2.5. Interim decision in relation to saflufenacil

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

Interim decision in relation to saflufenacil

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 saflufenacil 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 | Scheduling history | 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 saflufenacil was considered. The application proposed to amend the current Schedule 5 entry for saflufenacil to accommodate water-based suspension concentrates (SC).

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:

• The restriction of the current Schedule 5 entry to wettable granule formulations of saflufenacil (the only formulation proposed at the time of scheduling) was based on data from a dermal absorption study with a SC formulation conducted in rats.
• In 2011, the Scheduling Delegate and Committee concluded that the dermal absorption of saflufenacil from wettable granule formulations was very low.
• Based on the low dermal absorption of saflufenacil and substantial margins of exposure calculated for all the stipulated application methods of a wettable granule product (700 g/kg saflufenacil), together with slight skin and eye irritation for the wettable granule product, a cut-off to Schedule 5 for all water dispersible granule products containing saflufenacil was decided by the Delegate.
• The conclusions on dermal absorption for wettable granule formulations were based on a study conducted in rats with a SC formulation containing 342.2 g/L of saflufenacil.
• The product XXXXXXXXX (also a SC formulation), contains a lower amount of saflufenacil (250 g/L of saflufenacil), has low acute oral, dermal and inhalational toxicity, is not an eye irritant or skin sensitiser and is a slight skin irritant at most.

Current scheduling status

Saflufenacil is currently listed in Schedules 5 and 7 of the Poisons Standard as follows:

Scheduling history

In June 2009, the National Drug and Poisons scheduling Committee (NDPSC) decided to include saflufenacil in Schedule 7. The NDPSC particularly noted reports that saflufenacil increased skeletal malformations (bent scapula) in one animal species (redacted in minutes) at a relatively low dose in the absence of any significant signs of maternal toxicity. The NDPSC was concerned with the bent scapula effect, noting that this was an irreversible effect that was a highly unusual developmental toxicity marker.

In October 2009, the NDPSC considered post-meeting submissions requesting inclusion of saflufenacil in Schedule 6, which included new developmental toxicity data. The submissions claimed that the new developmental data demonstrated that there were marked interspecies differences with regard to protoporphyrin (PPO) inhibition by saflufenacil. The NDPSC noted that the study only considered saflufenacil's role in inhibiting one enzyme (protoporphyrinogen oxidase - PPO), where other PPO inhibitors had not produced the bent scapula effect. It was therefore argued that it was not possible to conclude that only this particular enzyme was responsible for the developmental toxicity effect. The NDPSC decided that the June 2009 Schedule 7 decision remained appropriate until the new data on developmental toxicity had been evaluated through the usual APVMA process.

In February 2010, the NDPSC was advised that the Applicant had updated its 2009 evaluation to include the new developmental toxicity data. The evaluator advised:

• Saflufenacil had low acute toxicity, it was a slight skin irritant and a minimal eye irritant, and had no skin sensitisation potentials. Notwithstanding its low acute toxicity, saflufenacil had shown developmental toxicity potential in XXXX (irreversible toxicity) but not in XXXXX. Consequently, the NDPSC may consider it appropriate to retain saflufenacil in Schedule 7.
• Alternatively, Schedule 6 may be more appropriate since the developmental toxicity was not seen in XXXXX, in vitro data indicated that saflufenacil was a PPO inhibitor and XXXXX are significantly more sensitive to this effect than rabbits and humans. However, the mode of action (MOA) for saflufenacil induced skeletal malformation had not been established, though there was limited evidence to suggest that PPO inhibition may not be relevant to the MOA.

The February 2010 NDPSC meeting confirmed the June 2009 Schedule 7 decision.

The Applicant subsequently submitted additional data to the APVMA in support of requested changes to the scheduling of their product. The Risk Assessment Technical Report on saflufenacil included a scheduling recommendation. A delegate agreed that this was a matter for a scheduling consideration and that advice from the ACCS was required.

