in the epithelium of the 

respiratory tract (no further details, Owen, 1980a). Concentrations ≥150 ppm in mice and 

≥500 ppm in rats produced clinical signs of respiratory tract irritation. As growth 

retardation was not significant, the NOAEC for systemic effects was 1500 ppm in rats and 

mice (5360 mg/m3). However with respect to the limited test parameters, the confidence of 

statements on systemic toxic effects was low. The NOAEC for local effects on the 

respiratory tract was 50 ppm in mice (180 mg/m3) and 150 ppm in rats (540 mg/m3). 

- The effects of vinyl acetate exposure on nasal epithelial cell proliferation were evaluated 

in male Sprague-Dawley-derived rats (5 rats per group) exposed for 1, 5, or 20 days (6 

h/d, 5 days per week) to 0, 50, 200, 600, or 1000 ppm (Bogdanffy et al., 1997). The test 

material was 99.9% pure. Impurities consisted of acetaldehyde (100 ppm), acetic acid (50 

ppm), hydroquinone stabiliser (3-7 ppm), ethylacetate (300 ppm), and methylacetate (200 

ppm). Respiratory tract tissues were examined for gross alterations. Cell proliferation was 

assessed by histopathological evaluation of five cross sections of the nose and by 

immunocytochemistry (level of BrdU incorporation following BrdU injection 16 hours 

after the last exposure). Data on feed consumption were not reported. There were no 

changes in body weight except to a reduced mean body weight in the 1000 ppm group 

from day 3 (maximum reduction on day 5 -14%) through day 26 (-11%). Following a 

single exposure, rats of the 600 and 1000 ppm groups showed concentration-related 

minimal to moderate degeneration, necrosis and exfoliation of the olfactory epithelium 

and only at 1000 ppm minimal degeneration and necrosis in the respiratory epithelium. 

Following 5 or 20 exposures, additional lesions consisted of mild to severe regenerative 

hyperplasia with attenuation and/or disorganisation of the olfactory mucosa, occasionally 

squamous metaplasia and only after 20 exposures minimal to severe degeneration and 

atrophy of olfactory nerve bundles. Respiratory epithelium showed minimal regenerative 

hyperplasia and only after 20 exposures minimal squamous metaplasia. A significant 

concentration-related increase in cell labelling was observed in the basal cells of the 

respiratory and olfactory epithelium following a single 6-hour exposure to 600 and 1000 

ppm vinyl acetate. No significant difference in labelling indexes of the respiratory and 

olfactory epithelium was observed after 5 days of exposure. Following 20 days of 

exposure, the response in the respiratory epithelium remained near control levels while 

that in the olfactory epithelium was significantly higher in the 600 and 1000 ppm groups 
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than control levels. Again basal cells were labelled, but additional labelling of cells were 

seen in the adluminal regions of regenerating epithelium. The NOAEC for nasal effects 

was 200 ppm in this study (710 mg/m3). 

- In a 90-day inhalation study groups of 10 male and 10 female Sprague-Dawley rats and 

CD-1 mice were exposed to vinyl acetate vapours (purity of test substance 99.9%) at 

concentrations of 0, 50, 200 or 1000 ppm (calculated as 0, 180, 710 or 3600 mg/m3), 6 

hours/day, 5 days/week (Owen, 1980a,b). Histopathological sections from several tissues 

from all animals of the high concentration and the control groups were examined, the 

nasal turbinates (without any information about the number of sections) were included. In 

mice, histopathology examinations were extended to 2 levels of nasal turbinates, 3 lobes 

of the lungs and 3 levels of the trachea for all animals of the low and intermediate groups. 

The reports did not contain histopathology summary tables; tabulated data were totally 

absent in the mouse study report. The findings of the nasal mucosa were not separately 

reported for the respiratory and olfactory epithelia. No feed consumption data are 

available. Exposure of rats to 1000 ppm vinyl acetate resulted in significantly decreased 

body weight gain (final body weight -19% in both sexes), clinical effects (intermittent 

incidence of respiratory distress, hunched postures and ruffled fur), increased lung-tobody weight ratio (assumed as due to lung congestion), and histomorphological changes in 

the respiratory tract (mild histiocytic alveolitis). The authors assumed that increased 

relative lung weights were related to congestion. This association seems not to be 

plausible because lung congestion was reported for one incidental death in the control 

group. The quality of the rat study was considered to be restricted, because most control 

and high dose rats suffer from parasitic infections indicated by eosinophilic gastritis and 

colon nematodiasis. Many rats from both groups had peribronchial/perivascular lymphoid 

hyperplasia, alveolar histiocytosis/ histiocytic pneumonia, chronic tracheitis and 

laryngitis, and lympadenitis. Except a higher incidence of alveolar histiocytosis in high 

dose rats (19/20 vs. 12/20 controls) no treatment-related toxic effect was seen in the 

organs examined. – The olfactory regions of nasal sections of 4 male and 3 female rats 

exposed to 1000 ppm were reviewed (Hardisty et al., 1999). The most severe lesions were 

seen in the dorsal medial meatus of the anterior nasal passages (level II), lesions extended 

posteriorly to the dorsal medial meatus of levels III and IV and the dorsal scroll of the 

third ethmoturbinates. Lesions were characterised by postdegenerative atrophy of the 

olfactory epithelium and focal erosion, with associated infiltration of neutrophils and 

eosinophils. Some losses of Bowman’s glands and of nerve bundles in the lamina propria 

were observed in the most severely affected areas. There was only a minimal evidence of 

regeneration of the affected epithelium. 

- In mice, exposure to 200 ppm vinyl acetate produced transient signs of respiratory distress 

and hunched posture through the first 9 days of exposure. High dose males and females 

exhibited ruffled fur, hunched posture and respiratory distress. Six high dose females, 

three high dose males and two male controls died during the course of the study, all except 

one death were associated to the routine blood sampling. There was a significant reduction 

of body weight gain in the groups of high dose males (-18%) and females (-17%). 

Microscopic changes including inflammatory, transudation and eosinophilic homogenous 

material in the nasal passages, hyperplasia of goblet cells hyperplastic and metaplastic 

changes of the nasal turbinates, (suspected) areas of epithelial metaplasia or hyperplasia of 

the trachea with loss of ciliated epithelium and epithelial atrophy, multifocal bronchiolitis, 

bronchiectasis, bronchial epithelial metaplasia and hyperplasia, and occasional 

bronchiolar and bronchial exudation were seen in high dose male and female mice. Mild 

to slight inflammation of the nasal turbinates were observed in one low dose female and 
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three intermediate dose females, a very mild accumulation of eosinophilic homogenous 

material was observed in the nasal passages of two low dose female mice, and two mid 

dose females exhibited mild bronchiolitis. The authors considered these mild changes to 

be similar to that seen in the control animals, although no findings were reported for 

control mice. Although similar lesions may occasionally be observed in historical 

controls, these findings were consistent to those of the high dose mice. Therefore this 

interpretation is considered to be equivocal. On the limited data of this studies, a NOAEC 

for systemic effects was 200 ppm (710 mg/m3) for the rat (due to growth retardation at 

1000 ppm) and 50 ppm (180 mg/m3) for the mouse (due to hunched posture at 200 ppm 

and above) However, it is uncertain whether hunched posture could be interpreted as a 

non-specific toxic effect, more likely it seems to be associated with the respiratory 

symptoms. The NOAEC for local effects on the respiratory tract was 200 ppm (710 

mg/m3) for rats due to respiratory distress and higher incidences of alveolar histiocytosis 

and 50 ppm (180 mg/m3) for mice due to respiratory distress at 200 ppm assumed that the 

morphologic lesions of the respiratory tract of mid and low dose were incidental. 

- In a combined chronic toxicity and carcinogenic study (Owen, 1988; Bogdanffy et al., 

1994b) male and female Sprague-Dawley rats and CD-1 mice including 60 animals per 

sex per dose and three satellite groups of 10 of each species and sex for interim evaluation 

at week 53 and week 83 and recovery studies (70 weeks of exposure followed by 15/16 

weeks of recovery) were exposed by inhalation to vinyl acetate vapour in concentrations 

of 0, 50, 200, and 600 ppm (equivalent to 0, 178.5, 714, 2142 mg/m3) over a period of 2 

years (6 hours/day, 5 days/week). The test material contained impurities of acetaldehyde 

(≤65 ppm), acetic acid (≤10 ppm), water (≤472 ppm) and hydroquinone (≤1 ppm). 

Examinations on hematology, clinical chemistry, urinalysis and gross and microscopic 

abnormalities were performed on satellite groups at week 51 and 81 and on the end of the 

main study. At the end of the study, a significant reduction in weight gain (no quantitative 

data available) was observed among rats and mice in the 600 ppm groups (final body 

weights -10% in males to -15% in females). Also, the overall body weight gain of 200 

ppm mice was significantly lower than that of the control groups (no quantitative data 

reported). Increases in weight gain were noted in the recovery groups of high dose male 

rats, the high dose male mice and females of all doses. Exposed animals of both species at 

all concentrations showed rough haircoat and hunched posture. There were effects on 

blood glucose (reduced in high dose female rats) and urinary parameters (decreased urine 

volume and pH values and increased specific gravity in high dose rats) which were 

attributed to (nonmeasured) reduced food and water consumption. The survival rates of 

600 ppm female rats were higher than that of controls, (64% vs. 36%), but overall there 

was no treatment-related increase in mortality in both species. 

In both species exposure-related effects were confined to the respiratory system. Mean 

lung weight was increased in high dose rats (relative weights) and mice (absolute and 

relative weights). Lung weight was also affected in low and intermediate dose rats and 

intermediate dose mice, however the effect was inconsistently found after several 

intervals of treatment. In both species of each sex, vinyl acetate induced morphological 

nonneoplastic lesions in the nasal cavity of the 200 and 600 ppm groups and in the 

trachea (mice only) and in the lungs of the 600 ppm groups (Tables 4.1.2.6 A + 4.1.2.6 

B). In addition, some high dose female mice showed hyperplastic lesions in the larynx 

(no data on exact number of affected animals), a focus of squamous epithelial hyperplasia 

with dysplastic changes was noted in a single female. - In rats, nasal lesions were 

restricted to the olfactory mucosa consisting of atrophy and basal cell hyperplasia, in 

severe cases lesions were accompanied with replacement of respiratory epithelium, non-
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keratinising squamous metaplasia, thickened and edematous submucosa, loss of nerve 

bundles and Bowman’s glands or with hyperplasia of glandular structures. In the 200 ppm 

groups, lesions were restricted or most pronounced in the anterior part of the dorsal 

meatus, which is normally covered by the olfactory epithelium. At 600 ppm, the lesions 

extended to the posterior parts of the olfactory epithelium. In this area, a layer of 

stratified non-differentiated epithelium containing small foamy structures resembling 

nerve bundles and groups of epithelial cells resembling acinar cells of the Bowman’s 

glands was evident in many rats of the 200 ppm groups and a few rats of the 600 ppm 

groups. They were often accompanied by keratinising squamous epithelium and epithelial 

nest-like infolds. The authors considered this being a complete regeneration. - Mice of the 

200 and 600 ppm groups showed similar lesions, however differed in that the olfactory 

epithelium was replaced by respiratory-like epithelium and the sustentacular cells were 

more frequently hypertrophic and showed loss of sensory cells. In high dose mice only, 

nonkeratinizing squamous metaplasia of the respiratory epithelium, nasal inflammatory 

infiltrate and exudate were observed. Also, the trachea was affected showing hyperplastic 

epithelium, occasionally with epithelial flattening, exfoliation, metaplasia and 

fibroepithelial projections. In the lung of both species exposed to 600 ppm 

bronchial/bronchiolar epithelium was flattened or exfoliated, and showed intraluminal 

fibroepithelial projections and alveolar (or interstitial) accumulation of macrophages with 

pigments, foamy or eosinophilic appearance. 

Treatment-related nasal and pulmonary lesions in rats and mice were similar in the 

interim and recovery groups to those seen in the main study and occurred at about the 

same incidence and the same or lower degree as in the main study. In the lungs bronchial 

exfoliation was not observed in any of the interim or recovery group rats. Cessation of 

treatment for 16 weeks showed no recovery from olfactory atrophy in rats and mice, 

although high dose mice did show a tendency to recover from the inflammatory changes 

and epithelial hyperplasia. No hyperplasia of the tracheal epithelium was seen in the 

recovery group of mice. 

In summary, the chronic inhalation of vinyl acetate vapour ≥200 ppm induced cytotoxic 

effects on the epithelia of the upper and lower respiratory tract of rats and mice 

accompanied by nasal inflammation in mice. The NOAEC for local effects on the 

respiratory tract was 50 ppm for both species (180 mg/m3). Based on the reduction of 

body weight gain, the NOAEC for systemic toxicity was 200 ppm for rats (710 mg/m3) 

and 50 ppm for mice (180 mg/m3). 
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TABLE 4.1.2.6 A 

Summary of statistically significant non-neoplastic changes in lungs and nose in rats: main study 

 Incidence of Lesions Other than Tumors a

 Males Females 

 Concentration (ppm): Control 50 200 600 Control 50 200 600 

Lungs: (58) (59) (60) (60) (60) (60) (60) (59) 

Bronchial exfoliation 

 very slight 

 slight 

 moderate 

0 

0 

0 

0 

0 

0 

0 

0 

0 

8** 

26** 

2 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

4 

0 

Intraluminal fibrous projections 

 very slight 

 slight 

 moderate 

 severe 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

16 *** 

14 *** 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

3 

28 *** 

8 ** 

1 

Pigment macrophage 

 very slight 

 slight 

 moderate 

1 

1 

0 

0 

3 

0 

0 

3 

1 

0 

33 *** 

2 

0 

6 

0 

0 

4 

0 

0 

1 

0 

1 

10 

4 

Peribronchiolar/perivascular 

lymphoid aggregates 

 very slight 

 slight 

 moderate 

5 

15 

1 

1 

18 

4 

0 * 

21 

1 

0 * 

14 

2 

0 

11 

2 

1 

14 

1 

2 

14 

2 

0 

23 * 

5 

Nose: (59) (60) (59) (59) (60) (60) (60) (59) 

Olfactory epithelial atrophy 

 very slight 

 slight 

 moderate 

 severe 

0 

0 

0 

0 

1 

2 

0 

0 

4 

47 *** 

2 

0 

0 

7 * 

33 *** 

10 ** 

0 

0 

0 

0 

1 

0 

0 

0 

4 

23 *** 

0 

0 

0 

18 *** 

30 *** 

3 

Olfactory epithelial squamous 

metaplasia 

 very slight 

 slight 

 moderate 

 severe 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

2 

12 ** 

9 ** 

1 

0 

0 

0 

0 

0 

0 

0 

0 

5 

0 

0 

0 

4 

26 *** 

7** 

0 

a Figures in parenthesis present the number of animals from which this tissue was 

 examined microscopically. Significance of differences in a pairwise (Fisher ́s) 

 test between each treatment and control incidence is indicated by * p < 0.05, 

 ** p < 0.01, *** p < 0.001. 

 Cited from Bogdanffy et al. (1994b) 
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TABLE 4.1.2.6 A

Summary of statistically significant non-neoplastic changes in lungs and nose in rats: main study 

(Continued) 

 Incidence of Lesions Other than Tumors a

 Males Females 

 Concentration (ppm): Control 50 200 600 Control 50 200 600 

Nose: (59) (60) (59) (59) (60) (60) (60) (59) 

Olfactory epithelial regeneration 

 very slight 

 slight 

 moderate 

0 

0 

0 

0 

0 

0 

3 

30*** 

2 

0 

1 

0 

0 

0 

0 

0 

0 

0 

3 

16*** 

3 

2 

7** 

0 

Olfactory epithelial inflammatory 

cell infiltrate 

 very slight 

 slight 

 moderate 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

7 * 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

5* 

1 

Epithelial nest-like infolds 

 very slight 

 slight 

 moderate 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

15*** 

1 

0 

0 

5 

5 

0 

0 

0 

0 

0 

0 

0 

0 

1 

0 

5 

0 

0 

0 

5* 

2 

Olfactory epithelial leukocytic 

exudate 

 very slight 

 slight 

 moderate 

 severe 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

11*** 

2 

1 

0 

0 

0 

0 

0 

0 

0 

0 

1 

0 

1 

0 

0 

5 * 

3 

0 

Basal cell hyperplasia 

 very slight 

 slight 

 moderate 

 severe 

 2 

 0 

 0 

 0 

5 

0 

0 

0 

3 

40*** 

11*** 

0 

1 

21*** 

22*** 

2 

0 

0 

0 

0 

0 

0 

0 

0 

7* 

24*** 

3 

0 

0 

35*** 

16*** 

0 

Turbinate leukocytic exudate 

 very slight 

 slight 

 moderate 

 severe 

0 

4 

3 

0 

2 

8 

6 

0 

0 

5 

3 

0 

0 

5 

8 

1 

1 

4 

0 

0 

1 

3 

1 

0 

3 

3 

1 

0 

1 

7 

7 ** 

0 

Submucosal inflammatory cell 

infiltrate 

 slight 

 moderate 

 severe 

 very severe 

2 

1 

0 

0 

0 

3 

0 

0 

1 

1 

0 

1 

2 

6 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

5 * 

0 

0 

a Figures in parenthesis present the number of animals from which this tissue was 

 examined microscopically. Significance of differences in a pairwise (Fisher ́s) 

 test between each treatment and control incidence is indicated by * p < 0.05, 

 ** p < 0.01, *** p < 0.001, cited from Bogdanffy et al. (1994b) 
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TABLE 4.1.2.6 B

Summary of statistically significant non-neoplastic changes in lungs and nose of mice: main study 

 Incidence of Lesions Other than Tumors a

 Males Females 

 Concentration (ppm): Control 50 200 600 Control 50 200 600 

Lungs: (51) (51) (56) (53) (56) (55) (55) (51) 

Accumulation of alveolar macrophages 

 very slight 

 slight 

 moderate 

 severe 

5 

10 

0 

1 

1 

2 * 

4 

1 

4 

4 

8 ** 

4 

3 

7 

4 

0 

5 

3 

2 

1 

2 

8 

1 

3 

6 

4 

1 

1 

1 

10 

12 ** 

1 

Intra-alveolar eosinophilic 

material 

 very slight 

 slight 

 moderate 

 severe 

0 

3 

0 

0 

0 

1 

0 

0 

3 

1 

0 

0 

1 

19 *** 

10 ** 

2 

0 

0 

0 

0 

0 

0 

0 

0 

2 

0 

1 

0 

1 

7 ** 

15 *** 

1 

Accumulation of brown pigmented macrophages 

 very slight 

 slight 

 moderate 

2 

0 

0 

2 

0 

0 

1 

5 

1 

11 * 

12 *** 

1 

3 

1 

0 

5 

1 

0 

1 

4 

0 

2 

21 *** 

2 

Intraluminal fibroepithelial 

projections 

 very slight 

 slight 

 moderate 

0 

0 

0 

1 

0 

0 

2 

0 

0 

3 

17 *** 

3 

1 

0 

0 

0 

2 

0 

0 

1 

0 

6 

19 *** 

7 ** 

Bronchial gland dilatation 14 16 26 17 8 17 20 * 15 

Bronchial/bronchiolar epithelial 

flattening and/or exfoliation 

 very slight 

 slight 

 moderate 

 severe 

0 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

4 

25 *** 

7 * 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

4 * 

28 *** 

4 * 

1 

Bronchial/bronchiolar epithelial 

disorganisation 

 very slight 

 slight 

 moderate 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

11 ** 

4 

0 

0 

0 

0 

1 

0 

0 

0 

0 

5 * 

18 *** 

0 

a Figures in parenthesis present the number of animals from which this tissue was 

 examined microscopically. Significance of differences in a pairwise (Fisher ́s) 

 test between each treatment and control incidence is indicated by * p < 0.05, 

 ** p < 0.01, *** p < 0.001, cited from Bogdanffy et al. (1994b) 
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TABLE 4.1.2.6 B

Summary of statistically significant non-neoplastic changes in lungs and nose of mice: main study 

(Continued) 

 Incidence of Lesions Other than Tumors a

 Males Females 

 Concentration (ppm): Control 50 200 600 Control 50 200 600 

Nose: (52) (48) (53) (50) (56) (57) (55) (51) 

Inflammatory exudate 0 0 2 15*** 0 0 1 5** 

Mucosal inflammatory infiltrate 1 0 0 12** 1 2 0 5 

Submucosal gland hyperplasia 

 slight 

 moderate 

3 

0 

3 

0 

28*** 

8** 

25*** 

15*** 

2 

0 

5 

0 

42*** 

7** 

35*** 

13*** 

Olfactory epithelial atrophy 

(mainly dorsal meatus) 

 very slight 

 slight 

 moderate 

 severe 

0 

0 

0 

0 

0 

0 

0 

0 

2 

5 

28*** 

4 

0 

0 

2 

3 

0 

2 

0 

0 

0 

4 

0 

0 

0 

8 

26*** 

4 

0 

0 

0 

1 

Olfactory epithelial atrophy 

(widespread) 

 slight 

 moderate 

 severe 

0 

1 

0 

0 

0 

0 

1 

8* 

4 

0 

5 

39*** 

0 

0 

0 

0 

0 

0 

0 

12*** 

2 

0 

5* 

45*** 

Squamous metaplasia at the 

naso/maxilloturbinate region 

very slight 

slight 

moderate 

severe 

0 

1 

0 

0 

0 

1 

1 

0 

0 

2 

0 

0 

0 

13** 

11*** 

0 

0 

4 

0 

0 

0 

2 

0 

0 

0 

0 

0 

0 

1 

13* 

6** 

1 

Replacement olfactory by 

respiratory epithelium 

slight 

moderate 

severe 

0 

0 

0 

0 

0 

0 

5 

1 

0 

11*** 

0 

0 

0 

0 

1 

0 

1 

0 

15*** 

5* 

0 

10*** 

10*** 

0 

Trachea/bronchi: (49) (46) (51) (48) (55) (56) (52) (48) 

Epithelial hyperplasia 0 0 2 19*** 1 1 0 11*** 

a Figures in parenthesis present the number of animals from which this tissue was 

 examined microscopically. Significance of differences in a pairwise (Fisher ́s) 

 test between each treatment and control incidence is indicated by * p < 0.05, 

 ** p < 0.01, *** p < 0.001, cited from Bogdanffy et al. (1994b)
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Oral application 

- In oral dose range-finding studies, groups of 5 male and 5 female rats or mice (SpragueDawley, CD-1) received vinyl acetate in drinking water at concentrations of 0, 50, 200, 

1000 or 5000 ppm (rats, equivalent to 5, 20, 100 or 500 mg/kg bw, calculated on an 

assumed water consumption of 10% of body weight) and 0, 50, 150, 1000 or 5000 ppm 

(mice, equivalent to 7.5, 22.5, 150, or 750 mg/kg bw, calculated on an assumed water 

consumption of 15% of body weight) for 4 weeks (Gale, 1979; no data on purity, 

frequency of dose solution preparation or analytical concentrations). Vinyl acetate was 

analysed by the commercial supplier containing 3 ppm acetic acid and 21 ppm 

acetaldehyde. The concentration of acetic acid was confirmed after delivery and after 

study completion. Test solutions were daily prepared containing the nominal vinyl acetate 

concentrations including a corrective over-formulation for losses within 24 hours. 

Formulations were analysed for vinyl acetate concentrations prior to the administration 

during the first days (rat, mouse) and at Day 29 (rat only) of the treatment period and 

reanalysed for stability 24 hours later. During the 4th week of treatment the dose level of 

50 ppm was increased to 10000 ppm. No deaths occurred during the course of the study in 

any of the experimental groups. With the exception of one single female mouse at 5000 

ppm female mice, which showed tremor and hypothermia, all animals remained healthy 

throughout the study. Reduction of body weight gain and water consumption was 

observed in rats, particularly in females, at ≥ 1000 ppm, in male rats at ≥ 5000 ppm and in 

male mice at 5000 ppm. Reduced water consumption was also apparent in male mice 

treated at ≥ 1000 ppm and in female mice at 5000 ppm, the latter consumed less food than 

control females. Lower feed consumption in rats was confined to females treated at 10000 

ppm. Data on mean body weight were not reported in the summary document available, 

the only quantitative data given was that reduction in feed consumption was 11% during 

the first 3 weeks of the study. Absolute and relative liver weights in rats of both sexes and 

female mice were lower in all treated groups compared to the controls. There are data on 

liver histopathology from 4 male and 4 female rats of the control and 5000 ppm groups 

showing mild multifocal portal and intralobular hepatitis similar to those lesions 

commonly observed in rats of this age and strain. No other organs were processed for 

microscopy and no laboratory examinations on clinical chemistry or hematology 

parameters were conducted. Thymus weights were reduced in male mice exposed to 5000 

ppm. There was no evidence of any treatment-related gross abnormalities in organs. The 

results provided the basis for selection of appropriate dose levels for 13-week studies. The 

NOAEL for rats was 200 ppm (20 mg/kg bw) (based on reduced body weight gain at 1000 

ppm) and in mice, the NOAEL was 1000 ppm (150 mg/kg bw) (based on tremor and, 

hypothermia in a single female mouse and reduced thymus weight at 5000 ppm). 

Reductions of water consumption and in body weight may reflect bad palatability of the 

test solutions, the toxicological relevance reduced liver weights (in the absence of any 

corresponding morphological or laboratory abnormalities) is equivocal. 

- In oral 13-week studies accepted as valid according to the requirements of the directive 

793/93/EEC, groups of 10 male and 10 female Sprague-Dawley rats and CD-1 mice were 

administered vinyl acetate in drinking water at concentrations of 0, 200, 1000 and 5000 

ppm (calculated mean dose levels: male rats 31, 163, 684, female rats 36, 193, 810 mg/kg 

bw/d; male mice 11, 60, 285, female mice 10, 72, 281 mg/kg bw/d) (Gale, 1980a, 1980b). 

The test substance was 99.9% pure and contained 0.01% acetaldehyde, 0.005% acetic 

acid, and 0.4% water. There were no deaths during the study and all animals appeared 

normal. A slight, non-significant degree of growth retardation became prevalent in male 

rats of the high dose group the mean body weight of these animals was 8% lower than that 
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of controls. The weekly water consumption of male and female rats at 5000 ppm was 

significantly lower than that of the controls. The overall water consumption was 23% and 

25% lower than in control males and females. A less marked reduction in water 

consumption was transiently seen for mid dose male and female rats. No treatment-related 

effects were seen with respect to hematology, blood chemistry, organ weights, or 

histopathology. In conclusion, administration of vinyl acetate in the drinking water for 13 

weeks at concentrations up to 5000 ppm produced no evidence of organ toxicity in rats 

and mice representing the NOAEL for both species. 

- 90-day drinking water studies were conducted in rats and mice to determine whether 

repeated exposure to vinyl acetate correlates with tissue toxicity, measured primarily by 

cell proliferation in and histopathology of upper digestive tract tissues (DuPont, 2000, 

Valentine et al., 2002). Males only were used since they appeared to be slightly more 

susceptible to neoplasia than females in the Japanese oral cancer study (Umeda et al., 

2004a). Test solutions were prepared twice weekly, samples of the low and high dose 

solutions were analysed for concentrations, stability and pH value. 

 Five groups of 20 male CDF (F-344)/CrlBr rats were administered vinyl acetate in the 

drinking water for 92 days at concentrations of 0, 1000, 5000, 10000, and 24000 ppm 

vinyl acetate (99.98%) (DuPont, 2000). Animals were weighed and individually observed 

for body weight development, water consumption and clinical signs of toxicity on a 

weekly basis. On test days 1, 8, 29, and 92, 5 rats per group were prepared for evaluation 

of oral cavity cell proliferation using pulsed 5-bromodeoxyuridine(BrdU) uptake 

techniques and histopathology of the upper digestive tract tissues (oral cavity, esophagus, 

forestomach, duodenum). Evaluations of the oral cavity for cell proliferation and 

histopathology were limited to level III (identical to level III of the oral cancer study by 

Umeda et al., 2004a) and level VI from high dose rats and controls. 

 Drinking water solutions were daily prepared. Vinyl acetate concentrations taken from 

solutions in drinking water bottles were stable within 10% of nominal concentrations for 

at least 4 days. The pH of test solutions decreased with increase of the vinyl acetate 

concentration and time, e.g., from 5.21 on day 0 to 3.74 by day 4 at 2400 ppm. At this 

concentration, spontaneous hydrolysis of test compound led to an increase of the acetic 

acid concentration from 55 ppm at day 0 to 650 ppm by day 4. 

 No mortalities or clinical signs of toxicity were attributed to vinyl acetate administration. 

Rats in the 5000, 10000, and 24000 ppm group had significantly lower mean body weights 

(-8.8, -7.4, -6-1%) and mean body weight gains (-13.4, -11, -9.2%) during the study 

relative to controls. Rats in the 10000 and 24000 ppm group significantly lower mean 

daily food consumption (-6, -7.4%) compared to controls. Mean daily water consumption 

was consistently and significantly lower during the study in rats administered water 

solutions containing 5000, 10000, and 24000 ppm vinyl acetate (-28, -37, -40.3%). Based 

on the overall mean water consumption data, the mean daily intake of vinyl acetate in rats 

from the 1000, 5000, 10000, and 24000 ppm groups was 81, 350, 660, and 1400 mg/kg 

bw, respectively. No test substance-related gross lesions were observed in the oral 

mucosa, esophagus, or forestomach of rats at any exposure level. Compared to controls, 

no test-substance related microscopic lesions were observed in the oral mucosa of rats at 

24000 ppm. In rats of this group, significant increases in mean cell proliferation occurred 

in the upper jaw on days 29 and 92 and in the lower jaw on test days 1 and 29. Labelling 

indices were increased less than 2-fold above the appropriate controls for these groups and 

were considered to be of equivocal biological significance. 
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 A similar study was conducted in B6D2F1/CrlBr mice (BDF1) (20 males/group) that 

received same concentrations of vinyl acetate. Evaluations of the upper and lower jaws for 

cell proliferation and histopathology were initially limited to level III and V from highdose and control mice. Subsequently, the lower jaw from the intermediate groups 

sacrificed at 92 days was additionally evaluated to determine a NOEL for cell 

proliferation. 

 All mice survived to their scheduled termination without any clinical sign of treatmentrelated toxicity. No vinyl acetate induced effect on body weight was observed. At various 

intervals during the study, mice from all test groups had significantly lower mean food 

consumption compared to controls. However for the period day 0-92 no significant 

difference was observed. The mean daily water was significantly lower in mice from all 

test groups at various intervals and for the period day 0-92 (-23, -30.5, -31.4, -35%). The 

mean daily intake of vinyl acetate in mice from the 1000, 5000, 10000, and 24000 ppm 

groups was 250, 1200, 2300, and 5300 mg/kg bw. No test substance-related gross lesions 

were observed in the oral mucosa, esophagus, or forestomach of mice at any exposure 

level. Compared to controls, no test-substance related microscopic lesions were observed 

in the oral mucosa of mice at 24000 ppm. Significant and dose-related increases in mean 

cell proliferation occurred in the lower jaw of mice from the 10000 and 24000 ppm groups 

but only at 92 days. The increases were approximately 2.4- to 3.4-fold above the control 

groups mean for the 10000 and 24000 groups, respectively. Based on the magnitude of the 

increases and the dose-related nature of the response, these increases were considered to 

be compound-related. 

 The author concluded that increases in cell proliferation in the lower jaw of mice 

qualitatively and quantitatively paralleled the tumor outcome data of the Japanese oral 

cancer study (Umeda et al., 2004a). The incidence of oral cavity neoplastic lesions was 

higher in the lower jaw than the upper jaw in either rats or mice (these details were not yet 

submitted to the rapporteur) and the incidence of these oral cavity lesions was about 3-

fold higher in mice compared to rats. It was reported to be unknown whether the increased 

sensitivity in the lower jaw is attributable to an innate difference in tissue responsiveness 

or due other phenomena, such as a gravity dependent enhancement in tissue dose to vinyl 

acetate. The increases in cell proliferation also paralleled the administered dose of vinyl 

acetate in rats (3- to 4-fold less on body weight basis) and mice. 

- No treatment-related histopathological findings were reported in a short communication 

on dose-range finding studies in rats and mice (no further data on strains, 

animals/sex/group, etc.) at concentrations of 0, 600, 1500, 3800, 10000 or 24000 ppm 

vinyl acetate in the drinking water after 13 weeks. Water consumption was affected at 

24000 ppm (calculated on an assumed water consumption of 10% in rats, resp. 15% in 

mice to be equivalent to 2400 mg/kg bw/d for rats, resp. 3600 mg/kg for mice) (Umeda et 

al., 2004a, main study reported in 4.1.2.8). 
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Other routes 

- No information on prolonged vinyl acetate exposure via other routes was available. 

Human data:

- No human data are available. 

Summary on repeated dose toxicity

- Inhalation exposure 

No premature deaths were confined to prolonged vinyl acetate treatment up to the highest 

tested concentrations of 2000 ppm in the rat and of 1000 ppm in mice. Rough haircoat and 

hunched posture was observed on rats and mice exposed to vapour concentrations of 50 ppm 

and higher for 2 years (Bogdanffy et al., 1994b, Owen, 1988). Prolonged inhalation exposure 

of rodents to higher concentrations of vinyl acetate vapour induced clinical signs of growth 

retardation, eye and nose irritation, hunched posture, rough fur, respiratory distress and 

reduced urine volume. A reduction of body weight gain observed in mice ≥ 200 ppm and in 

rats ≥ 600 ppm after exposure over 2 years may be associated to non-specific toxicity of vinyl 

acetate. It was interpreted to be attributed to lower food and water consumption, but the 2-

year study did not contain any data on the consumption of water/food and the food efficiency. 

Reduced urine volume observed in rats at 600 ppm of the 2-year study (Bogdanffy et al., 

1994b) were not accompanied by other morphological or functional abnormalities. No clear 

toxic effect could be identified in parenchyma outside the respiratory tract. 

Main effects of vinyl acetate were the local toxic effects on the upper and lower respiratory 

tract. Rats and mice exposed repeatedly demonstrated degeneration, partly accompanied by 

regenerative/reparative processes and occasionally inflammation, hyper- and metaplasia of the 

surface lining epithelia of the nose. Lesions of the nasal cavity were found in the epithelium 

of the olfactory and respiratory regions being more pronounced in the olfactory epithelium. 

Rats exposed to concentrations of 200 ppm or higher over a period of 2 years (Bodganffy et 

al., 1994b, Owen, 1988) developed degenerative lesions of the olfactory mucosa. In the 

respiratory epithelium of the nasal turbinates, lesions were evident in this species at 1000 ppm 

after 4 weeks of vinyl acetate inhalation (Bogdanffy et al., 1997). At the end of the study, cell 

proliferative rates were significantly increased in the olfactory epithelium at ≥600 ppm, but no 

response was seen in the respiratory epithelium up to 1000 ppm. Mice exposed at 200 ppm for 

a period of 2 years showed degenerative lesions of the olfactory mucosa. Squamous 

metaplasia were noted in the respiratory mucosa at a concentration of 600 ppm accompanied 

by prominent inflammatory infiltration (Bogdanffy et al., 1994b). Hyperplastic and 

metaplastic alterations of the larynx and trachea together with epithelial desquamation and 

fibrotic reactions of the tracheal epithelium were exclusively found in mice at a concentration 

of 600 ppm within 2 years (Bogdanffy et al., 1994b, Owen, 1988). Similar changes were 

found in the bronchial and bronchiolar airways of rats and of mice at this concentration and 

exposure duration. In addition histiocytic cell accumulation in the alveoli and interstitium of 

the lung was observed being possibly related to increased lung weights. 
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- Oral administration 

No specific organ toxicity was recorded after repeated oral administration with drinking water 

of vinyl acetate to rats and mice. A subchronic 13-week study revealed a slight (nonsignificant) reduction of food consumption and growth retardation in male rats at 5000 ppm 

(calculated to correspond to 684 mg/kg bw/d) (Gale, 1980a, b) that was supposed to be related 

to the 23% reduction in water consumption. No evidence of organ toxicity was detected in 

rats and mice of all dose groups. Thus, the NOAEL for both species was estimated to be 5000 

ppm. 

Elevated rates of cell proliferation in the mucosa of the oral cavity was observed in mice 

exposed for 92 days to vinyl acetate concentrations of 10000 ppm (5300 mg/kg bw/d) and rats 

exposed to 24000 ppm (1400 mg/kg bw/d) (DuPont, 2000; Valentine et al., 2002). The 

NOAEC for the mitogenic response was 5000 ppm (1200 mg/kg bw/d) in the mouse study and 

10000 ppm (6600 mg/kg bw/d) for the rat study. 

No/Lowest-observed-effect concentrations/levels 

- Inhalation exposure 

The combined chronic toxicity and carcinogenicity study on Sprague-Dawley rats and CD-1 

mice (Owen, 1988, Bogdanffy et al., 1994b) was selected for the derivation of effect levels. 

For local effects on the respiratory tract: 

2-year study/Sprague-Dawley rats and CD-1 mice/NOAEClocal 50 ppm 

(Equivalent to 178.5 mg/m3) 

For systemic toxic effects: 

2 year study/CD 1 mice/NOAECsys 50 ppm (equivalent to 178.5 mg/m3) 
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- Oral administration 

The 90-day drinking water studies of Gale (1980a,b) were performed according to current 

testing guidelines and therefore were considered to represent the most reliable data with 

respect to oral repeated-dose toxicity. 

90-day study/Sprague-Dawley rats and CD-1 mice/NOAEL 5000 ppm 

(Equivalent to 684 mg/kg bw/d for male rats, 810 mg/kg for female rats, 

285 mg/kg bw/d in male mice, 281 mg/kg bw/d for female mice). 

This value is well corresponding to the NOAEL from long-term studies (Section 4.1.2.8) 

which was 1000 ppm for Sprague-Dawley rats receiving drinking water for 2 years 

(Bogdanffy et al., 1994a, Shaw, 1988). The NOAEL of 5000 ppm observed in mice treated for 

2 years were considered to be less reliable, because the study did not contain laboratory 

investigations (Maltoni et al., 1997). 

The 5000 ppm vinyl acetate concentration in drinking water is proposed as a NOAEL for 

systemic effects (684 mg/kg bw/d for the rat, 281 mg/kg bw/d for the mouse) for quantitative 

calculations in the risk characterisation. 

Classification 

As lesions of the respiratory tract epithelia occurred at concentrations above the critical 

concentration values according to the Annex VI criteria, there is actually no need for 

classification and labelling with respect to repeated dose toxicity. 

 

4.1.2.7 Mutagenicity 

4.1.2.7.1 Studies in vitro 

Studies in vitro: bacterial gene mutations

Vinyl acetate was negative in bacterial gene mutation assays with Salmonella typhimurium 

strains TA 98, TA 100, TA1535 and TA1537 (McCann et al., 1975) with and without rat liver 

S-9 activation. Vinyl acetate was also negative in bacterial gene mutation assays with 

Salmonella typhimurium strains TA 98, TA 100, TA 1535 and E. coli WP2 uvr/pKM 101 

with and without metabolic activation (JETOC, 2004). Also a negative result was obtained 

with the strains TA 100 and TA1530 after metabolising vinyl acetate with mouse liver S-9 

mix and gas phase exposure of the bacteria up to 2% vinyl acetate (Bartsch et al., 1979). 

Jung et al. (1992) described a collaborative study to evaluate Salmonella typhimurium TA 102 

with three laboratories. Vinyl acetate was negative in all laboratories; experimental details are 
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84 CAS No.: 108-05-4 

available only for one lab (Hoechst, 1988). Here, vinyl acetate, diluted in ethanol, gave 

negative results in three tests for doses up to 5000 μg/plate with and without S-9 mix. 

