Publication of interim decisions amending, or not amending, the current Poisons Standard, June 2018

Scheduling medicines and poisons

7 June 2018

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2.2 Vinyl acetate

2. Joint meeting of the Advisory Committee on Chemicals and Medicines Scheduling (ACCS/ACMS #18)

2.2 Vinyl acetate

Delegate's interim decision

The delegate's interim decision is to amend the Schedule 6 entry for vinyl acetate in the Poisons Standard as follows:

Schedule 6 - Amend Entry

VINYL ACETATE MONOMER (excluding its derivatives) except:

  1. in preparations for therapeutic use; or
  2. in cosmetic preparations containing 0.01 per cent or less of vinyl acetate as residual monomer in a polymer; or
  3. in other preparations containing 1 per cent or less of vinyl acetate.
Proposed implementation date: 1 October 2018

The delegate considers the Committee's proposed implementation date of 1 October 2018 (to replace the 31 October 2017 decision) as being reasonable and appropriate in the circumstances.

Reasons:

The delegate has decided to retain the words 'as residual monomer in a polymer' and 'MONOMER' in the Schedule 6 entry for vinyl acetate to ensure that the intention of the schedule entry - to capture only monomer vinyl acetate and not polymer vinyl acetate - is clear for all stakeholders.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • Risks arise from evidence of carcinogenicity and mutagenicity. Although the evidence is limited, there is enough evidence to consider risk mitigation.
    • Vinyl acetate is a monomer that 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.
    • There is a risk that non-cosmetic and non-therapeutic products will be captured inappropriately.
    • Highly flammable.
    • Respiratory and carcinogenicity health effects on humans.
    • Domestic use has potential for general public to be exposed via vapour inhalation or dermal contact.
    • Use of chemical in cosmetics banned in Europe from 2015.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Vinyl acetate is used in paints, lacquers, varnishes, adhesives, sealants.
    • Vinyl acetate is also a starting raw material in polymer production.
    • Vinyl acetate may be present as an impurity in a wide range of products containing vinyl acetate polymers and copolymers, including in domestic products, cosmetics and therapeutic goods.
    • Domestic use - widespread in the general population.
    • Commercial/Industrial use - building, textile and paper.
    • Confined space/inappropriate use and storage and skin contact.
    • Potential variations or non-adherence to use and storage by general public.
    • Possible cosmetic application to skin - Vinyl Acetate use in cosmetics in Australia not known, but may potentially be present in some nail varnish preparations.
  3. the toxicity of a substance:
    • Potential carcinogen, based on limited evidence of carcinogenicity in experimental animals.
    • Potential mutagen (limited evidence), which may be due to formation of acetaldehyde (hydrolysis under aqueous conditions).
    • Respiratory irritancy, genotoxic potential at high doses and carcinogenic potential
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Can vary depending on product type and use for domestic products and in industrial manufacturing.
    • Packaging and presentation as per current proposed scheduling.
Scheduling proposal

The pre-meeting scheduling proposal for vinyl acetate was published on the TGA website on 21 December 2017 at Consultation: Proposed Amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS-ACMS meetings, March 2018.

Background information for vinyl acetate
Referred scheduling proposal

An application was submitted to amend the Poisons Standard with respect to vinyl acetate. The application proposes to amend the Schedule 6 entry for vinyl acetate.

Scheduling application

The proposed amendments to the Poisons Standard are:

Schedule 6 - Amend Entry

VINYL ACETATE

  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 used in direct contact with the body, such as cosmetic preparations.

The applicant's reasons for the proposal are:

  • The Inventory Multi-tiered Assessment and Prioritisation (IMAP) and scheduling documentation for the Schedule 6 entry for vinyl acetate for domestic use of 'with 0.01% or less of residual vinyl acetate monomer' to be implemented 1 October 2018 indicates that the scheduling is meant to be for polymers used in direct contact with the body (such as cosmetic preparations).
  • The chosen wording captures 'Do It Yourself' (DIY) type products containing polymers with trace residual vinyl acetate monomer >0.01% (e.g. paints).
  • The applicant ensures all its copolymer raw materials have <0.10% vinyl acetate, in line with Globally Harmonised System (GHS) hazard classification criteria to be not hazardous chemicals.
  • However, as the applicant's polymer products have trace residual vinyl acetate monomer in the range of 0.011 to 0.099% (∼0.01%), many of these polymer containing products would become Schedule 6 Poisons when formulated into domestic DIY products.
  • None of these DIY products are intended for body contact applications.
  • The proposed change to the wording makes it clear that these types of products, which will not be used in direct contact with the body, are not scheduled.
  • Then exception (b) of the Schedule 6 entry of vinyl acetate would be applied for vinyl acetate in preparations for domestic use containing 1% or less of vinyl acetate.
Current scheduling status

