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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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3.7. Dinotefuran

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the current Schedule 5 entry to exempt preparations containing 10 per cent or less of dinotefuran 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
  • DINOTEFURAN except in preparations containing 10 per cent or less of dinotefuran.

The applicant's reasons for the request are:

  • Toxicity studies of several products containing dinotefuran have confirmed low toxicity consistent with the proposed scheduling.
Current scheduling status

Dinotefuran is currently listed in Schedule 5 as follows:

  • Schedule 5
  • DINOTEFURAN.
Relevant scheduling history

In July 2015, the ACCS considered a proposal to include dinotefuran in the Poisons Standard. The committee recommended, and the delegate agreed, to include dinotefuran in the Poisons Standard 1 October 2015.

Although other members of the neonicotinoid class are listed in Schedule 6, on 22 July 2015 the delegate made a final decision for dinotefuran to create a new Schedule 5 entry due to its low toxicological profile consistent with the Scheduling Policy Framework (SPF) Schedule 5 criteria. However, evidence of mild/moderate skin/eye irritancy for the formulated product meant that it was inappropriate to provide a schedule exemption for the formulated product considered in the application.

Australian regulatory information

Dinotefuran 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.

A search of the Database of Adverse Events Notifications (DAEN) database for dinotefuran did not reveal any adverse events or safety issues from 1 January 1971 to 17 May 2017.

Dinotefuran is an APVMA approved active constituent and is contained in one APVMA registered product on the PubCRIS database.

APVMA Public Release Summary on the 'Evaluation of the new active Dinotefuran in the Product Starkle 200 SG Insecticide', August 2015

International regulations
The Joint FAO/WHO Meeting on Pesticide Residues (JMPR)

JMPR have previously evaluated dinotefuran. The report The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) has previously evaluated the toxicology of dinotefuran.

European Union (EU)

Dinotefuran was approved for use by the Committee for Medicinal Products for Veterinary Use (CVMP)/the European Medicines Agency's (EMA) in October 2013 as part of the registration a product.

United States of America (USA)

Dinotefuran was first registered with the USA Environmental Protection Agency in September 2004 by the applicant.

Substance summary

Dinotefuran is a member of the neonicotinoid class of chemicals that act through binding to nicotinic acetylcholine receptors. There are no new data or changes for the active constituent from the acute and repeat-dose toxicology data that was presented at the July 2015 ACCS meeting.

The following information was extracted from the AVPMA human health risk assessment (HHRA) technical report for the toxicology of dinotefuran.

Table 3.7.1: Chemical information for dinotefuran
Property Dinotefuran
CAS name N-methyl-N′-nitro-N″-[(tetrahydro-3-furanyl)methyl]guanidine
CAS number 165252-70-0
Chemical structure chemical structure of
Molecular formula C7H14N4O3
Molecular weight 202.2 g/mol
IUPAC and/or common and/or other names

1-Methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine (IUPAC);
2-Methyl-1-nitro-3-(oxolan-3-ylmethyl)guanidine;
1-Methyl-2-nitro-3-((tetrahydrofuran-3-yl)methyl)guanidine;
N (RS)-1-methyl-2-nitro-3-[(tetrahydro-3-furanyl) methyl] guanidine;
MTI-446.

Table 3.7.2: Acute toxicity end-points for dinotefuran
Toxicity Species Dinotefuran SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2450 Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 (no deaths) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >4090 (no deaths) Schedule 5
Skin irritation Rabbit Non-irritant N/A
Eye irritation Rabbit Moderate Schedule 5
Skin sensitisation (GPMT) Guinea pig Not sensitising N/A
Summary of products
  • Dust Insecticide (DU, dust), 2.5 g/kg dinotefuran;
  • Pressurised Fly Bait (AE), 10 g/kg dinotefuran;
  • Gel Cockroach Bait (BA, gel bait), 5 g/kg dinotefuran;
  • Pressurised Insecticide (PI or AE, aerosol), 5 g/kg dinotefuran;
  • WSG Insecticide (WG, water-soluble granules), 400 g/kg dinotefuran [58]

The submitted acute toxicity data supports a cut-off for dinotefuran from Schedule 5 at 10 per cent. Acute toxicity is summarised below.

Table 3.7.2: Acute toxicity end-points for dinotefuran
Toxicity[59] Dust (DU) Pressurised fly bait (AE) Pressurised insecticide PI (AE) Gel Bait (BA) Water-soluble granules (WG)
Dinotefuran Concentration (g/kg) 2.5 10 5 5 400
Acute oral toxicity LD50 (mg/kg bw) >5000 >5000 >5000 >5000 >5000
Acute dermal toxicity LD50 (mg/kg bw) >5000 >5000 >5000 >5000 >5000
Acute inhalational toxicity LC50 (mg/kg bw) >2080 >5090 >2050 >2070 >5090
Skin irritation Non-irritant Non-irritant Slight Non-irritant Non-irritant
Eye irritation Moderate – due to abrasive ground rock in formulation, not due to active Very slight Slight Slight Moderate
Skin sensitisation (Buehler) Not sensitising Not sensitising Not sensitising Not sensitising Not sensitising
SPF (2015) Classification Schedule 5/6 N/A-Schedule 5 Schedule 5/6 Schedule 5/6 Schedule 5

The proposed products all have low acute oral, dermal and inhalational toxicity, and none were skin sensitisers. The toxicity endpoints relevant to scheduling are skin and eye irritation. More details from these relevant acute toxicity studies on the products are summarised below in Table 3.

