Commission Regulation (EU) No 546/2011 of 10 June 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorisation of plant protection products Text with EEA relevance

The methods proposed must reflect the state of the art. The following criteria must be met in order to permit validation of the analytical methods proposed for post-registration control and monitoring purposes:

• 2.6.1.for formulation analysis:

• the method must be able to determine and to identify the active substance(s) and where appropriate any toxicologically, ecotoxicologically or environmentally significant impurities and co-formulants;

• 2.6.2.for residue analysis:

• (i) the method must be able to determine and confirm residues of toxicological, ecotoxicological or environmental significance;

• (ii) the mean recovery rates should be between 70 % and 110 % with a relative standard deviation of ≤ 20 %;

• (iii) the repeatability must be less than the following values for residues in foodstuffs: Residue level mg/kg Difference mg/kg Difference in % 0,01 0,005 50 0,1 0,025 25 1 0,125 12,5

  1

12,5 Intermediate values shall be determined by interpolation from a log-log graph;

• (iv) the reproducibility must be less than the following values for residues in foodstuffs: Residue level mg/kg Difference mg/kg Difference in % 0,01 0,01 100 0,1 0,05 50 1 0,25 25

  1

25

Intermediate values are determined by interpolation from a log-log graph;

• (v) in the case of residue analysis in treated plants, plant products, foodstuffs, feedingstuffs or products of animal origin, except where the MRL or the proposed MRL is at the limit of determination, the sensitivity of the methods proposed must satisfy the following criteria: Limit of determination in relation to the proposed provisional or EU MRL: MRL (mg/kg) limit of determination (mg/kg)

  0,5 0,1 0,5 – 0,05 0,1 – 0,02 < 0,05 MRL × 0,5

2.7.   Physical and chemical properties

• 2.7.1Where an appropriate FAO specification exists, that specification must be met.

• 2.7.2.Where no appropriate FAO specification exists, the physical and chemical properties of the product must meet the following requirements

• (a) Chemical properties: Throughout the shelf-life period, the difference between the stated and the actual content of the active substance in the plant protection product must not exceed the following values: Declared content in g/kg or g/l at 20 °C Tolerance up to 25 ±15  % homogeneous formulation ±25  % non-homogeneous formulation more than 25 up to 100 ±10  % more than 100 up to 250 ±6  % more than 250 up to 500 ±5  % more than 500 ±25  g/kg or ±25  g/l

- (b) Physical properties:

The plant protection product must fulfil the physical criteria (including storage stability) specified for the relevant formulation type in the ‘Manual on the development and use of FAO and WHO specifications for plant protection products’.

- 2.7.3.Where the proposed label claims include requirements or recommendations for use of the preparation with other plant protection products or adjuvants as a tank mix and/or where the proposed label includes indications on the compatibility of the preparation with other plant protection products as a tank mix, those products or adjuvants must be physically and chemically compatible in the tank mix.

PART B

UNIFORM PRINCIPLES FOR EVALUATION AND AUTHORISATION OF PLANT PROTECTION PRODUCTS CONTAINING AN ACTIVE SUBSTANCE THAT IS A MICRO-ORGANISM

Table of contents	Table of contents
Definitions	Definitions
1.	Evaluation
1.1.	Identity and manufacturing information
1.1.1.	Identity of the micro-organism contained in the plant protection product
1.1.2.	Quality control of the production of the micro-organism contained in the plant protection product
1.1.3.	Identity of the plant protection product
1.1.4.	Quality control of the plant protection product
1.2.	Biological, physical, chemical and technical properties
1.2.1.	Biological properties of the micro-organism in the plant protection product
1.2.2.	Physical, chemical and technical properties of the plant protection product
1.3.	Efficacy
1.4.	Identification/detection and quantification methods
1.4.1.	Analytical methods for the plant protection product
1.4.1.1.	Analytical methods for micro-organisms
1.4.1.2.	Analytical methods for metabolites of concern, relevant impurities, additives, co-formulants, safeners and synergist
1.4.2.	Analytical methods for the determination of residues and density of the micro-organism
1.4.2.1.	Density of the micro-organism
1.4.2.2.	Residues of metabolites of concern
1.5.	Impact on human and animal health
1.5.1.	Effects on human or animal health arising from the plant protection product
1.5.2.	Effects on human or animal health arising from residues of metabolites of concern
1.6.	Environmental occurrence of the micro-organism, including fate and behaviour of metabolites of concern
1.6.1.	Environmental occurrence of the micro-organism
1.6.2.	Environmental fate and behaviour of the metabolites of concern
1.7.	Effects on non-target organisms
1.8.	Conclusions and proposals
2.	Decision-making
2.1.	Identity
2.2.	Biological and technical properties
2.3.	Efficacy and absence of unacceptable effects on plants and plant products
2.3.1.	Efficacy
2.3.2.	Absence of unacceptable effects on plants and plant products
2.4.	Identification/detection and quantification methods
2.5.	Impact on human and animal health
2.5.1.	Effects on human and animal health arising from the plant protection product
2.5.2.	Effects on human and animal health arising from residues
2.6.	Fate and behaviour in the environment
2.7.	Effects on non-target organisms

