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Scheduling delegate's final decisions: ACCS/ACMS, April 2014

Scheduling medicines and poisons

14 April 2014

Book pagination

Part A - Final decisions on matters referred to an expert advisory committee (ACCS) - 1.6-1.12

1.6 2-amino-5-ethylphenol

Scheduling proposal

On 16 September 2013, the delegate received an application proposing inclusion of preparations containing more than 1 per cent of 2-amino-5-ethylphenol in Schedule 6.

The delegate's reason for referring this scheduling proposal to the ACCS was that this substance is likely to be an oxidative colorant component of hair dyes (at concentrations up to 1 per cent). The toxicological profile of the chemical warrants scheduling (based mainly on limited acute toxicity data, including irritancy and sensitisation potential) and that the toxicological profile appears to be consistent with the Scheduling Policy Framework factors for listing in Schedule 6. The advice of the ACCS was requested to confirm this scheduling proposal.

The delegate sought the following specific advice from the ACCS:

  • Does the ACCS support listing of 2-amino-5-ethylphenol in Schedule 6?
  • Is 2-amino-5-ethylphenol the most appropriate name for any listing (no need to specify the HCl salt?), or is another name appropriate (e.g. phenol, 2-amino-5-ethyl, hydrochloride)?
  • Is there a need to schedule the chemical at all, given that public exposure is only likely to occur with products in which this chemical is as a component of hair dyes used professionally in salons?
  • In the absence of any chronic toxicity studies, is the equivocal evidence of potential genotoxicity (micronucleus induction in vitro, but not in vivo) suggestive of a cautionary approach to scheduling this chemical?
  • While data suggests that there are unlikely to be health risks associated with hair dye preparations containing up to 1 per cent of 2-amino-5-ethylphenol HCl, is a cut-off from Schedule 6 at 1 per cent warranted?
  • Is there a need to develop specific Appendix E & F statements? If so, what does the ACCS suggest?
  • If exempted from scheduling at 1per cent, salon operators would not see any Schedule 6 labelling requirements, including signal heading and Appendix E & F statements. Does this argue against a cut-off to be applied to the Schedule 6 listing?
Substance details

Phenol, 2-amino-5-ethyl-, hydrochloride is an oxidative colouring agent for hair dye formulations at concentrations of up to 1 per cent.

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Figure 2. Structure of 2-amino-5-ethylphenol

image of Figure 2. Structure of 2-amino-5-ethylphenol

Acute toxicity

No acute toxicity studies were performed with the hydrochloride salt. The chemical showed low toxicity in the acute oral toxicity test with phosphate salt with LD50 > 2000 mg/kg bw. Taking into account the differences in molecular weight of the hydrochloride and phosphate salts and differences in pKa (Hydrochloride salt = 5.17; Phosphate salt = 5.28), it is calculated that the hydrochloride salt will contain 148 per cent more of the free base (assumed to be the main cause of toxicity) than the phosphate salt. This implies that a dose of 2000 mg/kg for the phosphate salt is equivalent to a dosing of 1350 mg/kg of the chloride salt (the notified chemical). Given a dose of 2000 mg/kg bw of the phosphate salt resulted in the death of 1 animal and other clinical signs of toxicity, it is expected that the LD50 of the hydrochloride salt will be less than 2000 mg/kg bw.

The neat chemical is considered likely to produce skin corrosion or irritation in in vitro tests. Further, the neat chemical is a severe eye irritant in an isolated chicken eye test with moderate swelling, severe corneal opacity and severe fluorescein retention by damaged epithelial cells.

An analogue of the chemical exhibits potential for skin sensitisation in a mouse local lymph node assay with an EC3 of 8.9 per cent.

Repeat toxicity

In a repeat-dose toxicity studies, the no observed adverse effect level (NOAEL) of the chemical was 16 mg/kg bw/day in an oral 13-week study in rats with organ changes consistent with haemolytic anaemia.

Carcinogenicity

There is no data provided on carcinogenicity of the chemical.

Genotoxicity

An analogue of the notified chemical is genotoxic in vitro in a human peripheral blood lymphocyte micronucleus test.

Developmental toxicity

Looking at developmental toxicity, the chemical induced a range of foetal effects at doses causing maternal toxicity. The NOAEL was 74 mg/kg bw/day.

Public exposure

It is expected that exposure to the general public and during transport, formulation and storage would be low.

Scheduling status

Phenol, 2-amino-5-ethyl-, hydrochloride is not currently scheduled.

Scheduling history

No scheduling history is available for phenol, 2-amino-5-ethyl-, hydrochloride.

Substances have previously been included in Schedules 5 and 6 in relation to their use in hair dye preparations. There are also exemptions relating to this use.

Public pre-meeting submissions

Two public submissions were received.