Vinyl acetate is unscheduled but is due to be included in Schedule 6 of the Poisons Standard October 2018 as follows:

Schedule 6

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

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

VINYL ACETATE

Warning Statement: 11 (Vapour may be harmful).

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

Scheduling history

In July 2017, the Joint Advisory Committee on Chemicals and Medicines Scheduling (ACCS-ACMS) considered an application to include vinyl acetate in Schedule 6 of the Poisons Standard with a cut-off of 1% of less in domestic products. The Joint ACCS-ACMS also considered a Schedule 10 entry for use in cosmetic products, and Appendix E and F entries. The main toxicological concerns discussed were respiratory irritancy, genotoxic potential at high doses and carcinogenic potential. Vinyl acetate was noted to be useful in a number of domestic formulations, with a lack of evidence for cosmetic use in Australia. A Schedule 10 listing was not considered necessary. The delegate made a final decision to include vinyl acetate in Schedule 6 with exceptions for therapeutic use, preparations for domestic use containing 1% or less of vinyl acetate and preparations containing 0.01% or less as residual monomer in a polymer, along with Appendix E and F entries. The implementation is 1 October 2018.

Australian regulations

Vinyl acetate is not in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018 but is listed in the previous determination (No. 5 of 2017) as follows:

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
5042 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 86 products listed on the Australian Register of Therapeutic Goods (ARTG) including a medical device (Class IIa), non-prescription medicines and prescription medicines.

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

International regulations
  • European Union (EU): Vinyl acetate is classed as Carcinogenic, Mutagenic, or toxic for Reproduction 2 (CMR 2) (carc.2) substance and is prohibited for use in cosmetics and personal care products in the EU from 1 January 2015, as per EU Regulation No 944/2013.
  • United States of America:
    • The Food and Drug Administration 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.[14,15]
    • The American Conference of Governmental Industrial Hygienists 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 work week.
    • The National Institute for Occupational Safety and Health recommends that exposure to vinyl acetate in the workplace not exceed 4 ppm over a 15-minute period.
Substance summary
Table 2.2A: Chemical information for vinyl acetate
Property Substance
CAS number 108-05-4
CAS name acetic acid ethenyl ester
Chemical structure Chemical structure of vinyl acetate
Molecular formula C4H6O2
Molecular weight 86.1 g/mol
IUPAC and/or common and/or other names

Ethenyl acetate (IUPAC);

Vinyl acetate (INCI, AAN).

Table 2.2B: Acute toxicity end-points for vinyl acetate
Toxicity endpoint Species Vinyl acetate SPF (2018) 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 the National Industrial Chemicals Notification and Assessment Scheme (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, 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. Vinyl acetate undergoes hydrolysis to form acetaldehyde and acetic acid. Acetaldehyde is also a Category 3 mutagen. 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 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).

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).

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 four hours at doses of 0.3-5 mM (Norppa et al., 1985).

Vinyl acetate induced DNA cross links in isolated human lymphocytes and rat nasal epithelial cells at 860 μ/mL (IARC, 1995).

Increased numbers of micronuclei were formed in human lymphoblastoid cells (TK6) following a 4-hour exposure to vinyl acetate 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 were observed in human whole blood and isolated human lymphocytes after exposure (similar to OECD TG 473) to vinyl acetate concentrations of 0.25, 0.5, 1 or 2 mM for 24 hours, without metabolic activation (REACH).

There was an increased frequency of chromosomal aberrations in cultured lymphocytes of humans following occupational exposure (IARC, 1995). No additional details were available.

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 two high doses, which caused increased mortality.

