Guideline for the regulation of biological agricultural products

1. Introduction

1.1. Certain biological products must be registered

The Australian Pesticides and Veterinary Medicines Authority (APVMA) assesses and registers agricultural and veterinary chemical products. A number of products of biological origin fall into the Agvet Code definition of an agricultural chemical product and therefore must be registered by the APVMA. In this document, these are referred to by the term 'biological agricultural product'.

1.2. The need for biological agricultural products

In many cases, biological products have different properties from conventional chemical products and therefore these separate guidelines and data requirements have been prepared to address the potential risks posed by biological agricultural products.

Many biological pesticides have a narrow host range. They may target specific pests, exhibit limited non-target effects and thus pose minimal adverse effects on humans and the environment. In the case of products that are degraded relatively readily in the environment, biological products may pose minimal long-term environmental effects. The APVMA recognises that, due to their inherently lower risk, some biological products may be more desirable than some synthetic pesticide chemicals. However, not all biological products are necessarily safer products and it is the responsibility of the APVMA to evaluate fully the risks associated with agricultural chemical products.

1.3. Flexibility and case-by-case approach

The APVMA recognises the need for flexibility in determining the data requirements for biological products. These guidelines allow for full implementation of any product that may give cause for concern, and these products will be evaluated on a case-by-case basis.

Biological products are not always as efficacious as synthetic pesticides and it may be sometimes necessary to trade off efficacy against other factors, for example, compatibility with organic farming systems or reduced environmental persistence.

These guidelines should be considered as guidelines and not as absolute requirements. If certain data are not considered necessary, relevant scientific arguments for their omission must be put forward.

1.4. Products covered by other legislation

Some agricultural chemical products are also covered by other legislation. Applications for the following groups of products must also satisfy the requirements of the following legislation:

• Biological control agents – Biosecurity Act 2015
• Genetically modified organisms – Gene Technology Act 2000 (Cwlth)
• Imported biological agents – Biosecurity Act 2015

The APVMA consults with the Office of the Gene Technology Regulator (OGTR) on any application for registration or permit for a product that is or contains, a genetically modified organism (GMO) or any product derived from a GMO. Further details on the role and function of the OGTR are available at ogtr.gov.au.

Imported biological agents require a permit from the Department of Agriculture, Fisheries and Forestry (DAFF) before they can be brought into Australia. Further information about the importation of biological products is available on the DAFF website.

2. What are biological agricultural products?

2.1. Definition

A biological chemical product is an agricultural chemical product where the active constituent comprises or is derived from a living organism (plant, animal, micro-organism, etc.), with or without modification. This includes many products that are commonly referred to as 'botanicals', 'organics' or 'herbals' (where the active constituent comprises an extract derived from an organism rather than the whole organism, it may be accompanied by unidentified components).

Applicants must check that their product is regarded by the APVMA as a biological agricultural product before adopting these biological product data requirements. Applicants should seek advice from the APVMA if they are unsure about how a product will be assessed.

There are 4 major groups of biological products:

• Group 1: biological chemicals (pheromones, hormones, growth regulators, enzymes and vitamins).
• Group 2: plant and other extracts (plant extracts, oils).
• Group 3: microbial agents (bacteria, fungi, viruses, protozoa).
• Group 4: other living organisms (microscopic insects, plants and animals plus some organisms that have been genetically modified).

Each of these groups of biological products is described in detail in Section 3.

2.2. Products not regarded to be biological chemical products

2.2.1. Products characterised as conventional agricultural chemical products

If the active constituent of a product is a biologically-derived chemical that has direct toxicity to the target species and can be purified, fully identified and a residue detection method applied, the product is not classed as a biological chemical product. Examples include products based on nicotine, strychnine, rotenone and ivermectin. Data requirements for these products are the same as those for agricultural chemical products as described elsewhere in the Regulatory Guidelines.

2.2.2. Specific exemptions

Certain classes of product are specifically exempted from registration under Schedule 3 of the Agvet Code Regulations. These include soil ameliorants, fertilisers, some classes of pest management lures, domestic disinfectants, hay, silage or legume inoculants based on bacteria or enzymes, cut flower preservatives, predatory insects, predatory mites and macroscopic parasites.

2.2.3. Plant growth-stimulating products

Plant growth-stimulating products that are not for pest control or specific growth regulation are covered under state/territory fertiliser regulations and need not be registered by the APVMA. However, products based on plant hormones must be registered.

2.2.4. Higher plants

While higher plants are not agricultural chemicals products, genes inserted in the genome of plants may require registration. Inserted genes that code for the production of pesticidal substances are considered to be a pesticide and must be registered (see Section 3.4). For example, the genes present in the genetically modified Bollgard II cotton which express the CryIAc and CryIIAb toxins of Bacillus thuringiensis are registered as a biological agricultural chemical product.

Other genetically manipulated plants do not require registration but may have implications that lead to registration by the APVMA. For example, herbicide-tolerant plants do not fall under the definition of an agricultural chemical product and therefore need not be registered. However, where the use pattern of a chemical product changes in association with a genetically modified crop plant, the APVMA will assess the new use pattern of the chemical. For example, glyphosate-tolerant soybeans could result in glyphosate use in that crop and glyphosate products would require assessment of a major new use for the products.

Similarly, the incorporation of genes that modify the physiology of a plant does not necessarily require regulation by the APVMA unless there are further implications that bring the plants within the definition of an agricultural chemical product.

2.3. Products based on GMOs

Products from any of the groups listed above can consist of, or be derived from, naturally occurring organisms – those which are produced by traditional breeding techniques or modified by genetic engineering techniques.

Products based on GMOs will have an extra data requirement for information concerning the genetic manipulation. Applicants must provide details about the:

• host organism
• donor organism
• genetic engineering techniques used in the genetic modification
• identity of the inserted or deleted gene segment (base sequence data or enzyme restriction map of the gene)
• information on the control region of the gene in question
• description of the new traits or characteristics that are intended to be expressed
• tests to evaluate genetic stability and exchange
• environmental expression and toxicology tests.

3. Groups of biological agricultural products

3.1. Group 1: biological chemicals

Biologically derived chemicals with indirect toxicity or modifying effects in target species (i.e. a mode of action other than direct toxicity) comprise one major group of biological products. This group includes pheromones, hormones, growth regulators, enzymes and vitamins. The detailed data requirements for biologically derived agricultural chemicals are listed in Section 4.

3.1.1. Semiochemicals

Pheromones belong to the class of compounds known as semiochemicals. Semiochemicals are chemicals emitted by plants or animals that modify the behaviour of receptive organisms of like or different kinds of plants or animals. Use of semiochemicals usually result in less exposure to humans and the environment than conventional pesticides because of:

• very low application rates
• high volatility
• application in bait, trap or encapsulated formulation.

These factors, as well as their potential for low toxicity, will be taken into account in determining data requirements for individual products. The APVMA will decide on a case-by-case basis whether synthetically derived analogues that mimic naturally occurring pheromones could be considered as biological products for the purpose of determining data requirements.

3.1.2. Hormones and growth regulators

Hormones are biochemical agents that are synthesised in one part of an organism and transported to another part of the same organism where they have controlling, behavioural or regulating effects.

Plant hormones include the natural plant regulators, which are chemicals produced by plants that have inhibitory, stimulatory or other modifying effects on the same or other species of plants. Insect growth regulators are chemicals that have inhibitory, stimulatory or other modifying effects on the insect growth cycle.

3.1.3. Enzymes and vitamins

Enzymes are natural substances produced by all living cells. All living organisms depend on enzymes to regulate energy-releasing reactions, synthesise the building blocks of cells and regulate virtually all other physiological processes.

Enzymes are high molecular-weight proteins composed of amino acids. They may also contain non-protein parts such as carbohydrates, lipids, phosphate groups and metallic ions.

