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Scheduling delegates' interim decisions and invitation for further comment: ACCS/ACMS, November 2017

Scheduling medicines and poisons

5 February 2018

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3.2. Metofluthrin

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Schedule 5, subclause b entry for metofluthrin to remove 'for use as a mosquito repellent' in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

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

  • Schedule 5 – Amend Entry
  • METOFLUTHRIN:
  1. in impregnated fabric mosquito repellent preparations for use in a vaporiser containing 15 mg or less of metofluthrin per disk; or
  2. when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin for use as a mosquito repellent.

The applicant's reasons for the request are:

  • The overall toxicity, oral toxicity and risk of inhalation toxicity of metofluthrin are low.
  • The formulation of the proposed product mitigates risk as it is in a polyethylene slow release matrix.
  • The main risk of children’s inhalation toxicity was found to be at acceptable levels independently of the proposed product use.
Current scheduling status

Metofluthrin is in Schedule 5 and 6 of the Poisons Standard as follows:

  • Schedule 6
  • METOFLUTHRIN except when included in Schedule 5.
  • Schedule 5
  • METOFLUTHRIN:
  1. in impregnated fabric mosquito repellent preparations for use in a vaporiser containing 15 mg or less of metofluthrin per disk; or
  2. when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin for use as a mosquito repellent.
Scheduling history

In February 2011, the Advisory Committee on Chemicals Scheduling (ACCS) considered a proposal to include metofluthrin in Schedule 6. This was based on its toxicity profile of moderate acute inhalation toxicity and neurotoxicity (with clinical signs of neurotoxicity seen at 100 mg/kg bw in a rat acute neurotoxicity study, and at 30 mg/kg bw/d in a 12-month oral study in dogs and in dams in an oral rat developmental study). This was recommended by the ACCS and agreed to by the delegate. The ACCS recommended a new Schedule 6 entry be created for metofluthrin. The delegate decided that the recommendations of the ACCS were clear and appropriately supported and included metofluthrin in Schedule 6. The delegate decided that a 6 month implementation period was appropriate.

In July 2014, the delegate referred a proposal to the ACCS to amend the current Schedule 6 to exclude mosquito repellent preparations containing 312 g/kg or less of metofluthrin from scheduling. The applicant indicated that the toxicity of the product (the substance impregnated onto non-woven polyester fabric, which is incorporated in a device that is designed to release the substance in the atmosphere) is the same as the toxicity of the substance. The committee recommended that, based on the toxicity profile and use pattern/exposure to the product, the current Schedule 6 metofluthrin entry be amended to exempt impregnated fabric mosquito repellent preparations for use in a vaporiser containing 15 mg or less of metofluthrin per disk to Schedule 5. They recommended that the schedule 5 entry should specifically include the preparation and the refill. The delegate accepted the advice provided by the ACCS and decided to include a new entry for metofluthrin in Schedule 5 and to amend the current Schedule 6 entry. The implementation date for this decision was 1 February 2015.

In March 2015, the ACCS considered a proposal to amend the Schedule 5 entry of metofluthrin to allow it to be used in an impregnated woven polyethylene sheet containing 250 mg or less of metofluthrin. While metofluthrin is a moderately toxic pyrethroid insecticide, the packaging and presentation of the product, i.e. the polyethylene slow release matrix and the overall low toxicity, and risk of inhalation toxicity was considered to be low due to the formulation of the product. This was considered to mitigate the overall exposure risk and warranted inclusion in Schedule 5. The committee recommended that the current Schedule 5 listing for metofluthrin be amended to include preparations impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin. The delegate agreed and made a final decision for metofluthrin on 22 July 2017.

Australian regulatory information

Metofluthrin is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017 and is not an excipient or active in any medicines on the ARTG.

There are no reported adverse events or safety issues in the Database of Adverse Events Notifications (DAEN) from 1971 to 2017 for methfluthrin.

Metofluthrin is not listed in the Australian Inventory of Chemical Substances (AICS).

One active constituent and two registered products were found on the PubCRIS database. Both registered products are for household use for mosquito control/repellent.

International regulations
European Union (EU)

Metofluthrin is included in Annex I of the Directive 98/8/EC. Biocidal products containing active substances that have been included in Annex I or IA of the Biocides Directive are subject to product authorisation or registration, respectively, as per the requirements of the Biocides Directive.

As of 23 July 2017, metofluthrin is not on the registered substances database.

United States of America (USA)

In New York State, two products containing metofluthrin have been registered with the following condition:

'The registrant is required to provide us with a summary of any adverse effects that have been associated with these products, including any FIFRA 6(a)(2) reports, on a quarterly basis'.

The US Environment Protection Authority (EPA) issued the metofluthrin Pesticide Fact Sheet in September 2006 (EPA Chemical Code 109709).

New Zealand

In April 2015, the New Zealand EPA approved the importation of metofluthrin as strips impregnated with 312 g/kg of metofluthrin. Each strip contains 13 mg of metofluthrin as part of a refill cartridge for a portable vaporiser to be used by the general public during outdoor activities.

