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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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3.2 Pydiflumetofen

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a new entry for pydiflumetofen in Schedule 5 of the Poisons Standard, with no exemption cut-off.

Scheduling application

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

  • Schedule 5 - New Entry
  • PYDIFLUMETOFEN.

The applicant's reasons for the request are:

  • Pydiflumetofen is a new broad-spectrum fungicide of the chemical group of N-methoxy-(phenyl-ethyl)-pyrazole-carboxamide. The active ingredient is a mixture of the R & S isomers of pydiflumetofen. The mode of action of pydiflumetofen is inhibition of respiration in phytopathogenic fungi at succinate dehydrogenase (or Electron Transport Chain Complex II) in mitochondria;
  • Two product applications were submitted for the registration by the APVMA. However, one product application has now been withdrawn;
  • Based on the observed slight eye irritation in rabbits, pydiflumetofen meets the Scheduling Policy Framework (2015) criteria for including it in Schedule 5 of the Poisons Standard with no cut-offs or exemptions;
  • Pydiflumetofen is not a reproduction or developmental toxin, is not neurotoxic and does not present a genotoxic or carcinogenic risk to humans; and
  • The product containing 20% w/v of pydiflumetofen has low acute oral toxicity in rats (LD50 2958 mg/kg bw), low acute dermal toxicity in rats (LD50 >5000 mg/kg bw, no deaths or clinical signs), low acute inhalation toxicity in rats (LC50 >3500 mg/m3 with 1 death at 3500 mg/m3), is not a skin irritant in rabbits or a skin sensitiser in the mouse (LLNA). The product produced slight transient eye irritation in the rabbit resolving after 1 hour and was not an irritant in an isolated chicken eye study.

Current scheduling status and relevant scheduling history

Pydiflumetofen is not currently scheduled and has not been previously considered for scheduling. Therefore, a scheduling history is not available.
Pydiflumetofen is not captured by any group entry nor is it a salt or derivative of any entry in the current (June 2017) Poisons Standard.

Scheduling and scheduling history of related compounds

Penthiopyrad was included in the Poisons Standard in Schedule 5 on 1 May 2012 following a delegate only decision.

Fluxapyroxad was included in the Poisons Standard in Schedule 5 on 1 May 2012 following referral to the ACCS.

Sedaxane was included in the Poisons Standard in Schedule 5 on 1 September 2012 following a delegate only decision.

Penflufen was included in the Poisons Standard in Schedule 5 on 1 January 2013 following referral to the ACCS.

Bixafen was included in the Poisons Standard in Schedule 5 on 1 February 2016 following a delegate only decision.

Isopyrazam was included in the Poisons Standard in Schedule 6 on 1 October 2016 following referral to the ACCS.

Australian regulatory information

Pydiflumetofen is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017, and is not an excipient or active in any products on the ARTG.

International regulations

Pydiflumetofen applications are currently pending in the EU (EC Regulation 1107/2009), Canada and Argentina.

Substance summary

Pydiflumetofen is a new broad-spectrum fungicide of the chemical group of N-methoxy-(phenyl-ethyl)-pyrazole-carboxamide. The active ingredient is a mixture of the R & S isomers of pydiflumetofen. The mode of action of pydiflumetofen is inhibition of respiration in phytopathogenic fungi at succinate dehydrogenase (or Electron Transport Chain Complex II) in mitochondria. An extensive data base of toxicology, metabolism and toxicokinetic studies have been provided for pydiflumetofen.

Table 3.2.1: Chemical information for Pydiflumetofen
Property Pydiflumetofen
Chemical structure and position of radiolabel for Pydiflumetofen chemical structure of pydiflumetofen
Molecular Formula C16H16Cl3F2N3O2
Molecular weight 426.7 g/mol
CAS number 1228284-64-7
IUPAC and/or common and/or other names 3-(difluoromethyl)-N-methoxy-1-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)ethyl]-1H-pyrazole-4-carboxamide (CAS); 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(RS)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide (IUPAC)
Table 3.2.2: Acceptable Daily Intake for pydiflumetofen[48])
Chemical ADI (mg/kg bw/d) NOAEL (mg/kg bw/d) Date Study
Pydiflumetofen 0.1 10 21 February 2017 1–year dietary rat study; a NOAEL of 10 mg/kg bw/d was based on reduced body weight gain, food consumption and food energy conversion efficiency at the next higher dose.
Table 3.2.3: Acute toxicity end-points for Pydiflumetofen
Toxicity Species Pydiflumetofen SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >5000 Nil
Acute dermal toxicity LD50 (mg/kg bw) Rat >5000 Nil
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >5110 Schedule 5
Skin irritation Rabbit Not irritant Nil
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation (LLNA) Mouse Not a sensitiser Nil