For the purposes of these guidelines, enzymes are defined as naturally occurring or genetically modified protein molecules that are the instrument for expression of gene action and that catalyse chemical reactions. This definition of 'proteins' includes peptides and amino acids but does not include toxic proteins such as endotoxins or exotoxins (to which normal agricultural chemical product data requirements apply).

The safety of enzyme products can be evaluated with respect to:

• potential risk to the environment in which the micro-organisms and/or their products are released
• possible health hazard for the staff working with the product
• safety of use on target plants.

Because enzymes are readily biodegradable, their environmental release is unlikely to cause any environmental problems. Furthermore, the containment of the production organism itself is controlled by the physical nature of the fermentation system and by the production organisms having been adapted to grow only under defined fermentation conditions.

Some occupational health risks may arise from the handling of enzyme preparations. Enzyme dusts may lead to respiratory allergies in susceptible individuals while certain proteases may cause irritation to the skin, eyes or mucous membranes. These risks can be avoided by protective measures and the use of specific formulations of the enzyme preparations.

To ensure human safety the microbial enzymes must be obtained from non-pathogenic and non-toxicogenic micro-organisms grown on raw materials that do not contain components that might be hazardous to human health.

Safety to target plants must also be demonstrated in appropriate trials.

Products based on vitamins also require registration with the APVMA. Data requirements for vitamins are similar to those for synthetic agricultural chemical products, other than recognised human vitamins.

3.2. Group 2: plant and other extracts

The second major group of biological agricultural products includes unpurified or partially purified extracts derived from plants or other organisms including oils or other extracts. Plant oils that cannot be totally characterised are classed as biological products. Similarly, plant extracts where the level of purification is incomplete and the chemical composition of the active constituent cannot be fully characterised are classed as biological products. For example, natural 'pyrethrum' may consist of a chemical mixture of a number of related pyrethrins. 'Neem oil' may consist of a mixture of several different chemical entities and 'neem extract' similarly may consist of a mixture of chemical components, some characterised and others not characterised. Some of these compounds may be of biological (and/or toxicological) significance while other compounds may be considered as inert.

For detailed data requirements for plant and other extracts see Section 4.

3.2.1. Plant extracts

It may be difficult to characterise every constituent present for this group of products, but applicants must provide as much information as possible.

In cases where biologically derived chemicals are poorly characterised and the purity and amounts of contaminants are unavailable, Part 2: Chemistry and Manufacture of the application must include all known details of the composition of the active constituent and the formulated product. In this situation, quality control of the product is very important. Applicants must demonstrate adequate batch analysis and process control and confirm that they can produce a consistent product that meets product specifications.

Additionally, the composition of the material used in the toxicology and other studies must be clearly identified and must conform closely to the declared composition of the extract to be used in the manufactured product.

Product labels must carry an active constituent statement that specifies the identity and concentration of the active constituent present. Applicants must propose a suitable active constituent statement for inclusion on their product label. Proprietary names for active components are not acceptable.

Stability data are required for all agricultural products to either demonstrate that the formulated product will remain within specification for at least 2 years at or above 25˚C or to provide data to support a shelf life period or additional storage instructions for that product.

3.2.2. Essential oils

Essential oils are the plant oils responsible for the odours of many aromatic plants. They consist of mostly terpenoids, but also include aliphatic and aromatic esters, phenolics and substituted benzene hydrocarbons. They may include:

• flavour and fragrance materials that are not steam distilled
• fragrances, flavour concentrates and perfumes.

Some synthetic substances that are not found in nature have at times been regarded as essential oils. The APVMA would consider these to be conventional chemical products to which the data requirements for an agricultural chemical product would apply.

Essential oils have traditionally been used in insect repellent and medicinal products over a long period of time – in some cases despite a lack of toxicology data. In some cases, a well-documented history of the safe use of such a substance can support its approval in an agricultural chemical product.

However, it should be recognised that some essential oils are intrinsically quite toxic so mere characterisation as an essential oil should not be presumed to equate with low toxicity. Some essential oils are scheduled poisons.

3.2.3. Food products

Extracts that are prepared from products generally regarded as human foods (for example garlic, chilli, vegetables) may be exempted from full data requirements when they are used in concentrations similar to those of the food product. Thus, a garlic or cabbage extract at physiological concentration may be considered to be of little health concern.

Purified and concentrated extracts from a food product, on the other hand, may pose risks that would necessitate a fuller data package; for example, a concentrated garlic or chilli extract may require detailed toxicological and occupational health and safety evaluation or relevant scientific argument in place of specific data requirements.

3.2.4. Other extracts derived from organisms

Other extracts derived from organisms will be considered on a case-by-case basis depending on the nature of the extract.

3.3. Group 3: microbial agents

The products referred to as microbial agents include (but are not limited to) naturally occurring or genetically modified micro-organisms, including bacteria, fungi, viruses, protozoa, microscopic nematodes or other microbial organisms. Macroscopic organisms can also be biological agricultural products, but macroscopic predators and parasites, including entomopathogenic nematodes, are excluded (see Section 2.2.2).

Microbial pest control agents may survive and reproduce in the environment and may infect other living organisms. Thus, the basic testing requirements are designed specifically to detect the potential to exhibit any of these characteristics. Requirements for further testing emphasise exposure or environmental expression in addition to expanded testing of infectivity and pathogenicity.

For detailed data requirements for microbial agents, see Section 5.

3.3.1. Microbial pesticides (viable)

The data requirements for microbial pesticides are designed to give basic hazard and exposure information for the micro-organism. If the microbial pesticide under consideration is taxonomically similar to a clinically or agriculturally significant micro-organism, its properties and effects must be examined in greater detail than suggested by the tests generally required.

The overall level of risk posed by a microbial pesticide used in agriculture is related to the possible hazards associated with the organism and the degree of exposure to humans and the environment. Potential hazards of microbial agents include toxin production, pathogenicity/infectivity, host range expansion and competition with existing microbial flora. Exposure factors include survival of the organism, replication in the environment, dissemination, persistence and horizontal gene transfer. Unreasonable risks include adverse effects on humans, commercially/economically important species, ecologically important plant and animal species and endangered plant and animal species. The origin of the microbial organism is also important, with organisms from overseas countries requiring closer scrutiny than Australian indigenous organisms.

3.3.2. Microbial pesticides (nonviable)

Microbial pesticides that have been rendered nonviable may be subject to special testing requirements depending on the specific characteristics of the micro-organism.

3.3.3. Genetically modified microbial pesticides

Genetically modified microbial pesticides will be subject to additional data or information requirements on a case-by-case basis depending on the particular micro-organism, its parent micro-organism, the proposed pesticide use pattern, and the manner and extent to which the organism has been genetically modified. Additional requirements may include information on the genetic engineering techniques used, the identity of the inserted or deleted gene segment (base sequence data or enzyme restriction map of the gene), and the control region of the gene in question. Descriptions of the 'new' traits or characteristics to be expressed, tests to evaluate genetic stability and exchange, and/or selected environmental expression and toxicology tests may also be required. Each new isolate of a microbial pesticide will generally be considered to be a new active constituent. If a subject isolate is sufficiently similar to a previously registered isolate, a case can be made for reduced data subject to any limitations on the use of data from the registered isolate.

Major concerns for microbial pesticide control agents are pathogenicity of the microbial pest control agent and of microbial contaminants; infectivity/unusual persistence of the microbial pest control agent and of microbial contaminants; or toxicity of the microbial pest control agent, microbial contaminants and preparation by-products.

Applicants must propose an active constituent statement for microbial products that specifies the identity and proportion of the organism present in the product. Proprietary names for active components are not acceptable.

3.4. Group 4: other living organisms

Predatory insects, predatory mites and macroscopic parasites are specifically excluded from the definition of an 'agricultural chemical product'. Other living organisms that may require evaluation by APVMA are mainly plants that have been modified by genetic manipulation to incorporate a gene that encodes for pesticidal activity or pest resistance.

