2.4 Interim decision in relation to methiozolin

2. Interim decisions on proposed amendments referred to the Advisory Committee on Chemicals Scheduling (ACCS #26, November 2019)

2.4. Interim decision in relation to methiozolin

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to amend the current Poisons Standard in relation to methiozolin as follows:

Proposed date of effect of the proposed amendment

1 June 2020

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Summary of pre-meeting public submissions | Summary of ACCS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to amend the current Poisons Standard with respect to methiozolin was considered. The application proposed to create a new Schedule 5 entry for methiozolin.

The Applicant's proposed amendments to the Poisons Standard were:

The Applicant's main points provided in support of the proposed amendments were as follows:

• It is proposed that methiozolin be included in Schedule 5 of the Poisons Standard, based on sufficient toxicological data being available to recommend a scheduling decision.
• The data supports that methiozolin has very low toxicity across the toxicological database and does not appear to present any substantial toxicological hazard. Methiozolin has very low acute toxicity by oral, dermal and inhalational routes.
• Methiozolin is not a skin irritant or sensitiser but causes a slight eye irritation in rabbits. The active was not genotoxic in a battery of in vivo and in vitro assays. There were no adverse effects on reproduction or development observed. Methiozolin was not neurotoxic in an acute study.
• The product, XXXXXXXXXXX (containing 250 g/L of methiozolin), has low acute toxicity by the oral, dermal and inhalational routes, is moderately irritating for the skin and eye, but is not a skin sensitiser in guinea pigs by the Buehler method. There are no other concerns in relation to the potential health hazard when used according to the proposed draft label.
• The management of methiozolin toxicological risks would be adequately achieved through a listing in Schedule 5 of the SUSMP with no cut-off or exemptions.

Current scheduling status

Methiozolin is not specifically scheduled and has not been previously considered for scheduling. Therefore, a scheduling history is not available. However, there is one other isoxazoline herbicide scheduled in the Poisons Standard as follows:

Scheduling history

Pyroxasulfone

In June 2011, the ACCS first considered pyroxasulfone for scheduling. The scheduling proposal was for a Schedule 7 entry with a cut-off to Schedule 6 for products containing 85 per cent or less pyroxasulfone for pre-emergence herbicidal use.

In September 2011, the Delegate made a decision to create new Schedules 6 and 7 entries for pyroxasulfone. This decision included a cut-off to Schedule 6 from Schedule 7 for water dispersible granule preparations when used as a pre-emergence herbicide. The Delegate made this decision following the recommendation from the ACCS. The ACCS noted that while there were minimal acute toxicity concerns, there were serious repeat dose concerns, noting effects on the cardiac muscle even in short term studies. In addition to the cardiac concerns, there were nerve tissue effects at quite low exposure levels, and developmental neurotoxicity in longer term study. The ACCS also noted that a high margin of exposure (MOE) had been determined by the evaluator. However, the ACCS felt that the severity of the endpoints was such that the ACCS could not ignore the possibility of exposure. The Committee generally agreed that Schedule 7 was appropriate for the pyroxasulfone parent entry.

The ACCS noted that the evaluator had asked for a cut-off to Schedule 6 for products containing 85 per cent or less pyroxasulfone for pre-emergence herbicidal use. The ACCS agreed that the percentage component was unnecessary, particularly as the toxicity difference between the high concentration cut-off and the 100 per cent substance was likely to be minimal.

The ACCS noted that the likely exposure to pyroxasulfone given the use pattern was dermal and via inhalation, and that repeat dermal exposure was the main concern. The ACCS noted that this concern was significant enough to not allow any cut-offs from a Schedule 7 parent entry. However, the ACCS contended that this concern was sufficiently mitigated for water dispersible granule formulations due to their lower absorption potential. The ACCS suggested that this presentation could be the basis for a cut-off to Schedule 6. The ACCS agreed, noting the high MOEs determined by the evaluator for the water dispersible formulations, its minimised exposure potential and the additional risk mitigation measures intended to be implemented by the regulator through labelling.

In March 2013, the ACCS considered a recommendation from the Office of Chemical Safety (OCS) to delete the existing Schedule 7 entry for pyroxasulfone and amend the Schedule 6 entry to a simple entry with no cut-offs. The recommendation was based on the evaluation of new data provided in support of an application for the registration of a water dispersible granule herbicide product containing 850 g/kg pyroxasulfone. The OCS recommendation was based on benign tumours seen in one species (rat) in one sex (male) and observed toxicity to the nervous system at low repeat oral doses (i.e. as the additional data and statistical analyses no longer indicated a concern for the developing foetus and child, with pyroxasulfone subsequently considered to represent a moderate hazard from repeated use and a low risk of producing irreversible toxicity).

The ACCS recommended, and the Delegate agreed, that pyroxasulfone be rescheduled from Schedule 7 to Schedule 6 with no cut-offs.

