3.2 Interim decision in relation to N-methyl-2-pyrrolidone (NMP)

3. Interim decision on proposed amendment referred to the Advisory Committee on Medicines and Chemicals Scheduling in joint session (Joint ACCS/ACMS #23, November 2019)

3.2. Interim decision in relation to N-methyl-2-pyrrolidone (NMP)

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision not to amend the current Poisons Standard in relation to NMP.

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's original scheduling proposal and reasons for the proposal | Current scheduling status | Australian regulations | International regulations | Delegate's referral to ACCS #24 | Advice of ACCS #24 | First interim decision | First interim decision public submissions | Summary of pre-meeting public submissions for ACCS-ACMS #23 | Summary of Joint ACMS-ACCS #23 advice/recommendations to the Delegate | Delegate's considerations | Reasons for interim decision

Applicant's original scheduling proposal and reasons for the proposal

An application to amend the Poisons Standard with respect to NMP was considered.

The Applicant's proposed amendments to the Poisons Standard were:

The Applicant's main points provided in support of the proposed amendments were as follows:

• the chemical has reported uses in cosmetic products available for sale in Australia;
• the chemical is expected to be readily absorbed through the skin;
• data from a quantitative risk assessment indicate that cosmetic uses at concentrations above 2 % may pose an unreasonable risk to the public;
• the chemical is prohibited for use in cosmetics in EU;
• the chemical is listed REACH Annex XVII which restricts the use of NMP in consumer applications to <0.3 %; and
• the chemical is classified as hazardous with the following risk phrases for human health in the Hazardous Chemical Information System (HCIS): Eye irritation - category 2A; Skin irritation - category 2; Specific target organ toxicity (single exposure) - category 3 and Reproductive toxicity - category 1B.

Current scheduling status

N-methyl-2-pyrrolidone is currently listed in Part 1, Schedules 5 and 6 and Appendix E, Part 2 of the Poison Standard as follows:

N-methyl-2-pyrrolidone is also cross referenced in the Schedule 5 and index entries for N-(N-dodecyl)-2-pyrrolidone, as highlighted in the green text below:

N-methyl-2-pyrrolidone is also cross referenced in the Schedule 5 and index entries for N-(N-octyl)-2-pyrrolidone, as highlighted in the green text below:

Australian regulations

• According to the TGA Ingredient Database^[262] NMP is:
  • Available for use as an active ingredient in: biologicals, prescription medicines;
  • Available for use as an excipient ingredient in: biologicals, export only, prescription medicines; and
  • Not available as an equivalent ingredient in any application.
• As of 12 December 2019 there are 12 products currently active on the Australian Register of Therapeutic Goods (ARTG)^[263] that contain NMP. Of these 12 products:
  • two products contain 160 mg NMP;
  • one product contains 165 mg NMP;
  • three products contain 193.9 mg NMP;
  • one product contains 258.5 mg NMP;
  • one product contains 278 mg NMP;
  • one product contains 833 mg NMP; and
  • for the remaining three, the NMP concentration has not been provided.
• The Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2019^[264] does not include NMP as an ingredient permitted to be included in listed medicines.
• No results were found on the Prescribing medicines in pregnancy database^[265] for NMP.
• There are no warning statements pertaining to NMP in the Medicines Advisory Statement Specification 2019 (RASML No.5 - Schedule 1).^[266]
• According to the Database of Adverse Event Notifications (DAEN),^[267] there are no reports of adverse events or deaths for products containing NMP as an active ingredient.
• As of 12 December 2019 there are 270 products (pesticides and veterinary parasiticides) containing NMP as a solvent currently approved for use by APVMA on the Public Chemical Registration Information System Search (PUBCRIS).^[268]
• APVMA's Adverse Experience Reporting Program^[269] (AERP) reporting for NMP for the last 10 years included:
  • 2015: 1 total report and 1 total possible. Presenting signs (probable and possible): headache (1), malaise (1) and nausea (1);
  • 2014: 1 total report and 1 total possible. Presenting signs (probable and possible): lack of effect (1)

International regulations

• European Union cosmetics legislation contains provisions on the use of substances classified as carcinogenic, mutagenic, or toxic for reproduction (referred to as CMR substances) in cosmetic products. In general, the use of CMR substances is prohibited, apart from in exceptional cases. The European Commission Cosmetic Ingredient Database^[270] lists NMP as a CMR substances of category 1A, 1B or 2. Therefore NMP is banned for use in cosmetic products.
• The European Chemicals Agency (ECHA)^[271] hazard classification for NMP is, 'Danger!'. According to the harmonised classification and labelling (ATP09) approved by the European Union, NMP may damage the unborn child, causes serious eye irritation, causes skin irritation and may cause respiratory irritation. Additionally, the classification provided by companies to ECHA in REACH^[272] registrations identifies NMP may damage fertility or the unborn child.
• NMP is listed in REACH Annex XVII^[273] which restricts the use of NMP in consumer applications to <0.3 %. This effectively bans the use of NMP in consumer products as it would have no functionality at this level in present consumer applications.

