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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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3.3 Duddingtonia flagrans

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a new entry for Duddingtonia flagrans in Schedule 5 of the Poisons Standard, with no exemption cut-off.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are:

Schedule 5 - New Entry

DUDDINGTONIA FLAGRANS

The applicant's reasons for the request are:

  • The ubiquitous fungus, Duddingtonia flagrans, is present in animal faeces, soil and compost where it feeds on parasitic nematodes of grazing animals. D. flagrans spores, known as chlamydospores, are robust and can survive passage through the digestive tract of animals to be excreted in faeces, where they then germinate. There are at least 25 characterised isolates of D. flagrans in Australia. Genetic characterisation of these isolates show they fall into four major phylogenetic groups. One of these isolates, D. flagrans (strain IAH 1297), is the microbial constituent (active) in the current application.
  • D. flagrans is not infective, pathogenic or acutely toxic, although the proposed product, containing a chlamydospore preparation of the fungus, was a slight eye irritant in rabbits. Large intratracheal doses of chlamydospore preparations to rats were obstructive and led to initial respiratory difficulties, as well as an associated induction of multifocal lesions and diffuse purulent pneumonia with necrosis in areas of the pulmonary tissue. However, once the spores were cleared adverse effects were resolved. It is unknown if the fungus is a skin or respiratory sensitiser. D. flagrans spore preparations are proteinaceous and in the absence of suitable studies its respiratory sensitisation potential or ability to induce a cell mediated immunological response cannot be ruled out. However, appropriate personal protective equipment (i.e. dust mask) can be recommended to minimise these risks.
  • Based on the observed slight eye irritation in rabbits, D. flagrans meets the Scheduling Policy Framework (2015) criteria for scheduling it to Schedule 5 of the Poisons Standard with no cut-off or exemptions.
  • No short-term or long-term toxicology studies were submitted. Further, there are no publicly available studies with other D. flagrans strains or their secondary metabolites. As D. flagrans is a ubiquitous non-pathogenic/non-infectious fungi that does not produce secondary metabolites at a level that are a concern to human health, longer term studies of toxicity and carcinogenicity are not required and have not been provided.
  • No in vitro or in vivo studies were submitted. However, the Applicant provided in silico Quantitative structure-activity relationship (QSAR) modelling study that predicts flagranone A, the major secondary metabolite of D. flagrans (strain IAH 1297), is not genotoxic and does not exceed the 'Threshold of Toxicological Concern'.

Current scheduling status and relevant scheduling history

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

Australian regulatory information

Duddingtonia flagrans is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017, and is not an excipient or active in any products on the ARTG.

International regulations

New Zealand

The EPA registered Duddingtonia flagrans on 3 August 2016.[49])

EU

EFSA provided an opinion on the safety of D. flagrans when used as a feed additive for calves in 2006.[50])

Substance summary

The ubiquitous fungus, Duddingtonia flagrans, is present in animal faeces, soil and compost where it feeds on parasitic nematodes of grazing animals. D. flagrans spores, known as chlamydospores, are robust and can survive passage through the digestive tract of animals to be excreted in faeces, where these then germinate. There are at least 25 characterised isolates of D. flagrans in Australia. Genetic characterisation of these isolates show they fall into four major phylogenetic groups. One of these isolates, D. flagrans (strain IAH 1297), is the microbial constituent (active) in the current application.

Table 3.3.1: Chemical information for Duddingtonia flagrans
Property Duddingtonia flagrans
IUPAC and/or common and/or other names Arthrobotrys flagrans (Dudd.) Sidorova, Gorlenko & Nalepina; Trichothecium flagrans Dudd.
Table 3.3.2: Acute toxicity end-points for Duddingtonia flagrans
Toxicity Species Duddingtonia flagrans SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >5000 (1.9 x 107 spores/kg bw) Nil
Acute dermal toxicity LD50 (mg/kg bw) Rat >5000 (1.7 x 105 spores/kg bw) Nil
Acute inhalational toxicity [49]) Rat 2.0 x 105 cfu/kg bw Nil
Skin irritation Rabbit Not irritant Nil
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation Not tested Not tested N/A

Acute toxicity

No deaths, treatment related clinical signs or abnormal histopathological findings were observed. The acute oral LD50 for D. flagrans chlamydospores (strain IAH 1297) was greater than 5000 mg/kg bw (1.9 x 107 spores/kg bw). Based on the data, D. flagrans has low acute toxicity. D. flagrans (strain IAH 1297) has very low toxicity in conventional acute toxicity tests. The organism will not be associated with animal produce and none of its metabolites exceed the Threshold of Toxicological Concern. Consequently the establishment of an Acceptable Daily Intake (ADI), or of an Acute Reference Dose (ARfD), is not required.

D. flagrans has not yet been approved for use in food producing animals internationally.

The proposed products are estimated to be of low toxicity as demonstrated by acute oral, dermal and intratracheal administration of various quantities of chlamydospores and the low toxicity of the excipient constituents.

Repeat-dose toxicity

No short-term studies of toxicity were submitted. However, the applicant made reference to three target animal safety studies performed with cattle, horses and sheep.

Cattle

D. flagrans spores (strain IAH 1297) when fed as a supplement to cattle at a minimum of 3.75 x 105/kg bw/d caused no deaths, treatment related clinical signs or abnormal bodyweight gain/loss over a 56 day period. No adverse biochemical or haematological signs were observed during the study.