Vinyl acetate was also negative in several investigations for which no adequate descriptions 

are available: bacterial gene mutation test in various Salmonella strains (Florin et al., 1980; 

Lijinski and Andrews, 1980; Brams et al., 1987) and SOS-chromotest with E. coli (Brams et 

al., 1987). 

In vitro tests: bacterial genotoxicity 

 Concentration range 

Test system With S-9 

mix 

Without 

S-9 mix 

Result Toxicity Remarks Reference 

Salm. typh. 

TA98, TA100, 

TA1535, TA1537 

yes yes neg no data rat liver S-9 mix; 

tested doses not 

clearly specified 

McCann et 

al., 1975 

Salm. typh. 

TA100, TA1530 

0.003%, 

gas phase 

 neg total toxicity at 

0.02% and 

higher doses 

mouse liver S-9 

mix with and 

without cofactors 

Bartsch et al., 

1979 

Salm. typh. 

TA102 

up to 

5000 

μg/plate 

up to 

5000 

μg/plate 

neg Jung et al., 

1992 

Salm. typh. 

TA98, TA100, 

TA1535, TA1537 

no data no data neg no data screening paper 

without details 

Florin et al., 

1980 

Salm. typh. 

TA98, TA100, 

TA1535, 

TA1537, 

TAQ1538 

up to 

1000 

ug/plate 

up to 

1000 

ug/plate 

neg no data screening paper 

without details; 

use of rat and 

hamster liver S-9 

mix 

Lijinski and 

Andrews, 

1980 

Salm. typh. 

TA97, TA87, 

TA100 

100 to 

500 

ug/ml 

100 to 

500 

ug/ml 

neg no data screening paper 

without details 

Brams et al., 

1987 

Salm. typh. 

TA98, TA100, 

TA1535, 

TA1537 

E. coli WP2 

uvr/pKM 101 

1.22-

5000 

μg/plate 

1.22-

5000 

μg/plate 

neg no data only test result 

tables, original 

data in Japanese 

JETOC, 2004 

E. coli PQ37 130 to 

8600 

ug/ml 

130 to 

8600 

ug/ml 

neg no data screening paper 

without details 

Brams et al., 

1987 
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Studies in vitro: chromosomal mutations, micronuclei, mouse lymphoma assay 

Norppa et al. (1985) investigated the induction of chromosomal aberrations in human 

lymphocytes (whole blood cultures and isolated lymphocytes) after 48-h treatment with vinyl 

acetate without S-9 mix. Positive effects were obtained for doses of 0.2, 0.5 and 1 mmol/l 

(isolated lymphocytes) or 0.5 and 1 mmol/l (whole blood cultures). Extremely steep doseeffect relationships were observed; the maximum effect was ca. 90% aberrant cells. Toxicity 

data were not given. 

In a similar investigation by Jantunen et al. (1986), with 24-h treatment of human 

lymphocytes (isolated lymphocytes and whole blood cultures), dose-dependent positive 

effects were found for doses of 0.25 to 2.0 mmol/l. Moderate to strong cytotoxic effects were 

seen for doses of 0.5 mmol/l and higher (inhibition of mitotic activity). Mustonen et al. (1986) 

used vinyl acetate as positive control in a chromosomal aberration test with human 

lymphocytes; 0.5 mmol/l led to an aberration frequency of 17.1% (excluding gaps). 

In an in vitro micronucleus test with human lymphocytes without S-9 mix (Mäki-Paakanen 

and Norppa, 1987), increased micronucleus frequencies were obtained for doses of 0.25 and 

1.0 mmol/l vinyl acetate with effects of 3.2% and 3.1% micronucleated cells (negative 

control, 0.9%). Data on toxicity were not given. 

A mouse lymphoma assay was reported to be positive with and without S-9 mix (Kirby, 

1983); however, a full report with detailed data is lacking. Vinyl acetate was tested in 

concentrations ranging, with S-9 mix, from 1.8 to 5 μl/ml and, without S-9 mix, from 1.9 to 4 

μl/ml; the highest dose of 5 μl/ml corresponds to 4650 μg/ml or 54 mmol/l. With S-9 mix, 

induced mutant frequencies were 2.4- to 7.4-fold that of the concurrent negative control; 

relative total growths ranged from 10 to 62%. Without S-9 mix, 5- to 10.3-fold increases in 

mutation frequencies were observed; relative total growths were between 5 and 26%. Further 

details on the investigation are not available. Therefore, the relationship between genotoxicity 

and cytotoxicity cannot be evaluated. Furthermore, it cannot be deduced whether the genetic 

effects were preferentially due to gene or chromosome mutations. 
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In vitro tests: chromosomal mutations, micronuclei, mouse lymphoma assay 

 Concentration 

range 

 

Test system With S9 mix Without 

S-9 mix 

Result Toxicity Remarks Reference 

 

chrom. ab. in 

human 

lymphocytes 

not 

done 

0.1 to 1 

mmol/l 

pos no data 48-h treatment; pos at 

0.2, 0.5 and 1 mmol/l 

(isol. lymp.), or 0.5 and 1 

mmol/m (whole blood); 

extremely steep doseeffect-relationship; max. 

eff. ca. 90% aberrant 

cells 

Norppa et 

al., 1985 

chrom. ab. in 

human 

lymphocytes 

not 

done 

0.125 to 

2.0 

mmol/l 

pos clear inhibition of 

mitotic activity at 

0.5 mmol/l and 

higher 

24-h treatment; pos at 

0.25 to 2.0 mmol/l (isol. 

lymph. and whole 

blood); max. eff. >40% 

aberrant cells 

Jantunen et 

al., 1986 

chrom. ab. in 

human 

lymphocytes 

not 

done 

0.5 

mmol/l 

pos no data vinyl acetate was used as 

positive control 

Mustonen et 

al., 1986 

micronuclei 

in human 

lymphocytes 

not 

done 

0.125 to 

2.0 

mmol/l 

pos no data 48-h treatment; pos for 

doses of 0.5 and 1.0 

mmol/l; max. eff. 3.2% 

micronucleated cells 

(negative control, 0.9%) 

MäkiPaakanen 

and Norppa, 

1987 

mouse 

lymphoma 

assay 

1.8 to 5 

μl/ml 

1.9 to 4 

μl/ml 

pos with S-9 mix, total 

growth ranged from 

10 to 62%; without 

S-9 mix, from 5 to 

26 % 

full report lacking; no 

data on mutation 

frequencies; no colonysizing 

Kirby, 1983 

Studies in vitro: SCE 

Vinyl acetate clearly induced sister-chromatid exchanges (SCE) in human lymphocytes in the 

absence of S-9 mix. According to Norppa et al. (1985) after 48-h treatment all tested doses ranging 

from 0.1 to 1 mmol/l were positive; the highest dose led to an SCE frequency of 120 per cell. He 

and Lambert (1985) demonstrated that the SCE induction was dependent on the treatment time. 

With 1-h treatment doses in the mmol/l-range were needed for positive effects; this investigation 

suffers from the disadvantage of unusual high negative controls of ca. 20 SCE per cell. 

SCE induction by vinyl acetate was also demonstrated in CHO cells (Norppa et al., 1985). With 24-

h treatment time without S-9 mix, effects were similar to those observed in human lymphocytes. 

After 4-h treatment effects were stronger in presence than in absence of S-9 mix. 
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In vitro tests: SCE 

 Concentration 

range 

 

Test system With S9 mix Without 

S-9 mix 

Result Toxicity Remarks Reference 

human 

lymphocytes 

not 

done 

0.1 to 1 

mmol/l 

pos strong inhibition of 

cell proliferation at 

high doses, but SCE 

induction not 

limited to doses with 

strong toxicity 

48-h treatment; pos at all 

tested doses; extremely 

steep dose-effect 

relationship; max. SCE 

frequency ca. 120 per 

cell 

Norppa et 

al., 1985 

CHO cells 0.2 to 2 

mmol/l 

0.1 to 5 

mmol/l 

pos strong inhibition of 

cell proliferation at 

high doses, but SCE 

induction not 

limited to doses with 

strong toxicity 

24-h treatment without S9 mix: strong pos effect 

at all tested doses; 4 h 

treatment: stronger effect 

with S-9 mix than 

without 

Norppa et 

al., 1985 

human 

lymphocytes 

not 

done 

0.1 to 2.4 

mmol/l 

pos no data investigation of time- and 

dose-dependency: with 

1-h treatment doses in 

the mmol/l-range needed 

for positive effects; 

extremely high negative 

controls of ca. 20 SCE 

per cell 

He and 

Lambert, 

1985 

Studies in vitro: DNA strand breaks 

Induction of DNA strand breaks in human lymphocytes by vinyl acetate was analysed using the 

alkaline elution technique by Lambert et al. (1985). 4-h treatment with concentrations of 10 and 20 

mmol/l did not result in an increase of DNA strand breaks. 

In vitro tests: DNA strand breaks 

 Concentration range 

Test system With S-9 

mix 

Without S9 mix Result Toxicity Remarks Reference 

alkaline elution, 

human 

lymphocytes 

not done 10 and 20 

mmol/l 

neg no data 4-h 

treatment 

Lambert et al., 

1985 

Studies in vitro: DNA-protein crosslinks (DPX) 

Kuykendall and Bogdanffy (1992) demonstrated the potential of vinyl acetate for induction of 

DNA-protein crosslinks (DPX) with purified plasmid DNA and calf thymus histone proteins. Doses 

ranging from 10 to 100 mmol/l were used. Induction of DPX was bound to the presence of rat liver 

microsomes. 
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Induction of DPX was also found in isolated cells from rat nasal tissues (respiratory and olfactory; 

Kuykendall et al., 1993). With treatment times of 1 to 2 h, very high doses ranging from 25 to 75 

mmol/l were needed for induction of DPX rates over the background level. 

In the alkaline elution investigation of Lambert et al. (1985; see 'DNA strand breaks' above) the rate 

of X-ray induced DNA strand breaks was decreased by vinyl acetate which indicates the formation 

of DPX; vinyl acetate doses were 10 and 20 mmol/l. 

In vitro tests: DNA-protein crosslinks 

 Concentration 

range 

 

Test system With S9 mix Without 

S-9 mix 

Result Toxicity Remarks Reference 

DPX, 

isolated 

DNA + 

histone 

proteins 

10 - 

100 

mmol/l 

10 - 100 

mmol/l 

pos use of rat liver 

microsomes instead of S9 mix; pos only in 

presence of microsomes 

Kuykendall 

and 

Bogdanffy, 

1992 

DPX, cells 

from rat 

nasal tissues 

(respiratory 

and 

olfactory) 

 5 to 75 

mmol/l 

pos totally toxic after 2-

h exposure to 50 

mmol/l 

12- to 15-fold increase of 

DPX levels after 1-2 h 

exposure; LOEC 25 

mmol/l 

Kuykendall 

et al., 1993 

alkaline 

elution, 

human 

lymphocytes 

not 

done 

10 and 

20 

mmol/l 

pos no data the induction of DNA 

strand breaks by X rays 

was decreased by 

treatment with vinyl 

acetate 

Lambert et 

al., 1985 

4.1.2.7.2 Studies in vivo 

Studies in vivo: micronuclei and chromosomal aberrations in bone marrow cells

A bone marrow micronucleus test with mice was done with single intraperitoneal administration of 

doses ranging from 250 to 2000 mg/kg; sampling was 30 h after treatment (Mäki-Paakanen and 

Norppa, 1987). Negative findings were obtained for doses of 250 and 500 mg/kg. After treatment 

with 1000 and 2000 mg/kg vinyl acetate weak increases in micronucleus frequencies were found: 

1.33% and 1.57% micronucleated polychromatic erythrocytes as compared to 0.6% in the negative 

control. However, these doses were in the highly toxic range and were lethal to 6 out of 14 or 8 out 

of 14 treated animals. The ratio of polychromatic to normochromatic erythrocytes, which indicates 

local cytotoxicity in the bone marrow, was clearly depressed at these doses. The relevance of these 

findings is highly questionable. 

Micronucleus frequencies were also determined within 3-months toxicity studies with rats and 

mice. Bone marrow smears were analysed at the end of treatment and it was found that 

micronucleus frequencies in vinyl acetate treated animals were not significantly different from 
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control animals. Treatments of rats and mice were done via drinking water (1000, 5000 and 10000 

ppm in drinking water; Gale, 1980a,b) or by inhalation (50, 200 and 1000 ppm; Owen, 1980a; 

1980b). At the higher doses toxic effects were seen in all studies. All these investigations were done 

according to inadequate methodologies, e.g. the analysed cell type was not specified and positive 

controls were lacking. Therefore, the findings are of low reliability. 

In a publication without detailed description of the methodology, results of a chromosomal 

aberration test with male Wistar rats were reported (Nersesyan et al., 1990). Vinyl acetate was 

given via the i.p.-route, the only dose was 160 mg/kg which corresponds to 20% of the LD50; 

sampling of bone marrow was done 26 h after treatment. From the 5 animals analysed, 8.2% of the 

cells carried chromosomal aberrations (negative control, 0.6%); gaps were included and the 

spectrum of induced aberrations was quite unusual. A positive control was not included and coding 

of the slides was not mentioned. Altogether, this finding is of low reliability. 

In vivo tests: micronuclei (MN) and chromosomal aberrations (CAb) in bone marrow 

Test 

system 

Doses Exposure 

regimen 

Sample 

time 

Result Local 

cytotox

General 

toxicity 

Remarks Reference 

MN in 

mouse 

bone 

marrow 

250 to 

2000 

mg/kg 

1 x i.p. 30h pos 500 

mg/kg 

and 

higher 

ca. 50% 

lethality at 

1000 and 

2000 mg/kg 

 Mäki-Paakanen 

and Norppa, 

1987 

MN in rat 

bone 

marrow 

1000 to 

5000 

ppm 

over 3 

months in 

drinking 

water 

 neg no data no inappropr. 

methodology 

Gale, 1980a 

MN in 

mouse 

bone 

marrow 

1000 to 

5000 

ppm 

over 3 

months in 

drinking 

water 

 neg no data no inappropr. 

methodology 

Gale, 1980b 

MN in rat 

bone 

marrow 

50 to 

1000 

ppm 

inhalation 

over 3 

months 

 neg no data no inappropr. 

methodology 

Owen, 1980a 

MN in 

mouse 

bone 

marrow 

50 to 

1000 

ppm 

inhalation 

over 3 

months 

 neg no data no inappropr. 

methodology 

Owen, 1980b 

CAb in 

rat bone 

marrow 

160 

mg/kg 

1 x i.p. 26 h pos no data 20% of LD50 no detailed 

data 

Nersesyan et 

al., 1990 

Studies in vivo: SCE in bone marrow cells 

Vinyl acetate induced sister-chromatid exchanges (SCE) in bone marrow cells of male BDF rats (3 

per group) after single intraperitoneal application (Takeshita et al., 1986). Weak effects were found 

at doses from 370 mg/kg upwards in non-hepatectomised rats and from 470 mg/kg upwards in 

hepatectomised rats. The maximum effect was ca. a doubling of the spontaneous SCE frequency at 
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560 mg/kg. The treatments were without clear influence on cell proliferation behaviour. Data on 

general toxicity were not given; it can be estimated that 370 and 470 mg/kg correspond to half of 

the LD50. 

In vivo tests: SCE bone marrow 

Test system Doses Expos. 

regimen 

Sample 

times 

Result Local 

cytotox. 

General 

toxicity 

Reference 

SCE, rat bone 

marrow 

370 to 560 

mg/kg 

1 x i.p. 21 h pos no no data Takeshita 

et al., 1986 

Studies in vivo: DNA binding in rat liver 

Binding to liver DNA was studied after administration of [14C]-vinyl-labelled vinyl acetate to 

groups of 3 rats (male and female F344, male Wistar) (Simon et al., 1985b). The test substance was 

given orally (1mCi = 0.1 mmol per animal) or by inhalation (1200 to 1800 ppm). Four hours after 

start of exposure the livers were processed. Although radioactivity was measured in DNA and 

nucleoproteins, none of those DNA adducts were found which occur after exposure to analogue 

vinyl halides and vinyl carbamate. The authors discussed that these findings should be viewed 

along with the rapid degradation of vinyl acetate to acetaldehyde and acetic acid by blood esterases. 

These intermediates may enter the metabolic C2-pool (via acetyl-CoA) giving rise to unspecific 

incorporation of the label into purine nucleotides.

In vivo tests: DNA binding 

Test system Doses Expos. 

regimen 

Result Remarks Reference 

DNA adducts, rat 

liver 

1200 to 1800 

ppm 

4 h inhalation neg Simon et al., 

1985b 

DNA adducts, rat 

liver 

0.1 mmol / 

animal 

1 x orally neg Simon et al., 

1985b 

Studies in vivo: germ cell effects 

Micronucleus frequencies in early spermatids of mice were analysed by Lähdetie (1988) 13 days 

after a single i.p. administration of vinyl acetate doses ranging from 250 to 1000 mg/kg. Doses of 

750 and 1000 mg/kg were in the lethal range where 8 out 9 or 1 out of 4 animals died; group sizes 

were quite low (1 to 4 animals). No increase in micronucleus frequencies was seen. 

Sperm abnormalities in mice were investigated 3 and 5 weeks after start of 5 daily i.p.-doses of 125 

to 1000 mg/kg vinyl acetate (Lähdetie, 1988). At 1000 mg/kg no treated animal survived. At 750 

mg/kg 1 out of 5 treated mice survived; the only surviving mouse showed an increased frequency of 

abnormal sperms 5 weeks after treatment, but not 3 weeks after treatment. 

All animals survived after i.p.-doses of 500, 250 and 125 mg/kg. Marked decreases in weight gain 

were reported for doses of 500 and 250 mg/kg. 
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At 500 mg/kg increased frequencies of sperm anomalies were detected in 2 of 7 animals at 3 weeksampling (variation, ca. 2-14%) and in 4 out of 8 animals at 5 week-sampling (extremely high 

variation, ca. 1 to 62%). At 250 and 125 mg/kg no effects on sperm abnormality were observed. 

Altogether, the effects on sperm abnormality were limited to doses in the highly toxic range. 

Furthermore, effects on sperm abnormality are not specific for mutagens but may be due to 

spermatotoxicity. Therefore, these findings are of low relevance for assessment of mutagenicity. 

In vivo tests: germ cell effects 

Test system Doses Expos. 

regimen 

Result General 

toxicity 

Remarks Reference 

MN in early 

spermatids of 

mice 

250 to 

1000 

mg/kg 

1 x i.p., 

13 days 

recovery 

neg lethality at 

750 and 

1000 mg/kg 

only 1 to 4 mice per 

group 

Lähdetie, 

1988 

sperm 

abnormality 

in mice 

125 to 

1000 

mg/kg 

daily i.p. 

for 5 days 

pos lethality at 

750 (4/5) 

and 1000 

mg/kg (5/5) 

effects limited to 

doses with high 

toxicity and not 

specific to 

mutagenesis 

Lähdetie, 

1988 

Studies in vivo: Human studies - chromosomal aberrations 

27 workers in the polyvinyl acetate production were analysed with respect to their frequencies of 

peripheral lymphocytes with chromosomal aberrations (Shirinian and Arutyunyan, 1980). No 

exposure data were given. Aberration frequencies varied from 2.2% (1976) to 2.5% (1977) and 

2.4% (1978). In a negative control group of 20 workers from the non-chemical industry the 

aberration frequency was 1.0% in 1978 (not analysed in 1976 and 1977). The negative control 

group was not 'matched', confounding factors were not considered. The authors do not claim a 

'positive' result and no clear conclusion can be drawn. 
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Human studies: chromosomal aberrations 

Test system Exposure No. of 

subjects 

Matched 

negative 

control 

Authors 

concl. 

Genetic effect Reference 

chromos. 

aberrations in 

peripheral 

lymphocytes 

not 

specified 

27 no ? 2.2 to 2.5 % 

(1.0% in 

negative control) 

Shirinian and 

Arutyunyan 

(1980) 

Genotoxicity of the acetaldehyde: possible contribution to vinyl acetate genotoxicity 

Acetaldehyde is a metabolite of vinyl acetate through esterase-mediated metabolism. It is discussed 

that vinyl acetate exhibits its genotoxicity via acetaldehyde. For example Kuykendall and 

Bogdanffy (1992) demonstrated that vinyl acetate induces DPX via acetaldehyde, and according to 

Norppa et al. (1985) chromosomal damage induced by vinyl acetate in mammalian cell cultures is 

through formation of acetaldehyde. 

A comprehensive overview on the genotoxicity of acetaldehyde is given by the SCCNFP Opinion 

on acetaldehyde (2004). According to this overview acetaldehyde is not mutagenic to the standard 

battery of Salmonella typhimurium strains with and without metabolic activation. In a number of 

investigations with mammalian cells in vitro various genetic effects were induced. The genotoxicity 

of acetaldehyde was not dependent on the presence of external metabolisation systems. The lowest 

concentrations with positive genetic effects were in the ranges of 4.4 μg/ml for chromosomal 

aberrations and micronuclei and 1.3 μg/ml for SCE. With respect to other positive genetic effects, 

such as mutations in the mouse lymphoma assay, DNA binding and DNA strand breaks, higher 

lowest-observed-effect concentrations were reported. Doses of 4.4 and 1.3 μg/ml correspond to 0.1 

and 0.03 mmol/l. 

In vivo, two investigations are available on the induction of micronuclei by acetaldehyde. In bone 

marrow cells of mice intraperitoneal administration of high acetaldehyde doses induced micronuclei 

(Morita et al., 1997). The lowest doses with observed effect were about 200 mg/kg in two 

independent investigations; this is approximately 50% of the LD50. In mouse spermatids no 

micronuclei were induced after single intraperitoneal administration of doses up to 500 mg/kg 

(Lähdetie, 1988). 

Acetaldehyde is a weak inducer of SCE in rodent bone marrow cells in Chinese hamsters (single 

intraperitoneal administration of 0.5 mg/kg; Korte et al., 1981) and mice (single intraperitoneal 

injections of 0.4 μg per animal [ca. 16 μg/kg]; Obe et al., 1979). 

DNA-protein crosslinks (DPX) were induced in nasal respiratory mucosa cells of Fischer 344 rats 

after inhalation exposure of 1000 or 3000 ppm (Lam et al. 1986). Similar ranges of DPX were 

produced following a single 6 h exposure and after 5 days of daily 6 hour inhalation period. Lower 

concentrations of 100 and 300 ppm were negative. Olfactory epithelium did not response at the end 

of a 6-hour exposure time at concentrations of 1000 and 3000 ppm, but exposure on 5 days resulted 

in a significant increase of DPX rates at 1000 ppm (no results on other test concentrations). The 

magnitude of response at 1000 ppm in vivo (DPX production of +12-13% at the end of 6 hour 

inhalation on 1 day or 5 days) was in the same range in homogenates of respiratory mucosa 

incubated with 100 mM acetaldehyde (DPX +14%). 
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Acetaldehyde is a naturally occurring substance in the metabolic pathways of animals and humans 

(metabolism of ethanol and sugars). It occurs in small quantities in human blood. Therefore, it may 

well be that acetaldehyde expresses its genotoxic potential in case of metabolic overload. 

Genotoxicity of acetic acid: possible contribution to vinyl acetate genotoxicity 

The vinyl acetate metabolite acetic acid is negative in bacterial genotoxicity tests (McCann et al., 

1975; Hude et al., 1988; Zeiger et al., 1992). 

Controversial findings were reported on in-vitro clastogenicity of acetic acid in CHL cells. 

According to Ishidate (1988; see also: Ishidate et al., 1984) acetic acid was negative for doses up to 

1000 μg/ml (= 16.7 mmol/l) without S-9 mix. Morita et al. (1990) found positive effects with and 

without S-9 mix for doses of 12 and 14 mmol/l (721 and 842 μg/ml), a dose of 16 mmol/l (961 

μg/ml) was totally toxic. Morita et al. (1990) concluded that acetic acid itself was non-clastogenic, 

but the effect was due to, unspecific, decreased pH values. 

In an in vitro SCE test acetic acid induced a marginal response at 5 and 10 mmol/l (Sipi et al., 

1992). The maximum effect was a 1.5-fold increase and probably due to unspecific cell-cycle delay. 

In a gene mutation test with transgenic mice a 2-fold increase in mutation frequency was obtained 

after single dermal administration of 30 μg/kg acetic acid (Myhr, 1991); a lower (12 μg/kg) as well 

as a higher dose (48 μg/kg) were without effect. In this early investigation on this test system no 

analysis of the mutation spectrum was done. Therefore, it cannot be deduced from the test data 

whether the effect is due to mutations induced by acetic acid or due to the clonal growth of a cell 

carrying a mutation (an effect which is known for promoters). 

Overall, the genotoxicity data on acetic acid give no relevant evidence that the genotoxic potential 

of vinyl acetate may be due to acetic acid. 

Conclusion:

Vinyl acetate is negative in bacterial mutagenicity tests. 

In mammalian cell cultures various cytogenetic effects were induced in the absence of S-9 mix 

(chromosomal aberrations, micronuclei, SCE) and in the presence of S-9 mix (SCE; chromosomal 

aberrations and micronuclei not analysed with S-9 mix). The lowest positive concentrations ranged 

from 0.1 to 0.2 mmol/l. A positive mouse lymphoma assay is in line with these results, but it cannot 

be deduced whether the positive effect is due to chromosomal or to gene mutations (no colony 

sizing). Mammalian cell culture investigations on DNA strand breaks (DSB) and DNA protein 

crosslinks (DPX) were negative (DSB), or extremely high concentrations were needed for positive 

effects (DPX). 

Very few reliable data are available on the in vivo mutagenicity of vinyl acetate. A weak induction 

of micronuclei in mouse bone marrow cells was clearly limited to intraperitoneal doses in the LD50 

range (1000 and 2000 mg/kg bw). In rats no induction of micronuclei was observed in spermatids 

(screening assay with intraperitoneal doses up to 1000 mg/kg bw). Further tests on induction of 

micronuclei or chromosomal aberrations were of too low reliability. 
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Also in an SCE test with rats positive effects were weak and limited to high and probably highly 

toxic intraperitoneal doses (370 and 470 mg/kg bw). Such weak increases in SCE frequencies may 

well be induced by unspecific effects on the cell cycle. 

No specific DNA binding was observed in rat livers after inhalation or oral administration. 

Induction of sperm abnormalities in mice again was limited to doses in the toxic range. 

Furthermore, it is not specific for mutagens. 

No clear conclusion can be drawn from a human study on the possible induction of chromosomal 

aberrations in workers exposed to vinyl acetate. 

Genotoxicity data on vinyl acetate metabolites are in line with the hypothesis that vinyl acetate 

genotoxicity is mediated by acetaldehyde. The genotoxicity of acetaldehyde is possibly limited to 

an overloading of defence mechanisms. 

Altogether, vinyl acetate has a mutagenic potential, which is preferentially expressed as 

clastogenesis. The data on in vivo genotoxicity are difficult to interpret, since their majority is of 

low reliability, or the effects are not specific to mutagenicity. The most important effect, a weak 

induction of micronuclei in mouse bone marrow, is limited to intraperitoneal doses of high toxicity. 

Therefore, it is unlikely that the genotoxic potential of vinyl acetate is expressed in germ cells in 

man. However, genotoxic effects locally in directly exposed tissues (site of first contact) cannot be 

excluded; the occurrence and strength of the effects will be dependent on the metabolic capacity of 

the directly exposed tissue. 

No classification of vinyl acetate in terms of germ cell mutagenicity is proposed. 

4.1.2.8 Carcinogenicity 

Animal data:

Inhalation exposure 

- In a combined chronic toxicity and carcinogenic study (Owen, 1988; Bogdanffy et al., 1994b) 

male and female Sprague-Dawley rats and CD-1 mice including 60 animals per sex per dose 

and three satellite groups of 10 of each species and sex for interim evaluation at week 53 and 

week 83 and recovery studies (70 weeks of exposure followed by 15/16 weeks of recovery) 

were exposed by inhalation to vinyl acetate vapour in concentrations of 0, 50, 200, and 600 ppm 

over a period of 2 years (6 hours/day, 5 days/week). Exposure-related tumor response was 

observed in the nasal cavity of rats only. Concomitant degenerative, hyperplastic and 

metaplastic changes of the respiratory tract are described in 4.1.2.6 (Tables 4.1.2.6.A + 

4.1.2.6.B). A tumor response of other organs related to vinyl acetate treatment was not evident 

in rats and mice. 
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TABLE 4.1.2.8.A

Summary of Statistically Significant Neoplastic Changes in Lungs and Nose of Rats by Vinyl acetate: 

Main Study 

 Incidence of Tumors (Numeric)a

 Males Females 

 Concentration (ppm): Control 50 200 600 Control 0 200 600 

Lungs: (58) (59) (60) (60) (60) (60) (60) (59) 

 Well differentiated adenoma [B] 0 0 0 0 1 0 0 0 

Nose: (59) (60) (59) (59) (60) (60) (60) (59) 

 Inverted papilloma [B] 0 0 0 4 0 0 0 0 

 Squamous cell carcinoma [M] 0 0 0 2 0 0 0 4 

 Papilloma [B] 0 0 1§ 0 0 0 0 0 

 Carcinoma in situ [M] 0 0 0 1 0 0 0 0 

 Total benign tumors 0 0 1 4 0 0 0 0 

 Total malignant tumors 0 0 0 3 0 0 0 4 

 Total nasal tumors 0 0 1 7** 0 0 0 4 

Larynx: (59) (60) (60) (60) (60) (60) (60) (59) 

 Squamous cell carcinoma [M] 0 0 0 0 0 0 0 1 

a

 Figures in parenthesis represent the number of animals from which this tissue was examined microscopically. 

[B] = benign, [M] = malignant. Significance of differences in a pairwise (Fisher’s) test between each 

treatment and control incidence is represented by ** (p<0.01). 

 Cited from Bogdanffy et al. (1994b), § exophytic papilloma in the olfactory mucosa zone, confirmed by 

personal communication 

A total of 11 nasal cavity tumors (Table 4.1.2.8.A) classified as papilloma, squamous cell 

carcinoma, carcinoma in situ in olfactory regions, and papilloma and squamous cell carcinoma in 

respiratory or anterior non-olfactory regions (distribution see Table 4.1.2.8.B) were evident in 7 

males (11.9%) and 4 females (6.7%) of the high dose rat group. In the intermediate dose groups a 

single tumor (benign papilloma of the olfactory region) was found in a male rat. In the larynx a 

squamous cell carcinoma was found in a high dose female. No tracheal or treatment-related lung 

tumor was observed. No respiratory tract tumor was seen in the control and low dose groups except 

a single adenoma of the lung in a control female. 

Table 4.1.2.8.B Regional distribution of vinyl acetate-induced nasal tumors in rats 
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Site of origin Tumor type 

Olfactory region 2 inverted papillomas 

 1 exophytic papilloma§ 

 1 squamous cell carcinoma 

 1 carcinoma in situ 

Respiratory region 2 inverted papillomas 

Cuboidal epithelium of zone Ba 2 squamous cell carcinoma 

unknown 3 squamous cell carcinoma 

#Cited from Bogdanffy et al., 1994b, § in a male of the 200 ppm group 

a

 Zone B is located within a cross section of the nose at the level of the nasolacrimal duct medial/ventral to the incisor tooth root 

In mice, no treatment-related increased incidence of tumors was observed in the nose, larynx, 

trachea, lung, or other tissues of mice in the main study and in the satellite groups. A single 

squamous cell carcinoma in a major lung bronchus of a high dose male and a single 

adenocarcinoma in the lung of a control male was noted. 

Oral application 

- The offspring of Fo-animals which received vinyl acetate in drinking water from the time of 

gestation at target concentrations of 0, 200, 1000 and 5000 ppm were investigated in a chronic 

and carcinogenicity study (Bogdanffy et al., 1994a; Shaw, 1988). Vinyl acetate was 

administered to male and female Sprague Dawley rats (60 offspring/sex/dose of the main study 

and 10 offspring/sex/dose for interim sacrifices at week 52 and week 78) via drinking water in 

concentrations of 0, 200, 1000, and 5000 ppm (average vinyl acetate consumption: 0, 10, 47, 

and 202 mg/kg/day in males, 0, 16, 76, 302 mg/kg/day in females) over a period of 2 years. The 

test substance contained contaminants in concentrations of ≤11.5 ppm acetic acid and ≤71 ppm 

acetaldehyde, ≤389 ppm water, the test solution was prepared daily. They were examined for 

clinical symptoms, body weight, food and water consumption, parameters of hematology, 

clinical chemistry and urinalysis, gross and microscopical abnormalities. Numerous organs were 

examined histopathologically, but no tissues from the oral cavity (except the tongue) were listed 

as protocol organs. Rats of the 1000 and 5000 ppm groups consumed less water and rats of the 

5000 ppm groups had decreased food consumption. Mean body weight gain of 5000 ppm males 

was significantly reduced compared to controls during the first (-11%) and second years (-17%). 

Mean body weight gain of 5000 ppm females was depressed (-11%) only during the second 

year. No treatment-related effect was seen for the mortality rates, or the test parameters of 

hematology, clinical chemistry or urinalysis. There was no evidence of systemic target organ 

toxicity. Some organ weights (brain, kidney, heart, liver, spleen, adrenal, pituitary) were altered 

at ≥1000 ppm, but were not associated with histopathological changes and were therefore 

considered to be related to lower body weight. The high concentration did not exceed the MTD 

since feed and water consumption can be attributed to the lower body weight gain. The authors 

concluded that there was no treatment-related oncogenic effect. Squamous carcinomas were 

seen in the oral cavity of two high dose males and additional single other oral cavity tumors 
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were observed in treated animals (fibrosarcoma in one low and mid dose males each, an 

odontoma in a mid dose female, and a malignant schwannoma in a high dose female). In 

addition, a single sarcoma was found in the stomach of a high dose male. All reported tumors 

(including those in control and treated animals, which were not reported here) were considered 

to be within normal rates and within the biological variation of the strain and age of rat. 

Due to the reduced body weight gain at 5000 ppm, the NOAEL for nonneoplastic effects was 

1000 ppm (47 mg/kg bw/d in male rats, 76 mg/kg bw/d in female rats). 

For reason of possible target organs not being routinely examined and the fact that dose-related 

and significantly increased tumor rates in this study were absent did not give sufficient proof 

that carcinogenic potential of vinyl acetate was negative. Even when oral cavity was not 

examined as a protocol organ, two squamous carcinomas were seen in high dose males. As 

squamous cell carcinomas were not seen in control animals and rarely occur in historical 

control rats of this strain, it comes into question - due the rapporteur's opinion - that this finding 

may be related to vinyl acetate administration. Assumption is supported by concordance with 

data from other oral cancer studies in rats and mice that reported squamous cell carcinomas in 

the oral cavity (Umeda et al., 2004a). 

- The chronic toxicity study of Lijinsky and Reuber (1983) revealed equivocal results concerning 

higher incidences of tumors in animals after oral administration of vinyl acetate. Groups of 20 

male and female F344 rats received vinyl acetate dissolved in drinking water at 1000 or 2500 

ppm over a period of 100 weeks and were observed up to 130 weeks. Three types of neoplasm 

appeared at higher incidences in the treated groups. These were neoplastic nodules in the liver 

(males 0/20, 3/20, 2/20; females 0/20, 0/20, 6/20, historical controls 3-9.1%), adenocarcinomas 

of the uterus (0/20, 1/20, 5/20; historical controls 0.8%-10.8%), C-cell adenomas and 

carcinomas of the thyroid (males 2/20, 2/20, 1/20; females: 1/20, 2/20, 6/20, historical controls: 

5-7.6%). Data on historical controls were reported from internal control animals and from 

literature. The study performance was inadequate since the vinyl acetate solutions were 

prepared only once a week, which resulted in hydrolytic degradation. Bogdanffy et al. (1994a) 

reported a 6% to 14% degradation of vinyl acetate in tap water after 1 day and 40% to 60% over 

a 7-day period. The group size was small comparing to test standards for carcinogenicity studies 

and only gross lesions were processed for histopathology. 

- In contrast to this, a recent carcinogenicity study of the Japan Bioassay Research Center 

(Umeda et al., 2004a, Celanese, 1998) reported to be in conformity to OECD Guideline 453 

indicated that higher tumor incidences were induced by oral treatment with vinyl acetate. 

Groups of 50 male and female F344/DuCrj rats received drinking water containing 0, 400, 2000, 

and 10000 ppm vinyl acetate (98%, major impurities: water, acetic acid (no data on ppm), and 5 

ppm hydroquinone, test solution was prepared twice a week) for 104 weeks (equivalent 

analysed doses in mg/kg bw/d, at 400 ppm: 21 in males and 31 in females, 2000 ppm: 98 in 

males, 146 in females, 10000 ppm: 442 in males and 575 in females). Groups of 50 male and 

female Crj:BDF1 mice also received drinking water containing 0, 400, 2000, 10000 ppm vinyl 

acetate for 104 weeks (equivalent mean doses in mg/kg bw/d calculated from body weight and 

amount of water consumed: 400 ppm: 42 in males, 63 in females, 2000 ppm: 202 in males, 301 

in females, 10000 ppm: 989 in males and 1418 in females). 

- The concentrations prepared for each group varied in comparison to the set concentration within 

a range of 81%-120.8% for the 400 ppm group, 89-102.7% for the 2000 ppm group, and 71.4-

112% for the 10000 ppm group in the rat study and for the mice, values ranged from 81-113.3% 

for the 400 ppm group, 88.4-118.4% for the 2000 ppm group, and 74.1-120% for the 10000 ppm 

group. The concentrations of vinyl acetate in the drinking water was measured with a gas 
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chromatograph and stability of vinyl acetate in the drinking water was also measured in the 

preparations around the time of administration of the animals over a four-day period. A 

comparison of the results was reported to confirm stability (no quantitative data available). 

During the study, the general condition of the animals was observed once daily, the body weight 

and food consumption were estimated once weekly for the first 14 weeks, thereafter body 

weight was checked once per two weeks and food consumption once monthly. For the first 14 

weeks water consumption was estimated twice a week and once per two week thereafter. 

Hematology and clinical chemistry examinations were performed in animals surviving until the 

time of scheduled necropsy during the 104th week after a fasting period of at least 18 hours. 

Urinalysis was done on fresh urine collected from the animals as surviving until the last week of 

administration. At present, no summary tables or individual data are available on laboratory 

examination. All animals underwent necropsy at the end of the study (week 97 for the rats, week 

94 for the mice), organ weight was measured on scheduled sacrificed animals on brain, lung, 

liver, spleen, heart, kidney, adrenal, testis, ovary. During the study the body weight and food 

consumption were estimated once weekly for the first two weeks, thereafter body weight was 

checked once per two weeks and food consumption once monthly. For the first two weeks water 

consumption was estimated twice a week, and once per two week thereafter. Hematology and 

clinical chemistry examinations and urinalysis were performed (no data on time). All animals 

underwent necropsy, organ weight was measured on scheduled sacrificed animals on brain, 

lung, liver, spleen, heart, kidney, adrenal, testis, ovary. Histopathology examination of all 

animals included 37 organs/tissues (including the nasal cavity and the oral cavity with sections 

on three different levels each on the maxilla and mandible). 

- The vinyl acetate concentrations in the drinking water measured 4 d after the preparation were 

found to decrease to 72-80% of the initial concentrations for rats and 86-96% for mice. The 

acetic acid concentration and the pH measured 4 d after the preparation were 9.2 ppm and pH 

4.0 for the 400 ppm vinyl acetate-formulated drinking water, 47 ppm and pH 4.2 for the 2000 

ppm water and 263 ppm and pH 3.6 for the 10000 ppm water at the end of the 4-day 

administration period. 