Table 3.7.4: Details for dinotefuran skin and eye irritation toxicity studies
Toxicity[60] Dust (DU) Pressurised fly bait (AE) Pressurised insecticide PI (AE) Gel Bait (BA) Water-soluble granules (WG)
Dinotefuran Conc (g/kg) 2.5 10 5 5 400

Skin irritation

NZ White rabbits, n=3

Results:

0.5 g (1.25 g of the 40% w/w test mixture).

Very faint erythema (score of 0.3) at 1 h post-application; Fully resolved by 24 h.

0.5 g.

No observed erythema or oedema

0.5 g.

Erythema (score of 1) in all rabbits at 1 h post-application, remaining in 2/3 animals at 24 hours, and fully resolving by 48 h.

0.5 mL.

Very slight erythema (score of 1) mean in 3/3 rabbits at 1 h post-application. Full recovery at 24 h.

40% solution.

No erythema or oedema was observed.
Conclusion Non-irritant Non-irritant Slight irritant Non-irritant Non-irritant

Eye irritation

NZ White rabbits, n=3

Results:

0.03 g.

Conjunctivitis and iritis in all animals within 1 h post-instillation; resolved by Day 7. One animal exhibited corneal opacity by 24 h, resolved by Day 4 was observed in the experimental period.

A ‘burst’ (0.3-0.5 g) to the right eye from a distance of approximately 10 cm.

Very slight (scores of 1/3) conjunctivae redness, and discharge in 2/3 eyes each at 1 h, fully resolved by 24 h.

0.1 mL.

Conjunctivitis in all animals at 1 h; recovery by 48 h. No corneal opacity or iritis were observed in the experimental period.

0.1 mL.

Conjunctivitis observed in all treated eyes within 1 h post-instillation, remaining in 1/3 eyes at 24 h, and fully resolving at 48 h.

0.07 g (0.1 mL).

Conjunctivitis and corneal opacity observed in all animals at 24 h, partially resolving at 48 h, and fully resolving by 72 h.
Conclusion Moderate irritant (due to ground rock in formulation, not due to active ingredient) Very slight irritant Slight irritant Slight irritant Moderate irritant
Pre-meeting public submissions

No submissions were received.

Summary of ACCS advice to the delegate

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

Schedule 5 – Amend Entry

DINOTEFURAN except in preparations containing 1 per cent or less of dinotefuran.

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; (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 recommendation comprised the following:

  1. the risks and benefits of the use of a substance:
  • Risks: dinotefuran has a potential for slight-moderate reversible eye irritancy.
  • Benefit: dinotefuran is a low-risk insecticide for both agricultural and commercial use, with possible domestic use.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Dinotefuran is a neonicotinoid, a relatively newer class of insecticide.
  • the toxicity of a substance:
    • Ready to use products containing dinotefuran are both slight eye irritants and skin irritants.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Packaging and labelling consistent with APVMA requirements.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • New data provided supports the recommended cut-off. This was not available in 2015 when dinotefuran was first entered into the Poisons Standard.
    Delegate's considerations

    The delegate considered the following regarding this proposal:

    Delegate's interim decision

    The delegate’s interim decision is to amend the current Schedule 5 entry of dinotefuran. The proposed Schedule entry is:

    Schedule 5 – Amend Entry

    DINOTEFURAN except in preparations containing 1 per cent or less of dinotefuran.

    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; (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 interim decision are the following:

    1. the risks and benefits of the use of a substance:
    • Risks: dinotefuran has a potential for slight-moderate reversible eye irritancy.
    • Benefit: dinotefuran is a low-risk insecticide for both agricultural and commercial use, with possible domestic use.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Dinotefuran is a neonicotinoid, a relatively newer class of insecticide.
  • the toxicity of a substance:
    • Ready to use products containing dinotefuran are both slight eye irritants and skin irritants.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Packaging and labelling consistent with APVMA requirements.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • New data provided supports the recommended cut-off. This was not available in 2015 when dinotefuran was first entered into the Poisons Standard.

    Footnotes
    1. The Human Health Risk Assessment Technical Report by the APVMA contains consideration of a water-soluble granule product formulation containing 40% w/v dinotefuran – but is not subject to the current re-scheduling request
    2. Standard species used (rat, rabbit, guinea pig, as appropriate)
    3. Standard species used (rat, rabbit, guinea pig, as appropriate)

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