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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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3.8. Afidopyropen

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to consider afidopyropen for scheduling 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:

  • Appendix B – New Entry
  • AFIDOPYROPEN

The applicant's reasons for the request are:

  • The available toxicological data for afidopyropen is considered to be sufficient for the purposes of recommending a scheduling decision.
  • The toxicity hazard profile for acute exposure to afidopyropen does not warrant a schedule.
  • Afidopyropen's mode of action may be similar to another insecticide, pymetrozine, which is in Schedule 5 on the basis of moderate acute eye irritation.
Current scheduling status

Afidopyropen is not currently scheduled.

The applicant states that the mode of action of Afidopyropen may be similar to another insecticide, pymetrozine (see Substance summary below), which is in Schedule 5 of the Poisons Standard as follows:

  • Schedule 5
  • PYMETROZINE.
Relevant scheduling history

Afidopyropen is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available

Scheduling history of pymetrozine

In February 1997, the National Drugs and Poisons Schedule Committee (NDPSC) considered an application to create a new Schedule 5 entry for pymetrozine. The committee considered toxicological data and considered that Schedule 5 was appropriate for pymetrozine on the basis of moderate eye irritation in the rabbit.

Australian regulatory information

Afidopyropen is not currently registered with the APVMA as an active constituent or product.

Afidopyropen 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.

International regulations
  • Applications for the approval of afidopyropen and its products have also been submitted in the United States of America, Canada and Mexico
  • Afidopyropen is not on the Environmental Protection Agency approved pesticide list.
  • Afidopyropen is being studied in Canada under the minor use pesticide program.
  • From the Codex Committee on Pesticide Residues: Afidopyropen is on the 2019 list of new compound evaluations for the Joint Food and Agriculture Organization of the United Nations/World Health Organisation Food Standards Programme for pesticide residues.
Substance summary

Afidopyropen (ISO approved name) is the first member of a new chemical class of insecticides that has not been previously considered by the Chemicals Scheduling Delegate or Advisory Committee on Chemicals Scheduling (ACCS).

A recent published report (May, 2017) suggests that its mode of action may be similar another insecticide pymetrozine, in that it overstimulates and eventually silences vanilloid-type transient receptor potential (TRPV) channels which are expressed exclusively in insect chordotonal stretch receptor neurons.[61] The consequence of this binding is to inhibit plant-sucking insects' ability to feed, resulting in starvation and eventually death. Afidopyropen and pymetrozine have overlapping binding sites, with afidopyropen having higher affinity than pymetrozine. Pymetrozine is in Schedule 5 on the basis of moderate acute eye irritation.

Table 3.8.1: Chemical information for Afidopyropen
Property Afidopyropen
CAS number 915972-17-7
Chemical structure

C33H39NO9

chemical structure of
IUPAC and/or common and/or other names

[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-(cyclopropylcarbonyloxy)-1,2,3,4,4a,5,6,6a,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridyl)-11H,12H-benzo[f]pyrano[4,3-b]chromen-4-yl]methyl cyclopropanecarboxylate (IUPAC);

[(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methyl cyclopropanecarboxylate (CAS)

The following information was extracted from APVMA assessment report [Interim Human Health Technical Report – afidopyropen – Versys Insecticide (BAS 440 001)].

Table 3.8.2: Acute toxicity end-points for afidopyropen
Toxicity Species Afidopyropen SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 (no deaths) Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 (no deaths) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >5480 (no deaths) Schedule 5
Skin irritation Rabbit Non-irritating N/A
Eye irritation Rabbit Slight (with ground powder) Schedule 5
Skin sensitisation (GPMT) Guinea pig Non-sensitising N/A
Acute toxicity

Based on the available data from studies done according to OECD guidelines, afidopyropen has low acute oral, dermal and inhalation toxicity in rats.

Skin irritation

Based on available data from an OECD Guideline-compliant study in rabbits, afidopyropen is not a skin irritant:

  • Three female rabbits received a single (semi-occlusive) topical application of 0.5 g afidopyropen moistened with 0.5 mL de-ionised water for 4 h. Observation for skin irritation was performed at 1, 24, 48 and 72 h after patch removal. Observations for signs of toxicity were made once daily. There were no clinical signs or dermal erythema, eschar or oedema
Eye irritation

Based on available data, afidopyropen in a fine powder is a slight eye irritant:

  • Six female rabbits were administered 0.1 g afidopyropen (powder) by ocular instillation. The eyes of three rabbits were irrigated with lukewarm water after 30 seconds. Observation for ocular irritation was performed at 1, 24, 48 and 72 h after instillation. Observations for signs of toxicity were made once daily. All rabbits survived until termination and displayed no clinical signs other than eye irritation. No corneal opacity or iritis occurred, but grade 1 (hyperaemia) conjunctival redness was present in two of three washed and two of three unwashed eyes at the 1-hour observation (see following table). Concomitantly, oedema grade 1 (above normal) or grade 2 (swelling with eyelids everted) was noted in two of three unwashed eyes, and all three unwashed eyes displayed discharge grade 1 (above normal), grade 2 (moistened eyelids and adjacent area) or grade 3 (moistened eyelids and wide surrounding area). Calculated by the method of Kay and Calandra, in unwashed eyes (animals 1 – 3), the highest mean total irritation score was 7.3 at 1 h after application. All signs of conjunctival irritation resolved within 24 h, and the observation period was ended at 72 h in the absence of any further findings. Under the study conditions described, afidopyropen was a slight eye irritant.
Sensitisation

Based on available data using the guinea pig maximisation test method according to OECD guidelines, afidopyropen is not a skin sensitiser.