- In the rat, no significant difference between the survival of the treated groups and that of the 

control group was observed in the males or females. A slight decrease in mean final body 

weight was observed in the high dose groups (-8% in males, -10% in females) compared to the 

control groups. As outlined in figures on body weight development, the growth curve from 

week 1 by week 16 was similar for all treatment and control groups. In this group, water 

consumption was on average 82% for the male rats and 75% for the female rats of that of the 

control groups. No significant difference in food consumption was seen for male and female 

groups that received vinyl acetate compared to the control values. Hematology tests reveal 

elevated concentrations for haemoglobin and MCH in high dose female rats. Male rats of this 

group exhibited an elevated albumin/globulin ratio and decreased levels of total cholesterol, 

phospholipids and calcium. Urinalysis revealed lower urinary pH values in male rats of the 400 

and 10000 ppm groups. At necropsy, mandibular nodules were noted in three high dose males 

and in 1 female in the 400 ppm group in the mandibular region and in the maxillary region of 1 

female of the 10000 ppm groups. A decrease in the actual weights of the kidneys and livers of 

male rats that received 10000 ppm. There were higher incidences of tumor rates in the oral 

cavity, esophagus, and stomach that were considered to be treatment-related (Table 4.1.2.8.C). 

In the oral cavity, increased numbers of squamous cell carcinomas were found in exposed 

groups of females (control: 0/50, 400 ppm: 1/50, 2000 ppm: 1/50, 10000 ppm: 3/50 with 

significance p<0.05 in the Peto test, not significant in the Fischer’s exact test and Cochran 

Armitage test), a significantly increased incidence occurred in males (control, 400 ppm and 

2000 ppm: 0/50, 10000 ppm: 5/50 with significance p<0.01 in the Peto test and p<0.05 in 
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Fischer’s exact test and Cochran Armitage test). Squamous cell carcinoma metastasis to the 

tongue was noted in 1 male of the 10000 ppm group. Squamous cell papilloma was observed in 

2/50 males in the 10000 ppm group (total tumor rate in high dose males 14%). In this dose 

group, basal cell activation was also observed in 2/50 males and 1/50 females. Epithelial 

dysplasia was seen in 2/50 of the 10000 ppm females. Mapping of neoplastic and preneoplastic 

lesions in the rat oral cavity of the high dose group showed that lesions were distributed 

throughout the cavity, but 4 of 8 carcinomas occurred at level VI (mandibular region at the 

anterior edge of the lower molar teeth). Tumors or lesions presumed to be preneoplastic lesions 

of the esophagus and stomach were only evident at 10000 ppm. One female out of 50 had a 

squamous cell carcinoma of the esophagus. In 1/50 males and 1/50 females, oesophageal 

squamous cell hyperplasia was observed. In addition, basal cell activation was observed in 4/50 

females. No stomach tumors were found, but basal cell activation occurred in 2/50 males and 

5/50 females in the 10000 ppm group. 

Peto test revealed an increasing trend in the occurrence of interstitial cell tumors in the testes of 

males (control group: 42/50; 400 ppm group: 40/50; 2000 ppm group: 44/50; 10000 ppm 

group: 47/50), and an increased trend in the occurrence of adenocarcinoma in the mammary 

glands of females (control group: 0/50; 400 ppm group: 0/50; 2000 ppm group: 0/50; 10000 

ppm group: 3/50). Both tumor rates were within the range of historical control data of the 

testing centre (82-98% (mean 89.6%) for interstitial cell tumors and 0-6% range (mean 2%) for 

mammary adenocarcinomas). 

Comment: The selected doses in this rat study albeit there are very high in the top dose were 

not considered to exceed the MTD since no indication on non-specific or specific systemic 

organ toxicity could be identified. The slight decrease in final body weight and increased 

haemoglobin values in female rats were most likely attributable to the significantly reduced 

water consumption. Lower kidney and liver weights might be reflective for lower body weight 

gain in high dose males, no lesions indicative for organ toxicity were reported. No indications 

for clinically observed cachexia were reported, and tumor masses in the oral cavity of 1 or 2 

animals out of 50 animals/dose groups were not to assume to interfere with food uptake 

because of the low number of animals affected; as to be expected the mean group food 

consumption in the dose groups was comparable to control values. 

The increased numbers of squamous cell tumors (malignant and benign) in the oral cavity of 

male and female rats of the high dose groups were considered as treatment-related. In the 

context of increased incidences of squamous cell carcinomas of the oral cavity in high dose 

males and females together with the occurrence of some benign tumors and preneoplastic 

lesions of this cell type at this dosage and under consideration of the fact that spontaneous 

tumors of this type and at this site are rare, the authors in agreement with the rapporteur also 

considered single squamous carcinomas at 400 and 2000 ppm likely to be associated to vinyl 

acetate treatment. The same can be assumed for all effects on the esophagus and stomach. 

- In mice no significant difference between the survival of the treated groups and that of the 

control group was observed in the males or females. A decrease in final body weight was 

observed in the high dose groups after week 60 with lower final body weights by 30% in males, 

and by 18% in females (starting after week 80) compared to the control groups. As outlined in 

figures on body weight development, the growth curve from week 1 by week 12 was similar for 

all treatment and control groups. Decreased mean water consumption was noted in the males of 

the 10000 ppm group (-15%), and dose-related in all female dose groups (-24% in the 400 ppm 

group, -8% in the 2000 ppm group, -17% in the 10000 ppm group, compared to control group 

values). There was no significant difference in food consumption between treated and control 
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groups. Hematology examinations revealed increased counts of platelets, neutrophils and 

decreases in lymphocyte counts for high dose males and decreased MCHC for high dose female. 

In males of the 400 group and males and females of the 10000 ppm groups serum glucose was 

reduced. In the males of 10000 ppm group, increased albumin/globulin ratios, increased ALP 

activity, and decreased total cholesterol, triglyceride and calcium levels were observed. 

Urinalysis in this group revealed decrease urinary pH values and increased urinary protein, in 

females at this dose level increased urinary protein and ketone bodies were noted. Clinical 

observation revealed tumor masses in the oral cavity in 6 males and 6 females of the 10000 ppm 

groups, the first appearance was noted in periods between week 65-78 in males and week 92-

104 in females. At necropsy, mandibular nodes were seen in 3 male and 5 females, maxillary 

nodes occurred in 3 males and 1 female in the 10000 ppm groups. Decreases in absolute weights 

and increases of relative weights of several organs were seen in male and female mice in the 

high dose group and the author thought this to be due to decreased body weight. Tumors 

associated with the vinyl acetate treatment were observed in the oral cavity, esophagus, 

forestomach and larynx. In the 10000 ppm group, squamous cell carcinomas of the oral cavity 

occurred in 13/50 males and 15/49 females (both significant) and squamous cell papilloma 

occurred in 4/50 males and 34/49 females (total incidence of squamous cell tumors in males 

32% and in females 37%), but no squamous cell tumors were seen in the control and low dose 

groups. Only at 10000 ppm, epithelial dysplasia was observed in 24/50 males and 17/49 

females. From doses at 2000 ppm and higher, squamous cell hyperplasia was also observed in 

2/50 males and 1/50 females at 2000 ppm, and in 13/50 males and 6/49 females at 10000 ppm. 

Basal cell activation was found in 1/50 males and females each at 2000 ppm and in 18/50 males 

and 17/49 females at 10000 ppm. More than 60% of the male mice and 35% of the female mice 

had two or more preneoplastic lesions at different sites of the oral cavity; their incidence was 

highest at level V of the mandibular region (at the middle point between lower incisor teeth and 

molar teeth). In the esophagus, there were squamous cell tumors consisting of carcinomas in 

7/50 males and 1/49 females of the 10000 ppm group and of one single papilloma in a 2000 

ppm female. In the 10000 ppm group, lesions of preneoplastic nature were epithelial dysplasia 

(2/50 males, 7/49 females, squamous cell hyperplasia (2/50 males and 2/49 females), and basal 

cell activation (9/50 males and 15/49 females). In the forestomach, squamous cell carcinomas 

occurred in 7/50 males and 3/49 females of the high dose group in comparison to none in the 

control and other dose groups. Benign squamous cell papilloma was evident in 2/50 males and 

1/49 females of this dose group. Males at 10000 ppm had epithelial dysplasia (1/50), squamous 

cell hyperplasia (3/50), and basal cell activation (1/50). Squamous cell hyperplasia occurred in 

2/50 females at 400 ppm and 4/49 at 10000 ppm and basal cell activation was observed in 1/49 

females at 10000 ppm. Furthermore, squamous cell carcinomas in the larynx were seen in 2/50 

males at 10000 ppm, 1/50 females at 2000 ppm and 1/49 females at 10000 ppm. In this group, 

there also occurred epithelial dysplasia (2/50 males and 3/49 females), squamous cell 

hyperplasia (1/50 males) and basal cell activation (3/50 males and 6/49 females). The stomach 

tumors were reported to arise from the forestomach in treated mice, for basal cell activation of 

the rat stomach no certain localisation was noted. No other tumor type at any other organ/tissue 

site increased in both studies. Metastasis of squamous cell carcinomas in the oral cavity were 

found in the lungs and lymph nodes of two males and two females in the 10000 ppm group and 

in the salivary glands of another female of this group. Squamous cell carcinoma metastases in 

the lungs with origin from the esophagus or stomach were also seen in two other males, 

squamous cell carcinoma in another female metastasised to the kidney, pancreas and lymph 

nodes. In the 10000 ppm groups, a total of 9 males and 7 females died of tumors in the above 

mentioned target organs such as oral cavity (6 males and 4 females), in the stomach (1 male and 

2 females) or larynx (1 male and 1 female) and in the esophagus (1 male). The authors 

concluded that squamous cell tumors (malignant and benign) occurring in the oral cavity, 
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larynx, esophagus, and stomach of male and female mice were caused by the administration of 

vinyl acetate. Atrophy of the salivary glands was noted in 6 males and 4 females in the 10000 

ppm group which were afflicted with tumors on the mandible and was thought to be a secondary 

change to tumor growth. 

- Comment: The observation that the high concentration (10000 ppm) administered to the top 

dose group animals have caused a reduction in final mean body weight might indicate that the 

MTD was exceeded. But, the following reasons support the view that the MTD was not reached: 

There was no significant difference in survival rates between dose and control groups, although 

relatively high numbers of animals died because of squamous cell tumors. Lower final body 

weight can be attributed to reduced water consumption. Growth curves seems to follow the 

curves of water consumption with a delay of some weeks. Both effects developed during the late 

phase of the study, reduction in water consumption began after week 60 (males) or 80 (females). 

The depressing effect of lower water consumption may be superimposed by the development of 

squamous cell tumors that resulted in a number of deaths. No indication on vinyl acetate-related 

systemic toxicity either as non-specific or organ-specific adverse effects could be identified. 

Otherwise, if the MTD would be exceeded, toxic signs were also to be expected for the early 

phase of a study where the mg/kg/d doses were much higher than in aged animals. The 

rapporteur’s comment is in agreement with the conclusion of the investigators that the MTD is 

not exceeded (Umeda et al., 2004b). 

- The authors concluded from these 2-year carcinogenicity studies in rats and mice that vinyl 

acetate given in drinking water caused squamous cell tumors in areas of the upper digestive tract 

with direct contact (predominantly in caudal and exterior regions of the mandible that were 

highly exposed) and squamous cell hyperplasia, basal cell activation and epithelial dysplasia 

represented early stages of squamous cell tumors. The lowest concentration associated with 

squamous cell tumors was 400 ppm in female rats and 2000 ppm in female mice. This is in line 

with the dose-related increases of tumor incidences at 31 mg/kg/d and 61 mg/kg/d, respectively, 

calculated as dose/bodyweight. A BMDL10 of 477 mg/kg/d for the combined incidences of 

squamous cell carcinomas and papillomas in the oral cavity of rats and mice (both species and 

both sexes combined for calculation) was estimated (BMDS version 1.3.1, US EPA’s NCEA, 

multistage model). 
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Table 4.1.2.8.C: Percentages of tumors and presumed preneoplastic lesions in a two-year carcinogenesis study on F344 rats 

and BDF1 mice with drinking water administration of vinyl acetate ( Umeda et al., 2004a) 

RAT 10000 ppm 2000 ppm 400 ppm control 

organ Tumor type/preneoplasia m# f m f M f m f 

oral cavity squamous cell carcinoma 10.0*↑ 6.0↑ - 2.0↑ - 2.0↑ - - 

 squamous cell papilloma 4.0 - - - - - - - 

 basal cell activation 4.0 2.0 - - - - - - 

 epithelia dysplasia - 4.0 - - - - - - 

esophagus squamous cell carcinoma - 2.0 - - - - - - 

 squamous cell hyperplasia 2.0 2.0 - - - - - - 

 basal cell activation - 8.0 - - - - - - 

stomach basal cell activation 4.0 10.0 - - - - - - 

MOUSE 10000 ppm 2000 ppm 400 ppm control 

organ Tumor type/preneoplasia m f m f M f m f 

oral cavity squamous cell carcinoma 26.0**↑↑ 30.6**↑

↑

- - - - - - 

 squamous cell papilloma 8.0↑↑ 6.0↑↑ - - - - - - 

 squamous cell hyperplasia 26.0 12.2 4.0 2.0 

 basal cell activation 36.0 34.6 2.0 2.0 

 epithelial dysplasia 48.0 34.6 

esophagus squamous cell carcinoma 14.0*↑↑ 2.0 - - - - - - 

 squamous cell papilloma - - - 2.0 - - - - 

 squamous cell hyperplasia 4.0 4.0 - - - - - - 

 basal cell activation 18.0 30.6 - - - - - - 

 epithelial dysplasia 4.0 14.2 - - - - - - 

forestomach squamous cell carcinoma 14.0*↑↑ 6.1↑↑ - - - - 2.0 - 

 squamous cell papilloma 4.0 2.0 - - - - - - 

 squamous cell hyperplasia 6.0 8.1 - - - 4.0 - - 

 basal cell activation 2.0 2.0 - - - - - - 

 epithelial dysplasia 2.0 - - - - - - - 

larynx squamous cell carcinoma 4.0 2.0 - 2.0 - - - - 

 squamous cell hyperplasia 2.0 - - - - - - - 

 basal cell activation 6.0 12.2 - - - - - - 

 epithelial dysplasia 4.0 6.0 - - - - - - 

m males, f females, - no tumor observed, #no of animals: 50 (except high-dose female mice: 49) 

statistical results only on tumors: sign. difference to controls * p<0.05, ** p<0.01 in Fisher’s exact test positive trend in Peto test or 

in Peto test and Cochran-Armitage test↑ sign. increase p<0.05 ↑↑ sign. increase p<0.01 
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- Another recent lifetime study on the carcinogenicity of vinyl acetate by Maltoni et al. (1997) 

reported increased tumor rates in Swiss mice orally treated with vinyl acetate. The study was 

started in the 80’s and the study design did not show conformity with the current guidelines for 

cancer studies. Daily fresh prepared vinyl acetate solutions were administered in ad libitum 

supplied drinking water at 0, 1000 and 5000 ppm (calculated to be equivalent to 0, 150, or 750 

mg/kg bw/d based on a water consumption of 15% of body weight) for 78 weeks. Data on vinyl 

acetate purity and analytical concentration in the drinking water and on water consumption were 

not given, but the test substance were reported to contain impurities of benzene (30-45 ppm), 

methyl and ethyl acetate (50 ppm), crotonaldehyde (6-16 ppm), acetaldehyde 2-11 ppm), and 

acetone (330-500 ppm). Male and female breeders (13-14 males and 37 females/group) and of 

male and female offspring (37-39 males and 44-48 females/group) were treated starting at 12th 

day of pregnancy. The animals were submitted daily to a clinical observation, the body weights 

were registered weekly within the first 13 weeks and every two weeks thereafter until the end of 

treatment at week 78, and than every 8 weeks until the end of the study. The evidence of gross 

lesions was checked weekly for the first 13 weeks and thereafter every second week. All 

animals were necropsied and histopathology was performed on 28 organs/tissues and any other 

organ with macroscopic lesions. With respect of the presumed target organs, five sections of the 

head were only included in animals treated longer than 100 weeks. Other target organs such as 

the tongue, esophagus, stomach, intestine were also examined microscopically, but not the 

larynx. No treatment-related effect on the body weights of male and female breeders and slight 

decreases in mean body weight in male and female offspring was seen. No treatment-related 

effect on survival rates occurred at the end of the study, the survival rates of the male and 

female offspring were slightly higher than control animals. It was reported that no behavioural 

changes or non-neoplastic lesions were observed by gross inspection and histological 

examination. Higher incidence of tumors and presumed neoplastic lesions occurred in treated 

animals in the following organs (see Table 4.1.2.8.D): Zymbal gland, oral cavity, tongue, 

esophagus, forestomach, glandular stomach, lung, liver, and uterus. The increase of stomach 

tumors was considered to be borderline increase, higher rates of hepatocarcinomas were only 

seen among male offspring. The tumors of the lung, liver, uterus and Zymbal gland were not 

consistent with the findings of the Japanese study (Umeda et al., 2004a). Regarding relatively 

high spontaneous occurrence of tumors at these sites in the control groups of the study, the 

interpretation of these results is difficult. As the test substance contained impurities of known 

carcinogens (e.g. benzene, hydroquinone), the authors assumed that these impurities were 

relevant for the tumor response. The rapporteur recognises the reduced reliability of this study 

due to impure test substance and the non-concordance with guideline testing procedures. 

However, this study showed some consistency with other studies. Compared to control animals 

that showed normal tissues (except some tongue tumors) there were markedly increased 

incidences of squamous cell tumor and dysplasia along the exposure route (oral cavity, tongue, 

esophagus, forestomach). For most effects on the epithelial surface of the upper digestive tract, 

the offspring were more sensitive than the parent animals. Tumors of this type at these sites 

were consistent to data from BDF1 mice in the study of Umeda et al. (2004a). The assumption 

of the authors is considered to be unlikely, as the concentrations of impurities were extremely 

low. Based on this study lacking laboratory investigations, the NOAEL for nonneoplastic 

lesions was 5000 ppm in mice (750 mg/kg bw/d). 
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Table 4.1.2.8.D: Percentages of tumors and presumed preneoplastic lesions in a lifetime carcinogenesis study in Swiss mice 

with drinking water administration of vinyl acetate for 78 weeks (Maltoni et al., 1997) 

group concentrations 5000 ppm 1000 ppm control 

 breeders offspring breeders Offspring breeders offspring 

organ tumor/preneoplastic 

lesion

13 m 37 f 49 m 48 f 13 m 37 f 37 m 44 f 14 m 37 f 38 m 48 f 

Zymbal 

glands 

carcinoma - 2.7§ 4.1 8.3 - - - 4.5 - - - - 

 squamous cell dysplasia 7.7 16.2 8.2 22.9 - 8.1 - 4.5 - 2.7 5.3 6.3 

oral cavity squamous cell carcinoma 7.7 2.7 20.4 18.8 - - - - - - - - 

tongue squamous cell carcinoma 7.7 8.1 14.3 25.0 - 2.7 - - - - 2.6 - 

 squamous cell dysplasia - 8.1 8.2 14.6 - - - 2.3 - - - - 

esophagus squamous cell carcinoma - 16.2 24.5 37.5 - - - - - - - - 

 acanthoma - 2.7 - 6.3 - - - - - - - - 

 squamous cell dysplasia 30.8 16.2 8.2 14.6 - - - - - - - - 

forestomach squamous cell carcinoma - 8.1 4.1 14.6 - - - - - - - - 

 acanthoma 7.7 13.5 16.3 22.9 - - 2.7 - - - - - 

 squamous cell dysplasia - - 2.0 - - - - - - - - - 

glandular 

stomach 

adenocarcinoma 7.7 2.7 - 2.1 - - - - - - 2.6 - 

 adenomatous polyp - - - - - - 2.7 - - - - - 

 glandular dysplasia - - 6.1 - - - - 2.3 - - - - 

lung adenocarcinoma 15.4 2.7 4.1 6.3 15.4 2.7 - 2.3 14.3 - 2.6 - 

 adenoma 23.1 16.2 22.4 22.9 15.4 16.2 16.2 6.8 14.3 8.1 15.8 12.5 

 animals bearing lung 

tumors 

30.8 18.9 26.5 22.9 30.8 16.2 16.2 9.1 28.6 8.1 18.4 12.5 

liver animals bearing 

hepatocarcinoma/s 

15.4 - 34.7 4.2 30.7 - 21.6 - 21.4 - 26.3 2.1 

uterus adenocarcinoma 16.2 16.7 5.4 13.6 2.7 10.4 

 leiomyosarcoma 5.4 8.3 - 4.5 2.7 - 

 leiomyoma 5.4 12.5 - 6.8 2.7 4.2 

 total malignant uterus 

tumors 

 21.6 25.0 5.4 18.2 2.7 10.4 

m males f females, - no tumor observed, § percentages, no statistical evaluation available 
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- Vinyl acetate was administered in drinking water at doses of 0, 1000 and 5000 ppm to 17-week 

old Sprague-Dawley rats (breeders, 13 or 14 males/group and 37 females/group) and to 12-day 

embryos (offspring, 53-107 males/group and 57-99 females/group) (Minardi et al., 2002). 

Treatment was continued for 104 weeks, thereafter animals were kept receiving tap water until 

their spontaneous death. Vinyl acetate purity was > 99%, impurities were benzene 30-45 ppm, 

methyl and ethyl acetate 50 ppm, crotonaldehyde 6-16 ppm, acetaldehyde 2-11 ppm, and 

acetone 330-5000 ppm. In treatment groups, the rates of total malignancies and carcinomas 

and/or precursor lesions were increased in oral cavity, lips, tongue, oesophagus, and 

forestomach.

- It was reported that there were no differences between treated animals and controls in mean 

body weight, survival, behaviour, or treatment-related non-oncological pathological changes (no 

summary data included in the publication). 

- Tumors of the oral cavity and lips occurred significantly more frequent in offspring males and 

females (24.5% and 15.5%, respectively, versus 0% in the controls, Table 4.1.2.8.E) exposed to 

5000 ppm concentration of vinyl acetate. No significant effect was seen at the end of life in the 

rat groups (breeders), which were treated from the 17th week onwards. Oral cavity squamous 

cell carcinomas were seen in two females (5.4%) of the 5000 ppm and in one female of the 1000 

ppm (breeder) group. No significant tumor response was seen at the tongue and the esophagus. 

Single females of the breeder group at 1000 and 5000 ppm and two females of the offspring 

group had squamous cell carcinomas of the tongue. However, squamous dysplasia was 

commonly observed in all treated groups of females, their incidences were significantly higher 

in the 5000 ppm (breeders and offspring) compared to the controls. In the esophagus, only one 

squamous cell carcinoma was observed in a male offspring exposed to a concentration of 5000 

ppm. In contrast, the incidences of squamous dysplasia were significantly higher in the breeder 

and offspring groups at 5000 ppm compared to the control groups. Spontaneous dysplasia in the 

forestomach was seen in a number of control animals of the breeders and the offsprings (3.7-

8.1%). Their rates increased significantly in offspring males and females at 1000 and 5000 ppm. 

(16.1% up to 24.6%). Squamous cell tumors at this site were significantly more frequent in the 

offspring males at 1000 and 5000 ppm and in the offspring females at 5000 ppm. 

- In conclusion, treatment-related significantly increased rates of tumors were seen in the oral 

cavity and lips in the 5000 ppm offspring groups of both sexes and in the forestomach of the 

offspring groups of male rats at 1000 ppm and above and of female rats at 5000 ppm. Squamous 

dysplasia considered as precursor lesions were increased in theses groups and also in the 

breeder groups at 5000 ppm. Although the numbers of animals in the breeders group were 

limited, the animals of the offspring group at which the treatment started at day 12 of pregnancy 

appeared to be more sensitive towards tumor and precursor development. 

- The study was not compliant to the current standard for a carcinogenicity study. The major 

limitations were the reduced number of animals tested in the breeders group, the variability of 

animal numbers among the test groups and the prolongation of the post-treatment period until to 

the spontaneous deaths. Instead of a study termination animals were allowed to live until their 

spontaneous death and the tumor incidences were not corrected for the lifetime. No data on food 

and water consumption were available.
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Table 4.1.2.8.E: Percentages of tumors and presumed preneoplastic lesions in a life-time carcinogenesis study in SpragueDawley rats with drinking water administration of vinyl acetate for 104 weeks (Minardi et al., 2002) 

group concentrations 5000 ppm 1000 ppm control 

 breeders offspring breeders Offspring breeders offspring 

organ tumor/preneoplastic 

lesion

13 m 37 f 53 m 57 f 13 m 37 f 83 m 87 f 14 m 37 f 107 m 99 f 

oral cavity squamous cell carcinoma 5.4 24.5** 15.8** - 2.7 - - - - - - 

 squamous cell dysplasia 5.7 2.3 0.9 

tongue squamous cell carcinoma - 2.7 1.9 3.5 - 2.7 - - - - - 

 squamous cell dysplasia - 18.9* 5.7 15.8**

§

- 8.1 - 2.3 § - - - - 

esophagus squamous cell carcinoma - - 1.9 - - - - - - - - - 

 squamous cell dysplasia 15.4 21.6*

§ 

35.8** 40.4**

§ 

7.7 5.4§ - 4.6§ - 2.7 - - 

forestomach squamous cell carcinoma 7.7 8.1 13.2** 7.0* 7.7 - 7.2* 3.4 - - - - 

 squamous cell dysplasia 30.8 29.7* 24.5**

§ 

24.6**

§ 

23.1 5.4 19.3**

§ 

16.1*

§ 

7.1 8.1 3.7 4.0 

*p<0.05, ** p<0.01 using χ2test, § p<0.001 using Cochrane-Armitage test for dose-response relationship 

Other information after oral administration 

- Newborn Wistar (4-5 animals per sex per group) rats were exposed orally to 100 or 200 mg/kg 

bw/d vinyl acetate (99% pure, impurity: 100 ppm hydroquinone) in condensed milk twice a day 

for three weeks. A subgroup of animals was additionally treated with phenobarbital in drinking 

water for 8 weeks to stimulate the growth of potentially occurring preneoplastic liver foci. 14 

weeks after the start of the study livers were dissected. No ATPase-free and gamma-GT-positive 

areas in the liver as indication for the development of liver nodules could be found (Laib and 

Bolt, 1986). 

Summary on carcinogenicity of vinyl acetate in experimental animals.

Vinyl acetate induced an increased number of nasal tumors (mainly papillomas and squamous cell 

carcinomas) in various regions of the nasal mucosa of rats after long-term inhalation. The total 

incidence was significantly increased at a concentration of 600 ppm, but a single papilloma already 

developed at 200 ppm. No significant tumor response was seen in mice after long-term inhalation of 

vinyl acetate vapour. Occasionally single squamous cell tumors occurred at other sites of the 

respiratory tract in rats and mice. 

Although the complete report was not available, published information from a recent oral cancer 

study in F344 rats and BDF1 mice (Umeda et al. 2004a) demonstrated significantly increased rates 

of squamous cell tumors in the oral cavity (rats and mice), esophagus and forestomach (mice) after 

a 2-year administration of 10000 ppm vinyl acetate with the drinking water (equivalent mean doses 

in rats were 442 mg/kg bw/d for males, 575 mg/kg bw/d for females, in mice 989 mg/kg bw/d for 

males, 1418 mg/kg bw/d for females). Maximum increase of tumor incidences was found in the oral 

cavity in both species. Squamous cell carcinomas were already observed at a dose of 400 ppm in 
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female rats (31 mg/kg bw/d). Consistently in another life-time study on a breeding and offspring 

generation of mice (Maltoni et al., 1997) which did not met actual standards on cancer bioassays, 

squamous cell tumors were also observed with increased incidences in several sites of the 

gastrointestinal tract (oral cavity, tongue, esophagus, forestomach) at a concentration of 5000 ppm 

in the drinking water (calculated dose 780 mg/kg bw/d). In addition, higher incidences of 

adenocarcinomas of the glandular region of the stomach were found in high-dose male breeders. 

Also some other organs (lung, liver, uterus) showed increased rates of benign and malignant tumors 

compared to that of the control groups. Tumors of the liver and the uterus have also been seen in the 

Lijinsky study (Lijinsky and Reuber, 1983). However, both studies hampered from methodical 

insufficiencies. Further, these data were inconsistent to the absence of parenchymal tumors in other 

more valid studies. Therefore interpretation of these tumors remains unclear. With respect to the 

carcinogenic potential of vinyl acetate, the results of Lijinsky and Reuber (1983) were considered 

not to be reliable due to several methodological deficiencies. No indication for an increased 

incidence of enzyme-altered liver foci was seen in another study (Laib and Bolt, 1986). 

No clear positive tumor response was found in another oral rat cancer study at vinyl acetate 

concentrations up to 5000 ppm (Shaw, 1988, Bogdanffy et al., 1994a). Except the tongue, tissues of 

the oral cavity were not included as standard protocol tissues for histopathology. Although, this 

study showed the occurrence of two squamous cell carcinomas in the oral cavity of males of the 

5000 ppm group. 

Recently published data on rats exposed to drinking water containing 1000 or 5000 ppm vinyl 

acetate confirmed significant increases in squamous cell carcinomas of the oral cavity and the 

forestomach (Minardi et al., 2002). Treatment of offsprings resulted in higher tumor rates than in 

rats with treatment begin at week 17 of life. However, this study has a number of limitations in its 

design. Thus, tumor response along the gastrointestinal could be interpreted to be supportive to the 

results from the Umeda study. 

Human data:

Information on repeated human exposure to vinyl acetate is small. Quantitative data on exposure 

and effects were not well investigated or documented. Workers had also been exposed to other 

compounds, so that effects cannot be attributed clearly to vinyl acetate. Confounding factors (i.e. 

smoking habits) were not ruled out. Therefore the relevance of the observed effects to evaluate risks 

to human health is questionable. Despite of these limitations some data from literature are cited 

below: 

- A retrospective study on 21 chemical operators in a production plant with mean age of 45.3 

years and mean exposure time of 15.2 years to vinyl acetate vapour with concentrations up to 

49.3 ppm (TWA 5.2-8.2 ppm) revealed no vinyl acetate-related injury or differences in medical 

and biochemical parameters. Local irritant reactions were attributed to occasionally high acute 

exposures (Deese and Joyner, 1969). 

- In a cohort study, 4806 male workers who were exposed to 19 different chemicals (vinyl 

chloride, polyvinylchloride dust, chlorinated solvents, acrylates, acrylonitrile and others) 

including vinyl acetate, between the years 1942 and 1973 had an excess risk of cancer of the 

respiratory system and the CNS. A subgroup (of cases with lung cancer) with undifferentiated 

large cell lung cancer was associated to a slightly higher cumulative exposure to vinyl acetate 

(Waxweiler et al., 1981). 
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- A nested case-control study (Ott et al., 1989) was undertaken in a cohort of 29139 men 

employed in two chemical manufacturing facilities and a research and development center, who 

had died in 1940-1978 with non-Hodgkin`s lymphoma, multiple myeloma, lymphocytic or nonlymphocytic leukemia. Exposure odds ratios (OR) were examined in relation to 111 work areas, 

21 specific chemicals (OR based on an ever/never basis), and 52 chemical activity groups. 

Exposure to vinyl acetate was associated with non-Hodgkin’s lymphoma in seven of 52 men 

(OR 1.2), multiple myeloma in three of 20 men (OR 1.6), non-lymphocytic leukemia in two of 

39 men (OR 0.5), and with lymphocytic leukemia in two of 18 men (OR 1.8). Examination of 

OR related to the exposure duration was not done because of the OR <1.3 or number of cases 

<4. 

Summary of human data

Data on human experience were not specifically associated to the exposure with vinyl acetate. In 

summary, the above-mentioned epidemiological data are insufficient to evaluate the carcinogenic 

potential of vinyl acetate in humans. 

Other information from metabolites 

Toxicity/carcinogenicity data from both metabolites, acetaldehyde and acetic acid, were considered 

with respect to their possible role in vinyl acetate toxicity: 

Acetaldehyde 

With respect to the effects from external exposure to acetaldehyde the endogene level of 

acetaldehyde has to be taken into consideration: 

Endogene acetaldehyde: 

Acetaldehyde is a naturally occurring substance in the metabolic pathways of animals and humans 

(metabolism of ethanol and sugars). It occurs in low concentrations in human blood. 

A range of 0.1 - 2.1 μM for pulmonary blood acetaldehyde concentrations has been calculated in 

normal control subjects (Eriksson, 1987). The exact determination of the endogenous blood 

acetaldehyde level is impaired by the difficulty to exclude an artefactual acetaldehyde formation 

during the analytical procedures. Whole blood-associated acetaldehyde (WBAA) levels in 

teetotalers of 7.9 ± 0.7 μM (102 males) and 7.7 ± 0.6 μM (123 females) were measured by 

Halvorson et al. (1993). Acetaldehyde levels of 0.7 ± 0.5 μM in male human volunteers (n = 4) 

were obtained in the supernatants without precipitates from whole blood after headspace 

chromatography (Fukunaga et al., 1993). 

In male Long-Evans rats treated with the aldehyde dehydrogenase inhibitors cyanamide and 

disulfiram endogenous blood concentrations of up to 2-5 μM were measured whereas no 

endogenous blood acetaldehyde could be detected in control animals (Eriksson, 1985). These 

results may indicate the existence of an endogenous acetaldehyde in protein bound forms. 

Repeated dose effects following external exposure to acetaldehyde: 
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Inhalation exposure/animal data 

- Although explant experiments on rat nasal turbinalia with olfactory or respiratory epithelium 

failed to demonstrate a cytotoxic potential of acetaldehyde at a concentration of 50 mmol on the 

olfactory and respiratory epithelia (Kuykendall et al., 1993), repeated dose studies demonstrated 

cytotoxic properties of acetaldehyde on the rat nasal epithelium. 

- No histopathological abnormality was observed in the respiratory epithelium of rats (5 

males/group), which were nose-only exposed to 750 ppm or 1500 ppm acetaldehyde on 3 

consecutive days (6 h/d) (Cassee et al., 1996). In the olfactory region, a few necrotic cells were 

seen in 3/5 rats at 750 ppm, and 4/5 exposed to 1500 ppm showed cell necrosis (range few to 

many necrotic cells). 

- In rats exposed to 0, 400, 1000, 2200 or 5000 ppm (790-9000 mg/m3) acetaldehyde on 4 weeks 

(6 h/d, 5 d/w) treatment-related changes at 5000 ppm were dyspnoe, excitation during the first 

30 min of each exposure, yellow-brown fur, severe growth retardation, more neutrophils and 

less lymphocytes in the blood, a reduced production of urine with a high density, increased lung 

weights, and severe degenerative, hyperplastic and metaplastic changes of the nasal, laryngeal 

and tracheal epithelium. The most severe lesions of the nose were found in the olfactory 

epithelium, but focal lesions were also observed especially in the posterior part of the nasal 

cavity covered with respiratory epithelium. Some minor alveolar alterations such as 

accumulation of pigment-laden macrophages and focally increased cellularity/thickening of 

alveolar septa were occasionally observed in the 5000 ppm group. Major lesions seen at 1000 

and 2200 ppm (1800-3960 mg/m3) comprised growth retardation and an increased production of 

urine in males, slight to moderate degeneration with or without hyper- and metaplasia of the 

olfactory epithelium, and only at 2200 ppm, minimal epithelial changes in the larynx and 

trachea. Focal degenerative lesions without hyperplasia were also observed single males and 

half of the females at 1000 and 2200 ppm of acetaldehyde. The only change observed at the 400 

ppm level that could be attributed to acetaldehyde was slight degeneration of the nasal olfactory 

epithelium seen as loss of microvilli and thinning and disarrangement of the layer of epithelial 

cells (Appelman et al., 1982). 

- A concentration without histopathological alterations on the respiratory tract was estimated to 

be 150 ppm (6 h/d, 5d/wk) in a 4-week inhalation study on male Wistar rats (Appelman et al., 

1986). Nasal lesions observed at 500 ppm were similar as described for 400 ppm consisting of 

degeneration of the olfactory epithelium with a mean severity of slight to moderate. 

- In a carcinogenicity study on rats exposed to 0, 750, 1500, 3000 (gradually reduced to 1000 

ppm) ppm acetaldehyde vapour (6 h/d, 5 d/w) for up to 28 months treatment related-effects 

included increased mortality, growth retardation, nasal tumors (Table 4.1.2.8.F), and nonneoplastic nasal changes in each of the test groups. At day 468, the mortality rate in the highdose group was 50% (28/55) for males and 42% (23/55) for females. By day 715, all high dose 

rats hat died and, at termination of the study at day 844, only a few animals were still alive in 

the mid-dose group. At the end of the study dose-related nasal changes comprised: 

degeneration, metaplasia and adenocarcinomas of the olfactory epithelium at all exposure 

levels. The respiratory epithelium showed squamous metaplasia and squamous cell carcinomas 

of the respiratory epithelium at the 2 highest exposure levels, and slight to severe rhinitis and 

sinusitis in top-concentration rats (Table 4.1.2.8.G). In the larynx, hyperplasia and keratinised 

squamous metaplasia of the epithelium in the vocal cord region were seen in many rats of the 

mid- and top-concentration groups. One female rat of the 1500 ppm group had developed a 

laryngeal carcinoma in situ (Woutersen et al., 1986). 
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TABLE 4.1.2.8.F 

Tumor incidence in the nasal cavity of rats exposed to acetaldehyde vapour for at most 28 months

 Tumor incidences a

Site/type of tumor Males Females 

control 750 1500 3000/ 

1000 

control 750 1500 3000/ 

1000 

Nose (49)# (52) (53) (49) (50) (48) (53) (53) 

 

Papilloma 0 0 0 0 0 1 0 0 

 

Squamous cell carcinoma 1 1 10* 15*** 0 0 5 17*** 

 

Carcinoma in situ 0 0 0 1 0 0 3 5 

Adenocarcinoma 0 16*** 31*** 21*** 0 6* 26*** 21*** 

 

Larynx (50) (50) (55) (52) (53) (52) (54) (54) 

Carcinoma in situ 0 0 0 0 0 1 0 0 

a

 The number of animals examined is given in brackets. 

Statistics: Fisher Exact Test *P<0.05 **P<0.012 ***P<0.001 

# Number of tissues examined (Data from Woutersen et al. 1986) 
111 

TABLE 4.1.2.8.G: Treatment-related non-neoplastic lesions in the nasal cavity of rats exposed to acetaldehyde vapour for at 

Site/type of lesions Males Females

control 750 1500 3000/1000 control 

Nose (49) (52) (53) (49) (50) Respiratory epitheliumSquamous metaplasia without keratinisation 0 1 11** 1 0 Squamous metaplasia with keratinisation 0 0 5 19*** 0 Papillomatous hyperplasia 0 0 0 2 0 Simple/pseudoepitheliomatous hyperplasia 0 5 16*** 8** 0 Olfactory epitheliumSquamous metaplasia without keratinisation 0 0 0 0 0 Squamous metaplasia with keratinisation 0 0 0 3 0 Basal cell hyperplasia without atypia 0 37*** 9** 0 0 Basal cell hyperplasia with atypia 0 1 17*** 0 0 Submucosal atypical basal cells 0 0 23*** 0 0 Proliferation of glands in the thickened submucosa 0 0 14*** 5 0 Larynx (50) (50) (51) (47) (51) Squamous metaplasia without keratinisation 2 2 10* 9* 1 Squamous metaplasia with keratinisation 1 4 13*** 32*** 0 Proliferation of dysplastic epithelium 0 0 1 0 0 Lungs (55) (54) (55) (52) (53) Keratinised stratified squamous metaplasia of bronchial epithelium 0 0 0 1 0 

 The number of animal examined is given in brackets. 