In June 2011, the ACCS considered a proposal to reschedule saflufenacil from Schedule 7 to Schedule 6. The Delegate also sought advice on potential cut-offs from Schedule 6 to Schedule 5, including the possibility of a 70 per cent cut-off limited to water dispersible granule formulations. The Committee recommended that an exemption be created from the Schedule 7 saflufenacil parent entry to Schedule 5 for water dispersible granule preparations.

Australian regulations

• Saflufenacil is not listed on the TGA Ingredient Database.
• Saflufenacil is not used in human medicines. As of 7 May 2019, there are no medicines on the Australian Register of Therapeutic Goods (ARTG)^[39] that contain saflufenacil as an active ingredient.
• Saflufenacil 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^[40].
• As of May 2019, the Database of Adverse Event Notifications (DAEN)^[41] contains no reports of adverse events for products containing saflufenacil as an active ingredient.
• Saflufenacil is an APVMA approved active constituent.
• As of 7 May 2019, there is one (1) registered product containing saflufenacil listed on the Public Chemical Registration Information System Search (PUBCRIS)^[42].

International regulations

• The European Chemicals Agency (ECHA) hazard classification for saflufenacil is, 'Warning! According to the classification provided by companies to ECHA in CLP notifications this substance is very toxic to aquatic life and is very toxic to aquatic life with long lasting effects'.
• Saflufenacil is approved for use in the United States, Canada and New Zealand.
• Saflufenacil is not approved for use in the European Union.

Substance summary

Table 1: Chemical information for saflufenacil

Property	Saflufenacil
Chemical structure
Molecular formula	C17H17ClF4N4O5S
Molecular weight	500.85 g/mol
CAS name	2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoro-N-[[methyl(1-methylethyl)amino]sulfonyl]benzamide
CAS number	372137-35-4
IUPAC and/or common and/or other names	N'-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydro-1(2H)-pyrimidinyl)benzoyl]-N-isopropyl-N-methylsulfamide (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 amending the Schedule 5 entry for saflufenacil in the Poisons Standard 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; and (f) any other matters that the Secretary considers necessary to protect public health

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • The scheduling recommendation is consistent with the 2011 scheduling decision for Schedule 5 inclusion of water based suspension.
   • Benefits:
     • Allowing a new product formulation.
2. the purposes for which a substance is to be used and the extent of use of a substance:
   • Nil.
3. the toxicity of a substance:
   • Nil.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Nil.
5. the potential for abuse of a substance:
   • Nil.
6. any other matters that the Secretary considers necessary to protect public health:
   • The Committee suggests APVMA reconsiders safety directions in light of the pregnancy warnings.

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 saflufenacil;
• 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; and (f) any other matters that the Secretary considers necessary to protect public health;
• 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; and (f) any other matters that the Secretary considers necessary to protect public health.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the scheduling factors for Schedule 5.

I have made the decision to amend the current Poisons Standard by amending the Schedule 5 entry for saflufenacil and I have set out my reasons below.

I have taken into account the toxicological data on the substance provided by the Applicant and I am of the opinion that amending the Schedule 5 entry to include use in water-based suspension concentrates will not present an increased risk to public health. In making this decision, I have considered that the current Schedule 5 entry for water dispersible granules was made on the basis of low dermal absorption and that the study supporting this decision was conducted using a suspension concentrate formulation of a higher concentration. I acknowledge that saflufenacil has the potential to cause developmental toxicity. However, as no new data have been presented since the last scheduling decision in 2011, I consider the risk of the suspension concentrate formulation to be equivalent to that of the water dispersible granule formulation.

I agree with the Committee's recommendation that the toxicity data for saflufenacil is consistent with the scheduling factors for Schedule 5 on the grounds that the assessed product has low acute oral, dermal and inhalational toxicity, it is not an eye irritant or skin sensitiser and it is at most a slight skin irritant. I find that the substance has a low potential for causing harm and any potential harm is reduced through the use of appropriate packaging with simple warnings and safety directions on the label.

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