Canada

In October 2011, another product was registered for use as a personal insect repellent. Within the first year of its registration, the Pest Management Regulatory Agency (PMRA) received six human incident reports associated with this product. A wide range of symptoms such as dizziness, swelling, nausea, lethargy, muscular weakness, pruritus, irregular heart rate, or loss of consciousness was noted. The effects reported were considered to be either possibly or probably related to pesticide exposure. The product currently holds a registration that is conditional upon the submission of additional data on product exposure. The PMRA indicated that:

'Although only a few incidents were reported, this is a new product and the PMRA will continue to monitor incidents reported in the following year'.

In 2016, the Canadian Pest Management Regulatory Agency approved metofluthrin in similar to the NZ clip-on devices. The Canadian evaluation report is publicly available.

Substance summary
Table 3.2.1: Chemical information for metofluthrin
Property Metofluthrin
CAS name 2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate
CAS number 240494-70-6
Chemical structure chemical structure of
Molecular formula C18H20F4O3
Molecular weight 360.3 g/mol
IUPAC and/or common and/or other names 1-propenyl)cyclopropanecarboxylate;

[2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2-dimethyl-3-[(E)-prop-1-enyl]cyclopropane-1-carboxylate (IUPAC);

(2,3,5,6-tetrafluoro-4-methoxymethylphenyl)methyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate;

Matofluthrin

Metofluthrin is a synthetic pyrethroid ester insecticide. This class of chemicals act on the nervous system of insects, disturbing the function of neurons by interacting with sodium channels.

Other pyrethroid insecticides include transfluthrin, permethrin, deltamethrin, esfenvalerate and alpha-cypermethrin. While some of these share structural similarity with metofluthrin, this does not appear to be sufficient to class metofluthrin as a derivative (for the purpose of scheduling) of any of these compounds.

The following information was extracted from APVMA assessment report - Human Health Risk Assessment Technical Report – metofluthrin.

Table 3.2.2: Acute toxicity end-points for metofluthrin
Toxicity Species Metofluthrin SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >1080 and ≤1960 Schedule 6
Skin irritation Rabbit Slight irritant Schedule 5
Eye irritation Rabbit Non-irritant Schedule 5
SSkin sensitisation (Guinea Pig Maximisation Test) Guinea pig Non-sensitiser Schedule 5

Hazard profiles of metofluthrin and of the product containing 250 mg or less of metofluthrin impregnated into a polyethylene slow release matrix have previously been considered at the March 2015 ACCS scheduling meeting.

After conducting an online search for metofluthrin toxicology data, the APVMA concludes that these hazard profiles remain appropriate.

It is noteworthy that although metofluthrin was a slight skin irritant, the proposed product containing 250 mg or less of metofluthrin impregnated into a polyethylene slow release matrix was a non-irritant to rabbit skin.

The previous assessment of the product, supporting the "metofluthrin July 2015 scheduling decision", considered the main concern to be exposure by inhalation, especially in toddlers and young children. The APVMA estimated the theoretically maximum attainable metofluthrin concentration in air, noting that this approach is very conservative, and that the actual metofluthrin concentration in air is always less than the theoretically maximum attainable concentration. Using the theoretically maximum attainable metofluthrin concentration in air, the APVMA estimated the inhalation exposure for 1-2 year old children, and concluded that exposure to the product was unlikely to pose an unacceptable health risk (margins of exposure at 20˚C and 35˚C were 1350 and 204, respectively).

Pre-meeting public submissions

No submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that the Schedule 5 entry for metofluthrin be amended as follows:

Schedule 5 – Amend Entry

METOFLUTHRIN:

  1. in impregnated fabric mosquito repellent preparations for use in a vaporiser containing 15 mg or less of metofluthrin per disk; or
  2. when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin for use as a mosquito repellent.

The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.

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 recommendation comprised the following:

  1. the risks and benefits of the use of a substance:
  • Risks: the proposed amendment presents no increased risk compared with current scheduling.
  • Benefits: the chemical is a highly effective pyrethroid insecticide, which is beneficial for Queensland, particularly Far North Queensland, due to the high incidence of mosquito borne diseases during wet season.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Broad applications to other insect pests.
  • the toxicity of a substance:
    • Metofluthrin has overall low toxicity, and the risk of inhalation of the product is low due to its formulation.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Polyethylene slow release matrix mitigates risk of toxicity of the product.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • Nil
    Delegate's considerations

    The delegate considered the following regarding this proposal:

    Delegate's interim decision

    The delegate’s interim decision is to amend the Schedule 5 entry for metofluthrin by removing the phrase "for use as a mosquito repellent" from subclause (b). The proposed Schedule entry is:

    Schedule 5 – Amend Entry

    METOFLUTHRIN:

    1. in impregnated fabric mosquito repellent preparations for use in a vaporiser containing 15 mg or less of metofluthrin per disk; or
    2. when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin.

    The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.

    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 the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

    The reasons for the interim decision are the following:

    1. the risks and benefits of the use of a substance:
    • Risks: the proposed amendment presents no increased risk compared with current scheduling.
    • Benefits: the chemical is a highly effective pyrethroid insecticide, which is beneficial for Queensland, particularly Far North Queensland, due to the high incidence of mosquito borne diseases during wet season.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Broad applications to other insect pests.
  • the toxicity of a substance:
    • Metofluthrin has overall low toxicity, and the risk of inhalation of the product is low due to its formulation.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Polyethylene slow release matrix mitigates risk of toxicity of the product.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • Nil

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