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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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2.5 Vinyl acetate

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create new entries for vinyl acetate in Schedules 6 and 10 of the Poisons Standard.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are:

Schedule 6 – New Entry

VINYL ACETATE (if appropriate, exempt up to 1% concentration in domestic products).

Schedule 10 – New Entry

VINYL ACETATE for cosmetic use.

Appendix E, Part 2 – New Entry

VINYL ACETATE

Standard Statement: A (For advice, contact a Poisons Information Centre or a doctor).

Appendix F, Part 3 – New Entry

VINYL ACETATE

Warning Statement: 6 (May cause cancer).

Safety Directions: 4 (Avoid contact with skin); 8 (Avoid breathing vapour); 9 (Use only in well ventilated area).

The applicant's reasons for the request are:

  • Vinyl acetate is highly volatile, a respiratory irritant, and may have genotoxic and carcinogenic potential;
  • Domestic uses of vinyl acetate in Australia were identified in paints, lacquers, varnish, adhesives and possibly in automotive products;
  • Domestic uses identified overseas include products containing vinyl acetate up to 67% in a home maintenance paste (US Household Products Database). However, available data suggest that most products contain 1% or less; glues/adhesives (0-1%), foam sealants (0.1-2%), or paints/varnish/primer (0.1-0.5%) (US Household Products Database);
  • Previously allowed cosmetic use was for a film forming substance (in 2006) in the European Union (EU); this use has been prohibited from 1 January, 2015 under Reg 944/2013 (CosIng); and
  • When vinyl acetate is used in domestic products, the potential for respiratory irritation, mutagenicity and carcinogenicity from vapours clearly presents a risk. The risk can be controlled by imposing concentration restrictions and warning labels for domestic uses. If there is any cosmetic use of vinyl acetate in Australia, it should be prohibited.

Current scheduling status and relevant scheduling history

Vinyl acetate is not currently scheduled and has not been previously considered for scheduling. Therefore, a scheduling history is not available.

Australian regulatory information

Vinyl acetate is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 as follows:

Table 2.5.1: Permissible ingredients and requirements applying to vinyl acetate when contained in a medicine
Column 1 Column 2
Ingredient Name
Column 3
Purpose of the ingredient in the medicine
Column 4
Specific requirements(s) applying to the ingredient in Column 2
5014 VA/BUTYL MALEATE/ISOBORNYL ACRYLATE COPOLYMER E

Vinyl acetate is a mandatory component of VA/butyl maleate/isobornyl acrylate copolymer.

The concentration of vinyl acetate in the medicine must be no more than 0.01% or 100 ppm.

Only for use in topical medicines for dermal application and not to be included in medicines intended for use in the eye.

The concentration in the medicine must be no more than 5%.

According to the TGA Ingredient Database, vinyl acetate is available for use as an:

  • Excipient only in biologicals, devices and prescription medicines; and
  • Equivalent ingredient in devices, listed medicines and prescription medicines.

Vinyl acetate is in 59 products listed on the Australian Register of Therapeutic Goods (ARTG):

  • 1 Medical device (Class IIa);
  • 24 Non-prescription medicines; and
  • 34 Prescription medicines.

Vinyl acetate is not listed in the Database of Adverse Events Notification (DAEN) - Medicines.

International regulations

EU

Vinyl acetate is classed as a CMR 2 (carc.2) substance[6]and is prohibited for use in cosmetics and personal care products in the European Union (EU) from 1 January 2015, as per EU Regulation No 944/2013.

USA

The Food and Drug Administration (FDA) has determined that vinyl acetate may be safely used as a coating or a part of a coating (e.g. an adhesive) that is used in plastic films for food packaging, and as a modifier of food starch.[7][8]

The American Conference of Governmental Industrial Hygienists (ACGIH) has established an exposure limit of 10 parts of vinyl acetate per million parts of workplace air (10 ppm) for an 8-hour workday, 40-hour workweek.11

The National Institute for Occupational Safety and Health (NIOSH) recommends that exposure to vinyl acetate in the workplace not exceed 4 ppm over a 15-minute period.11

Substance summary

Vinyl acetate is a clear, colourless liquid. It has a sweet, pleasant, fruity smell, but the odour may be sharp and irritating to some people. Vinyl acetate can be smelt when it is in the air at levels around 0.5 ppm. It readily evaporates into air and dissolves easily in water.

