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Scheduling delegate's final decisions: ACCS, July 2015

23 July 2015

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Part B - Final decisions on matters not referred to an expert advisory committee

2. Agriculture and Veterinary Chemicals

SUMMARY OF DELEGATE-ONLY FINAL DECISIONS

Substance Final Decision
Pyriofenone Schedule 6 - amendment

PYRIOFENONE except when included in Schedule 5.

Schedule 5 - New Entry

PYRIOFENONE in preparations containing 30 per cent or less of pyriofenone

Implementation date - 1 October 2015.

Dinotefuran Schedule 5 - New Entry

DINOTEFURAN

Implementation date - 1 October 2015

2.1 PYRIOFENONE

Scheduling proposal

An application to the APVMA seeking registration of a product for agricultural uses requested that the delegate consider the scheduling of the active constituent, a suspension concentrate (SC) solution containing 300 g/L pyriofenone. In May 2015, the OCS, performed a risk assessment based on the information submitted to the APVMA

Substance summary
Structure of pyriofenone

Structure of pyriofenone

Acute toxicity

Pyriofenone TGAC acute toxicity end-points are listed in the below table.

Toxicity Species Pyriofenone SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 (female, no deaths) Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 (male and female no deaths) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >5180 (male and female, no deaths) Schedule 5
Skin irritation Rabbit Non-irritant Not scheduled/

Appendix B

Eye irritation Rabbit Non-irritant Not scheduled/

Appendix B

Skin sensitisation (maximization test) Guinea pig Sensitiser Schedule 6

ISK Pyriofenone 300 SC Fungicide acute toxicity end-points are listed in the below table.

Toxicity Species ISK Pyriofenone 300 SC Fungicide SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 (male and female, no deaths) Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 (male and female no deaths) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >2780** (male and female, no deaths) Schedule 5
Skin irritation Rabbit Not a skin irritant Not scheduled/

Appendix B

Eye irritation Rabbit Slight eye irritant Schedule 5
Skin sensitisation (Buehler, 9 inductions) Guinea pig Not a skin sensitiser Not scheduled/

Appendix B

**Maximum achievable concentration

Repeat-dose toxicity

A NOEL of 9 mg/kg bw/d was established for Pyriofenone based on a 1-year and a 2-year chronic rat study for signs of altered liver function, bilirubin and alkaline phosphatase decrease in males and increased kidney chronic nephropathy incidence in females at 42.9 and 46.5 mg/kg bw/d in males and females, respectively. Repeat dose toxicity studies' findings are compatible with Schedule 5.

Mutagenicity & Genotoxicity

Pyriofenone was not mutagenic in bacterial and mammalian cells and not clastogenic in mammalian cells, with and without metabolic activation. Pyriofenone did not induce micronuclei in vivo in mouse bone marrow following oral administration up to and including the limit dose of 2000 mg/kg bw. Therefore, from the available data, there is no evidence that pyriofenone is an in vivo genotoxicant.

Carcinogenicity

Pyriofenone was not carcinogenic in rats and mice.

Reproduction and developmental toxicity

Pyriofenone did not demonstrate evidence of reproductive/developmental toxicity potential. In rats, the NOEL for reproductive toxicity was 5000 ppm (equivalent to 339/485 mg/kg bw/d in males/females), the highest dose tested. The NOEL for offspring was 1000 ppm (equivalent to 65.2/92.3 mg/kg bw/d in male/female pups) based on lower absolute and relative splenic weights seen in F1 and F2 pups at 5000 ppm (equivalent to 339/485 mg/kg bw/d in male/female pups).

Observation in humans

No information was provided.

Public exposure

ISK Pyriofenone 300 SC Fungicide is for professional use only. No worker exposure studies or calculations of exposure have been submitted, but enough information was provided for the OCS to carry out exposure estimations. The OCS concluded that acceptable margins of exposure (MOE) were expected without any personal protective equipment (PPE) when mixing/loading and spraying the product with airblast, ground boom or handwand. PPE were required to ensure acceptable MOE in the assessment when areas were sprayed with equipment carried on the back of the user. Finally, the OCS determined that potential harm caused by ISK Pyriofenone 300 SC Fungicide could be reduced through the use of appropriate packaging with simple warnings/precautionary statements and safety directions on the label, according to Schedule 5.

