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Scheduling delegate's final decisions: ACCS, November 2015
Scheduling medicines and poisons
3.2 BLAD (banda de Lupinus albus doce)
Part B - Final decisions on matters not referred to an expert advisory committee
3. Agriculture and veterinary chemicals
3.2 BLAD (banda de Lupinus albus doce)
In August 2015, the APVMA has referred the proposal to create a new entry for BLAD in Appendix B for use as a biofungicide on various crops and ornamentals for consideration by the delegate for inclusion in the SUSMP.
The reasons for the request are:
- the substance is proposed to be used in a biofungicidal product
- the product contains 20 per cent of the active substance BLAD
- the product is expected to have low acute oral, dermal and inhalational toxicity
- the product is expected to be a mild eye irritant, a slight skin irritant and is not a skin sensitiser
- the US EPA regulations for use of this substance was an exemption from the requirement of a tolerance for residues of BLAD in or on food commodities when applied as a fungicide and used in accordance with label directions and good agricultural practices. This was due to reasonable certainty that no harm to the population will result from aggregate exposure to residues of BLAD.
The toxicology data and other information on the product provided and considered during this assessment justify the Safety Directions established. The information on the product provided and the additional information considered in this assessment was used to evaluate the additional use patterns. The proposed use of the product will not be an undue health hazard to humans according to the criteria stipulated in Section 14 of the Ag/Vet Code Act of 1994.
The applicant has applied for approval of a new active constituent (BLAD) and registration of the associated product and approval of the product label (Category 2 Application). The applicant has submitted Part 3 (toxicology) and Part 6 (OHS) data for assessment. The APVMA has requested an assessment of the toxicity and OHS of the active and the product and recommendations (if any), for health standards, scheduling and/or labelling e.g. safety directions.
The active constituent is a polypeptide termed BLAD (from the Portuguese 'banda de Lupinus albus doce' or band from sweet Lupinus albus). BLAD is a naturally-occurring seed storage protein, which accumulates exclusively in the cotyledons of Lupinus species (for example, Lupinus albus), between days four and twelve after the onset of germination. It is a 20 kDa polypeptide of β-conglutin, or characterized as a fragment of the amino acid sequence of β-conglutin. The β-conglutin protein is classified as a 7S globulin which is part of the broader family of cupin proteins, which provides a major nitrogen source for germination of the developing plant.
The product is a non-systemic biofungicide applied as a foliar spray with claimed strong antifungal activities both for prevention and control.
The biochemical pesticide is manufactured as an end-use product with neither isolation of the technical grade active constituent nor formation of a manufacturing product (MUP). The product contains 20% of the active ingredient, BLAD (pure active constituent). The product is intended to be registered as a new biofungicide for the control and suppression of powdery mildew, botrytis, anthracnose and other fungal diseases in various crops and ornamentals and can be used as a foliar spray alone, in alternating spray programs or in tank mixes with other registered pesticides using conventional spray equipment.
The active ingredient and the formulated product fungicide are effectively equivalent formulations. While the product contains added adjuvants which comprise 14% of the formulation, there is removal of the aqueous solvent during manufacture so that the concentration of the BLAD active constituent remains unchanged at 20% (w/w) for both the TGAC and the formulated product. On this basis the toxicity profile of BLAD and the fungicide are considered identical as the only difference between them is a change in the concentration of inert non-reactive ingredients (described as a commonly used surfactant and an antifoam).
The mechanism of fungicidal action by BLAD is an important determinant of its lack of mammalian toxicity. BLAD, used as a fungicide, is a naturally occurring 20 kilo Dalton (kDa) polypeptide of β-conglutin formed during days 4 to 12 of the germination process of the flowering plant, sweet lupines (Lupinus albus). It is also characterized as a fragment of the amino acid sequence of β-conglutin and the main storage protein in sweet lupines providing a major nitrogen source for germination of the developing plant. Lupines albus, commonly known as white or sweet lupine or lupin, is a member of the genus Lupinus in the family of Fabaceae. Lupines albus contains the full range of essential amino acids and for hundreds of years has been widely cultivated worldwide, thus sweet lupines have a long history of safe use in human and livestock consumption without any adverse effects. BLAD is directly extracted from the flowering plant, sweet lupines. It has a dark brown colour with a sweet odour and is stated to be 60% biodegradable within 14 days after application. Physicochemical information is provided at Appendix 1.