Vinyl acetate is flammable and may be ignited by heat, sparks, or flames. Vinyl acetate is used to make other industrial chemicals (such as polyvinyl acetate polymers and ethylene-vinyl acetate copolymers). These are used mainly to make glues for the packaging and building industries. These are also used to make paints, textiles, and paper.[9]

Table 2.5.2: Chemical information for Vinyl acetate
Property Substance
Chemical structure chemical structure of vinyl acetate
Molecular formula C4H6O2
Molecular weight 86.1 g/mol
CAS name Acetic acid ethenyl ester
CAS number 108-05-4
IUPAC and/or common and/or other names Ethenyl acetate (IUPAC);
Vinyl acetate (INCI, AAN).

The following information was extracted from the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for Acetic acid, ethenyl ester, publicly available on the NICNAS website.

Table 2.5.3: Acute toxicity end-points for vinyl acetate
Toxicity Species Vinyl acetate SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 2500-3500 Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rabbit 2335 Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat 4490 ppm or ~15810 mg/m3 (vapour) Schedule 5
Skin irritation Rabbit Slight Schedule 5
Eye irritation Rabbit Slight Schedule 5
Skin sensitisation (LLNA ) Mouse Negative N/A

Acute toxicity

Vinyl acetate has low acute oral and dermal toxicity in animals (LD50 >2000 mg/kg bw).

Based on the available data, vinyl acetate (as a vapour) has moderate acute inhalation toxicity in rats.

Irritation

Vinyl acetate has been classified by NICNAS as a respiratory irritant based on: effects observed in humans following exposure to vinyl acetate; necropsy findings from acute inhalation studies in animals and clinical signs of toxicity observed in repeat dose inhalation studies in animals.

In male Sprague Dawley (SD) rats exposed (whole body) to vinyl acetate vapour on either one, five or 20 occasions (for six hours per day, five days per week) at concentrations of 50, 200, 600 or 1000 ppm (whole body), a dose related increase in the severity of microscopic lesions in the olfactory epithelium was observed at 600 ppm and above. Following a single exposure, degeneration, necrosis and exfoliation of olfactory epithelial cells were observed (REACH).

In three-month inhalation studies conducted in rats and mice, clinical signs of toxicity included intermittent symptoms of respiratory distress, hunched posture and ruffled fur in animals exposed to vinyl acetate at 200 – 1000 ppm concentrations. Increased lung weight observed in rats and mice exposed to vinyl acetate at 1000 ppm was attributed to lung congestion arising from respiratory irritation. Treatment-related lesions were observed at necropsy in the lungs, trachea and nasal epithelium of mice exposed to vinyl acetate at 1000 ppm (REACH).

Vinyl acetate may cause slight eye and skin irritation.

Sensitisation

Based on the negative results observed for vinyl acetate in a well conducted (OECD TG 429 compliant) local lymph node assay (LLNA) in CBA/CaOlaHsd mice, vinyl acetate is not considered to be a skin sensitiser.

Repeat-dose toxicity

Vinyl acetate is not considered to cause severe effects following repeated oral exposure. No data are available on repeated dermal exposure.

Repeated inhalation exposure to vinyl acetate may cause symptoms consistent with respiratory irritation and inflammation. Based on the available data, vinyl acetate is not considered to cause severe systemic effects following repeated inhalation exposure, apart from causing histopathological changes in the olfactory epithelium and respiratory system, which are considered possible evidence of precursor events to tumour formation (see Carcinogenicity).

Genotoxicity

Vinyl acetate showed positive results for genotoxicity, both in vitro and in vivo. Based on the weight of evidence from the available genotoxicity data, vinyl acetate may have genotoxic potential and NICNAS classified it as a Category 3 Mutagen according to the Approved Criteria for Classifying Hazardous Substances.