One submission indicated in principle it did not support the delegate's proposal. The submission requested that any consideration on scheduling of 2-amino-5-ethylphenol should ensure that the limitation applies to the diluted hair dye for in-use preparation i.e. diluted for use, rather than in the purchased concentrated products use rather than to the product packaged for sale.

The other submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that 2-amino-5-ethylphenol HCL in hair dye preparations be included in Schedule 6 with an exception cut-off for hair dye preparations containing 1 per cent or less 2-amino-5-ethylphenol HCL when the immediate container and primary pack are labelled with the appropriate warning statements located in the SUSMP.

The ACCS also recommended that 2-amino-5-ethylphenol HCL be listed in Appendix E and Appendix F.

The committee also recommended an implementation date of 1 February 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (a) the risks and benefits of the use of a substance; and (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Risk associated with use outside of professional salon requires mandated labelling.
  • Potential skin sensitisation, corrosion of the skin and severe eye irritation in its concentrated form.
Delegate's interim decision

The delegate agrees with the advice of the ACCS that new entries be created in Schedule 6 and Appendices E & F, to regulate the use of 2-amino-5-ethylphenol HCl in hair dyes. The main source of exposure is expected to be associated with this use and the schedule wording is specific for this use, to reduce the likelihood of inadvertent capture of other types of products. Furthermore, consistent with Schedule 6 entries for some other hair dye ingredients with a similar toxicological profile, an exemption from Schedule 6 has been provided for products that meet specific labelling requirements.

The delegate agrees with the implementation date being 1 February 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (c) the toxicity of a substance and (d) the dosage, formulation, labelling, packaging and presentation of the substance.

The reasons for the recommendation comprised the following:

  • The toxicity profile is consistent with SPF Schedule 6 factors, including severe skin and eye irritancy potential for preparations containing high concentrations.
  • There is a need for warning statements on product labels to facilitate safe use; for products used either inside or outside professional hair salons.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors6;
  • Other relevant information.
Submissions on interim decision

Two submissions were received. One noted that as the delegate's interim decision had no impact on therapeutic goods, it had no further comments on delegate's interim decision on this item.

The other indicated that the proposed 1% exemption cut-off would not allow for higher strength preparations currently available overseas to be exempted from schedule 6, even if labelled with the required warning statements. Such higher-strength preparations are intended to be mixed with other solutions to achieve an 'on-head' final concentration of no more than 1% 2-amino-5-ethylphenol. The submission proposed changes to the wording of the Schedule 6 entry to allow for this, by modifying the words to: " ... except in preparations giving rise to 1 per cent or less on-head concentration of 2-amino-5-ethylphenol when the immediate container and primary pack are labelled with the following statements..."

Delegate's final decision

The delegate has considered the submission received following publication of the interim decision to list 2-amino-5-ethylphenol in Schedule 6. The submission calls for clarification of the schedule entry to allow higher strength preparations to meet the 1% exemption cut-off, provided they are labelled with appropriate warning statements and directions to be diluted to no more than 1% in the final 'on-head' preparation.

However, this advice is in conflict with advice considered by the ACCS, that the concentration in hair dye products are likely to be 1% or less, and further diluted to an 'on-head' concentration of 0.5% or less. Given the need to provide appropriate warnings to professional users in-salon and to non-professional users in a domestic setting, the delegate has determined that the interim scheduling decision should stand. This means that preparations containing more than 1%

2-amino-5-ethylphenol would have the full labelling required by Schedule 6 listing, while products containing 1% or less would have only the required warning statements.

The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Scheduling entry
Schedule 6 - new entry

2 AMINO 5 ETHYLPHENOL in hair dye preparations except in preparations containing 1 per cent or less of 2-amino-5-ethylphenol when the immediate container and primary pack are labelled with the following statements:

KEEP OUT OF REACH OF CHILDREN; and

WARNING - This product contains ingredients which may cause skin irritation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes and eyebrows; to do so may be injurious to the eye.

written in letters not less than 1.5 mm in height.

Appendix E, part 2
Poison Standard Statements
2-amino-5-ethylphenol A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once). E1 - If in eyes washout immediately with water.
Appendix F, part 3
Poison Warning Statements Safety Direction
2-amino-5-ethylphenol 21. This product contains ingredients which may cause skin irritation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes and eyebrows; to do so may be injurious to the eye. -

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1.7 2-butanone, oxime (also known as methyl ethyl ketone oxime)

Scheduling proposal

On 29 August 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process, requested that the delegate consider a proposal to include the substance in Schedule 6, due to concerns regarding critical effects to human health namely, severe eye irritation, skin sensitisation and harmful effects through contact with skin during short-term or acute exposure. Long-term exposure may cause carcinogenicity.

