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Scheduling delegate's final decisions: ACCS, July 2015

23 July 2015

Book pagination

Part A - Final decisions on matters referred to an expert advisory committee 1.6 - 1.7

1.6 FLUPYRADIFURONE

Scheduling proposal

In January 2015, the OCS, based on an application made to the APVMA to register a new active constituent, referred a proposal to create a new entry for flupyradifurone in Schedule 6 to be considered by the chemicals scheduling delegate. A product was also included in the application, and consideration of a cut-off level to exempt from scheduling for the product was also requested.

The reasons for the request are discussed below.

Flupyradifurone was the subject of a Global Joint Review evaluation between the North American Free Trade Agreement (NAFTA) agencies (US EPA, Health Canada PMRA and Mexico), Brazil and OCS. OCS was the primary evaluator for this project.

Flupyradifurone (also known as BYI 02960) is a new insecticidal compound from the butenolide chemical class.  Chemicals in the butenolide family include ascorbic acid.

Flupyradifurone acts by interfering with insect nicotinic acetylcholine receptors, a class of neurotransmitter-gated cation channels which are involved in excitatory neurotransmission in the nervous system of insects.  The compound acts as an agonist, leading to disorder of the nervous system and death.

Flupyradifurone is currently not listed in the Poisons Standard.  The proposed product contains flupyradifurone at 200 g/L.

The scheduling considerations for flupyradifurone discussed below are based on the SPF. They take into account the toxicological profile of the chemical and the intended use patterns associated with products containing flupyradifurone as the active constituent.

OCS considers that flupyradifurone has a generally low acute toxicity profile, with the exception of slight eye irritation potential and a weak acute neurotoxicity potential following single oral gavage administration. The OCS notes that no Guideline-compliant skin sensitisation study was provided on the active constituent—the study evaluated was considered deficient, and thus no classification for skin sensitisation is possible.

The systemic findings in short-term, subchronic and chronic dietary studies were not considered to warrant scheduling, and flupyradifurone was not considered to be an in vivo genotoxicant, a reproductive toxicant in rats, a developmental toxicant in rabbits, or an immunotoxicant in rats. Additionally, flupyradifurone was not carcinogenic in mice or rats.  While not a developmental toxicant in rats, there was limited evidence of a slight developmental delay in rats exposed to maternotoxic doses (LOAEL = 150 mg/kg bw/d) of flupyradifurone.  As noted above, while weak acute neurotoxicity potential was identified, neuropathology was unremarkable, and subchronic and developmental neurotoxicity studies did not report adverse neurotoxic effects.

Consideration of the SPF criteria and application of the cascading principles outlined in the SPF indicates that the active constituent flupyradifurone meets the scheduling factors for Schedule 6, with an acute oral LD50 between 300 and 2000 mg/kg bw (with reported deaths).

The product containing 200 g/L of flupyradifurone has a low acute toxicity profile, though the product elicited slight eye irritation in rabbits and the undiluted product (i.e. 100% neat form) was a dermal sensitiser in a Guideline-compliant mouse LLNA.  Modelling of occupational exposure (professional use) to the active constituent from the proposed use patterns resulted in acceptable MOEs (>100) for the highest exposure scenarios without a specific requirement for protective clothing. Post-application activities were predicted to be of low risk.

In the first draft of this evaluation, the OCS noted that the product containing 200 g/L of flupyradifurone was a dermal sensitiser in a Guideline-compliant mouse LLNA, and that this would be consistent with a Schedule 6 listing (i.e. no exemptions or cut-offs are considered appropriate in this case, again noting the lack of Guideline-compliant skin sensitisation data for the active constituent flupyradifurone).

The applicant in their response to the OCS draft report in November 2014 requested that OCS recommend a Schedule 5 listing (i.e. a cut-off/exemption) for the product. This was considered by OCS and not agreed to.

On 18 December 2014, the applicant replied indicating that they had no further comment to the rejoinder and the revised draft, though they foreshadowed providing comments to the Delegate/Secretariat during an anticipated public comment phase for this application, particularly around the skin sensitisation issue.

A broad overview of the toxicology of the chemical is provided in the substance summary below.

Delegate's reasons for referring this to the committee

While the toxicological profile of flupyradifurone is relatively straightforward and could satisfy scheduling criteria for either Schedule 5 or 6, there is disagreement between the sponsor and the OCS with regard to interpretation of its sensitisation potential, and hence the appropriate schedule for the product under consideration for registration. Accordingly, the delegate sought advice from the ACCS.

