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

5 February 2018

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3.3. Alpha-cypermethrin

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the current entry for alpha-cypermethrin in Schedule 6 to increase the cut-off in aqueous preparations from 25 per cent or less to 30 per cent or less 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 6 – Amend Entry
  • ALPHA-CYPERMETHRIN:
  1. in aqueous preparations containing 2530 per cent or less of alpha-cypermethrin; or
  2. in other preparations containing 10 per cent or less of alpha-cypermethrin,.
  • except when included in Schedule 5.
  • The applicant's reasons for the request are:

    • The proposed product is a suspension concentrate formulation containing alpha-cypermethrin at 300 g/L (30%). It has low oral, dermal and inhalational toxicity. It is a moderate eye irritant, non-irritant to skin and is unlikely to be a skin sensitiser.
    • Based on the low toxicity and non-corrosive properties, the proposed product should be less than Schedule 7.
    • A Schedule 6 entry is appropriate as the toxicity fits the criteria of acute inhalation LC50 between 500–3000 mg/m3.
    • The toxicity of the product is low enough to warrant an entry in Schedule 5, considering the acute inhalational LC50 was at the maximum attainable concentration.
    • This recommendation is based on the acute toxicity data provided by the applicant and also data provided for the 25% product previously considered by the Committee (NDPSC November 2000).
    • Other synthetic pyrethroids included in Schedules 5 or 6 include transfluthrin, permethrin, deltamethrin, esfenvalerate and metafluthrin.
    • The product is for commercial agricultural use only.
    Current scheduling status

    Alpha-cypermethrin is in Schedule 5,6 and is cross-referenced in the Index to cypermethrin as follows:

    • Schedule 7
    • ALPHA-CYPERMETHRIN except when included in Schedule 5 or 6.
    • Schedule 6
    • ALPHA-CYPERMETHRIN:
    1. in aqueous preparations containing 25 per cent or less of alpha-cypermethrin; or
    2. in other preparations containing 10 per cent or less of alpha-cypermethrin,
  • except when included in Schedule 5.
  • Schedule 5
  • ALPHA-CYPERMETHRIN:
    1. in aqueous preparations containing 3 per cent or less of alpha-cypermethrin; or
    2. in other preparations containing 1.5 per cent or less of alpha-cypermethrin.
    Scheduling of CYPERMETHRIN:
    • Schedule 6
    • CYPERMETHRIN except when included in Schedule 5.
    • Schedule 5
    • CYPERMETHRIN in preparations containing 10 per cent or less of cypermethrin.
    • Index
    • CYPERMETHRIN
      cross reference: ALPHA-CYPERMETHRIN AND BETA-CYPERMETHRIN, ZETA-CYPERMETHRIN
    • Schedule 6
      Schedule 5

    Scheduling of BETA-CYPERMETHRIN
    • Schedule 6
    • BETA-CYPERMETHRIN.
    Scheduling of ZETA-CYPERMETHRIN
    • Schedule 6
    • ZETA-CYPERMETHRIN in preparations containing 10 per cent or less of zeta-cypermethrin.
    • Schedule 7
    • ZETA-CYPERMETHRIN except when included in Schedule 6.
    Relevant scheduling history

    In November 1994, the National Drugs and Poisons Schedule Committee (NDPSC) created new entries for alpha-cypermethrin in Schedule 6 and 7 of the Poisons Standard, with a general cut-off in Schedule 6 of 10%.

    In February 1998, the NDPSC decided to down-schedule alpha-cypermethrin to Schedule 5, with a general cut-off of 1.5%, irrespective of formulation. Although alpha-cypermethrin has greater toxicity when it is formulated in oil rather than aqueous suspensions, the committee considered that the 1.5% cut-off provides a reasonable safety factor.

    In May 1999, the NDPSC decided that the Schedule 5 cut-off could be increased from 1.5% to 3% for aqueous formulations. The committee did not support an increase in the cut-off for formulations in oil.

    In November 1999, the NDPSC made an amendment to the Schedule 5 entry for alpha-cypermethrin. The entry content was changed from alpha-cypermethrin to alpha-cypermethrin.

    In November 2000, the NDPSC decided amend the Schedule 6 entry to its current cut-offs.

    In June 2003, the NDPSC made a minor editorial amendment to the Schedule 6 entry, that did not alter its meaning or cut-offs, to its current entry.