Statistics: Fisher exact Test *P<0.05 , **P<0.01 , ***P<0.001, Data from Woutersen et al. 1986 
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Lesions comparable to those seen after 28 months were observed in the acetaldehyde 

exposed rats of additional interim sacrifice groups killed at 13, 26 (subgroups of each 5 

animals/sex/group) and 52 weeks (10 animals/sex/group) after the same dose regimen as 

reported above (Wouterson et al., 1986) clearly demonstrating severe abnormalities in the 

nose and larynx, minor changes in the trachea and nasal tumors (Woutersen et al. 1984). 

Of the animals killed at these intervals, only one had a tumor of the respiratory tract: a 

female in the high dose group killed in week 53, bearing a nasal squamous-cell 

carcinoma. 

- Increased numbers of nasal tumors were also evident in rats which inhaled 750, 1500 or 

3000/1000 ppm acetaldehyde vapour for 78 weeks as well as in rats exposed to 

acetaldehyde for 52 weeks followed by a recovery period of at most 26 weeks (Woutersen 

and Feron, 1987). 

- Inhalative exposure of hamsters to 2500 ppm (4500 mg/m3) gradually decreased to 1650 

ppm (2970 mg/m3) for a period of 52 weeks (7 h/d, 5 d/w) resulted in hyper- and 

metaplastic changes of the nasal epithelium, and hamsters developed nasal tumors (3/52) 

and laryngeal tumors (11/47) (Feron et al., 1982). 

Oral administration/animal data 

- A subacute oral toxicity study of acetaldehyde was carried out in Wistar-derived rats 

(Cpb:WU) (Til et al., 1988). Groups of ten male and female rats received drinking water 

containing 0, 25, 125 and 675 mg/kg bw/d acetaldehyde for a period of 4 weeks. Food and 

water intake was decreased in the top dose groups. There was no significant effect on 

parameters of hematology, clinical chemistry and urinalysis. The only adverse effect was 

slight to moderate hyperkeratosis of the stomach of high dose males and females. 

- Soffritti and his colleagues (Soffritti et al., 2002) published the results of an oral 

carcinogenicity study that may correspond to the positive carcinogenicity bioassay that 

were announced by Maltoni et al. (1997). Acetaldehyde was administered to 50 male and 

50 female Sprague-Dawley rats for 104 weeks in drinking water at concentrations of 0, 

50, 250, 500, 1500, or 2500 mg/L. Increased rates of tumors at several organs were 

observed in treated groups. However, the effects were not dose-related and no clear 

conclusion could be drawn from this study. 

- In a study on cell proliferative activity, 20 Wistar rats were given either water containing 

acetaldehyde at a concentration of 120 mM (324 mg/kg/d) or tap water to drink for 8 

months (Homann et al., 1997). Tissue specimens were taken from the tongue, epiglottis, 

and forestomach of each animal and immunohistochemically stained for markers of 

cellular proliferation (Ki67 nuclear antigen) or differentiation (cytokeratins 1,4,10,11,14, 

and 19). The mean epithelial thickness of each sample was measured via light microscopy 

and differences between control and treated groups were analysed by use of unpaired 

Student’s t test. Although no tumors were observed, staining for cytokeratins 4 and 14 

revealed an enlarged basal layer of squamous epithelia in the rats receiving acetaldehyde. 

In these animals, cell proliferation was significantly greater than that observed in the 

control animals for samples from the tongue (p<0.0001), epiglottis (p<0.001) and 
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forestomach (p<0.0001). In addition, the epithelia from acetaldehyde-treated rats were 

significantly thicker than in epithelia from control animals (p<0.05 for all three sites). 

Oral uptake/human data 

- Alcoholic consumption is a well-known risk factor for squamous cell cancer of the 

oropharynx, larynx and esophagus. Findings of consistence in the mutational spectrum 

induced by acetaldehyde in human lymphocytes and in the p53 tumor suppressor gene of 

oesophageal tumors were interpreted to support the assumption that tumors of the upper 

gastrointestinal tract are attributable to acetaldehyde which is the primary oxidation 

product of ethanol (Noori and Hou, 2001).

Other data relevant for acetaldehyde carcinogenicity 

- In the recent evaluation on acetaldehyde given by the Scientific Committee on Cosmetic 

Products and Non-Food, (SCCNFP, 2004) data including additional human data from 

case were reported: 

 Acetaldehyde is a naturally occurring substance, also in human metabolic pathways. It is 

metabolised to acetic acid. Acetaldehyde itself is the main metabolite of ethanol and this 

reaction is catalysed by alcohol dehydrogenases (ADH). Five ADHs have been 

characterized in humans, two of which (ADH2 and ADH3), are known to be 

polymorphic. In particular, polymorphism for ADH3 seems to strongly influence the 

metabolism of ethanol to acetaldehyde, with ADH3 1 allele carriers being faster 

metabolisers than ADH3 2 carriers. Acetaldehyde is metabolised by phase II enzymes, 

including aldehyde dehydrogenases (ALDH) and glutathione S-transferases (GST). 

ALDH2 is polymorphic; its mutant allele, ALDH2 2, which leads to enzyme inactivity, is 

prevalent in Asian populations. GSTM1 is also polymorphic, with a null genotype 

GSTM1 0 present mainly in European populations (Coutelle et al., 1997). Therefore, 

carriers of ADH3 2, ALDH2 2 and GSTM1 0 alleles are likely to be exposed to higher 

levels of acetaldehyde than are other people, following intake of a comparable amount of 

alcohol. Supportive data were gained from testing in ALDH2-/- knockout mice in which 

a doubling of blood acetaldehyde concentrations and more severe toxicity was observed 

in comparison to wild-type (ALDH2+/+) mice (Isse et al., 2005). 

 An increased relative frequency of bronchial and oral cavity tumours was found among 

nine cancer cases in one study of chemical workers exposed to various aldehydes. Three 

case–control studies assessed the risk of oral, pharyngeal, laryngeal and oesophageal 

cancer following heavy alcohol intake, according to genetic polymorphism of enzymes 

involved in the metabolism of ethanol to acetaldehyde (alcohol dehydrogenase 3) and in 

the further metabolism of acetaldehyde (aldehyde dehydrogenase 2 and glutathione Stransferase M1). Despite limitations in the study design and the small size of most of the 

studies, these studies consistently showed an increased risk of alcohol related cancers 

among subjects with the genetic polymorphisms leading to higher internal doses of 

acetaldehyde following heavy alcohol intake as compared to subjects with other genetic 

polymorphisms. 

 Oesophageal tumours have been associated with genetically determined high metabolic 

levels of acetaldehyde after drinking alcohol. A Japanese case–control study (Yokoyama 

et al., 1996) of ALDH2-related risk for oesophageal squamous-cell carcinoma in 

alcoholics (40 cases and 55 controls) and non-alcoholic drinkers (29 cases and 28 
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controls) during 1991–95 showed a higher risk for oesophageal cancer in those with one 

ALDH2 2 allele in both alcoholics (crude odds ratio, 7.6; 95% confidence interval (CI), 

2.8–20.7) and non-alcoholic drinkers (odds ratio, 12.1; 95% CI, 3.4–42.8). Mantel–

Haenszel adjustment for age and daily alcohol consumption had virtually no influence on 

the risk estimates [adjusted odds ratios not given]. As persons who have the mutant 

ALDH2 2 allele have a high concentration of blood acetaldehyde after drinking alcohol, 

the results of this study were interpreted as strongly suggesting a carcinogenic role of 

acetaldehyde in humans. 

 The IARC has concluded that there is inadequate evidence in humans for the 

carcinogenicity of acetaldehyde and that there is sufficient evidence in experimental 

animals for the carcinogenicity of acetaldehyde. 

 The overall conclusion was that acetaldehyde is possible carcinogenic to humans (Group 

2B). 

 In the EU, acetaldehyde is a carcinogen classified in EU as a Category 3 carcinogen and a 

Category 3 mutagen. 

Acetic acid 

Inhalation exposure/no repeated dose animal study with guideline equivalence is available. 

The lowest concentration inducing histopathological lesions in the nasal mucosa of mice 

exposed for 4, 9 or 14 days (6 h/d) was 55.4 ppm acetic acid (Zissu, 1995). Only the olfactory 

mucosa was affected. 

A 4-hour nose-only inhalation of acetic acid at target concentrations of 600 μl/l or 1300 μl/l 

(0.6 or 1.3 ppm) followed by a 20 hour observation period resulted in very focal lesion in the 

respiratory epithelium of the dorsal meatur of level 1 of the nasal cavity in three out of five 

exposed rats (Kilgour et al., 2000). In vitro exposure to 53.3 mM acetic acid, a concentration 

calculated to correspond to the in vivo air concentration, to olfactory and respiratory 

turbinates for 4 or 24 hour resulted in a significant reduction in ATP and potassium 

concentrations. 

Discussion on vinyl acetate carcinogenesis

The manufacturing industry postulated a non-genotoxic mode of action for vinyl acetateinduced carcinogenic effects being similar for the respiratory tract and the gastrointestinal 

tract. The acceptance of this hypothesis will be discussed in the following part of this 

assessment report for each organ system as suggested by the IPCS framework on cancer risk 

assessment subdivided into: postulated mode of action, key events associated with hypothesis, 

dose-response relationship, temporal relationship, strength, consistency, specificity of 

association, biological plausibility and coherence, inconsistencies, uncertainties and data 

gaps, assessment of mode of action for tumors (according to the IPCS framework on cancer 

risk assessment, 1999). 
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I. Respiratory tract tumors: 

Ia. Postulated mode of action

Bogdanffy and his co-workers postulated that vinyl acetate metabolism in the respiratory and 

olfactory epithelium of the nasal mucosa increases local concentration of intracellular H+

 and 

hence produced tissue acidification. This lowered pH causes toxicity, atrophy, degeneration 

and subsequently reparative hyperplasia. The stimulation of hyperplastic activity for a 

significant time of the animal’s life span increases the probability of mutation and tumor 

formation. This hypothesis emphasises the role of cytotoxicity with a minor contribution of 

the acetaldehyde as a mutagenic DNA-protein cross-linking agent. It was stated that ‘with 

sufficient genetic damage, induced by spontaneous mutation and acetaldehyde induced DNAprotein cross-links (DPX) olfactory degeneration progresses to a state of elevated 

proliferation and eventually, at high vinyl acetate to neoplastic transformation’ (Bogdanffy 

and Plowchalk, 2001). Later on, the considerations on the mode of action was slightly 

modified (Bogdanffy, 2002, Hinderliter et al., 2005). Intracellular acidification was still 

thought to be the crucial step in a sequence of responses including acidification-induced 

mitogenic cellular proliferation of nasal respiratory epithelium and acidification-induced 

cytotoxic cell proliferation in olfactory epithelium. 

Ib. Key events associated with hypothesis

Step 1: From inhalation to cytotoxicity: 

- Metabolic enzyme activities (Table 4.1.2.8.H and Table 4.1.2.8.I): 

The enzymes responsible for the hydrolysis of vinyl acetate to acetic acid and acetaldehyde, 

and its further oxidation to acetic acid are carboxylesterase and aldehyde dehydrogenase (see 

4.1.2.1). In principle, both were detected in the respiratory and olfactory epithelium of the rat 

nasal cavity (Bogdanffy et al., 1986, 1987, 1998, 1999a). 

Carboxylesterase 

Earlier data on tissue homogenates and using p-nitrophenyl butyrate to measure carboxyl 

esterase activity pointed to the fact that a higher sensitivity of the olfactory epithelium to 

toxic effects of vinyl acetate could be attributed to 6fold higher hydrolytic enzyme activity at 

this epithelium (Bogdanffy et al., 1987). These results were confirmed in tissue homogenates, 

where carboxylesterase-mediated hydrolysis of vinyl acetate was more efficient (4-7fold, 

related to protein content) in the olfactory epithelium than in the respiratory epithelium 

(Bogdanffy and Taylor, 1993). Km was in the same low range in the olfactory and respiratory 

epithelium. 

Data using an in vitro gas uptake method on organ explants from rat turbinates or sections of 

intact nasal tissue from humans demonstrated much lower esterase activity than seen in tissue 

homogenates. When the epithelial volume was considered into calculations, a similar esterase 

activity in both (olfactory and respiratory) regions was observed for the rat and a much higher 

activity was found for the respiratory epithelium for the human (Bogdanffy et al., 1998). 
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Data on carboxylesterase activity in human nasal tissues are sparse. Mainwaring et al. (2001) 

found that the ratio of carboxylesterase activity (methyl methacrylate as substrate) between 

olfactory and respiratory microsomes was similar for the rat as well as for the man Esterase 

activity for both species was about 3fold higher in olfactory microsomes which is in line with 

a 2fold higher activity in olfactory microsomes reported by Bogdanffy et al. (1999a). In 

respiratory microsomes Mainwaring et al. (2001) estimated a 4fold higher activity for the rat 

than in the human samples. The activity in rat olfactory S9 mix (24fold) was much higher 

than in olfactory S9 mix from human origin. Although there may be some carboxylesterases 

activity outside the microsomes, as demonstrated for liver cells, where carboxylesterase 

activity has also been identified in the cytosol (Tabata et al., 2004), the low values for V in 

olfactory and respiratory microsomes or S9-mix may indicate a lower hydrolytic activity in 

the human nasal tissues compared to those of the rat. 

Table 4.1.2.8.H: Metabolic rate (V) for carboxylesterase activity (towards methyl 

methacrylate) in nasal tissues (adopted from Mainwaring et al., 2001) 

Tissue V (nmol/min/mg protein) 

 Human Rat 

Respiratory microsomes 2.7a 14.3 

Respiratory S9 0.15a 3.5a

Olfactory microsomes No data 38.6 

Olfactory S9 0.48a 12a

Liver microsomes 494.0a 46.6 

 

a

The values for rat S9 fractions and for all human tissues are for single rate measured at substrate concentration 

of 1.0 mM methyl methacrylate. 

A more than 35fold higher activity of carboxylesterase was also reported for rat nasal tissue 

homogenate (pooled from all regions, no region identified) compared to human respiratory 

epithelium from polyp tissue (which may not be representative for enzyme activity in normal 

tissue, expression is reduced in hyperplastic epithelium, see also Lewis et al., 1994) at similar 

enzyme affinity, when α-naphthyl butyrate was used as a substrate (Mattes and Mattes, 1992). 

While p-nitrophenyl butyrate was shown to be a competitive substrate of rat nasal α-naphthyl 

butyrate esterase, it did not affect human α-naphthyl butyrate esterase indicating that there are 

differences in substrate specificity of rat and human carboxyl esterases. Due to the limitations 

by tissue selection, this preliminary study could only be interpreted to support the rats’ 

significantly higher enzyme activity. 
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Liver microsomal carboxylesterases are inducible by exogenous compounds (Satoh and 

Hosokawa, 1995). Yet unknown, this could not be excluded for the nasal epithelial cells. 

Aldehyde dehydrogenase 

Specific aldehyde dehydrogenase activity is more than 2-fold higher in tissue homogenates 

from the respiratory mucosa than in homogenates from the olfactory mucosa (Stanek and 

Morris, 1999). After adjustment to the cell volume the aldehyde dehydrogenase activity of the 

respiratory epithelial cells was threefold higher in rats than that of humans (Bogdanffy et al., 

1998). 

Two aldehyde dehydrogenases were identified in the rat nasal tissues: a high Km isoenzyme, 

which was 5-8fold more efficient in the respiratory mucosa than in the olfactory mucosa (not 

normalised to cell volume), and a low Km isoenzyme of aldehyde dehydrogenase (with 

comparable low activity in both areas) (Casanova-Schmitz et al., 1984). 

- Localisation of enzyme activity in various cell types of the upper respiratory tract: 

Carboxylesterase 

In the rats’ olfactory epithelium, carboxylesterase was histochemically (Bogdanffy et al., 

1987) and immunohistochemically (Lewis et al., 1994) most prominently localised in the 

Bowman’s glands, the ducts of the Bowman’s gland and in sustentacular cells of the olfactory 

epithelium, and it was absent in the basal cells, the neuronal sensory cells and the overlying 

mucus. The apical (supranuclear) and basal portions of the sustentacular cell cytoplasm were 

intensely immunoreactive for carboxylesterase (Olson et al., 1993). The exact subcellular 

location of carboxylesterase has not yet been identified for nasal mucosa cells. In many other 

tissues, carboxylesterases from the mammalian multigene family were mainly localised in the 

endoplasmatic reticulum (Potter et al., 1998, Satoh and Hosokawa, 1995). A striking 

abundance of endoplasmatic reticulum in the supranuclear area of the rat sustentacular cells 

where P450 enzymes are localised (Farbman, 1992) suggests that carboxylesterases may also 

be associated to the endoplasmatic reticulum in this type of cell (as in other tissues, Satoh 

and Hosokawa (1995)). Together with the absence of carboxylesterase enzyme activity in the 

neuronal cells this indicates that sustentacular cells are involved in the vinyl acetate 

metabolism. 

At the respiratory epithelium various cell types of the epithelium (ciliated epithelial cells and 

cuboidal cells > nonciliated cells) demonstrated strong to moderate carboxylesterase activity 

by immunohistochemical staining. The goblet cells and the submucosal seromucous glands 

showed a negative or weak staining. Consistent with the low immunoreactivity, the overlying 

mucous was negative. Carboxylesterase activity of the basal cells of the respiratory 

epithelium was reported to be weak-moderate by Bogdanffy et al. (1987), and no or weak 

immunoreactivity was found by Lewis et al. (1994) and Olson et al. (1993). No presence of 

carboxylesterase could be attributed to the mucous by in situ immunostaining or by 

determination of activity in nasal lavage fluid: The Vmax value of nasal lavage 

carboxylesterase activity was 0.134 μmol/min/mg and 160times lower than that observed in 

nasal respiratory mucosal homogenates und far more lower than in the olfactory region 

(Bogdanffy et al., 1999a). 

Similar to the rat, carboxylesterase immunoreactivity was diffuse in ciliated and secretory 

cells of the normal respiratory mucosa of the human, some subepithelial glands were also 
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positive (Lewis et al., 1994). Sections were from eight patients (7 females, 7 non-smokers) 

showing a large variation across samples from normal respiratory epithelium, local 

inflammation to hyperplasia and squamous hyperplasia where carboxylesterase 

immunostaining was completely absent. Human data on carboxylesterase (immuno-) 

localisation in samples of the olfactory region were not available. 

The observations on enzyme activity, distribution and cytosolic localisation in nasal mucosa 

cells does not support Bogdanffy’s assumption that carboxylesterase is bound to or embedded 

in the plasma membrane of the nasal epithelium, and may act as a protective mechanism by 

removal of toxicants prior to the entry into the cell cytoplasm. With respect to the 

sustentacular cells, the main site of carboxylesterase in the olfactory epithelium, there is no 

evidence of a secretory function for mammalian species (Farbman, 1992). As indicated by the 

absence of carboxylesterase in mucous, no hydrolytic cleavage occurs preliminary to the vinyl 

acetate uptake. 

Aldehyde dehydrogenase 

Immunohistochemically, aldehyde dehydrogenase was detected in the respiratory epithelium 

(ciliated epithelial cells>nonciliated epithelial cells>goblet cells>cuboidal cells), while the 

olfactory epithelium showed negligible immune-reactivity (weak in the basal cell layer, weak 

to negligible reaction in Bowman’s glands, no immune-reactivity in sustentacular and sensory 

cells) (Bogdanffy et al., 1986). In addition, epithelial cells of the trachea and ciliated cells of 

the lower bronchioles demonstrated little activity, which increased distally, and Clara cells of 

the lower bronchioles showed high activity of aldehyde dehydrogenase. 

At the subcellular level aldehyde dehydrogenase isoenzymes are located in the cytosol and in 

the mitochondria. Intracellular distribution for aldehyde dehydrogenase for human nasal 

tissue is not known. There are at least two isoenzymes of aldehyde dehydrogenase, a high 

affinity mitochondrial aldehyde dehydrogenase-2 and an aldehyde dehydrogenase-1 in the 

cytosol. Polymorphism of isoenzymes which impair enzyme activity and acetaldehyde 

metabolism are well known in subpopulations of Asian origin and may result in higher tissue 

concentration of a acetaldehyde after alcohol consumption (Ginsberg et al. 2002) . 

The following Table 4.1.2.8.I summarises the available in situ immunohistochemistry data, in 

vitro data on tissue homogenates, and data on enzyme activity for the respiratory and 

olfactory epithelium in the rat and the man. 

Overall, data from in-situ investigations using (immuno-)histochemistry methods and 

semiquantitative determination of staining intensity were consistent with the results from 

investigations on the enzyme activity of carboxylesterase and aldehyde dehydrogenase. The 

differences in epithelial thickness and the dilution effects by a contribution of non-epithelial 

cells in the cell homogenates may account for uncertainties in the estimated absolute values 

for enzyme activity, especially for human tissues. No (or few) data are available on the 

isoenzymes of carboxylesterases and aldehyde dehydrogenases in nasal tissues from the rat 

compared to those of the human. 
119 

Table 4.1.2.8.I Data on enzyme localisation and activity in the nasal mucosa of rat and man  Respiratory epithelium 

 (RE) 

Olfactory epithelium 

(OE) 

 Rat Man Rat Man 

Carboxylesterase 

Enzyme activity in cell homogenates 

Vmax

35.7 mg/h if normalised to epithelial volume: Vmax64 mg/h Prediction from gas uptake model: Vmax63 mg/h 

undetectable Vmax

133.1 mg/h or normalised to epithelial volume: Vmax39mg/h Prediction from gas uptake model: Vmax45.4 mg/h 

Undetectable, except sample: 478 nmol/min/mg pro

Enzyme activity in microsomes or S9 mix 

Vmax

14.3 nmol/min/mg protein 3.5 nmol/min/mg protein 

Vmax

2.7 nmol/min/mg protein 0.15 nmol/min/mg protein 

Vmax

38.6 nmol/min/mg protein12 nmol/min/mg protein 

Vmax

No data* 0.48 nmol/min/mg pr(only one individual) 
120 

Enzyme activity in microsomes 

23.8 μmol/min/mg/protein 41.4 μmol/min/mg/protein 

Enzyme activity in cell homogenates 

+ Vmax 22-46 μmol 

acetaldehyde/min/mg protein Km 0.3-0.43 mM 

 +++ 

Vmax 89-165 μmol 

acetaldehyde/min/mg protein Km 0.2-0.55 mM 

 

Enzyme activity in cell homogenates 

Vmax 0.1 μmol/min/mg 

protein 

Km 20.8 ±1.7 mM±SE 

 Vmax 0.6 μmol/min/mg 

protein 34.4 Km ±3.9 mM±SE 

 

Immunohistochemistry Ciliated cells: +, 

Goblet cells: ±Basal cells: - submucosal glands: ±

All ciliated and secretory cells: + submucosal glandular epithelium: some +

Bowman‘s glands/-ducts: +Sustentacular cells: + Basal cells: - Neuronal cells: −

No data 

Immunohistochemistry Overall: + 

At cellular level: Mucous: −

Ciliated cells, cuboidal cells: ++, nonciliated cells, basal cells + Goblet cells, submucosal seromucous glands: ±

 Overall: +++ 

At cellular level: Mucous: −

Bowman‘s glands/-ducts: +++ Sustentacular cells: ++ Basal cells: ±Neuronal cells: −

 
121 

Aldehyde dehydrogenase 

Enzyme activity in tissue homogenates 

64 nmol/min/mg protein 28 nmol/min/mg protein 

Enzyme activity in cell homogenates 

Vmax

3.38 mg/h 

No data Vmax

0.94 mg/h 

No data 

Enzyme activity High Km isoenzyme: 128 

nmol/min/mg protein low Km isoenzyme: 

0.8 nmol/min/mg protein 

 High Km isoenzyme: 

28 nmol/min/mg protein low Km isoenzyme: 

2.2 nmol/min/mg protein 

 

Immunohistochemistry Ciliated cells +++ 

nonciliated cells ++ goblet cells + cuboidal cells: ±

Sustentacular cells: −Sensory cells: −Bowman’s glands: ±Basal cells: + 

 
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- Considerations on the role of enzymes: 

Regarding that the olfactory region was more sensible towards the cytotoxic effect and the 

tumor response (as indicated by the lower concentrations at which preneoplastic lesions 

occurred, 200 ppm, see Table 4.1.2.6.A), and the regional characteristics of the enzymes 

involved, the local concentration of acetaldehyde might be of critical value for the regional 

susceptibility for tumorigenicity. 

Bogdanffy et al. (1998) considered the metabolite acetic acid to be the initiator of cellular 

degeneration. Indeed, in vitro testing demonstrated cytotoxic potential of acetic acid. 1 hexposure of rat nasal turbinate explants of respiratory and olfactory mucosa induced cytotoxic 

effects at 50 mM acetic acid (without a clear difference in susceptibility among olfactory and 

respiratory mucosa) (Kuykendall et al., 1993). Cytotoxicity was examined after 1 hr exposure 

to concentrations of 50 mM of test substances by enzyme leakage of acid phosphatase as into 

the media. No cytotoxic effect was observed on olfactory and respiratory mucosa by 

acetaldehyde, while a 3-fold enzyme release versus control levels by vinyl acetate (no 

difference among olfactory and respiratory epithelium), and a 4-fold release by acetic acid 

were seen. At equimolar concentrations, acetaldehyde demonstrated no potential for 

cytotoxicity and vinyl acetate was less cytotoxic than acetic acid. No significant difference in 

cytotoxicity was found between the olfactory and the respiratory epithelium. The absence of 

cytotoxicity in the acetaldehyde testing appears not plausible (at least for the respiratory 

epithelium where the activity of aldehyde dehydrogenase is high) assuming that acetic acid 

should rapidly be produced by aldehyde dehydrogenase activity. The nil response may 

indicate that either acetaldehyde did not reach the cytosol, no acetic acid was produced (e.g. 

by enzyme inactivity in the in vitro model) or that the produced acetic acid (which dissociates 

into acetate anions and protons) which were buffered. No cytotoxic effect was observed at 25 

mM vinyl acetate for incubation times up to 2 hours (no data for acetic acid). Using the 

transformation into the inhalation concentration as proposed by Bogdanffy (2002) 25 mM 

corresponds to about 100 ppm vinyl acetate (50 mM ≈ 200 ppm). Results of in-vitro tests 

could be interpreted to fit well for the lowest observed effect level for cytotoxicity in the area 

of the olfactory region, which was 200 ppm. However, in-vivo observations on the respiratory 

epithelium revealed cytotoxicity at 1000 ppm. 

Assuming that acetic acid will be the main cytotoxic agent, the lack of cytotoxicity up to 600 

ppm in the respiratory epithelium may indicate that the local concentration of acetic acid in 

this area does not result in cellular damage. Thus the occurrence of tumors in this region (at 

600 ppm) could not be attributed to acetic acid-related cytotoxicity. 

For mechanistic considerations, the in situ distribution and activity of involved enzymes 

carboxylesterase and aldehyde dehydrogenase are of special interest. Both nasal regions, the 

respiratory and olfactory epithelium are capable to metabolise vinyl acetate because the 

presence of both enzymes has been demonstrated by immunostaining and activity 

measurements. 

Regarding the different mucosal regions, the enzyme activity of carboxylesterase is higher in 

the olfactory region (4-7fold, related to protein content) compared to those of the respiratory 

region (Bogdanffy et al., 1999a, Bogdanffy and Taylor, 1993). This difference is consistent 

with the intensity of immunostaining in these regions (Olson et al., 1993). 
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Comparing the absolute capacities among the enzymes, data indicated that the capacity of 

aldehyde dehydrogenase to aldehyde dehydrogenase is much lower than that for 

carboxylesterase to vinyl acetate in rat nasal tissues. In the olfactory epithelium, Vmax of 

aldehyde dehydrogenase was lower than the activity of carboxylesterase (30-40fold lower 

towards their respective substances). The difference is less marked for the respiratory 

epithelium, aldehyde dehydrogenase activity is 13-19fold lower than the carboxylesterase 

activity (Bogdanffy et al., 1998). 

It is concluded that at the same local concentration of vinyl acetate above Km of 

carboxylesterase, the intraepithelial concentration of acetaldehyde in the olfactory epithelium 

is expected to exceed that of cells in the respiratory epithelium. Because of the differences in 

Vmax of aldehyde dehydrogenase as compared with carboxylesterase at concentrations above 

Km the oxidation (and thereby the detoxification) of acetaldehyde to acetic acid is limited and 

may result in intracellular accumulation of acetaldehyde. From the absence of aldehyde 

dehydrogenase activity in the sustentacular cells and sensory cells it may be assumed that 

acetaldehyde concentrations will be higher at the same external vinyl acetate concentration. 

Compared to the olfactory epithelium, the lower carboxylesterase activity in the respiratory 

epithelium yielded a lower in situ production of acetic acid and acetaldehyde. This might be 

reflected by the higher LOAEC for cytotoxic effects (1000 ppm) and hyperplastic lesions 

(1000 ppm) in the respiratory epithelium than that for the olfactory epithelium (LOAEC 200 

ppm for both effects, see Table 4.2.1.8.E). 

Quantitative information on aldehyde dehydrogenase activities in the anterior (respiratory 

mucosa) and posterior (olfactory mucosa) nasal tissues of F344 rats is given in a paper by 

Stanek and Morris (1999). Activities averaged 210 and 160 nmol/min, respectively, 

corresponding to 64 and 28 nmol/min/mg protein. Nasal uptake was measured at three 

inspired concentrations of 10, 300, and 1500 ppm acetaldehyde and resulted in an uptake 

efficiency of 54, 37, and 34% demonstrating a concentration dependence of uptake. Stanek 

and Morris (1999) elaborated convincing evidence that the underlying saturable process is the 

metabolism of acetaldehyde by aldehyde dehydrogenase. Capacity limitation for nasal ALDH 

is suggested to occur at inspired concentrations of 300 ppm or more. 

Carboxylesterase localisation indicates intracellular metabolism of vinyl acetate in the above 

cited cell types, but did not explain why selective toxicity was evident in carboxylesterasenegative olfactory neuronal cells. Bogdanffy et al. (1998) concluded that the toxic effect was 

more likely a result from cell-specific sensitivity to cytotoxicity and to a lesser extent the 

function of metabolic capacity. The discrepancies between cells with metabolic capacities and 

affected neuronal cells could suggest that additional mechanisms are involved (e.g. selective 

sensitivity of cells, local distribution of metabolic products). The latter has been discussed by 

Bogdanffy who assumed intercellular communication via tight junctions to play a role in 

transportation of acid metabolites from the sustentacular cells to the sensory cells, the most 

sensitive target cells of the olfactory mucosa (Bogdanffy, 1990). Indications on a potential of 

acetaldehyde to disrupt tight junctions are available from a human colonic mucosa model 

(Basuroy et al., 2005). Indirect effects following damage to the sustentacular cells could 

explain high vulnerability of neuronal (sensory) cells to vinyl acetate (as for many esters). 

These cells are adjacent to the sensory cells and have supporting functions. The toxic insult 

(here: by increase of tissue concentration of acetaldehyde and/or other metabolites) primarily 

damages the sustentacular cells, their dysfunction may initiate the neuronal cell death. Since 

no aldehyde dehydrogenase activity was localised in the sustentacular cell, the detoxification 
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capacity through oxidation of acetaldehyde is lacking. This observation is in line with 

experience from other substances (e.g. methyl bromide, Schwob et al., 1995) where the 

inhalation of a gas that needs metabolic transformation for toxification results in selective 

vulnerability of sustentacular cells and olfactory sensory neuronal cells whereas the basal 

cells are spared from toxic insult. Also, from others it was suspected in earlier studies that 

toxic metabolites might diffuse from cells of the Bowman’s glands (Olson et al. (1993). 

For interspecies comparison, data on the absolute enzyme capacities in rats and humans 

indicated that the capacity of aldehyde dehydrogenase is much lower than that for 

carboxylesterase, in rats and in human nasal tissues. In the olfactory epithelium, Vmax of 

aldehyde dehydrogenase was 30-40fold lower for the rat and 20fold for humans than the 

activity of carboxylesterase. The difference is less marked for the respiratory epithelium; 

aldehyde dehydrogenase activity is 13-19fold lower in rats and 5fold lower in humans than 

the carboxylesterase activity (Bogdanffy et al., 1998). Taking these data into the account, 

there is no indication on a higher sensitivity of humans exposed to vinyl acetate compared to 

that observed in rats. 

- Contribution of cellular acidification: 

Due to the low activity of aldehyde dehydrogenases in the olfactory region the metabolic 

oxidation of acetaldehyde and thereby additional generation of acetic acid is considered of 

minor importance for the olfactory region. Compared to the olfactory mucosa, the lower 

carboxylesterase activity and the relatively high activity of aldehyde dehydrogenase in the 

respiratory region is supposed to prevent the accumulation of acetaldehyde in this area by the 

oxidative pathway generating acetic acid. However, at higher vinyl acetate concentrations 

aldehyde dehydrogenase capacity may be exceeded and intracellular accumulation of 

acetaldehyde will occur. 

It has been assumed that the intracellular production of acetic acid exceeds cellular buffering 

capacity and results in elevated H+

 concentrations which is thought to be associated with 

cytotoxicity (Plowchalk et al., 1996, 1997). The existence of intracellular acidification was 

supported by findings on cultured carboxylesterase-containing hepatocytes exposed to various 

concentrations of a vinyl acetate-PBS solution (10-1000 μM). Dose-dependent reductions of 

intracellular pH values were observed at concentrations of 10-200 μM (expected mucous 

concentration resulting from inhalation exposure to 50-670 ppm vinyl acetate), a marked 

decrease in intracellular pH appeared at 500 μM, no further drop occurred at 800 and 1000 

μM. The maximal drop was 0.5-0.6 pH units. The reduction of intracellular pH was rapidly 

reversible within hepatocytes after withdrawal of vinyl acetate (Bogdanffy, 2002). 

Uncertainty existed about the carboxylesterase activity of hepatocytes, which may differ 

significantly from those of the respiratory and olfactory mucosa cells. Earlier studies showed 

a hydrolysis rate about an order of magnitude higher in the rat liver than in the lung (no 

examination of nasal tissues) (Simon et al., 1985a). For the rat model, the carboxylesterase 

activity appears to be comparable in the liver and the olfactory microsomes and was nearly 

3fold higher than in the respiratory epithelium microsomes (Mainwaring et al., 2001). In 

contrast, human liver microsomal activity towards methyl methacrylate is much higher 

(>100fold) than those of the olfactory and respiratory epithelium. 
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Interestingly this model showed that no (acute) cytotoxic effect was associated with the 

lowered pH-value up to the maximum reduction of 0.55 units at 500 μM and above 

(corresponding to inhaled concentrations above 1000 ppm). As cells returned to pre-treatment 

pH-values within 50 sec after treatment with 200 μM vinyl acetate, a high rate of proton 

efflux was thought to prevent from intracellular proton accumulation. The assumption of the 

authors that the proton export is in the same range as its intracellular production appears to 

conflict to the proposal that acidification through acetic acid is - via cytotoxicity - the initial 

step in tumorigenesis. The lack of cytotoxicity is in line with resistance of hepatocytes 

reported by Farkas and Tannenbaum (2005). A high concentration of 1000 μM vinyl acetate 

induced no secretion of protein and urea and some release of lactate dehydrogenase from 

hepatocytes that indicated 20 percent of cell death occurred at 24 hours after treatment. 

Corresponding in-vivo data on the effect of vinyl acetate on intracellular pH of nasal mucosa 

cells were not available. In vitro exposure of isolated respiratory and olfactory epithelium 

cells to concentrations of 100-1000 μM vinyl acetate resulted in concentration-related 

decrease in intracellular pH in the respiratory epithelial cells (Lantz et al., 2003). A slight 

reduction in intracellular pH was seen at 100 μM, a plateau was reached at 500 μM and 1000 

μM did not further increase the acidification. The maximal decrease was –0.3 pH units (pHi

7.16 vs. resting pHi 7.49). In the olfactory epithelium, a bimodal distribution of pH values was 

observed. In contrast to the respiratory epithelium cells, olfactory epithelial cells consisted of 

two populations with different behaviour. Only one population responded dose-dependently 

to 100, 250, 500 and 1000 μM vinyl acetate treatment by reduction in intracellular pH. The 

maximum decrease in the responders was –0.3 pH units (peak pHi changed from 7.32 in 

control cells to 7.0 for the highest concentration). Changes in pH values were reversible in all 

cells after washing.100 μM vinyl acetate did not decrease pH when a carboxylesterase 

inhibitor (BNPP) inhibited carboxylesterase. Interestingly, a plateau for maximal acidification 

was also reached for respiratory cells at 500 μM as in the liver cell model of Bogdanffy 

(2002). The lowest concentration tested (100 μM) already disturbed the intracellular proton 

homeostasis, but the overall extent of acidification was rather low (-0.06 in the respiratory 

epithelium and – 0.03 in the olfactory epithelium). - Additional studies by Lantz et al. (2003) 

on explants from ethmoturbinates (olfactory) and maxilloturbinates (respiratory) using pHsensitive fluorescence imaging responses to vinyl acetate observed only minimal acidification 

(-0.05 pH units) in the presence of 1000 μM vinyl acetate in the respiratory epithelial cells 

(peak pHi 7.4 in cells of control explant). Accordingly to the isolated cells, cells of the 

olfactory epithelium explant (peak pHi 7.4 in cells of control explant) responded by a bimodal 

distribution of cells with reductions of -0.2 and -0.8 pH units indicating the presence of two 

different cell populations. In conclusion, the overall lower acidification of the respiratory 

epithelium appears to correspond to the lower carboxylesterase activity compared to the 

olfactory epithelium. However, the difference in responses produces uncertainty in the data 

reliability (e.g. -0.3 pH units in isolated respiratory cells and –0.05 pH units in the respiratory 

epithelial cells of the explant model). Responsive and non-responsive cell populations may 

reflect the differences in carboxylesterase activity among cell types of the olfactory 

epithelium (lack of enzyme in neuronal cells, negligible in basal cells, and marked activity in 

sustentacular cells and Bowman’s glands). 

As acetic acid is responsible for intracellular acidification, the lack of further decrease in pH 

values above 500 μM in the above mentioned in vitro models indicates that the production of 

acetic acid is limited. The relevance of the minimal drop in pH (-0.2 pH units in hepatocytes, 

-0.2 pH units in respiratory epithelial cells, -0.14 pH units in olfactory epithelial (Bogdanffy, 

2002, Lantz et al., 2003)) at tumor dose-equivalent concentrations of 200 μM for cell 
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proliferative activity or tumor growth is questionable. The lacking reactivity of hepatocytes at 

minor pH drops is in line with the observed tolerance of tracheal mucous epithelium to 

acidity. In tracheal tissue explants a reduction in ciliomotility, cell membrane destruction and 

intra- and intercellular oedema started in acidic environment at pH 6.70 and complete 

ciliostasis occurred below pH 4.9 (Holma et al., 1977). 

Whether the predictions on carboxylesterase activity and intracellular acidification from the 

modelling in hepatocytes, nasal mucosa cells and explants are assignable in a quantitative 

manner to the in vivo situation of the human nasal targets remains uncertain. Considering the 

resistance to cytotoxicity and minor reductions in intracellular pH in hepatocytes exposed to 

up to 1000 μM vinyl acetate, which were consistent to the low extent of acidification and its 

reversibility observed in in-vitro single cell or turbinate explants of the respiratory and 

olfactory epithelium, the overall low aldehyde dehydrogenase activity in rat and human 

olfactory mucosa (which limits the additional production of acetic acid), and the lack of 

cytotoxicity up to 1000 ppm for the respiratory mucosa, where tumors were already seen, lead 

to the conclusion that the contribution of intracellular acidification as the presumed mode for 

tumor development is – if at all- only minor. 

