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Scheduling delegate's final decisions: ACMS, July 2014

Scheduling of medicines & poisons

3 July 2014

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

2. Agriculture and Veterinary Chemicals

2.1 Halauxifen methy

Scheduling proposal

The chemicals scheduling delegate (the delegate) considered a proposal to include halauxifen methyl, also known as XDE-729 methyl, in Appendix B.

The delegate decided to make a delegate-only decision. The Advisory Committee on Chemicals Scheduling (ACCS) was not consulted.

Scheduling status

Halauxifen methyl is not specifically scheduled.

Scheduling history

Halauxifen methyl has not been previously considered for scheduling therefore scheduling history is not available.

Substance summary

Halauxifen methyl is the first member of a new chemical class of synthetic auxin herbicides, the arylpicolinates. Halauxifen methyl mimics the effect of a persistent high dose of the natural plant hormone auxin, causing over-stimulation of specific auxin-regulated genes which result in the disruption of several growth processes in susceptible plants. Tissues that are undergoing active cell division and growth are particularly susceptible to injury5.

Figure 1. Structure of halauxifen-methyl

Figure 1. Structure of halauxifen-methyl

Note that halauxifen methyl hydrolysis into halauxifen acid as such the toxicity studies had been conducted using both substances. Toxicity information provided in this document is for halauxifen methyl and halauxifen acid and these have been specified appropriately.

Toxicity of the technical grade active constituent

The summary of acute toxicity studies is shown in the table below.

Toxicity Species Halauxifen methyl SPF* classification
Acute oral toxicity LD50 (mg/kg bw) Rats >5000 (one male died and no deaths for females) Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rats >5000 (no deaths) Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Please see below - -
Skin irritation Rabbits Non-irritant
Eye irritation Rabbits Non-irritant**
Skin sensitisation Local lymphnode assay Non-sensitiser
  • *SPF - Scheduling Policy Framework for Medicines and Chemicals (2010)
  • ** halauxifen acid was a slight eye irritant.

Regarding inhalational toxicity, the OCS indicated that waiver request by the applicant for the acute inhalation toxicity studies was accepted based on inability to generate a guideline-compliant respirable dry powder aerosol. The OCS indicated that the substance was not considered to be an acute inhalational hazard.

Repeat-dose toxicity potential

Short-term to chronic oral studies with mice, rats and dogs administered halauxifen acid demonstrated the kidney to be the target organ of toxicity with effects on urinalysis and clinical chemistry parameters and correlating histopathological changes including urinary bladder and renal tubules. These findings do not warrant scheduling.

Short-term to sub-chronic oral studies in rats with halauxifen methyl demonstrated that the most sensitive endpoint of toxicity was the liver, and was observed at doses lower than doses of halauxifen 9 acid causing kidney toxicity in short-term and sub-chronic studies in mice, rats and dogs.

Carcinogenic potential

Carcinogenicity studies in mice and rats with halauxifen acid did not reveal any treatment related neoplastic changes. Additionally, considering the above genotoxicity data and systemic toxicity data including mode of action (MOA) data and physiologically-based pharmacokinetic (PBPK) modelling, halauxifen methyl is not considered to be a carcinogenic hazard to humans.

Genotoxicity potential

Genotoxicity assays for gene mutation in vitro in bacterial cells and mammalian cells, and cytogenetic assays in vitro in rat and human peripheral lymphocytes were negative with and without metabolic activation for both halauxifen methyl and halauxifen acid. Additionally, an in vivo cytogenetic assay in mice peripheral erythrocytes with halauxifen acid was negative.

Developmental and reproductive toxicity potential

In developmental studies with halauxifen acid in rats and rabbits, foetotoxicity was only observed in rats (decreased foetal body weight and delayed ossification) at a maternotoxic dose of 526 mg/kg bw/d causing increase increased mortality, decreased gravid uterine weights, increased kidney weight, clinical signs, and decreased body weight gain and food consumption in dams, and is considered a secondary non-specific consequence of such. In developmental studies in rabbits, no fetotoxcity was observed up to and including maternotoxic doses.