The delegate asked the committee the following questions:

  • Flupyradiflurone appears to have a relatively low toxicity potential. The oral LD50 estimate in the range 300-2000 mg/kg is consistent with SPF criteria for listing in Schedule 6, although other aspects of the toxicology are possibly consistent with Schedule 5. The OCS evaluation has noted a non-compliant study of sensitisation potential for flupyradiflurone itself, along with a positive result in a study with the undiluted product containing 200g/L flupyradiflurone. The OCS has interpreted the sensitisation potential as 'moderate', justifying listing in Schedule 6 with no cut-off to Schedule 5, while sponsor has argued that it is 'slight'. The ACCS is requested to comment on this disparity and to recommend an appropriate schedule listing for both the active and the product.
  • Are there any other elements of the toxicity evaluation likely to influence the scheduling determination? 
Substance summary

Flupyradifurone belongs to the chemical class of butenolides, and acts by interfering with insect nicotinic acetylcholine receptors, a class of neurotransmitter-gated cation channels which are involved in excitatory neurotransmission in the nervous system of insects.

Structure of Flupyradifurone

Structure of Flupyradifurone (C12H11ClF2N2O2)

Acute toxicity

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

Toxicity Species Flupyradifurone SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 300 < LD50 < 2000 (F only) Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat LD50 > 2000  (no deaths) Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rat LC50 > 4671 mg/m3

(no deaths)
Schedule 5
Skin irritation Rabbit Not irritating N/A
Eye irritation Rabbit Slight irritation, cleared by 48 h Schedule 5
Skin sensitisation (modified LLNA) Mouse N/A (study not reliable) N/A

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

Toxicity Species Product SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat LD50 > 2000 mg/kg bw (no deaths)

N/A

Acute dermal toxicity LD50 (mg/kg bw) Rat LD50 > 2000 mg/kg bw (no deaths)

N/A

Acute inhalational toxicity LC50 (mg/m3/4h) Rat LC­50 > 4483 mg/m3 (no deaths)

Schedule 5

Skin irritation Rabbit Not irritating N/A
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation (Standard LLNA) Mouse Sensitiser (neat formulation  SI ≥ 3.0) Schedule 5 or 6?
Toxicokinetics/ADME

In a series of seven toxicokinetic studies (e.g. absorption, distribution, metabolism and excretion (ADME) studies), flupyradifurone was rapidly absorbed and distributed throughout the body, moderately metabolised and rapidly excreted primarily via the urinary pathway.  There was no marked sex differences in the ADME of flupyradifurone regardless of the different positions of radiolabel, with the exception of a higher proportion of C1 or C2 fragments and expired 14C-carbon dioxide in males treated with [furanone-4-14C]-flupyradifurone.  Excretion was rapid and extensive, with the majority of the administered dose excreted within 24 hours indicating a low probability of bioaccumulation of the parent compound or metabolites.  The main metabolic pathway for flupyradifurone consists primarily of hydroxylation followed by conjugation with glucuronic acid, cleavage of the difluoroethyl group forming difluoroacetic acid (DFA) and cleavage of the molecule at the pyridinylmethyl bridge, forming BYI 02960-difluoroethyl-amino-furanone.

Repeat-dose toxicity

The systemic toxicity of flupyradifurone in dietary studies consisted primarily of body weight and body weight gain decreases, liver toxicity (presenting as increased liver weight and centrilobular hepatocellular hypertrophy with associated clinical chemistry changes), and thyroid effects (e.g. follicular cell hypertrophy) generally seen at higher dose levels in rats, mice (studies over 3 months in duration) and dogs.  This systemic toxicity profile was observed in short-term, subchronic and chronic toxicity studies in rats, mice and dogs, with the available data indicating that the dog was the most sensitive species.  In dogs only, myofiber degeneration of skeletal muscle in both sexes was seen in the 1 year dietary study at relatively low dose levels.

No treatment related adverse effects were seen in a short-term dermal study in the rat at up to 500 mg/kg bw/d.

Mutagenicity/Genotoxicity

There was no evidence of a mutagenic/genotoxic potential in vitro with and without metabolic activation, or a genotoxic potential in vivo.

Carcinogenicity

No increased incidence was seen in any tumour type in male or female mice in a 78-week dietary study or in male and female rats in a two year dietary study.