International regulations

The OCS found no evidence of pyriofenone based product being registered for use in any overseas jurisdiction. Pyriofenone active constituent and end-use product were submitted to the EU EFSA for approval in March 2010. Target crops were grapevines and wheat. An application for approval of an import tolerance (MRL) in grapevines, cucurbit vegetables; and berry & small fruit, has been submitted to the US EPA and is due in 2016. These applications in the EU and in the USA appear to remain pending.

Scheduling history

Based on an application for scheduling, the delegate made a delegate-only decision to include pyriofenone in Schedule 6. This decision was published on 28 October 2014.

Delegate's considerations
  • The delegate considered the following in regards to this proposal:
  • Scheduling proposal;
  • OCS evaluation report;
  • Section 52E of the Therapeutic Goods Act 1989;
  • SPF scheduling factors7;
  • Other relevant information.
Delegate's final decision
  • Pyriofenone, a fungicide in the aryl phenyl ketone chemical family. While its overall toxicological is consistent with SPF criteria for listing in Schedule 5, evidence of sensitising potential resulted in it being listed in Schedule 6 (in February 2015). The current application seeks re-scheduling of a suspension concentrate product containing 30% of the active ingredient. The OCS report notes that testing of this product in the Guinea Pig maximisation test for sensitisation showed no evidence of sensitisation. The delegate therefore accepts the advice of the OCS to make an exception to the Schedule 6 entry allowing for listing of this product in Schedule 5. The delegate notes that the applicant has not objected to the OCS scheduling proposal.
  • The delegate has confirmed the proposed implementation date of 1 October 2015.
Schedule Entry
Schedule 6 - amendment

Pyriofenone except when included in Schedule 5.

Schedule 5 - New Entry

Pyriofenone in preparations containing 30 per cent or less of pyriofenone

2.2 DINOTEFURAN

Scheduling proposal

In April 2015, the OCS, based on an application made to the APVMA to approve a new active ingredient, requested that the delegate consider creating a new entry for dinotefuran in Schedule 5 of the SUSMP. The reasons for the request were:

  • An applicant submitted a data package to the APVMA seeking approval of the new active ingredient dinotefuran, a member of the neonicotinoid class of chemical. As a new chemical for AgVet use, it will require consideration by the delegate for scheduling prior to final registration of products containing this active constituent.
  • Currently proposed products attached to this application are for agricultural use. However, in pre-submission meetings with the active ingredient applicant, it has been foreshadowed that veterinary chemical products (e.g. spot-on flea treatments) containing dinotefuran are also proposed for registration in the future.
Substance summary
Structure of dinotefuran. The position of the 14C radiolabels used in ADME studies are indicated by an asterisk *

Structure of dinotefuran. The position of the 14C radiolabels used in ADME studies are indicated by an asterisk *

Acute toxicity

The acute toxicity end-points for dinotefuran are listed in the below table.

Toxicity Species Dinotefuran SPF Classification
Acute oral toxicity LD50 (mg/kg bw) SD Rat

CD-1 Mouse

2450

2371

Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) SD Rat >2000 (no deaths) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Wistar Rat >4090 (no deaths) Schedule 5
Skin irritation NZW rabbit Non-irritant
Eye irritation NZW rabbit Moderate irritant (OCS classification)

Not classified as eye irritant by NOHSC Approved Criteria

Skin sensitisation (GPMT method) BR Guinea pigs Not sensitising
Repeat-dose toxicity

Short-term and subchronic toxicity studies in rats, mice and dogs reported decreases in body weight and decreased body weight gain as the main treatment-related effects. These effects were observed at generally high doses in rodents, and at lower doses in dogs. It should be noted that no NOEL could be established in the 13 week dog dietary study for females due to reduced body weight and body weight gains in all treatment groups. A short-term dermal toxicity study in rats did not elicit similar responses to those seen in the oral studies, with only skin-specific effects seen in rats treated with 1000 mg/kg bw/d. A short-term inhalational study in rats elicited similar responses to those seen in the oral studies at all treatment levels in females. Long term studies in rats, mice and dogs were consistent with the observations noted in shorter duration repeat dose studies.