Plants used as biological control agents are not considered to require registration. Thus, chrysanthemum plants that produce pyrethrins are not regulated by the APVMA. However, substances that are extracted from plants and used as pesticides (plant extracts) do require registration (see the description for Group 2 in Section 3.2 above).

This distinction is reasonable in light of the potential for increased and unique exposures due to large-scale application of extracted chemicals to plants that do not naturally produce them. The use of extracted chemicals as insecticides can involve exposure to the pesticide over large areas, whereas the exposure associated with chemicals contained in living plants would not be expected to reach such proportions.

Plants that have a naturally evolved resistance (for example, herbicide resistance or insect resistance) do not require registration with the APVMA, nor do plants that have been conventionally bred to have, say, increased resistance to insect attack.

Genetic manipulation technology has opened the possibility of novel pesticides being produced within a plant by introduced genes not normally found in that plant. These pesticidal substances require regulation by the APVMA due to their potential impact on human health and safety or the environment.

There are a number of substances produced in plants that enable plants to resist pest attack and disease. These substances include both those pesticidal substances that would be considered normally a component of a plant and those that would be considered new to a plant. Examples of plant pesticides that would be considered normally a component of a plant are phytoalexins (plant-produced substances that act against phytopathogenic micro-organisms). An example of a plant pesticide that would not be considered normally a component of a plant is the insecticidal delta-endotoxin that is produced in the bacterium Bacillus thuringiensis (Bt).

Where a resistance gene that produces a pesticidal substance (toxin or enzyme) is transferred from one species of plant to another one where that gene does not occur naturally, an application must be made to the APVMA.

Genetically modified plants with genes for herbicide tolerance will not themselves require registration, but applicants must check on APVMA requirements relating to herbicide use before the release of seeds or plants.

A proposed new use pattern for a chemical to be used on a genetically modified plant will require a label change application for the relevant chemical product as discussed above.

For detailed data requirements for other living organisms, see Section 5.

4. Data requirements for groups 1 and 2 (biologically derived chemicals)

Applications for registration of agricultural chemical products containing biologically derived chemicals must follow the overall outline set out in relevant sections of the Regulatory Guidelines. Modifications and/or additions should be made to every part of the application, as indicated below.

4.1. Part 1: Application overview

The application overview must be prepared according to the format outlined in the relevant section of the Regulatory Guidelines.

Extra sections must be added as follows:

• Biological properties of the active constituent
  • Natural occurrence and distribution in Australia of the source organism
  • Natural occurrence of the chemical or, if synthesised, relationship to the form occurring in an organism
  • Mode of action
  • Specificity of action
  • Likely biological effects arising from use
• Biological properties of the formulated product (if different from above)

4.2. Part 2: Chemistry, manufacture and biological properties for biologically derived chemicals

Biologically derived chemicals are often poorly characterised and the purity and amounts of contaminants are not readily available. It is imperative that the chemistry part of the application includes all known details of the composition of the active constituent and the formulated product.

These notes must be read in conjunction with the detailed discussion in Part 2: Chemistry and Manufacture in the Regulatory Guidelines.

An active constituent application must include the information given below. If any particular section of the following list of data requirements is not considered relevant to a particular active constituent, the applicant must provide a reason for its exclusion.

4.2.1. Active constituent

• Active constituent identification:
  • Common name, including an application to Standards Australia (where appropriate)
  • Chemical name (IUPAC)
  • CAS registry number
  • Common or distinguishing name
  • Chemical formula, molecular structure and molecular weight (where appropriate)
  • Chemical and physical properties
  • Stability
• Active constituent approval or standard:
  • Active constituent approval number or the approval application number
  • Compendial or manufacturer's standard (where appropriate)
• Manufacturer details:
  • Name of manufacturer
  • Address (street and postal)
• Manufacturing plant details:
  • Name
  • Address (street and postal)
• Manufacturing process:
  • Process chemistry/production method (purification processes and resultant yields must be fully described)
  • Quality control during manufacture
  • Declaration of composition of active constituent/manufacturing concentrate (in the case of crude extracts please provide as much information as possible)
  • If the product of a GMO, describe the genetic manipulation method, together with a detailed description of the donor organism or the gene isolated from it, the vector and the recipient organism
• Analytical methods:
  • Active constituent
  • Impurities
  • Toxic impurities (including discussion of unintentional ingredients/micro contaminants)
• Batch analyses:
  • Normal number required is 5 batches within the past 5 years
• Packaging
• Provision of analytical reference materials to the National Analytical Reference Laboratory (National Measurement Institute)
• Biological properties:
  • Natural occurrence and distribution in Australia of source organism
  • Natural occurrence of the chemical or, if synthesised, relationship to the form occurring in an organism. For GMOs, include information about the source gene(s)
  • Mode of action
  • Specificity of action
  • Likely biological effects arising from use
  • Effect of storage and other conditions on biological activity

4.2.2. Product

The following information must be included in Part 2: Chemistry and Manufacture of the application for registration of the product. If any particular section of the following list of data requirements is not considered relevant to a particular product, the applicant must provide a reason for its exclusion.

• Product identification:
  • Distinguishing name
  • Formulation type
  • Active constituent(s) and concentration(s)
• Formulation composition
• Chemical and physical properties
• Formulator:
  • Name
  • Address (street and postal)
• Formulation plant:
  • Name
  • Address (street and postal)
• Formulation process
• Quality control in product formulation
• Analytical methods:
  • Active constituent in the formulation Storage stability
  • Storage conditions
  • Proposed shelf-life (date-controlled agricultural chemical products)
  • Toxic products/degradation products
• Product Specifications (including allowable variations)
• Packaging
• Biological properties (where different from active constituent):
  • Describe any biological properties of the formulated product that differ from the active constituent (i.e. binding to substrates)

4.3. Part 3: Toxicology for biologically derived chemicals

The composition of the material used in the toxicology studies must be clearly identified and must conform closely to the declared composition. Further details of study types may be obtained from Part 3: Toxicology in the Regulatory Guidelines.

The toxicology data requirements in this guideline are based on current approaches to hazard assessment. As new areas of concern arise, further testing may be expected. If a particular study is not submitted, a statement indicating why the study is not considered necessary must be provided.

4.3.1. Primary toxicology data

• Active constituent:
  • Acute oral toxicity
  • Acute dermal toxicity
  • Acute inhalation toxicity
  • Genotoxicity
  • Short-term studies (route depending on likely source/s of human exposure)
• Product:
  • Acute oral toxicity
  • Acute dermal toxicity
  • Acute inhalation toxicity
  • Eye irritation
  • Skin irritation
  • Skin sensitisation

4.3.2. Supplementary toxicological studies (active constituent)

When other potential hazards are indicated by the results from the above studies or through other means (such as information on class effects), appropriate supplementary data may be required as follows:

• Subchronic toxicity studies by an appropriate route.
• Developmental studies.
• Reproduction studies.
• Chronic toxicity/oncogenicity studies.
• Human exposure data.
• Additional genotoxicity studies.
• Other studies to determine special forms of toxicity.

4.4. Part 4: Metabolism and kinetics for biologically derived chemicals

Biochemical pesticides that may require metabolic/kinetic studies are those where:

• the active constituents have been identified
• the concentration of the product, when applied following the recommended use pattern, results in levels that can be differentiated from background levels.

An additional section must be added to include tests to show that minor contaminating biological substances/organisms are not biomagnified in the field.

Details of study types in each section may be obtained from Part 4: Metabolism and Kinetics in the Regulatory Guidelines.