Definitions

For the purposes of Part B, in addition to general introduction, the following definitions apply:

• (1) ‘strain’ means a genetic variant of an organism in its taxonomic level (species) that is made up of the descendants of a single isolation in pure culture from the original matrix (e.g. the environment) and usually is made up of a succession of cultures ultimately derived from an initial single colony;

• (2) ‘Microbial Pest Control Agent as manufactured’ (‘MPCA as manufactured’) means the outcome of the manufacturing process of the micro-organism(s) intended to be used as active substance in plant protection products, consisting of the micro-organism(s) and any additives, metabolites (including metabolites of concern), chemical impurities (including relevant impurities), contaminating micro-organisms (including relevant contaminating micro-organisms) and the spent medium/rest fraction resulting from the manufacturing process or, in case of a continuous manufacturing processes where a strict separation between the manufacturing of the micro-organism(s) and the production process of the plant protection product is not possible, a non-isolated intermediate;

• (3) ‘relevant contaminating micro-organism’ means a pathogenic/infective micro-organism unintentionally present in the MPCA as manufactured;

• (4) ‘spent medium/rest fraction’ means the fraction of the MPCA as manufactured consisting of remaining or transformed starting materials, and excluding the micro-organism(s) that is the active substance, metabolites of concern, additives, relevant contaminating micro-organisms, and relevant impurities;

• (5) ‘starting material’ means substances used in the manufacturing process of the MPCA as manufactured as substrate and/or buffering agent;

• (6) ‘ecological niche’ means an ecological function and actual physical spaces occupied by a particular species within the community or ecosystem;

• (7) ‘host range’ means the range of different biological host-species that can be infected by a microbial species or strain;

• (8) ‘infectivity’ means the ability of a micro-organism to cause an infection;

• (9) ‘infection’ means the non-opportunistic introduction or entry of a micro-organism into a susceptible host, where the micro-organism is able to reproduce to form new infective units and persist in the host, whether or not it causes pathological effects or disease;

• (10) ‘pathogenicity’ means the non-opportunistic ability of a micro-organism to inflict injury and damage to the host upon infection;

• (11) ‘non-opportunistic’ means a condition under which a micro-organism exerts an infection or inflicts injury or damage when the host is not weakened by a predisposing factor (e.g. immune system impaired by an unrelated cause);

• (12) ‘opportunistic infection’ means an infection occurring in a host weakened by a predisposing factor (e.g. immune system impaired by an unrelated cause);

• (13) ‘virulence’ means the degree of pathogenicity that a pathogenic micro-organism is able to exert in the host;

• (14) ‘metabolite of concern’ means a metabolite produced by the micro-organism under assessment, with known toxicity or known relevant antimicrobial activity, which is present in the MPCA as manufactured at levels that may present a risk to human health, animal health or the environment, and/or for which it cannot be adequately justified that in-situ production of the metabolite is not relevant for the risk assessment;

• (15) ‘background level of a metabolite’ means a level of a metabolite that is likely to occur in relevant European environments (including also sources different than those of plant protection) and/or in food and feed (e.g. edible plant parts), when the micro-organisms are in conditions to grow, reproduce and to produce such metabolite in presence of a host or availability of carbon and nutrient sources, under consideration of high host densities and nutrients;

• (16) ‘ in-situ production’ means the production of a metabolite by the micro-organism after application of the plant protection product containing that micro-organism;

• (17) ‘antibiosis’ means a relationship between two or more species in which one species is actively harmed (as by the production of toxins by the harming species);