A validation study for the application of a human PBPK model with controlled human 

inhalation exposures to vinyl acetate showed that the human nasal model predicts the 

experimental observations with regard to vinyl acetate and acetaldehyde in the airstream of 

human nasopharyngeal cavity in a concentration range from 1 to 10 ppm (Hinderliter et al., 

2005). 

Step 2: From cytotoxicity to cancer: 

The degeneration and inflammation of the olfactory epithelium observed in the toxicity and 

carcinogenicity studies after repeated/prolonged inhalation exposure gave indication that 

cytotoxicity of target cells contributed to the tumor development in this nasal region. 

Concomitant lesions representing attempts to repair/regenerate the damaged olfactory 

epithelium were observed (Bogdanffy et al., 1994b). In the view that finally tumors occurred 

at this site, metaplastic and hyperplastic changes could be interpreted to represent the 

sequential steps in carcinogenesis. The olfactory epithelium was more sensitive to develop 

degenerative lesions than the respiratory epithelium (Bogdanffy et al., 1997). 

Early degenerative changes were evident in the sustentacular cells, but these cells primarily 

targeted by cytotoxic effects of vinyl acetate were not identical to the cell types of tumor 

origin. As no tumor of the neuro(esthesio-)blastoma type were found in carcinogenicity 

studies on vinyl acetate, cells of tumor origin are more likely less differentiated cells with 

origin of the basal cell, intermediary cells of squamous type or of the respiratory-cell like type 

rather than of the olfactory sensory cell type. The majority of tumors seen in the nose were of 

the squamous cell type indicating that cells of squamous metaplasia or surviving basal cells 

that undergo squamous cell differentiation were the tumor cell origin. Increased regenerative 

cell proliferative activity could trigger the accumulation of cells with spontaneous DNA 

damage and thereby cause an increase in cancer. In addition, cells replacing the olfactory 

epithelium may have an altered susceptibility to noxious insults. 

No data on carboxylesterase activity and aldehyde dehydrogenase activity are available for 

cells of hyperplasia and respiratory metaplasia in the olfactory epithelium. In human samples 

of hyperplastic tissue of the respiratory mucosa, a dramatic reduction in enzyme 
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immunostaining was found and enzyme was lacking in squamous metaplasia. The absence of 

activity fits well to the lack of carboxylesterase activity in the squamous epithelium in the 

cranial portion of the nose (Olson et al., 1993). It might be assumed that the lack of 

carboxylesterase in hyperplastic/metaplastic respiratory tissue protects against the vinyl 

acetate toxicity at this sub-site. However, chronic damage of the olfactory epithelium 

characteristically consists of a mixture of different epithelial/cell types (respiratory-like 

hyperplastic area, squamous metaplasia and dysplasia, atrophic/hypertrophic olfactory areas). 

There remain uncertainties on the exact mechanisms of the olfactory epithelium cell death and 

the disturbances in control of regenerating cell proliferation leading to carcinogenesis. 

Ic. Dose-response relationship

Degenerative (atrophic) lesions of the olfactory mucosa were seen in rats at concentrations of 

200 ppm or higher when exposed over 2 years (Bogdanffy et al., 1994b, Owen, 1988). In this 

species, the respiratory epithelium was less sensitive to damage showing no lesions up to 600 

ppm (Bogdanffy et al., 1994b), the lowest concentration with respiratory epithelial damage 

was 1000 ppm vinyl acetate after 4 weeks of inhalation (Bogdanffy et al., 1997). Lesions of 

the lower parts of the respiratory tract (larynx, trachea, bronchi, bronchioli) were seen at 600 

ppm vinyl acetate in rats. 

A clear increase of nasal tumors at the olfactory, respiratory and other/unknown localisation 

occurred in rats at concentrations of 600 ppm. The total incidence of (all) nasal tumors was 

11.9% in male rats and 6.8 % in female rats of the group (see Table 4.1.2.8.A). 

Figure 4.1.2.8.A 

Nasal tumor precursors

 in the olfactory epithelium (OE) of rats 

(Bogdanffy et al. 1994b) 

0

20

40

60

80

0 ppm 50 ppm 200 ppm 600 ppm

Vinyl acetate concentration

Percentage 

OE metaplasia

OE Basal cell

hyperplasia

OE atrophy
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Figure 4.1.2.8.B

Regarding males and females at each dose group together (see above Figure 4.1.2.8.B), the 

incidence of tumors with site of origin in the olfactory region was 4% at 600 ppm (in 118 

males and females). With respect to the olfactory epithelium, toxic lesions occurred at lower 

concentrations (200 ppm) (see above Figure 4.1.2.8.A) than those inducing an increase of 

tumor incidences (600 ppm). Dose-dependently the restorative basal cell proliferation 

increased in parallel to the degenerated (atrophic) olfactory epithelium. The dose-response 

curves for all effects assumed to be precursors of tumor development were non-linear, the 

NOAEC was 50 ppm. Olfactory epithelium metaplasia was occasionally seen at 200 ppm (in 

5/60 female rats, none in males). A single benign tumor was seen in the area with olfactory 

epithelium in a male rat at 200 ppm. As spontaneous tumors at this site are very rare, an 

association to vinyl acetate exposure could not be excluded. A significant increase in 

metaplastic lesions was evident at the clearly tumorigenic concentration of 600 ppm. 

Figure 4.1.2.8.C 

Nasal tumors in the non-olfactory regions in rats 

No precursor lesions evident (Bogdanffy et al. 1994b)

0

2

4

6

8

10

0 ppm 50 ppm 200 ppm 600 ppm

Vinyl acetate concentration

Percentage

non-OE Tumors

Nasal tumors 

 in the olfactory epithelium (OE) of rats 

(Bogdanffy et al. 1994b) 

0

2

4

6

8

10

0 ppm 50 ppm 200 ppm 600 ppm

Vinyl acetate concentration

Percentage 

OE Tumors
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Tumors at other non-olfactory regions (tumors of unknown origin were included here) 

occurred in 6% of male and female rats (7 out of a total of 118) (Figure 4.1.2.8.C). At the 

respiratory epithelium of the rat nose no cytotoxicity and no other precursor lesion was 

reported at 600 ppm, the concentration which induced tumors at this site after 2-year 

inhalation (Bogdanffy et al., 1994b). Toxic effects at this site occurred only at dose levels 

above those inducing tumors. 

A dose-response relationship of degenerative (atrophic) and other precursor effects (basal cell 

hyperplasia and metaplasia) and tumor development was identified for the olfactory region. 

No dose- response relationship was evident for cytotoxicity or other metaplastic changes 

could not be identified for the respiratory region. 

Id. Temporal relationship

A temporal relationship of cytotoxicity-related tumor growth can be assumed for the tumors 

of the rat olfactory epithelium, because early degenerative findings were seen in studies with 

4-week duration (Bogdanffy et al., 1997). As no underlying toxic event could be identified in 

the respiratory epithelium of the rat nose at or below the tumor-inducing dose, a statement on 

the time progression is not possible. 

No complete recovery of the olfactory atrophy was observed in the recovery groups of the 

combined chronic and carcinogenicity studies on rats and mice (Owen 1988, Bogdanffy et al., 

1994b). This is comparable to the recovery status known from acetaldehyde studies. A 

replacement of the damaged olfactory epithelium by respiratory-like epithelium (without 

sensory cells) as well as regeneration with a less differentiated olfactory-like epithelium was 

reported (Woutersen and Feron, 1987). 

Ie. Biological plausibility and coherence

From historical data it is known that nasal tumors have a very low spontaneous incidence in 

aging rats (St. Clair and Morgan, 1992, Brown et al., 1991). Malignant nasal neoplasm were 

also rare in humans (overall rate <1/100 000; Lund, 1994). 

The sequence of events (cytotoxicity, hyperplasia, benign and malignant tumors) observed at 

the olfactory epithelium is consistent with the general knowledge on the tumor pathogenesis 

of substances for which genotoxicity could be excluded as mode of action. In case of vinyl 

acetate it has to be discussed whether acetaldehyde genotoxicity contributes to the sequence 

of events. 

The evidence of tumors of squamous origin indicated that DNA damage occurred in cells of 

squamous metaplasia or in surviving basal cells that are precursor cells of squamous cell 

metaplasia or squamous cell tumors. 

Vinyl acetate effects seem to coincide with acetaldehyde effects. Nasal tumors were observed 

after long term inhalation of vinyl acetate or acetaldehyde. In comparison with the vinyl 

acetate data mentioned above, the primary tumor site after chronic acetaldehyde exposure of 

rats also was the nose, and tumors of the larynx were occasionally observed in this species 

after chronic inhalation to each of the test substances. Except those nasal adenocarcinomas 

were not found in vinyl acetate cancer studies, tumor response from both substances was 

comparable at least for the rat. Whereas vinyl acetate was not tested in the hamster, the 

prevalent tumor site was the larynx, and only few tumors were seen in the nose of 
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acetaldehyde exposed hamsters (Feron et al., 1982). This indicates that these localisation do 

have the enzymatic capabilities; the difference in distribution was suspected to be due to 

species-specific differences in susceptibility of the epithelium to acetaldehyde, a difference in 

impact of acetaldehyde on the epithelium, a difference in breathing pattern, and/or a 

combination of all factors (Wouterson et al., 1984). 

The nature of the effect - cytotoxicity – evoked by inhalation of acetaldehyde on nasal tissues 

seems to be comparable to that of vinyl acetate. The rat respiratory epithelium was shown to 

be less sensitive towards toxic lesions than the olfactory epithelium. (Wouterson et al., 1984, 

1986, Appelman et al., 1982). 

If. Inconsistency, uncertainties and data gaps

The presence of degenerative lesions at the olfactory epithelium demonstrates its specific 

sensitivity to cytotoxicity. The evidence of dose and temporal relationships and the evidence 

of sequential alterations (cytotoxicity, hyper- and metaplasia, benign and malignant tumors) 

support that cytotoxicity is associated to the tumor development. This was seen in a long-term 

study on the rat, but was not consistent to the negative results from the mouse cancer study. 

• Interspecies comparison to the mouse: 

Degenerative lesions of the olfactory mucosa were seen in mice at concentrations of 200 ppm 

or higher when exposed over 2 years. Treated mice showed lesions at the respiratory 

epithelium at 200 ppm after 2-year inhalation of vinyl acetate (Bogdanffy et al., 1994b, Owen, 

1988). Lesions of the lower parts of the respiratory tract (larynx, trachea, bronchi, bronchioli) 

were seen at ≥200 ppm vinyl acetate in mice. 

In mice, it is noteworthy that toxic lesions beginning at 200 ppm at both localisations of the 

nasal epithelia, but no nasal tumor occurred at concentrations tested up to 600 ppm. 

Reparative replacement of the olfactory epithelium by respiratory-like epithelium and 

squamous metaplasia as well as hyperplasia of the submucosal glands were similar to the 

effects seen in the rat, but no progression to tumors occurred in this target region. It can not 

be excluded that the single squamous cell carcinoma of the lung bronchus was also associated 

to the vinyl acetate treatment occurring at the same concentration which induced epithelial 

exfoliation/disorganisation and fibrohyperplastic projections of the bronchus/bronchioles with 

high incidences (Bogdanffy et al., 1994b, Owen, 1988). 

In mice vinyl acetate is also efficiently hydrolysed in nasal mucosa. Since the values for 

carboxylesterase activities in the respiratory and olfactory regions were in the same range 

(olfactory: 0.4-0.5 μmol/min/mg protein in the mouse compared to 0.6 μmol/min/mg protein 

in the rat, respiratory: 0.1-0.2 μmol/min/mg protein in the mouse compared to 0.1 

μmol/min/mg protein in the rat, Bogdanffy et al. 1987) or were found at even higher ranges as 

in the rat (Bogdanffy and Taylor, 1993), a significant tumor response in the nasal mucosa 

should be expected for the mouse. This raises questions on species-specific differences in the 

susceptibility of the nasal mucosa. Is the mouse nose less sensitive to tumor generation 

(consider the tumors of the gastrointestinal tract of the mouse)? Or does the mouse have a 

high activity of aldehyde dehydrogenase (in contrast to the low ALDH activity in rat olfactory 

mucosa) that effectively contributes to acetealdehyde elimination and thereby prevents in situ 

accumulation of acetaldehyde? Determination of aldehyde dehydrogenases activity revealed 

low Vmax in whole nasal tissue homogenates of mouse and hamster compared to rats 
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(Morris, 1997). However, origin of epithelial material was not specified and whole tissue 

homogenates might be less predictive. 

DNA adduct formation was observed in the rat nose, but no data were available for the nasal 

mucosa of the mouse. To explain the lack of nasal tumors in mice, further data are needed. 

The mouse was negative for the inhalation route, but sensitive towards tumor development for 

the oral route (see 4.1.2.8). 

• Uncertainties related to the role of intracellular acidification: 

The role of pH changes remained unsolved for some critical points. In olfactory epithelium, 

target cells undergoing cell death (primarily sustentacular cells) were not identical with cells 

that were involved in regenerative proliferation. There are two types of basal cells, the 

horizontal basal cells and the globosal basal cells. In healthy tissue, the latter represents the 

majority of basal cells and is mainly involved in normal regeneration of olfactory cells (Ohta 

and Ichimura, 2001). Even if there is no significant reduction in intracellular pH values that 

plays a critical role in the process of cell damage, is there any pH-dependent effect on 

proliferation stimulus on basal cells? Comparing to other toxicants that also induce selective 

cell death in sustentacular/sensory cells, reparative cell replication appears to be a unique 

mechanism that is not necessarily linked to cellular acidification in degenerating cells. The 

evidence of tumors at non-olfactory sites demonstrated that proliferative activity was not 

necessarily associated with cell death and therefore might not be related to the cell 

acidification. 

Bogdanffy (2002) claimed that intracellular acidification as demonstrated in the hepatocyte 

model precedes the morphological signs of cytotoxicity. However, 1000 μM vinyl acetate was 

not cytotoxic in hepatocytes at the end of 6 days of culturing as evidenced by protein and 

LDH leakage (Farkas and Tannenbaum, 2005). Further proof is needed that intracellular 

acidification is the initial lesion in cytotoxicity, at least for the olfactory region. 

A reduction of intracellular pH as demonstrated in the rat hepatocytes (Bogdanffy, 2002) was 

– even at a lower level - assignable to cells of the olfactory and respiratory mucosa. For the 

rat, carboxylesterase activity appears to be in the same range in the rat liver as in the rat 

olfactory mucosa as demonstrated in microsomes using methyl methacrylate as a test 

substrate (Mainwaring et al., 2001) (Table 4.1.2.8.H). In contrast, carboxylesterase activity is 

much higher in the human liver than in the human olfactory mucosa. 

The changes in intracellular pH were relative small in the test systems mentioned above. 

However, no prediction could be made on pH homeostasis after prolonged exposure. The 

experimental studies available examined vinyl acetate or acetaldehyde effects following acute 

(seconds to minutes) exposure. No data exist on the consequences of prolonged acidification. 

The small reduction of intracellular pH may be explained by the low activity and nearly 

absence of aldehyde dehydrogenases in the olfactory mucosa, which limits the production of 

acetic acid. Therefore the intracellular acidification may be a process of minor relevance for 

(cyto-)toxicity and tumor induction at this site. Besides the uncertain relationship between 

small changes in pH and cytotoxicity other pH-related effects on cell transformation could be 

considered. On irradiated cells with DNA double-strand breaks it was demonstrated that 

lowering of the extracellular pH from 6.8 to 6.0 causes inhibition of DNA repair (Jayanth et 

al., 1994). Whether this is relevant for the carcinogenicity of vinyl acetate is unknown. 
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• Uncertainties related to the modes of action for the respiratory mucosa: 

Beside the nasal tumors originating from the olfactory epithelium, there were also some nasal 

tumors, which were located in areas of the nasal cavity consisting of non-olfactory epithelial 

types (Table 4.1.2.8.B). No toxic event was identified as a critical step in the development of 

these tumors, e.g. at the respiratory epithelium of the nose. Whereas rhinitis and metaplasia 

occurred in the respiratory epithelium of the mouse nose, cytotoxic and/or inflammatory 

responses to vinyl acetate exposure were not reported in rat studies at concentrations which 

induce tumors (Owen, 1988, Bogdanffy et al., 1994b). Thus, clear data demonstrating that the 

toxic lesions in this area were associated to disregulated cellular regeneration resulting in 

tumor formation are missing. The absence of cytotoxic events at the respiratory epithelium at 

tumor-inducing concentrations demonstrated that cytotoxicity did not seem to be the 

necessary precondition for carcinogenicity of vinyl acetate. 

Increased rates of cell turnover were observed in both respiratory and olfactory mucosa after a 

single 6-hour exposure. When vinyl acetate vapour was inhaled on 20 days (5 d/wk, 6 h/d) 

(Bogdanffy et al., 1997), increased cell proliferation was only evident in the olfactory 

mucosa. These findings were inconsistent with the fact that tumors were observed at both 

regions. 

Also, it was suggested that acidification causes mitogenic response as a critical step in tumor 

growth of the respiratory mucosa. In-vitro exposure of cells of a Barrett’s adenocarcinoma 

cell line to acid media increases cell proliferation and decreases apoptosis via an activation of 

the mitogen-activated protein kinase pathway (MAPK) (Souza et al., 2002). However, the 

mode of the development of Barrett’s carcinoma of the oesophageal squamous mucosa 

appears of limited predicted value, since in this in-vitro model cells were exposed to markedly 

lower pH values (pH 4.0) than those observed in the nasal mucosa following vinyl acetate 

exposure. Up to now no substantial evidence of decreased apoptosis has been shown for vinyl 

acetate-related acidification and no studies investigating mitogenic effects for the inhalation 

route were available. Instead, some data from oral administration of acetaldehyde and vinyl 

acetate may be informative: Long-term cell proliferation experiments demonstrated mitogenic 

effects of acetaldehyde which induced diffusely enlarged basal cell layer and increased cell 

proliferation rates (Homann et al., 1997). Compared to vinyl acetate metabolism to acetic acid 

where 3 protons were delivered per molecule vinyl acetate, acetaldehyde oxidation delivers 

only 1 proton per molecule. This indicates that the mitogenic response is more likely an effect 

of acetaldehyde than an effect of acidification. The mechanism by which acetaldehyde exerts 

its mitogenic effect is yet unknown. Whereas only one acetaldehyde concentration (120 mM 

= 324 mg/kg bw/d) was applied with drinking water in the Homann study, the study of 

Valentine et al. (2002) observed concentration-dependent increases in cell proliferation rates 

in the oral mucosa of rats receiving 10000 ppm vinyl acetate or more with the drinking water. 

No effect was observed at 1000 and 5000 ppm, cytotoxicity was absent in all concentrations 

tested. In conclusion, acetaldehyde and vinyl acetate have mitogenic properties, that of vinyl 

acetate is likely to be mediated through acetaldehyde and has a clear no-effect level. 

• Uncertainties related to genotoxic effects: 

Since no tumors occurred below the LOAEC for cytotoxic effects in the olfactory region it is 

unlikely that genotoxic effects were active below the threshold concentration for cytotoxicity. 
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In contrast no dose-response could be identified for preceding events in the nonolfactory regions. Dose-related mitogenic effects were demonstrated for the oral route 

where it is assumed that vinyl acetate exerts its acetaldehyde-caused clastogenic 

effects most efficiently in proliferating cells. This might also be assumed for the sites 

of contact following inhalation. However, at the moment there are no studies 

confirming the hypothesis and identifying a LOAEC for this effect in the respiratory 

tract. 

Ig. Actual considerations on the assessment of the mode of action for tumors of the 

respiratory tract (see Table 4.2.1.8.K) 

Acetaldehyde is the critical metabolite with a carcinogenic potential. 

The distribution and capacity of enzymes responsible for vinyl acetate toxicification and 

detoxification are of major importance to create a preliminary understanding of the modes of 

carcinogenic action. The present understanding is that acetaldehyde plays a critical role in the 

tumorigenicity of vinyl acetate. 

The principal similarities of toxic and carcinogenic effects of vinyl acetate to those of 

acetaldeyhde suggest that the hydrolysis product acetaldehyde is the active carcinogenic 

metabolite of vinyl acetate. 

Acetaldehyde is a biological constituent of many cells and is – beside the release from the 

man-made sources - ubiquitarily present in many foods and natural sources. Exposure to vinyl 

acetate induces concentration-related increases in intracellular concentrations of the 

hydrolytic products acetaldehyde and acetic acid. Efficiency of the absorption is optimal at 

lowest concentrations and decreases with increasing concentration (see 4.1.2.1). Increasing 

concentrations of the vinyl acetate may result in an accumulation of acetaldehyde when the 

cellular detoxification capacity of aldehyde dehydrogenase is overwhelmed. The toxicity 

and/or carcinogenicity reflect the function of metabolic capacity of the target epithelium. The 

regional and cellular susceptibility to cytotoxicity corresponds to the distribution and activity 

of the enzymes involved. 

Acetaldehyde is thought to be the responsible metabolite for the genotoxic effects seen in 

mammalian cell cultures on vinyl acetate. 

A hypothesis of a cytotoxicity-related carcinogenesis is likely to induce tumors in the 

olfactory region. 

• The rat olfactory tissue efficiently catalyses the formation of acetaldehyde and acetic 

acid. 

• Absorption and metabolic transformation of vinyl acetate by carboxylesterase is a 

concentration dependent process. Due to the absent or low aldehyde dehydrogenase 

activity (as compared to the carboxylesterase activity) only low concentrations of 

acetaldehyde can be oxidised. Above a yet non-identified exposure concentration, the 

production of acetaldehyde exceeds further oxidation, which results in an intracellular 

accumulation of acetaldehyde. 
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• Acetic acid-related cytotoxicity following vinyl acetate hydrolysis appears to be the 

initial event in tumorigenicity for tumors with origin in the olfactory epithelium. 

- A direct genotoxic action of the metabolite acetaldehyde on the restorative epithelium 

could contribute to tumor initiation. 

- Cell death induces increased cell turn over of surviving cells or basal cells. DNA 

synthesis is elevated and the incidence of genotoxic effects is expected to increase. 

In conclusion, it appears plausible to explain the sequential steps from cytotoxicity to 

carcinogenesis for the olfactory epithelium. The sites of epithelial damage correlated with 

increased cell proliferation as evidenced by basal cell hyperplasia and transformation to 

squamous metaplasia. The latter was considered to be a precursor lesion of benign and 

malignant tumors that were squamous cell papillomas and carcinomas. 

The contribution of intracellular acidification as the initial step leading to cytotoxicity and 

thereby to carcinogenicity remains uncertain. Short term testing indicated that the degree of 

intracellular acidification was only minor and reversible. Also, the site-specific changes in 

intracellular acidification as predicted in the PBPK-model (Plowchalk et al., 1997) were not 

consistent with the in-vivo preference of cytotoxicity. Genotoxicity data indicate a possible 

genotoxic effect of vinyl acetate mediated by its metabolite acetaldehyde, which may 

contribute to the tumor development at concentrations, which were cytotoxic. 

At present, a narrative for a threshold concentration for tumor development could be 

identified for the olfactory region by its cytotoxicity. 

 A threshold mode of action is thought to be active for tumors with origin in the other nasal 

regions. 

For the other (non-olfactory) tumor sites of the upper respiratory tract (mainly the nasal 

respiratory epithelium), cytotoxicity was clearly not a critical event in tumor formation, 

because tumors occurred at lower exposure concentrations than cytotoxicity. The predictions 

from the PBPK model, with respect to the degree of acidification and thereby of the cytotoxic 

response did not reflect the observed study data. During the last years, scientific working 

groups recognised the lack of evidence for the early proposals on acidification as the relevant 

mode and introduced considerations about the role of intracellular acidification in stimulation 

of cell growth and transformation (Lantz et al., 2003). These secondary responses occur only 

at higher doses. 

The following aspects support the hypothesis of a threshold mode of action: 

- Absorption and metabolic transformation of vinyl acetate is a concentration dependent 

process. 

- Carboxylesterase activity in the respiratory epithelium is at least half than that of the 

olfactory epithelium in man and rats. The hydrolysis rates of vinyl acetate and thereby the 

intracellular concentrations of acetic acid and acetaldehyde are expected to be markedly 

lower than in the olfactory epithelium. 

- Aldehyde dehydrogenase (ALDH) is the key enzyme for the elimination of acetaldehyde. 

Its activity is more than 2fold higher in the respiratory epithelium than in the olfactory 
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epithelium. The enzyme activity is sufficient to cope with low concentrations of vinyl 

acetate and its produced metabolite acetaldehyde. At high concentrations of intracellular 

acetaldehyde ALDH activity will not be sufficient to oxidise all acetaldehyde to acetic 

acid and acetaldehyde may accumulate. Saturation of metabolism of acetaldehyde by 

ALDH indicating limited enzyme capacity is suggested to occur at acetaldehyde 

concentrations of 300 ppm (Stanek and Morris, 1999). 

- No toxicity was observed in respiratory epithelium up to 600 ppm in 2-year studies. 

Regarding acetic acid as the cytotoxic metabolite, acetic acid generation at 600 ppm is 

below the threshold for cytotoxicity. 

- No increase in proliferative activity either measured as proliferation index or as 

hyperplastic/metaplastic changes up to 600 ppm vinyl acetate in (LOAEC 1000 ppm). It is 

assumed that increased cell proliferative activity is acetaldehyde-related. As no 

cytotoxicity or other relevant effect was seen up to 600 ppm, no significant intracellular 

concentration of acetaldehyde is expected to occur. 

- In accordance to data from oral studies on mitogenic action of vinyl acetate a mitogenic 

action could be assumed above a threshold concentration. Due to the lack of adequate 

studies on the respiratory tract, evidence from studies on gastrointestinal tract was 

considered: Basal cell hyperplasia and epithelial hyperplasia in the gastrointestinal tract 

without preceding cytotoxicity were evident at ≥10000 ppm (NOAEL 5000 ppm ≈1200 

mg/kg/d, 92-day mouse study, Valentine et al., 2002). 

- Tumor response was seen at ≥600 ppm vinyl acetate, no tumors were observed at 

concentrations below. 

- It is assumed that acetaldehyde-caused genotoxicity is active at vinyl acetate 

concentrations that cause acetaldehyde accumulation. 

- The toxicological relevance of minimal reduction in pH remains questionable. 

- Actually, an exact threshold concentration for acetaldehyde accumulation could not be 

estimated for the non-olfactory region. 

- Since no biological response in the respiratory mucosa was observed in long-term 

inhalation studies up to 200 ppm vinyl acetate exposure, it is concluded that the cellular 

integrity is not disrupted. 
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Table 4.1.2.8.K: Critical steps in vinyl acetate tumor formation in the respiratory tract: 

VA Absorption 

Ø

Metabolism of vinyl acetate to acetaldehyde and acetic acid in: 

Olfactory epithelium 

Sustentacular cells + neuronal (sensory) cells:

Carboxylesterase activity +++ 

ALDH activity - 

Ø 

Olfactory epithelium 

Basal cells + Bowman’s glands: 

Carboxylesterase activity +++ 

ALDH activity (+) 

Ø 

Respiratory epithelium 

Respiratory epithelium cells: 

Carboxylesterase activity + 

ALDH activity +++ 

Ø 

High acetaldehyde production 

No detoxification of acetaldehyde 

Intracellular accumulation of acetaldehyde 

Cytotoxicity at 200 ppm 

Ø 

High acetaldehyde production 

Very limited detoxification of acetaldehyde

Intracellular accumulation of acetaldehyde 

Ø 

Limited acetaldehyde production 

• Up to a threshold concentration: 

Efficient detoxification though high 

ALDH capacity 

No toxic effect up to 200 ppm 

C. Above threshold concentration: 

Imbalance of acetaldehyde production and

detoxification 

Intracellular accumulation of acetaldehyde 

Ø 

Secondarily to cytotoxicity of the primary target cells: 

Restorative cell proliferation of surviving basal cells 

Replacement by respiratory-like epithelium 

and squamous cell metaplasia 

Ø 

Cell proliferation due to direct mitogenic effec

Ø 

Genotoxic effects of acetaldehyde on proliferating cells (inclusive tumor relevant genes) 

Tumor initiation and development 

Tumor response: LOAEC 600 ppm 

Cytotoxicity: LOAEC 200 ppm/NOAEC 50 ppm 

Genotoxic effect of acetaldehyde on 

proliferating cells (inclusive tumor relevant 

genes) 

 Tumor initiation and development 

Tumor response: 

LOAEC 600 ppm/NOAEC 200 ppm 
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II. Gastrointestinal tract tumors 

IIa. Postulated mode of action

From the recently reported carcinogenicity studies in rats and mice (Umeda et al., 2004a, 

Maltoni et al., 1997, Minardi et al., 2002) which at the first time gave indication that vinyl 

acetate is also carcinogenic after oral administration, it is assumed that carcinogenicity of 

vinyl acetate is a direct effect on the surface epithelium of the oral cavity, larynx, esophagus, 

and forestomach exposed. Temporarily, it was assumed that vinyl acetate metabolism in these 

tissues leads to cytotoxicity accompanied by reparative hyperplasia. The continuous 

reparative stimulus in the presence of high concentrations of acetic acid and acetaldehyde 

then leads to mutation, cellular transformation, and tumor development. 

Meanwhile increased cell proliferation due to mitogenic response to the long-term uptake of 

vinyl acetate was discussed to lead to tumor formation instead of apparently absent 

cytotoxicity-related mode of action (Valentine et al., 2002). Similar to the nasal regions, it 

was thought that in the presence of excess, non-physiological levels of acetaldehyde and low 

pH inducing mutations in genetic material will result in tumor formation. 

IIb. Key events associated with the hypothesis

Hydrolytic esterase activities, mainly carboxylesterases, were also found in the mucosal 

epithelium of the oral cavity (Yamahara and Lee, 1993). Different mucosal regions of the oral 

cavity possess vinyl acetate hydrolysis activity in the concentration range of 0.05-10 mM 

vinyl acetate. The enzyme activity Vmax was 90 and 6 nmol/min in rat and mouse oral mucosal 

tissue, respectively. The Km for vinyl acetate hydrolysis were 0.5 and 0.9 mM, respectively, 

and were at about 100fold below the concentrations of vinyl acetate that were administered 

orally suggesting that saturating conditions would exist. The total activity was similar in 

pooled homogenates from F344 rats and BDF mice. About 2% of total activity were found in 

the oral rinse fluid; the saliva and/or oral bacteria are possible sources of esterase activity. In 

both species the dorsal interior region contained more activity than other regions (Morris et 

al., 2002). No indication on cytotoxicity was observed in the oral rinse fluid assessed for 

leakage of acid phosphatases and Evans blue dye after intravenous administration. The 

concentration of acid phosphatase was not significantly altered. Evans blue dye was 

significantly increased at 10 mM (intended to correspond to the dosage of 24000 ppm in the 

90-day study, DuPont, 2000). However, Evans blue extravasation is not specific, since 

sensory nerve activation and/or increased salivation could also interfere with plasma 

extravasation. 

The distribution and immune-reactivity of carboxylesterases in the oral mucosa have been 

characterised by Robinson et al. (2002). In general, the staining was most intensive in the 

stratum corneum, less prominent in the stratum spinosum and (nearly) absent in the basal cell 

layer. The staining was markedly variable among different sites within the oral cavity (range 

from slight to intensive). High staining intensity was found in the buccal mucosa and the 

upper palate, which is in line with the high activity reported for the dorsal interior (hard 

palate) region by Morrris et al. (2002). Overall the carboxylesterase activity is significantly 

lower in the oral mucosa than in the olfactory epithelium (about 100fold). 

Furthermore, aldehyde dehydrogenase activity is present in the upper gastrointestinal tract. 

Enzyme activities were detected in human mucosa of the gingiva, tongue, oral cavity and 

stomach (Dong et al., 1996, Hedberg et al., 2000, Yin et al., 1997). The aldehyde 
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dehydrogenase activities at 20 mM acetaldehyde were determined to be 169 ±19 and 50.3 

±8.1 nmol/min/g tissue for the gingiva and tongue, respectively (Dong et al., 1996) It is also 

assumed that rats and mice possess aldehyde dehydrogenase activity in the oral cavity. For 

rats, enzyme activity was demonstrated for the stomach, liver, small intestine, large intestine, 

and rectum (Koivisto and Salaspuro (2003), Pronko et al., 2002, Green et al., 2002), but so far 

mouse data on aldehyde dehydrogenase were only available for the forestomach and stomach 

(Green et al., 2002). Determination of enzyme activity using 5 mM acetaldehyde revealed 

lower activity than in the respiratory tract, at least for the rat (Pronko et al., 2002). 

Data on in situ distribution among the different regions and cell layers and data on the 

intracellular localisation of aldehyde dehydrogenase in the upper digestive tract are yet not 

available. No information about the enzymatic activity is available for the oral cavity and 

esophagus. 

The potential of vinyl acetate for reducing the intracellular pH was confirmed in a slice 

preparation of buccal mucosal cells from the mouse (Nakamoto et al., 2005). The pH dropped 

0.35 pH units during a 2.5 min exposure time to a concentration of 1 mM vinyl acetate. While 

no response was seen at 0.1 mM vinyl acetate, dose-dependent reduction in intracellular pH 

occurred at concentrations from 0.3-1 mM (ΔpH ca. 0.1 at 0.3 mM). Interestingly, the extent 

of acidification was greater for isolated single cells of buccal mucosa than for intact 

epithelium. 

In line with the foregoing examinations, none of the oral cancer studies reported that 

cytotoxicity of the surface epithelia of the gastrointestinal tract nor any other organ lesion 

occurred in rats and mice treated with vinyl acetate via drinking water. Measurement of cell 

proliferation in 92-day drinking water studies demonstrated significantly increased 

proliferation rates of oral mucosa cells in rats and mice without any histopathological lesions 

of the surface epithelia (DuPont, 2000, Valentine et al., 2002). 

IIc. Dose-response relationship

There are no data on dose response of effects after oral administration suggestive to be a 

critical cytotoxic step in the tumor development. 

Lesions which accompanied the vinyl acetate-induced tumors in mice receiving vinyl acetate 

by the drinking water for 2 years were basal cell activation, epithelial dysplasia and squamous 

cell hyperplasia of the gastrointestinal tract epithelia (Umeda et al., 2004a). Because of their 

nature it can be supposed that they represent preneoplastic alterations in the sequential 

development to squamous cell papillomas and carcinomas. At some target localisations, these 

lesions were also evident at concentration below tumor-inducing concentrations of 10000 

ppm (see Table 4.1.2.8.C). The lowest dose at which squamous cell hyperplasia of the 

stomach occurred was 400 ppm in the mouse study of Umeda et al. (2004a). The earliest 

changes in the oral cavity were basal cell activation and squamous cell hyperplasia at 2000 

ppm. Mice, which received vinyl acetate via drinking, water for 78 weeks (Maltoni et al., 

1997) showed tumors and dysplastic lesions of the gastrointestinal tract at 5000 ppm (Table 

4.1.2.8.D). Relatively low, but in comparison to the controls elevated incidences of tumors or 

dysplasias were found in some test groups at 1000 ppm but data were inconsistent between 

groups of breeders and offspring. For these groups, it can be argued that the treatment 

duration of 78 weeks was too short and that the treatment-free period until the end of the 

study allowed at least in part recovery from dysplasia and hyperplasia. A clear increase in 
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dysplastic changes was seen at the end of life of rats treated for 104 weeks with drinking 

water containing ≥1000 ppm vinyl acetate (Minardi et al., 2002). 

There seems to be some evidence that a dose-relationship of hyperplastic and dysplastic 

lesions with the tumor growth which started at 2000 ppm in the oral mouse cancer bioassay. 

In the rat, preneoplastic lesions were seen at the same dose which induced a marked increase 

of tumors in the oral cavity (10000 ppm, Umeda et al., 2004a; Table 4.1.2.8.A), but no 

preneoplasias were found at lower dosages. Single squamous cell carcinomas of the oral 

cavity occurred in female rats at the lower doses of 400 ppm and 2000 ppm without being 

accompanied by any other change. Although the incidences of this single tumor are not 

significantly different from control group, the tumors were of the same nature as those seen at 

10000 ppm and could therefore not excluded to be treatment-related. With a conservative 

view, the no-effect level for tumor response was 2000 ppm in mice and no such effect-level 

was derived for the rat, where the lowest concentration tested was the lowest-observed effect 

level of 400 ppm. 

Cell proliferative hyperactivity was a clearly dose-related effect occurring only at high 

concentrations. 2- to 3-fold increases in cell proliferation rates were found in mice after 92 

days of exposure to 10000 or 24000 ppm vinyl acetate compared to control mice (Valentine et 

al., 2002). In rats, cell proliferation was also significantly increased at 24000 ppm. Increase at 

this concentration was lower than in mice (less than 2-fold higher than in control rats) which 

may be attributed to lower doses per g bodyweight in rats (1400 mg/kg bw/d) than in mice 

(2300 or 5300 mg/kg bw/d). 

Increases in proliferation rates were higher in mandibular than in maxillar regions and were 

interpreted to parallel the tumor outcome (Umeda et al., 2004a). Also, the distribution pattern 

might be reflective for the normal proliferative activity which was shown to be highest in the 

floor of mouth and ventral tongue of samples from healthy humans (Thomson et al., 1999). 

The incidence of oral cavity neoplastic lesions was reported to be higher in the lower jaw than 

the upper jaw either in rats and mice and the incidence of these oral cavity lesions was about 

3-fold in mice compared to rats. Although hydrolytic activity was 2-15-fold higher in 

homogenated mucosa from the dorsal interior region than in other regions (Morris et al., 

2002), the prevalence of tumors in the lower jaw can be explained by gravity-related exposure 

of the lower jaw regions during feed consumption. In addition, the metabolic activity of 

homogenated tissues may not correctly reflect the in situ activity. 

The effective tumor doses of vinyl acetate doses appeared high for the oral route compared to 

the tumor effective concentration of the inhalation route. This may be discussed as related to 

relatively low vinyl acetate hydrolytic activity in the oral cavity, which was 100-fold less than 

those in nasal tissue homogenates. 

The highest concentrations/dosages chosen in the studies available were considered not to 

exceed the maximal tolerated dose (MTD) (cf. Appendix Vinyl Acetate_MTD_0209). 

Unspecific signs of toxicity such as reduction of body weight gain were attributable to lower 

water consumption (where measured) and/or feed consumption (secondarily to the low water 

uptake?), as no indications on target organ toxicity or other signs of systemic toxicity were 

identified. 
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IId. Temporal relationship

As no underlying toxic event was evident in oral studies, and none of the cancer studies 

contained interim sacrifice groups, no data are available to give information on the 

temporality of sequential steps for tumor development based on cytotoxicity as the initial 

step. The appearance of mitogenic effects after 92-days of drinking water is assumed to be a 

precursor event in tumor development (DuPont, 2000). The relatively small increase of 

proliferative index was interpreted as well corresponding to the long latency period of tumor 

development. 

IIe. Strength, consistency, specificity of association

In contrast to the mode of action postulated, the evidence of basal cell activation observed at 

several sites of the gastrointestinal tract and increase in cell proliferation in oral cavity 

mucosa gave arguments for that the development of tumors was preceded by increased 

proliferative activity of basal epithelial cells without any cell death preceding. The normal 

differentiation and maturing of cells was replaced by dysplastic and metaplastic changes 

representing intermediate stages of tumor development. This observation and the absence of 

preceding cytotoxicity does not support the postulated a cytotoxicity-related mode of action. 

IIf. Biological plausibility and coherence

Hyperproliferation may be associated to inflammation and cell death of superficial epithelial 

cells in spontaneous human diseases or in rodents exposed to xenobiotica. This general 

assumption is insufficient to proof that vinyl acetate carcinogenesis needs such toxic 

precursor stages. 

At 10000 ppm vinyl acetate, higher tumor incidences in the oral cavity in mice than in rats 

parallels the higher cell proliferative activity in mice (Valentine et al., 2002). 

