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Scheduling delegate's final decisions, June 2016

Scheduling of medicines and poisons

23 June 2016

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1.14 Isopyrazam

Part A - Final decisions on matters referred to an expert advisory committee

1. Scheduling proposals referred to the March 2016 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#16)

1.14 Isopyrazam

Referred Delegate's scheduling proposal
  • The scheduling proposal is to create a new Schedule 6 entry for isopyrazam.
Applicant's application and scheduling proposal

In December 2015, the OCS has referred the following scheduling proposal to be considered by the delegate:

  • A proposal to create a new entry for Isopyrazam in Schedule 6 of the SUSMP, with no exemption cut off.

The reasons for the request were:

  • The APVMA have received an application for approval of the new active constituent isopyrazam, a carboxamide broad-spectrum foliar fungicide with an inhibitory mode of action on the enzyme succinate dehydrogenase (complex II) within the fungal mitochondrial respiration chain.
  • Isopyrazam is a skin sensitiser in a local lymph node assay (LLNA) and a slight eye irritant in rabbits.
  • Isopyrazam has a low acute oral toxicity with LD50 ≤ 2000 mg/kg bw in rats.
Substance summary

Isopyrazam is a new carboxamide broad-spectrum foliar fungicide with an inhibitory mode of action on the enzyme succinate dehydrogenase (complex II) within the fungal mitochondrial respiration chain. The proposed product is intended for the control of black spot (Venturia inaequalis) and powdery mildew (Podosphaera leucotricha) in apples, and for control of black spot (Venturia pirina) in pears. Isopyrazam contains two diastereoisomers, designated syn and anti-isomers. Both of the isomers are biologically active.

The European Food Safety Authority has also published a report on the risk assessment for isopyrazam (pdf,523kb)*.

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Figure 11. Structure of Isopyrazam
Figure 11. Structure of Isopyrazam

The majority of metabolism and toxicology studies submitted were performed with syn:anti material with a ratio of around 93:7, but there were also a number of studies performed with material with an isomeric ratio of around 70:30 and a number of comparative studies where the test materials ranged from 100% syn through to 100% anti-isomer to help determine if the isomeric ratio had an influence on the mammalian toxicity of the test material.

Acute toxicity

The acute toxicity end-points for isopyrazam are listed in the following table.

Toxicity Species Results SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 550 > LD50 ≤2000 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat LD50 > 5000 Appendix B
Acute inhalational toxicity LC50 (mg/m3/4h) Rat LD50 > 5000 Appendix B
Skin irritation Rabbit Non irritant Appendix B
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation (LLNA) Mouse Sensitiser Schedule 6

*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

The acute toxicity end-points for Seguris Flexi (containing 12.5% isopyrazam) are listed in the table below.

Toxicity Species Results SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 1750 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat LD50 > 5000 Appendix B
Acute inhalational toxicity LC50 (mg/m3/4h) LD50 Rat > 2710 (no deaths) Appendix B
Skin irritation Rabbit Moderate irritant Schedule 5
Eye irritation Rabbit Severe irritant Schedule 6
Skin sensitisation (LLNA) Mouse Non-sensitiser Appendix B

Isopyrazam active constituent was found to be of low acute oral toxicity (550 < LD50 < 2000 mg/kg bw), low acute dermal toxicity (LD50 > 5000 mg/kg bw) and low acute inhalational toxicity (LC50 > 5280 mg/m3/4h).

Irritation

Isopyrazam was found to be a slight irritant to the eye, and non-irritating to skin in rat studies.

Sensitization

Isopyrazam was found to be a sensitiser in local lymph node assay in mice.

Repeat-dose toxicity

The systemic toxicity of isopyrazam in oral studies consisted primarily of decreased bodyweight and bodyweight gain, liver toxicity such as increased liver weight, hepatocellular hypertrophy with associated changes in clinical chemistry. The LOEL or NOEL established in chronic studies for the different species were: rats (LOEL = 5.5/6.9 mg/kg bw/d, M/F, 104-week), mice (NOEL = 7.8/9.9 mg/kg bw/d, M/F, 80-week study) and dogs (NOEL = 25 mg/kg bw/d, 52-week study).

Mutagenicity/Genotoxicity

Isopyrazam was neither mutagenic nor genotoxic in an array of studies including Ames test, cytogenetic assay, chromosomal aberration test and mouse lymphoma mutation assay in vitro, and UDS assay and micronucleus test in vivo. There was no evidence of a mutagenic/genotoxic potential of mandestrobin or its primary metabolites in vitro with and without metabolic activation.