Based on the weight of evidence from the available genotoxicity data, vinyl acetate may have genotoxic potential. NICNAS classified vinyl acetate as a Category 3 Mutagen according to the Approved criteria for Classifying Hazardous Substances.

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 inhalational exposure to vinyl acetate, NICNAS classified vinyl acetate as a Category 3 carcinogen according to the Approved Criteria for Classifying Hazardous Substances.

Evidence of vinyl acetate carcinogenicity was obtained in groups of Swiss mice and SD rats (n = 60/sex/dose) exposed (via inhalation) at 0, 50, 200 or 600 ppm, six hours per day, five days per week, for 104 weeks. 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).

Additional evidence of carcinogenicity in animals has been published 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 forestomach, and upper gastrointestinal tract). Female mice also showed tumours in the uterus at 5000 ppm (Soffritti et al., 2008).

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 USA 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).

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.

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 are available. 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 20oC; 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 that supported the proposal.

The main points provided in support of the amendment were:

  • Vinyl Acetate may be present (typically as a residual monomer from synthesis of vinyl acetate copolymers) in both industrial and domestic goods and may also be present in some agricultural products.
  • It was noted that the Schedule 6 entry due to be published 1 October 2018 may adversely impact a range of products currently on the market that were not identified during the consultation and consideration of vinyl acetate. These may include industrial and agricultural products.
  • Clarification of the wording of the Schedule 6 entry would ensure a clear and consistent risk management approach is applied to domestic, industrial and agricultural products containing vinyl acetate that have the same risk profile.
  • One submission noted that although the proposal is supported, a slight change to the terminology would ensure that domestic, industrial and agricultural uses are treated equally. These uses do not have intentional direct application to the body. This would minimise undue cost, ensure consistent seamless communication in the supply chain and maintain a balanced risk profile.

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

Summary of ACCS advice to the delegate

The committee recommended that the Schedule 6 entry for vinyl acetate be amended in the Poisons Standard as follows:

Schedule 6 - Amend Entry

VINYL ACETATE (excluding its derivatives) except:

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

The committee also recommended an implementation date of 1 October 2018, to override the July 2017 decision.

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; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice were:

  1. the risks and benefits of the use of a substance:
    • Risks arise from evidence of carcinogenicity and mutagenicity. Although the evidence is limited, there is enough evidence to consider risk mitigation.
    • Vinyl acetate is a monomer that 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.
    • There is a risk that non-cosmetic and non-therapeutic products will be captured inappropriately.
    • Highly flammable.
    • Risk of adverse respiratory health effects and carcinogenicity in humans.
    • Domestic use has potential for general public to be exposed via vapour inhalation or dermal contact.
    • Use of chemical in cosmetics banned in Europe from 2015.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Vinyl acetate is used in paints, lacquers, varnishes, adhesives, sealants.
    • Vinyl acetate is also a starting raw material in polymer production.
    • Vinyl acetate may be present as an impurity in a wide range of products containing vinyl acetate polymers and copolymers, including in domestic products, cosmetics and therapeutic goods.
    • Domestic use - widespread in the general population.
    • Commercial/Industrial use - building, textile and paper.
    • Confined space/inappropriate use and storage and skin contact.
    • Potential variations or non-adherence to use and storage by general public.
    • Possible cosmetic application to skin - Vinyl Acetate use in cosmetics in Australia not known, but may potentially be present in some nail varnish preparations.
  3. the toxicity of a substance:
    • Potential carcinogen, based on limited evidence of carcinogenicity in experimental animals.
    • Potential mutagen (limited evidence), which may be due to formation of acetaldehyde (hydrolysis under aqueous conditions).
    • Respiratory irritant.
    • Respiratory irritancy, genotoxic potential at high doses and carcinogenic potential
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Can vary depending on product type and use for domestic products and in industrial manufacturing.
    • Packaging and presentation as per proposed scheduling.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS-ACMS advice;
  • Public submissions received;
  • Scheduling Policy Framework (SPF 2018); and
  • Section 52E(1) of the Therapeutic Goods Act 1989 in particular: (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; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

Footnotes

  1. ToxFAQsTM for Vinyl Acetate
  2. Electronic Code of Federal Regulations, Part 175-Indirect Food Additives: Adhesives and Components of Coatings.

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