You are here

Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2016

Scheduling medicines and poisons

12 May 2016

Book pagination

1.12 Di-Bak Parkinsonia

Part A - Interim decisions on scheduling proposals referred to an advisory committee (March 2016)

1. Advisory Committee on Chemicals Scheduling (ACCS#16)

1.12 Di-Bak Parkinsonia

Referred scheduling proposal
  • To consider the need for scheduling a new biological pesticide containing three fungal strains, Lasiodiplodia pseudotheobromae (strain NT039), Neoscytalidium novaehollandiae (strain QLD003), and Macrophomina phaseolina (strain NT094).
Scheduling application

In December 2015 the Office of Chemical Safety (OCS), based on an application made to the APVMA to approve three new biological active constituents, requested that the Delegate consider creating new entries for Lasiodiplodia pseudotheobromae (strain NT039), Neoscytalidium novaehollandiae (strain QLD003) and Macrophomina phaseolina (strain NT094) in Schedule 5 of the SUSMP with cut off exemptions. The proposed new entries are as follows:

  • Lasiodiplodia pseudotheobromae (strain NT039) except when used in capsule preparations at a concentration of 16 CFU/dosage unit or less
  • Neoscytalidium novaehollandiae (strain QLD003) except when used in capsule preparations at a concentration of 16 CFU/dosage unit or less
  • Macrophomina phaseolina (strain NT094) except when used in capsule preparations at a concentration of 16 CFU/dosage unit or less

The reasons for the request are:

  • Available literature on human clinical case studies suggests that human infection (where reported) is generally opportunistic, although instances of infection in the absence of identifiable injury or immunocompromised state have been described.
  • Acute intraperitoneal sighting studies in rat show evidence of infectivity by all the active constituents individually. Pathogenicity could not be definitively determined from these studies, though under the study conditions pathogenicity was considered unlikely.
  • Acute intraperitoneal and oral toxicity/pathogenicity studies with the product did not show evidence of infectivity; however, these studies have reduced regulatory value due to deviations from the test guidelines. Pathogenicity could not be definitively determined from these studies, though under the study conditions pathogenicity was considered unlikely.
  • The skin sensitisation study (by local lymph node assay) did not indicate a skin sensitisation potential for Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae or Macrophomina phaseolina; however, this study has limited regulatory value due to lack of verification of the test item extraction method.
  • No acute inhalational or dermal toxicity or skin or eye irritation studies were submitted. Cases of severe sinus and eye infection by Lasiodiplodia pseudotheobromae in humans have been recorded in the academic literature, where no obvious mode of acquisition or underlying medical condition was present. The number of reported case studies internationally demonstrates a low rate of infection. Given the information provided, the risks associated with exposure to the constituent fungi in the proposed product is considered by the OCS to be low, though the potential for minor human pathogenicity by the active constituents cannot be ruled out.
  • Repeat-dose studies were not undertaken; however it is considered that the proposed formulation and intended use pattern of the product present a low potential for the active constituents to cause harm.
  • The carcinogenicity, genotoxicity and immunotoxicity potential of Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina cannot be determined at this time.
  • The OCS considers that the likelihood of infectivity/pathogenicity associated with the use of the active constituents and product can be mitigated through appropriate label warnings, as indicated in the proposed safety directions ("Avoid contact with the eyes and skin", "When using the product wear elbow-length chemical resistant gloves" and "Wash hands after use") and precautionary statements ("Avoid direct contact with the contents of capsules" and "Not for food-producing use").
  • Consideration of the SPF criteria and application of the cascading principles outlined in the SPF indicates that the biological active constituents Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina meet the scheduling factors for a Schedule 5 listing in the SUSMP with an exemption cut off (to unscheduled) for the product when used in capsule preparations containing 16 CFU/dosage unit or less, based on the active constituents presenting a low health hazard and the intended product use pattern and formulation minimising the potential for the active constituents to cause harm.
Specific issues/questions raised by the delegate

The delegate's reasons for referring this to the Committee were to seek ACCS advice to determine whether the toxicity data package is sufficiently comprehensive to make a scheduling decision, and whether the evidence of potential infectivity justifies listing in Schedule 5, with an exemption for a product containing low levels of the three fungal strains.

The Delegate has sought advice on the following questions:

  • Noting that there is reasonably strong evidence of infectivity in humans and rodents with all three fungal strains in the product under consideration, can the ACCS advise on any concerns about the potential pathogenicity of the fungal strains, and whether this property justifies listing in one of the schedules?
  • To what extent does evidence of the presence of these fungi in the natural environment ameliorate the need for scheduling?
  • Do the proposed label warning statements ameliorate the risk to the extent that scheduling does not confer any additional safeguards for users of the products or bystanders?
  • To what extent does the proposed method of use (insertion into a hole in the tree, with subsequent sealing) obviate the need for scheduling to control the risks?
  • If listing in the schedules is supported by the ACCS, advice is required on the wording of the schedule entry. Should there be three separate entries for each of the fungal strains?
  • How should the entries be worded if the proposal to exempt the product from scheduling is supported? Should any exemption clauses specify that only the encapsulated product is exempt from scheduling?
Substance summary

Di-Bak Parkinsonia is a new biological herbicide consisting of three fungal species - Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina – combined with a millet substrate in gelatine capsule formulation.

