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Scheduling delegate's final decisions: ACCS/ACMS, June 2013

Scheduling medicines and poisons

28 June 2013

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Part B: New chemical entities - chemicals

3.1 Cyazofamid

Scheduling proposal

The Office of Chemical Safety (OCS) evaluated the data provided in support of an application for the approval of a new active constituent namely cyazofamid. The OCS recommended that decoquinate be included in Schedule 5 in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).

The applicant was provided a copy of the evaluation report, but did not provide any comments.

The delegate considered this proposal and made a delegate-only decision. The Advisory Committee on Chemicals Scheduling (ACCS) was not consulted.

Toxicology

Technical grade active constituent

Cyazofamid has a low acute oral (LD50 > 5000 mg/kg), dermal (LD50 > 2000 mg/kg) and inhalational (LC50 > 5500 mg/m3) in rats. It was a slight irritant to rabbit eyes and a slight irritant to rabbit skin. It was not considered likely to be a skin sensitiser in guinea pigs, based on the results of a maximisation test.

In short-term dermal and subchronic oral repeat dose studies in rats and dogs, cyazofamid showed low toxicity to organs with no treatment related and toxicologically significant findings up to the highest dose tested.

In chronic oral studies in mice, rats and dogs treatment related and toxicologically significant effects were limited to an increase in histopathological changes in the ovaries (hematocysts) of mice and decreased body weight gain and increased incidence of ocular cataracts in female rats (of a similar intensity to that seen in control females) at the highest dose tested, There were no treatment related and toxicologically significant findings male mice and rats or in dogs. The above findings observed at high doses following chronic dietary exposure are not considered to require scheduling.

Cyazofamid was not carcinogenic in mice.

The uniform negative findings in a range of in vitro and in vivo studies indicate cyazofamid is not mutagenic or genotoxic.

There were no treatment related effects on reproductive or developmental parameters, with treatment related and toxicologically significant findings limited to pup toxicity (decreased body weight gain at weaning only) at the highest dose tested in a two-generation study in rats.

Neurotoxicity data were not submitted and repeat dose studies in rats did not investigate sensory reactivity to different stimuli and/or conduct a Functional Observation Battery (FOB). However, as the repeat dose toxicity data for cyazofamid indicate general low toxicity in mice, rats and dogs, and treatment related neurohistopathological lesions were not observed in chronic/carcinogenicity studies the absence of data for neurotoxicity is not considered to be of concern in this instance.

OCS has noted potential scheduling issues with regard to carcinogenicity, reproductive and developmental toxicity in their paper for the delegate's consideration.

Product

The product data was not provided with the application.

Scheduling status

Cyazofamid is not specifically scheduled and is not captured by any entry in the Standard for the Uniform Scheduling of Medicines and Poisons.

Scheduling history

Cyazofamid has no scheduling history.

Scheduling consideration

The delegate considered the following in regards to this application:

  • the evaluation Report (not publicly available);
  • section 52E of the Therapeutic Goods Act 1989; and
  • scheduling factors for inclusion in Schedule 516.

Delegate's final decision

The delegate has made a delegate-only decision to include cyazofamid in Schedule 5 of the Standards for the Uniform Scheduling of Medicines and Poisons.

The implementation date for this decision is 1 September 2013.

The delegate decided that the relevant matters under section 52E of the Therapeutic Goods Act 1989 include: (c) toxicity of cyazofamid.

The delegate's decision to include cyazofamid in Schedule 5 was comprised of the following reasons:

  • Cyazofamid has low acute toxicity, with slight eye/skin irritancy potential. The toxicological profile of cyazofamid is consistent with Scheduling Policy Framework guidance for inclusion in Schedule 5.
  • Observed effects in carcinogenicity, developmental toxicity and reproductive toxicity studies are not toxicologically significant in respect to scheduling.
  • There is insufficient evidence available to consider any cut-off to exempt status.

Schedule entry

Schedule 5 - New entry

CYAZOFAMID.