    Australian regulatory information

    Alpha-cypermethrin is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.

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

    Eighty five (85) registered or approved insecticide, herbicide, vertebrate poison and parasiticide products were found on the APVMA’s PubCRIS database.

    International regulations
    United States of America (USA)

    Alpha-cypermethrin was registered for use in the USA in January 2013 as an insecticide.

    EU/ECHA
    • [1.alpha.(S*),3.alpha.]-(.alpha.)-cyano-(3-phenoxyphenyl)methyl3-(2,2-dichlor-oethenyl)-2,2-dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylate (alpha-Cypermethrin).
    • EC/List no.: 614-054-3.
    • Hazard classification and labelling: Danger! According to the classification provided by companies to ECHA in CLP notifications this substance is toxic if swallowed, is very toxic to aquatic life, is very toxic to aquatic life with long lasting effects, may cause damage to organs through prolonged or repeated exposure, is harmful if inhaled and may cause respiratory irritation.
    • Alpha-cypermethrin has been found in the following regulatory activities:
    New Zealand
    Substance summary
    Table 3.3.1: Chemical information for alpha-cypermethrin
    Property Alpha-cypermethrin
    CAS name (R)-cyano(3-phenoxyphenyl)methyl (1S,3S)-rel-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate;

    Note: Cypermethrin is a racemic mixture of 8 enantiomers. Alpha-cypermethrin consists of two of the cis isomers (i.e. alpha-cypermethrin constitutes 25% of technical cypermethrin, namely the 1-R cis S and 1-S cis R isomers)

    CAS number 67375-30-8
    Chemical structure chemical structure of
    Molecular formula C22H19CI2NO3
    Molecular weight 416.3 g/mol
    IUPAC and/or common and/or other names

    Alphamethrin;
    IUPAC names:

    1. racemate comprising (R)-α-cyano-3-phenoxybenzyl (1S,3S)-3-(2,2-dichlorovinyl)-2,2-imethylcyclopropanecarboxylate and (S)-α-cyano-3-phenoxybenzyl (1R,3R)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate; or
    2. racemate comprising (R)-α-cyano-3-phenoxybenzyl (1S)-cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate and (S)-α-cyano-3-phenoxybenzyl (1R)-cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate.

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

    Table 3.3.2: Acute toxicity end-points for alpha-cypermethrin
    Toxicity Species Alpha-cypermethrin and product SPF (2015) Classification
    Acute oral toxicity LD50 (mg/kg bw) Rat

    >5000 mg/kg bw for 50% aqueous suspension

    >2000 mg/kg bw for product

    N/A

    Schedule 5
    Acute dermal toxicity LD50 (mg/kg bw)

    Mouse

    Rat

    >100 mg/kg bw alpha-cypermethrin (concentration unknown)

    >2000 mg/kg bw for product

    Schedule 7

    Schedule 5
    Acute inhalational toxicity LC50 (mg/m3/4h)

    Not given

    Rat

    >400 mg/m3 (30% silica powder dust)

    >1150 mg/m3 (4h) (maximum attainable concentration) for the product

    Schedule 7

    Schedule 6
    Skin irritation Rabbit

    Slight for active constituent

    Nil for product

    Schedule 5

    N/A
    Eye irritation Rabbit

    Slight for active constituent

    Moderate for product

    Schedule 5

    Schedule 5
    Skin sensitisation (Buehler) Guinea pig

    Negative for active constituent

    Negative for product

    N/A

    N/A
    Acute toxicity

    The acute toxicity profile of alpha-cypermethrin varies with vehicle and/or species. The acute oral toxicity in rats ranges from low in 50% aqueous suspension (LD50 > 5000 mg/kg bw) to high in 5% corn oil (LD50 = 79 mg/kg bw). The comparable LD50 values for mice are 798 mg/kg bw (50% aqueous suspension) and 35 mg/kg bw (5% corn oil). The major sign of toxicity was clonic convulsions. An acute dermal toxicity study in mice gave an LD50 > 100 mg/kg bw. There is one acute inhalational LC50 value for alpha-cypermethrin of > 400 mg/m3 which is based on a study using a 30% silica powder dust. Based on the acute toxicity studies with the proposed product, which contains 30% alpha-cypermethrin, the product has low acute oral, dermal and inhalation toxicity.

