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Final decisions amending, or not amending, the current Poisons Standard, April 2018

Scheduling medicines and poisons

10 April 2018

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4.1 Bacillus amyloliquefaciens MBI 600

Part B - Final decisions on matters not referred to an expert advisory committee

4. Delegate-only decisions on agricultural and veterinary chemicals

4.1 Bacillus amyloliquefaciens MBI 600

Delegate's final decision
Final decision:

The delegate's final decision is to amend the current Appendix B entry for Bacillus amyloliquefaciens, strain QST 713 to remove 'strain QST 713'; thereby creating a group entry for all Bacillus amyloliquefaciens strains and capturing both strain QST 713 and MBI 600. The amended Appendix B and Index entries are as follows:

Appendix B - Amend Entry

BACILLUS AMYLOLIQUEFACIENS

Date of entry: June 2018
Reason for entry: a (Low Toxicity).
Areas of use: 1.3 (fungicide).

Index - Amend Entry

BACILLUS AMYLOLIQUEFACIENS
cross reference: BACILLUS SUBTILIS, STRAIN QST 713; BACILLUS AMYLOLIQUEFACIENS, STRAIN MBI 600

Appendix B, Part 3

Implementation date: 1 June 2018
Reasons:

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate include:

  1. the risks and benefits of the use of a substance:
    • Benefits: B. amyloliquefaciens is a ubiquitous bacterium found in water, soil, air, decomposing plant material, on fresh produce and is widely used for the production of enzymes and specialty chemicals.
    • Risks: Risks posed by B. amyloliquefaciens strains are very low. There may be a small risk to groups susceptible to infection.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • There are a range of benefits for preventing fungal disease in certain food crops.
  3. the toxicity of a substance:
    • The toxicity of strain MBI 600 is essentially identical to strain QST 713 which, in July 2017, was considered by the delegate not to require control by scheduling (Appendix B) due to the low risk of infectivity, pathogenicity and low toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Bacillus amyloliquefaciens is a naturally occurring microorganism with very low infectivity, low pathogenicity and a low risk of causing skin irritancy.
  5. the potential for abuse of a substance:
    • Nil.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Nil.
Applicant's scheduling proposal and reasons for proposal

In November 2017, the Australian Pesticides and Veterinary Medicines Authority (APVMA) submitted a proposal to not include Bacillus amyloliquefaciens MBI 600 in any schedule. A consideration should be given to creating a generic entry for all B. amyloliquefaciens strains in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) - the Poisons Standard.

The applicant's reasons for the request are:

  • B. amyloliquefaciens is a ubiquitous bacterium found in water, soil, air, decomposing plant material, on fresh produce and is widely used for the production of enzymes and specialty chemicals. B. amyloliquefaciens MBI 600 is described as being antagonistic towards fungal plant pathogens via nutrient competition, site exclusion and colonisation.
  • The acute toxicity profile for B. amyloliquefaciens, strain MBI 600 is essentially identical to strain QST 713 with the oral LD50 being >109 viable spores/rat, the dermal LD50 >5050 mg/kg bw in rats (or >2 x 109 cfu/kg bw in rabbits) and the inhalational LC50 being >5310 mg/m3/4 h. There was no evidence of pathogenicity or infectivity in the lungs following intratracheal inoculation and lethality by intravenous administration is low (LD50 >107 spores). B. amyloliquefaciens MBI 600 was not a skin irritant but was a slight eye irritant (probably as a result of the size of the bacillus bacteria) and a skin sensitiser in the guinea pig maximisation test. However, since B. amyloliquefaciens MBI 600 is unable to penetrate the skin barrier due to its size this GPMT result is likely to be a false positive. A Buehler assay, which is better suited to detect sensitisation for occupational exposure, was not performed on the active constituent but was negative for the formulated product.
  • The acute toxicity profile of the formulated product (11% B. amyloliquefaciens MBI 600) was low following oral, dermal and inhalational routes of administration. The formulated product was not irritating or sensitising to the skin (Buehler) but it was a slight eye irritant possibly due to abrasive nature of one of the excipients.
  • B. amyloliquefaciens MBI 600 was negative in an Ames test for mutagenicity.
  • Repeat dose toxicity, carcinogenicity, reproductive toxicity, developmental toxicity and neurotoxicity studies were not performed as it was a microbial preparation.
Current scheduling status

Bacillus amyloliquefaciens MBI 600 is not currently scheduled.

Bacillus amyloliquefaciens strain QST 713 will be included in Appendix B (Reasons: a, low toxicity; Area of Use: 1.3 fungicide) in the 1 February 2018 update of the Poisons Standard.

