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Scheduling delegate's final decisions, October 2017

Scheduling of medicines and poisons

31 October 2017

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5.1 Florpyrauxifen-benzyl

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to exempt florpyrauxifen-benzyl from scheduling.

Scheduling application

This was a general application. The applicant’s reasons for the request are:

  • Low acute and repeat dose toxicity.
  • Mode of action (plant hormone mimic) is unique to plants.
  • A related arylpicolinate synthetic auxin herbicide, halauxifen-methyl, is listed in Appendix B of the Poisons Standard.

Current scheduling status and relevant scheduling history

Florpyrauxifen-benzyl is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available. However, a related arylpicolinate synthetic auxin herbicide, halauxifen-methyl, is listed in Appendix B of the Poisons Standard as follows:

Appendix B

HALAUXIFEN METHYL

Date of entry into the Poisons Standard: October 2014.
Reason for entry: a (Low Toxicity).
Areas of use: 1 (Agriculture), 1.1 (Herbicide).

Scheduling history of halauxifen methyl

An application for halauxifen methyl was submitted for consideration by the Advisory Committee on Chemicals Scheduling (ACCS). At this time, halauxifen methyl was the first member of a new chemical class of synthetic auxin herbicides, the arylpicolinates. The delegate noted that the toxicology profile is based mainly on studies with halauxifen acid, to which haluxifen methyl is rapidly hydrolysed during systemic absorption. Both compounds have a very low toxicity profile and do not satisfy any of the Scheduling Policy Framework (SPF) factors for inclusion in any of the Poisons Standard schedules. On 3 July 2014 the delegate made a delegate only final decision for halauxifen methyl and decided to include haluxifen methyl in Appendix B with an implementation date of 1 October 2014.

Australian regulatory information

Florpyrauxifen-benzyl has not previously been registered with APVMA as an active constituent or product.

Florpyrauxifen-benzyl is not listed on the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017, and is neither an excipient nor active in any medicines on the ARTG.

Florpyrauxifen-benzyl is not listed on the Australian Inventory of Chemical Substances (AICS).

International regulations

Florpyrauxifen-benzyl is undergoing assessment for approval/registration in Europe and USA.

Substance summary

Florpyrauxifen-benzyl belongs to the arylpicolinate group of synthetic auxin herbicides. It mimics the effect of a persistent high dose of the natural plant hormone auxin, causing over-stimulation of specific auxin-regulated genes, which results in the disruption of several growth processes in susceptible plants. Tissues which are undergoing active cell division and growth are particularly susceptible.

Table 5.1a: Chemical information for florpyrauxifen-benzyl
Property Florpyrauxifen-benzyl
Chemical structure chemical structure of vinyl acetate
Molecular formula C20H14CI2F2N2O3
Molecular weight 439.2 g/mol
CAS name Phenylmethyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-2-pyridinecarboxylate
CAS number 1390661-72-9
IUPAC and/or common and/or other names Benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylate (IUPAC); benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (IUPAC);
Table 5.1b: Acute toxicity end-points for florpyrauxifen-benzyl
Toxicity Species florpyrauxifen-benzyl SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >5000 Appendix B
Acute dermal toxicity LD50 (mg/kg bw) Rat >5000 Appendix B
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >5230 Appendix B
Skin irritation Rabbit Non-irritant Appendix B
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation (LLNA ) Mouse Slight sensitiser (EC3 = 19.1%) Schedule 5

Acute toxicity

Florpyrauxifen-benzyl has low acute oral toxicity in rats (LD50 >5000 mg/kg; no deaths or treatment-related clinical signs), low dermal toxicity in rats (LD50 >5000 mg/kg; no deaths or treatment-related clinical signs) and low inhalational toxicity in rats (LC50 >5230 mg/m3; no deaths but soiling in some animals which resolved by day 3).

Skin irritation

Florpyrauxifen-benzyl was not a skin irritant in rabbits, with the only clinical sign being slight erythema which had resolved by 24 h.

Eye irritation

Florpyrauxifen-benzyl was a slight eye irritant in rabbits, with the only clinical sign being conjunctival redness which had resolved by 72 h (conjunctival redness scores of 0.33 to 0.67).

Sensitization

Florpyrauxifen-benzyl demonstrated some skin sensitisation potential in a Local Lymph Node Assay (LLNA) in mice. The estimated concentration that would cause a 3-fold increase in proliferation compared to vehicle control (EC3) was calculated to be 19.1%.

Acute toxicity of the formulated SC product – GF-3301 (300 g/L florpyrauxifen-benzyl)

  • Low acute oral toxicity in rats (LD50 >5000 mg/kg bw; no deaths or treatment-related clinical signs).
  • Low dermal toxicity in rats (LD50 >5000 mg/kg bw; no deaths or treatment related clinical signs).
  • Low inhalational toxicity in rats (LC50 >5660 mg/m3; no deaths or treatment related clinical signs).
  • Not a skin irritant in rabbits (slight erythema, which had resolved by 48 hours).
  • Slight eye irritant in rabbits (conjunctival redness scores of 0.00 to 0.33, which had resolved by 48 hours).
  • Not a skin sensitiser in guinea pigs (Buehler method).