The delegate's reason for referring this scheduling proposal to the ACCS was that this referral from the NICNAS IMAP program relates to a chemical likely to be a component of alkyd paints, lacquers, varnishes and adhesives (at concentrations up to 1 per cent in finished products) that might be used in a domestic setting. NICNAS suggests that the toxicological profile of the chemical warrants scheduling (based mainly on limited acute toxicity data, including severe eye irritancy and sensitisation potential) and that the toxicological profile appears to be consistent with the Scheduling Policy Framework factors for listing in Schedule 6. The advice of the ACCS was requested to confirm this scheduling proposal.

The delegate sought the following specific advice from the ACCS:

  • Does the ACCS support listing of 2-butanone, oxime in Schedule 6?
  • Is 2-butanone, oxime the most appropriate name for any listing, or is another name appropriate (e.g. Methyl ethyl ketoxime, MEKO, Butanone, Ethyl methyl ketoxime Methyl ethyl ketone oxime)?
  • There are existing Schedule 5 entries for methyl ethyl ketone and methyl ethyl ketone peroxide. To what extent would these entries cover MEKO or inform its scheduling? Is the 25 per cent concentration exemption to unscheduled for MEK an appropriate cut-off for MEKO, or is 5 per cent a more appropriate cut-off, based on the presumed threshold for sensitisation effects?
  • Is there a need to schedule the chemical at all, given that public exposure is only likely to occur where it is a component of alkyd paints, lacquers, varnishes and adhesives, at such low concentrations that are unlikely to represent a health hazard?
  • Is there a need to develop specific Appendix E & F statements? If so, what does the ACCS suggest?
Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report, which is available on from the NICNAS website.

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Scheduling status

2-Butanone, oxime is not specifically scheduled.

Methyl ethyl ketone and methyl ethyl ketone peroxide are included in Schedule 5 and Appendices E and F.

Schedule 5

METHYL ETHYL KETONE except in preparations containing 25 per cent or less of designated solvents.

Schedule 5

METHYL ETHYL KETONE PEROXIDE.

Scheduling history

In May 1978, the Poisons Scheduling (Standing) Committee decided to amend the Schedule 5 ketones entry (including methyl ethyl ketone) to exclude from scheduling for preparations containing 25 per cent or less of designated solvents.

Public pre-meeting submissions

Two submissions were received.

One submission indicated that the proposed amendment is not limited to cosmetic products and noted that the TGA ARTG contains an ingredient entry for methyl ethyl ketone. Given that the schedule entry applicable to salts and derivatives, the submission was concerned about the possibility that there may be some impact on therapeutic goods.

The other submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that methyl ethyl ketone oxime be included in Schedule 6 except in preparations containing 1 per cent or less of methyl ethyl ketone oxime.

The ACCS also recommended that Appendix E and F statements were required.

The ACCS recommended an implementation date of 1 June 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (a) the risks and benefits of the use of a substance and (c) the toxicity of the substance.

The reasons for the recommendation comprised the following:

  • Potential use in the wide range of products available for domestic use and the risk of sensitisation and severe eye irritation.
  • Cut-off level is based on skin sensitisation to exempt based on default limit supply by GHS and Hazard Substances Information System (HSIS.)
Delegate's interim decision

The delegate accepts the advice of the ACCS to include methyl ethyl ketone oxime in Schedule 6. The critical toxicological endpoints driving this categorisation (severe eye irritancy and sensitisation potential) are consistent with SPF factors for listing in Schedule 6, with the public health risk sufficiently ameliorated for products containing less than 1% to be exempted from scheduling. The delegate noted ACCS advice that intermittent use of products containing this chemical would be unlikely to pose a significant carcinogenic risk, despite the 'Limited evidence of carcinogenic effect' noted in the NICNAS report. The delegate supports a separate listing for methyl ethyl ketone oxime in Schedule 6, noting that the current Schedule 5 entries for apparently related chemicals (methyl ethyl ketone and methyl ethyl ketone peroxide) would not generically cover methyl ethyl ketone oxime. 

The delegate agrees with the implementation date being 1 June 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (a) the risks and benefits of the use of a substance and (c) the toxicity of the substance.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors7;
  • Other relevant information.
Submissions on interim decision

One public submission was received. The submission indicated that as the delegate's interim decision on the substance had no impact on therapeutic goods, it had no further comments in relation to the delegate's interim decision.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Scheduling entry
Schedule 6 - new entry

METHYL ETHYL KETONE OXIME except in preparations containing 1 per cent or less of methyl ethyl ketone oxime.

Appendix E, part 2
Poison Standard Statements
Methyl ethyl ketone oxime A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once). E1 - If in eyes washout immediately with water. S1 - If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water.
Appendix F, part 3
Poison Warning Statements Safety Direction
Methyl ethyl ketone oxime 5. Irritant. 28. (Over) (Repeated) exposure may cause sensitisation 1. Avoid contact with eyes. 4. Avoid contact with skin

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1.8 Diethylene glycol monobutyl ether

Scheduling proposal

On 13 September 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process, recommended that the delegate consider amending the current Schedule 5 diethylene glycol monobutyl ether (DEGBE) entry, and amending the SUSMP to include requirements for first aid instructions, warning statements and safety directions for DEGBE.