Reproduction and developmental toxicity

In a dietary two generation reproductive toxicity study in rats, parental systemic toxicity was seen at the top dose level (1800 ppm).  Effects presented as decreased body weights seen in dams of both generations throughout pre-mating and gestation, decreased body weight gain, alterations in food consumption, increased thyroid weight in males (both generations), and increased liver weights in males and females (both generations); however, treatment-related histopathological changes were only seen in P1 males.  Reproductive findings were also seen at 1800 ppm, including decreased litter size observed in F2 pups, a lower number of oestrus cycles, a lower number of implantations in P2 dams, and a slight reduction in epididymal sperm count in P1 and P2 males and in testicular sperm count in P2 males was observed at 1800 ppm.  In offspring, decreased pup body weight and pup body-weight gain (F2 only) and delayed vaginal patency and preputial separation (F1 pups only) were seen at 1800 ppm, though the slight delay in sexual maturity was considered a secondary non-specific consequence of decreased mean bodyweights in these animals.

OCS supplementary comments

In reviewing the OCS draft report, the applicant raised a disagreement with the interpretation of the parental female toxicity in the two-generation study. The applicant response is quoted below:

'[The Applicant] disagrees with the interpretation of OCS that the NOAEL for parental female toxicity was 500 ppm (minimum of 38.7 mg/kg bw/d).  Although not statistically significant, declines in BW (mean decrease of -5.9%) accompanied decreases in BW gain (BWG, mean decrease of -16.3%, statistically significant) in P1 females beginning on Day 0 and continuing throughout the premating period at this dose level.  Statistically significant decreases in BW were also observed throughout gestation (mean decrease of -7.1%) and lactation (mean decrease of -7.5%), as well as for terminal BW compared to control animals.  Thus, significant BW decreases were seen during all phases in F1 generation females at 500 ppm, the same dose level that resulted in reduced F2 pup BW late in the lactation phase (LD 14, -6.9%; LD 21, -7.4%) compared to controls.  The BW decreases observed in the F1 females were comparable in magnitude to those seen in the F2 pups at 500 ppm.  Based on these points, [the applicant] believes that the parental NOAEL should match that for the offspring.'

The GJR position was that the parental NOAEL was 500 ppm, and that the body weight changes in this case were not considered a factor in the parental NOAEL selection.

The OCS re-affirms that Flupyradifurone is not considered a reproductive toxicant. However, in reviewing the argument raised by the applicant, the OCS acknowledges that there does appear to be a toxicologically significant effect at 500 ppm regarding parental female body weight and body weight gain, and notes that there appears to be some carry over effect into the second generation (particularly decreased pup weights at 500 ppm). When taken together, the OCS acknowledges that a parental toxicity effect in dams cannot be discounted, and that the parental female NOAEL in this case should be revised down from 500 ppm to 100 ppm (equivalent to a minimum of 7.7 mg/kg bw/d).

In an oral (gavage) developmental toxicity study in rats an increase in the incidence of salivation in the majority of 150 mg/kg bw/d dams was noted, along with a lower gestational bodyweight gain and statistically significant decreased food consumption.  In foetuses, there were no test substance-related effects on the incidence of malformations or external variations. However, at 150 mg/kg bw/d, the incidence of the variations 'parietal (unilateral/bilateral): incomplete ossification' and 'hyoid centrum: incomplete ossification' were higher than in the control group and were outside the in-house historical control at both litter and foetal levels. These findings were indicative of a slightly delayed foetal development at doses where maternal toxicity was also observed.  However, under the conditions of this study, the test substance did not demonstrate a teratogenic potential in the rat.

In an oral (gavage) developmental toxicity in rabbits, there was no evidence of developmental toxicity at doses up to those that produced signs of marked maternal toxicity (e.g. body weight loss (-12% vs controls between GD 6–29)).  Thus, flupyradifurone was not considered to be a developmental toxicant in rabbits.

Other toxicology endpoints

In an acute oral (gavage) neurotoxicity study in rats, a weak neurotoxic potential was seen in both sexes at ≥50 mg/kg bw, presenting as piloerection, dilated pupils, rapid respiration, lower muscle tone, low arousal, repetitive licking of lips, decreased rearing, exaggerated flexor reflexes, gait incoordination and flattened body posture, and higher incidence of tremors in both sexes on the day of administration only.  However, no neuropathological changes were seen upon examination of the brain. 