Repeat-dose toxicity

Repeat-dose toxicity studies indicate:

  • 28 and 90-day oral toxicity in mice – increased circulating bilirubin levels
  • 28-day oral toxicity in rats suggested that the liver, female reproductive system, renal system and haematopoietic system are possible target organs for the test compound in rats by dietary administration
  • 90-day oral rat - based on haematological abnormalities, increased urinary excretion of urobilinogen and protein, elevated blood potassium and BUN levels and ALT and AST activity, hepatic enlargement, and histopathological abnormalities within the liver and heart at and above a dietary concentration of 1000 ppm, the NOAEL was 300 ppm, equal to 18.3 mg/kg bw/d
  • 90-day oral (gelatin capsules) dog - the NOAEL was 15 mg/kg bw/d, based on vomiting, reduced bodyweight gain and toxicity to the liver at and above the next highest dose of 30 mg/kg bw/d
  • 1-yr oral (gelatin capsules) dog - based on vacuolation within brain tissues, biochemical and histological evidence of liver injury, and histological abnormalities in the intestine and gall bladder at 20 mg/kg bw/d and above, the NOAEL was 8 mg/kg bw/d. The depression in bodyweight and bodyweight gain in males at 8 mg/kg bw/d is discounted because bodyweight gain was increased in females treated at this dose
Genotoxicity

Afidopyropen gave negative results in an adequate range of assays for genotoxicity in vitro and in vivo.

Carcinogenicity

Having regard to the submitted experimental findings (see assessment report) on afidopyropen and available body of evidence from experimental and clinical studies with bromocriptine and other dopamine agonists, the reviewing toxicologist has concluded that afidopyropen should be regulated as a non-genotoxic, threshold dose, reproductive system carcinogen in female rats, which is of low relevance and risk to humans under the anticipated magnitude and conditions of exposure.

Reproduction and developmental toxicity

The NOAEL in rats for reproductive toxicity was 1500 ppm (equal to 122 mg/kg bw/d in dams) due to impaired implantation at and above the maternal dose of 3000 ppm. The NOAEL for parental toxicity was 150 ppm (equal to 9.6 mg/kg bw/d in dams) based on depressed seminal vesicle weight, maternal food consumption and gestational bodyweight gain, and increased maternal liver weight at 1500 ppm and above. The NOAEL for offspring toxicity was 150 ppm (equal to 9.6 mg/kg bw/d) based on increased post-natal mortality, depressed bodyweight and decreased spleen weight in pups at and above the maternal dose of 1500 ppm.

In rats, a concentration of 1500 ppm (equal to 122 mg/kg bw/d in dams) afidopyropen in the parental diet did not cause developmental malformations in pups exposed in utero. In another rat study, under the study conditions, afidopyropen did not cause foetal malformations at up to 100 mg/kg bw/d, the highest dose administered. In rabbits, the NOAEL for effects on foetal survival, growth and development was 32 mg/kg bw/d, the highest administered dose. Under the study conditions, afidopyropen did not cause developmental malformations in rabbits.

Public exposure

No submissions were received.

Pre-meeting public submissions

No submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that afidopyrofen be included in Schedule 5 as follows:

Schedule 5 – New Entry

AFIDOPYROPEN.

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; (c) the toxicity 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: acute toxicity appears to be low. However, in repeat dose studies the low dose effect was seen in offspring as well as the liver.
  • Benefit: the benefit is to horticultural industry, where this chemical presents as another insecticide option.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Nil.
  • the toxicity of a substance:
    • There are reservations regarding repeat dose studies and in offspring.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Nil.
  • the potential for abuse of a substance:
    • Nil.
  • any other matters that the Secretary considers necessary to protect public health
    • This is a new chemical class that has similar mechanism of action to existing Schedule 5 entries.
    Delegate's considerations

    The delegate considered the following in regards to 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 notes the committee's advice. However, the delegate's interim decision is to create a new Appendix B entry for afidopyropen in the Poisons Standard. The proposed Schedule entry is:

    Appendix B – New Entry

    AFIDOPYROPEN

    Reasons for Entry: b (Use pattern restricts hazard)
    Areas of Use: 1.2 (Insecticide)

    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; (c) the toxicity of the 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: the acute toxicity profile is low and of no relevance to humans.
    • Benefit: the benefit is to horticultural industry, where afidopyropen presents as another insecticide option.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Nil.
  • the toxicity of a substance:
    • The low acute toxicity profile does not warrant inclusion in a schedule.
    • The delegate is of the opinion that the low dose effects seen in repeat dose studies are unlikely to be achieved in humans and are therefore of no relevance to humans, particularly when the product is used in accordance with directions.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • Nil.
  • the potential for abuse of a substance:
    • Nil.
  • any other matters that the Secretary considers necessary to protect public health:
    • Although this is a new chemical class that has similar mechanism of action to existing Schedule 5 entries, there is insufficient data to warrant inclusion in Schedule 5.
    • Inclusion in Appendix B will not prevent reconsideration of the scheduling of afidopyropen where adverse information becomes available about its Appendix B entry

    Footnotes

    1. Kandasamy R et al., (2017) Afidopyropen: New and potent modulator of insect transient receptor potential channels. Insect Biochem Mol Biol 84: 32-39.

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