• (18) ‘antimicrobial resistance’ (‘AMR’) means the intrinsic or acquired ability of a micro-organism to multiply in the presence of an antimicrobial agent at concentrations which are relevant for therapeutic measures in human or veterinary medicine, making that substance therapeutically ineffective;

• (19) ‘antimicrobial agent’ means any antibacterial, antiviral, antifungal, anthelmintic or antiprotozoal agent that is a substance of natural, semi-synthetic, or synthetic origin that at in vivo concentrations kills or inhibits the growth of micro-organisms by interacting with a specific target;

• (20) ‘acquired antimicrobial resistance’ means a non-intrinsic and acquired novel resistance enabling a micro-organism to survive or multiply in the presence of an antimicrobial agent at concentrations higher than that which inhibits wild type strains of the same species;

• (21) ‘intrinsic antimicrobial resistance’ means all inherent properties of a microbial species that limit the action of antimicrobial agents thereby allowing it to survive and multiply in presence of the antimicrobial agents at concentrations that are relevant for their therapeutic uses. Inherent properties of micro-organisms are considered not transferable and can include structural characteristics such as lack of drug targets, the impermeability of cellular envelopes, activity of multidrug efflux pumps, or metabolic enzymes. An antimicrobial resistance gene is considered intrinsic if it is located on a chromosome in the absence of mobile genetic element and shared by the majority of wild type strains of the same species;

- (22) ‘relevant antimicrobial activity’ means the antimicrobial activity caused by relevant antimicrobial agents;

• (23) ‘relevant antimicrobial agents’ means all antimicrobial agents important for therapeutic use in humans or animals, as described in the latest available versions at the time of submission of the dossier:
• — in a list adopted by means of Commission Regulation (EU) 2021/1760 ([^E0011]) in accordance with Article 37(5) of Regulation (EU) 2019/6 of the European Parliament and of the Council ([^E0012]), or
• — by the World Health Organisation ([^E0013]) in the lists of Critically Important Antimicrobials, Highly Important Antimicrobials and Important Antimicrobials for Human Medicine.

Member States shall consider during the evaluations that:

• — micro-organisms are living organisms capable of replication that may be naturally present in high numbers in the environment, and the specific micro-organism under assessment may already be occurring in relevant European environments at a relevant taxonomic level,

• — the biological properties and the mode of action of a micro-organism are the first and crucial step in the evaluation process, because they define which are the relevant aspects and elements on which the evaluation should focus, and also which aspects are not relevant for a robust informed decision making,

• — extensive information on the micro-organism under assessment (at the relevant taxonomic level) may be available in the public domain (e.g. history of use, peer-reviewed scientific literature). Best use of this information shall be made. Where applicable, regulatory experimental studies may be needed to determine the specific properties of the micro-organism under evaluation.

Metabolism is inherent of all living organisms. If secondary metabolites that are known to be hazardous to humans or other non-target organisms have been identified during the assessment of the micro-organism, the evaluation of a plant protection product containing this micro-organism shall include an assessment of the risk due to exposures to such metabolites expected from the intended use.

Member States shall implement the following principles in the evaluation of the data and information submitted in support of applications, without prejudice to the general principles prescribed in Section 2 of the general introduction.

1.1.   Identity and manufacturing information

An overall assessment is necessary for those data on the identity and manufacturing information required according to Section 1 of Part B of the Annex to Regulation (EU) No 283/2013 and Section 1 of Part B of the Annex to Regulation (EU) No 284/2013.

• 1.1.1.Identity of the micro-organism contained in the plant protection product

• Member States shall verify the identity of the micro-organism that is the active substance based on information provided under point 1.3 of Part B of the Annex to Regulation (EU) No 283/2013.

• Furthermore, Member States shall evaluate if the MPCA as manufactured used for manufacturing of the plant protection product complies with specification of the MPCA as manufactured characterised and quantified as required in point 1.4 of Part B of the Annex to Regulation (EU) No 283/2013 (e.g. in terms of content and identity of the micro-organism(s), metabolites of concern, additives, relevant contaminating micro-organisms, and relevant impurities).