In a 90-day dietary neurotoxicity study, there was no evidence of neurotoxic findings during the FOB analysis or neuropathological examinations. 

In a developmental neurotoxicity study, there was no evidence of neurotoxic findings during the FOB analysis or neuropathological examinations.  There was a non-statistically significant increase in both motor and locomotor activity was seen in males at the high dose level that are not considered adverse. 

Thus, OCS considers that the available data from the three studies only provide evidence of a weak acute neurotoxicity potential following gavage administration.

Flupyradifurone was not immunotoxic in rats.

A series of acute, repeat dose and genotoxicity studies were conducted on 4 major metabolites of flupyradifurone.  The test substances included 6-chloronicotinic acid, difluroacetic acid, and BYI-02960-difluroethyl-amino-furanone, which are mammalian metabolites (rat ADME studies), phytometabolites, and were found in soils (6-chloronicotinic acid and (difluroacetic acid) and groundwater (difluroacetic acid only) in laboratory and field studies.  The metabolites were either of a similar toxicity or reduced toxicity compared with the parent compound.  While the metabolite BYI 02960-difluoroethyl-amino-furanone was weakly positive without metabolic activation in an in vitro cytogenetic assay, in vivo studies indicated that the substance was, on weight of evidence, not mutagenic.

Observation in humans

No information was provided.

Public exposure

No domestic (general public) exposure is expected for flupyradifurone at the time of this application. The intended use of flupyradifurone is as an insecticide on food crops. The proposed product (flupyradifurone 200 g/L) is proposed for the control of aphids, silverleaf whitefly and greenhouse whitefly in a range of vegetable crops.

Professional use exposure estimates have been modelled as part of the OCS evaluation and the product does not exceed margins of exposure that would be considered as unsafe. Risks may be mitigated by the use of the prescribed Personal Protective Equipment and adherence to the label and re-entry statements recommended.

International regulations

No specific information is available. Noting that the evaluation of this chemical was carried as a Global Joint Review collaboration, both the US EPA and Health Canada have published registration documents recently outlining their positions on flupyradifurone.

Scheduling status

Flupyradifurone is not specifically scheduled.

Scheduling history

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

Pre-meeting public submissions

One submission was received stating that they believe that the weight of the evidence and supporting data justify placement of formulated products containing flupyradifurone at 200 g/L into Schedule 5 of the Poisons Standard. The submission notes that the acute toxicity of the substance is low, and that the results of the dermal sensitization study support the conclusion of having very slight sensitizing potential. The submission also notes that the favourable toxicology profile of the active ingredient, flupyradifurone, further supports the formulated product as having a low health hazard and unlikely to cause harm or injury to humans.

Edited versions of these submissions are available at

Summary of ACCS advice to the delegate

The committee recommended that a new entry be created for flupyradifurone in Schedule 6.

The committee supported the implementation to occur as soon as possible.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Acute toxicity of the active and skin sensitisation of active and product is consistent with Schedule 6
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors6;
  • Other relevant information.
Delegate's interim decision

The Delegate accepts the advice from the ACCS and agrees to include a new entry for flupyridafurone in Schedule 6.

The delegate has considered the sponsor's submission and the OCS response in relation to the sensitisation potential of the product, noting that the data in a non-compliant LLNA study submitted was inadequate to define the sensitisation potential of flupyridifurone, the active pesticide. The discussion at the ACCS was centred on whether the results of the LLNA test on the formulated product should be classified as 'moderate' or 'slight'. Moderate-severe skin sensitisation is one of the SPF criteria for listing in Schedule 6 listing and the delegate accepts the advice of the ACCS that there is sufficient doubt about whether the LLNA test results could allow the determination of a concentration cut-off to a lower schedule. Accordingly, the delegate does not propose any exception to the Schedule 6 listing of the active pesticide at this time.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (c) the toxicity of the substance.

The proposed implementation date is 1 October 2015. An early implementation date is proposed to facilitate marketing of the product when registered by the APVMA.

Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The delegate has confirmed the proposed implementation date of 1 October 2015.

Schedule entry
Schedule 6 – New Entry

FLUPYRADIFURONE

1.7 METOFLUTHRIN

Scheduling proposal

In December 2014, the applicant via the OCS, based on an application made to the APVMA to amend the current metofluthrin entry, requested that the delegate consider amending the current entry for metofluthrin in Schedule 6 and creating a new entry for metofluthrin in Schedule 5 when impregnated into a polyethylene slow release matrix containing 212 mg or less of metofluthrin.