Repeat-dose toxicity

Short- and long-term repeat dose toxicity studies were conducted with florpyrauxifen-benzyl in mice, rats, rabbits and dogs. Except for an issue with palatability in rabbits at 1000 mg/kg bw/day in the palatability probe study, which was not repeated in the developmental study, no treatment-related adverse effects were observed at the highest doses tested in the dietary repeat dose studies (300 or 800-1000 mg/kg bw/day) or the 28-day dermal toxicity study (1000 mg/kg bw/day).

The limit dose (1000 mg/kg bw/day) was usually the highest dose tested, except in the 18-month dietary oncogenicity study in mice, the two-year dietary chronic toxicity/oncogenicity in rats and the dietary two-generation toxicity study in rats, where the highest doses tested were 800 mg/kg (females only), 300 mg/kg bw/day and 300 mg/kg bw/day, respectively.

The high dose of 800 mg/kg/day for female mice in the 18-month dietary oncogenicity study was selected based on the observation of lower body weights and decreased body weight gains in females given 1000 mg/kg/day in the 90-day dietary toxicity study, which was subsequently considered to be a non-adverse effect. The high dose of 300 mg/kg bw/day in the rat toxicity/oncogenicity and two-generation toxicity studies was informed by the toxicokinetic analyses from the 28-day and 90-day dietary toxicity studies in rats, which showed toxicokinetic non-linearity in systemic levels of the major metabolite, florpyrauxifen, at florpyrauxifen-benzyl dose levels from 300 mg/kg bw/day.

Florpyrauxifen-benzyl did not demonstrate oral or dermal toxicity, or neurotoxic, immunotoxic, carcinogenic, developmental or reproductive toxicity potential in the repeat dose studies.

Neurotoxicity

Repeat dose neurotoxicity testing was integrated into the 90 day dietary toxicity study in rats. There were no treatment-related effects in functional observational battery or on neuropathological observations at levels up to and including the highest dose tested (1000 mg/kg).

Immunotoxicity

The immunotoxicity potential of florpyrauxifen-benzyl was assessed in the 90 day dietary toxicity study in rats via the evaluation of the primary antibody response to sheep red blood cells (SRBC). Florpyrauxifen-benzyl did not result in a treatment-related effect on the primary immune response to SRBCs in male and female rats at levels up to and including the highest dose tested (1000 mg/kg).

Genotoxicity

There was no evidence that florpyrauxifen-benzyl was carcinogenic in mice and rats at levels up to and including the highest dose tested (mice – 800 or 1000 mg/kg bw/day for 18 months; rats – kinetically-derived maximum dose of 300 mg/kg bw/day for 2 years). Further, florpyrauxifen-benzyl was tested for genotoxicity in an adequate range of in vitro and in vivo assays (Salmonella typhimurium reverse mutation test, Rat Lymphocyte chromosomal aberration test, Chinese Hamster Ovary (CHO) Cell forward mutation test, mouse micronucleus assay) and based on these studies florpyrauxifen-benzyl is not genotoxic.

Carcinogenicity

Florpyrauxifen-benzyl was tested for its oncogenic potential in a 18 month dietary study in mice and a 2 year dietary study in rats. There was no evidence that florpyrauxifen-benzyl was carcinogenic in mice and rats at levels up to and including the highest dose tested (mice – 800 or 1000 mg/kg bw/day for 18 months; rats – kinetically-derived maximum dose of 300 mg/kg bw/day for 2 years).

Reproduction and developmental toxicity

Florpyrauxifen-benzyl was not a reproductive toxicant in the dietary two-generation reproduction toxicity study in rats at levels up to and including the highest dose tested (kinetically-derived maximum dose of 300 mg/kg bw/day), nor in the dietary reproduction/developmental screening test at levels up to and including the highest dose tested (1000 mg/kg bw/day). Further, the submitted studies on developmental toxicity showed that florpyrauxifen-benzyl was not teratogenic in rats and rabbits up to and including the highest dose tested (1000 mg/kg bw/day).

Observation in humans

No human data are available. Florpyrauxifen-benzyl is a new active constituent undergoing regulatory assessment in Australia and overseas (Europe and USA), and product is not yet commercially available. No significant adverse effects were observed in employees working in florpyrauxifen-benzyl R&D, pilot production and formulation in Midland Michigan from 2009 to August 2015.

Public exposure

No human data/studies are available.

Delegate’s considerations

The delegate’s final decision is to create a new Appendix B entry for florpyrauxifen-benzyl as follows:

Appendix B – New Entry

FLORPYRAUXIFEN-BENZYL

Reason for entry: a (Low Toxicity).
Areas of use: 1 (Agriculture), 1.1 (Herbicide).

The reasons for the decision are:

  • Low acute toxicity of florpyrauxifen-benzyl consistent with Appendix B or Schedule 5 (slight eye irritation and slight skin sensitisation).
  • No systemic toxicity reported in repeat dose studies.
  • The formulated product (florpyrauxifen-benzyl, 300 g/L) has low acute toxicity (slight eye irritation).
  • • A related arylpicolinate synthetic auxin herbicide, halauxifen-methyl, is listed in Appendix B of the Poisons Standard.

The implementation date is 1 February 2018.

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