Although in vitro assays utilising bacterial cells have shown negative results for mutagenicity, positive results have been obtained using mammalian cells (in vitro and in vivo), particularly for chromosome effects (ACGIH, 2001; IARC, 1995; Norppa et al., 1985; REACH). It has been hypothesised that the genotoxicity of vinyl acetate may be attributable to the formation of acetaldehyde, although the lowering of cell pH that occurs when large doses of vinyl acetate are metabolised to acetic acid may also be a contributing factor (Albertini, 2013).

Vinyl acetate undergoes hydrolysis under aqueous conditions to form acetaldehyde and acetic acid, which both have a negative effect on cells. Genotoxicity of vinyl acetate may be attributable to the formation of acetaldehyde, which is a Category 3 mutagen. Acetic acid that acts to lowering cell pH may also be a contributing factor.

Vinyl acetate vapour or liquid tested negative for mutagenicity in Salmonella typhimurium strains TA 98, 100, 1535, 1537 and 1538, in the presence or absence of metabolic activation (ACGIH, 2001).

All other in vitro assays showed positive results with vinyl acetate:

  • A dose-dependent and statistically significant increase in sister chromatid exchange (SCE) was observed in human lymphocytes (whole blood culture) following exposure for 48 hours to concentrations of 0.1 mM of vinyl acetate and above. A dose-dependent increase in chromosome aberrations was also observed. An increased number of aberrant cells (gaps included or excluded), number of cells carrying chromatid-type aberrations or chromatid-type exchanges was statistically significant at 0.5 mM (Norppa et al., 1985).
  • A dose-dependent increase in SCE was observed in Chinese hamster ovary (CHO) cells following exposure to vinyl acetate for 24 hours at doses of 0.125-1 mM or exposure to vinyl acetate for 4 hours at doses of 0.3-5 mM (Norppa et al., 1985).
  • Induced DNA cross links in isolated human lymphocytes and rat nasal epithelial cells at 860 μg/mL (IARC, 1995).
  • Increased numbers of micronuclei in human lymphoblastoid cells (TK6) following a 4-hour exposure to concentrations of 0.25, 0.5, 1 or 2 mM in a micronucleus assay (a similar protocol to OECD TG 487). Acetaldehyde, a metabolite of vinyl acetate, was also found to be positive in this same assay at concentrations of 0.25, 0.5 and 1 mM (REACH).
  • Increased chromosome aberrations in human whole blood and isolated human lymphocytes after exposure (similar to OECD TG 473) to concentrations of 0.25, 0.5, 1 or 2 mM for 24 hours, without metabolic activation (REACH).

Three in vivo genotoxicity studies showed positive results with vinyl acetate (REACH):

  • A dose-dependent increase in micronuclei was observed in C57BL mice that received an intraperitoneal injection of vinyl acetate at 250, 500, 1000 or 2000 mg/kg bw (similar to OECD TG 474). Increases were statistically significant at the 2 high doses that caused increased mortality.
  • Male mice that received vinyl acetate for 5 days at 125, 250, 500 or 750 mg/kg bw/day via i.p. injection showed effects on testicular weight (reduced at 125 and 500 mg/kg bw/day), sperm count (decreased with increased dosing) and morphology (5 weeks after treatment 3/7 had sperm abnormalities at 500 mg/kg bw/day). One mouse (1/5) survived at the highest dose, and showed an increased level of abnormal sperm.
  • There was an increased frequency of chromosomal aberrations in cultured lymphocytes of humans following occupational exposure (IARC, 1995). No additional details were available.

Carcinogenicity

According to the International Agency for Research on Cancer (IARC), vinyl acetate is a Group 2B carcinogen 'possibly carcinogenic to humans' (IARC, 1995). The IARC classification was based on limited evidence in experimental animals, although the evidence in humans was considered to be insufficient to establish carcinogenicity (IARC, 1995). Vinyl acetate has a harmonised GHS classification in the EU as a Category 2 carcinogen (suspected of causing cancer).

