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Final decisions amending, or not amending, the current Poisons Standard, April 2018

Scheduling medicines and poisons

10 April 2018

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4.4 Metamitron

Part B - Final decisions on matters not referred to an expert advisory committee

4. Delegate-only decisions on agricultural and veterinary chemicals

4.4 Metamitron

Delegate's final decision
Final decision:

The delegate's final decision is to create a new Schedule 6 entry for metamitron as follows:

Schedule 6 - New Entry

METAMITRON.

Implementation date: 1 June 2018
Reasons:

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

  1. the risks and benefits of the use of a substance:
    • Nil.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Metamitron is a triazinone herbicide that acts by inhibiting photosynthesis.
  3. the toxicity of a substance:
    • Metamitron has moderate acute oral toxicity and low acute dermal and inhalational toxicity; it is not a skin or eye irritant and is not a skin sensitiser in animal studies.
    • It is not neurotoxic, mutagenic, genotoxic, carcinogenic or teratogenic. The available toxicological data for metamitron supports its inclusion in Schedule 6.
  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:
    • Metamitron is not currently scheduled in Australia.
    • Metribuzin, a related trazinone herbicide in Schedule 6, has the same mode of action as metamitron.
Applicant's scheduling proposal and reasons for proposal

In November 2017, the Australian Pesticides and Veterinary Medicines Authority (APVMA) submitted a proposal to include METAMITRON in Schedule 6 in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) - the Poisons Standard.

The applicant's proposed amendments to the Poisons Standard are:

Schedule 6 - New Entry

METAMITRON.

The applicant's reasons for the request are:

  • The available toxicological data for metamitron is considered to be sufficient for the purposes of recommending a scheduling decision.
  • A related trazinone herbicide with the same mode of action as metamitron is metribuzin.
  • From the available data and international assessment reports, metamitron has moderate acute oral toxicity and low acute dermal and inhalational toxicity. It is not a skin or eye irritant, and is not a skin sensitiser. It is not neurotoxic, mutagenic, genotoxic, carcinogenic or teratogenic. The toxicity profile of metamitron supports consideration for listing in Schedule 6.
  • Metamitron, a herbicide, is approved for use in the EU. However, the formulated product evaluated in the EU in 2007 at the time of metamitron approval was a suspension concentrate (SC) containing 700 g/L metamitron.
  • In 2015, registration of a granular (WG) 150 g/kg metamitron product (Brevis) was granted in the EU. This product is identical to the one proposed for registration in Australia.
Current scheduling status

Metamitron is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.

Australian regulations

Metamitron is not currently approved in Australia.

Metamitron does not appear to be in any products on the Australian Register of Therapeutic Goods (ARTG).

Metamitron does not appear in the current Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.

International regulations
  • EU: Metamitron is registered with REACH (Annex III) and is approved for use in certain EU countries for the control of annual grasses and broad-leaved weeds.
  • NZ: Metamitron is registered to the ACVM Act (No P7241) and is an approved pursuant to the HSNO Act (No HSR000535).
  • USA: Metamitron is registered with the US FDA.
Substance summary
Table 4.4.1: Chemical information for metamitron
Property Metamitron
Chemical structure

chemical structure of metamitron

Mol Wt 202.2 g/mol

Molecular formula C10H10N4O
CAS names 4-amino-3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one
CAS numbers 41394-05-2
IUPAC and/or common and/or other names 4-amino-4,5-dihydro-3-methyl-6-phenyl-1,2,4-triazin-5-one
Table 4.4.2: Acute toxicity end-points for metamitron
Toxicity Species Metamitron SPF (2015) Classification[3]
Acute oral toxicity LD50 (mg/kg bw) Rat 1183 6
Acute dermal toxicity LD50 (mg/kg bw) Rat > 4000 -
Acute inhalational toxicity LC50 (mg/m3/4h) Rat 3910 (2 deaths) 5
Skin irritation Rabbit Not irritating -
Eye irritation Rabbit Not irritating -
Skin sensitisation (GPMT) Guinea pig Not a sensitiser -

Metamitron is a triazinone herbicide that acts by inhibiting photosynthesis. Toxicity studies on metamitron and its product have been submitted to the APVMA in support of the active approval and product registration. These studies have been reviewed by EFSA and are described in the Draft Assessment Report, 2007. The DAR for metamitron is available.

Acute toxicity

Studies in rats done according to OECD guidelines show that metamitron has moderate acute oral toxicity, low acute dermal toxicity, and low inhalation toxicity.