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3.2 Decoquinate

Scheduling proposal

The Office of Chemical Safety (OCS) evaluated the data provided in support of an application for the approval of a new active constituent namely decoquinate and registration of a new antiprotozoal product containing decoquinate at 60 g/kg (6 per cent w/w) powder. The OCS recommended that decoquinate be included in Schedule 5 in the Standard for the Uniform Scheduling of Medicines and Poisons.

The applicant was provided a copy of the evaluation report, but did not provide any comments.

The delegate considered this proposal and made a delegate-only decision. The Advisory Committee on Chemicals Scheduling (ACCS) was not consulted.

Toxicity

Technical grade active constituent (TGAC)

Decoquinate had low acute oral toxicity in the rat (LD50 > 5000 mg/kg bw, no deaths) and low acute inhalational toxicity in the rat (4-hr LC50 > 4190 mg/m3, nose-only). No studies on acute dermal toxicity were provided for evaluation. Decoquinate was not irritating to the eye or skin of rabbits and was not a skin sensitiser in guinea pigs.

Decoquinate did not cause any effects on reproductive parameters in a 3-generation reproduction study in rats, neither were any other toxic effects noted up to the highest dose tested (60.6 mg/kg bw/d).

In developmental studies in rats, no maternal effects were noted at the highest dose tested (300 mg/kg bw/d), however, minor developmental variations (retarded skeletal ossification) was noted at this top dose in foetal animals. In rabbits, no evidence of teratogenicity or maternal toxicity was seen at up to 300 mg/kg bw/d, the highest dose tested. However, based on equivocal results suggesting reduced mean numbers of live foetuses per litter at ≥ 100 mg/kg bw/d, and insufficient observational data to clarify the treatment-related relevance of this finding, the foetotoxicity NOEL in the rabbit developmental study was established at 60 mg/kg bw/d.

Decoquinate was negative in a range of in vitro mutagenicity/genotoxicity studies. Although one mouse lymphoma forward mutation assay showed equivocal results, the weight-of-evidence indicates decoquinate is not genotoxic.

Formulated product

No acute toxicity studies were provided on the product. Therefore, the potential acute oral, dermal, and inhalational toxicity, and the eye and skin irritancy and skin sensitisation potential were extrapolated from toxicity data on the active constituent and the excipients.

Based on the toxicity estimation, the product has a similar toxicity profile to the active, decoquinate, with low acute toxicity from the oral, dermal and inhalational routes expected, and not a skin irritant. The product is not expected to be a skin sensitiser. The product is a veterinary feed formulation with constituents which may cause mechanical irritation to the eyes. Additionally, one excipient present at 1 to 2 per cent of the formulation may cause health effects if chronically inhaled, however, other constituents in the formulation are expected to reduce the dusting potential.

Scheduling status

Decoquinate is not specifically scheduled.

Scheduling consideration

The delegate considered the following in regards to this application:

  • the evaluation Report (not publicly available);
  • section 52E of the Therapeutic Goods Act 1989; and
  • scheduling factors for inclusion in Schedule 517.

Delegate's final decision

The delegate has made a delegate-only decision to include decoquinate in Schedule 5 of the Standards for the Uniform Scheduling of Medicines and Poisons.

The implementation date for this decision is 1 September 2013.

The delegate decided that the relevant matters under section 52E of the Therapeutic Goods Act 1989 include: (c) toxicity; (d) dosage, formulation and packaging; (e) potential for abuse; and (f) any other matters.

The decision to include decoquinate in Schedule 5 included the following reasons:

  • The toxicological profile of decoquinate is consistent with Scheduling Policy Framework guidelines for inclusion in Schedule 5.
  • The slight skin/eye irritancy is sufficient to warrant inclusion in Schedule 5, despite the overall low acute and chronic toxicity.
  • There is insufficient evidence available to consider any cut-off to exempt status.

Schedule entry

Schedule 5 - New entry

DECOQUINATE.


Footnotes

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