Sheep

D. flagrans spores (strain IAH 1297) when fed as a supplement to sheep at a minimum of 1.5 x 105/kg bw/d caused no deaths, treatment related clinical signs or abnormal bodyweight gain/loss over a 43 day period. No adverse biochemical or haematological signs were observed during the study.

Horses

D. flagrans spores (strain IAH 1297) when fed as a supplement to horses at a minimum of 3 x 105/kg bw/d caused no deaths, treatment related clinical signs or abnormal bodyweight gain/loss over a 56 day period. No adverse biochemical or haematological signs were observed during the study.

Skin irritation

The proposed product (containing approximately 1.7 x 104 chlamydospores of D. flagrans (strain IAH 1297)) when applied to rabbit skin resulted in no clinical signs of systemic toxicity. No local dermal signs of irritation were observed in the treated animals up to 72 hours after patch removal. D. flagrans is not a skin irritant.

Eye irritation

The effects of the proposed product (containing approximately 1 x 103 chlamydospores of D. flagrans (strain IAH 1297)) were judged to be irritating, but not sufficient to classify them as severe to isolated chicken eyes. The irritating nature of the test item in the study is likely attributable to its particulate nature. They are estimated to be slight eye irritants.

Genotoxicity

No in vitro or in vivo studies were submitted. Further, there are no publicly available studies with other D. flagrans strains or their secondary metabolites. However, the Applicant provided in silico Quantitative structure-activity relationship (QSAR) modelling that predicts that flagranone A, the major secondary metabolite of D. flagrans (strain IAH 1297), is not genotoxic.

Carcinogenicity

No studies were submitted. Further, there are no publicly available studies with other D. flagrans strains or their secondary metabolites.

As D. flagrans is a ubiquitous non-pathogenic/non-infectious fungi that does not produce toxins or antimicrobials at a level that are a concern to human health, longer term studies of toxicity and carcinogenicity are not required and have not been provided.

Reproduction and developmental toxicity

No studies were submitted. Further, there are no publicly available studies with other D. flagrans strains or their secondary metabolites.

As D. flagrans is a ubiquitous non-infectious fungi that does not produce toxins or antimicrobials at a level that are a concern to human health, reproductive and developmental studies are not required and have not been provided.

Other studies

In silico QSAR modelling for the secondary metabolite flagranone A using Derek Nexus and Leadscope software was submitted. Flagranone A is not likely to be genotoxic, toxic to reproduction, or carcinogenic. Flagranone A is predicted not to exceed the TTC for a non-genotoxic substance.

Public exposure

Both the proposed products are planned for use with food animals (cattle, sheep and goats). Feeding animals D. flagrans through the use either proposed products will expose animal to large levels of the fungus. Most fungal components will undergo normal digestive processes with the chlamydospores passing through the animals largely intact. The major secondary metabolite of D. flagrans (strain IAH 1297), flagranone A, is unstable and is unlikely to survive digestion. As such, the likelihood that components of D. flagrans (strain IAH 1297) and flagranone A will accumulate in the tissues of treated animals is negligible. Therefore, public exposure to D. flagrans (strain IAH 1297), and its major secondary metabolite flagranone A, through consumption of treated animal products (e.g. meat and milk) is highly unlikely.

Exposure of the public (other than owners of horses) to the products as a result of use will be limited. Some public may visit farms and other areas where animals are kept but they are unlikely to be involved in feeding or handling feed containers. Therefore, public exposure is expected to be highly unlikely.

Pre-meeting submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that a new Appendix B entry for Duddingtonia flagrans strain IAH 1297 be created as follows:

Appendix B - New Entry

DUDDINGTONIA FLAGRANS, STRAIN IAH 1297

Reason for Entry - a, low toxicity

Area of Use - 2.7, anthelmintic

The committee also recommended an implementation date of 1 February 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice were:

  • Duddingtonia flagrans strain IAH 1297 has a low risk to human health and safety. However, it is a slight eye irritant.
  • A toxicological profile is only available for this specific strain. Any further applications of other strains should be considered independently.
  • There is a slight risk of adverse outcomes from accidental exposure to Duddingtonia flagrans. However, there is no data available on children. The risk is expected to be low and appropriate packaging and labelling will minimise this risk.
  • Duddingtonia flagrans strain IAH 1297 is proposed to be used for the prevention and treatment of nematode infestations in grazing animals. It is intended to be used as a feed supplement in animals in a farm environment.

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS advice
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create a new Appendix B entry for Duddingtonia flagrans strain IAH 1297. The proposed Schedule entry is as follows:

Appendix B - New Entry

DUDDINGTONIA FLAGRANS, STRAIN IAH 1297

Reason for Entry - a, low toxicity

Area of Use - 2.7, anthelmintic

The proposed implementation date is 1 February 2018, as this is the earliest possible implementation date.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the interim decision are:

  • Duddingtonia flagrans strain IAH 1297 has a low risk to human health and safety. However, it is a slight eye irritant.
  • A toxicological profile is only available for this specific strain. Any further applications of other strains should be considered independently.
  • There is a slight risk of adverse outcomes from accidental exposure to Duddingtonia flagrans. However, there is no data available on children. The risk is expected to be low and appropriate packaging and labelling will minimise this risk.
  • Duddingtonia flagrans strain IAH 1297 is proposed to be used for the prevention and treatment of nematode infestations in grazing animals. It is intended to be used as a feed supplement in animals in a farm environment.

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