Acute toxicity

Pydiflumetofen has low to very low acute oral toxicity in the rat (LD50 > 5000 mg/kg bw with no deaths and no clinical signs after 4 hours - 1 animal had a slight reduction in activity at < 4 h), has low to very low acute dermal toxicity in the rat (LD50 > 5000 mg/kg bw with no deaths but decreased activity during day 1) and low to very low acute inhalation toxicity in rats (LC50 > 5110 mg/m3 with 1 death and clinical signs of toxicity). Pydiflumetofen is neither a sensitiser in a mouse LLNA assay nor a skin irritant in rabbits but was a slight eye irritant in rabbits (Initial pain reaction, discharge conjunctival redness, all resolving by 72-hours. No corneal effects).

Eye irritation

Pydiflumetofen is a slight eye irritant in rabbits (Initial pain reaction, discharge conjunctival redness, all resolving by 72-hours. No corneal effects).

Sensitization

Pydiflumetofen is not a sensitiser in a mouse LLNA assay.

Repeat-dose toxicity

In repeat dose toxicity studies the primary target organ of toxicity was the liver with increased liver weight, associated with hepatocyte hypertrophy, generally defining the LOAEL in conjunction with reduced body weight gains. Mode of action studies demonstrated that these observations were associated with induction of microsomal enzymes in a phenobarbital like pattern.

Genotoxicity

The overall weight of evidence is that pydiflumetofen does not present a genotoxic risk to humans.

Carcinogenicity

Pydiflumetofen was not carcinogenic in a rat chronic study but did increase the incidence of hepatic carcinoma and adenoma in male mice. The mechanism of action of pydiflumetofen in the production of mouse hepatic cancers was examined in a series of studies that demonstrated a mode of action that is not relevant to humans (a phenobarbital like activation of Constitutive Androstane Receptor - CAR - with a consequent induction of Cyp450, increased cell proliferation, hepatomegaly and hepatocyte hypertrophy).

Reproduction and developmental toxicity

Pydiflumetofen was neither a reproductive toxin in rats nor a developmental toxin in rats and rabbits. The compound was tested in a battery of in vivoand in vitrogenotoxicity studies. With the exception of a positive after 22 hours of exposure in the absence of S9 in a human lymphocyte clastogenicity assay, all assays were negative.

Public exposure

Both products are intended for use in agriculture and the applicant has not sought approval for home garden use, although the toxicological profile of pydiflumetofen is not inconsistent with the criteria for this use pattern. Public exposure to the product concentrate and in use dilutions is likely to be negligible other than possibly to spray drift moving into public areas. Under normal use scenarios such exposure is likely to be uncommon, short term and infrequent.

Pre-meeting submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that a new Appendix B entry for pydiflumetofen be created as follows:

Appendix B – New Entry

PYDIFLUMETOFEN

Reason for Entry – a, low toxicity

Area of Use – 1.3, fungicide

The committee also recommended an implementation date of 1 February 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice were:

  • The risks associated with pydiflumetofen are minimal. Pydiflumetofen meets the SPF criteria for Schedule 5 for low acute inhalation toxicity and slight temporary eye irritation. However, it is unscheduled based on its low acute oral and dermal toxicity. Pydiflumetofen has no skin irritation or sensitisation demonstrated.
  • Pydiflumetofen is a fungicide for agricultural use.
  • The APVMA is well placed to develop suitable warning statements, safety directions and first aid instructions for the product label of future products containing pydiflumetofen.

Delegate's considerations

  • The delegate considered the following regarding this proposal:
  • Scheduling proposal
  • ACCS advice
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create a new Appendix B entry for pydiflumetofen. The proposed Schedule entry is as follows:

Appendix B – New Entry

PYDIFLUMETOFEN

Reason for Entry – a, low toxicity

Area of Use – 1.3, fungicide

The proposed implementation date is 1 February 2018, as this is the earliest possible 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 a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the interim decision are:

  • The risks associated with pydiflumetofen are minimal. Pydiflumetofen meets the SPF criteria for Schedule 5 for low acute inhalation toxicity and slight temporary eye irritation. However, it is unscheduled based on its low acute oral and dermal toxicity. Pydiflumetofen has no skin irritation or sensitisation demonstrated.
  • Pydiflumetofen is a fungicide for agricultural use.
  • The APVMA is well placed to develop suitable warning statements, safety directions and first aid instructions for the product label of future products containing pydiflumetofen.

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