Mutagenicity/Genotoxicity

There was no evidence of mutagenic and genotoxic potential in vitro, or a genotoxic potential in vivo.

Carcinogenicity

There was no evidence of carcinogenic potential in the long-term rodent tests.

Reproduction and developmental toxicity

Dinotefuran was not a reproductive toxicant in rats. Effects were restricted to reduced body weight and body weight gain in parental and neonates of both generations. Dinotefuran was not a developmental toxicant in rats or rabbits, with effects restricted to reduced body weight and body weight gain in parental animals. No foetal effects were seen.

Other toxicology endpoints

Dinotefuran was found to not be acutely neurotoxic at relatively high doses (1500 mg/kg bw) with neuropathology negative up to the highest dose tested. Other than reduced body weight and body weight gains at high doses (3413 mg/kg bw/d) no effects were seen to indicate neurotoxicity in a 13 week dietary study. Dinotefuran was not a developmental neurotoxicant in rats at levels that induced maternal toxicity.

In guideline-compliant immunotoxicity studies in mice and rats, no effects were seen from treatment with dinotefuran. Dinotefuran is not considered to pose any immunotoxicity risk.

Observation in humans

No information was provided.

Public exposure

At this time, the proposed agricultural use of dinotefuran is not expected to result in general public (i.e. domestic) exposure. Spray drift considerations have not been considered.

As indicated above, the applicant has foreshadowed that veterinary chemical products (e.g. spot-on flea treatments) are in development—these veterinary products have been approved in other jurisdictions such as Europe.

International regulations

Dinotefuran has been approved for use by the US EPA for agricultural use and by EMA for veterinary spot-on use European Medicines Agency.

JMPR has also evaluated the toxicology of dinotefuran previously.

Scheduling history

Dinotefuran has not been previously considered for scheduling; therefore, scheduling history is not available.

According to the Poisons Standard (2015), a number of chemicals in this class (neonicotinoids) have been previously scheduled; imidacloprid, acetamiprid, clothianidin, thiacloprid and thiamethoxam are listed in Schedule 6. Exemptions to Schedule 5 were noted for the following chemicals:

  • imidacloprid in preparations containing 20 percent or less;
  • clothianidin in preparations containing 20 percent or less; and
  • thiamethoxam in preparations containing 60 percent or less,

There are additional exemptions (to not requiring scheduling) for the following chemicals:

  • acetamiprid in preparations containing 1 percent or less; and
  • imidacloprid in preparations containing 5 percent or less.
Delegate Considerations:
  • The delegate considered the following in regards to this proposal:
  • Scheduling proposal;
  • OCS evaluation report;
  • Section 52E of the Therapeutic Goods Act 1989;
  • SPF scheduling factors8;
  • Other relevant information.
Delegate's final decision

Dinotefuran is an insecticide in the neonicotinoid class. While other members of this class have a primary listing in Schedule 6 (with some product exemptions to Schedule 5), the toxicological profile of dinotefuran is clearly consistent with SPF guidance for inclusion in Schedule 5. Evidence of mild/moderate skin/eye irritancy for the formulated product means that is inappropriate to provide a schedule exemption for the formulated product considered in the application.

The delegate confirmed the implementation date of 1 October 2015.

Schedule entry
Schedule 5 - New Entry

DINOTEFURAN

Footnotes

  • 8 National Coordinating Committee on Therapeutic Goods (NCCTG): Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010) [Scheduling Policy Framework]

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