The reasons for the request were:

  • The product has low acute toxicity via oral and dermal exposure and does not cause skin or eye irritation or skin sensitization which is consistent with Schedule 5.  A risk assessment provided by the applicant demonstrated that the product has low inhalational risk to users, consistent with Schedule 5.

The Scheduling Policy Framework has been used in the consideration for inclusion of the active ingredient, metofluthrin, in Schedule 5 based on its content in the proposed product.

Delegate's reasons for referring this to the committee

At the July 2014 ACCS meeting, advice was provided to the delegate to include a new entry for metofluthrin in Schedule 5 to allow for a mosquito repellent motorised vaporiser containing metofluthrin. The current proposal seeks a further amendment to Schedule 5 to allow for metofluthrin to be used in an impregnated woven polythene sheet. The delegate understands that previous committees (NDPSC, PSSC) have rejected applications to de-schedule mosquito nets or clothing impregnated with synthetic pyrethroid insecticides, although the ACCS recommended, in July 2013, that a mosquito net impregnated with deltamethrin should be exempted from scheduling. The July 2013 advice was based on a presumption that impregnation of the netting in a factory would be less hazardous than do-it-yourself treatment of mosquito nets with liquid insecticides.  This current application appears to be different in that the size of the polythene sheet (8 x 15 cm) is too small to function as a mosquito net and that it will be enclosed in a plastic frame to minimise skin contact or ingestion potential. The mosquito repellent and knock-down properties of the product appear to rely on airflow over the fabric to release metofluthrin.

The delegate asked the ACCS the following questions:

  • Does the ACCS support inclusion of a clause in the Schedule 5 entry for metofluthrin allowing for this use of the specified product? Does the proposed wording give effect to this proposal or is more specific wording required?
  • Is the ACCS satisfied that the inhalation risks have been appropriately evaluated and that packaging/labelling of the product provides for sufficient mitigation of inhalation risks, and that the risks of skin contact or sucking of the material by small children is negligible? 
Substance summary

Metofluthrin is a pyrethroid ester.  This class of chemicals act on the nervous system of insects, disturbing the function of neurons by interacting with sodium channels.

Structure of metofluthrin

Structure of metofluthrin.

Acute toxicity

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

Toxicity Species Metofluthrin SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >1080 and ≤ 1960 Moderate to high toxicity
Skin irritation Rabbit Slight irritant
Eye irritation Rabbit Non-irritant
Skin sensitisation (Guinea Pig Maximisation Test) Guinea Pig Non-sensitiser

The applicant has provided an acute oral and an acute dermal study in rats as well as a skin irritation study in rabbits and a skin sensitisation study in guinea pigs on the formulated product.  The applicant did not provide an acute inhalational toxicity study or an eye irritation study on the formulated product.  The applicant has argued that the product consists solely of metofluthrin impregnated in an inert net; therefore, the toxicology of the end-use product is the same as that of the active constituent.  Therefore the acute inhalational toxicity of the product and the eye irritation potential is based on the toxicity of the active.

The acute toxicity of the product forming the basis for the current scheduling proposal is included in the table below:

Toxicity Species Product SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000* Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000* Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >1080 and ≤ 1960# Moderate to high toxicity
Skin irritation Rabbit Non-irritant*
Eye irritation Rabbit Non-irritant#
Skin sensitisation (Guinea Pig Maximisation Test) Guinea Pig Non-sensitiser*

*Based on toxicological studies on the product.
#Based on toxicological studies on metofluthrin.

Absorption, distribution, metabolism, excretion

Metofluthrin (radiolabelled), following single oral doses of 1 or 20 mg/kg bw was well absorbed, with systemic absorption of approximately ~40-77% following bile duct cannulation in rats, and with a Tmax of 3-7 hours.  In distribution studies, nearly all of the metofluthrin was found in intestinal tract, or had been excreted, with the highest tissue concentrations in the liver and muscle (2-5% and 1-2% of applied dose respectively at 6 h).  There was no evidence of bioaccumulation in any particular tissue even after repeat-dosing.  Absorbed metofluthrin was nearly completely metabolised, with no particular metabolite dominating the profile.  Some unchanged metofluthrin was detected in faeces, presumably representing unabsorbed compound.  Following a single dose, metofluthrin was excreted in both urine (10-26%) and faeces (30-56%), with less than 1.4% of the dose excreted in the expired air.  Following repeated administration (21 days), approximately 56.7-74.6% was excreted in urine and 21.7-38.3% in the faeces. The excretion of metofluthrin was rapid, and appeared to be limited by the absorption.