4.5. Part 5: Residues for biologically derived chemicals

Residue studies are usually not required for biologically derived chemicals. The applicant must request an exemption from the need for a maximum residue limit (MRL) and provide reasoned scientific argument for the exemption together with information on potential hazard and exposure where applicable. Scientific argument against the need for residue data and requests for exemption from the need for an MRL will be considered on a case-by-case basis. Situations where residues do not or should not occur in foods or animal feeds; or where the residues are identical to, or indistinguishable from, natural food components or are otherwise of no toxicological significance, are generally considered not to require MRLs.

If the product is exempt overseas from the need for MRLs or tolerances, this information must be provided in the application. The information must include detail of the reasons for the exemption.

If residue studies data are required in Part 5 of the application, the data must be set out as described in Part 5A: Residues in the Regulatory Guidelines and the following additional data must include:

• analytical method:
  • analytical methodologies are to be provided for the active constituent(s)
  • complete descriptions of detection, identification and quantification techniques
  • details of specificity, sensitivity and reliability of the detection techniques.
• fate of residues during storage, processing and cooking:
  • information must be provided on the effect on food quality.

4.5.1. Applicant's proposed entry in the MRL Standard

It is particularly important with biological products to address the question of residue definition for inclusion in the APVMA's MRL Standard: Maximum Residue Limits in Food and Animal Feedstuffs.

4.6. Part 6: Occupational health and safety for biologically derived chemicals

The occupational health and safety (OHS) data requirements are based on the toxicity of the biological chemical and the potential for occupational exposure. Biological activity of the biological product in humans is an important consideration for occupational health. Biologically derived chemicals such as semiochemicals and hormones, which have acute as well as chronic health effects, may also require comprehensive OHS data.

Where information is not available or the requirements are not considered relevant, the reasons must be provided by the applicant. Reasons provided for each case will be considered on their merits.

4.6.1. Occupational exposure data

Applicants must address all potential occupational exposure to biological products within Australia, including manufacturing/laboratory procedures, formulation, packaging, transport, handling, use and disposal. Exposure arising from products that have been treated with the biologically derived chemicals must be addressed (i.e. during harvesting or processing).

Information must also be provided on the use pattern, application equipment and methods, application rates, frequency of application and the most common routes of exposure.

For each of the work categories, the approximate number of workers who have the potential for exposure/infection, the nature of the work carried out and the maximum duration of exposure (in hours per day and days per year) must be provided. Measures to prevent worker exposure must be provided. Precautions for handling the product must include details of precautions to be taken at each stage of product handling (for example, in the preparation of bacterial culture).

4.6.2. Health surveillance and health conditions contraindicating work with biologicals

Medical examination of workers before work placement in addition to routine health surveillance for workers must be considered where relevant. Details of the examination and clinical tests performed before placement and for routine health surveillance must be provided. The examination must include serological testing to set a baseline for immunological parameters. A routine pre-placement examination must be able to detect immuno-compromised workers and workers with a history of hypersensitivity disorders. Where relevant, methods for biological and atmospheric monitoring must be included. Details on sampling techniques and sampling equipment and a brief description of the analytical method(s) used must be provided.

Workers with health conditions, such as asthma, or a history of allergy, may not be suited to work with some biological products. Details must be provided on health conditions that are absolute contraindications, and conditions that require extra precautions during handling.

4.6.3. Follow-up information

Follow-up information on workers is required and must include any symptoms, signs and results of tests, where required. For further details, refer to Part 6: Occupational Health and Safety in the Regulatory Guidelines.

4.6.4. Information provision

4.6.4.1. Label and safety data sheets (SDS)

For further details refer to the Ag Labelling Code in the Regulatory Guidelines.

4.6.4.2. Education and training

Biological products may provide a special class of hazard and workers need to be trained in handling them in addition to the education and training on other chemical and physical hazards at the workplace. For further details, refer to Part 6: Occupational Health and Safety in the Regulatory Guidelines.

4.7. Part 7: Environmental studies for biologically derived chemicals

Data requirements are the same as those for conventional agricultural and veterinary products, and the applicant must consult Part 7: Environment in the Regulatory Guidelines (and must include a table of contents and summary as Section 7.1 and Section 7.2 respectively).

As noted in this document, the environmental requirements for registration of biological agricultural products are flexible in order to allow for the differing degrees and nature of environmental exposure that arise from their use.

Applicants are advised to submit as complete an account as possible on what is already known of effects on the environment arising from the use or natural occurrence of the chemical. This must take the form of a review of existing knowledge describing likely effects on the environment and living organisms, as well as the fate in soil and water and the potential for accumulation.

The relevant studies must then be appended in the format detailed in Part 7: Environment in the Regulatory Guidelines. The APVMA is prepared to be flexible in its data requirements (e.g. less data might be required for a chemical that was very specific to, say, Lepidoptera), but data or scientific argument is required to support the claim.

The following 2 hypothetical examples may help applicants understand the APVMA's approach.

4.7.1. Example for Group 1 – an insect growth regulator

A new product, NoMolt, contains a new insect growth regulator – a protein of plant origin but able to be isolated in pure form. NoMolt was proposed for use for the control of aphids and white fly on tomatoes and cucurbits in glasshouses. An assessment indicated that it was readily degraded in soil and water. The toxicity reflected its mode of action and was most pronounced for certain sucking insects.

Table 7.3 in Part 7 of Regulatory Guidelines indicates that glasshouse crops are considered to reflect localised use with confinement by the glasshouse, but would generally require the base set in Tables 7.1 and 7.2 of Part 7 of Regulatory Guidelines as well as 7.1.6(b) – (d), 7.1.7(a) and 7.1.8(b) of Table 7.1. That is, besides the base set covering the assessment of the extent of and potential for environmental exposure, physicochemical degradation and biodegradation, data would be required for biodegradation, field dissipation (soils only) and accumulation (soils only).

In the above example for NoMolt, the applicant would be able to argue that, as the active constituent, a protein, readily degraded to constituent amino acids, it was not likely to be mobile and leach to groundwater, or accumulate in soils. Therefore, data for 7.1.6(b) – (d), 7.1.7(a) and 7.1.8(b) of Table 7.1 would not be necessary.

For a persistent chemical, however, field dissipation and accumulation studies would be essential, particularly if exposure is high. In this case, the scale of field use (e.g. glasshouse versus broad acre) could not be used to justify the omission of such data (see Part 7: Environment of Regulatory Guidelines for more details).

4.7.2. Example for Group 2 – a plant extract

The product Riddoff contains the active constituent disbug2 which, although characterised, is extracted from a plant. The applicant, A Riddell & Co., is able to control the manufacturing process so that the purity of disbug2 is at a level of 25±1% in the manufacturing concentrate, but with other compounds that appear to be inactive.

Another company, GEE Puzzled Pty Ltd, has submitted another product, Destruct-a-pest, which also contains disbug2, again extracted from plants but using another process. However, in this case, the process is not well characterised and results in a final product in which disbug2 is at a level of 0.5 to 5%.

Both applicants were able to submit scientific literature that indicated the fate and effects of disbug2. A Riddell & Co were able to submit data that demonstrated that the purified active constituent would break down through abiotic (principally photolysis) and biotic processes. The effects studies indicated that disbug2 was highly to very highly toxic to several aquatic invertebrates, while only moderately to highly toxic to fish. They showed only slight toxicity to other taxa considered (which included mammals, birds and plants).

GEE Puzzled Pty Ltd, however, presented data in which it was obvious that their process resulted in an active constituent in which the active disbug2 was quite variable (from 0.5 to 5%). There also appeared to be a range of compounds in their active constituent, some with similar structures to disbug2. The company provided only limited fate and effects data, with the source of the active constituent unclear (e.g. it was unclear whether the studies were performed with the same active constituent to be used in the product). From the range of results varying from slightly to highly toxic, it was impossible to predict the true toxicity of the poorly characterised active constituent.