In developmental studies with halauxifen methyl in rats and rabbits, foetotoxicity was only observed in rabbits (decreased foetal body weight and delayed ossification of the pubis) and at the maternotoxic dose of 71.6 mg/kg bw/d causing liver toxicity, including histopathological changes in does, and was considered a secondary non-specific consequence of such.

Halauxifen acid was not a reproductive toxicant in a rat 2-generation study.

Neurological toxicity potential

Acute and subchronic neurotoxicity studies with halauxifen acid in rats did not reveal any neurobehavioural or neurohistopathological changes up to the highest dose tested.

Toxicity of the product

The summary of acute toxicity studies on the product is shown in the table below.

Toxicity Species Halauxifen methyl SPF* classification
Acute oral toxicity LD50 (mg/kg bw) Rats >5000 (females) Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rats >5000 (both males and females) Low toxicity
Acute inhalational toxicity LC50 (mg/L) Rats 5.16 (both males and females) Low toxicity
Skin irritation Rabbits Slight-irritant
Eye irritation Rabbits Slight-irritant
Skin sensitisation Mice (local lymph node assay) Sensitiser

The OCS indicated that the product's slight skin and eye irritation and skin sensitisation potential was not considered to be due to halauxifen methyl but likely the product ingredients and the inclusion of a second active constituent, which is classified on Hazardous Substances Information System (HSIS) as a skin sensitiser.

Delegate's consideration

The delegate considered the following in regards to this application for re-scheduling.

  • evaluation report (not publically available);
  • section 52E of the Therapeutic Goods Act 1989;
  • scheduling factors6; and
  • other relevant information.
Delegate's final decision

Halauxifen methyl is a new type of auxin herbicide. The delegate notes 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 SPF factors for inclusion in any of the SUSMP schedules. Therefore the delegate has determined that halauxifen methyl does not require scheduling, and proposes to list halauxifen methyl in Appendix B. The implementation date is 1 October 2014.

Schedule entry
Appendix B - New entry
Substance Date of entry Reason for listing Area of use
HALAUXIFEN METHYL October 2014 a. Low toxicity

1. Agricultural

1.1 Herbicide

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2.2 Imepitoin

Scheduling proposal

The chemicals and medicines scheduling delegates (the delegates) considered a proposal to include imepitoin in Schedule 4.

The delegates decided to make a delegate-only decision. The joint committee of the Advisory Committee on Chemicals Scheduling (ACCS) & the Advisory Committee on Medicines (ACMS) was not consulted.

Scheduling status

Imepitoin is not specifically scheduled.

Other antiepileptic substances, including phenytoin (listed in Schedule 4 and Appendix F) and fosphenytoin (listed in Schedule 4) are listed in the SUSMP.

Scheduling history

Imepitoin has not been previously considered for scheduling therefore scheduling history is not available.

The scheduling history of fosphenytoin is provided below.

In May 2000, the NDPSC decided to include fosphenytoin sodium in Schedule 4. This decision was based on the fact that the use of fosphenytoin sodium requires medical management.

In October 2006, the NDSPC decided to amend the fosphenytoin sodium entry to read fosphenytoin.

Substance summary

Imepitoin, is an anti-epileptic medicine. Epilepsy is caused by excessive electrical activity in the brain. Imepitoin partially activates the receptors for the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Neurotransmitters such as GABA are chemicals that allow nerve cells to communicate with each other. In the brain GABA is involved in reducing the electrical activity. By activating its receptors, imepitoin increases GABA’s effects and helps to prevent seizures. Imepitoin also has a weak blocking effect on calcium channels. These are pores which let calcium move into the nerve cells allowing electrical impulses to be transmitted between nerve cells. This may also help in controlling seizures7.

Figure 1. Structure of imepitoin

Figure 1. Structure of imepitoin

 

Acute toxicity of the technical grade active constituent

The acute toxicity end-points for the chemical are listed in the below table.