NICNAS proposed that these include safety directions such as avoid skin and eye contact, avoid breathing aerosols and use of products in well-ventilated area. These safety directions were necessary to mitigate risk for products with higher concentrations (>10 per cent) of the chemical or for products that are spray-applied.

The critical health effects in the risk characterisation on which the NICNAS recommendation was based were the local effects (eye irritation and potential skin irritation following repeated exposure to the chemical). Reversible changes in the lungs have been observed in animals following exposure to >100 mg/m3. The chemical does not appear to produce the haemolytic effects observed with the shorter chain ethylene glycol butyl ether, 2-butoxyethanol. Changes to haematological parameters were only noted following oral exposure to high doses (1 000 mg/kg bw/d).

The reason for referring this scheduling proposal to the ACCS was that DEGBE was last reviewed by the DPSC in 2004, at which time it was decided that its toxicological profile was more consistent with Schedule 5, rather than the generic Schedule 6 entry for ethylene glycol monoalkyl ethers and their acetates. Accordingly, the DPSC created a new Schedule 5 entry, with a cut-off to exempt at 10 per cent.

The chemical had been referred for re-consideration of scheduling as an outcome of the NICNAS IMAP process. A related chemical (hexyloxyethanol) had been referred to the July 2013 ACCS meeting, which recommended its listing in Schedule 6 as a separate entry from the generic entry for diethylene glycol monoalkyl ethers.) The NICNAS IMAP report on DEGBE includes recommendations for strengthening hazard statements and concentration restrictions on use in products such as cosmetics, domestic cleaners, paints and floor sealants. The advice of the ACCS was needed to implement any scheduling amendments.

The delegate sought the following specific advice from the ACCS:

  • The NICNAS IMAP assessment particularly notes potential developmental toxicity with relatively high oral NOAELs, although somewhat lower dermal NOAELs. The report also notes risk assessments suggesting a relatively low margin of exposure (MOE) for some uses of DEGBE (particularly in cosmetics). Does the ACCS consider that Schedule 5 listing (with 10 per cent cut-off to exempt) remains appropriate for DEGBE?
  • Is there a need to include an entry in Appendix C to prohibit the use of DEGBE in cosmetics (or other domestic products?) at concentrations above those listed in the NICNAS IMAP report?
  • There are currently no First Aid statements, Warning Statements or Safety Directions for scheduled products containing DEGBE. Can the ACCS suggest suitable entries in Appendices E and F?
  • Does the current entry for ethylene glycol monoalkyl ethers in Appendix I (Uniform Paint Standard) adequately address uses of DEGBE?
  • What information would be needed to assess the regulatory impacts of any proposed changes to the scheduling of DEGBE (e.g. in AGVET products)?
Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report, which is available on from the NICNAS website.

Scheduling status

Preparations containing more than 10 per cent diethylene glycol monobutyl ether are listed in Schedule 5.

Scheduling history

In November 1984, the Poisons Scheduling Standing Committee (PSSC) included ethylene glycol monoalkyl ethers and their acetates in Schedule 6.

This scheduling was reaffirmed at the May 1992 NDPSC meeting.

At its June 2003 meeting the NDPSC confirmed that diethylene glycol monobutyl ether was included in Schedule 6 by virtue of the provisions of Part 1, paragraph 2(c) of the SUSMP.

In February 2004 the NDPSC decided to create a specific separate Schedule 5 entry for diethylene glycol monobutyl ether. The NDPSC also decided to exempt from scheduling, preparations containing 10 per cent or less of diethylene glycol monobutyl ether.

Public pre-meeting submissions

Two submissions were received.

The first submission indicated that it was unsure of the new first aid, warning and safety directions being proposed. The submission asserted that preparations containing 10 per cent of the substance already have appropriate statements on the label to enable safe use of their products, and that this was only to be expected for products carrying the "CAUTION" signal heading. If specific first aid, warning and safety directions are considered necessary, the submissions suggested that there needs to be further consultation with industry including the proposed specific statements to ensure that the impact on companies using this substance is minimised (need for new artwork/template, relabelling, etc.) The submission asserted that based on the IMAP report, there were no concerns with the current exemption of products containing 10 per cent or less of DEGBE.

The second submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that the current scheduling of diethylene glycol monobutyl ether remains appropriate.

The ACCS recommended that Appendix E and F statements are required.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (a) the risks and benefits of the use of a substance and (c) the toxicity of a substance.

Delegate's interim decision

The delegate accepts the ACCS advice that the current Schedule 5 entry for diethylene glycol monobutyl ether (DEGBE) remains appropriate, but that new Appendix E & F statements are required for products not exempted under that entry. The delegate also notes ACCS advice that the 10% cut-off to exempt also remains appropriate, having considered the relatively low MOE calculations for dermal application in cosmetics in the NICNAS report.