Of the above information given by the 2 companies, the data for the active constituent provided by GEE Puzzled Pty Ltd would be unsatisfactory whilst that from A Riddell & Co would be satisfactory. The APVMA would need to have data indicating the variability of the active constituent to be used in Destruct-a-pest with respect to fate and effects because of the active constituent's variable nature (with respect to the level of disbug2, as well as the other compounds). That is, while not all components might be identified or characterised, the APVMA would have to be convinced that the mixture could be obtained reproducibly and that the transport, fate and effects of the active could be adequately predicted from the supplied data.

4.8. Part 8: Efficacy and safety for biologically derived chemicals

Efficacy and safety data requirements for biologically derived chemicals are largely similar to those for conventional agricultural products and applicants are referred to Part 8: Efficacy and Safety in the Regulatory Guidelines. The Legislative Instrument on efficacy criteria (Agricultural and Veterinary Chemicals Code (efficacy criteria) Determination 2014) is relevant to certain biological products in the particular circumstances that are outlined in that document.

In some cases, a lower level of efficacy may be accepted for a product that has advantages in reduced hazard to humans or the environment. The applicant must provide evidence in support of any claimed reduced hazard to enable a risk assessment to be carried out by the APVMA. The product label must also make it clear to the user than standard commercial levels of efficacy may not be achieved.

5. Data requirements for groups 3 and 4 (organisms)

Because microbial pest control agents represent a diverse range of micro-organisms, not all studies or data requirements may be appropriate for a specific micro-organism. Applicants must consider the unique characteristics of their proposed micro-organism when addressing specific data requirements and protocols, and are encouraged to consult the Pesticides Program of APVMA before testing begins. In addition, exemptions from certain data requirements will be considered when accompanied by a sound scientific rationale. These requirements can be determined on a case-by-case basis through a request for pre-application assistance (PAA).

Before consulting the APVMA, applicants must familiarise themselves with these guidelines and be prepared to provide information and propose studies deemed appropriate to address the APVMA requirements.

An agricultural chemical product containing organisms is defined in the Agvet Code Regulations as a 'date-controlled agricultural chemical product'. A date-controlled agricultural chemical product must have an expiry date on the label and the product cannot be supplied after the expiry date.

The data submission supporting the application should include the following data parts.

5.1. Part 1: Application overview for organisms

The overview must be prepared as indicated in Part 1: Application Overview in the Regulatory Guidelines.

Replace the section on Chemistry and Manufacture of this overview with the following:

5.1.1. Biology and manufacture

• Active constituent identification:
  • Approved common name and scientific name
  • Distinguishing name
  • Full taxonomic description (including strain and serotype)
  • Manufacturer's code number(s) and/or synonym(s) (if applicable)
  • Physical properties, including state and stage of the organism (i.e. spores, mycelium, larvae)
• Active constituent approval or standard:
  • Active constituent approval or standard
  • Active constituent approval number or application for approval
• Manufacture:
  • Name of manufacturer
  • Address (street and postal) of manufacturer
  • Name and address of manufacturing plant (if different)
• Biological properties of the active constituent:
  • Provide a summary of the biology of the organism
• Product characterisation (if different from active constituent):
  • Distinguishing name
  • Formulation type
  • Active constituent concentration(s)
  • Formulation composition
  • Physical properties
  • Storage stability
  • Proposed shelf-life (including storage conditions)
  • Toxic products
• Product formulation:
  • Name and address of formulator
  • Name and address of formulation plant
  • Summary of formulation process
• Biological properties of product (if different from active constituent):
  • Provide a summary of the biological properties of the product

5.2. Part 2: Chemistry, manufacture and biological properties for organisms

These guidelines must be read in conjunction with Part 2: Chemistry and Manufacture in the Regulatory Guidelines.

The following information must be included in Part 2: Chemistry and Manufacture of the application for registration of the product. If any particular section is not relevant to a particular product, the applicant must provide a reason for its exclusion.

5.2.1. Active constituent

• Active constituent identification:
  • Scientific and common name, including an application to Standards Australia (where appropriate)
  • Manufacturer's code number(s) and/or synonym(s) (if applicable)
  • Identification of active organism (i.e. genus, species, strain, type) – include relevant taxonomic methods (e.g. phenotypic, biochemical, genetic, molecular) and relationship to organisms which are important in agriculture is also relevant
  • Physical description of the organism including physical state and stage of the organism (e.g. spores, mycelium, larvae)
• Active constituent approval or standard:
  • Active constituent approval number or application for approval
  • Compendial or manufacturer's standard (where appropriate)
• Manufacturer details:
  • Name
  • Address (street and postal)
• Manufacturing plant details:
  • Name
  • Address (street and postal)
• Manufacturing process:
  • Source of active organism and all other biological media
  • Brief description of growth media, fermentation processes etc.
  • If the organism is a GMO, description of the method that was used, together with a detailed description of the donor organism or the gene isolated from it, the vector and the recipient organism
• Quality control in production
• Analytical methods:
  • Active constituent
  • Contaminants (chemical and/or microbiological)
  • Methods to verify genetic integrity (if a GMO)
• Batch analyses:
  • Potency assay, no. organisms/mL etc. (where relevant)
• Tests showing absence of contaminating organisms, chemicals or toxins
• Packaging
• Evidence of provision of analytical reference materials to the National Analytical Reference Laboratory (National Measurement Institute)
• Biological properties:
  • Geographic origin and natural occurrence of the organism in Australia
  • History of the organism and its uses
  • Life cycle and growth characteristics of the organism
  • Specificity, host range and indication of whether the agent is closely related to a crop pathogen or to a pathogen of a vertebrate species or a non-target invertebrate species
  • Pathogenicity or antagonism to target host species
  • Pathogenicity/infectivity in humans
  • Site of infection, mode of action and of entry into host
  • Infective dose level and indication of numbers of organisms to be used or released
  • Transmissibility and persistence of the organism under different climatic conditions
  • Genetic stability of the agent under environmental conditions of proposed use (GMOs only)
  • Likely biological effects arising from use

5.2.2. Product (if different from active constituent)

• Product identification:
  • Distinguishing name of product
  • Formulation type
  • Name(s) and concentration(s) of active constituent(s)
• Formulation composition:
  • Composition/specifications of other constituents
• Physical properties (where applicable)
• Effect of storage and other conditions on biological activity
• Formulator:
  • Name
  • Address (street and postal)
• Formulation plant:
  • Name
  • Address (street and postal)
• Formulation process:
  • Quality control in product formulation
  • Analytical method for active agent in the formulation (if different from above)
• Storage stability:
  • Storage conditions
  • Proposed shelf-life
• Product specifications (including allowable variations)
• Biological properties (where different from active constituent)
  • Describe any properties of the formulated product that differ from the active organism, including those that are designed to reduce hazards (e.g. encapsulation of spores, binding to substrates)

5.3. Part 3: Toxicology for organisms

The data requirements in this guideline are based on current approaches to hazard assessment. As new areas of concern arise, further testing may be expected. Further details of study types may be obtained from Part 3: Toxicology in the Regulatory Guidelines.

If a particular study is not submitted, a statement indicating why the study is not considered necessary must be provided.

5.3.1. Microbial agents

For microbial agents, it must be established that the active constituent is not a known pathogen of humans or other mammals and that the preparation does not contain such pathogens or mutants as contaminants, as determined by acceptable test(s).