Delegate's referral to ACCS #24

Pursuant to regulation 42ZCZK, the Delegate referred proposed amendments to the Poisons Standard with respect to NMP, to the March 2019 meeting of the ACCS. No submissions were received in response to the notice inviting comment on the scheduling proposal.

Advice of ACCS #24

In March 2019, the Advisory Committee on Chemicals Scheduling #24 (ACCS #24) considered an application to amend the Poisons Standard entry for N-methyl-2-pyrrolidone (NMP) in Schedule 6 to expand its use in cosmetics with a separate exemption concentration cut-off and to clarify the concentration cut-off for non-cosmetic use.

The Committee did not make a recommendation regarding the Applicant's proposal to amend the Poisons Standard with respect to N-methyl-2-pyrrolidone. This was largely because, the Committee did not reach a consensus on whether statements in the application relating to developmental toxicity were supported by the evidence presented. There were some reservations about the interpretation of the reproductive toxicity data, and the Committee was unable to provide advice to the Delegate until the reproductive toxicity data were clarified; specifically, it is unclear whether developmental toxicity outcomes were directly associated with the substance or were secondary to maternal toxicity. The status of the scheduling of products other than cosmetic could be affected depending on the outcome of the reproductive and developmental toxicity data assessment. The scheduling of designated solvents and other consumer products could also be affected. The Committee recommended that further toxicological evaluation of the reproductive toxicity data be sought.

As the Committee was unable to reach a consensus on whether statements in the application relating to developmental toxicity were supported by the evidence presented, consideration was not given to the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 at the meeting.

First interim decision

On 6 June 2019,^[274] the Delegate, under regulation 42ZCZN, at that time made an interim decision not to amend the Poisons Standard in relation to NMP and to seek further advice at the Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS) and further evidence on the reproductive toxicity data from the Applicant.

First interim decision public submissions

No public submissions were received in response to the notice published under regulation 42ZCZP advising of the interim decision and invitation for further comment on substances referred to the March 2019 ACMS/ACCS meeting.^[275]

Summary of pre-meeting public submissions for ACCS-ACMS #23

The Delegate did not engage in further public consultation when referring NMP to the November 2019 meeting of the Joint Committee on Medicines and Chemicals Scheduling (ACMS-ACCS #23).

Summary of Joint ACMS-ACCS #23 advice/recommendations to the Delegate

The Committee, while acknowledging the potential risks of any use of NMP, recommended that the TGA review the toxicology (especially the developmental toxicity) and safety of NMP use across all regulatory jurisdictions to provide more evidence to inform the need for further scheduling considerations.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) the 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 of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Risks: There is some evidence that NMP may be a developmental toxicant, especially if multiple products are used.
b - the purposes for which a substance is to be used and the extent of use of a substance	NMP has broad usage including as an ingredient in 12 prescription medicines, in 254 Agvet products, as a solvent in paint stripping, in automotive products, paints, varnishes, stain removers, writing inks and in some cosmetics. Some use in cosmetics - mascara, skin moisturiser, hair dye stain remover.
c - the toxicity of a substance	There is some evidence that NMP may be a developmental toxicant. However, there is little human evidence and NMP has been used extensively for many years, including as an ingredient in prescription medicines.
d - the dosage, formulation, labelling, packaging and presentation of a substance	There are various presentations of NMP and a range of exposure routes.
e - the potential for abuse of a substance	Nil.
f - any other matters that the Secretary considers necessary to protect public health	If NMP is considered to lead to a risk on the basis of developmental toxicity evidence, then a broad risk assessment may be necessary taking into account uses across different regulatory jurisdictions. The assessment of reproduction toxicity should include all available studies XXXXXXXXXXXXXXXXXXXXXX.

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to NMP;
• The Meeting of the Advisory Committee on Chemicals Scheduling (ACCS #24)'s advice;
• The Delegate's first interim decision;
• The Joint Meeting of the Advisory Committee on Chemicals Scheduling and the Advisory Committee on Medicines Scheduling (Joint ACMS-ACCS#23)'s advice;
• Section 52E 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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018);
• Scheduling Handbook (V 1.1, July 2019); and

Reasons for interim decision

I agree with the Committee's finding that the relevant provisions of section 52E of the Therapeutic Goods Act 1989 are: (a) the 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 of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health. packaging and presentation of a substance.