Australian regulations

• Methiozolin is not listed on the TGA Ingredient Database.
• There are no medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[182] that contain methiozolin as an active ingredient.
• Methiozolin is not permitted to be included in listed medicines as it is not included in the current Therapeutic Goods (Permissible Ingredients) Determination No.4 of 2019.^[183]
• The Database of Adverse Event Notifications (DAEN)^[184] contains no reports of adverse events for products containing methiozolin as an active ingredient.
• There are no products containing methiozolin listed on the Public Chemical Registration Information System Search (PUBCRIS).^[185]

International regulations

• According to the Applicant, methiozolin is currently registered in Japan and Korea, and is under consideration in the USA.
• Methiozolin is not listed with the European Chemicals Agency (ECHA)^[186] and according to the University of Hertfordshire Pesticide Properties DataBase (PPDB),^[187] the substance is not currently approved for use in the European Union (EU) under EU Regulation 1107/2009 (on the Placing of Plant Protection Products on the Market) (pdf,7.37Mb)*.^[188]
• While methiozolin is not listed in the United States Environmental Protection Agency's (US EPA) Office of Pesticides Programs^[189] as an approved active constituent, it is currently under consideration for registration by the herbicide branch of the US EPA's Pesticide Registration Division.^[190]
• Methiozolin is not listed as a registered active ingredient in Health Canada's Pesticide Product Information Database.^[191]
• Methiozolin is not included in the New Zealand EPA's Inventory of Chemicals (NZIoC).^[192]
• Methiozolin, under the trade names 'XXXXXXXX' and 'XXXXXXX,' was registered in Korea in April 2010 and in Japan in June 2016, respectively.^[193]

Summary of pre-meeting public submissions

No submissions were received in response to the notice published under regulation 42ZCZK advising of the proposed amendment.

Summary of ACCS advice/recommendations to the Delegate

The Committee recommended the Poisons Standard be amended as follows:

The Committee also recommended an implementation date of 1 June 2020.

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; (b) the purposes for which a substance is to be used and the extent of 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 advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Methiozolin has low acute toxicity by oral, dermal and inhalational routes. The long-term repeat dose effects of methiozolin are unknown.
b - the purposes for which a substance is to be used and the extent of use of a substance	Repeat use herbicide treatment of turf possibly including domestic use. Low persistence reflected in its re-application rate.
c - the toxicity of a substance	Methiozolin has very low acute toxicity by oral and dermal routes. Eye irritation is slight. No lifetime studies in mice and rats were presented for methiozolin. However, there was insufficient evidence to conclude under the conditions of exposure and the toxicity data available that methiozolin is likely to pose a carcinogenic risk to humans. Methiozolin was not a reproductive or developmental toxin in tested species and was not neurotoxic in an acute study. Methiozolin was not genotoxic in in vivo and in vitro assays.
d - the dosage, formulation, labelling, packaging and presentation of a substance	Due to formulation, the proposed product does not have lower toxicity. No cut off concentration is relevant. The product is expected to be packaged in 500 mL and 1 L high density polyethylene (HDPE) containers.
e - the potential for abuse of a substance	Nil.
f - any other matters that the Secretary considers necessary to protect public health	Nil

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to methiozolin;
• Advisory Committee on Chemicals Scheduling's advice;
• Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• Scheduling Handbook (V 1.1, July 2019).

Reasons for the interim decision

I agree with the Committee's finding that the relevant provisions of section 52E of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use of the substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

In my view, the relevant parts of the SPF 2018 are the Scheduling Factors for Schedule 5 and Schedule 6 and in particular Scheduling Factors 1 (toxicity profile of a substance) and 2 (hazard profile of a substance) for both Schedules.

I am satisfied that the data provided in the application supports inclusion of methiozolin in Schedule 5. The acute toxicity of methiozolin is consistent with the SPF Schedule 5 Scheduling Factors on the basis that it has low acute toxicity by oral and dermal routes (LD₅₀ >2000 mg/kg bw and LD₅₀ >2000 mg/kg bw, respectively), is a slight eye irritant and was not genotoxic in in vivo and in vitro assays. Additionally, and consistent with a Schedule 5 entry, the hazard profile for methiozolin is considered to be low as it does not exhibit significant reproductive or developmental toxicity and was not found to be neurotoxic in an acute study.

When the Scheduling Factors for Schedules 5 and 6 are considered, I find that while the acute inhalational toxicity for methiozolin is compatible with Schedule 6 at the maximum attainable concentration, I have given more weight to the oral, dermal and eye irritancy having met Schedule 5. I also note that methiozolin is neither a skin irritant nor skin sensitiser and does not meet the Scheduling Factors for inclusion in Schedules 5 or 6.

I note the Committee's concern that there were data gaps in the application on carcinogenicity and irreversible toxicity. Given that the sub-chronic studies in rats and dogs did not show evidence of histopathology/degenerative changes to any organ system and that methiozolin was negative in the genotoxicity studies conducted, I find that there is insufficient evidence to conclude that under the conditions of exposure and the toxicity data available that methiozolin is likely to pose a carcinogenic risk to humans. Consequently, I agree with the Committee recommendation that the absence of this data is insufficient to warrant a Schedule 6 entry.

Taking into consideration that that the proposed APVMA labelling will include First Aid Instructions and Safety Direction to mitigate any potential health risks associated with the use of methiozolin and the lack of submissions opposing the proposed the Schedule 5 cut-off entry, I am satisfied that the weight of evidence supports that the management of methiozolin toxicological risks can be achieved through a listing in Schedule 5 of the Poisons Standard with no cut-off or exemptions.

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