The delegate has decided that the implementation date is to be 1 June 2015.

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 and (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • First aid, warning statements and safety directions were not applied when diethylene glycol monobutyl ether was originally included in Schedule 5. Provision of such label statements address the potential hazards and should enhance consumer safety when using such products.
  • The toxicity profile of diethylene glycol monobutyl ether is consistent with SPF factors for Schedule 5, with the 10% cut-off to exempt still appropriate.
Delegate's considerations
  • The delegate considered the following in regards to this proposal:
  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors8;
  • Other relevant information.
Submissions on interim decision

Two public submissions were received.

One submission noted that while it had no objections to delegate's interim decision to include the substance in Appendix E and F, an extended implementation period, i.e. 1 June 2016, may be required for the companies to adopt the labelling changes.

The other submission indicated that as the delegate's interim decision on the substance had no impact on therapeutic goods, it had no further comments regarding delegate's interim decision.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Scheduling entry
Appendix E, part 2
Poison Standard Statements
Diethylene glycol monobutyl ether A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor E1 - If in eyes wash out immediately with water. S1 - If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water.
Appendix F, part 3
Poison Warning Statements Safety Directions
Diethylene glycol monobutyl ether 5. Irritant 1. Avoid contact with eyes. 4. Avoid contact with skin. 8. Avoid breathing dust (or) vapour (or) spray mist. 9. Use only in well-ventilated area.

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1.9 Ethylene glycol monomethyl ether

ACCS advice to the delegate

The committee noted that the name of the substance should be diethylene glycol, monomethyl ether rather than ethylene glycol monomethyl ether as it was published on the public notice inviting public comments.

As the name of the substance was incorrectly published, the committee indicated that it was unable to provide a recommendation to the delegate owing to issues associated with transparency and natural justice. The committee decided not to proceed with this matter at this meeting and recommended the delegate include diethylene glycol, monomethyl ether on the next public notice inviting public comments.

Delegate's interim decision

The delegate agreed with this recommendation and referred the diethylene glycol, monomethyl ether to the July 2014 committee meeting.

Delegate's final decision

The delegate apologises for the error in the name ethylene glycol monomethyl ether as it was published on the public notice inviting public comments for the November ACCS meeting, and confirms that consideration of this chemical under its correct name, diethylene glycol, monomethyl ether (DEGME) will be referred to a future meeting of the ACCS (July 2014).

1.10 Tetrahydrofuran

Scheduling proposal

On 17 September 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process, recommended to the delegate that for domestic uses, tetrahydrofuran (THF) be a new entry in Schedule 5 with possible exemptions at low concentration levels.

The NICNAS report recommended that further risk management was required for the chemical, believing that sufficient information was available to recommend the chemical be risk managed for public safety from its potential use in domestic products through scheduling, and occupational health and safety through classification and labelling. Further assessment is recommended to examine the need for a hazard classification for potential carcinogenicity of the chemical.

The delegate's reason for referring this scheduling proposal to the ACCS is that the toxicological profile of the chemical warrants scheduling and that the toxicological profile appears to be consistent with the Scheduling Policy Framework for Medicines and Poisons (SPF, 2010) factors for listing in Schedule 5. The advice of the ACCS was requested to confirm this scheduling proposal.

This scheduling submission for THF is one of several NICNAS-referred chemicals from the IMAP program. THF is a solvent used at relatively low concentrations in a range of consumer products, including cleaners, adhesives and stain removers. A number of solvents with comparable toxicity have been included in Schedules 5 and 6, including the related furan 1,2-dioxane. The NICNAS IMAP report on THF includes recommendations for strengthening hazard statements for products such as householder cleaners.

The delegate sought ACCS advice to implement any scheduling amendments, specifically:

  • The NICNAS IMAP assessment highlights the skin/eye irritancy potential for THF, in an otherwise relatively low toxicity profile. Does the ACCS support listing of THF in Schedule 5, with a cut-off to exempt at a yet to be determined per cent?
  • Is THF the most appropriate name under which to list this chemical in the schedules? Is it necessary to cross-reference the IUPAC name (oxolane) or the abbreviation (THF) in the SUSMP index?
  • Does the ACCS agree that the observed hepatocellular and renal carcinogenic responses seen in rats and mice are of little consequence from a scheduling perspective?
  • Can the ACCS suggest suitable First Aid statements, warning statements and safety directions in Appendices E and F for scheduled products containing THF?
  • What information would be needed to assess the regulatory impacts of any proposed scheduling of THF (e.g. in AGVET products)?
Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report, which is available on from the NICNAS website.

Scheduling status

THF is not specifically scheduled and is not captured by any entry in the SUSMP.

Scheduling history

Not applicable.

Public pre-meeting submissions

Three public submissions were received.