Toxicity Species Imepitoin SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rats >2150 Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Not provided Not provided Unable to assess
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Not provided Unable to assess
Skin irritation Not provided Not provided
Eye irritation Not provided Not provided
Skin sensitisation Guinea pigs Non-sensitiser
  • *Scheduling Policy Framework for Medicines and Chemicals (2010)
Repeat-dose toxicity

In a study, rats were administered gavage doses of 0, 31.6, 100 or 316 mg/kg bw/day imepitoin for 4 weeks. Additional animals were given the control and high dose for 4 weeks followed by a treatment-free period of 6 weeks. There was no treatment related mortality. Clinical signs were seen in rats given 100 mg/kg bw/day (coordination disturbances, sunken sides) and 316 mg/kg bw/day (hypokinesia, coordination defects, salivation, piloerection, stilted gait, sunken sides, full stomach, and emaciation). Reflexes, hearing, dental and ophthalmological examinations were unaffected. Food intake and body weight gains were depressed, erythrocyte counts, haemoglobin, haematocrit, triglycerides and total protein were decreased and reticulocytes, alanine aminotransferase, blood urea nitrogen, cholesterol and albumin:globulin ratio were increased in animals given 316 mg/kg bw/day. Urinalysis was similar between groups. Dilation of the heart was found in some animals in the high dose groups. The liver exhibited increased weight in males given 316 mg/kg bw/day and all treated female groups, marginal at the lowest dose. At the highest dose, hepatocellular hypertrophy was increased in incidence in females and in severity in males and cytoplasmic eosinophilia was observed. Adrenal weights were higher in males given 316 mg/kg bw/day and this was a reflection of the greater severity in cortical vacuolization in both sexes at this dose.

Mutagenicity

No information provided.

Genotoxicity

Imepitoin was not mutagenic or clastogenic in a range of genotoxicity assays.

Carcinogenicity

No information provided.

Reproduction and developmental toxicity

Atrophy of the testicular tubules, prostate, seminal vesicles, uterus and vagina were found in rats and atrophy of testicular tubules, Leydig cells and prostate were seen in dogs. The testicular effects were not reversible. The mechanism for these atrophic changes in reproductive tissues has not been investigated. Monkeys had no testicular toxicity. The findings in reproductive organs of rats and dogs suggested that imepitoin may have an impact on reproduction. Testicular tubular atrophy and the irreversible effects on sperm production would be expected to reduce fertility. The other atrophic changes in males and females could impair reproductive capacity and performance. Therefore, imepitoin should be regarded as possibly toxic to reproduction at the doses associated with toxicity in reproductive organs.

Developmental toxicity studies in rats and rabbits revealed increased embryotoxicity and retarded foetal development in both species, external and visceral foetal abnormalities in rats and skeletal variations in rats and rabbits. These findings were only apparent at doses associated with clinical signs and death or premature abortions in dams. The embryo and foetal toxicity was considered secondary to the severe maternal toxicity.

Acute toxicity of the product

The evaluator indicated that no data were submitted on the toxicity of the tablet formulations. The formulations are of different strengths but the concentration of ingredients in each is the same. Therefore, the acute toxicity estimates were based on the available information on the active and excipient components and their concentration in the formulation.

The acute toxicity end-points for the product are listed in the below table.

Toxicity Species Imepitoin SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rats >2150 Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Not provided Not provided Unable to assess
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Not provided Unable to assess
Skin irritation Rabbits Possible irritant
Eye irritation Rabbits Possible irritant
Skin sensitisation Guinea pigs Non-sensitiser
  • *Scheduling Policy Framework for Medicines and Chemicals (2010)
Observation in humans

A series of randomised, double-blind, placebo controlled Phase I studies was conducted in healthy male volunteers to investigate the pharmacokinetics of and the tolerance to imepitoin. A total of 124 subjects were enrolled in the 3 separate studies.