5.3.2. Primary toxicology data

• Active constituent:
  • Acute infectivity: intravenous (for bacteria and viruses); intraperitoneal (for fungi and protozoa); and intracerebral (for neurotropic agents) – these are single studies with a single high dose of active constituent injected
  • Acute oral toxicity/infectivity
  • Acute dermal toxicity/infectivity
  • Acute inhalation toxicity/infectivity
  • Eye irritation/infectivity
  • Skin irritation
  • Hypersensitivity/allergy incident reports
  • Genotoxicity on appropriate extracts
  • Short-term studies (route depending on likely source(s) of human exposure)
• Product:
  • Acute oral toxicity/infectivity
  • Acute dermal toxicity/infectivity
  • Acute inhalation toxicity/infectivity
  • Eye irritation
  • Skin irritation
  • Skin sensitisation

5.3.3. Supplementary toxicological data

Further studies may be required, depending on indications of toxin production, significant signs of infectivity or unusual persistence of the microbial pesticide. For example:

• Subchronic toxicity studies
• Developmental studies
• Reproduction studies
• Immunotoxicity studies (for viruses)
• Additional genotoxicity studies

5.3.4. Other living organisms

Active constituent:

• Acute oral toxicity/infectivity
• Acute dermal toxicity/infectivity
• Acute inhalation toxicity/infectivity
• Eye irritation/infectivity
• Hypersensitivity/allergy incident reports

5.3.5. Microscopic parasites

Active constituent:

• Acute oral toxicity/infectivity
• Acute dermal toxicity/infectivity
• Acute inhalation toxicity/infectivity
• Eye irritation/infectivity
• Hypersensitivity/allergy incident reports

5.4. Part 4: Metabolism and kinetics for organisms

In general, kinetic and metabolism data are not relevant for microbial agents and other living organisms unless the organism produces a mammalian toxin.

If the organism produces or is suspected of producing, a toxin or toxic metabolite, then these must be identified, and also isolated if possible. Toxins or toxic metabolites may be subject to the complete requirements outlined in Part 4: Metabolism and Kinetics in the Regulatory Guidelines.

5.5. Part 5: Residues for organisms

Residue data are generally not necessary for microbial agents. The applicant must request an exemption from the need for an MRL and provide reasoned scientific argument for the exemption. The APVMA will consider such an exemption on a case-by-case basis. Situations where residues do not or should not occur in foods or animal feeds; or where the residues are identical to or indistinguishable from natural food components; or are otherwise of no toxicological significance are generally considered as not requiring MRLs.

If the product is exempt from the need for MRLs or tolerances overseas, this information must be provided in the application. The information must include detail of the reasons for the exemption.

5.6. Part 6: Occupational health and safety for organisms

The OHS data requirements are based on the toxicity of the biological product and the potential for occupational exposure. Biological activity of the biological product in humans is an important consideration for occupational health.

Where information is not available or the requirements are not relevant, the reasons for this must be given. Each case will be treated on its merits.

5.6.1. Occupational exposure data

Applicants must address all potential occupational exposure to biological products within Australia, including manufacturing/laboratory procedures, formulation, packaging, transport, handling, use and disposal. Exposure arising from products that have been treated with the microbial product (e.g. during harvesting or processing of crops) must be addressed.

Information must also be provided on the use pattern, application equipment and methods, application rates, frequency of application and the most common routes of exposure. Consideration must also be given to other chemical and physical hazards related to handling the biological product at the workplace (e.g. liquid nitrogen). While the microbial agent itself may not be toxic when grown in pure culture, the culture components and fermentation by-products may be. In this case, exposure information must include the potential for exposure to the end-use product and, where relevant, for each of the components.

For each of the work categories, the approximate number of workers who have potential for exposure/infection, the nature of the work carried out and the maximum duration of exposure (in hours per day and days per year) must be provided. Measures to prevent worker exposure must be provided. Precautions for handling must include details of precautions to be taken at each stage of product handling (e.g. in the preparation of bacterial culture). Some microbial agents may release toxins on the crop after application. In these situations, exposure estimates for workers handling the crops must be provided and re-entry restrictions must be considered.

Some microbial agents may be toxic by routes other than oral, dermal or inhalation (e.g. intraperitoneal or intracerebral injection). The exposure data requirements in these cases will be based on the risk of contracting infection in the normal occupational use rather than the hazard of the microbial by non-occupational exposure routes.

For some microbial agents (or other living organisms), the capacity to multiply within a suitable host/ non-target organism (for example, humans) is of concern. If it is established that the microbe has a potential for multiplication, potential long-term effects of the microbial exposure must be considered.

5.6.2. Health surveillance and health conditions contraindicating work with biologicals

Medical examination of workers before work placement in addition to routine health surveillance for workers must be considered where relevant. Details of the examination and clinical tests performed before placement and for routine health surveillance must be provided. The examination must include serological testing to set a baseline for immunological parameters. A routine pre-placement examination must be able to detect immuno-compromised workers and workers with a history of hypersensitivity disorders. Where relevant, methods for biological and atmospheric monitoring must be included. Details on sampling techniques and sampling equipment and a brief description of the analytical method(s) used must be provided.

Workers with health conditions, such as asthma, or a history of allergy, may not be suited to work with some biological products. Details must be provided on health conditions that are absolute contraindications, and conditions that require extra precautions during handling.

5.6.3. Follow-up information

Follow-up information is required to be provided on workers, including any symptoms, signs and results of tests where required. For further details, refer to Part 6: Occupational Health and Safety in the Regulatory Guidelines.

5.6.4. Information provision

5.6.4.1. Label and Safety Data Sheets (SDS)

For further details, refer to the Ag Labelling Code in the Regulatory Guidelines.

5.6.4.2. Education and training

Biological products are a special class of hazard and workers need to be trained in handling them in addition to the education and training on other chemical and physical hazards at the workplace. For further details, refer to Part 6: Occupational Health and Safety in the Regulatory Guidelines.

5.7. Part 7: Environmental studies for organisms

5.7.1. Format

The following format must be followed when preparing Part 7 of the application:

• 7.1 Table of contents
• 7.2 Summary
• 7.3 Review of current knowledge
• 7.4 Chemical and biological properties of the active constituent (refer to Part 2 of this section)
• 7.5 Fate and behaviour in the environment
• 7.6 Environmental toxicology and pathogenicity/infectivity studies to non-target organisms
• 7.7 Environmental hazard assessment

5.7.2. Review of current knowledge

For Section 7.3 (see also Part 2 of this section), applicants must submit a review of current knowledge on:

• Systematic position of the agent/organism, and the extent to which the systematics of the group to which it belongs is characterised
• Natural occurrence, distribution, habitat and ecological role of the agent/organism and its close relatives in Australia
• Target species occurrence, distribution and ecological role in Australia
• Target species predators, parasites and competitors
• Host range
• Infectivity and pathogenicity to non-target organisms
• Environmental fate, including exposure routes, and ability to survive and persist in the environment
• Direct and indirect environmental effects of release and use of the agent/organism, including effects on natural ecosystems

5.7.3. Overview of issues to be considered

Table 5.1 gives an indication of some issues that need to be considered by the applicant and the sections of the environment application where information on each must be included. Further details are provided in the Explanatory notes in the following sections.

Table 5.1: Environmental studies issues to be considered in Part 7 of an application

Key issues	Examples	Include in Section
Purity, consistency and strain stability	The organism might have closely allied forms that may produce exotoxins (e.g. Bt)	7.4
Population dynamics of the agent/organism	This might include describing the organism's life history and its preferred habitats and conditions etc.	7.5
Method of disruption to the target organism	Bt, for example, disrupts gut tissues, causing septicaemia	7.5
Ability to survive in a niche or host after release to the environment	Some organisms may have very specific requirements for survival (e.g. obligative anaerobes c.f. facultative anaerobes)	7.5
Pathogenicity and infectivity to non-target organisms	Some organisms might be shown to be quite specific from laboratory screening data and literature references	7.6
Potential (directly or indirectly) for disrupting natural ecosystem dynamics	Some conclusion may be made from the above information, or there may be some field data available	7.6 and 7.7
Potential (directly or indirectly) for adversely affecting environmentally significant biota	Some conclusion may be made from the above information, or there may be some field data available	7.6 and 7.7
Other issues
Environmental impacts of the presence of any contaminating organisms	Some organisms or their products (e.g. exotoxins) may contaminate the end-use product, potentially causing an uncharacterised harm	7.4
Hypersensitivity of non-target organisms	While the control of the target organism might be very efficacious, some non-target organisms may be much more sensitive to it	7.6
Potential for the agent/organism to initiate severe local tissue damage through the immunological consequences of exposure	Again, non-target organisms may be much more sensitive to the control agent than the target pest organisms	7.6

5.7.4. Data requirements and exemptions

The applicant must append specific studies relating to the environmental fate and effects (e.g. Sections 7.5 and 7.6) of the proposed agent on those organisms and sectors of the environment that have been identified as likely to be exposed to, and adversely affected by, the agent/organism.