Repeat-dose toxicity

Metofluthrin was administered in the diet at doses of up to approximately 1000 mg/kg bw/d in rats, 590 mg/kg bw/d in mice, 250 mg/kg bw/d in rabbits (developmental study) and 100 mg/kg bw/d in dogs.  Systemic effects noted in mice, rats, rabbits and dogs following exposure to metofluthrin were generally limited to decreased bodyweight and bodyweight gain, decreased food consumption, liver effects (rodents only), and neurological signs (discussed separately below in the section on neurotoxicity potential).  In many cases, reductions in bodyweight were observed without any significant reductions in food consumption. 

The lowest NOEL in repeat dose studies was 200 ppm in the 2-year rat study (equivalent to 8.24 and 10.12 mg/kg bw/d, in males and females respectively).  Effects at the next highest dose of 900 ppm included liver effects (discussed below), reduced food consumption, bodyweight and bodyweight gain, and changes in haematology and biochemical parameters. 

In repeat-dose toxicity studies by the oral route, the liver was identified as the target organ in rodents.  Effects included increased liver weight, dark and enlarged livers, hepatocellular hypertrophy, increases in smooth endoplasmic reticulum and biochemical changes (increases in cholesterol, triglycerides, phospholipids, albumin and globulin). 

Treatment related effects on haematology parameters were noted in male and female rats in the 104 week dietary study.  These changes included increased red blood cells and prothrombin time and reduced mean corpuscular volume (MCV).  The NOEL for this study was 200 ppm (8.24 and 10.12 mg/kg bw/d in males and females respectively), based on decreased food consumption, reduced bodyweight and bodyweight gain, changes in haematology and biochemical parameters and effects on the liver.

Mutagenicity

Metofluthrin was not mutagenic in vitro, with and without metabolic activation.

Genotoxicity

Metofluthrin was not genotoxic in in vitro or in vivo studies.

Neurotoxicity

Metofluthrin has similar neurotoxic effects to other pyrethroids. Clinical signs of toxicity observed in rats and dogs including tremor, vomiting (dogs only) and increased salivation (dogs only). In dogs, tremor was noted at 30 mg/kg bw/d and above.  In rats, tremor was observed in maternal animals at 30 mg/kg bw/d in a rat developmental study.  Vocalization and hyperactivity were also noted in a 90 day dermal study in rats at doses of 30 mg/kg bw/d and above.

In an acute oral neurotoxicity study in the rat, alterations in the FOB (landing foot splay) and motor activity were observed early after the treatment period at doses of 100 mg/kg bw/d. Histopathology of selected organs and tissues and specific locations of the central and peripheral nervous system revealed no treatment-related effects following both acute and repeated doses of metofluthrin.

Carcinogenicity

Liver tumours were observed in the 104-week combined chronic/oncogenicity study in rats at or exceeding the MTD. There was an increased incidence of hepatocellular adenoma and carcinoma in male rats at 38 mg/kg bw/d, and in hepatocellular adenomas and carcinomas in female rats at 47 and 96 mg/kg bw/d respectively. These tumours were associated with increased liver weight, hepatocellular hypertrophy and an increased incidence of clear cell foci, eosinophilic foci and mixed cell foci in the liver. Metofluthrin was not found to be carcinogenic in mice and was not mutagenic and/or genotoxic in vitro and in vivo.

However, it is considered that metofluthin induced liver tumours in the rat described above occur via a mode of action that is similar to phenobarbital and is not relevant to humans.

Reproduction and developmental toxicity

Metofluthrin is not a reproductive toxicant in rats, or a developmental toxicant in rats or rabbits.

Observation in humans

No information was provided.

Public exposure

The product is intended for domestic use as an insect repellent and is not intended to be used directly on food or food preparation areas or food utensils. The product is suitable for use in standard size rooms (4 x 4 m, approximately 2.1 g of metofluthrin). The product should be placed upright or hung in a desired spot near or around the house where air gently circulates such as entry points or near overhead fans. The product provides up to 28 days continuous protection, after which the whole device should be replaced.

Based on the expected use pattern of the product in domestic settings, the most likely route of exposure will occur when occupying areas where the product is in use.  There is also the potential for accidental oral and dermal exposure in children from touching the product and from hand-to-mouth exposure after touching the product.