The first submitter indicated that it did not believe that THF or other organic solvents require scheduling controls. However, if any scheduling is considered necessary for THF, it would be necessary to consider all organic solvents for their irritation potential. This would also require further consultation and consideration of the impact on industry. Any scheduling consideration should also be limited THF (and any other solvents) rather than to salts and derivatives to ensure that other substances are not inadvertently captured e.g. a number of fragrances are derivatives of THF.

The second submission indicated that it was unclear on what concentration cut-off had been proposed and requested that the committee to consider that while not all these ingredients appear on the TGA ARTG ingredient list, some of these substances may be included in proprietary ingredients that are used in therapeutic goods. The submission further requested that the committee consider existing usage within proprietary ingredients and to propose cut-off concentrations that will not impact existing use in proprietary ingredients and in therapeutic goods.

The final submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that THF does not require listing in the Schedules.

Delegate's interim decision

The delegate accepts the ACCS advice that there is no need to include tetrahydrofuran in any of the schedules of the SUSMP. Industrial uses are adequately regulated under other legislation. The toxicology profile of the chemical is relatively low, although it could meet SPF factors for listing in Schedule 5 based on its irritancy potential (a property common to many organic solvents that are not scheduled). However, its use in products available in the domestic retail market is generally at such low concentrations that do not warrant controls via poisons legislation and there is insufficient information to determine an appropriate cut-off to exempt should listing in Schedule 5 be made.

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 for a substance and (c) the toxicity of a substance.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors9;
  • Other relevant information.
Submissions on interim decision

Two public submissions were received.

One submission indicated that it supports delegate's decision not to list the substance in a schedule.

The other submission noted that as the delegate's interim decision had no impact on therapeutic goods, it had no further comments on this issue.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

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1.11 2-nitrotoluene

Scheduling proposal

On 13 September 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process, requested that the delegate consider a proposal to include the substance in Appendix C. The basis for this recommendation is that the main critical effects to human health include genotoxicity, carcinogenicity and potential reproductive/fertility effects.

The delegate's reason for referring this scheduling proposal to the ACCS was that 2-nitrotoluene is prohibited as an ingredient of cosmetics in several international regulatory programs, and NICNAS is seeking similar controls over its use in cosmetics10 in Australia. NICNAS suggests that the toxicological profile of the chemical warrants scheduling and that the toxicological profile appears to be consistent with the Scheduling Policy Framework for Medicines and Poisons (SPF, 2010) criteria for listing in either Schedule 6 or 7 (based on its mutagenicity and carcinogenicity profile). The advice of the ACCS was requested to confirm this scheduling proposal.

The delegate sought the following specific advice from the ACCS:

  • Does the ACCS support listing of 2-nitrotoluene in Schedule 6 or 7?
  • Is there likely to be any conflict with current Schedule 6 listings for nitrobenzene or nitrophenols?
  • Is 2-nitrotoluene the most appropriate name for any listing, or is another name appropriate (e.g. o-nitrotoluene, 2-methyl-1-nitrobenzene)?
  • Is there a need to include a specific listing in Appendix C to restrict its use in cosmetics, or is a Schedule 7 listing, with an appropriate Appendix J condition a sufficient level of control?
  • Is there a need to develop specific Appendix E & F statements (and Appendix J if listed in S7)? If so, what does the ACCS suggest?
Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report, which is available on from the NICNAS website.

Scheduling status

2-nitrotoluene (also known as benzene,1methyl-2-nitro-) is not specifically scheduled.

The major chemical class, benzene, is listed in Schedule 7, Appendices E, F and J and the major chemical subclass, nitrobenzene is listed in Schedule 6, Appendices E and F.

Scheduling history
Benzene

In February 1971, the Poisons Schedule Sub-Committee (PSSC) decided to include preparations containing more than 1 per cent benzene in Schedule 7. The PSSC decided to exclude motor fuels containing 5 per cent or less of benzene and motor fuels containing more than 5 per cent but not more than 20 per cent when packed in 5 gallons or less containers.

In November 1985, the Poisons Schedule Committee (PSC) decided to amend the Schedule 7 entry to exempt preparations containing 15 mL/L or less of benzene and petrol containing 50 mL/L or less of benzene from this listing.

Nitrobenzene

In May 1956, the Poisons Schedule Committee (PSC) decided to include nitrobenzene in Schedule 6. The PSC also decided to exempt nitrobenzene in solid or semi-solid polishes, in soaps containing 1 per cent or less of nitrobenzene and in other preparations containing 0.1 per cent or less of nitrobenzene.

There was no rationale given for these decisions. The Secretariat was unable to find a record of the decision to include these substances in Appendices E, F and J.

Public pre-meeting submissions

One public submission was received.

The submitter did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that that 2-nitrotoluene be included in Schedule 7.

The ACCS recommended an implementation date of 1 June 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (a) the risks and benefits of the use of a substance.