Based on the positive carcinogenicity findings in animals following both oral and inhalation exposure to vinyl acetate, NICNAS classified vinyl acetate as a Category 3 carcinogen according to the Approved Criteria for Classifying Hazardous Substances.

Groups of Swiss mice and SD rats (n = 60/sex/dose) exposed (via inhalation) to vinyl acetate at 0, 50, 200 or 600 ppm, six hours per day, five days per week, for 104 weeks showed evidence of carcinogenicity. One lung squamous cell carcinoma was reported in a high dose male mouse. Several non-neoplastic lesions in mice were reported in the respiratory tract (olfactory epithelium atrophy, respiratory metaplasia, squamous metaplasia of respiratory epithelium in nasal cavity, tracheal epithelial hyperplasia). There was an increased incidence of squamous cell carcinoma in the nasal cavity in high dose female rats (4/59) compared with controls. There was a statistically significant increase in the total number of nasal tumours (benign and malignant) in high dose male rats. Non-neoplastic observations in rats included thinning of the olfactory epithelium of the nasal cavity, accompanied by basal cell hyperplasia (IARC, 1995).

There is additional evidence of carcinogenicity in animals since the IARC decision in 1995. Vinyl acetate administered to Wistar rats and Swiss mice at 5000 ppm in drinking water resulted in statistically significant increases in the percentage of animals with malignant tumours (cancers in the oral cavity, tongue, oesophagus and fore-stomach, and upper gastrointestinal tract). Female mice also showed tumours in the uterus at 5000 ppm (Soffritti et al., 2008).

Reproduction and developmental toxicity

Based on the available data following oral and inhalation exposure in animals, vinyl acetate is not considered to cause reproductive or developmental toxicity. Developmental effects in rats were only observed at maternally toxic doses.

Observation in humans

Respiratory irritation: Volunteers exposed to vinyl acetate at 19.4-71 ppm for 0.5-4 hours reported respiratory irritation. In workers exposed to vinyl acetate at average levels of 5-10 ppm (with possible acute exposures of 300 ppm), irritation of the throat and eyes was reported at levels of 21 ppm, but eye irritation was not reported under 10 ppm (ACGIH, 2001).

Carcinogenicity: In a cohort study of 4806 men employed at a chemical manufacturing plant in the US between 1942-1973, the cohort had an excess risk of cancer (as compared to national rates) in the respiratory system. One subgroup, with undifferentiated large-cell lung cancer, had higher exposure to vinyl acetate (IARC, 1995).

A nested case-control study in the US investigated individuals who had died between 1940 and 1978 from certain cancers following exposure to 21 chemicals, including vinyl acetate. Potential exposure to vinyl acetate was reported for 7/52 deaths associated with non-Hodgkin's lymphoma, 3/20 deaths associated with multiple myeloma, 2/18 deaths associated with lymphocytic leukaemia and 2/39 deaths associated with non-lymphocytic leukaemia (IARC, 1995).

Public exposure

The critical health effects for vinyl acetate include local effects (respiratory irritation) and systemic long term effects (carcinogenicity and genotoxicity).

Vinyl acetate has domestic uses identified in Australia in adhesives, paints, lacquers and varnish, and possibly in automotive products. No use concentrations of vinyl acetate in these products areavailable. Based on these uses, the general public may be exposed to vinyl acetate via inhalation and/or dermal contact.

Vinyl acetate is highly volatile (vapour pressure = 90.2 mm Hg at 20°C; ChemIDplus). Reducing the concentration in domestic products to result in vapour pressure similar to or below the assigned exposure standard for vinyl acetate (10 ppm time-weighted average (TWA); HSIS, SWA) may eliminate the risk of respiratory irritation from inhalation of chemical vapour.

From the calculation below, a concentration limit of about up to 1% in domestic products is estimated to generate vapour concentration similar to the assigned TWA exposure standard for vinyl acetate:

Saturated vapour concentration for vinyl acetate at 100% = 90.2/760 x 100%
= 11.87% or 118,700 ppm
Concentration required generating vapour pressure similar to 10 ppm TWA = 100%/118,700 ppm x 10 ppm
= 0.84%

It is possible that vinyl acetate may be used in cosmetics in Australia, as it was allowed to be used as a film forming agent (concentration not available) in cosmetics in the EU until January 2015.

