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Scheduling delegate's final decisions: ACCS, March 2015
scheduling medicines and poisons
Part B - Final decisions on matters not referred to an expert advisory committee
3. Agricultural and veterinary chemicals
In January 2015, the OCS, based on an application made to the APVMA to register a new active constituent (and a new production source for the active constituent) for agricultural uses, requested that the delegate consider confirming the existing entry for metaflumizone in Schedule 5 of the SUSMP.
The reasons for the request are discussed below.
A toxicological data package was submitted by the applicant to support the approval of a new active constituent, metaflumizone (for agricultural use), and to seek registration of a new product which contains 0.063% metaflumizone. The product is used for the control of nuisance ant species on gardens, golf courses, lawns, parks, turf and sports grounds, and industrial areas (including home garden use).
The OCS notes that this is the first consideration of metaflumizone for agricultural use. Previous applications to the OCS and referral of the chemical to the NDPSC for consideration in 2007 have been for veterinary uses of metaflumizone. The current application provides supplementary toxicology information on metaflumizone, which were considered and relied on in the evaluation report and recommendations to the APVMA.
Metaflumizone is a new semicarbazone insecticide. It works by binding selectively to the slow-inactivated state of a sodium channel, hence blocking sodium channels in target insects, and resulting paralysation and damaged nerve activity. It is proposed to be used in products for treating gardens, golf courses, industrial areas, lawns etc.
Figure 5. Structure of metaflumizone (E- and Z-isomers)
The acute toxicity end-points for this chemical are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||> 5000 (no deaths)||N/A|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||> 5000 (one death, not substance-related)||N/A|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||> 5200 (head/nose exposure)||N/A|
|Skin irritation||Rabbit||Non irritant||N/A|
|Eye irritation||Rabbit||Slight irritant||Schedule 5|
|Skin sensitisation (M&K method)||Guinea Pig||Non-sensitiser||N/A|
The acute toxicity end-points for the applied product are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||> 2000 (F only, no deaths)||N/A|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||> 2000 (M&F, no deaths)||N/A|
|Acute inhalational toxicity LC50 (mg/m3/4h)||N/A||No data||N/A|
|Skin irritation||Rabbit||Slight irritant||Schedule 5|
|Eye irritation||Rabbit||Non irritant||N/A|
|Skin sensitisation (Standard LLNA)||Guinea Pig||Sensitiser (up to 25% positive response on challenge)||Schedule 6#|
# While a dermal sensitiser would be considered consistent with Schedule 6 listing according to the SPF, the OCS emphasises that a GLP-compliant dermal sensitisation study was conducted on the active constituent, which reported no sensitisation response. This suggests that the sensitisation observed in the study with the product formulation is likely attributable to product excipients rather than the active constituent.
Overall, oral absorption of metaflumizone was low, with ~23% oral bioavailability when taken up in feed admixtures and ~11% when administered by oral gavage. Recovery of administered material was high, with the majority of the material eliminated in faeces and minimal urinary excretion.
There was strong evidence of metaflumizone accumulation in tissues, particularly in the fat. After 14 days of daily dosing at 30 mg/kg bw, the metaflumizone concentration was up to 43 times higher in the fat than that detected following a single dose (26 times higher in muscle and plasma, 13 times higher in liver and kidney) (Afzal & Zulalian, 2002). The uptake of lipophilic compounds from blood into fat is essentially a passive process and a compound like metaflumizone with a high Log Kow will readily partition into the fat of animals. The rate of entry and exit into fat are governed by both the lipophilicity and the effective concentration gradient between blood and fat (Fick’s laws of diffusion). A high plasma to fat tissue ratio of ~1:250 for metaflumizone was apparent after 14 days of repeated dosing in rats.
Toxicity in rats and dogs was characterised by general non-specific signs of toxicity including reduced food consumption, reduced bodyweight gain, poor general state, ataxia, salivation and lateral position after repeated dosing. Mice were considered to be the least sensitive species for metaflumizone and did not exhibit any of these signs of toxicity up to a dose of 1000 mg/kg bw/d inclusive during a lifetime study. The lowest dose for metaflumizone's effects was 30 mg/kg bw/d in dogs (the LOEL in a 3-month and 1-year oral study). General signs of toxicity were also observed in a 2-generation rat reproduction study at a maternotoxic LOEL of 50 mg/kg bw/d, in a rat developmental study at a maternotoxic LOEL of 120 mg/kg bw/d and in a 3-month rat neurotoxicity study at a LOEL of 150 mg/kg bw/d.