The reasons for the recommendation comprised the following:

  • No essential use in Australia.
  • Toxicological profile for reproductive, genotoxic and carcinogenicity consistent with Schedule 7.
Delegate's interim decision

The delegate accepts ACCS advice that 2-nitrotoluene be listed in Schedule 7. Features of its toxicological profile suggest a significant genotoxic, carcinogenic and reproductive toxicity potential that would be consistent with SPF factors for listing in Schedule 7. While there appear to be no essential uses of 2-nitrotluene in Australia, listing in Schedule 7 would provide for effective control over imported products (e.g. cosmetics).

The delegate notes and accepts ACCS advice that listing in Appendix C is not an appropriate means of controlling the possible use of 2-nitrobenzene in cosmetics, given the range of international restrictions already in place. There does not appear to be any conflict with existing (but rather old) Schedule 6 entries for related substances, nitrobenzene and nitrophenols.

The delegate agrees to the implementation date of 1 June 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee 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 for a substance and (c) the toxicity of the substance.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors11;
  • Other relevant information.
Submissions on interim decision

One public submission was received. The submission indicated that as the delegate's interim decision on 2-nitrotoluene has no impact on therapeutic goods, it has no further comments regarding delegate's interim decision on the substance.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Scheduling entry
Schedule 7 - new entry

2-NITROTOLUENE.

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1.12 Furfural (also known as 2-furancarboxaldehyde)

Scheduling proposal

On 17 September 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process, recommended that the delegate consider including 2-furancarboxaldehyde in Schedule 6 with exemption at very low concentrations which may be applicable for specific uses. The basis for this was to mitigate risk from its use in cosmetics and domestic products.

The NICNAS report recommended risk management for public safety from its potential use in cosmetics and/or domestic products through scheduling, and occupational health and safety through classification and labelling.

The delegate referred a proposal to include 2-furancarboxaldehyde in Schedule 6 (with an appropriate cut-off to exemption) to mitigate risk from its use in cosmetics and domestic products.

This scheduling submission for 2-furancarboxaldehyde (furfural) is one of several NICNAS-referred chemicals from the IMAP program, where the primary public exposure is likely to be via use of cosmetics, fragrances, flavourings and other domestic products (adhesives, cleaners) at very low concentrations. There are other possible uses as a solvent or component of pest control products and it may be found in food at levels up to 63 mg/kg. The primary purpose for this referral by NICNAS was to limit the concentration of furfural in cosmetics/flavouring, in accordance with EU restrictions on such uses.

The delegate sought ACCS advice on how best to manage the scheduling aspects of such submissions, specifically:

  • Furfural has a moderately high toxicity profile, with an acute and chronic toxicity consistent with the SPF criteria for Schedule 6 (or possibly Schedule 7 if concerns about equivocal genotoxicity and/or carcinogenicity are relevant). However, public exposure is only likely to occur through the use as a fragrance ingredient (possibly up to 0.1 per cent), at which concentration adverse health effects are unlikely. Does the ACCS consider that listing in the SUSMP is appropriate? If so, should it be listed in Schedule 6 or Schedule 7, with an appropriate cut-off to exempt?
  • If scheduled, what name should be used in the listing (2-furancarboxaldehyde or the more common name, furfural)?
  • The EU Scientific Committee on Cosmetic Products and Non-food Products (SCCNFP) is of the opinion that furfural can be safely used as a fragrance/flavour ingredient at a maximum concentration of 0.036 per cent in the fragrance compound. The maximum concentration of furfural that can be safely used as a fragrance/flavour ingredient in toothpaste is 0.002 per cent in the fragrance compound. Are these suitable cut-offs to exempt a Schedule 6 or Schedule 7 entry for furfural, or is a more generic cut-off (0.1 per cent?) more appropriate?
  • Is there a need to develop Appendix E & F statements to cover products that would not meet schedule exemption concentrations? If so, please suggest such statements.
  • Is scheduling furfural likely to have unintended consequences - e.g. capture of AGVET or other products where solvent use or residues may exceed cut-off levels?
Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report, which is available on from the NICNAS website.

Scheduling status

2-furancarboxaldehyde has not been specifically scheduled.

Scheduling history

2-furancarboxaldehyde has not been considered for scheduling previously; however, the following related chemicals have been considered. 2,3,4,5-bis-(2-butylene)-tetrahydro-2-furfuraldehyde; and butadiene furfural copolymer.

2,3,4,5-bis-(2-butylene)-tetrahydro-2-furfuraldehyde

At its meeting in February 1986, the DPSC directed that the Agricultural and Veterinary Chemicals Association (AVCA) be contacted for a list of products containing the above substance and that the matter be placed on the agenda of its November 1986 meeting. However, this matter was not included in the November 1986 agenda.

Butadiene furfural copolymer

At its May 1974 meeting the PSSC was of the opinion that butadiene furfural copolymer should be exempted from the requirement of scheduling.

Public pre-meeting submissions

Three submissions were received.