• 1.1.2.Quality control of the production of the micro-organism contained in the plant protection product

• Member States shall evaluate the quality assurance criteria proposed for the production of the active substance. Process control, good manufacturing practice, operational practices, process flows, cleaning practices, microbial monitoring and hygiene conditions shall be present and ensure stable quality of the MPCA as manufactured.

• 1.1.3.Identity of the plant protection product

• Member States shall evaluate the detailed quantitative and qualitative information provided on the composition of the plant protection product as required in point 1.4 of Part B of the Annex to Regulation (EU) No 284/2013, e.g. micro-organism (active substance), metabolites of concern, relevant impurities, relevant contaminating micro-organisms, co-formulants, safeners and synergists.

- 1.1.4.Quality control of the plant protection product

• Member States shall evaluate the quality assurance criteria proposed, in particular whether strict maintenance of environmental conditions and quality control analysis during the manufacturing process have been assured by the producer, in order to ensure compliance with the limits for relevant contaminating micro-organisms, relevant impurities and metabolites of concern.

1.2.   Biological, physical, chemical and technical properties

Member States shall carry out an overall assessment of the information on biological, physical, chemical, and technical properties of the plant protection product provided under Section 2 of Part B of the Annex to Regulation (EU) No 283/2013 and Section 2 of Part B of the Annex to Regulation (EU) No 284/2013.

• 1.2.1.Biological properties of the micro-organism in the plant protection product

• 1.2.1.1.Member States shall evaluate information on the origin, occurrence and history of use of the micro-organism contained the plant protection product, giving particular relevance to both the location from which the strain was isolated, and the geographical distribution of the micro-organism at the relevant highest taxonomic level in relevant European environments.

• 1.2.1.2.Member States shall evaluate information on the ecology and the life cycle of the micro-organism, taking also into consideration the population densities of the micro-organism in relation to host densities as provided for in point 2.3 of Part B of the Annex to Regulation (EU) No 283/2013. In particular, for bacteriophages, the lysogenic and lytic properties of the virus shall be evaluated.

• 1.2.1.3.Member States shall evaluate information on the mode of action on the target organisms for the plant protection product to identify potential risks and function of the active substance that is a micro-organism according to the proposed conditions of use. In particular, Member States shall evaluate the role of possible infectivity, pathogenicity, toxicity and relevant antimicrobial activity in the mode of action against the target organism. If applicable, factors that enhance the pathogenicity/virulence of a micro-organism and environmental factors affecting a pathogenic mode of action shall be described.

• Information on the mode of action can be a very valuable tool in identifying potential risks and purpose of the micro-organism in the plant protection product.

• Aspects to be considered in the evaluation are, for instance:

• (a) invertebrate pathogenicity;

• (b) parasitisation;

• (c) competition for the ecological niche (e.g. nutrients, habitats);

• (d) endophytic growth;

• (e) interference with the virulence of a pathogenic target organism;

• (f) induction of plant defence;

• (g) antibiosis.

• 1.2.1.4.Member States shall evaluate data provided on the host range of the micro-organism, taking into account any available information on the relationship of the micro-organism to known pathogens to humans, animals, plants and other non-target species, at the most appropriate taxonomic level.

• 1.2.1.5.Member States shall evaluate information on growth requirements, by defining limiting factors e.g. UV light, humidity, pH, temperatures and other relevant agro-environmental conditions influencing the growth of the micro-organism.

• 1.2.1.6.Member States shall evaluate the genetic stability of a micro-organism that is a non-virulent variant of a plant pathogen virus, taking into consideration the likelihood of the micro-organisms to regain virulence, and the risk that could be caused by this occurrence.

• 1.2.1.7.In order to determine whether the micro-organism produces metabolites of concern, Member States shall take into account the information on production, toxicity and exposure concerning metabolites as provided for in points 2.8, 6.1, 6.2, 5.5, 7.2 and 8.8 of Part B of the Annex to Regulation (EU) No 283/2013.

• 1.2.1.8.For bacteria, Member States shall evaluate information on phenotypical resistance to relevant antimicrobial agents. Member States shall evaluate, taking into consideration that resistance genes in bacteria can be horizontally transmitted, and that this may potentially interfere with the effectiveness of relevant antimicrobial agents, information on the presence and transferability of genes coding for resistance to such antimicrobial agents.