Applicants will also need to demonstrate target species specificity where claimed, for example by presenting information on unique modes of action and the molecular basis for specificity, and/or some confirmatory tests.

Data exemptions may be accepted where it can be demonstrated that:

• the agent/organism will not survive in the Australian environment
• a particular class of organism or sector of the environment will not be significantly exposed to the biological product
• it is known that the agent/organism is a member of a group of organisms known never to have been pathogenic to organisms other than the target group. 

Details of registration status (both in Australia and overseas) and environmental safety assessments of overseas regulatory agencies must be appended where available. In the case of GMOs and their products, the review must include a record of approval by the OGTR.

5.7.5. Explanatory notes on environmental fate and behaviour

The purpose of environmental fate testing for biological products is to evaluate:

• the population dynamics of the agent/organism
• the ability of the agent to survive or propagate in a niche or host, and to disseminate in the Australian environment, after introduction. 

Therefore, depending on the circumstances, studies in the following areas may be relevant:

• Amount of agent to be introduced, application rates, method(s) of application, geographic areas of proposed use
• Extent of, and potential for, exposure during manufacture and/or formulation
• Spread, mobility, multiplication and persistence of the agent in air, water and soil
• Ability to infect or cause disease in non-target organisms
• Ability to be expressed in terrestrial, freshwater, marine or estuarine environments
• Fate in food chains

In the case of GMOs or GMO products, in addition to the above, a summary review of the information presented to OGTR will need to be provided. This could include, for example, summary information on the potential for unintended transfer of the inserted genetic material (the 'transgene' or genetic construct) to organisms other than the 'host' agent/organism through processes such as hybridisation and recombination, on the environmental fate and persistence of the transgene itself, and on competition of the GMO with the non-genetically modified host agent/organism. The APVMA is able, under its legislation, to require further testing of data in regard to GMOs and GMO products, as it is for other agricultural or veterinary products.

5.7.6. Explanatory notes on environmental toxicology and pathogenicity/infectivity to non-target organisms studies

These studies are needed to determine possible infectivity, toxicity, pathogenicity to or hypersensitivity of, non-target organisms resulting from the introduction of the proposed agents into the environment, and to evaluate the potential for direct or indirect adverse impacts on significant biota (e.g. endangered wildlife or flora) or on natural ecosystems. Tests may be on the agent/organism and/or the proposed product, as relevant, and may involve glasshouse or field tests under controlled conditions or simulations. If such studies were performed in Australia, the APVMA would require that it be satisfied that there was no unintended harm to the environment from conducting such studies (e.g. a condition of the study might be that the experimental plots be fumigated afterwards). Data requirements may depend on whether the agent and its relative are endemic, native or otherwise already present in Australia, to better determine the novelty of the environmental exposure on release.

The following environmental toxicology studies may be relevant, depending on the likely routes and patterns of exposure (see Explanatory notes on environmental fate and behaviour, above):

• Toxicity and/or pathogenicity or infectivity studies on a range of organisms, including mammals, birds or other wild vertebrates, fish, freshwater aquatic invertebrates (such as Daphnia manga), honey bees, earthworms and other soil invertebrates, soil micro-organisms, and marine and estuarine organisms.
• Plant toxicity (phytotoxicity) and infectivity/pathogenicity studies (non-target native vegetation).
• Algal growth studies.
• Toxicity and/or pathogenicity or infectivity studies on important parasitoids and predators of target species. 

Tests would need to include an appropriate taxonomic range of test organisms, involve appropriate exposure routes (oral, dermal, subcutaneous, intravenous, pulmonary, eye irritation, etc.) and dosages (including safety margins), apply other testing protocols as appropriate, and use adequately sensitive detection methods. Toxicity studies could generally be acute studies, but subacute and short-term studies may also be needed where environmentally significant effects are known from acute studies (e.g. known toxicity to birds or fish). Toxicity studies conducted overseas could be used for predictions of effects on suspected predators or parasites in Australia.

Specific tests on Australian biota may be required where environmentally significant wildlife, flora or ecosystems are identified, or where commercially significant organisms or systems may be adversely affected, depending on the nature of the agent/organism and anticipated exposures.

5.7.7. Explanatory notes on environmental hazard

As for conventional agricultural products, it is recommended that the applicant perform an assessment of environmental hazard posed by introduction of the agent/organism. Due to the inherent variability of organisms, the complexity of ecological interactions, and the consequent inappropriateness and lack of standard testing protocols, the assessment may be predominantly qualitative in nature where specifically designed tests are not practicable or would not be definitive.

Some overseas regulatory authorities, such as in the United States and Canada, adopt a tiered approach to testing for environmental effects. Tests relevant to the requirements listed above could be from the lowest tier only in cases where data showed no persistence or survival in the environment, and/or no adverse effects, and/or where environmental expression was not significant. However, where such tests had shown (or it was otherwise known) that the agent was likely to persist and be expressed in the Australian environment and/or significant hazards were expected, higher level testing would be required. Such higher tier testing might include, for example, chronic effects, reproduction and field testing, or other tests relevant to evaluating fate, expression in, and impacts on the environment.

5.7.7.1. Further advice

It is recommended that the applicant seek advice from the APVMA for further guidance on the level of testing that may be required through a request for a PAA.

If known toxins are produced by the agent/organism, data outlined in Table 7.1 of Part 7: Environment must be provided. Advice should be sought from the APVMA.

In the case of GMOs or GMO products, a summary review of the pathogenicity and/or infectivity information and ecotoxicity information already presented to OGTR will need to be appended to the application for registration. This could include, for example, information on the impacts of the GMO on non-target and beneficial organisms, information on the ecotoxicity effects of the novel expression of a toxin in a pathogen, or predictions on altered epizootiology.

5.7.7.2. Examples

The following hypothetical examples may help applicants understand the approach of the APVMA.

5.7.7.2.1. Example for Group 3 – a virus

The product Thegvirus is a GMO in which a scorpion toxin gene has been inserted into a virulent strain of TGV ('The Grail Virus') and claimed to be specific to a few genera of coleopteran (beetle) pests, most of which are native to Australia. The purpose of genetic modification is to shift the nature of control away from that of a viral biological control agent towards that of a knockdown biocide.

The company provided information on the biochemical characteristics, mode of action, toxicity and effects of the scorpion toxin per se from various literature sources. The company also provided information on the nature and stability of the genetic construct inserted into TGV, expression levels in target hosts, infectivity and pathogenicity of TGV in target species, and information on the host specificity of related strains of TGV.

The APVMA generally accepted these data, including that the fate of the expressed toxin per se, as expressed in target species, would probably be as predicted from the literature sources, taking into account that it is a well-studied protein toxin. Further data would be needed, however, relevant to a number of concerns not addressed in the application. These are new concerns identified and consequent upon the novel presence of the scorpion toxin gene in the viral genome, and the novel expression of the scorpion toxin in hosts of TGV.

Potential adverse ecological impacts could result from novel epidemiology as the GMO TGV-infected target species that also are part of natural ecosystems, and/or from extended GMO TGV host range due to genetic recombination among closely related TGV strains (with differing host ranges). New information would be needed to enable assessment, including information on relatedness and host range of related TGV strains, background ecology of the TGVs and hosts in natural systems, GMO TGV epizootics, likelihood of genetic recombination and TGV persistence.