Carcinogenicity

No evidence of oncogenic potential was observed in mice treated with diets containing isopyrazam concentrations up to 3500 ppm (432.6/553.6 mg/kg bw/d, M/F). Isopyrazam is considered to be carcinogenic in rats at a dose of 3000 ppm (173.5/232.8 mg/kg bw/d, M/F), based on the treatment related increase in uterine adenocarcinomas, thyroid follicular cell adenomas in males and hepatocellular adenomas in females (Milburn GM, 2008). The NOEL for carcinogenicity was 500 ppm (27.6/34.9 mg/kg bw/d, M/F) in this study.

Multiple mechanisms of action (MOA) studies were submitted by the applicant postulating mechanism by which isopyrazam induced liver tumours. The available data was analysed using IPCS framework and it was established that isopyrazam-induced rat liver tumours occurs via a MOA that is similar to phenobarbital which is known to be non-genotoxic, a CAR (constitutive androstane receptor) activator, inducer of liver CYP2B isoforms and induce hepatocellular tumours in rodents but is not a human carcinogen.

The key factors in the weight of evidence evaluation for the carcinogenicity of isopyrazam are: (a) there were no carcinogenic findings in mice in a study where the top dose produced a highly significant decrease in body weight gain (up to 40% in males and up to 20% in females); (b) treatment-related increases in tumour incidence (liver and uterus) were only observed in one sex, one species and confined to a significantly toxic dose level i.e. greater than the MTD (defined as a greater than 10% reduction in body weight gain); (c) isopyrazam was shown not to be oestrogenic in the rat thus excluding the most obvious potential mode of action for uterine tumours; and (d) clear NOELs have been established for liver and uterine tumours indicating that these are a high-dose threshold-based phenomenon.

Reproduction and developmental toxicity

Isopyrazam was not a reproductive or developmental toxicant. The NOEL for reproductive or fertility parameters was 3000 ppm (217.4 mg/kg bw/d) in a two generation rat study.

Neurotoxicity and immunotoxicity

No neurotoxic effects were observed in the acute (single dose) and sub-chronic (90-days) studies in rats. No immunotoxicity findings were observed up to a dose of 5000 ppm (127 mg/kg bw/d) in a 28-day dietary Crl:CD1 female mouse study.

Observation in humans

No information was provided.

Public exposure

No information was provided.

International regulations

Isopyrazam is conditionally approved in the European Union. The United States Environmental Protection Agency (US EPA) has established tolerances for residues of isopyrazam in or on apples and peanuts for which there are no accompanying United States registrations. Isopyrazam is a fungicide not currently registered for use in Canada, however a maximum residue limit (MRL) has been proposed by the Health Canada's Pest Management Regulatory Agency (PMRA) for isopyrazam on bananas to permit the import and sale of foods containing such residues.

Current scheduling status

Isopyrazam is not specifically scheduled.

Scheduling history

Isopyrazam has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

In response to the Delegate's request, the Committee has advised the substance meets Schedule 6 criteria, on the basis of acute oral toxicity and potential developmental toxicity being consistent with Schedule 6 factors.

In relation to different isomer mixtures used in testing, the Committee advised that the isomer ratio has an impact on the acute toxicity of isopyrazam but appears to have little influence on repeat-dose effects. The available studies were considered adequate to characterise the toxicity potential of the substance.

In relation to the mode of action for the carcinogenic effects in rats, the Committee advised that the proposed mode of action had not been conclusively demonstrated. However, isopyrazam was not an in vivo genotoxicant, and NOELs were identified for tumour findings which were only seen at the top dose levels which exceeded the maximum tolerated dose. The Committee noted the observed tumours in rats were associated with high doses and are not a relevant consideration for scheduling.

The committee advised that a new Schedule 6 entry be created for Isopyrazam as follows:

Schedule 6 - New Entry

ISOPYRAZAM.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) Acute oral toxicity and concern for potential developmental toxicity.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors14;
  • Other relevant information.
Delegate's interim decision

The delegate notes, and accepts, ACCS advice that a new entry for isopyrazam be created in Schedule 6. The delegate notes that this advice is primarily based on the acute toxicity profile, including potential skin sensitisation, being consistent with SPF scheduling criteria for listing in Schedule 6. Also noted are some concerns about the developmental eye defects (microphthalmia) seen in some rabbit studies, although not consistently found in other studies.

The proposed implementation date is 1 October 2016. An early implementation for this scheduling proposal will facilitate registration of the product by the APVMA.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.

Schedule 6 - New Entry

ISOPYRAZAM

Public submissions on the interim decision

No submissions were received.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.

The implementation date is 1 October 2016.


Footnote

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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