The administration of single oral doses of enteric coated capsules resulted in linear pharmacokinetics at doses of up to 300-400 mg. At higher doses, peak plasma levels were achieved slower, increases in concentration were sub-linear and increases in area under the curve (AUC) were supra-linear. The administration of a non-coated capsule gave a markedly higher maximum plasma concentration, but a similar AUC as compared to the same dose in coated form. In a multi-dosing experiment with 100-500 mg/kg dw/day, volunteers received non-coated capsules three times a day for up to 22 days. Maximum plasma levels and AUC were supra-linear. Plasma concentrations prior to dosing (trough levels) revealed accumulation of imepitoin following repeated exposure and showed that a steady state had been attained at day 7 or later.

In single oral doses of up to 800 mg, imepitoin was well tolerated in human subjects. Vertigo, fatigue, headache, disequilibrium, dizziness and nausea were reported in subjects treated with escalating doses of imepitoin (300 mg once on day 1, 300 mg three times/day on days 2-8, 400 mg three times/day on days 9-15, 500 mg three times/day on days 16-21 and then 500 mg once on the final day 22) and were considered possibly associated with treatment. Imepitoin, in oral doses of up to 500 mg three times a day was tolerated in human subjects with only minor adverse reactions.

Public exposure

The product will be administered to dogs by owners. Dermal exposure is likely through hand contact with the product formulation during administration. Oral exposure may occur as a result of hand to mouth transfer or the accidental direct ingestion of the product by a young child.

Contact with the hands is likely during normal use of the product. Skin contact will occur when the tablets are removed from the packaging and eye contact may occur as a transfer from hands. Acute toxicity following dermal doses and the extent of dermal absorption are not known. However, the small amounts on skin are not expected to lead to significant absorption and therefore are unlikely to pose a meaningful systemic risk. Skin sensitisation is not expected based on acute toxicity results. Slight skin and eye irritation are possible so label statements to avoid contact with eyes and to wash hands after using the product are required.

Contact with oral mucosa may occur through hand to mouth transfer. These amounts would be small and unlikely to result in significant exposure. A statement to wash hands after use would also mitigate the risk.

The most extreme situation in relation to oral exposure would be if a young child (weighing 10 kg) accidentally ingested a tablet. Such an event would not be expected to occur repeatedly so the risk will be determined against the potential effects of imepitoin following acute administration. The lowest acute oral no observed adverse effect levels (NOAEL) were 30 mg/kg bw in animals and 11 mg/kg bw in humans.

The intake of imepitoin and the margins of exposure (MOEs) for each product, calculated against this NOAEL, are given in the table.

Intakes of imepitoin and MOEs for a 10 kg child are provided in the below table.

Dose/Exposure Product A Product B
mg/kg bw 10 40
MOE versus animal NOAEL 3 nil
MOE versus human NOAEL 1 nil

The evaluator indicated that the above MOEs are unacceptable. It is clear that children must be denied access to product. The company has proposed that the product formulation will be packaged in high density polyethylene bottles with a polypropylene child-resistant tamper-proof closure which would limit the likelihood of access by children. The label statements required for a Schedule 4 substance will indicate the need to keep the products out of the reach of children. Imepitoin may also be reproductive toxicant. For these reasons a label statement indicating the products are harmful if swallowed would be appropriate.

International regulations

Imepitoin is licensed in the European Union for the treatment of canine idiopathic epilepsy.

Scheduling consideration

The delegates considered the following in regards to this application:

  • evaluation report (not publically available);
  • section 52E of the Therapeutic Goods Act 1989;
  • scheduling factors8; and
  • other relevant information.
Delegates' final decision

Imepitoin is a new benzodiazepine derivative with anti-epileptic properties. It is intended for administration by veterinarians for the control of epilepsy in dogs. It is a straightforward scheduling matter that imepitoin should be listed in Schedule 4, to enable appropriate clinical diagnosis and management of treatment. The toxicological and pharmacological profiles are consistent with other anti-epileptic medicines and there are no issues that would warrant additional controls via any other schedule. The issues raised in the evaluation report regarding appropriate label warning statements and packaging with child-resistant closures are a matter for the Australian Pesticide and Veterinary Medicines Authority (APVMA) and not a scheduling matter. The implementation date for this decision is 1 October 2014.

Schedule entry

Schedule 4 - New entry

IMEPITOIN.

Footnotes

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