Publication of interim decisions amending, or not amending, the current Poisons Standard, June 2018

Scheduling medicines and poisons

7 June 2018

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3.1 Mefentrifluconazole

3. Advisory Committee on Chemicals Scheduling (ACCS #22)

Mefentrifluconazole

Delegate's interim decision

The delegate's interim decision is to create a new Schedule 5 entry for mefentrifluconazole in the Poisons Standard as follows:

Schedule 5 - New Entry

MEFENTRIFLUCONAZOLE except in preparations containing 7.5 per cent or less of mefentrifluconazole.

Proposed implementation date: 1 October 2018

The delegate considers the Committee's proposed implementation date of 1 October 2018 as being reasonable and appropriate in the circumstances.

Reasons:

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:


  1. the risks and benefits of the use of a substance:
    • Benefit: Control of fungal disease in plants.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Foliar spray of plant crops.
  3. the toxicity of a substance:
    • Skin sensitisation.
    • Low acute toxicity for the product.
Scheduling proposal

The pre-meeting scheduling proposal for mefentrifluconazole was published on the TGA website 21 December 2017 at Consultation: Proposed Amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS-ACMS meetings, March 2018.

Background information for mefentrifluconazole
Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to amend the Poisons Standard with respect to mefentrifluconazole. The application proposes to exclude mefentrifluconazole from scheduling.

Scheduling application

The applicant's reasons for the proposal are:

  • The available toxicity data for mefentrifluconazole is considered to be sufficient for the purposes of recommending a scheduling decision;
  • Advice from the APVMA is that there are no objections on human health grounds for the approval of the active constituent; and
  • The ACCS may consider that the toxicity hazard profile for acute exposure to mefentrifluconazole does not warrant scheduling.
Current scheduling status and scheduling history

Mefentrifluconazole is not scheduled in the Poisons Standard and has not been previously considered for scheduling. Therefore a scheduling history is not available.

Related triazole fungicides are in the Poisons Standard as follows:

Appendix B, Part 3

PROTHIOCONAZOLE.

Schedule 5

CYPROCONAZOLE except in preparations containing 10 per cent or less of cyproconazole.

DIFENOCONAZOLE.

EPOXICONAZOLE.

FENBUCONAZOLE.

HEXACONAZOLE except in preparations containing 5 per cent or less of hexaconazole.

IPCONAZOLE in preparations containing 2 per cent or less of ipconazole.

MYCLOBUTANIL.

PENCONAZOLE.

PROPICONAZOLE in preparations containing 20 per cent or less of propiconazole.

TEBUCONAZOLE.

TETRACONAZOLE in preparations containing 20 per cent or less of tetraconazole.

TRIADIMEFON in wettable powders containing 25 per cent or less of triadimefon.

TRIADIMENOL.

TRITICONAZOLE.

Schedule 6

FLUQUINCONAZOLE.

FLUTRIAFOL except in fertilisers containing 0.5 per cent or less of flutriafol.

IPCONAZOLE except when included in Schedule 5.

PROPICONAZOLE except when included in Schedule 5.

TETRACONAZOLE except when included in Schedule 5.

TRIADIMEFON except:

  1. when included in Schedule 5; or
  2. in fertilisers containing 5 g/kg or less of triadimefon.
Australian regulations

Mefentrifluconazole is not approved in Australia. The proposed product is a suspension concentrate formulation containing 75 g/L mefentrifluconazole.

Mefentrifluconazole is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018, and is not an excipient or active in any medicine on the Australian Register of Therapeutic Goods (ARTG).

International regulations

United States of America, Canada, Mexico and Brazil

Applications for the approval of mefentrifluconazole have been made.

European Union: Mefentrifluconazole has undergone public consultation and approval is pending according to Regulation (EC) No 1107/2009.

Substance summary
Table 3.1A: Chemical information for mefentrifluconazole
Property Mefentrifluconazole
CAS name alpha-[4-(4-chlorophenoxy)-2-(trifluoromethyl) phenyl]- alpha-methyl-1H-1,2,4-triazole-1-ethanol
CAS number 1417782-03-6
Chemical structure Chemical structure for Mefentrifluconazole
Molecular formula C18H15ClF3N3O2
Molecular weight 397.8 g/mol
IUPAC and/or common and/or other names

(2RS)-2-[4-(4-chlorophenoxy)-2- (trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl) propan-2-ol (IUPAC);

Mefentrifluconazole (ISO);

1H-1,2,4-Triazole-1-ethanol, alpha-(4-(4-chlorophenoxy)-2- (trifluoromethyl)phenyl)-alpha-methyl-;

2-[4-(4-chloro-phenoxy)-2-trifluoromethyl-phenyl]-1-[1,2,4]triazol-1-yl-propan-2-ol

Mefentrifluconazole (ISO approved name) belongs to a new sub-group of triazole fungicides, the isopropanol azoles, due to its unique isopropanol moiety. It belongs to the group of sterol biosysthesis inhibitors in the sub group of demethylation inhibitors, which block ergosterol biosynthesis through inhibition of cytochrome P450 sterol 14-demethylase (Cyp51). The depletion of ergosterol and accumulation of non-functional 14-methyl sterols in the fungi results in inhibition of growth and cell membrane disruption.

