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

Scheduling medicines and poisons

17 May 2017

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3.7 Aureobasidium pullulans (strains DSM 14940 and DSM 14941)

3. Advisory Committee on Chemicals Scheduling (ACCS #19)

3.7 Aureobasidium pullulans (strains DSM 14940 and DSM 14941)

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a Schedule 5 entry for Aureobasidium pullulans (A. pullulans) (strains DSM 14940 and DSM 14941) with no exemption cut-offs.

Current scheduling status and relevant scheduling history

A. pullulans is not currently scheduled and has not been previously considered for scheduling; therefore a scheduling history is not available.

Scheduling application

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

Schedule 5 - New Entry

AUREOBASIDIUM PULLULANS.

The applicant's reasons for the request are:

  • A. pullulans is a saprophytic fungus (feeding on dead and decaying organic matter) ubiquitous in the environment, readily isolated from soil, decaying vegetation, wood, air, shower curtains and other damp surfaces. Background levels of the organism on apple leaves for example are approximately 104 to 105 Colony Forming Units (CFU - i.e. viable organisms) per gram dry weight.
  • The proposed fungicide consists solely of the freeze dried fermentation liquid containing the cultured strains of A. pullulans (DSM 14940 & 14941) and food grade constituents that act as drying and granulating aids.
  • The fungicide is intended for use as a fungicide for the prevention of Botrytis cinerea infection of grapes through spray application, at a maximum rate of 1 kg/ha. XXX fungicide contains 5 x 109 CFU/g of A. pullulans mixed strains DSM14940 and DSM14941. The fungicide will be applied to vineyards as a foliar spray after dilution of the product (wettable granule) in water by vineyard workers. The fungicide is not proposed for home garden use or for use in urban environments.
  • In support of the application the applicant has submitted acute toxicity studies on a European Registered product, XXXX, which contains the same two strains at approximately 2.5 x 109 CFU per strain making up 44%, with the balance of that product consisting of food grade non-active constituents.
  • XXXX protect has low acute oral & dermal toxicity in rats (LD50 > 2000 mg/kg bw and > 6 x 109 CFU/kg, respectively) producing no deaths or signs of toxicity or infectivity at the limit doses. A 10% suspension of XXXXX in water had an LC50 of > 5170 mg/m3 with no deaths and no clinical signs of toxicity or infectivity, however the actual concentration of the product in the air was only 497 mg/m3 (1.5 x 109 CFU /m3). The product was not a skin or eye irritant in rabbits but was a moderate skin sensitiser in Guinea pigs by the Buehler method. XXXXX was not genotoxic in the mouse in vivo micronucleus assay. When XXXXX was administered subcutaneously to rats at 2000 mg/kg bw (3 x 109 CFU/kg bw) 1/5 males had to be euthanised at day 5 due to massive inflammation at the injection site, but all other animals survived to scheduled sacrifice. In all animals, the spleen was visibly enlarged, and mature puss filled abscesses were present at the injection sites. These observations reflect both route of administration and the large quantity of foreign biological materials injected rather than infection or pathogenesis per se.
  • A. pullulans strain DSM 14941 was not infectious, toxic or pathogenic when administered to rats by the oral (4 x 108 CFU), subcutaneous (107 CFU), or intratracheal routes (0.8 x 108 CFU) and viable organisms did not persist at the site of administration or migrate to other tissues. Following intratracheal administration, viable spores were isolatable from the lungs only at 3 hours after administration but were not present at or after 3 days. Acute pulmonary inflammation was observed at 3 hrs and 3 days after application, progressing towards resolution by day 21.
  • As A. pullulans is an ubiquitous non-pathogenic/infectious fungi that does not produce toxins or antimicrobials, studies of carcinogenicity, reproductive, developmental and neuro-toxicity are not required and have not been provided.
  • When isolated from human clinical specimens A. pullulans is generally considered to be a laboratory contaminant, but under specific circumstances where the patient is debilitated or immune-suppressed some strains of this organism have infrequently been identified as pathogens. Pathogenic strains, where investigated, are able to grow at, or close to, body temperatures whereas strains isolated from the environment are generally unable to grow or survive at temperatures above 30 - 35°C or so, as has been shown to be the case for the two strains in the fungicide. No skin or pulmonary sensitisation or allergenic response of, or clinical findings in, any of the production or agricultural workers handling the fungus or XXXXX have been observed.
  • XXXXX is registered in Europe and both the fungicide and XXXXX have been registered in the USA. Neither jurisdiction has considered the establishment of an ADI or ARfD to be required for Aureobasidium pullulans DSM 14940 & 14941.
Australian regulatory information