The product is a non-systemic biofungicide with claimed strong antifungal activities making it useful for prevention and control of fungal infections such as powdery mildew and grey mould on fruit, vegetable and ornamental crops and blossom blight on stone fruit. The non-toxic mode of action is described as binding very strongly to chitin in fungal cell walls, inhibiting any fungal growth. The active ingredient degrades chitin by catalysing the removal of the N-acetyl-D-glucosamine terminal chitin monomers, and destroying the fungal cells.
As noted, the TGAC and product can be considered equivalent in toxicity. The acute toxicity of the fungicide in laboratory animals was low via the oral, dermal, and inhalation routes of exposure. The fungicide is mildly irritating to the skin and eyes but is not a dermal sensitizer.
The applicant has provided copies of waiver requests made to the United States Environmental Protection Agency (USEPA) seeking exemption from the need to provide various studies as follows: 90-Day Oral, 90-Day Dermal, 90-Day Inhalation, Prenatal Development, Bacterial Reverse Mutation Test, In vitro Mammalian Chromosome Aberration. The arguments provided by the applicant were uniformly that: the active ingredient is a naturally occurring product with a history as a food and feed item (sweet lupines), it has very low acute toxicity by any route, is rapidly biodegraded (60% is biodegradable within 14 days in the environment) and its use according to label directions will lead to negligible subchronic exposure. These arguments were considered reasonable and have been accepted by other regulatory agencies.
Reproductive, developmental and chronic toxicity and carcinogenicity
No long term toxicology or carcinogenicity studies have been conducted on BLAD and the applicant seeks a waiver to the requirements for these studies using the same arguments as for the lack of subchronic studies, i.e. that the active ingredient is a naturally occurring product with a history as a food and feed item (sweet lupines), it has very low acute toxicity by any route, is rapidly biodegraded and its use according to label directions will lead to negligible chronic exposure. In particular, dietary risks to humans are considered negligible, based on the lack of dietary toxicological endpoints for BLAD and its nontoxic mode of action as a fungicide. These arguments were considered reasonable and have been accepted by other regulatory agencies.
Additionally, both USEPA and the Canadian Pest Management Regulatory Agency (PMRA) reviewed studies pertaining to the chronic exposure of lupine products. Ballester et al (1984) reported a study of the potential reproductive and developmental toxicity of lupin protein. In that study, sweet lupine flour was fed for 9 months to two generations of rats (F1 and F2) at a level that provided 20% dietary protein. The diets were supplemented with 0.2% DL-methionine. The lupine diet had no effect on the general condition, mortality or behaviour of the animals. The growth rate of males fed sweet lupine was significantly higher than that of the controls. Haematological parameters and tests of liver function were normal in all treatment groups. At autopsy there were no significant changes in the weight of the heart, kidney, spleen, brain and gonads but the relative weight of the liver of lupine-fed rats was significantly lower than that in the controls. However, there were no histological changes in these livers. The lupin protein was reported to have no effect on either fertility or reproductive parameters in any of the generations.
Chronic life-time studies (i.e. 700 and 800 days) in rats fed sweet lupin seeds did not reveal any evidence of carcinogenicity in lupin-treated animals, and no signs of toxicity or decreases in body weight occurred (Grant et al, 19933; Grant et al 19954).