Metaflumizone or its impurities/metabolites were not genotoxic.
Metaflumizone was not carcinogenic.
Reproduction and developmental toxicity
Metaflumizone was not a reproductive or developmental toxicant at the doses tested in the various studies.
Other toxicology endpoints
On the basis of this evidence, metaflumizone is not considered likely to be a neurotoxicant in humans. No evidence of developmental neurotoxicity was noted in the range-finding DNT study.
Metaflumizone was not immunotoxic by the sRBC or the splenic NK cell assays.
Observation in humans
No information was provided.
The product is proposed to be used in gardens, golf courses, industrial areas, lawns, parks, turf and sports grounds. The product may be used by domestic users, as well as professional users. While exposure modelling as part of the OCS evaluation concluded that the systemic risks were acceptable and margins of exposure were not considered unsafe, the OCS noted that Section 3.6.5 of the current APVMA Data Guidelines (Guideline for pesticides intended for domestic use) indicates that: "Domestic pesticide products should present a low risk from repeated use. For instance, such products should be unlikely to induce irreversible toxicity." The OCS considers that the dermal sensitisation potential of the product does not match the 'low risk from repeated use' criteria, noting that there is no specific PPE prescribed for dermal sensitisers, and has recommended a restriction to 'professional use only' for the product.
The Applicant has indicated in their initial comments on the report that new risk reduction technologies are being developed and that a subsequent application for use of the product in domestic situations will be assembled in the future. This is not expected to have any specific bearing on the scheduling proposal (noting OCS' comments above regarding the lack of dermal sensitisation potential for the active constituent metaflumizone).
No specific information is available.
Metaflumizone is currently listed in Schedules 5.
Metaflumizone was first time considered by the National Drugs and Poisons Scheduling Committee (NDPSC) in October 2007. The committee noted the following from the draft report:
- On the basis of its overall low toxicity profile and its accumulative and persistent nature, the approval of metaflumizone is supported subject to the following conditions:
- the active metaflumizone is only for use in non-food producing animals or on non-food producing plants; and
- the active metaflumizone is only suitable for those use patterns where there is no human exposure to the product containing metaflumizone or to its residues; and
- any application for a product containing the active metaflumizone and proposing a new use pattern would require an occupational health and safety assessment for each new product application and use pattern.
- Whilst noting that the acute toxicity of metaflumizone was low, on the basis of the slight eye irritation in rabbits and its tendency to accumulate in body fat, the NDPSC may wish to consider placing it in Schedule 5.
The Committee noted that the metaflumizone toxicological database was complete and all of the submitted studies were well conducted and performed in accordance with contemporary test guidelines. All submitted studies were considered adequate and were relied upon to enable the recommendations to be made.
The Committee generally agreed that the toxicity of metaflumizone was very low, with only slight eye irritation being of any note. However, Members noted that metaflumizone was very lipid soluble and could bioaccumulate.
The Committee generally agreed the low toxicity together with the bioaccumulation potential, constituted a risk that could be adequately addressed through a Schedule 5 listing and the product registration process.
The delegates considered the following in regards to this proposal:
- Scheduling proposal;
- OCS evaluation report (not publicly available);
- Section 52E of the Therapeutic Goods Act 1989;
- SPF scheduling factors;
- Other relevant information.
Delegate's final decision
The toxicology profile of metaflumizone is consistent with SPF criteria for listing in Schedule 5, and consistent with the 2007 decision of the NDPSC to list it in Schedule 5. No new information is contained in the current submission that would cause that decision to be changed. This position is supported in both the OCS evaluation report and by the product sponsor. Accordingly, the delegate confirms that listing of metaflumizone in Schedule 5 remains appropriate, with no exemption cut-off. The delegate decided that the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 include (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) toxicity.