• 1.2.2.Physical, chemical and technical properties of the plant protection product

• 1.2.2.1.Member States shall evaluate shelf-life and storage stability of the plant protection product, taking into account the packaging, optimal (recommended) storage temperature, and light conditions. Possible changes in composition due to growth or decline of the micro-organism or of relevant contaminating micro-organisms, or the production of metabolites of concern during storage, etc., shall be considered.

- 1.2.2.2.Member States shall evaluate the physical and chemical properties of the plant protection product and the retention of these characteristics after storage and take into consideration, unless a suitable FAO specification exists, all relevant physical and chemical properties of the plant protection product.

• 1.2.2.3.Where the proposed label includes requirements or recommendations for use of the plant protection product in combination with other plant protection products or adjuvants as a tank mix, Member states shall evaluate whether the plant protection product is physically and chemically compatible with those other plant protection products or adjuvants in the tank mix.

1.3.   Efficacy

Member States shall evaluate the efficacy of the plant protection product based on those data submitted in accordance with Section 6 of Part B of the Annex to Regulation (EU) No 284/2013.

• 1.3.1.Where the proposed use concerns the control of or protection against an organism, Member States shall evaluate if the target organism could be a danger to plant health under the agricultural and environmental (including climatic) conditions in the area of the proposed use.

• 1.3.2.Member States shall evaluate whether significant damage to plants or plant products or loss in yields could occur under the agricultural and environmental (including climatic) conditions in the area of proposed use, if the plant protection product was not used.

• 1.3.3.Member States shall evaluate the efficacy data provided for in Part B of the Annex to Regulation (EU) No 284/2013 for the plant protection product, having regard to the degree of control or the extent of the effect desired and to relevant experimental conditions such as:

• (a) the choice of the crop or cultivar;

• (b) the agricultural and environmental (including climatic) conditions (if necessary for a specific use such data/information shall also be given for the time before and after application);

• (c) the presence and density of the target organism;

• (d) the development stage of crop and target organism;

• (e) the application rate of the plant protection product;

• (f) if required on the label, the application rate of adjuvant to be added;

• (g) the frequency and timing of the applications;

• (h) the type of application equipment to be used;

• (i) the need for any special cleaning measures for the application equipment before and after use.

• 1.3.4.Member States shall evaluate the efficacy of the plant protection product under the range of agricultural, plant health and environmental (including climatic) conditions likely to be encountered in practice in the area of proposed use. The evaluation shall include the compatibility with integrated pest management. In particular, consideration shall be paid to:

• (a) the level, consistency and duration of the effect sought in relation to the proposed dose;

• (b) the comparison of the proposed dose with a suitable reference product or products, where they exist, and an untreated control;

• (c) where relevant, the effect on yield or reduction of loss in storage, in terms of quantity and/or quality, in comparison with a suitable reference product or products, where they exist, and an untreated control;

• (d) the risk of occurrence and development of resistance or cross-resistance in populations of target organism.

• Where no suitable reference product exists, Member States shall evaluate the efficacy of the plant protection product to determine whether there is a consistent and defined benefit under the agricultural, plant health and environmental (including climatic) conditions likely to be encountered in practice in the area of proposed use.

• 1.3.5.Member States shall evaluate possible occurrence of adverse effects and their degree, on the treated crop after use of the plant protection product in accordance with the proposed conditions of use in comparison, where relevant, with a suitable reference product or products, where they exist, and/or an untreated control.

• (a) This evaluation shall take into consideration the following information:
• (i) efficacy data;
• (ii) other relevant information on the plant protection product such as nature of the plant protection product, dose, method of application, number and timing of applications, incompatibility with other crop treatments;
• (iii) all relevant information on the micro-organism, including biological properties e.g. mode of action, survival, host range specificity.

• (b) This evaluation shall include:
• (i) the nature, frequency, level and duration of observed phytotoxic/phytopathogenic effects and the agricultural, plant health and environmental (including climatic) conditions that affect them;
• (ii) differences between main cultivars with regard to their sensitivity to phytotoxic/phytopathogenic effects;
• (iii) the part of the treated crop or plant products where phytotoxic/phytopathogenic effects are observed;
• (iv) adverse impact on the yield of the treated crop or plant products in terms of quantity and/or quality, and on transformation processes;
• (v) adverse impact on treated plants or plant products to be used for propagation, in terms of viability, germination, sprouting, rooting and establishment;
• (vi) where micro-organisms are disseminated, in particular for weed control, any adverse impact on adjacent crops.