Given the level of scientific uncertainty about some of the above hazards, new emphasis might need to be placed on empirical GMO TGV specificity testing of a wider range of non-target species.

5.7.7.2.2. Example for Group 4 – a microscopic nematode

The product Nemamusdy contains Nemamus nemesis, a microscopic nematode isolated in Brazil, and is claimed to specifically control beetle larvae. The product is formulated as a dry granular formulation for incorporation into the soil, or application on top of the soil. The formulation contains 5 ´ 105 eggs per gram and is proposed to be imported. As such, it is also the subject of the DAFF approval (see Section 1.3) and consideration may also be required by Wildlife Australia for approval under the Wildlife Protection (Regulation of Imports and Exports) Act 1982.

The applicant has made various claims and provided some data, but several concerns remain, as summarised in Table 5.2.

Table 5.2: The environmental assessment concerns about Nemamusdy

No	Claim	Information provided by sponsor	The environmental assessment concerns
1	Specific to soil-dwelling beetle larvae	Literature references, including reviews, for the genus	Arguments provided are largely speculative, with data from other studies indicating other species of the genus to be at least parasitic in a wide range of soil invertebrates, including earthworms
2	No persistence of nematodes in soil	Efficacy studies performed overseas (e.g. the exporting country)	Only juvenile nematodes can be detected; there is a possibility that the nematodes persist as eggs, which cannot be identified
		Laboratory studies	Data indicating the need for re-inoculation were collected only from laboratory studies
3	Genus is cosmopolitan and likely to have a very similar species in Australia	Various comparative data for 2 other species	Not adequately demonstrated as the key taxonomic features are not well defined, with the genus under revision overseas
		Literature references

The table suggests that a major concern is the potential for adverse impacts on a wide taxonomic range of non-target species. Furthermore, while Nemamus is distributed throughout the world, the genus includes a diverse range of species, differing in their geographic occurrence and parasitic host ranges. The genus is known to occur in Australia, but there is no clear knowledge on the range of species present, whether they are endemic and/or native or on their host ranges. The taxonomy of the genus is not well known, with taxonomic revisions on overseas species underway. This makes it difficult to assess how novel N. nemesis is in the context of Australian species diversity and, therefore, to assess potential impacts in the absence of new information.

The applicant was therefore asked to provide data relevant to addressing these major concerns such as further data supporting claims of specificity (e.g. empirical data on infectivity and pathogenicity in non-target organisms and/or evidence relating to the biological basis [biochemical/molecular] for specificity) and congruent data to support claims of relatedness to, and genetic distance of N. nemesis from, other Australian species, or adequate information to demonstrate that N. nemesis already exists in Australia.

Adequate genetic information to demonstrate that N. nemesis is identical or extremely similar to other Australian species of this microscopic nematode would diminish environmental concerns relating to release in Australia.

5.8. Part 8: Efficacy and safety for organisms

5.8.1. Summary and evaluation of efficacy data

Efficacy data must be provided for all microbial and other living organisms used as pest control agents. Efficacy of end-use products can vary significantly due to biological variation and other factors such as manufacturer of the active constituent, site of manufacture of the active constituent, manufacturing process, formulation process of end-use product and ingredients in the formulation.

A microbial product will generally not be considered to be closely similar to a registered product unless it is a simple repack of an existing product. Thus, microbial product applications are more likely than chemical products to be treated as Item 5 applications rather than Item 6 or 7 applications. Refer to the Regulatory Guidelines for further details on product application items. Bridging data will be required for all significant changes, including source or process of manufacture, strain or formulation of product.

Because of this variability, active approval applications cannot be accepted without an accompanying end-use product application.

5.8.2. Justification for use

Information must be provided as follows:

• The nature and economics of the pest/disease in Australia.
• Performance of the microbial pest control agent, according to prescribed label conditions and claims.
• Current management tools – status, benefits, problems.
• The contribution of the microbial pest control agent to risk reduction and sustainable pest management in the specific crop/resource production system. 

The purpose of justifying the use of the product is to promote balanced regulatory decisions that incorporate consideration of the potential unique or long-term benefits of the microbial product to sustainable crop/pest management or risk reduction with possible drawbacks or disadvantages. It is anticipated that microbial products will demonstrate special characteristics that adapt well to integrated management programs or may exhibit desirable safety features. Formal documentation of these characteristics is an important component of risk management decision-making.

5.8.3. Product performance

Product performance is defined as the ability of the product to fulfil the claims made on the proposed label. It includes the nature and extent of control/management of the pest or disease problem and also considers beneficial or adverse effects on the host crop and the crop production system.

Product performance data must provide information regarding the microbial agent's pest host range and time to mortality and the minimum dosage required to achieve the desired or claimed standard of performance, according to the specifics of the proposed use scenario. Such information is developed in order to support label performance claims and use recommendations and is also important to non-target organism safety assessment. Performance data will also serve to confirm, where applicable, the utility of the microbial product in the development of sustainable pest management practices, including integrated management strategies, resistance management and risk reduction.

5.8.4. Requirement for local data

Where practicable, performance data packages must be based on original Australian data. Overseas data, which are collected under conditions comparable to intended Australian use situations and which meet Australian requirements, may be used to support Australian data.

For uses under confined or controlled-environment conditions (e.g. greenhouses, interior plantscapes), overseas data will normally be acceptable, provided the test conditions and crop management practices are demonstrably similar to those found in Australia. Home garden products must be tested under Australian conditions, which usually differ significantly from conditions in overseas countries.

5.8.5. Efficacy data requirements for agricultural products

The following must be addressed:

• Advantages of the product
• Laboratory assays (if relevant)
• Preliminary range-finding tests
• Field experiments under practical conditions in representative areas of Australia
  • For new products (including new species or strains), experiments must be carried out over at least 2 seasons and in representative areas in at least 2 states in which the product is to be used.
  • For minor formulation changes to products already registered (e.g. a change in source or process of manufacture, or formulation), either:
    • experiments must be carried out over at least 2 seasons and in representative areas in at least 2 states in which the product is to be used, or
    • the same number of experiments must be carried out over one season, also in representative areas in at least 2 states in which the product is to be used.
• Information on resistance management if this is an issue
• Consideration of any limitations posed by pest pressure
• Compatibility with chemical products (where appropriate):
  • Chemical products that have been shown to be mutagens must not be mixed with biological agents.
• Compatibility with integrated pest management and organic farming systems (where relevant):
  • Observations concerning undesirable or unintended side effects (e.g. on beneficial and other non-target organisms) on succeeding crops, other plants or parts of treated plants used for propagation purposes (e.g. seeds, cuttings, runners).

5.8.6. Phytotoxicity studies

• Safety to target crop/animal
• Phytotoxicity to non-target crops and other plants
• Animal safety

Further information on efficacy and phytotoxicity data requirements is given in Part 8: Efficacy and Safety in the Regulatory Guidelines.

6. Abbreviations

CAS	Chemical Abstracts Service
GMO	Genetically modified organism
IUPAC	International Union of Pure and Applied Chemistry
MRL	Maximum residue limit
OGTR	Office of the Gene Technology Regulator
OHS	Occupational health and safety
SDS	safety data sheet
TGV	'The Grail Virus'

7. References

Australian Government, Agricultural and Veterinary Chemicals Code Act 1994, No. 47 of 1994, Australian Government Printer.
Australian Government, Agricultural and Veterinary Chemicals Code Regulations, Statutory Rules 1995. No. 27. ISBN 0 644 43724 0.
Australian Pesticides and Veterinary Medicines Authority 2007. MRL Standard: Maximum Residue Limits in Food and Animal Feedstuffs. APVMA, Canberra, available at apvma.gov.au/node/10806.
Australian Pesticides and Veterinary Medicines Authority 2014. Regulatory Guidelines. APVMA, Canberra, available at apvma.gov.au.