Skin and eye irritation

OECD guideline-compliant studies in rabbits show that metamitron is not a skin or eye irritant.

Sensitisation

An OECD guideline-compliant study shows that metamitron is not a skin sensitiser in the guinea pig maximisation test.

Repeat-dose toxicity

The liver was the main target organ for metamitron toxicity in rodents and dogs, based on clinical chemistry parameters indicative of liver toxicity, organ weight and histopathological changes in the liver and effect on red blood cell parameters suggestive of anaemia.

In an 18-month dietary study in mice, the NOAEL was 7.1 mg/kg bw/d based on liver effects at dose levels of ≥ 35.9 mg/kg bw/d.

In a 2-year dietary toxicity study in rats, the NOAEL was 4.9 mg/kg bw/d based on changes in red blood cell parameters and liver toxicity including increased cholesterol, increased relative liver weights and histopathological changes in the liver at dose levels of ≥ 19.5 mg/kg bw/d.

In a 1-year dietary toxicity study in dogs, the NOAEL was 1.1 mg/kg bw/d based on effects on haematology and clinical chemistry indicative of liver toxicity in mid- and high-dose animals treated at ≥ 13.6 mg/kg bw/d. In a 2-year dietary toxicity study in dogs, the NOAEL was 3.0 mg/kg bw/d based on increased cholesterol at dose levels of ≥ 11.3 mg/kg bw/d considered to be indicative of impaired liver function.

Neurotoxicity

There was no evidence that metamitron was neurotoxic.

Genotoxicity and Carcinogenicity

Overall, metamitron is not considered to be a genotoxic compound based on the weight of evidence from a range of in vitro and in vivo genotoxicity studies. Metamitron was not carcinogenic in rats receiving up to 81.5 mg/kg bw/d. Metamitron was not carcinogenic in mice up to 174 mg/kg bw/d.

Reproduction and developmental toxicity

No reproductive toxicity of metamitron was observed in two multi-generation reproduction dietary studies in rats. The NOAEL was 3.9 mg/kg/d based on decreased body weight gain in parents and offspring at 19.8 mg/kg/d. In the second study reduced numbers of corpora lutea and implantations were seen at the highest dose of 239 mg/kg/d. There was no evidence of reproductive toxicity at 97.2 mg/kg/d, which was the overall reproductive NOAEL. The overall parental and developmental NOAEL was 7.3 mg/kg/d based on reduced body weight gain in both studies and reduced pup survival in the second study.

In two oral gavage developmental toxicity studies in rats and one study in rabbits, metamitron was not teratogenic. The maternal and developmental NOAEL was 10 mg/kg bw/d and 100 mg/kg bw/d, respectively, based on reduced body weight gain at 100 mg/kg bw/d. In the oral gavage developmental toxicity study in rabbits, the maternal NOAEL was 40 mg/kg bw/d based on reduced body weight gain at 160 mg/kg bw/d. The developmental NOAEL was 160 mg/kg bw/d, the highest dose tested, based on lack of relevant findings.

Summary

From the available data and the EFSA assessment report, metamitron has moderate acute oral toxicity and low acute dermal and inhalational toxicity. It is not a skin or eye irritant, and is not a skin sensitiser. It is not neurotoxic, mutagenic, genotoxic, carcinogenic or teratogenic. The toxicity profile of metamitron supports consideration for listing in Schedule 6.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2018)
  • Other relevant information
Delegate's final decision

The delegate's final decision to be implemented on 1 June 2018 is to create a new Schedule 6 entry for metamitron as follows:

Schedule 6 - New Entry

METAMITRON.

Reasons for the final decision:

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

  1. the risks and benefits of the use of a substance:
    • Nil.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Metamitron is a triazinone herbicide that acts by inhibiting photosynthesis.
  3. the toxicity of a substance:
    • Metamitron has moderate acute oral toxicity and low acute dermal and inhalational toxicity; it is not a skin or eye irritant and is not a skin sensitiser in animal studies.
    • It is not neurotoxic, mutagenic, genotoxic, carcinogenic or teratogenic. The available toxicological data for metamitron supports its inclusion in Schedule 6.
  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:
    • Metamitron is not currently scheduled in Australia.
    • Metribuzin, a related trazinone herbicide in Schedule 6, has the same mode of action as metamitron.

Footnotes

  1. See TGA website for SPF classification guideline - AHMAC - Scheduling policy framework for medicines and chemicals

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