The first submission indicated that the International Fragrance Association (IFRA) Standard sets the limit on furfural at 10 ppm for skin contact products and 500 ppm for non-skin contact products. While it may not be the role of the ACCS or the Delegate to decide whether to adopt the IFRA Code into the Australian cosmetics and consumer products regulatory framework, this was an issue that must be considered. It was suggested that it was not practical or efficient to reconsider all fragrances and flavours through the scheduling process. It was recommended that when there is an international body like IFRA that investigates issues surrounding flavours and fragrance in depth, it makes little sense to duplicate this work, particularly when most companies comply with the IFRA Code voluntarily. The New Zealand Cosmetic Products Group Standard has already adopted the IFRA Code. The submission further suggested a separate discussion, if possible, on the adoption of internationally accepted standards like the IFRA Code. The submission requested excluding furfural from scheduling when used as a fragrance or flavour in cosmetics, and that any scheduling consideration of furfural should ensure that other furan-based fragrances and indeed other furan-based chemicals for use other than as fragrances were not inadvertently caught in the scheduling of furfural.

The second submission indicated that it was unclear on what concentration cut-off had been proposed and requested that the committee consider that while furfural may not appear on the TGA ARTG ingredient list, it may be included in proprietary ingredients that are used in therapeutic goods. The submission further requested that the committee consider existing usage within proprietary ingredients and to propose a cut-off concentration that will not impact existing use in proprietary ingredients and in therapeutic goods.

The last submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on the delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that preparations containing furfural be included in Schedule 6 except in preparations containing 0.1 per cent or less of furfural.

The ACCS also suggested entries for furfural to be included in Appendix E and F.

The ACCS recommended an implementation date of 1 June 2014.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee 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 recommendation comprised the following:

  • Appropriate use of the substance other than when used as a fragrance e.g. as a solvent in domestic products.
  • Moderate to high toxicity profile, acute oral and inhalation toxicity consistent with the Scheduling Policy Framework for Schedule 6.
Delegate's interim decision

The delegate accepts the advice of the ACCS that a new Schedule 6 entry be created for furfural, based on a toxicological profile that is consistent with SPF factors for listing in Schedule 6. However, the delegate also notes that there were significant divisions within the ACCS on whether the use of this chemical as a component of fragrances requires scheduling, given the very low final concentrations likely to be present in consumer products. The delegate therefore accepts ACCS advice that a cut-off to exempt at 0.1% be included in the schedule entry, to accommodate its use in products where the public health hazard is insignificant. The delegate also accepts ACCS advice that new entries in Appendices E & F be created to provide appropriate labelling for products categorised via the Schedule 6 listing.

The delegate agrees to the implementation date of 1 June 2014.

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.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors12;
  • Other relevant information.
Submissions on interim decision

Two submissions were received.

One submission indicated that it tentatively supports the delegate's interim decision. The submission requested the proposed exemption from scheduling should exempt current Australian uses of furfural when used as a fragrance.

The other submission indicated that it supports the delegate's interim decision.

Delegate's final decision

The delegate has confirmed the interim decision, with a minor modification to the proposed SUSMP index cross-referencing, as no evidence has been received to alter the substance of the interim decision.  The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

Based on comments received, there should be no regulatory impact on products already in the Australian marketplace, so an early implementation date is considered appropriate.

Scheduling entry
Schedule 6 - new entry

FURFURAL except in preparations containing 0.1 per cent or less of furfural.

Appendix E, part 2
Poison Standard Statement
Furfural A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once). E1 - If in eyes wash out immediately with water. S1 - If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water
Appendix F, part 3
Poison Warning Statements Safety Directions
Furfural 5. Irritant 1. Avoid contact with eyes 4. Avoid contact with skin

Note that the name used in the NICNAS report is 2-furancarboxaldehyde (also used in the pre-meeting publication inviting comment). The delegate proposes that cross references be included in the SUSMP index, as follows:

  • 2-FURANCARBOXALDEHYDE
    • See FURFURAL
  • FURFURAL
    • See also 2-FURANCARBOXALDEHYDE

The delegate notes the comment in one of the submissions received following publication of the interim decision, that a second cross-referencing proposed for the SUSMP index is unnecessary, since there is no proposed schedule listing under the name 2-FURANCARBOXALDEHYDE. Accordingly, a second proposed cross-referencing has been deleted.

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Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (2010)
  2. Scheduling Policy Framework for Medicines and Chemicals (2010)
  3. Scheduling Policy Framework for Medicines and Chemicals (2010)
  4. Scheduling Policy Framework for Medicines and Chemicals (2010)
  5. 2-nitrotoluene is likely to be a component of cleaning/washing agents, paints, lacquers and varnishes at concentrations up to 0.9 per cent in finished products
  6. Scheduling Policy Framework for Medicines and Chemicals (2010)
  7. Scheduling Policy Framework for Medicines and Chemicals (2010)

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