There is one product (registered medicine) on the Australian Register of Therapeutic Goods (ARTG) that contains A. pullulans. The indicated use of the product is for the diagnosis and treatment (hypo-sensitization therapy) of patients who experience allergic symptoms.

According to the TGA Ingredient database, A. pullulans is available for use as an Active Ingredient in Export Only, List Medicines, Over the Counter and Prescription Medicines. It is also available for use as a homeopathic ingredient in Listed Medicines and as an Excipient and Equivalent Ingredient in Prescription Medicines.[89]

A. pullulans is listed on the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017, permitted for use as an Active and Homeopathic preparation Ingredient. There are no specific requirements specified in the determination.

International regulations

A. pullulans is registered for use as a fungicide in the USA (January 2012) and Canada (December 2012) for the control of botrytis in grapes. It is also registered in New Zealand (June 2015) for control of fire blight in pip fruit and control of Psa in kiwifruit.

A. pullulans has been registered by the European Food Safety Authority (EFSA) for control of fire blight in pome fruit with appropriate personal protective equipment (PPE) requirements.

A. pullulans is unclassified in New Zealand.

Substance summary

The genus Aureobasidium includes between 14 and 26 named species depending on the consulted registry. Among these, A. pullulans is the only well-known species, of which two well documented varieties are associated with indoor environment and health problems: A. pullulans var. pullulans and A. pullulans var. melanogenum. On the other hand, the fungal database of the International Mycological Association lists 6 varieties of A. pullulans.

Aureobasidium pullulans is an ubiquitous saprophyte mould, which is generally considered as an environmental contaminant. It is most common in temperate zones with numerous recordings from the British Isles and the USA, but also found in Canada, Alaska, Antarctica, Europe and Russia. It is found in forest soil, freshwater, aerial portions and on leaf surfaces of plants as well as on seeds (wheat), cereals (barley, oats) and some nuts such as pecans. It is also found as spoilage agent on fruits (pears, grapes and tomatoes) or in fruit drinks. It has been associated with the deterioration of pears and oranges in storage or in transit.

A. pullulans is commercially used for the production of pullulan, a linear homopolysaccharide of glucose (α-(1→6) maltotriose). Together with its derivatives, Aureobasidium pullulans has a range of uses in foods, pharmaceuticals, manufacturing, and electronics, such as un-derivatised films which readily dissolve in water and which can be used as edible food coatings.

Table 3.7A: General information
Property A. pullulans
CAS names N/A
CAS numbers N/A
IUPAC and/or common and/or other names Aureobasidium pullulans DSM 14940, CF10; Aureobasidium pullulans DSM 14941, CF40; Pullularia pullulans Fungus; A. pullulans
Approved Herbal Name (AHN) Aureobasidium pullulans
Taxonomy

Kingdom: Fungi

Phylum: Ascomycota

Class: Dothideomycetes

Order: Dothideales

Family: Dothioraceae

Genus: Aureobasidium

Species: Pullulans

XXXXX consists solely of the freeze dried fermentation liquid containing the cultured strains of A. pullulans (DSM 14940 & 14941) and food grade constituents that act as drying and granulating aids.