    Skin irritation

    Alpha-cypermethrin is a slight skin irritant in rabbits. Based on an acute dermal irritation study, the proposed product is not a skin irritant.

    Eye irritation

    Alpha-cypermethrin is a slight eye irritant in rabbits. Based on available data, the proposed product is a moderate eye irritant:

    Three female rabbits were administered the proposed product by ocular instillation. Ocular irritation was scored according to the Draize scale and compared with the untreated eye for each animal at 1, 24, 48, 72, 96 hours and 5, 6 and 7 days after treatment. All three animals exhibited ocular lesions (conjunctival oedema, redness and corneal opacity) in the treated eye from 1h till day 6 post instillation. These lesions were reversible and comparable to the untreated eye on day 7. Thereafter all animals appeared healthy and gained body weight during the study. No signs of gross toxicity or behavioural changes were observed in any of the animals. Under the study conditions described, with corneal opacity for 6 days that was reversible on day 7, the proposed product is a moderate eye irritant.

    Sensitisation

    Alpha-cypermethrin did not cause skin sensitisation in guinea pigs. Based on a guideline-compliant Buehler study, the proposed product is not a skin sensitiser.

    Repeat-dose toxicity

    In 4- to 13-week dietary studies in rats and dogs, neurotoxicity was the primary effect. Clinical signs of toxicity included ataxia, body tremors, agitation, and abnormal gait. Histopathological changes were seen in the liver (glycogenic vacuolation of parenchyma), and axonal degeneration of the sciatic nerve. There was decreased bodyweight gain, and increased liver and kidney weights. The NOAEL was 6.4 mg/kg bw/d in rats and 4.7 mg/kg bw/d dogs.

    Genotoxicity

    Alpha-cypermethrin was not mutagenic in bacteria or yeast. It did not break DNA or induce chromosome damage in in vivo assays in rat and was not clastogenic in the rat liver cells in vitro.

    Reproduction and developmental toxicity

    There are no long term repeat dose, reproduction or developmental studies conducted using alpha-cypermethrin that have been previously evaluated.

    Observation in humans

    Human volunteers participated in two oral dose-excretion studies using alpha-cypermethrin. On two occasions, two volunteers per dose received a single oral dose of 0.25, 0.5 or 0.75 mg alpha-cypermethrin in corn oil (as a gelatine capsule) with 24-h urine collections. Urinary excretion was rapid, with 43% - 49% of the dose excreted within the first 24 h, 1-5% on Day 2 and 1-7% on Day 6.

    Public exposure

    The product is not intended for home garden use. Dermal absorption of alpha-cypermethrin is low. Public exposure to the product is unlikely to occur.

    Pre-meeting public submissions

    No submissions were received.

    Summary of ACCS advice to the delegate

    The committee recommended that the Schedule 6 entry for alpha-cypermethrin be amended as follows:

    Schedule 6 – Amend Entry

    ALPHA-CYPERMETHRIN:

    1. in aqueous preparations containing 2530 per cent or less of alpha-cypermethrin; or
    2. in other preparations containing 10 per cent or less of alpha-cypermethrin,.

    except when included in Schedule 5.

    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: (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:
    • Nil.
  • 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 acute oral and inhalation toxicity at 30% of alpha-cypermethrin is consistent with Schedule 6 criteria (SPF 2015). These hazards can be controlled with appropriate labels and handling protocols.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • alpha-Cypermethrin is intended for agricultural use and not for domestic use.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • This is an extension of the current Schedule 6 entry, which is consistent with the toxicity data.
    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 6 entry for alpha-cypermethrin by increasing the permitted concentration from 25% to 30% in aqueous preparations. The proposed Schedule entry is:

    Schedule 6 – Amend Entry

    ALPHA-CYPERMETHRIN:

    1. in aqueous preparations containing 30 per cent or less of alpha-cypermethrin; or
    2. in other preparations containing 10 per cent or less of alpha-cypermethrin,

    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: (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:
    • Nil.
  • 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 acute oral and inhalation toxicity at 30% of alpha-cypermethrin is consistent with Schedule 6 criteria (SPF 2015). These hazards can be controlled with appropriate labels and handling protocols.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • alpha-Cypermethrin is intended for agricultural use and not for domestic use.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • This is an extension of the current Schedule 6 entry, which is consistent with the toxicity data.

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