2.4. Interim decision in relation to trifludimoxazin

Interim decisions on proposed amendments referred to the Advisory Committee on Chemicals Scheduling (ACCS #25, June 2019)

Interim decision in relation to trifludimoxazin

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 trifludimoxazin as follows:

Proposed date of effect of the proposed amendment

1 February 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 | Australian regulations | International regulations | Substance summary | 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 trifludimoxazin was considered. The application proposed to exempt trifludimoxazin from control by scheduling, by creating an Appendix B entry for agricultural use as a herbicide.

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

Appendix B, Part 3 - New Entry

Substance	Date of entry	Reason for listing	Area of use
TRIFLUDIMOXAZIN	[TBD]	a (Low Toxicity)	1.1 (Herbicide)

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

• The toxicology profile of trifludimoxazin is well characterised. There is low acute toxicity, with no deaths or adverse clinical signs seen at the highest tested dose. The product is not intended to be used in the home garden, with intended uses limited to the agricultural sector. Due to the low toxicity, no personal protective equipment was required during use of the product.

Current scheduling status

Trifludimoxazin is not currently scheduled and has not been previously considered for scheduling.

Australian regulations

• Trifludimoxazin is not listed on the TGA Ingredient Database.
• As of 7 May 2019, trifludimoxazin is neither an excipient nor active ingredient in any medicines on the Australian Register of Therapeutic Goods (ARTG)^[36].
• Trifludimoxazin is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2019^[37].
• As of 7 May 2019, the Database of Adverse Event Notifications (DAEN)^[38] contains no reports of adverse events for products containing trifludimoxazin as an active ingredient.
• As of 7 May 2019, there are no products containing trifludimoxazin listed on the Public Chemical Registration Information System Search (PUBCRIS)
• Trifludimoxazin is not a previously endorsed APVMA active constituent.

International regulations

• Trifludimoxazin is not listed on the European Chemicals Agency (ECHA) website.
• Trifludimoxazin has yet to be registered in any other country.

Substance summary

Table 1: Chemical information for trifludimoxazin

Property	Trifludimoxazin
Chemical structure
Molecular formula	C16H11F3N4O4S
Molecular weight	412.35 g/mol
CAS name	Dihydro-1,5-dimethyl-6-thioxo-3-[2,2,7-trifluoro-3,4-dihydro-3-oxo-4-(2-propyn-1-yl)-2H-1,4-benzoxazin-6-yl]-1,3,5-triazine-2,4(1H,3H)-dione
CAS number	1258836-72-4
IUPAC and/or common and/or other names	1,5-dimethyl-6-thioxo-3-[2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1,3,5-triazinane-2,4-dione (IUPAC)

Summary of pre-meeting public submissions

No public submissions were received in response to the proposed amendment.

Summary of ACCS advice/recommendations to the Delegate

The Committee recommended that a new Schedule 6 entry be created for trifludimoxazin as follows:

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

It was 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:

1. risks and benefits of the use of a substance:
   • Risks:
     • Repeat dose exposure in animal studies cause neurotoxic effects at comparatively high doses.
     • Moderate health hazard with moderate risk of irreversible toxicity with repeated exposure.
   • Benefit:
     • Agriculture benefit - pre-planting of cereal crop weed reduction. Estimates of exposure during appropriate use at 12.5% have resulted in adequate safety margins.
2. the purposes for which a substance is to be used and the extent of use of a substance:
   • Agricultural use only for weed reduction pre-planting.
3. the toxicity of a substance:
   • Schedule 6 - Repeat dose exposure in animal studies show neurotoxic effects at comparatively high doses.
   • Moderate health hazard with moderate risk of irreversible toxicity with repeated exposure. Consistent with Schedule 6.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • In proposed formulation and usage, substance poses low risk.
5. the potential for abuse of a substance:
   • Nil.
6. 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 trifludimoxazin;
• Advisory Committee on Chemicals Scheduling's advice;
• Section 52E of the Therapeutic Goods Act 1989, in particular: (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 Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• The Australian Health Ministers' Advisory Council's Scheduling Handbook (V 1.0, January 2018).

Reasons for interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (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.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the scheduling factors for Schedule 5 and Schedule 6 and the considerations for amending Appendix B.

Contrary to advice provided by the Committee, I have made the decision to amend the current Poisons Standard by creating a new Schedule 5 entry for trifludimoxazin. I have set out my reasons below.

I have taken into account the toxicological data on trifludimoxazin that was provided by the Applicant and I note that the acute toxicity for all endpoints is low and does not appear to pose a risk. Based on my analysis of the available data, I consider that the adverse effects noted in repeat dose toxicity studies (neurogenerative changes and endocrine disruption) were only seen at high to very high doses after prolonged exposure. The margins of exposure for these toxicological endpoints have been calculated to be in excess of 10 to 1000-fold the proposed Acceptable Daily Intake (ADI) that has been used in establishing the dietary and Occupational Health & Safety risk assessments by the Applicant (APVMA).

When all the scheduling factors for Schedules 5 and 6 are considered as a whole, I find that trifludimoxazin to be most consistent with the scheduling factors for Schedule 5, based on its low acute toxicity, low health hazard (other than at high to very-high exposures), the potential for it to cause minor effects to humans in normal use, and that the substance has a low potential to cause harm when used with appropriate packaging and labelling. Appropriate packaging and labelling have been proposed by the pesticide regulator (APVMA) in its consideration of the approval of the substance, trifludimoxazin, and the registration of a trifludimoxazin-containing product.

I agree with the Committee's advice to include a cut-off to unscheduled at 12.5% due to the low acute toxicity seen at this concentration and the acceptable margins of exposure. I do not agree with the Committee's advice to include a specific limitation on the use of the substance for agricultural purposes in the proposed Scheduling entry. As the substance will be used in products intended for use as a preplanting herbicide in grain crops, the pesticide regulator (APVMA) has already considered its appropriate use. Should the use of the substance be expanded in the future, the pesticide regulator is the most appropriate authority to undertake a risk assessment to determine whether such use is approved.

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