IIg. Inconsistency, uncertainties and data gaps

Overall, the database for the oral route is less than for the inhalation route. 

The oral carcinogenicity studies did not give any hint for cytotoxicity as a first step of tumor 

development. Additionally, none of the short and medium term oral studies in rats neither the 

90-day drinking water studies in rats and mice demonstrated irritative/toxic effects on the 

gastrointestinal tract epithelium. 

The test substance administered in positive oral cancer studies contained impurities, which 

were suspected to contribute to carcinogenesis. The test substance of Japanese oral cancer 

study contains 5 ppm hydroquinone, a metabolite of benzene, which was shown to increase 

tumor rates in the kidney of male F344 rats, the incidences of mononuclear cell leukemia in 

female F344 rats, and of hepatocellular tumors in female B6C3F1 mice (Kari et al., 1992). 

The test substance of the Maltoni study (Maltoni et al., 1997) contained benzene (30-45 ppm) 

methyl and ethyl acetate (50 ppm) crotonaldehyde (6-16 ppm), acetaldehyde (2-11 ppm). 

acetone (330-500 ppm). At least the tumors of the Zymbal glands observed in the Maltoni 

study may be discussed to be associated to the benzene impurity (Maltoni et al., 1989, NTP, 

1986, Huff et al., 1989). However, the concentrations of impurities were extremely low to 

support this assumption. 
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The higher tumor incidences in mice than in rats, both exposed to a concentration of 10000 

ppm, were neglected if the intake of vinyl acetate per kg bodyweight was calculated 

(Valentine et al., 2002). Although tumor rates should be expected to mirror the vinyl acetate 

concentration, an explanation for the species differences could not yet be given (e.g., due to 

lack of data on aldehyde dehydrogenase activity).

Nakamoto et al. (2005) stressed the importance of intracellular acidification for the induction 

of the mitogenic response conferring the vinyl acetate-related cell proliferation to those 

observed in the gastrointestinal reflux disease (Barrett’s oesophagus). Whether the excess 

drop of pH seen in Barrett’s disease could be transferred to vinyl acetate exposure remains 

speculative due to the little reduction in intracellular pH. 

IIh. Actual considerations on the assessment of mode of action for tumors of the 

gastrointestinal tract

Based on the actual information, the assumption of cytotoxicity-mediated carcinogenicity of 

vinyl acetate was considered not to be plausible for the gastrointestinal tract. Up to now, the 

link between observed cytotoxicity and tumors in the gastrointestinal tract of animal studies 

supporting the postulated mode of action is missing. Therefore, the contribution of other 

mode of actions has to be considered. Although the overall database is much less than for the 

inhalation route there are similarities among the tumor sites. 

Acetaldehyde is the critical metabolite with a carcinogenic potential. 

Although carboxylesterase activity is low in the epithelium lining of the gastrointestinal tract, 

acetaldehyde is thought to be significant for tumor development. The high test concentrations 

needed to induce tumor response are thought to be reflective of the low hydrolytic activity. 

 A thresholded mode of action is assumed to be active in the tumor development in the 

gastrointestinal tract. 

- Vinyl acetate is hydrolysed by the mucosal carboxylesterase to acetic acid and 

acetaldehyde. 

- Due to the fact that cytotoxicity could be ruled out as a precedent lesion and considering 

that the metabolism is in principle comparable to the nasal regions the pathways of tumor 

development in the upper gastrointestinal tract is expected to be comparable to the nonolfactory (respiratory) regions. 

- Acetaldehyde is oxidised by aldehyde dehydrogenase. The enzyme activity will be high 

enough for the oxidation of the physiological concentrations of acetaldehyde. As 

significant increases in tumor response were seen at rather high concentrations of vinyl 

acetate (10000 ppm for rat and mouse (Umeda et al., 2004a), ≥5000 ppm for mice 

(Maltoni et al., 1997, 1000 ppm for the rat (Minardi et al., 2002)) enzyme activity might 

cope for the low concentrations of produced acetaldehyde without any harmful effect on 

cell viability and integrity. However, it is unlikely that there is enough activity for 
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effective acetaldehyde oxidation at higher concentrations of vinyl acetate; and 

acetaldehyde may accumulate. 

- Accumulated acetaldehyde produces genotoxic effects. 

- High concentrations of vinyl acetate are mitogenic. A dose-related increase of cell 

proliferative activity increased dose-related above 10000 ppm in mice (≥2300 mg/kg 

bw/d), no effect was seen at 5000 ppm. In rats, a less than 2-fold increase in proliferative 

activity was observed at 24000 ppm in rats (1400 mg/kg bw/d). 

- Cytotoxicity was not obvious up to tumor-inducing concentrations and therefore could be 

ruled out as a precedent change in the tumor development. The cleavage product acetic 

acid is also discussed to induce intracellular acidification. A reduction of intracellular pH 

was also seen for buccal mucosa. As for the nasal mucosa the extent of pH-reduction is 

low, which raises the question on the significance of this low range shift in intracellular 

pH. 

- The exact concentration of vinyl acetate where production of acetaldehyde and its 

removal starts to be imbalanced could not be estimated by data available. It is therefore 

proposed to select the most sensitive biological effect with putative toxicological 

relevance as a starting point to estimate a threshold. Since no clear NOAEL could be 

determined from the carcinogenicity studies, the vinyl acetate concentration (400 ppm) 

inducing the single tumors in the rat oral cavity were chosen as the LOAEL. 

Conclusion:

In animals, long-term inhalation and oral administration of vinyl acetate produce tumors at 

the primary site of exposure, the surface epithelium of the respiratory tract and of the upper 

gastrointestinal tract. There was no indication on systemic toxicity on any other organ or 

tissue outside the administration routes. Tumors observed in other organs following oral 

uptake could not clearly be attributed to vinyl acetate administration. 

Experience from human exposure did not give indication that vinyl acetate exposure was 

associated to increased tumor rates. 

Based on animal data a clear tumor response to vinyl acetate exposure was seen at 600 ppm 

(rat, Bogdanffy et al., 1994b) for the inhalation route; for the oral route a marked increase of 

tumor rates has been observed at 1000 ppm (rat (offspring); 70 mg/kg bw/d, Minardi et al., 

2002), at 5000 ppm (mouse; 750 mg/kg/day, Maltoni et al., 1997) and at 10000 ppm (male rat 

442 mg/kg bw/d, female rat 575 mg/kg bw/d, Umeda et al., 2004a). Due to limitations in the 

study design in the studies of Maltoni et al. and Minardi et al., the study of Umeda is 

considered of higher predictivity. For lower doses, there is concern that occasional findings of 

tumors of the same types that have been observed at high doses and which might also be 

related to vinyl acetate exposure. Thus, the lowest concentration suspected to be carcinogenic 

was 200 ppm for the inhalation route (LOAEC) and 400 ppm for the oral route (LOAEL, 

male rat 21 mg/kg bw/d, female rat 31 mg/kg bw/d, Umeda et al., 2004a). Clearly tumor free 

dosages were not established in carcinogenicity studies for the oral route, since 400 ppm were 

the lowest concentrations tested. Subchronic inhalation studies did not reveal any indication 

on proliferative response at concentrations of 50 ppm, and this concentration was verified in 
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carcinogenicity studies. Therefore the concentration of 50 ppm is considered as NOAEC for 

risk characterisation on carcinogenicity via inhalation. For the oral route, no NOAEL was 

estimated, 400 ppm (21 mg/kg bw/d male rat, 31 mg/kg bw/d female rat) is proposed as 

LOAEL for the risk characterisation. 

Table 4.1.2.8.L: Effective concentrations for toxic and proliferative responses to vinyl acetate 

at tumor sites 

Target tissues Upper respiratory tract Upper digestive tract

Effect Olfactory region Other non-olfactory 

regions 

Cytotoxicity 

Epithelial 

degeneration/necrosis

/atrophy 

Rat ≥200 ppm*

Mouse ≥200 ppm* 

Rat 1000 ppm ** No indication of 

cytotoxicity up to 

24000 ppm*** 

No-adverse-effect 

concentration for 

toxic effects 

Rat ≥50 ppm*

Mouse ≥50 ppm* 

Rat 600 ppm* 

Mouse 600 ppm* 

Rat 24000 ppm#

Mouse 24000 ppm#

Preneoplasias and Neoplasias 

Hyperplasias 

Metaplasias 

Rat ≥200 ppm* 

Mouse ≥200 ppm* 

Rat ≥1000 ppm** 

Mouse ≥600 ppm* 

Mouse ≥2000 ppm##

Weak or questionable 

tumor response 

Rat ≥200 ppm* Rat ≥400 ppm## 

Mouse 2000 ppm##

Clear tumor response Rat ≥600 ppm* Rat ≥600 ppm* Rat 10000 ppm##

Mouse ≥5000 ppm###

Concentration without 

tumor response 

Rat 50 ppm* 

Mouse 600 ppm* 

Rat 200 ppm* 

Mouse 600 ppm* 

 Rat LOAEC 400 ppm#

Mouse 2000 ppm###

*Bogdanffy et al., 1994b **Bogdanffy et al., 1997 #DuPont, 2000 ## Umeda et al., 2004a###Maltoni et al., 1997 

In conclusion, vinyl acetate exposure produced tumors at the site of first contact along the 

exposure routes. A thresholded mode of carcinogenic action is thought to be active. The 

observed tumor responses are reflecting the target site-specific enzyme activities: 

Following inhalation and oral exposure vinyl acetate is rapidly hydrolysed by 

carboxylesterases leading to the formation of acetic acid and acetaldehyde which is further 

converted into acetic acid in the presence of aldehyde dehydrogenases. Intracellular aldehyde 
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dehydrogenase activity is limited, at higher concentrations of vinyl acetate it will not be 

sufficient for the oxidation of generated acetaldehyde. Thus, at high vinyl acetate 

concentrations non-physiologically high concentrations of acetaldehyde are produced. 

Acetaldehyde is a physiological intermediate with low background concentrations. Its adverse 

effects (genotoxicity and mutagenicity) are limited to non-physiologically high 

concentrations. Therefore, a threshold mode of action is assumed for vinyl acetate. 

Above threshold concentrations, cytotoxicity (only at the olfactory mucosa), mitogenic 

actions and genotoxic actions occurred. 

Cytotoxicity mainly contributed by acetic acid is the earliest lesion in the olfactory mucosa. 

Next stages in the continuum to tumor development include the responsive restorative cell 

proliferation and simultaneously occurring genotoxic effects of acetaldehyde. 

Increased cell proliferative activity was observed at high concentrations of acetaldehyde or 

vinyl acetate. Its occurrence was not linked to cell toxicity as a precondition. 

Data on vinyl acetate are in line with the idea that vinyl acetate genotoxicity is mediated by 

acetaldehyde. Increasing concentrations of acetaldehyde produce genotoxic actions at the site 

of contact. It has to be taken into consideration that acetaldehyde occurs naturally in 

mammalians cells and is part of the physiological cellular metabolism. 

The systemic bioavailability of vinyl acetate or its metabolite is low (cf. 4.1.2.1). In vivo 

genotoxicity tests showed that systemic genotoxicity appears to be limited to toxic doses. This 

is in line with the absence of systemic carcinogenic effects. 

The threshold concentration leading to acetaldehyde accumulation could not yet be estimated. 

Using in vitro test systems as a surrogate for a site of contact model, in vitro data for several 

genotoxic endpoints are suggesting for a threshold concentration above which acetaldehyde 

exerts its genotoxic action. A NOAEC of 0.1 mmol/l for chromosomal aberrations and 0.03 

mmol/l for SCE was determined. Since for the in vivo situation no biomarker for the 

limitation of acetaldehyde oxidation is available, it is proposed to use the identified NOAEC, 

respectively the LOAEL from the most sensitive biological effects as a surrogate to derive a 

threshold concentration for risk characterisation purposes. 

Overall, it is considered that the critical events in vinyl acetate carcinogenesis do fit to the 

criteria for the exceptional cases where genotoxic action is thought to be thresholded7

. 

 

7

 Technical Guidance Document on Risk Assessment, Human Health Risk Characterisation, revised chapter, 

4.13.3 

There are two general cases where mutagenicity may be shown to have a threshold: (1)... does not apply 

here.(2) where the toxico-kinetic considerations clearly demonstrate that mutagenic metabolites will only be 

produced in vivo at very high exposures to the parent substance which are unlikely to be achieved in realistic 

human exposure scenarios. For example, where the active metabolite is only produced by a metabolic pathway 

that occurs when other preferential pathways are saturated, or where there is very rapid removal of the active 

metabolite by conjugation or detoxification, such that no biological significant amounts reach the DNA in vivo, 

except when these pathways are overwhelmed. 
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From animal data it is concluded that vinyl acetate might pose a cancer risk for humans 

exposed to the substance via the inhalation or oral route. Carcinogenicity is thought to act via 

a secondary mechanism and the concern may be relevant above threshold concentrations. 

The observed effects are thought to be relevant for the human. For the respiratory tract 

humans may be less sensitive than the rat due to a lower carboxylesterase activity in the nasal 

mucosa. 

Classification 

According to the EU criteria for classification vinyl acetate is proposed to be classified as a 

Carcinogen, Category 3 and labelled as Harmful, Xn, R 40. 

Justification: 

- There is no adequate database on humans.

- Relevant cancer studies for the classification proposal were Owen (1988), Bogdanffy et 

al. (1994b), Umeda et al., (2004a), Minardi et al. (2002) and Maltoni et al. (1997). Test 

concentrations in these studies did no exceed the MTD (cf. Appendix Vinyl 

Acetate_MTD_0209). 

- Vinyl acetate was carcinogenic in two animal species each at both sexes. 

- Carcinogenic potential was demonstrated for two administration routes: inhalation and 

oral. 

- Vinyl acetate was carcinogenic at the site of first contact, the surface epithelium along the 

exposure routes. 

- Spontaneous rates of nasal tumors and epithelial tumors from the upper and lower airways 

and from the upper gastrointestinal tract in the test species used are known to be very low. 

- All target organs of tumor development were considered to be relevant for humans. 

- No species-specific mode of action for vinyl acetate carcinogenesis was identified. 

- The carcinogenic effect of vinyl acetate is thought to be related to genotoxic activity of 

the metabolite acetaldehyde. Comparable tumor findings and genotoxicity data from 

acetaldehyde support this assumption. 

- A threshold mechanism is thought to be active. Tumor development is reflecting the target 

site-specific enzyme activities involved in the hydrolysis of vinyl acetate and the 

metabolism of acetaldehyde. At higher concentrations the enzyme activities will not be 

high enough for the oxidation of generated acetadehyde. Then acetaldehyde accumulates 

intracellularly and is causing increased cell proliferative activity, increased DNA adduct 

formation and DNA damage (clastogenicity). Cell proliferative activity of acetaldehyde 

and DNA adduct formation are only active above certain (threshold) concentrations. 
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- As for acetaldehyde, mitogenic action was seen at high local concentrations of vinyl 

acetate. 10000 ppm or higher concentrations of vinyl acetate produced proliferative 

hyperactivity in mice whereas no such effect was observed at concentrations up to 5000 

ppm. The exact mechanisms how the mitogenic response is initiated are unknown. 

- Cytotoxicity was assumed as one contributing mode of carcinogenesis in the olfactory 

mucosa diminishing the resistance of the olfactory mucosa due to its site-specific high 

carboxylesterase activity and the low aldehyde dehydrogenase activity. The assumption 

was thought to be supported by consistent dose-response and time-response relationships 

between cytotoxic effect and tumor growth. 

- In the olfactory epithelium a multistage hypothesis of carcinogenesis is likely to be based 

to initial cytotoxicity, responsive cell proliferation and associated with genotoxic action of 

its metabolite acetaldehyde. 

- For the other tumor sites, the non-olfactory (respiratory) epithelium as well for the 

mucosa of the upper gastrointestinal tract, concentration-dependent increased cell 

proliferation coupled with the genotoxic action of acetaldehyde at high concentrations of 

acetaldehyde were assumed to result in tumor development. 

- For the inhalation route, cytotoxicity in the olfactory mucosa is thought to be the most 

sensitive effect related to the tumor response and is therefore taken for quantitative risk 

assessment. Cytotoxicity and related reparative cell proliferation are assumed to be early 

events in the tumor development in this region. A NOAEC (50 ppm) established for the 

cytotoxic effects in the olfactory mucosa is proposed to be used as a threshold 

concentration. For the oral route, the lowest tumor dose (400 ppm corresponding to 21 

mg/kg bw/d) is proposed as basis to calculate a threshold concentration. 

In September 2007 the TC C&L agreed on Carc. Cat. 3; R40. 

4.1.2.9 Toxicity for reproduction 

Animal data:

Fertility impairment

Groups of male and female Crl:CD(SD) rats were administered vinyl acetate in drinking 

water at nominal concentrations of 0 (control), 200, 1000 or 5000 ppm v/v (equivalent to 

about 20, 100, or 500 mg/kg bw/d, calculated on an assumed water consumption of 10% of 

body weight) over two generations. The test solutions were freshly prepared daily and overformulated by 5% to correct for vinyl acetate losses over 24 hours. F0 rats (18 males and 36 

females per dose group) received vinyl acetate for 70 days prior to mating and the treatment 

continued throughout gestation and lactation. From the first litters groups of 25 male and 25 

female pups (F1) were selected. They continued to receive vinyl acetate for 70 days after 

weaning and were then allowed to mate within their groups to produce the second generation 

(F2). The study was terminated following weaning of the F2 litters. 
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The reproductive performance of the F0 and F1 animals was evaluated from indices which 

included litter number, viability and size. Weights of the F1 and F2 pups were recorded from 

birth to weaning (on lactation days 1, 7, 21) as were developmental and functional parameters 

(on lactation day 21). Post-mortem examinations were carried out on the F0 and F1 parental 

animals and on 10 male respectively female pups from each group of the F1 and F2 litters. 

Neither clinical abnormalities nor treatment-related mortality was observed in any of the 

groups. Water consumption was significantly reduced in the 5000 ppm groups in the F0 and 

F1 generations and in the 1000 ppm females. This was associated with significantly reduced 

body weight gain during lactation in the F0 females at 5000 ppm and in the F1 females at 

5000 and 1000 ppm. Pup weights in the F1 generation, but not in the F2 generation were 

statistically significantly lower at 5000 ppm than those of controls when evaluated on 

lactation day 21. No effects were observed in the reproductive performance of the F0 animals, 

but the mating of the F1 animals resulted in a lower number of pregnancies in the 5000 ppm 

group (19/24) compared with controls (24/25) leading to a reduced number of litters. The 

difference was slight and not statistically significant, however the effect was attributed to 

lower fertility. Therefore an additional cross-mating trial of control and 5000 ppm male and 

female rats of the F1 generation was performed. Fewer pregnancies occurred when the control 

females were mated with the 5000 ppm males resulting in a mating index of 76% and a 

fertility index of 100% indicating that the lower numbers in pregnancies were rather 

attributable to poor mating than to impaired fertility. No decrease was apparent when the 

5000 ppm females were mated with the control males. All other observations, including those 

made at necropsy and subsequent histopathological examinations showed no adverse effects 

due to vinyl acetate. There were no compound-related testicular changes evident in this study. 

In summary, no effects were seen on reproductive performance, or on the resulting litters of 

male and female rats exposed to 200 or 1000 ppm vinyl acetate in drinking water. At 5000 

ppm a lower number of females became pregnant, although cross-mating studies suggested 

that the effect, which was marginal and not statistically significant, was associated with male 

reproductive performance. Effects on litters of animals exposed to vinyl acetate were confined 

to the 5000 ppm group of the F1 pups only, were a significant reduction in weight gain was 

observed on lactation day 21. No such effect was observed for the F2 pups. The lower weight 

gain at weaning of the F1 pups was associated with significantly reduced water consumption 

and body weight gain of their mothers during the lactation period. Under the conditions of the 

study, the NOAEL was considered to be 1000 ppm (Mebus et al., 1995). 

In hybrid (C57Bl/6JxC3H/He) F1 male mice, intraperitoneal injections of 125, 250, 500, 750, 

or 1000 mg/kg bw (vinyl acetate dissolved in olive oil) on 5 consecutive days resulted in 80 

respectively 100% mortality at the 750 and 1000 mg/kg dose level and in a dose-related loss 

of body weight and a dose-dependently reduced regain in body weight during the injection 

period at the lower dose levels. From these generally toxic dose levels reduced mean relative 

testicular weight was observed at the 125 and 500 mg/kg dose levels, however not at the 250 

mg/kg dose level, as well as sperm abnormalities at the dose level of 500 mg/kg bw. 

Epididymal sperm counts at 5 weeks after treatment amounted to 5.60 + 0.51, 5.58 + 1.38, 

6.17 + 1.03, and 4.10 + 1.80 millions/ml for the control, 125, 250, and 500 mg/kg dose groups 

(Lähdetie, 1988). 

Developmental toxicity
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Groups of 23 mated female Crl:CD(SD)BR rats were given vinyl acetate in drinking water 

(Hurtt et al., 1995, Irvine, 1980) from day 6 to day 15 of gestation at nominal concentrations 

of 0 (control), 200, 1000, or 5000 ppm (about 0, 25, 100, or 500 mg/kg bw/d). The test 

solutions were freshly prepared daily and over-formulated by between 7 and 10% to correct 

for vinyl acetate losses over 24 hours. On day 20 of gestation terminal examination of the 

dams and their uterine contents was conducted. 

There were no statistically significant differences between treated and control groups of 

animals in appearance, behaviour or pregnancy index. Initially, there was a slightly reduced 

intake in food and water associated with slight retardation of body weight gain in the 5000 

ppm group; the statistically significant lowered water intake was assumed to reflect the bad 

palatability of the vinyl acetate water solution. No changes attributed to treatment were 

observed in the post mortem examinations of the dams or in the examination of fetal 

parameters including the total incidence of abnormalities. It was concluded that the 

administration of vinyl acetate in drinking water at doses up to 5000 ppm v/v, a dose which 

resulted in slight maternal toxicity, was not embryotoxic or teratogenic in the rat. 

Groups of 24 mated female Crl:CD(SD)BR rats were exposed to vinyl acetate vapours (Hurtt 

et al., 1995) from day 6 to day 15 of gestation at concentrations of 0 (control), 50, 200, or 

1000 ppm (equivalent to about 100, 205, and 1025 mg/kg bw/day, based on a respiratory rate 

of 0.8 l/min/kg for rats) for 6 h/d. At 1000 ppm, severe maternal toxicity (marked reduction in 

body weight gain, congestion of the lungs) and some signs of fetotoxicity occurred. Fetal 

toxicity was evident by a statistically significant decrease in mean fetal weight and mean 

crown-rump length in the fetuses of the 1000 ppm group. In addition, there was a statistically 

significant increase in the incidence of minor skeletal alterations (mainly delayed ossification) 

in fetuses from dams exposed to 1000 ppm. In summary, vinyl acetate did adversely affect 

both the dam and the conceptus at an inhaled concentration of 1000 ppm, but not at lower 

exposure levels. The NOAEC for the inhalation study was considered to be 200 ppm. 

Human data:

No data available. 

Summary for toxicity of reproduction 

Vinyl acetate has been investigated in rats for adverse effects on reproductive performance 

and fertility via the oral (drinking water) route of exposure and in mice for adverse effects on 

male reproductive organs via the i.p. exposure route. Vinyl acetate was shown to reduce 

testicular weight and to induce sperm abnormalities in mice, however at toxic dose levels 

inducing mortality and body weight loss. Vinyl acetate was further shown to have marginal 

influences on reproduction at oral exposure levels that lead to significantly reduced water 

intake (probably due to palatability) associated with significantly reduced body weight gain. 

The observed effects comprised reduced pup weights and slightly lower numbers of 

pregnancies. Distinct reproduction related adverse effects of vinyl acetate were not evidenced 

from a two generation study with rats for drinking water concentrations of up to and including 

1000 ppm. 

The developmental toxicity of vinyl acetate has been investigated in rats via oral (drinking 

water) and inhalation exposure routes during organogenesis. No embryo/fetotoxic or 
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teratogenic effects were observed for the oral route of administration at drinking water 

concentrations of up to and including 5000 ppm. Fetotoxic effects, revealed during inhalation 

exposure, were confined to high dose levels only, where severe maternal toxicity was 

observed. However, vinyl acetate did not adversely affect both the dam and the conceptus at 

an inhaled concentration of up to and including 200 ppm. 

A NOAEL/fertility of 1000 ppm (equivalent to dosages of about 100 mg/kg bw/day) was 

derived from a study with oral exposure, and a NOAEC/developmental toxicity of 200 ppm 

(equivalent to dosages of about 205 mg/kg bw/day) was derived from a study with inhalation 

exposure. 

Comment: 

In Germany, vinyl acetate is assigned to the MAK-pregnancy category "D" denoting that the 

current database is not sufficient for final evaluation of developmental toxicity. However it is 

outlined that vinyl acetate was evaluated for reproductive toxicity in one species (rat) already 

with negative results. If this latter outcome could be verified in additional species vinyl 

acetate could be assigned to category "C" denoting that no risk for adverse developmental 

effects have to be expected for female workers in compliance with the respective MAK value 

of 10 ppm. 
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4.1.3 Risk characterisation 

4.1.3.1 General aspects 

Following oral and inhalation exposure of rats vinyl acetate is rapidly hydrolysed by 

carboxylesterases leading to the formation of acetic acid and acetaldehyde the latter of which 

is further converted into acetic acid by aldehyde dehydrogenases. 

The in vivo uptake of vinyl acetate was measured in the isolated upper respiratory tract of rats 

(anaesthetised rat, unidirectional flow, 1 h-exposure). Disappearance of vinyl acetate from the 

airstream was highest at the lowest exposure concentrations. Greater than 94% extraction was 

observed at vinyl acetate exposure concentrations of 76 ppm or below. With increasing 

exposure concentration (76 to 550 ppm), extraction decreased progressively to about 40% and 

remained at this level up to concentration of approximately 2000 ppm. The impact on bloodflow extraction on vinyl acetate deposition has been calculated by simulating vinyl acetate 

exposure in the absence of carboxylesterase activity. It could be demonstrated, that blood 

flow extraction accounts for less than 15 % of total vinyl acetate deposition. Hence, 15 % 

inhalative uptake can be taken forward to risk characterisation of systemic effects by 

inhaltional exposure as a worst case scenario. 

After oral administration of 297 mg/kg/bw 14C vinyl acetate, 63 % of the applied radioactivity 

was excreted as metabolites in exhaled air, urine and faeces. Based on the fact that vinyl 

acetate can be metabolized in the upper GI tract epithelium it can be assumed, that a 

considerable extent of metabolism takes place presystemically which is supported by an oral 

PBPK model. This model led to the conclusion, that clearance of vinyl acetate and its 

metabolites into the systemic circulation would be negligible. Hence, 63 % absorption would 

represent an overestimation of systemically available amounts of vinyl acetate. However, the 

PBPK model developed for oral vinyl acetate exposure did not include systemic components 

and furthermore, the model was developed in the absence of valid data for carboxylesterases 

in animal and human tissues. Based on the fact, that carboxylesterase activity in the GI tract is 

lower compared to that in nasal tissues, 50 % absorption can be assumed as a worst case for 

systemically available amounts of vinyl acetate after oral uptake. However, no clear 

assumptions can be made for systemically available metabolites of vinyl acetate 

(acetaldehyde, acetic acid). 

There are no valid quantitative data on the systemic bioavailability of vinyl acetate and its 

metabolites following dermal exposure. However, based on an acute dermal study in rabbits 

and based on the fact that carboxylesterase activities are lower in skin compared to nose or 

oral cavity, it can be assumed that systemic bioavailablility of vinyl acetate and/or vinyl 

acetate-derived metabolites is higher after dermal exposure when compared to oral or 

inhalative exposure. Based on the currently available data 90 % dermal absorption should be 

taken forward to the risk characterisation. 

Research on human and rat nasal respiratory and olfactory tissue with whole turbinates in 

vitro has shown that rat nasal respiratory carboxylesterase activity was about 3-fold higher 

than those of humans. Rat respiratory aldehyde dehydrogenase activity was about twice that 

of humans. Activities of the rat olfactory enzymes (carboxylesterase and aldehyde 
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dehydrogenase) were about equivalent to those of humans. The Km values for both enzymes 

are not different between the two species. Aldehyde dehydrogenase activities determined in 

whole nasal tissue homogenates from mouse, rat, hamster and guinea pig showed significantly 

different ratios Vmax/Km for the various species indicating the existence of species differences. 

To provide validation data for the application of a physiologically based pharmakokinetic 

(PBPK) model in humans, controlled human exposures to vinyl acetate concentrations of 1, 5 

and 10 ppm were conducted (5 volunteers). Data from ion trap mass spectrometry 

measurements of labelled vinyl acetate and labelled acetaldehyde were compared with the 

predictions of the human nasal model. For the vinyl acetate data a good fit was demonstrated 

(r = 0.9). The quality of the acetaldehyde data fit is less (r = 0.6) than that of vinyl acetate. 

The results show that the human nasal model predicts the experimental observations with 

regard to vinyl acetate concentrations and the acetaldehyde washout in the airstream of human 

nasopharyngeal cavity in a concentration range from 1 to 10 ppm. Uncertainties of the model 

consist in the enzyme kinetic data used to parameterise the model. Nevertheless, according to 

the sensitivity analysis the modelled data can be taken for risk characterisation. 

The results of PBPK modeling are taken forward for consideration on the appropriate 

adjustment factors. As vinyl acetate is acting locally, a systemic metabolism has not to be 

considered which reduces the interspecies factor from 10 (default) to 2.5. Remaining 

uncertanties in toxicodynamic differences are recognized, i. e. humans could be more 

sensitive than rats towards local toxicity of vinyl acetate metabolites which could not be 

excluded due to the lack of (primarily human) data. Thus, for risk charaterization an 

interspecies adjustment factor of 2.5 is established. Concerning intraspecies variability the 

same consideration as for interspecies extrapolation applies. No systemic metabolism has to 

be taken into consideration, reducing the intraspecies adjustment factor to 2.5. 

Vinyl acetate exhibits low acute toxicity by the oral and dermal routes, but acute inhalation 

toxicity is to be classified as harmful according to EU criteria. The oral LD50 for rats is found 

to about 3500 mg/kg body weight. Acute dermal toxicity is reported for rabbits to exceed 

7400 mg/kg. However, acute inhalation toxicity is characterised by a LC50 value of 15.8 

mg/l/4 hours for rats. In a scarcely documented study an LC50 value of 14.1 mg/l/4 hours is 

mentioned. 

Except a general notice from occupational use no substantiated human data on 

irritation/corrosion caused by vinyl acetate are available. The pure substance shows mild 

irritation to skin and eyes. Acute inhalation tests with rats demonstrated severe irritation to 

the respiratory system (R 37). Vinyl acetate does not show corrosive properties after a single 

skin contact of not more than 4 hours. 

There is no information available on skin sensitization in humans. No cases of sensitization 

from the handling of vinyl acetate in the workplace have been reported in the last years. There 

are no reports on allergic contact dermatitis by vinyl acetate from routine patch testing or 

experimental studies in man. Results from an animal skin sensitization study (Buehler Test) 

showed a moderate skin sensitizing potential of vinyl acetate (commercial grade). In a Local 

Lymph Node Assay an increased stimulation index was determined with 5 and 10 % vinyl 

acetate solutions but not at higher concentrations. Thus, vinyl acetate is not devoid of a skin 

sensitising potential. However, the phrase R 43 is not warranted. 

Direct information on respiratory sensitization from studies in humans is lacking. 
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The major toxic effects after prolonged inhalation of vinyl acetate in experimental animals 

were lesions of the surface epithelium of the upper and lower respiratory tract. Degeneration, 

regenerative/reparative processes, inflammation, hyperplasia and metaplasia were noted in the 

nasal mucosa. They were most pronounced in the olfactory epithelium occurring at 200 ppm 

in rats and mice during and at the end of a 2-year exposure period. Lesions of the respiratory 

epithelium were seen in mice exposed to 600 ppm during and at the end of 2 years, whereas 

rats demonstrated lesions at this site only at a high concentration of 1000 ppm (4 week study). 

Characteristic alterations of the larynx and trachea of mice in the 600 ppm groups were 

hyperplasia and metaplasia along with desquamation and fibrosis in the trachea. Similar 

changes of the bronchial and bronchiolar airways were reported for rats and mice at this 

concentration at the end of the 2-year exposure period. In addition, clinical signs of nonspecific toxicity and irritation were evident, but no relevant toxic effect on any organ could be 

identified. From the 2-year studies, the NOAEC for local toxic effect on the respiratory tract 

was 50 ppm (178.5 mg/m3) in rats and mice. Based on growth retardation in rats of the 600 

ppm groups and mice of the 200 ppm groups, the NOAEC for systemic toxicity was 

considered to be at 50 ppm (mice 178.5 mg/m3

). 

No specific organ toxicity was recorded after repeated oral administration of vinyl acetate 

with drinking water to rats and mice. A subchronic 13-week study revealed a slight (nonsignificant) reduction of food consumption and growth retardation in male rats at 5000 ppm 

(684 mg/kg bw/d). As NOAEL for systemic effects the value of 684 mg/kg bw/d (male rat) 

will be used in the risk characterisation. 

Vinyl acetate is negative in bacterial mutagenicity tests. 

In mammalian cell cultures various cytogenetic effects were induced in the absence of S-9 

mix (chromosomal aberrations, micronuclei, SCE) and in the presence of S-9 mix (SCE; 

chromosomal aberrations and micronuclei not analysed with S-9 mix). The lowest positive 

concentrations ranged from 0.1 to 0.2 mmol/l. A positive mouse lymphoma assay is in line 

with these results, but it cannot be deduced whether the positive effect is due to chromosomal 

or to gene mutations (no colony sizing). Mammalian cell culture investigations on DNA 

strand breaks (DSB) and DNA protein corsslinks (DPX) were negative (DSB), or extremely 

high concentrations were needed for positive effects (DPX). 

Very few reliable data are available on the in vivo mutagenicity of vinyl acetate. A weak 

induction of micronuclei in mouse bone marrow cells was clearly limited to intraperitoneal 

doses in the LD50 range (1000 and 2000 mg/kg). In rats no induction of micronuclei was 

observed in spermatids (screening assay with intraperitoneal doses up to 1000 mg/kg). Further 

tests on induction of micronuclei or chromosomal aberrations were of too low reliability. 

Also in an SCE test with rats positive effects were weak and limited to high and probably 

highly toxic intraperitoneal doses (370 and 470 mg/kg). Such weak increases in SCE 

frequencies may well be induced by unspecific effects on the cell cycle. 

No specific DNA binding was observed in rat livers after inhalation or oral administration. 

Induction of sperm abnormalities in mice again was limited to doses in the toxic range. 

Furthermore, it is not specific for mutagens. 

No clear conclusion can be drawn from a human study on the possible induction of 

chromosomal aberrations in workers exposed to vinyl acetate. 
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Genotoxicity data on vinyl acetate metabolites are in line with the hypothesis that vinyl 

acetate genotoxicity is mediated by acetaldehyde. The genotoxicity of acetaldehyde is 

possibly limited to an overloading of defence mechanisms. 

Altogether, vinyl acetate has a mutagenic potential, which is preferentially expressed as 

clastogenesis. The data on in vivo genotoxicity are difficult to interpret, since their majority is 

of low reliability, or the effects are not specific to mutagenicity. The most important effect, a 

weak induction of micronuclei in mouse bone marrow, is limited to intraperitoneal doses of 

high toxicity. Therefore, it is unlikely that the genotoxic potential of vinyl acetate is expressed 

in germ cells in man. However, genotoxic effects locally in directly exposed tissues (site of 

first contact) cannot be excluded; the occurrence and strength of the effects will be dependent 

on the metabolic capacity of the directly exposed tissue. 

No classification of vinyl acetate in terms of germ cell mutagenicity is proposed. 

In cancer studies, vinyl acetate inhalation induced an increased number of nasal tumors 

(mainly papillomas and squamous cell carcinomas) in various regions of the nasal mucosa of 

rats. The total incidence was significantly increased at a concentration of 600 ppm (2142 

mg/m3

) but a single papilloma already developed at 200 ppm. No significant tumor response 

was seen in a mice cancer bioassay. Occasionally single squamous cell tumors occurred at 

other sites of the respiratory tract in rats and mice. 

Oral cancer studies were also positive. Significantly increased incidences of benign and 

malignant squamous cell tumors in the oral cavity in rats and mice, in the esophagus and 

forestomach in mice were observed in 2-year drinking water studies at vinyl acetate 

concentration of 10000 ppm (dose ranges in rats 364-1062 mg/kg bw/d, in mice 800-2185 

mg/kg bw/d). Similar results were found in another non-guideline conform cancer study on 

two generations of mice treated orally with 5000 ppm vinyl acetate in the drinking water (780 

mg/kg bw/d). Higher rates of tumors were noted in the oral cavity, tongue, esophagus, 

forestomach (squamous cell carcinoma at all sites) as well as in the glandular stomach. 

Vinyl acetate is considered as a threshold carcinogen because it is thought that carcinogenic 

action affects the site of first contact only a high concentrations. Cytotoxicity was assumed as 

one underlying mode of carcinogenesis in the olfactory mucosa. The assumption was thought 

to be supported by consistent dose-response and time-response relationships between 

cytotoxic effect and tumor growth. No cytotoxicity as a prerequisite of tumor development 

was identified for the other tumor sites, the non-olfactory regions and the upper 

gastrointestinal tract. However, increases in cell proliferation combined with increased 

formation of DNA adducts were only seen a high concentrations of vinyl acetate. Both effects 

are considered to be mediated by acetaldehyde that accumulates intracellularly when the 

physiological balance of intracellular formation and detoxification is disrupted above a 

certain, albeit unknown concentration of acetaldehyde. Instead, the most sensitive effects, the 

cytotoxicity of the olfactory region for the inhalation route (NOAEC 50 ppm), and the tumors 

of the upper gastrointestinal tract for the oral route (LOAEL 400 ppm), are recommended for 

risk characterisation. 

No adequate data from human experience are available. Based on the carcinogenic potential 

of vinyl acetate in two animal species and at the inhalative and oral route and the absence of 

reliable human data the substance might pose a cancer risk for humans. Carcinogenicity is 

thought to act via a secondary mechanism and the concern may only be relevant above 

threshold concentrations. 
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Vinyl acetate was shown to have marginal influences on reproduction in animal studies only 

at oral exposure levels that produced certain signs of general toxicity. Distinct reproduction 

related adverse effects of vinyl acetate were not evidenced from a two generation study on 

rats with drinking water concentrations of up to and including 1000 ppm (NOAEL, equivalent 

to a dosage of 100 mg/kg bw/d). No embryo-/fetotoxic or teratogenic effects were observed in 

an oral study on rats for dose levels up to and including 5000 ppm vinyl acetate. A 

NOAEL/fertility of 1000 ppm (equivalent to about 100 mg/kg bw/d) was derived. Fetotoxic 

effects, revealed during inhalation exposure to rats, were confined to high dose levels (1000 

ppm) only, where severe maternal toxicity was observed. A NOAEC for developmental 

toxicity of 200 ppm (corresponding to 205 mg/kg bw/d) was established from this study.

4.1.3.2 Workers 

4.1.3.2.1 Introductory remarks 

For occupational risk assessment of vinyl acetate the MOS approach as outlined in the revised 

TGD is applied. This occupational risk assessment is based upon the toxicological profile of 

vinyl acetate (chapter 4.1.2) and the occupational exposure assessment (chapter 4.1.1.2). The 

threshold levels identified in the hazard assessment are taken forward to this occupational risk 

assessment. 