Acute toxicity

The acute toxicity end-points for Di-Bak Parkinsonia are listed below.

Toxicity Species Result SPF* Classification
Acute intraperitoneal toxicity/pathogenicity LD50 Rat > 16 CFU/strain/animal^ N/A
"Acute" oral toxicity LD50 (mg/kg bw)^ Rat > 2g/kg bw/d^ [Unscheduled]
Acute dermal toxicity LD50 (mg/kg bw) n/a
Acute inhalational toxicity LC50 (mg/m3/4h) n/a
Skin irritation n/a
Eye irritation n/a
Skin sensitisation LLNA^ Mice Unlikely to be a skin sensitiser^ [Unscheduled]

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

^ Study has reduced regulatory value

Repeat-dose toxicity

Repeat-dose studies were not undertaken; however it is considered that the proposed formulation and intended use pattern of the product present a low potential for the active constituents to cause harm.

Reproduction and developmental toxicity, neurotoxicity and genotoxicity

No information was provided.

Observations in humans

Mycoses by M. phaseolina and L. pseudotheobromae appear generally to be cutaneous or subcutaneous in nature and often follow some sort of trauma or injury. However, cases of severe eye and sinus infection by L. pseudotheobromae in humans have been recorded in the academic literature where no obvious mode of acquisition or underlying medical condition was present.

Public exposure

No information was provided.

No domestic (general public) exposure is expected for Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina. The intended use of Di-Bak Parkinsonia Bioherbicide is as a bioherbicide for Parkinsonia aculeata trees present in grazing land. The OCS notes that Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina fungal species are already present in trees native to Australia.

International regulations

No information was provided.

Current scheduling status

Di-Bak Parkinsonia Bioherbicide or its component fungal species are not specifically scheduled.

Relevant scheduling history

Di-Bak Parkinsonia Bioherbicide or its component fungal strains have not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

No public submissions were received.

ACCS advice to the delegate

In response to the Delegate's request, the Committee has advised that the product warrants inclusion in Schedule 5 due to infectivity potential, despite exposure risks being minimal due to the formulation presentation and the presence of the fungi in the natural environment. It was noted the fungi are present in concentrated form and thus increases the risks. The Committee advised that warning statements recommended for inclusion under APVMA registration requirements would sufficiently ameliorate risks.

The committee advocated for a new Schedule 5 entries be created for Lasiodiplodia pseudotheobromae, Neoscytalidium novaehollandiae and Macrophomina phaseolina with appropriate exemptions and cut off as follows:

Schedule 5 - New entries

LASIODIPLODIA PSEUDOTHEOBROMAE except when used in capsule preparations at a concentration of 16 CFU or less per capsule.

NEOSCYTALIDIUM NOVAEHOLLANDIAE except when used in capsule preparations at a concentration of 16 CFU or less per capsule.

MACROPHOMINA PHASEOLINA except when used in capsule preparations at a concentration of 16 CFU or less per capsule.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) Potential for the substance to be infective in some individuals; d) the presentation of the active ingredient in capsule form sufficiently reduces exposure to the extent that scheduling is not required if in capsules and labelled in accordance with APVMA labelling requirements.

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 factors12;
  • Other relevant information.
Delegate's interim decision

The delegate notes, and accepts, ACCS advice that the three fungal spores contained in the referred biological herbicide product be listed in Schedule 5, with an exemption cut-off at 16CFU or less in an encapsulated dose form. The delegate notes that this advice is primarily based on the potential infectivity to humans of these naturally-occurring fungi, and that there is no specific SPF guidance on the use of infectivity and/or pathogenicity data in making a scheduling decision. It was also noted that the proposed method of use (insertion of capsules into holes bored in trees) further reduces the risk of exposure to the public, and justifies exempting the specific product from the schedule entry. While these proposals would lead to the scheduling capture of any other product formulated with these three fungi, it is not envisaged that the natural occurrence of any of these fungal strains in the environment would be captured by the schedule entry.

The delegate thinks it necessary to further specify the type of agricultural use as a herbicide, as well as specifying the encapsulated nature of the product, in the schedule entry.

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: (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.

Schedule 5 - New entries

LASIODIPLODIA PSEUDOTHEOBROMAE except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule.

NEOSCYTALIDIUM NOVAEHOLLANDIAE except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule.

MACROPHOMINA PHASEOLINA except when used as a herbicide in capsule preparations at a concentration of 16 CFU or less per capsule.


Footnotes

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

Book pagination