Domestic users may be directly exposed to the product when opening the packaging, hanging the product in the desired location, disposing of the used product and entering treated areas.

As mosquitoes persist in many area of Australia all year round, it is expected that the duration of product use would be long-term.

Dermal exposure was considered to be negligible due to the use pattern of the product and the low vapour pressure of the active constituent.  Therefore the risk assessment was conducted for inhalational exposure only.

The daily systemic exposure was estimated to be 0.00216 mg/kg bw/d for adults and 0.0065 mg/kg bw/d for 1-2 year old children.  The MOE values for adults and children aged 1‑2 years were acceptable (i.e. MOE >100), therefore the OCS considers that there will be no undue risk to domestic users (adults or children) from use of the product.

International regulations

No information was provided.

Scheduling status

Metofluthrin is currently listed in Schedule 6.

Schedule 6

METOFLUTHRIN.

Scheduling history

Metofluthrin was first considered by the ACCS in February 2011. Toxicological evaluation of metofluthrin and risk assessment was carried out by the OCS (then OCSEH). OCSEH proposed that based on its toxicity profile of moderate acute inhalation toxicity and neurotoxicity (with clinical signs of neurotoxicity seen at 100 mg/kg bw in a rat acute neurotoxicity study, and at 30 mg/kg bw/d in a 12-month oral study in dogs and in dams in an oral rat developmental study), it was appropriate to include metofluthrin in Schedule 6.

The ACCS recommended a new Schedule 6 entry be created for metofluthrin. The delegate concluded that the recommendations of the ACCS were clear and appropriately supported and decided to include metofluthrin in Schedule 6.  The delegate also agreed that an implementation period of six months was appropriate.

In July 2014, the delegate referred a scheduling proposal to the ACCS to amend the current Schedule 6 to exclude mosquito repellent preparations containing 312 g/kg or less of metofluthrin from scheduling. The applicant indicated that the toxicity of the product (the substance impregnated onto non-woven polyester fabric, which is incorporated in a device that is designed to release the substance in the atmosphere) is the same as the toxicity of the substance. The committee recommended that based on the toxicity profile and use pattern/exposure to the product, the current Schedule 6 metofluthrin entry be amended to exempt impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk to Schedule 5. They agreed that the schedule 5 entry should specifically include the preparation and the refill.

The delegate accepted the advice tendered by the ACCS and agreed to include a new entry for metofluthrin in Schedule 5 and to amend the current Schedule 6 entry. While metofluthrin is a moderately toxic pyrethroid insecticide, the packaging and presentation of the product mitigates the exposure risk and warrants Schedule 5 inclusion. The implementation date for this decision was 1 February 2015.

Schedule 5 – New entry

METOFLUTHRIN in impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk.

Schedule 6 - Amendment

METOFLUTHRIN except when included in Schedule 5.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that the current Schedule 5 metofluthrin entry be amended:

METOFLUTHRIN,

  • in impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk; or
  • when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin for use as a mosquito repellent

The committee supported the implementation being as soon as possible.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the 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 recommendation comprised the following:

  • Polyethylene slow release matrix mitigates risk
  • Overall low toxicity, and risk of inhalation toxicity is low due to the formulation of the product
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors7;
  • Other relevant information.
Delegate's interim decision

The delegate accepts the advice of the ACCS and agrees to amend the current Schedule 5 entry for metofluthrin. While metofluthrin is a moderately toxic pyrethroid insecticide, the packaging and presentation of the product in a framed polymer matrix mitigates the exposure risk and warrants inclusion in Schedule 5.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included:  (c) the toxicity of the substance; and (d) dosage, formulation, labelling, packaging and presentation of a substance.

The proposed implementation date is 1 October 2015. An early implementation date is proposed to facilitate marketing of the product when registered by the APVMA.

Schedule entry
Schedule 5 – Amendment

METOFLUTHRIN

  • in impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk; or
  • when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin for use as a mosquito repellent.
Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The delegate has confirmed the proposed implementation date of 1 October 2015

Schedule entry
Schedule 5 – Amendment

METOFLUTHRIN

  • in impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk; or
  • when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin for use as a mosquito repellent.

Footnotes

  • 6, 7Australian Health Ministers' Advisory Council (AHMAC): Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015) [Scheduling Policy Framework]

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