Pre-meeting public submissions

Two (2) public submissions were received and both supported the proposal. One submissions also noted that specifying cosmetic use in the Schedule 10 entry, and domestic use in the Schedule 6 entry would ensure that industrial uses, including as a manufacturing intermediate, would be unaffected.

The public submissions will be made available on the TGA website.

Summary of ACCS-ACMS advice to the delegate

The committee recommended that a new Schedule 6 entry be created for vinyl acetate, and Appendix E, Part 2 and Appendix F, Part 3 entries as follows:

Schedule 6 – New Entry

VINYL ACETATE MONOMER (excluding its derivatives) except:

  1. in preparations for therapeutic use; or
  2. in preparations for domestic use containing 1 per cent or less of vinyl acetate; or
  3. in preparations containing 0.01 per cent or less of vinyl acetate as residual monomer in a polymer.

Appendix E, Part 2 – New Entry

VINYL ACETATE

Standard Statements: A (For advice, contact a Poisons Information Centre or a doctor); R1 (If inhaled, removed from contaminated area. Apply artificial respiration if not breathing).

Appendix F, Part 3 – New Entry

VINYL ACETATE

Warning Statement: 11 (Vapour may be harmful).

Safety Directions: 8 (Avoid breathing vapour); 9 (Use only in well ventilated area).

The committee also recommended an implementation date of 1 June 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.

The reasons for the advice were:

  • Vinyl acetate is a monomer and industrial chemical used in the manufacture of products, e.g. paints, adhesives and possibly in automotive products.
  • Vinyl acetate is useful in a number of domestic formulations that require liquid consistency which polymerises or “sets” to give a solid finish e.g. paints, sealants, adhesives, etc. It is not expected to be a simple matter to replace this technology.
  • Vinyl acetate is a respiratory irritant and in high doses has genotoxic potential.
  • Based on limited evidence of carcinogenicity in experimental animals, vinyl acetate is a potential carcinogen. This may be due to formation of acetaldehyde (hydrolysis under aqueous conditions).

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS-ACMS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create a new Schedule 6 entry for vinyl acetate, with supporting Appendix E, Part 2 and Appendix F, Part 3 entries. The proposed Schedule entry is as follows:

Schedule 6 – New Entry

VINYL ACETATE MONOMER (excluding its derivatives) except:

  1. in preparations for therapeutic use; or
  2. in preparations for domestic use containing 1 per cent or less of vinyl acetate; or
  3. in preparations containing 0.01 per cent or less of vinyl acetate as residual monomer in a polymer.

Appendix E, Part 2 – New Entry

VINYL ACETATE

Standard Statements: A (For advice, contact a Poisons Information Centre or a doctor); R1 (If inhaled, removed from contaminated area. Apply artificial respiration if not breathing).

Appendix F, Part 3 – New Entry

VINYL ACETATE

Warning Statement: 11 (Vapour may be harmful).

Safety Directions: 8 (Avoid breathing vapour); 9 (Use only in well ventilated area).

The proposed implementation date is 1 June 2018. A later implementation date is proposed in order to allow for industry alignment.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.

The reasons for the interim decision are:

  • Vinyl acetate is a monomer and industrial chemical used in the manufacture of products, e.g. paints, adhesives and possibly in automotive products.
  • Vinyl acetate is useful in a number of domestic formulations that require liquid consistency which polymerises or “sets” to give a solid finish e.g. paints, sealants, adhesives, etc. It is not expected to be a simple matter to replace this technology.
  • Vinyl acetate is a respiratory irritant and in high doses has genotoxic potential.
  • Based on limited evidence of carcinogenicity in experimental animals, vinyl acetate is a potential carcinogen. This may be due to formation of acetaldehyde (hydrolysis under aqueous conditions).

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