Scheduling history

Bacillus amyloliquefaciens MBI 600 is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.

Bacillus amyloliquefaciens strain QST 713 was considered by the ACCS in July 2017. The Committee recommended B. amyloliquefaciens strain QST 713 to be included in Appendix B. The reasons for the recommendation were that:

  • The risks posed by B. amyloliquefaciens strain QST 713 are very low. There may be a small risk to groups susceptible to infection;
  • That there are a range of benefits for preventing fungal disease in certain food crops;
  • B. amyloliquefaciens is a naturally occurring microorganism with very low infectivity, low pathogenicity and a low risk of causing skin irritancy. The risks should be mitigated by personal protective equipment worn on mixing/loading and application in accord with APVMA labels; and
  • Worker data shows that B. amyloliquefaciens strain QST 713 is unlikely to be a respiratory sensitiser.

The delegate accepted the committee advice and agreed to place B. amyloliquefaciens in Appendix B on 1 February 2018.

Australian regulations

Bacillus amyloliquefaciens MBI 600 does not appear to be in any products on the Australian Register of Therapeutic Goods (ARTG).

Bacillus amyloliquefaciens MBI 600 does not appear in the current Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.

Bacillus amyloliquefaciens MBI 600 is not currently approved by the APVMA.

International regulations
  • USA: B. amyloliquefaciens MBI 600 (antecedent Bacillus subtilis MBI 600) was registered in 1994 with the US EPA; B. amyloliquefaciens strain D747 was registered in 2011; and B. amyloliquefaciens strain PTA-4838 was registered in 2017. The US EPA lists Bacillus amyloliquefaciens MBI 600 is exempt for pesticide chemical residues in food, including residues resulting from post-harvest uses, when applied or used in accordance with good agricultural practices.
  • EU: B. amyloliquefaciens MBI 600 was approved in September 2016, in accordance with EC No 1107/2009 and EU No 540/2011, at a minimum purity of 5.0 × 1014 CFU/kg. Member States were instructed to pay particular attention to the protection of workers and operators due to B. amyloliquefaciens being considered to be a potential sensitiser.
Substance summary

A structural diagram has not been provided as Bacillus amyloliquefaciens MBI 600 is a whole organism.

Acute toxicity
Table 4.1.1: Acute toxicity end-points for Bacillus amyloliquefaciens
Toxicity Species Bacillus amyloliquefaciens MBI 600 SPF* classification
Acute oral toxicity
LD50 (mg/kg bw)
Rat >5000 -
Acute dermal toxicity
LD50 (mg/kg bw)
Rat >5050 -
Acute inhalational toxicity
LC50 (mg/m3)
Rat >5310 -
Skin irritation Rabbit None -
Eye irritation Rabbit Slight 5
Skin sensitisation (GPMT) Guinea pig Positive 6

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

Repeat-dose toxicity

Repeat dose toxicity studies were not conducted based on the absence of findings in the acute toxicology and infectivity/pathogenicity studies. This is reasonable and appropriate for a non-pathogenic biological active ingredient of this type.

Genotoxicity

No evidence of genotoxicity have been shown to be produced by B. amyloliquefaciens.

Carcinogenicity

No information was available.

Reproduction and developmental toxicity

No information was available.

Clinical observations

EFSA conducted a review update of the safety concerns for the Qualified Presumption of Safety (QPS) status of biological agents that are added intentionally to food and animal feeds including Bacillus species (EFSA, 2013). The observations reported and summarised in the QPS document were considered clinically relevant to the current assessment and addressed reports of claims where B. amyloliquefaciens was a causative agent in clinical cases. The relevant QPS review text is presented below (with minor edits). Collectively, there was no substantive new evidence that confirmed that B. amyloliquefaciens was the causative agent in the clinical reports and also confirmed the existing EFSA position of non-toxigenic/non-pathogenic potential of B. amyloliquefaciens towards humans.

'In total, 230 articles found by relevant search terms were screened. A bacteraemia related to a pacemaker wire infection was caused by B. licheniformis (Idelevich et al., 2012). B. amyloliquefaciens and B. licheniformis were identified as the cause of a bacteraemia in a patient with an oesophageal perforation (La Jeon et al., 2012). Kim et al., (2012) reported a case of bacteraemia caused by B. licheniformis following vertebrotherapy in a patient with a lung cancer. Safety concerns for food producing animals were also considered in the search because 'the body of knowledge about the organisms for which QPS is sought must be sufficient to provide adequate assurance that any potential to produce adverse effects in humans, livestock or the wider environment is understood and predictable' (EFSA, 2007). A Bacillus sp. was isolated from abscesses in several sheep and goats, but authors could not identify the isolates to the species level by phenotypic tests and sequence of 16s rRNA gene (Mariappan et al., 2012). Gangrenous mastitis in several goats was caused by Bacillus spp., one of the isolates was identified B. cereus, but other isolates were not identified at the species level (Mavangira et al., 2013). B. amyloliquefaciens was isolated, together with staphylococcus, from milk of goats with subclinical mastitis (Razi et al., 2012), but without evidence that B. amyloliquefaciens was the cause of the mastitis.