The following information was extracted from the APVMA assessment report [Human Health Technical Report - mefentrifluconazole].

Table 3.1B: Acute toxicity end-points for mefentrifluconazole
Toxicity Species Mefentrifluconazole SPF (2018) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 (no deaths) -
Acute dermal toxicity LD50 (mg/kg bw) Rat >5000 (no deaths) -
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >5314 (no deaths) -
Skin irritation Rabbit Non-irritating -
Eye irritation Rabbit Non-irritating -
Skin sensitisation (GPMT) Guinea pig Moderate sensitiser 5

Acute toxicity

Based on the available data from studies done according to OECD guidelines, mefentrifluconazole has low acute oral, dermal and inhalation toxicity in rats.

Skin and eye irritation

Based on available data from OECD guideline-compliant studies in rabbits, mefentrifluconazole is not a skin or eye irritant.

Sensitisation

An OECD guideline-compliant study shows that mefentrifluconazole is a moderate skin sensitiser in the guinea pig maximisation test.

Repeat-dose toxicity

A common, dominant finding in all mefentrifluconazole repeat dose studies is an increase in absolute and relative (to body weight) liver weights associated at higher doses with hepatocellular hypertrophy. In most studies, a simplistic interpretation of these findings would establish a no-observed-adverse-effect-level (NOAEL) at doses below those producing significant, adverse, toxicological effects. However, mode of action studies have demonstrated that mefentrifluconazole is an inducer of CYP450 in a partially phenobarbital like pattern. This is known to result in the liver effects observed with mefentrifluconazole across a range of species including in the rat, dog and non-human primate. These effects are generally recognised to be adaptive responses to a xenobiotic load and are not generally associated with progression to adverse histopathological or functional outcomes.

Evidence of hepatic effects consistent with enzyme induction (hepatocyte hypertrophy, increased liver weight) was modest in 28- and 90-day rat studies at doses of 388/334 and 256/314 mg/day in males/females in the 28 day and 90 day studies, respectively. For mefentrifluconazole, there is little evidence across the toxicological database of frank liver toxicity in rats or dogs.

The mechanistic data indicated that liver effects in C57BL/6J mice consisting of increased serum alanine transaminase (ALT) levels, increased liver weight, hypertrophy and liver cell proliferation are CAR-mediated, mouse specific and, in the absence of histologically demonstrable liver toxicity (necrosis) is likely to be of limited relevance for human risk assessment. Although the data do not indicate that liver effects are exclusively mediated by CAR-activation, it does indicate the mouse is likely to be more rather than less sensitive than humans.

Genotoxicity and carcinogenicity

There was no evidence that mefentrifluconazole was carcinogenic in mice and rats. Furthermore, mefentrifluconazole was tested for genotoxicity in an adequate range of in vitro and in vivo assays and based on these studies it is not genotoxic. Therefore, mefentrifluconazole does not warrant scheduling for these endpoints.

Reproduction and developmental toxicity

The NOAEL for general, systemic toxicity is 75 mg/kg/day for the F0 and F1 parental rats, based on decreased food consumption and body weight gain observed at 200 mg/kg/day. The NOAEL for fertility and reproductive performance for the parental rats is 200 mg/kg/day, the highest tested dose. The NOAEL for pup toxicity in the F1 and F2 generations is 75 mg/kg/day, based on pup mortality and the decrease in the pre-weaning pup body weights/pup weight gains observed at 200 mg/kg/day dose. Therefore, mefentrifluconazole is not a reproductive toxicant in rats.

In developmental studies, the effects of mefentrifluconazole in dams was limited to reduced body weight gains at 400 mg/kg/day in rats (NOAEL = 150 mg/kg/day) and no effects in rabbits at one half the LD50 (25 mg/kg) in non-pregnant rabbits. The NOAEL for fetal and developmental toxicity was at the highest dose tested in rats and rabbits (i.e. 400 and 25 mg/kg/day respectively). Mefentrifluconazole was not teratogenic in rats or rabbits.

Other toxicity studies

Neurotoxicity was investigated in rats by giving them a single dose of mefentrifluconazole up to 2000 mg/kg. Comprehensive behavioural and histopathological investigations revealed no evidence of neurotoxicity.

Observations in humans

No information available.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that a new Schedule 5 entry be created for mefentrifluconazole, as follows:

Schedule 5 - New Entry

MEFENTRIFLUCONAZOLE except in preparations containing 7.5 per cent or less of mefentrifluconazole.

The committee also recommended an implementation date of 1 October 2018.

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 purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.

The reasons for the advice were:

  1. the risks and benefits of the use of a substance:
    • Benefit: Control of fungal disease in plants.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Foliar spray of plant crops.
  3. the toxicity of a substance:
    • Skin sensitisation.
    • Low acute toxicity for the product.
  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:
    • Nil.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS advice;
  • Scheduling Policy Framework (SPF 2018); and
  • Section 52E(1) 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; and (c) the toxicity of a substance.

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