Systemic availability for different routes of exposure 

Measurement at isolated upper respiratory tract of rats of in vivo uptake of vinyl acetate 

demonstrated, that blood flow extraction accounts for less than 15 % of total vinyl acetate 

deposition (see chapter 4.1.2.1). Hence, 15 % inhalative uptake is taken as a worst case 

scenario for risk characterisation of systemic effects. 

After oral administration of 297 mg/kg 14C vinyl acetate, 63 % of the applied radioactivity 

was excreted as metabolites in exhaled air, urine and faeces. However, 63 % absorption 

would represent an overestimation of systemically available amounts of vinyl acetate (see 

chapter 4.1.2.1). 50 % absorption can be assumed as a worst case for systemically available 

amounts of vinyl acetate after oral uptake. 

Based on an acute dermal study in rabbits and based on the fact that carboxylesterase 

activities are lower in skin compared to nose or oral cavity, it can be assumed that systemic 

bioavailability of vinyl acetate and/or vinyl acetate-derived metabolites is higher after dermal 

exposure when compared to oral or inhalative exposure. Therefore 90 % dermal absorption is 

taken forward to the risk characterisation. 

Altogether the following absorption percentages are used in the following risk assessment: 

15% inhalative uptake for the assessment of systemic effects, 50% absorption after oral 

uptake of vinyl acetate and 90% absorption after dermal contact. 
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Occupational exposure and internal body burden 

In table 4.1.3.2.A the exposure levels of tables 4.1.1.2.4.A and 4.1.1.2.4.B are summarised 

and the route-specific and total internal body burdens are identified. Risk assessment for 

combined exposure requires the calculation of a total internal body burden; to this end the 

derived route-specific percentages for absorption are used (15% for inhalation and 90% for 

dermal exposure). 

Table 4.1.3.2.A: Occupational exposure levels and internal body burden of vinyl acetate 

Internal body burden of workers after 

repeated exposure 

Inhalation

shift 

average 

Dermal contact

shift average 

Inhalation(1) Dermal(2) Combined Exposure scenario 

mg/m3

 mg/p/d mg/kg/d mg/kg/d 

1. Production and polymerisation 

in the chemical industry 3(3) 42(5) 0.6 0.064 0.54 0.60 

a) polymerisation 

step (vinyl 

acetate 

monomer) 

420(6) 6 5.4 5.71 

2. 

Manufacturing of 

formulation

s and 

products 

b) formulation 

step (vinyl 

acetate 

(co)polymer) 

14.6(3) 

1.36) 0.02 

0.31 

0.018 0.33 

3. Use of formulations and 

products containing residual 

vinyl acetate monomer 

2.6(4) 12.6(6) 0.18 0.056 0.16 0.22 

(1) based on the assumption of 15% inhalative absorption; breathing volume of 10 m3

 per shift 

(2) based on the assumption of 90% systemic availability of vinyl acetate after dermal contact 

(3) reasonable worst case 

(4) worst case 

(5) EASE (90 % protection by suitable gloves) 

(6) EASE (without gloves) 

 MOS approach 

The MOS approach for human risk characterisation is described in detail in the TGD (Human 

Health Risk Characterisation, Final Draft). The following chapter contains a short 

introduction to the MOS approach used. The basic principle of the MOS approach is a 

comparison of scenario-specific MOS values (the relationship between the experimental 

NOAEL respectively the adjusted starting point and the exposure level) with a reference MOS 

(product of various assessment factors). 

MOS calculation and the adequate starting point 
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Basically, MOS values are calculated as quotient of a relevant NOAEL from experimental 

animal testing or human studies and actual workplace exposure levels. In specific situations, 

the MOS approach requires to convert the original NOAEL into an adequate starting point or 

corrected NOAEL previously to MOS calculation in order to be directly comparable to the 

exposure assessment. If the route of application in animal or human studies is different from 

the actual occupational exposure, the dose units of the experimental data should be converted 

to the dose unit of the exposure data. Additionally, possible differences in bioavailability 

between routes, as well as possible differences in bioavailability between animals and humans 

should be accounted for the calculation of the corrected NOAEL. If route-specific information 

on oral and inhalation absorption is not available, the TGD recommends to assume a 50% oral 

absorption and a 100% inhalation absorption. For vinyl acetate 15% absorption after 

inhalation, 50% after oral exposure, and 90% absorption after dermal contact is assumed (see 

chapter 4.1.2.1). 

For occupational risk assessment, the corrected NOAEC for inhalation accounts for the 

difference of the standard respiratory volume (6.7 m3) and the respiratory volume for light 

activity (10 m3). 

MOS values are calculated for different routes of exposure and for different toxicological 

endpoints. The routes of exposure specifically considered in occupational risk assessment are 

exposure by inhalation and dermal contact. 

In addition, for risk assessment of combined exposure (exposure by inhalation and dermal 

contact) an adequate NOAEL is derived from external NOAELs and specific information on 

route-specific absorption. For MOS calculation, the adjusted internal starting point is divided 

by the internal body burden. Depending on route-specific exposure and absorption, inhalation 

exposure and/or dermal exposure may contribute to the internal body burden. With respect to 

the possible outcome of an assessment for combined risks, interest focuses on scenarios with 

conclusion ii at both exposure routes. Based on theoretical considerations, combined exposure 

will not increase the most critical route-specific risk component more than twice. 

 Reference MOS 

The MOS values calculated have to be compared with a reference MOS. The reference MOS 

is an overall assessment factor, which is obtained by multiplication of individual assessment 

factors. The Technical Guidance Document emphasises several aspects which are involved in 

the extrapolation of experimental data to the human situation. For these assessment factors, 

default values are recommended. It is important to point out that any relevant substancespecific data and information may overrule the defined default values. 

Interspecies extrapolation on the one hand is based on allometric scaling (factor 4 for rats, 

factor 7 for mice, and factor 2.4 for rabbits). For remaining interspecies differences the TGD 

proposes an additional factor of 2.5. Interspecies extrapolation conceptually might be 

considered to consist of a toxicokinetic and toxicodynamic phase. As to vinyl acetate PBPK 

models essentially describe the relationship between airborne concentration of vinyl acetate 

and intracellular acetaldehyde concentration. However, uncertainties of the model consist in 

the enzyme kinetic data used to establish the model. Therefore, data on toxicokinetic and 

toxicodynamic outcome derived from the model should be taken with caution. For 

occupational risk characterisation an interspecies factor of 2.5 is proposed (abutted at the 

default value for the remaining uncertainties of interspecies differences). For workers, an 
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adjustment factor for intraspecies differences of 5 is recommended. Based on an evaluation of 

empirical data by Schneider et al. (2004) it is anticipated that a factor of 5 will be sufficient to 

protect the major part of the worker population (about 95%). In the case of vinyl acetate 

PBPK results are available (see chapter 4.1.2.1 and 4.1.3.2), which suggest that the 

toxicodynamic portion of the default intraspecies factor (10 for the whole population, 5 for 

workers) remains as overall intraspecies factor since the toxicokinetic part (4) is not applied 

(no systemic metabolism as it is virtually impossible that vinyl acetate will reach the systemic 

circulation). The remaining uncertainties are covered by application of a reduced adjustment 

factor for workers in the range of 1.25 and 2.5. 

For chemical substances it is usually expected that the experimental NOAEL will decrease 

with increasing duration of application. Furthermore, other and more serious adverse effects 

may appear with prolonged exposure duration. For duration adjustment, a default factor of 6 

is proposed for extrapolation from a subacute to chronic exposure. The duration adjustment 

factor is lower (a factor of 2) for the transition from subchronic experimental exposure to 

chronic exposure. Since chronic studies are available for vinyl acetate, a specific factor for 

duration adjustment of repeated dose toxicity is not necessary. 

The TGD defines two further adjustment factors (uncertainty in route-to-route extrapolation 

and dose-response relationship including severity of effect). In specific cases these factors 

may be different from one. For vinyl acetate no further adjustment factors are used in the risk 

assessment. 

Comparison of MOS and reference MOS 

The MOS values for different toxicological endpoints and different exposure scenarios are 

compared with the substance- and endpoint-specific reference MOS. MOS values clearly 

above the reference MOS do not lead to concern, whereas MOS values that are clearly below 

the reference MOS are cause for concern. There may be various risk-related aspects which are 

not covered by default assessment factors. These additional qualitative aspects should be 

carefully considered when performing a risk assessment and should have adequate influence 

on finding of conclusions. 

Critical Exposure Levels 

In a parallel procedure, which gives identical but more direct results, the adjusted 

toxicological starting point is directly divided by the reference MOS. As a result, an exposure 

level (in mg/m3 or mg/kg/d) is identified, which may serve as a direct trigger for decisions 

when compared with the occupational exposure levels. In the context of this risk assessment 

report this trigger value is called “critical exposure level”. Concern will be expressed for 

scenarios with occupational exposure levels higher than the relevant “critical exposure level”. 
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4.1.3.2.2 Occupational risk assessment 

Acute toxicity 

- Inhalation 

LC50–values of 14.1 and 15.8 mg/l (4 h) were determined in rats. No animals died at the 

lowest tested dose of 7 mg/l (4 h). Gross pathology revealed no remarkable effects, but red 

and irritated extremities were observed as clinical signs. 

Comparing the LC50-value of ca. 15,000 mg/m3

 and the concentration of 7,000 mg/m3 without 

lethality with the highest exposure concentration of 15 mg/m3

 (scenario 2, reasonable worst 

case) and the highest short-term exposure of 47 mg/m3

 (scenario 2) a relevant risk concerning 

acute toxicity is not expected under normal workplace conditions. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

- Dermal contact 

The LD50 in rabbits was 7,440 mg/kg (24 h, occlusive). At the lowest tested dose of 

3,720 mg/kg no mortalities and no clinical signs were observed, but gross pathology revealed 

effects in liver, spleen, kidney and the lungs. 

Comparing the LD50 of 7,440 mg/kg and the dose of 3,720 mg/kg (no mortalities, but effects 

in different organs) with the highest dermal exposure of 6 mg/kg (scenario 2a, use of vinyl 

acetate monomer) a relevant risk concerning acute toxicity is not expected under normal 

workplace conditions. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 
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- Irritation/Corrosivity 

- Dermal/Eyes 

A general notice from occupational use describes principally local irritant reactions of the 

skin, eyes and respiratory tract (information by the vinyl acetate industry, without further 

details, possibly only historical relevance). 

Due to the only valid tests (RCC, 2003a and c) mild irritation on the skin and eyes of rabbits 

were observed that do not warrant classification. Earlier studies of limited reliability indicated 

pronounced irritation or corrosion of skin after extended exposure periods. 

All data were not substantive enough for a classification with the corresponding R-phrases. 

No concern for dermal or eye irritation at the workplace is expressed. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Inhalation 

According to chapter 4.1.2.3/4.1.2.4 vinyl acetate has proven to cause severe irritation in the 

respiratory tract of rats. Additional information on acute irritation can be obtained from 

chapter 4.1.2.6. Sprague-Dawley-rats were exposed for 1, 5 and 20 days in an inhalation study 

(6 h/day, 5 days/week) to 0, 50, 200, 600, or 1,000 ppm (Bogdanffy et al., 1997). Following 

the single exposure of one day, rats of the 600 and 1,000 ppm groups showed concentrationrelated minimal to moderate degeneration, necrosis and exfoliation of the olfactory 

epithelium. Additionally a minimal degeneration and necrosis in the respiratory epithelium 

occurred at 1,000 ppm. So the value of 200 ppm (corresponding to 710 mg/m3

) will be used 

as NOAEC, concerning local effects after short term inhalative exposure. 

A MOS calculation would result in a value of about 79 mg/m3

 (inhalation starting point of 

476 mg/m3 with the NOAEC of 710 mg/m3

 multiplied by 6.7/10 (activity-driven differences 

of respiratory volumes in workers) divided by a reference MOS of about 3 – 6 (intraspecies 

differences factor 1.25 – 2.5 and interspecies factor of 2.5). 

Comparing the critical exposure level of 79 mg/m3

 with the highest exposure of 14.6 mg/m3

(scenario 2) a relevant risk concerning irritation after inhalation is not expected under normal 

workplace conditions. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

4.1.3.2.B: Local effects after inhalative exposure to vinyl acetate 
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 Acute exposure, Repeated exposure, 

Starting point for MOS calculation 476 mg/m3 90 mg/m3

Reference MOS 6 5.1 

Critical exposure level 79 mg/m3 17.6 mg/m3

Exposure (mg/m3) 

MOS Conclusions Exposure (mg/p/d) 

MOS Conclusions 

1. Production and polymerization in 

the chemical industry 3 159 ii 3 30 ii 

2. Manufacturing of formulations and 

products 14.6 33 ii 14.6 6 Borderlin

e iii 

Short-term exposure 47 10 ii 

3. Use of formulations and products 

containing residual vinyl acetate 

monomer 

2.6 183 ii 2.6 35 ii 

Sensitization 

Dermal contact 

No cases of skin sensitization from the handling of vinyl acetate in the workplace have been 

reported in the last years. 

Results from an animal skin sensitization study (Buehler Test) showed a moderate skin 

sensitising potential of vinyl acetate. In a Local Lymph Node Assay (LLNA) no positive 

stimulation responses were seen at concentrations of 5% - 100%. However, the results 

obtained with this LLNA may not fully reflect the potential of concentrations >10%, since 

higher concentrations of vinyl acetate show increasing volatility, due to decreased proportions 

of acetone/olive oil. Since the positive threshold level was not exceeded in the LLNA, 

classification and labelling with R 43 is not warranted. No concern is expressed. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Inhalation 
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No information on respiratory sensitisation is available. However, in view of the fact that 

during all the years of use specific case reports have not been reported, vinyl acetate seems at 

least not to be a strong respiratory sensitizer in humans. For the time being no animal model 

is available which would be able to verify the question of respiratory sensitisation. In 

summary concern is not expressed. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Repeated dose toxicity 

Local effects 

Inhalation 

In a combined chronic toxicity and carcinogenic study (Owen, 1988; Bogdanffy et al., 1994b) 

male and female Sprague Dawley rats and CD-1 mice were exposed by inhalation to vinyl 

acetate vapour in concentrations of 0, 50, 200, and 600 ppm (equivalent to 0, 178.5, 714, 

2,142 mg/m3

) over a period of 2 years (6 hours/day, 5 days/week). Examinations on 

haematology, clinical chemistry, urinalysis and gross and microscopic abnormalities were 

performed on satellite groups at week 51 and 81 and on the end of the main study. In both 

species of each sex, vinyl acetate induced morphological nonneoplastic lesions in the nasal 

cavity of the 200 and 600 ppm groups and in the trachea (mice only) and in the lungs of the 

600 ppm groups. Based on these findings the NOAEC for local effects on the respiratory tract 

was 50 ppm (180 mg/m3

). This NOAEC is taken as starting point for the risk assessment of 

local effects after repeated exposure. 

The experimental NOAEC of 180 mg/m3

 is (1) adapted by a factor of 6/8 to account for 

differences between the experimental inhalation duration of 6 hours per day and the average 

working day of 8 hours per day, and (2) is multiplied by a factor of 6.7/10 for activity-driven 

differences of respiratory volumes in workers. This results in an adjusted inhalation starting 

point of 90 mg/m3

 (180 • 6/8 • 6.7/10) 

The reference MOS accounts with the intraspecies differences with a factor of 1.25 – 2.5 (see 

chapter 4.1.3.2.1 reference MOS). The interspecies differences deal with a factor of 2.5 (the 

factor for allometric scaling is already implicitly applied). Duration adjustment is not 

necessary, because a long term study is available. 

This would result in a reference MOS of about 3 – 6 (5 • 1.25 – 2.5) and a critical exposure 

level of 15 to 30 mg/m3

 depending on how big the factor for intraspecies differences is dealt 

with. Comparing this range for a critical exposure level of vinyl acetate with the OEL of 17.6 

mg/m3

 (5 ppm) which was set by the Scientific Committee on Occupational Exposure Limits, 

the value is very close at the lower value of 15 mg/m3

. For pragmatic reasons the occupational 

exposure value of 17.6 mg/m3

 (5 ppm), which was set by SCOEL (2005) is taken forward to 

this risk assessment. The SCOEL value corresponds to a reference MOS value of 5.1. 
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The highest shift average value for inhalation is reported as 14.6 mg/m3

 for manufacturing of 

formulations and products of vinyl acetate in scenario 2. Compared with the OEL of 17.6 

mg/m3 the scenario reaches borderline. Conclusion iii is drawn for scenario 2 since there is 

the uncertainty concerning the reduction of the intraspecies factor. The other scenarios do not 

reach concern (for corresponding MOS values see table 4.1.3.2.B). 

Conclusion iii) 

There is a need for limiting the risks; risk reduction measures which are already being applied 

shall be taken into account. 

Dermal contact 

Dermal studies with repeated application are not available. Besides the tests described in 

chapter 4.1.2.4 only a general notice from occupational use describes principally local irritant 

reactions of the skin, eyes and respiratory tract. 

The data demand no classification and are not substantiated enough for raising a concern for 

repeated dermal contact. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Systemic effects 

Distinct systemic effects after inhalation or oral administration of vinyl acetate are not 

reported. The only indicator for systemic effects after repeated inhalation of vinyl acetate 

could be a decreased body weight gain observed in rats at 2,142 mg/m3

 (600 ppm) and in 

mice at 714 mg/m3

 (200 ppm) and above, observed in a combined chronic toxicity and 

carcinogenicity study (Owen, 1988; Bogdanffy et al., 1994b). 

Inhalation 

The combined chronic toxicity and carcinogenicity study (Owen, 1988; Bogdanffy et al., 

1994b, see above), which was used for the risk assessment of local effects after repeated 

inhalation serves also for the risk assessment of systemic effects. A decreased body weight 

gain, but no target organ toxicity, was observed in rats at 2,142 mg/m3

 (600 ppm) and in mice 

at 714 mg/m3

 (200 ppm) and above. This decrease may be associated to non-specific toxicity 

of vinyl acetate. It was interpreted to be attributed to lower food and water consumption, but 

the 2-year study did not contain any data on the consumption of water/food and the food 

efficiency. Based on the reduction of body weight gain the NOAEC of 50 ppm (180 mg/m3

) 

of the mice is taken for the MOS calculation. 

The derivation of the starting point and the reference MOS are identical with the values which 

are derived for carcinogenicity (values see under chapter carcinogenicity). The critical 
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exposure level regarding systemic toxicity after repeated inhalation is identified as 17.6 

mg/m3

 (90 / 5.1). 

The highest shift average value for inhalation is reported as 14.6 mg/m3

 for manufacturing of 

formulations and products of vinyl acetate in scenario 2. Compared with the OEL of 17.6 

mg/m3

 the scenario is a borderline case. Conclusion iii is drawn for scenario 2 since there is 

the uncertainty concerning the reduction of the intraspecies factor. The other scenarios do not 

reach concern (for corresponding MOS values see table 4.1.3.2.C). 

Conclusion iii) 

There is a need for limiting the risks; risk reduction measures which are already being applied 

shall be taken into account. 

Dermal contact 

Dermal studies with repeated application are not available. Thus the studies with other routes 

of application are taken into account. A target organ of systemic toxicity was not observed in 

the oral or inhalation studies. The systemic LOAEC of inhalation toxicity was defined by a 

decreased body weight gain, which was interpreted to be based on lower food and water 

consumption (see above). The central drinking water study in rats and mice over 13 weeks 

revealed no significant systemic effects up to the highest tested dose of 5000 ppm (684 - 810 

mg/kg/day for rats; 281 - 285 mg/kg/day for mice). 

Since a quantitative risk assessment regarding repeated dermal contact is connected with high 

uncertainties regarding systemic availability, route-to-route extrapolation and the missing of 

distinct systemic effects, only a rough estimation is done. For this the following 

considerations regarding the assessment of repeated dermal exposure are taken into account: 

Neat vinyl acetate (1 mg/m3

) would evaporate within about 10 seconds from skin under usual 

working conditions of non occlusive exposure. From the experimental data there is no distinct 

systemic effect described (highest tested dose of 810 mg/kg/day from the drinking water 

study). 

Compared with the highest dermal exposure of 6 mg/kg (scenario 2a, use of vinyl acetate 

monomer) there seems to result no concern for repeated dermal contact. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 
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Combined exposure 

Besides scenario 2 no further scenario reaches concern. 

Conclusion iii) 

There is a need for limiting the risks; risk reduction measures which are already being applied 

shall be taken into account 

Table 4.1.3.2.C: Repeated dose toxicity, systemic effects of vinyl acetate 

 Inhalation Dermal Combined 

Starting point for MOS 

calculation 90 mg/m3 no quantitative calculation, see text 

no quantitative 

calculation, see text 

Reference MOS 5.1 - - 

Critical exposure level 17.6 mg/m3 -- - Exposure (mg/m3) MOS Conclusion Exposure (mg/kg/d) MOS Conclusion 

Internal body burden(mg/kg/d) MOS Conclusion 

1. Production and 

polymerisation in the 

chemical industry 

3 30 ii 0.6 ii 0.6 ii 

a) 

polymerisatio

n step (vinyl 

acetate 

monomer) 

6 ii 5.71 iii1) 

2. Manufacturing of 

formulation

s and 

products 

b) 

formulation 

step (vinyl 

acetate 

(co)polymer) 

14.6 6.2 Border

line iii

0.02 ii 0.33 iii1) 

3. Use of formulations and 

products containing residual 

vinyl acetate monomer 2.6 34.8 ii 0.18 ii 0.22 ii 

(1)conclusion iii already results from inhalation exposure

Mutagenicity 
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Vinyl acetate is negative in bacterial mutagenicity tests. 

The substance has a mutagenic potential, which is preferentially expressed as clastogenesis. 

The data on in vivo genotoxicity are difficult to interpret, since their majority is of low 

reliability, or the effects are not specific to mutagenicity. The most important effect, a weak 

induction of micronuclei in mouse bone marrow, is limited to intraperitoneal doses of high 

toxicity. 

It is unlikely, that the genotoxic potential of vinyl acetate is expressed in germ cells in man, 

because vinyl acetate genotoxicity is limited to toxic doses. For vinyl acetate a threshold 

mechanism of action is assumed. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Carcinogenicity 

Regarding the carcinogenicity of vinyl acetate, no adequate human data base is available. 

Long-term inhalation and oral administration of vinyl acetate in experimental animals 

produced tumors at the primary site of exposure, the surface epithelium of the respiratory tract 

and the upper gastrointestinal tract. After inhalation a tumor response to vinyl acetate 

exposure was seen at 600 ppm in rats (Bogdanffy et al., 1994b), for the oral route an increase 

of tumor rates has been observed at 10,000 ppm (male rat 442 mg/kg/day, female rat 575 

mg/kg/day, Umeda et al., 2004a). 

Vinyl acetate carcinogenicity is assumed to be mediated by the metabolic product 

acetaldehyde. Based on the nonlinear kinetics of intracellular aldehyd dehydrogenase activity 

there is a marked increase of intracellular acetaldehyde only at high concentrations of vinyl 

acetate. With reference to this non-linear dose response relationship for the critical metabolite 

acetaldehyde risk assessment is performed with the MOS approach. 

Inhalation

The study, which serves as key study for the risk assessment of carcinogenicity of vinyl 

acetate is the combined chronic toxicity and carcinogenic study from Owen (1988) and 

Bogdanffy et al (1994b), which was already taken for the risk assessment of repeated dose 

toxicity. Exposure-related tumor response was observed in the nasal cavity of rats at the 

highest concentration of 600 ppm. A total of 11 nasal cavity tumors were evident in 7 males 

and 4 females, classified as papilloma and/or carcinoma cell types (see table 4.1.2.8.A). In the 

intermediate group (200 ppm) one single tumor (benign papilloma) was found in a male rat. 

No respiratory tract tumor was seen in the control and low dose groups (50 ppm) except for a 

single adenoma of the lung in a control female. From this study a NOAEC of 50 ppm (180 

mg/m3

) is derived and used as a threshold concentration. 

The experimental NOAEC of 180 mg/m3

 is (1) adapted by a factor of 6/8 to account for 

differences between the experimental inhalation duration of 6 hours per day and the average 
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working day of 8 hours per day, and (2) is multiplied by a factor of 6.7/10 for activity-driven 

differences of respiratory volumes in workers. This results in an adjusted inhalation starting 

point of 90 mg/m3

 (180 • 6/8 • 6.7/10). 

The reference MOS would account with the intraspecies differences with a factor of 1.25 – 

2.5 (see chapter 4.1.3.2.1 reference MOS). The interspecies differences would deal with a 

factor of 2.5 This would altogether result in a reference MOS of about 3 to 6. The critical 

exposure level regarding carcinogenicity would then lie between 15 and 30 mg/m3

 (90 / 6 or 

3), depending on how big the intraspecies differences are dealt with. Looking at the 

recommendation of the Scientific Committee on Occupational Exposure Limits, the 

committee decided in 2005 to set an OEL for vinyl acetate of 17.6 mg/m3 (5 ppm). This value 

is in the same order than the lower value of 15 mg/m3. For pragmatic reasons the occupational 

exposure value of 17.6 mg/m3

 (5 ppm), which was set by SCOEL (2005) is taken forward in 

this risk assessment. The SCOEL value corresponds to a reference MOS value of 5.1. 

For scenario 2 (manufacture of formulations and products), the exposure is 14.6 mg/m3

. Since 

there is the uncertainty concerning the reduction of the intraspecies factor and the mode of 

action for carcinogenesis for this borderline scenario conclusion iii is drawn. The other 

scenarios are out of concern. For corresponding MOS values see table 4.1.3.2.D. 

Conclusion: iii) 

There is a need for limiting the risks; risk reduction measures which are already being applied 

shall be taken into account. 

Dermal contact 

Dermal carcinogenicity studies are not available. An oral drinking water study with rats 

(Umeda et al., 2004a) showed higher incidences of tumor rates at the local site of contact: 

squamous cell carcinoma in the the oral cavity, esophagus, and stomach, which were 

considered to be treatment related. 

Vinyl acetate should be able to reach vivid skin cells and a potential to induce skin tumours 

cannot be excluded. A quantitative approach is not possible, since a quantitative route to route 

extrapolation of local effects is generally not performed. For risk characterisation purposes it 

should be further considered, that the high vapour pressure of vinyl acetate leads to reduced 

retention time on skin absorption. 

The highest dermal exposure value (6 mg/kg/day) was estimated for the use of pure vinyl 

acetate during manufacture of formulations and products (scenario 2a). The magnitude of this 

exposure value is also based on the knowledge, that gloves are not regularly worn in small 

and medium-sized enterprises. The other scenarios have exposure values at least one order of 

magnitude below (<0.6 mg/kg/day). This is due to a high acceptance of gloves in the largescale chemical industry (scenario 1) and the fact, that vinyl acetate is only available as a 

residual monomer (< 2 – 3000 ppm) in scenario 2b and 3. 

Based on this information and the fact that especially the high doses led to a significant 

carcinogenic response in experimental studies, scenario 2a with the highest exposure due to 

non-effective skin protection is considered to be associated with a significant risk, which 
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should require further specific measures. The other scenarios (scenario 1, 2b, 3) are 

considered to be of lower concern and a low risk level is assumed. 

Concern for scenario 2a (manufacturing of formulations and products with the vinyl acetate 

monomer, see table 4.1.3.2.D). 

Conclusion: iii) 

There is a need for limiting the risks; risk reduction measures which are already being applied 

shall be taken into account 

Combined exposure

Concern was already expressed for scenario 2a after dermal contact. Thus Scenario 2a reaches 

also concern for combined exposure. 

Because of the lower exposure values for scenarios 1, 2b and 3 no concern is expressed. 

Conclusion: iii) 

There is a need for limiting the risks; risk reduction measures which are already being applied 

shall be taken into account 
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Table 4.1.3.2.D: Carcinogenicity of vinyl acetate 

 Inhalation Dermal Combined 

Starting point for MOS 

calculation 90 mg/m3 no quantitative calculation, see text 

no quantitative 

calculation, see text 

Reference MOS 5.1 

Critical exposure level 17.6mg/m3 Exposure (mg/m3) MOS Conclusion Exposure (mg/kg/d) MOS Conclusion 

Internal body burden(mg/kg/d) MOS Conclusion 

1. Production and 

polymerisation in the 

chemical industry 

3 30 ii 0.6 ii 0.6 ii

a) 

polymerisatio

n step (vinyl 

acetate 

monomer) 

6 iii 5.71 iii(1) 

2. Manufacturing of 

formulation

s and 

products 

b) 

formulation 

step (vinyl 

acetate 

(co)polymer) 

14.6 6.2 Border

line iii

0.02 ii 0.33 iii1) 

3. Use of formulations and 

products containing residual 

vinyl acetate monomer 2.6 34.8 ii 0.18 ii 0.22 ii

(1)conclusion iii already results from inhalation and/or dermal exposure

Reproductive toxicity 

Fertility impairment and developmental toxicity 

With respect to toxicity for reproduction no human data are available. 

Distinct reproduction related adverse effects of vinyl acetate are not reported from a two 

generation drinking water study with rats for concentrations including 1000 ppm. 

The developmental toxicity of vinyl acetate has been investigated in rats via oral (drinking 

water) and inhalation exposure routes during organogenesis. No embryo/fetotoxic or 

teratogenic effects were observed for the oral route of administration at drinking water 
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concentrations including 5000 ppm. Fetotoxic effects, revealed during inhalation exposure, 

were confined to high dose levels only, where severe maternal toxicity was observed. 

In addition, any specific teratogenic potential and/or impairment of embryo/fetal development 

are not indicated from the same data. Therefore no MOS calculation is performed for this 

endpoint. 

Conclusion ii 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

4.1.3.2.3 Summary of conclusions for the occupational risk assessment 

Table 4.1.3.2.E indicates the toxicological endpoints of concern for vinyl acetate. Concern 

results for carcinogenicity after dermal exposure. For the other endpoints no concern is 

expressed. 

Table 4.1.3.2.E: Endpoint-specific overall conclusions 

Toxicological endpoints General conclusion Exposure 

Scenarios 

inhalation ii 

Acute toxicity dermal ii 

combined ii 

dermal ii 

Irritation/ Corrosivity eye ii 

acute respiratory tract ii 

skin ii 

Sensitisation 

respiratory ii 

inhalation, local iii 2a 

inhalation, systemic iii 2a 

dermal, local ii 

dermal, systemic ii 

Repeated dose toxicity 

combined, systemic iii 2a

Mutagenicity ii 

inhalation iii 2a 

Carcinogenicity dermal iii 2a 

combined iii 2a(1) 
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inhalation ii 

Reproductive toxicity dermal ii 

combined ii 

(1)conclusion iii already results from inhalative and/or dermal exposure, therefore no specific concern for the 

combined exposure scenario is indicated 

Risk estimation is mainly based on animal inhalation studies and oral studies. The following 

absorption percentages are assumed for the different exposure ways: 15% inhalative uptake 

for the assessment of systemic effects, 50% absorption after oral uptake of vinyl acetate and 

90% absorption after dermal contact. 

The most pronounced effects of vinyl acetate are local effects after repeated inhalation contact 

and carcinogenicity. The value of 17.6 mg/m3 designates the critical exposure level as well

for carcinogenicity as repeated dose toxicity after inhalation. Following inhalation, the 

substance is rapidly hydrolysed by carboxylesterases leading to the formation of acetic acid 

and acetaldehyde which is further converted into acetic acid. At higher concentrations of 

vinyl acetate the capacity of the intracellular enzymes is not big enough to oxidize all of the 

generated acetaldehyde. Thus, at high vinyl acetate concentrations, non-physiologically high 

concentrations of acetaldehyde are produced. This intermediate, develops adverse effects at 

non-physiologically high concentrations, which result in the formation of tumors at the 

exposed tissue. Because of the carcinogenic effects only occur at the site of first contact at 

high concentrations of vinyl acetate, the substance is considered as a threshold carcinogen. 

On the background of cancer risks and repeated dose toxicity (local and systemic effects), air 

concentrations of vinyl acetate at the workplace should be controlled to a level in the range of 

17.6 mg/m3

 (critical exposure level). However, scenario 1 and 3 of the inhalation exposure 

scenarios, specified in this report describe lower exposure values and are thus out of concern. 

Scenario 2 (manufacture of formulations and products), with an exposure value of 14.6 mg/m3

is a borderline case. Since there is the uncertainty concerning the reduction of the intraspecies 

factor and the mode of action for carcinogenesis for this borderline scenario conclusion iii is 

drawn for repeated dose toxicity and carcinogenesis. Skin contact of vinyl acetate should be 

reduced in scenario 2a (manufacturing of formulations and products, vinyl acetate monomer), 

even if evaporation of the substance reduces the contribution of dermal exposure. 

4.1.3.3 Consumers 

Following the exposure assessment there is no direct exposure of the consumer to vinyl 

acetate besides of the release of monomers from polymers. Overall exposure to vinyl acetate 

occurs mainly via inhalation due to emissions from carpets, paints and adhesives. For 

comparison with acute effects, the estimate for short-term exposure to concentrations of a 

about 1 mg/m3 from carpets will be used. With regard to chronic effects, the concentration of 

0.036 mg/m3 for long-term exposure will be used resulting in an exposure of 9.2 μg/kg bw/d 

for men, of 4.6 μg/kg bw/d for women, and of 18 μg/kg bw/d for children. The inhalation 

exposures numbers representing residual monomeric vinyl acetate still overestimate realistic 
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chronic exposure because according to the biochemical data remarkable amounts of vinyl 

acetate will be metabolized rapidly to acetaldehyde in the olfactory and respiratory epithelium 

(see chapter 4.1.2.1) thus only very small amounts of vinyl acetate will reach the systemic 

circulation. Furthermore, the consumer may be exposed to vinyl acetate by using hair setting 

lotions (1 μg/kg bw/d) by the dermal route and by migration of the substance from plastics 

coming into contact with foods via oral route. Since this exposure scenario is regulated (see 

chapter 4.1.1.3) there is no need for MOS calculation. 

Acute Toxicity 

Following the exposure assessment, consumers are not expected to be exposed to vinyl 

acetate in the range of doses which can be derived from acute oral or dermal toxicity figures 

based on animal LD 50 values (oral and dermal: > 3500 mg/kg body weight). Therefore the 

substance is of no concern in relation to acute oral or dermal toxicity. 

The inhalation route of exposure should be of no concern, because in rats vinyl acetate has 

demonstrated LC50 values of > 14 mg/l/4h. For short-term exposure from carpets 

concentrations of 0.001 mg/l have been calculated. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Irritation/Corrosivity 

Vinyl acetate causes only mild irritation to the skin and eyes of rabbits, but causes severe 

irritation in the respiratory tract of rats. Human data on irritation/corrosivity caused by vinyl 

acetate are not available. 

Following the exposure assessment it can be assumed that consumers are exposed only to 

such concentrations which are far below the effective concentrations. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 
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Sensitization 

Data obtained from a Buehler Test demonstrate that vinyl acetate (commercial grade) is a 

moderate skin sensitizer. The results of a Local Lymph Node Assay confirm the weak to 

moderate effects in the Buehler Test, but do not warrant classification and labelling. 

No reports of allergic contact dermatitis caused by vinyl acetate from routine patch testing or 

experimental studies in man are available. Furthermore, no direct information is available 

from studies in humans on respiratory sensitization. In view of the widespread occupational 

use, the absence of any reports suggests that vinyl acetate may not be a respiratory sensitizer. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Repeated dose toxicity/Non-neoplastic lesions

Following the exposure assessment there may be chronic exposure to vinyl acetate resulting 

from release of residual monomers out of polymers. 

The major toxic effects after prolonged inhalation of vinyl acetate in experimental animals 

were lesions of the surface epithelium of the upper and lower respiratory tract. Degeneration, 

regenerative/reparative processes, inflammation, hyperplasia and metaplasia were noted in the 

nasal mucosa as non-neoplastic effects. These effects were most pronounced in the olfactory 

epithelium occurring at 200 ppm in rats and mice during and at the end of a 2-year exposure 

period. Lesions of the respiratory epithelium were seen in mice exposed to 600 ppm during 

and at the end of 2 years, whereas rats demonstrated lesions at this site only at a high 

concentration of 1000 ppm (4 week study). Characteristic alterations of the larynx and trachea 

of mice in the 600 ppm groups were hyperplasia and metaplasia along with desquamation and 

fibrosis in the trachea. Similar changes of the bronchial and bronchiolar airways were 

reported for rats and mice at this concentration at the end of the 2-year exposure period. In 

addition, clinical signs of non-specific toxicity and irritation were evident, but no relevant 

toxic effect on any organ could be identified. The NOAEC for local toxic effects on the 

respiratory tract of 50 ppm (178.5 mg/m3) was derived from the 2-year studies on rats and 

mice. Based on growth retardation in rats of the 600 ppm groups and due to hunched posture 

in mice of the 200 ppm groups, the NOAEC for systemic toxicity was considered at 50 ppm 

for mice (178.5 mg/m3

) and 200 ppm for rats (714 mg/m3). 

No specific organ toxicity was recorded after repeated oral administration of vinyl acetate 

with drinking water to rats and mice. A subchronic 13-week study revealed a slight (nonsignificant) reduction of food consumption and growth retardation in male rats at 5000 ppm 

(684 mg/kg bw/d). 

For the decision on the appropriateness of MOS, the following aspects regarding the critical 

effect as well as exposure have been considered and taken into account: 
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- overall confidence in the database 

The data taken into account for performing the risk characterization have been evaluated with 

regard to their reliability, relevance and completeness according to section 3.2 of the TGD. 

The data were published in peer reviewed journals or submitted to the Competent Authority 

in private reports being adequately detailed and in accordance with internationally recognized 

guidelines and to GLP. 

The findings of all studies are not contradictory so that the judgement can be based on the 

database (cf. 4.1.2.6 and 4.1.2.8). 

There are no reasons to assume limited confidence. 

- uncertainty arising from the variability in the experimental data 

The studies cited above consistently indicated degeneration of the nasal epithelium in several 

studies on rats and mice. From a well performed 2-year inhalation study on rats and mice a 

NOAEC for local effects of 178 mg/m3

 (50 ppm) was derived and the results were in 

conformity with the findings of the other studies. 

- intra- and interspecies variation 

The results of PBPK modeling are taken forward for consideration on the appropriate 

adjustment factors. As vinyl acetate is acting locally, a systemic metabolism has not to be 

considered, which reduces the interspecies factor from 10 (default) to 2.5. Remaining 

uncertanties in toxicodynamic differences are recognized, i. e. humans could be more 

sensitive than rats towards local toxicity of vinyl acetate metabolites which could not be 

excluded due to the lack of (primarily human) data. Thus, for risk charaterization an 

interspecies adjustment factor of 2.5 is established. Concerning intraspecies variability the 

same consideration as for interspecies extrapolation applies. No systemic metabolism has to 

be taken into consideration, reducing the intraspecies adjustment factor to 2.5. 

- the nature and severity of the effect 

The main effects considered as „critical effects“ are the degenerative lesions of the olfactory 

mucosa (irreversible, serious health effect). 

There are no reasons to assume that the effects shown in the animal experiments are limited to 

the species tested, thus being not of relevance for humans. Because of the seriousness of the 

effect there is concern, which has to be expressed in the magnitude of the MOS. 

- dose-response-relationship 

In rats as well as mice no steep dose-response-relationship is observed for the irritation effects 

at the olfactorium. At the LOAEC (714 mg/m3

, 200 ppm) only minimal to slight changes in 

the olfactory epithelium were observed. 
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There is no reason to assume concern which has to be expressed in an increased MOS taking 

into account the exposure level.