These infections in humans were linked to specific predisposing factors and did not suggest a risk for the consumer via exposure through the food and feed chain. The abscesses reported in sheep were not sufficiently characterised to determine whether Bacillus species from the QPS list were involved. In respect to the report of mastitis in goats, the co-isolation of S. aureus, a well-known agent of mastitis, raised doubt regarding the role of B. amyloliquefaciens in the infection.

Public exposure

A review article on foodborne illness(es) caused by Bacillus species, including some QPS Bacillus species was published in 2012 (Logan, 2012). The outcomes of the review were in line with the previous QPS assessment (EFSA, 2008) concerning the rare implication of QPS Bacillus species in foodborne illnesses, and the likely implication of peptidolipides with toxic activities produced by the responsible strains. Two articles described some biological activities of peptidolipides with biosurfactants produced by B. amyloliquefaciens. A biosurfactant produced by a strain of B. amyloliquefaciens caused epithelium cell vacuolisation and microvilli damage in the midgut of an insect larvae (LC50 approx. 200 ng/mg according to Ghribi et al., 2012) and a B. amyloliquefaciens strain isolated from a Korean fermented soybean paste produced up to 48 mg surfactin per kg in the fermented food, and the surfactin inhibited growth of human breast cancer cells (IC50 10 μg/mL, Lee et al., 2012).

The applicant identified a range of clinically relevant publications in which B. amyloliquefaciens was associated with a range of disease manifestations (Ochoa, 2015, Aoki et al., 2015; Baur & Bakehe, 2014; Hong et al., 2008; Inomata et al., 2007; Long et al., 2014; Pavic et al., 2005; Stickel et al., 2008). Collectively, these publications identified B. amyloliquefaciens as being present along with other possible co-causative agents. The case subjects (human and domestic/farm animals) often had pre-existing conditions or a reasonable likelihood of compromised immune system function. B. amyloliquefaciens was not identified as being associated with a clinical condition in the citations and no citation suggested an association between B. amyloliquefaciens with genotoxic, carcinogenic or reproductive toxicity potential. Broadly, the citations were consistent with the EFSA QPS review summary discussed above.

Please refer to the HHRA technical report for further information on the toxicology of Bacillus amyloliquefaciens.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2018)
  • Other relevant information
Delegate's final decision

The delegate's final decision to be implemented on 1 June 2018 is to amend the current Appendix B entry for Bacillus amyloliquefaciens, strain QST 713 to remove the phrase 'strain QST 713' thereby creating a group entry for all Bacillus amyloliquefaciens strains and capturing both strain QST 713 and MBI 600. The amended Appendix B and Index entries are as follows:

Appendix B - Amend Entry

BACILLUS AMYLOLIQUEFACIENS

Date of entry: June 2018
Reason for entry: a (Low Toxicity).
Areas of use: 1.3 (fungicide).

Index - Amend Entry

BACILLUS AMYLOLIQUEFACIENS
cross reference: BACILLUS SUBTILIS, STRAIN QST 713; BACILLUS AMYLOLIQUEFACIENS, STRAIN MBI 600

Appendix B, Part 3

Reasons for the final decision:

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate include:

  1. the risks and benefits of the use of a substance:
    • Benefits: B. amyloliquefaciens is a ubiquitous bacterium found in water, soil, air, decomposing plant material, on fresh produce and is widely used for the production of enzymes and specialty chemicals.
    • Risks: posed by B. amyloliquefaciens strain MBI 600 are very low. There may be a small risk to groups susceptible to infection.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • There are a range of benefits for preventing fungal disease in certain food crops.
  3. the toxicity of a substance:
    • The toxicity of strain MBI 600 is essentially identical to strain QST 713 which, in July 2017, was considered by the delegate not to require control by scheduling (Appendix B) due to the low risk of infectivity, pathogenicity and low toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Bacillus amyloliquefaciens is a naturally occurring microorganism with very low infectivity, low pathogenicity and a low risk of causing skin irritancy.
  5. the potential for abuse of a substance:
    • Nil.
  6. any other matters that the Secretary considers necessary to protect public health:
    • Nil.

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