The strains were isolated at the University of Konstanz in 1989 from apple leaves of an untreated apple plantation (Malus sylvestris var. domestica cv. "Golden Delicious") and were designated CF10 and CF40. The manufacturing code has designated CF10 as Aureobasidium pullulans DSM 14940, and CF40 as Aureobasidium pullulans DSM 14941.

Table 3.7B: Acute toxicity end-points for A. pullulans strains DSM14940 and DSM14941
Toxicity Species Result[90] SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 mg/kg bw Schedule 5 / Appendix B
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 mg/kg bw Schedule 5 / Appendix B
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >5170 mg/m3 for a 10% suspension in water Schedule 5 / Appendix B
Skin irritation Rabbit Not irritant Nil
Eye irritation Rabbit Not irritant Nil
Skin sensitisation (Buehler) Guinea Pigs Moderate sensitiser Schedule 5 or Schedule 6

A technical report for the toxicology of A. pullulans strains DSM14940 and DSM1494 was provided to the committee and the delegate.

Mutagenicity

Not mutagenic in vivo (mouse micronucleus test).

Public exposure

Specific toxicity, pathogenicity and infectiveness studies were not provided.

Pre-meeting public submissions

One (1) public submission was received, which supported the proposal due to purported low toxicological profile and that it is not an infective agent.

Summary of ACCS advice to the delegate

The committee advised that a new Appendix B entry be created.

Appendix B - New Entry

AUREOBASIDIUM PULLULANS (Strains DSM14940 and DSM14941).

The committee also advised an implementation date of 1 October 2017.

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; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice comprised the following:

  • There are no known cases of skin sensitisation or pulmonary hypersensitivity to the two strains of A. pullulans being considered.
  • There is a wide range of benefits from the use of pullulans manufactured using A. pullulans. Pullulans is used in a wide range of products including in food, cosmetics, pharmaceuticals, electronics and biomedical applications.
  • The toxicity of A. pullulans is very low to nil with no evidence of skin or eye irritancy. A. pullulans is not mutagenic, pathogenic or infective and does not product toxins or active metabolites. A. pullulans is a moderate skin sensitiser (Buehler method); however there are no known reports of occupational sensitisation despite industrial and farm use.
  • Risk of sensitisation to A. pullulans can be mitigated through personal protective equipment controlled through APVMA labelling regulations.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACCS advice
  • Public submissions received
  • 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 for Aureobasidium pullulans. The proposed Schedule entry is as follows:

Appendix B - New Entry

AUREOBASIDIUM PULLULANS (Strains DSM14940 and DSM14941).

The proposed implementation date is 1 October 2017.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the 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 the following:

  • The delegate acknowledges the committee's advice.
  • There are no known cases of skin sensitisation or pulmonary hypersensitivity to the two strains of A. pullulans being considered.
  • There is a wide range of benefits from the use of pullulans manufactured using A. pullulans. Pullulans is used in a wide range of products including in food, cosmetics, pharmaceuticals, electronics and biomedical applications.
  • The toxicity of A. pullulans is very low to nil with no evidence of skin or eye irritancy. A. pullulans is not mutagenic, pathogenic or infective and does not product toxins or active metabolites. A. pullulans is a moderate skin sensitiser (Buehler method); however there are no known reports of occupational sensitisation despite industrial and farm use.
  • Risk of sensitisation to A. pullulans can be mitigated through personal protective equipment controlled through APVMA labelling regulations.

Footnotes

  1. Note: Only the name and definition of a substance have been reviewed to allow it to be included in the ingredient repository. The approval for use of the ingredient in therapeutic goods is a decision made by the relevant TGA regulatory area. This approval process may require submission of further information, for example safety data for the ingredient or for the finished goods, to meet legislative and regulatory requirements.
  2. Based on the product, XXXX, containing 2 x 109 CFU/g of each of DSM14940 and 14941.

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