In my view, the relevant parts of the SPF 2018 are the Scheduling Factors for Schedule 6.

I have considered the available evidence in support of a Schedule 6 entry for NMP for cosmetics with a concentration cut-off of less than 2 per cent and a 25 per cent cut-off in other preparations involving non-cosmetic use and have made the decision that at this time, the current scheduling of NMP remains appropriate.

In March 2019, the ACCS #24 considered an application to amend the Schedule 6 entry for NMP to expand its use in cosmetics with a separate exemption concentration cut-off and to clarify the concentration cut-off for non-cosmetic use. The Committee were unable to reach a consensus on whether statements relating to developmental toxicity were supported by the evidence presented. Given the uncertainty regarding the likely exposure to NMP and the reliability of the summary of reproductive and developmental toxicity data, the Delegate at that time made an interim decision^[276] not to amend the Poisons Standard in relation to NMP and to seek further evidence from the Applicant on matters listed in 52E(1) to clarify the reasons for their proposed amendment and to refer the matter to the Joint Advisory Committee on Medicines and Chemicals Scheduling given the number of medicines on the ARTG that contain NMP.

The main use of NMP that the Applicant raised in the original application as a concern was cosmetic use. However, the Applicant's proposed amendments did not align with international regulations and no evidence-based public-health rationale has been presented to support the proposed 2 per cent restriction. In the European Union, NMP is banned in cosmetics and for other consumer products, the concentration restriction will be lowered from 5% to 0.3% (GHS based - moving from specific concentration limit to generic concentration limit). This effectively will ban the use of NMP in all consumer products as it would have no functionality at this level in present consumer applications. Furthermore, a significant number of uses for NMP were identified outside of cosmetic use that were across a number of regulatory jurisdictions (i.e. TGA, APVMA and NICNAS) which needed to be taken into consideration if scheduling changes are to be implemented to protect public health. In addition to cosmetics, NMP was also used as an ingredient in human medicines, in agricultural and veterinary products, as a solvent in paints and paint strippers, in automotive products, varnishes and stain removers and in writing inks and it is unknown how many products are currently supplied in Australia. Given its broad usage and various presentations, NMP has a range of exposure routes for which there was currently insufficient evidence available to support that these uses pose unacceptable risks to the public. If changes to the scheduling of NMP were to be made on the basis of developmental toxicity, then a broad review of all its uses will be required to ensure that any scheduling changes address risks across all NMP uses, not only its cosmetic use.

While there is some evidence that NMP may be a developmental toxicant, there is little human evidence. Given the uncertainty regarding the interpretation of the reproductive toxicity data, it is unclear whether developmental toxicity outcomes are directly associated with NMP or are secondary to maternal toxicity. NMP has been used extensively for many years in a range of products, including as an ingredient in prescription medicines at up to 833 mg NMP per dose (subcutaneous injection with NMP comprising 50 per cent of the administered dose). While I note that products containing NMP currently on the ARTG are usually contraindicated in pregnancy due to the active ingredient, there has been no consideration given to the effects of these therapeutic concentrations of NMP on developmental outcomes. Furthermore, NMP is also present in high concentrations in paint strippers and automotive refinishing products; is a designated solvent at concentrations at up to 60 per cent in APVMA-approved agricultural and veterinary chemical products; and is present many other industrial and domestic products. If the evidence on developmental toxicity is deemed significant enough to restrict concentration in cosmetics to 2 per cent, a careful consideration of all existing uses of NMP and its wide-spread use across all regulatory sectors is required to ensure any scheduling changes are based on all potential risks and not just risks associated with cosmetic use. In addition to the uncertainty regarding the developmental toxicity of NMP, there is also uncertainty regarding likely exposure to NMP given it use in a range of products that cross jurisdictional boundaries. This makes it difficult to ascertain the reasonable foreseeable harm to consumers and to assess the risk to human health from repeated use. Given these uncertainties, and the lack of safety signals warranting an amendment, the weight of evidence supports that on balance, the current scheduling of NMP remains appropriate.

I note that the US EPA has recently (November 2019) published a Draft Risk Evaluation for N-Methylpyrrolidone (NMP) and has sought public comment on it draft risk evaluation.^[277] The finalised report (date to be determined by the authority) may provide information that reduces the uncertainty around the toxicity, and in particular the developmental toxicity, of NMP.

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