Food Standards Australia New Zealand (FSANZ) has expressed concern about possible food allergies arising from consumption of lupins but has yet to undertake regulatory action. PMRA notes increasing reports of allergy resulting from the use of lupine derived seed products in prepared foods, indicating some concern that the germinated sweet lupine seed extract in the product may also be allergenic. Based on informatics, susceptibility to protease digestion, and estimates of dietary intake, BLAD polypeptide is expected to be of low potential to cause allergic reactions and to cross-react with known allergens from other legumes, such as peanuts and soybean. PMRA notes that the proteins (conglutins) in lupine seed that are responsible for allergic reactions in sensitive individuals are not present.
As no chronic studies have been conducted on BLAD no appropriate toxicology endpoints have been established for deriving an ADI or ARfD. Given the minimal exposure during short-term use and the expected lack of residues on crops there is no need for these health guideline values.
Selection of a NOEL for OHS Risk Assessment
Occupational exposure to the product is characterized as short-term and is predominately by the dermal and inhalation routes as it is mildly irritating to the eyes and to the skin. Dermal absorption of BLAD polypeptide is not expected.
The USEPA has approved and the PMRA is about to approve products containing BLAD.
USA EPA: In March 2013, the US EPA established an exemption from the requirement of a tolerance for residues of BLAD in or on all food commodities when applied as a fungicide and used in accordance with label directions and good agricultural practices. In establishing this exemption from the requirement for a pesticide chemical residue in or on a food, the USEPA stated that:
"All of the data requirements to support a tolerance exemption were fulfilled by the applicant. EPA concluded that the data are acceptable and no additional data are required. No acute, subchronic, or chronic toxicity endpoints were identified in guideline studies or in data obtained from open technical literature. Moreover, BLAD is not a mutagen, and is not a developmental toxicant. There are no known effects on endocrine systems via oral, dermal, or inhalation exposure."
"BLAD has the following properties and characteristics: BLAD is used in human and animal nutrition as a food and feed item; and ii. BLAD has a nontoxic mode of action against fungal pests and 60% is biodegradable within 14 days in the environment, thereby minimizing any potential for toxic risk, such that there is no concern for potential exposure.
In April 2013, The U.S. EPA granted registration for the Food Machinery Corporation (FMC) end use product Fracture containing BLAD as a fungicide for use on grapes, stone fruit, strawberries and tomatoes.
The Pest Management Regulatory Agency of Canada published a Proposed Registration Decision (PRD) for BLAD on 6 February 2015. This PRD states that:
"BLAD polypeptide is unlikely to affect human health when it is used according to label directions. Potential exposure to BLAD polypeptide may occur when handling and applying the end-use product. In laboratory animals, the acute toxicity of the end-use product containing BLAD polypeptide, was low via the oral, dermal, and inhalation routes of exposure. Product is mildly irritating to the skin and eyes; ...and is not a dermal sensitizer. ...A request to bridge acute toxicity data from the end-use product to the technical grade active ingredient was considered to be acceptable. The active ingredient, BLAD polypeptide, was considered to be of low acute toxicity via the oral, dermal, and inhalation routes of exposure. ...BLAD polypeptide is not expected to cause effects in developing young or to cause damage to genetic material when used according to the label instructions. ...Occupational risks are not of concern when used according to the proposed label directions, which include protective measures."
BLAD is not specifically scheduled.
BLAD has not been previously considered for scheduling therefore scheduling history is not available.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- Public submissions received;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors17;
- Other relevant information.
Delegate's final decision
Appendix B - New Entry
BLAD (banda de Lupinus albus doce)
Part 1: Reasons for entry a – low toxicity
Part 2: Areas of Use 1.3 - fungicide
Reasons for delegate's decision
The low toxicity profile of this product does not suggest any need to list it any of the Schedules of the Poisons Standard. This is reinforced by the fact that systemic exposure to this polypeptide has occurred through food consumption of sweet lupins. Accordingly, the delegate accepts the recommendation of the OCS evaluation report that scheduling is not required, and that a listing in Appendix B be developed to signify this decision.
The delegate decided that the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 include (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.
The implementation date is 1 February 2016.