- differences in exposure (route, duration, frequency and pattern) 

Following the exposure assessment, the consumer may be exposed to vinyl acetate via 

inhalation, whereas oral and dermal exposures are assumed of minor importance. 

a) Inhalation route

The NOAEC used for the discussion of the MOS regarding exposure from carpets is derived 

from a 2-year inhalation study on rats. Because vinyl acetate acts primarily at the nasal cavity, 

systemic effects have not been considered. Moreover, the NOAEC for systemic effects was 

considered to be 714 mg/m3

 for rats and 178 mg/m3 for mice in the same study. 

b) Oral route

The oral route is not relevant for risk characterization (see introductory remarks). 

c) Dermal route

Following the exposure assessment, the consumer may be exposed dermally to vinyl acetate 

via usage of hair setting lotions. The estimated dermal body burden (1 μg/kg bw/d) with an 

assumed absorption of 100% is compared with a NOAEL from an oral 90-day study due to 

the lack of a dermal study. 

There are no reasons to assume that special concern can be derived from this procedure nor 

from the available toxicokinetic information (concerning absorption via different routes was 

set with 100%). 

- the human population to which the quantitative and/or qualitative information on exposure 

applies 

Following the inhalation exposure there is no reason to assume a special risk for elderly, 

children or other people suffering from special diseases. 

- other factors 

There are no other factors known requiring a peculiar margin of safety. 
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MOS for 

Inhalation exposure scenario 

Long-term exposure to 0.036 mg/m3 vinyl acetate is assumed to result via emission from 

carpets. The margin of safety for non-neoplastic effects between the 

 measured exposure level of 0.036 mg/m3

and the 

 NOAEC for local irritation effects of 178 mg/m3 

is judged to be sufficient taking into account the nature of the observed effects (degenerative 

lesions of the olfactory mucosa) and the fact that no steep dose-response relationship is 

observed for the these effects. Considering the short-term exposure, see section Acute 

toxicity. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

MOS for 

Dermal exposure scenario 

The calculation of the dermal exposure due to hair setting lotions leads to an external 

exposure of 1 μg/kg bw/d. The margin of safety between the 

 external dermal exposure 1 μg/kg bw/d 

and the 

 oral NOAEL of 684 mg/kg bw/d 

is judged to be sufficient. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 
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Mutagenicity 

Vinyl acetate is not mutagenic to bacteria, but it induces chromosomal aberrations, gene 

mutations and SCE in several tests with mammalian cells from different sources in culture. 

Furthermore, at high concentrations the formation of DNA-protein-crosslinks and DNADNA-crosslinks is shown with mammalian cells. 

The in vivo genotoxicity of vinyl acetate appears to be limited to toxic doses. Therefore, the 

substance may express its genotoxic potential only when defence mechanisms are overloaded 

and thus it may be reasonable to assume a threshold mechanism of action for vinyl acetate 

genotoxicity. 

Taking into account the low consumer exposure (in the range of up to 20 μg/kg bw/d) based 

on the present knowledge it may be concluded that there is presently no concern regarding in 

vivo mutagenicity. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Carcinogenicity

In cancer studies, vinyl acetate inhalation induced an increased number of nasal tumors 

(mainly papillomas and squamous cell carcinomas) in various regions of the nasal mucosa of 

rats. The total incidence was significantly increased at a concentration of 600 ppm (2142 

mg/m3

) but a single papilloma already developed at 200 ppm. Thus, the NOAEC of 50 ppm 

(178 mg/m3) will be used for the risk characterisation. No significant tumor response was 

seen in a mice cancer bioassay. Occasionally single squamous cell tumors occurred at other 

sites of the respiratory tract in rats and mice. 

For the oral route a marked increase of tumor rates has been observed at 1000 ppm (rat 

(offspring); 70 mg/kg bw/d), at 5000 ppm (mouse; 750 mg/kg/d) and at 10000 ppm (male rat 

442 mg/kg bw/d, female rat 575 mg/kg bw/d). Due to limitations in the study design in the 

studies of Maltoni et al. (1997) and Minardi et al. (2002), the study of Umeda et al. (2004a) is 

considered of higher predictivity (cf. 4.1.2.8). For lower doses, there is concern that 

occasional findings of tumors of the same types that have been observed at high doses and 

which might also be related to vinyl acetate exposure. Thus, the lowest concentration 

suspected to be carcinogenic was 400 ppm for the oral route (LOAEL, male rat 21 mg/kg 

bw/d, female rat 31 mg/kg bw/d, Umeda et al., 2004a). Clearly tumor free dosages were not 

established in carcinogenicity studies for the oral route. Thus, 400 ppm (21 mg/kg bw/d male 

rat) is proposed as LOAEL for oral risk characterisation. Since carcinogenicity is a critical 

toxicological endpoint a risk characterisation for the oral route was calculated. 

Vinyl acetate exposure produced tumors at the site of first contact along the exposure routes 

by inhalative and oral uptake. A thresholded mode of carcinogenic action is thought to be 

active. Uncertainties exist in the proposed mode of action and should taken into account. 
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MOS for 

Inhalation exposure scenario 

Long-term exposure to 0.036 mg/m3 vinyl acetate is assumed to result via emission from 

carpets. The margin of safety for non-neoplastic effects between the 

 measured exposure level of 0.036 mg/m3

and the 

 NOAEC 178 mg/m3 

is judged to be sufficient. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

MOS for 

Oral exposure scenario 

The oral route is not relevant for risk characterization (see introductory remarks). 

Reproductive toxicity 

Since no hazards have been identified regarding fertility and developmental toxicity a risk 

characterisation should not be performed. This decision is further supported by the fact that 

the systemic availability of vinyl acetate is very low. 

4.1.3.4 Man exposed indirectly via the environment 

Indirect exposure to humans via the environment occurs mainly by air. Following the local 

scenario data (at a point source) a maximum intake of a total daily dose of 0.036 mg/kg bw/d 

is calculated. For the regional scenario, the respective figure is 0.00247 μg/kg bw/d. 

The main route of indirect exposure of both scenarios (local and regional) is the intake via 

inhalation of air (cf. 4.1.1.4). Therefore the local concentration of 0.288 mg/m3

 for site 26 was 

selected (Table 3-11; highest value, in chapter 3.1.3.11) and used for risk characterisation. 
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Repeated dose toxicity 

Inhalation 

Local effects on the respiratory tract are not to be expected because of the low concentrations 

in the air of 0.288 mg/m3

 (local exposure). The NOAEC for local toxic effects on the 

respiratory tract of 50 ppm (178.5 mg/m3) was derived from the 2-year studies on rats and 

mice. 

MOS for 

Inhalation exposure scenario 

The margin of safety for non-neoplastic effects between the 

 estimated exposure level of 0.288 mg/m3

and the 

 NOAEC 178 mg/m3 

is judged to be sufficient. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Mutagenicity 

Vinyl acetate is not mutagenic to bacteria, but it induces chromosomal aberrations, gene 

mutations and SCE in several tests with mammalian cells from different sources in culture. 

Furthermore, at high concentrations the formation of DNA-protein-crosslinks and DNADNA-crosslinks is shown with mammalian cells. The in vivo genotoxicity of vinyl acetate 

appears to be limited to toxic doses thus it may be reasonable to assume a threshold 

mechanism of action for germ cell mutagenicity. 

Taking into account the exposure estimates resulting for a point source from a worst case 

calculation and from regional background concentrations it may be concluded that there is 

presently no concern regarding in vivo mutagenicity. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 
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Carcinogenicity 

Vinyl acetate inhalation induced an increased number of nasal tumors (mainly papillomas and 

squamous cell carcinomas) in various regions of the nasal mucosa of rats (cf. 4.1.2.8, 4.1.3.3). 

The total incidence was significantly increased at a concentration of 600 ppm (2142 mg/m3) 

but a single papilloma already developed at 200 ppm. Thus, the NOAEC of 50 ppm (178 

mg/m3) will be used for risk characterisation purposes. 

MOS for 

Inhalation exposure scenario 

The margin of safety for neoplastic effects between the 

 estimated exposure level of 0.288 mg/m3

and the 

 NOAEC 178 mg/m3 

is judged to be sufficient. 

Conclusion ii) 

There is at present no need for further information and/or testing or for risk reduction 

measures beyond those which are being applied already. 

Reproductive toxicity

Since no hazards have been identified regarding fertility and developmental toxicity a risk 

characterisation should not be performed. This decision is further supported by the fact that 

the systemic availability of vinyl acetate is very low. 
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4.2 HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES) 

4.2.1 Exposure assessment 

4.2.1.1 Occupational exposure 

Refer to chapter 4.1.1.1 

4.2.1.2 Consumer exposure 

4.2.1.3 Indirect exposure via the environment 

4.2.2 Effects assessment: Hazard identification and Dose (concentration) - 

 response (effect) assessment 

4.2.2.1 Explosivity 

Vinyl acetate is not explosive. 

4.2.2.2 Flammability 

Vinyl acetate is highly flammable. 

4.2.2.3 Oxidizing potential 

Due to its chemical structure, vinyl acetate is not expected to possess any oxidizing 

properties. 

4.2.3 Risk characterisation 

4.2.3.1 Workers 

Vinyl acetate is highly flammable. Adequate worker protection measures must be observed. 

Risk reduction measures beyond those which are being applied already are not considered 

necessary. 

Conclusion: ii 
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4.2.3.2 Consumers 

4.2.3.3 Man exposed indirectly via the environment 
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5 CONCLUSIONS / RESULTS 

Overall results of the risk assessment: 

( ) i) There is need for further information and/or testing 

(x) ii) There is at present no need for further information and/or testing and for risk 

reduction measures beyond those which are being applied already 

(x) iii) There is a need for limiting the risks; risk reduction measures which are already 

being applied shall be taken into account 

Summary of conclusions: 

Environment

As a follow up to conclusion (i), which was drawn in the first draft of the Environment Section 

of the Comprehensive Risk Assessment Report of Vinyl acetate (August 2002), further acute 

and long-term toxicity tests were performed for the aquatic compartment and more data on a 

number of production and processing sites were obtained, leading to the following revised risk 

characterisation. 

conclusion iii): 

Terrestrial compartment

A risk to the local terrestrial compartment can be identified for the life cycle stage of vinyl 

acetate processing. This conclusion applies to the generic processing scenario for the local 

main source. The unknown processing sites account for a missing tonnage of 325,000 t/a (or 

41 % of the total production volume of 800,000 t/a), compared to a verified processing 

tonnage of 475,000 t/a. 

The risk characterisations for selected (worst case) production and processing sites with site 

specific data indicate no actual risk to the terrestrial compartment. However, the highest 

PEC/PNEC ratio calculated with site specific data (0.86) is not very far from the PEC/PNEC 

ratio calculated for the generic processing scenario (2.33), and there was also a risk at one of 

the production sites (which has been eliminated during the time of the preparation of this 

RAR). Consequently, it is not completely implausible that unknown processing sites pose a 

risk to the terrestrial environment. 

The risk characterisation for the terrestrial compartment could still be revised by requesting 

further testing (i.e. OECD 207 Earthworm acute toxicity test and OECD 208 Terrestrial plants 

growth test). However, a further data improvement by means of testing is not considered a 

reasonable next step by the rapporteur for the following reasons. 
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Further information on the toxicity of vinyl acetate to terrestrial organisms allows for a reevaluation of the potential risk that emanates from the unknown processing sites, but delays 

risk reduction measures in case that a risk still remains with the new data. The rapporteur 

therefore proposes to enter directly into the risk reduction phase, which would be more 

effective than further data improvement at this stage of the risk assessment. 

Risk reduction measures should be considered for all facilities with a vinyl acetate processing 

capacity exceeding 20,000 t/a. This threshold is derived from the generic processing scenario, 

assuming that vinyl acetate is released to soils via sludge application and aerial deposition. 

Sites already applying advanced techniques would not require further consideration of risk 

reduction measures. It is known from some processing/production sites that techniques such 

as waste water distillation, sludge incineration or deposition in a landfill, waste gas 

incineration or vapour recovery systems can avoid significant releases of vinyl acetate to 

soils. 

In principle, the rapporteur agrees with the proposal of SCHER that considering the volatility 

of the substance, terrestrial plants might be exposed via air. However, no guidance is 

available how to derive a PNEC for the air compartment. In addition, the available guidelines 

for terrestrial plants (OECD 208 / 227) are designed to include exposure through soil or by 

wet residues (e.g. spray drift of plant production products). To determine effects of volatile 

compounds, testing needs to be conducted in closed greenhouses or chambers under 

continuous exposure conditions. We feel this kind of testing is not appropriate for vinyl 

acetate, because no indications for high toxicity for plants exist. For other soil organisms, a 

continuous exposure to volatile compounds like vinyl acetate is negligible since the substance 

is expected to evaporate from the soil. 

conclusion ii): 

Aquatic compartment

A risk to the local or regional aquatic compartment (surface water and sediments) was not 

identified for production and processing of vinyl acetate. This conclusion applies to all sites. 

Atmospheric compartment

Based on a qualitative risk characterisation, no unacceptable risk for the atmosphere is 

expected from vinyl acetate. The substance is rapidly removed from air by chemical 

breakdown, adsorption to airborne particles or aerosols, and wet deposition. Furthermore, air 

concentrations indicate a negligible risk with regard to ecotoxicity. 

Non-compartment specific effects

Non compartment specific effects (secondary poisoning) of vinyl acetate are not expected as 

there is no indication that the substance has potentially bioaccumulative properties. 

Marine Assessment including PBT assessment

VAM does not meet the PBT/vPvB criteria. A risk for the regional or local marine 

environment is not expected. 
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Human Health

Workers 

conclusion iii) 

Conclusion iii is expressed for the endpoint of carcinogenicity after dermal contact. Skin 

contact of vinyl acetate should be reduced at scenario 2a (manufacturing of formulations and 

products, vinyl acetate monomer), even if evaporation of the substance reduces the 

contribution of dermal exposure. 

On the background of cancer risks and repeated dose toxicity, air concentrations of vinyl 

acetate at the workplace should be controlled to a level in the range of 17.6 mg/m3

 (critical 

exposure level). Conclusion iii is derived for repeated dose toxicity after inhalation for 

scenario 2 (manufacturing of formulations and products). This scenario with an exposure 

value of 14.6 mg/m3

 is a borderline case. Since there is the uncertainty concerning the 

reduction of the intraspecies factor and the mode of action for carcinogenesis for this 

borderline scenario conclusion iii is drawn.

Consumers 

conclusion ii) 

There is at present no need for further information and/or testing and for risk reduction 

measures beyond those which are being applied already 

Man exposed indirectly via the environment 

conclusion ii) 

There is at present no need for further information and/or testing and for risk reduction 

measures beyond those which are being applied already 
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Appendix I

of the Risk Assessment Report

Vinyl acetate

CAS-No.: 108-05-4 

Estimation of Abiotic Degradation 

April 2005 

1 CAS-No.: 108-05-4 
AOP V1.91 ESTIMATION OF ABIOTIC DEGRADATION 

EstimateSMILES : C=COC(=O)C 

CHEM : C:\EPISUITE\VAM.mol 

MOL FOR: C4 H6 O2 

MOL WT : 86.09 

SUMMARY (AOP v1.91): HYDROXYL RADICALS 

Hydrogen Abstraction = 0.0422 E-12 cm3/molecule-sec 

Reaction with N, S and -OH = 0.0000 E-12 cm3/molecule-sec 

Addition to Triple Bonds = 0.0000 E-12 cm3/molecule-sec 

Addition to Olefinic Bonds = 26.3000 E-12 cm3/molecule-sec 

Addition to Aromatic Rings = 0.0000 E-12 cm3/molecule-sec 

Addition to Fused Rings = 0.0000 E-12 cm3/molecule-sec 

OVERALL OH Rate Constant = 26.3422 E-12 cm3/molecule-sec 

HALF-LIFE = 1.218 Days (12-hr day; 0.5E6 OH/cm3) 

HALF-LIFE = 14.617 Hrs 

** Designates Estimation(s) Using ASSUMED Value(s) 

SUMMARY (AOP v1.91): OZONE REACTION 

OVERALL OZONE Rate Constant = 0.175000 E-17 cm3/molecule-sec 

HALF-LIFE = 6.549 Days (at 7E11 mol/cm3) 

Experimental Database Structure Match: 

Chem Name : Vinyl acetate 

CAS Number: 000108-05-4 

Exper OH rate constant : 25 E-12 cm3/molecule-sec 

Exper OH Reference: (Saunders,S.M. et al.,1993) 

Exper Ozone rate constant: 3.2 E-18 cm3/molecule-sec 

Exper NO3 rate constant : --- cm3/molecule-sec 

Hydrogen Abstraction Calculation: 

Kprim = 0.136 F(-C(=O)OR)=0.136(0.310)= 0.042 

H Abstraction TOTAL = 0.042 E-12 cm3/molecule-sec 

OH Addition to Olefinic Bonds Calculation: 

Kd = K(CH2=CH-)C(-O **)= 26.300(1.00) = 26.300 E-12 cm3/molecule-sec 

ASSUMED Values designated by: ** 

Ozone Reaction with Olefins Calculation: 

Ko = K(CH2=CH-R)O x(-Default Value **)= 0.175000(1.000) = 0.175000 E-17 

cm3/molecule-sec 

ASSUMED Values designated by: ** 

 

2 CAS-No.: 108-05-4 
Appendix II

of the Risk Assessment Report

Vinyl acetate

CAS-No.: 108-05-4 

Estimation of Biodegradability 

April 2005 

1 CAS-No.: 108-05-4 
BIOWIN V4.00 ESTIMATION OF BIODEGRADABILITY 

SMILES : C=COC(=O)C 

CHEM : vinyl acetate 

--------------------------- BIOWIN v4.00 Results ---------------------------- 

Linear Model Prediction: Biodegrades Fast

Non-Linear Model Prediction: Biodegrades Fast

Ultimate Biodegradation Timeframe: Weeks 

Primary Biodegradation Timeframe: Days 

MITI Linear Model Prediction: Readily Degradable

MITI Non-Linear Model Prediction: Readily Degradable

TYPE | NUM | BIOWIN FRAGMENT DESCRIPTION |COEFF | VALUE 

------------------------------------------------------------------------------------- 

 Frag | 1 | Ester [-C(=O)-O-C] |0.1742 | 0.1742 

 MolWt | * | Molecular Weight Parameter | | -0.0410 

 Const | * | Equation Constant | | 0.7475 

RESULT | LINEAR BIODEGRADATION PROBABILITY | | 0.8807 

TYPE | NUM | BIOWIN FRAGMENT DESCRIPTION |COEFF | VALUE 

Frag | 1 | Ester [-C(=O)-O-C] |4.0795 |4.0795 

MolWt| * | Molecular Weight Parameter | | -1.2225 

RESULT | NON-LINEAR BIODEGRADATION PROBABILITY | | 0.9972 

A Probability Greater Than or Equal to 0.5 indicates: Biodegrades Fast 

A Probability Less Than 0.5 indicates: Does NOT Biodegrade Fast

TYPE | NUM | BIOWIN FRAGMENT DESCRIPTION | COEFF | VALUE 

Frag | 1 | Ester [-C(=O)-O-C] | 0.1402 | 0.1402 

MolWt| * | Molecular Weight Parameter | | -0.1903 

Const| * | Equation Constant | | 3.1992 

RESULT | SURVEY MODEL - ULTIMATE BIODEGRADATION | | 3.1491 

------------------------------------------------------------------------------------- 

 TYPE | NUM | BIOWIN FRAGMENT DESCRIPTION | COEFF VALUE 

------------------------------------------------------------------------------------- 

 Frag | 1 | Ester [-C(=O)-O-C] | 0.2290 | 0.2290 

 MolWt| * | Molecular Weight Parameter | | -0.1242 

 Const| * | Equation Constant | | 3.8477 

 

2 CAS-No.: 108-05-4 
RESULT | SURVEY MODEL - PRIMARY BIODEGRADATION | | 3.9525 

 Result Classification: 5.00 -> hours 4.00 -> days 3.00 -> weeks 

 (Primary & Ultimate) 2.00 -> months 1.00 -> longer 

TYPE | NUM | BIOWIN FRAGMENT DESCRIPTION | COEFF | VALUE 

------------------------------------------------------------------------------------- 

Frag | 1 | Ester [-C(=O)-O-C] | 0.3437 | 0.3437 

Frag | 1 | Methyl [-CH3] | 0.0004 | 0.0004 

Frag | 3 | -C=CH [alkenyl hydrogen] | 0.0062 | 0.0186 

MolWt| * | Molecular Weight Parameter | | -0.2561 

Const| * | Equation Constant | | 0.7121 

RESULT | MITI LINEAR BIODEGRADATION PROBABILITY | | 0.8187 

TYPE | NUM | BIOWIN FRAGMENT DESCRIPTION | COEFF | VALUE 

------------------------------------------------------------------------------------- 

Frag | 1 | Ester [-C(=O)-O-C] | 2.4462 | 2.4462 

Frag | 1 | Methyl [-CH3] | 0.0194 | 0.0194 

Frag | 3 | -C=CH [alkenyl hydrogen] | 0.0285 | 0.0855 

MolWt| * | Molecular Weight Parameter | | -2.4853 

RESULT | MITI NON-LINEAR BIODEGRADATION PROBABILITY | | 0.9303 

------------------------------------------------------------------------------------- 

A Probability Greater Than or Equal to 0.5 indicates --> Readily Degradable 

A Probability Less Than 0.5 indicates --> NOT Readily Degradable 

3 CAS-No.: 108-05-4 
Appendix III

of the Risk Assessment Report

Vinyl acetate

CAS-No.: 108-05-4 

Distribution and fate 

April 2005 

1 CAS-No.: 108-05-4 
Distribution and Fate

time d Tag

melting point:

vapour pressure:

water solubility:

part. coefficient octanol/water:

molecular weight:

gas constant:

temperature:

conc. of suspended matter

in the river:

density of the solid phase:

volume fraction water in susp. matter:

volume fraction solids in susp.matter:

volume fraction of water in sediment:

volume fraction of solids in sediment:

volume fraction of air in soil:

volume fraction of water in soil:

volume fraction of solids in soil:

aerobic fraction of the sediment comp.:

product of CONjunge and SURFair:

MP 180 K.

VP 12000Pa .

SOL 20000mg . l 1 .

LOGPOW 0.7

MOLW 0.086 kg . Mol 1 .

R 8.3143J. Mol 1 . K 1 .

T 293 K.

SUSP water 15 mg . l 1 .

RHOsolid 2500 kg . m 3 .

Fwater susp 0.9

Fsolid susp 0.1

Fwater sed 0.8

Fsolid sed 0.2

Fairsoil 0.2

Fwater soil 0.2

Fsolid soil 0.6

Faer sed 0.1

product 10 4 Pa .

Distribution air / water: Henry-constant 

HENRY VP MOLW .

SOL HENRY 51.6 Pa m3 . Mol 1 = .

log HENRY

Pa m3 . Mol 1 .

= 1.713

K air_water

HENRY

R T. K air_water = 0.021

2 CAS-No.: 108-05-4 
Solid / water-partition coefficient Kpcomp and 

total compartment/water-partition coefficient Kcomp_water

a 0.52 (a,b from TGD, p. 541 for nonhydrophobics)

b 1.02 K OC 10

a LOGP OW . b

l

. kg 1 . K OC 24.21 l kg 1 = .

Suspended matter

Kp susp 0.1 K OC . Kp susp 2.421 l kg 1 = .

K susp_water Fwater susp Fsolid susp Kp susp . RHOsolid . K susp_water = 1.505

factor for the calculation of Clocalwater

:

faktor 1 Kp susp SUSPwater . faktor 1 =

Sediment

Kp sed 0.05 K OC . Kp sed 1.211 l kg 1 = .

K sed_water Fwater sed Fsolid sed Kp sed . RHOsolid . K sed_water = 1.405

Soil

Kp soil 0.02 K OC . Kp soil 0.484 l kg 1 = .

K soil_water Fairsoil K air_water . Fwater soil Fsolid soil Kp soil . RHOsolid .

K soil_water = 0.931

Sludge (activated sludge)

K p_sludge 0.37 K OC . K p_sludge 8.958 l kg 1 = .

Raw sewage

K p_sewage 0.30 K OC . K p_sewage 7.263 l kg 1 = .

Elimination in STPs 

rate constant in STP: k = 1 h -1 elimination P = f ( k, logpow, logH) = 90 % 

fraction directed to surface water Fstp water = 0,1

3 CAS-No.: 108-05-4 
Biodegradation in different compartments

surface water

kbio water 0.047 d 1 . (TGD, table 5)

soil

DT50bio soil 30 d. (TGD, table 6)

kbio soil

ln 2( )

DT50bio soil

kbio soil 0.023 d 1 =

sediment

kbio sed

ln 2( )

DT50bio soil

Faer sed . kbio sed 2.31 10 3 . d 1 =

Degradation in surface waters

khydr water 0.0407d 1 .

kphoto water 1 10 10 . d 1 .

kdeg water khydr water kphoto water kbio water

kdeg water 0.088 d 1 =

Atmosphere

calculation of CONjunge * SURFaer for the OPS-model

VPL VP

exp 6.79 1 MP

285 K. . VP wenn MP 285 K ( ) > . , VPL, VP VP 1.2 104 = . Pa

Fass aer

product

VP product

degradation in the atmosphere Fass aer 8.333 10 9 = .

kdegair = 0,0475 h-1 (see AOP-calculation)

4 CAS-No.: 108-05-4 
Appendix IV

of the Risk Assessment Report

Vinyl acetate

CAS-No.: 108-05-4 

Continental and regional exposure 

 May 2006 

1 CAS-No.: 108-05-4 
SimpleBox2.0a INPUT - Vinyl acetate 

Unit Input 

Physicochemical properties

COMPOUND NAME [-] Vinyl acetate Substance

MOL WEIGHT [g.mol-1] 86 Molecular weight 

MELTING POINT [° C] -93.2 Melting Point

VAPOR PRESSURE(25) [Pa] 12000 Vapour pressure at 25°C 

log Kow [log10] 0.7 Octanol-water partition coefficient 

SOLUBILITY(25) [mg.l-1] 20000 Water solubility 

Distribution - Partition coefficients 

 - Solids water partitioning (derived from Koc)

Kp(soil) [l.kgd

-1] 0.484 Solids-water partitioning in soil 

Kp(sed) [l.kgd

-1] 1.211 Solids-water partitioning in sediment 

Kp(susp) [l.kgd

-1] 2.421 Solids-water partitioning in sudpended matter 

 - Biota-water

BCF(fish) [l.kgw

-1] 3.16 Biocentration factor for aquatic biota 

Degradation and Transfromation rates 

 - Characterisation and STP

PASSreadytest [y / n] y Characterization of biodegradability 

 - Environmental Total Degradation

kdeg(air) [d-1] 1.14E+00 Rate constant for degradation in air 

kdeg(water) [d-1] 8.80E-02 Rate constant for degradation in bulk surface water 

kdeg(soil) [d-1] 2.30E-02 Rate constant for degradation in bulk soil 

kdeg(sed) [d-1] 2.31E-03 Rate constant for degradation in bulk sediment 

Sewage treatment (e.g. calculated by SimpleTreat)

 - Continental

FR(volatstp) [C] [-] 1.16E-01 Fraction of emission directed to air (STPcont) 

FR(effstp) [C] [-] 1.00E-01 Fraction of emission directed to water (STPcont) 

FR(sludgestp) [C] [-] 2.00E-03 Fraction of emission directed to sludge (STPcont) 

 - Regional

FR(volatstp) [R] [-] 1.16E-01 Fraction of emission directed to air (STPreg) 

FR(effstp) [R] [-] 1.00E-01 Fraction of emission directed to water (STPreg) 

FR(sludgestp) [R] [-] 2.00E-03 Fraction of emission directed to sludge (STPreg) 

Release estimation

 - Continental

Edirect(air) [C] [t.y-1] 2879,52 Total continental emission to air 

STPload [C] [t.y-1] 364.78 Total continental emission to wastewater 

Edirect(water1) [C] [t.y-1] 0 Total continental emission to surface water 

Edirect(soil3) [C] [t.y-1] 0 Total continental emission to industrial soil 

Edirect(soil2) [C] [t.y-1] 0 Total continental emission to agricultural soil 

Edirect(air) [R] [t.y-1] 319,95 Total regional emission to air 

STPload [R] [t.y-1] 40.53 Total regional emission to wastewater 

Edirect(water1) [R] [t.y-1] 0 Total regional emission to surface water 

Edirect(soil3) [R] [t.y-1] 0 Total regional emission to industrial soil 

2 CAS-No.: 108-05-4 
Edirect(soil2) [R] [t.y-1] 0 Total regional emission to agricultural soil 

SimpleBox2.0a OUTPUT - Vinyl acetate 

Physicochemical properties

COMPOUND NAME [-] Vinyl acetate Substance

Output

 - Continental

PECsurfacewater (total) [mg.l-1] 9,22E-07 Continental PEC in surface water (total) 

PECsurfacewater (dissolved) [mg.l-1] 9,22E-07 Continental PEC in surface water (dissolved) 

PECair [mg.m-3] 1,87E-06 Continental PEC in air (total)

PECagr.soil [mg.kgwwt-1] 1,10E-07 Continental PEC in agricultural soil (total) 

PECporewater agr.soil [mg.l-1] 2,02E-07 Continental PEC in pore water of agricultural soils 

PECnat.soil [mg.kgwwt

-1] 4,64E-08 Continental PEC in natural soil (total) 

PECind.soil [mg.kgwwt

-1] 4,64E-08 Continental PEC in industrial soil (total) 

PECsediment [mg.kgwwt

-1] 9,51E-07 Continental PEC in sediment (total) 

 - Regional

PECsurfacewater (total) [mg.l-1] 8,33E-06 Regional PEC in surface water (total) 

PECsurfacewater (dissolved) [mg.l-1] 8,33E-06 Regional PEC in surface water (dissolved) 

PECair [mg.m-3] 9,67E-06 Regional PEC in air (total)

PECagr.soil [mg.kgwwt

-1] 9,05E-07 Regional PEC in agricultural soil (total) 

PECporewater agr.soil [mg.l-1] 1,66E-06 Regional PEC in pore water of agricultural soils 

PECnat.soil [mg.kgwwt

-1] 2,40E-07 Regional PEC in natural soil (total) 

PECind.soil [mg.kgwwt

-1] 2,40E-07 Regional PEC in industrial soil (total) 

PECsediment [mg.kgwwt

-1] 8,62E-06 Regional PEC in sediment (total) 

3 CAS-No.: 108-05-4 
Vinyl Acetate_MTD_0209.doc 

Appendix: MTD exceeded in vinyl acetate studies? The question has been raised whether the highest concentrations/doses tested exceed the maximum tolerated The MTD has been exceeded if a test concentration induce the following effects:  Significantly reduced body weight (BW) gain (reduction of ≥10%) as sign of nonspecific toxicity or as conseque

effects 

• Treatment-related mortalities, associated with significantly reduced life spans in long-term studies • Indications on severe systemic toxicity from clinical, functional, laboratory or morphological examinations The following repeated dose studies with inhalation and oral exposure to vinyl acetate have been analysed: (Sequences of studies analogue to RAR Chapters on Repeated dose toxicity/Inhalation studies and Carcinogen

Reference Treatmentrelated 

Mortalities 

Mean BW/gain reduction 

% Decrease in final BW or BW gain 

Food and water consumption estimated/ reduced 

Respiratory tract toxicity 

Clinof to

Inhalation route 

Gage, 1970 3 w study on rats 0, 100, 250, 

630, 2000 ppm 

(shortly summerized data only) 

No incidental deaths in rats 

Low BW gain in M/f 2000 ppm & F≥250 ppm 

No quantitative data 

No data 2000 ppm 

alveolar histiocytosis 

2000 eye/irritarespdiffic

Owen, 1979a,b 4 wk range finding studies on mice & rats

0, 150, 500, 

No incidental deaths in rats and mice 

Significant lower BW gain in m/f mice at 1000 ppm Non-significant 

No tables or figures available 

No data No data Mice 

& ratppm resphunc
Vinyl Acetate_MTD_0209.doc 

1000, (50/)1500 ppm 

decrease in BW gain in rats up to 1500 ppm 

post

Bogdanffy et al., 1997 1,5 or 20 d (cell proliferation) studies on rats

0, 50, 200, 600, 1000 ppm 

No incidental deaths 

Reduced mean BW at 1000 ppm day 3 to day 26 

-11% at the end of study, max – 14% in week 5 

No data Olfactory 

degeneration ≥600 ppm, minimal degenration in respiratory mucosa at 1000 ppm 

No eobseed 

Owen, 1980 a,b 90 day studies on rats & mice

0, 50, 200, 1000 ppm 

Rat: One 

incidental death in a control rat, 

Mice: in 6 f and 

3 m of high dose, 2 m controls, all died during blood sampling procedure 

Rats & mice: 

Lower mean final BW and significantly educed BW gain at 1000 ppm 

Rats: Mean 

final BW in m and f -19% Mean BW gain 

– 38% (m), - 54% (f) lower in 1000 ppm rats Mice: Mean 

final BW in m –18% and in f17%, Mean BW gain

No data Rats: Lung 

effects (related to parasitic infection), 

Mice at 1000 

ppm metahyperplasia, inflammation in nasal mucosa (type of epithelium not identified), 

Mice 

and ppm respdistrhuncpostfur 
Vinyl Acetate_MTD_0209.doc 

– 60% (m) –50% (f) in 1000 ppm mice 

trachea, bronchia 

Owen, 1988, Bodanffy et al., 1994b 53 wk, 83 wk, 2 years, or 70 wk plus 16 wk recovery on rats and mice 0, 

50, 200, 600 ppm 

No treatment related mortalities 

Rats & mice: 

End of study: significantly lower BW gain at 600 ppm and in mice at 200 ppm: 

Rats & Mice: 

mean final BW at the end of study rats: (m) –10% (f) –15% ( no data specified), mice at 600 ppm (m&f) –15%), not quantified for 200 ppm 

Rats:

Decreased blood glucose (f at 600 ppm) and reduced urine volume (m & f at 600 ppm) are contributed to the nonmeasured reduced food and water consumption 

Rats & Mice: 

≥200 ppm olfactory degeneration, metaplasia Trachea (in mice at 600 ppm) metahyperplasia rough haircoat, hunched posture, lung (600 ppm rats & mice) increased weight, degeneration of bronchiolar epithelium, alveolar histiocytosis 

Rats 

≥50 hairchuncpost
Vinyl Acetate_MTD_0209.doc 

Oral administration 

Reference Treatmentrelated 

Mortalities 

Mean BW/gain reduction 

% Decrease in final BW or BW gain 

Food and water consumption estimated/ reduced 

Gastrointestinal tract toxicity 

Clsito

Gale, 1979 4-wk dose rangefinding studies on rats & mice

0, 50 (to 10000 ppm in wk 4), 150, 1000 or 5000 ppm in water 

No mortalities Reduced BW 

gain in rats f≥1000 ppm and m ≥5000 

ppm and in male mice at 5000 ppm 

No data Rats: Reduced 

water consumption f≥1000 ppm and m≥5000 ppm, reduced food consumption f at 10000 ppm (-11%) 

Mice: Reduced 

water consumption in m at ≥1000 ppm and f≥5000 ppm, reduced food consumption in f at 5000 ppm 

- M

anhyin 

50

Gale, 1980 13-wk studies (OECD 408) in rats & mice, o, 

200, 1000, 5000 ppm 

No treatmentrelated mortalities 

Nonsignificantly lower mean BW in m rats at 5000 ppm (-8%) 

Mice: no effect 

on overall BW gain 

- Rats: significantly 

reduced water consumption in m & f at 5000 ppm (-23%, -25%) , transiently reduced in m&f at 1000 ppm 

Mice: no change 

of water and food consumption 

- No 

ob
Vinyl Acetate_MTD_0209.doc 

DuPont, 2000 92-day study on cell proliferation of oral cavity in rats 0, 1000, 

5000, 10000, 24000 ppm, males only 

No mortalities lower mean BW 

≥5000 ppm & lower BW gain ≥5000 

lower mean BW -8.8, -7.4, - 6.1% lower BW gain ppm -13.4, -11, -9.2% 

significantly lower water consumption ≥5000 ppm, (-28, -37, -40.3%) lower overall food consumption nonsign. At 5000 ppm (-7.2%), signif. At ≥10000 ppm (-6%, - 7.4%) , no effect on food efficiency 

Oral cavity: Increased proliferation rates ≥10000 ppm thoughout & at the end of the study 

No sigor les

DuPont 2000 92-day study on cell proliferation in the oral cavity in mice 0, 1000, 

5000, 10000, 24000 ppm, males only 

No mortalities no effect on 

BW/BW gain 

- significantly lower 

water consumption at ≥1000 ppm (-23, -30.5, -31.4, -35%), no effect on overall food consumption & efficiency 

Oral cav ity: Increased cell proliferation at day 92 only 

No sigor les

Bogdanffy et al., 1994a 2 years, interim sacrifices at wk 52, 78 rats 0, 

200, 1000, 5000 ppm 

No treatmentrelated mortalities 

Reduced BW gain at 5000 ppm m –11% in 1st year, -17% 

2nd year, f -11% 

2nd year 

Significantly lower water consumption at 1000 ppm (m -4.5% to max. –11%, f –5%-max. 16% at various intervals), at 5000 ppm (m –18% to max. – 34%, f –20% to max. 39%) reduced food consumption in m 

No tissues from oral cavity examined for histopathology, no effect on tongue and stomach 

No sigor reles
Vinyl Acetate_MTD_0209.doc 

at 5000 ppm (-3% to max. –12%) 

Lijinsky and Reuber, 1983 130 wk, rats at 

0, 1000 or 2500 ppm 

No treatmentrelated mortalities 

No data - No data No data No 

Celanese, 1998 (=Japanese Bioassay) 104 wk rats & mice

0, 400, 2000, 10000 ppm 

No treatmentrelated mortalities 

Rats: lower 

mean in m& f at 10000 ppm at the end of study

Mice: Lower 

mean BW in 2nd

year in m &f at 10000 ppm 

Rats: about 6-

7% below controls (calculated from graphics) 

Mice: m 37 g 

versus 52 g in controls, about –20%(f) to 30% (m) at the end of study 

Rats: lower water 

consumption at 10000 ppm throughout the stud, about –27% to –30% at the end of study (calculated from graphics) 

Mice: Low water 

consumption in 2nd

year at 10000 ppm, at the end of study about –18% (f) to –35% (m) (calculated from graphics), No effect on food consumption 

No data on toxic effects 

No cli
Vinyl Acetate_MTD_0209.doc 

Conclusion: 1. From inhalation studies on repeat-dose toxicity (subacute, subchronic, chronic) or carcinogenicity (2 yea• there were no treatment-related mortalities, • no indication on systemic toxicity • significantly reduced body weigth gain and final body weight Reduced body weight gain is one of the critieria indicative for an excess of MTD. In inhalation studies on vinyl amean final body weight or mean body weight gain was seen at concentrations of 1000 ppm in rats and mice expWhen rats and mice were exposed to vinyl acetate during 2 years, lower BW gain was observed at 600 ppm, wsignificant increase in nasal tumors in rats and the highest dose tested. Significantly reduced urine volume and 

end of study indicated that lower body weight gain can be attributed to reduction in the water and food consumpand all other studies. 

Although not examined, it is likely, that reduced BW gain and lower bw gain was interpreted to be related to redconsumption. Therefore, for concentrations up to 600 ppm exposed during 2 years the MTD was not exceeded. 2. For the oral studies on repeat-dose toxicity (subacute and subchronic) • There were no treatment-related mortalities, • no indication on nonspecific or systemic/specific toxicity • and reduced mean BW (gain) was interpreted to be related to the lower water/food consumption. Presumably due to a bad palatibility in drinking water, rats and mice of the oral studies had a reduced water or wBecause of the absence of other toxic effects and the consistency of dose-responses, the lower mean BW or B

reduced consumption of water and food. 

Therefore, for doses up to 24000 ppm administered up to 2 years, the MTD was not exceeded.