• 1.3.6.Where the proposed label of the plant protection product includes recommendations or requirements for the use of the plant protection product with other plant protection products and/or adjuvants as a tank mix, Member States shall make the evaluations referred to in points 1.3.3 to 1.3.5 with regard to the information supplied for the tank mix, and shall evaluate the appropriateness of the mix and of its conditions of use.

• 1.3.7.Member States shall evaluate potential effects (e.g. antagonism, fungicidal effects) on the activity of the micro-organism after mixing or spraying in sequence (or employing other relevant types of applications) with other plant protection products in accordance with the instructions proposed by the applicant on the label.

• 1.3.8.Where the available data indicate that the micro-organism has adverse effects on plants, or that metabolites of concern that have adverse effects on plants can persist in soil, and/or persist in/on plants in significant quantities after use of the plant protection product in accordance with the proposed conditions of use, Member States shall evaluate the degree of adverse effects on succeeding crops, taking into consideration the relevant information provided for under point 6.6 of Part B of the Annex to Regulation (EU) No 284/2013.

• 1.3.9.Member States shall evaluate potential negative effects of the micro-organism on beneficial organisms, either deliberately released, or as part of other practices (e.g. conservation biological control), taking into consideration the relevant information provided for under point 6.7 of Part B of the Annex to Regulation (EU) No 284/2013.

• 1.3.10.Where the proposed use of a plant protection product is intended to have an effect on vertebrates, Member States shall evaluate the mechanism by which this effect is obtained and the observed effects on the behaviour and health of the target animals. When the intended effect is to kill the target animal they shall evaluate the time necessary to obtain the death of the animal and the conditions under which death occurs.

• This evaluation shall take into consideration the following information:

• (a) all relevant information as provided for under Part B of the Annex to Regulation (EU) No 283/2013 and the results of the evaluation thereof, including the toxicological studies;

- (b) all relevant information on the plant protection product as provided for under Part B of the Annex to Regulation (EU) No 284/2013, including toxicological studies and efficacy data.

• 1.3.11.If there is evidence of development of resistance of the target organism towards the plant protection product requiring a resistance management strategy, the Member State shall evaluate if the submitted resistance management strategy, required according to point 6.4 of Part B of the Annex to Regulation (EU) No 284/2013, addresses this adequately and sufficiently.

1.4.   Identification/detection and quantification methods

Member States shall assess data on the identification/detection and quantification methods submitted in accordance with Section 4 of Part B of the Annex to Regulation (EU) No 283/2013 and Section 5 of Part B of the Annex to Regulation (EU) No 284/2013.

Member States shall evaluate the analytical methods proposed for control and monitoring purposes, of the micro-organism both in the plant protection product and, where relevant, in or on edible parts of treated crops. In addition, where relevant, the analytical methods relating to metabolites of concern and relevant impurities present in the plant protection product shall also be evaluated. Appropriate validation data shall be provided by the applicant as regards the pre-authorisation analytical methods and post-authorisation monitoring methods. Methods that are considered suitably validated for post-authorisation monitoring shall be clearly identified.

• 1.4.1.Analytical methods for the plant protection product

• The evaluation concerning analytical methods for the plant protection product shall take into consideration the relevant information provided for under point 4.1 of Part B of the Annex to Regulation (EU) No 283/2013 and under point 5.1 of Part B of the Annex to Regulation (EU) No 284/2013.

• 1.4.1.1.Analytical methods for micro-organisms

• Member States shall evaluate the methods proposed to identify and quantify the micro-organism, and especially methods that discriminate that micro-organism from closely related strains. These methods shall include the most appropriate molecular analytical and phenotypic methods, to allow unequivocal distinction between the micro-organism under assessment, and other strains belonging to the same species. Member States shall also evaluate the methods proposed to identify and quantify relevant contaminating micro-organisms.

• 1.4.1.2.Analytical methods for metabolites of concern, relevant impurities, additives, co-formulants, safeners and synergist

• Where applicable, Member States shall evaluate the analytical methods proposed to identify and quantify metabolites of concern identified according to point 2.8 of Part B of the Annex to Regulation (EU) No 283/2013, relevant impurities, co-formulants, safeners and synergists.

• 1.4.2.Analytical methods for the determination of residues and density of the micro-organism

• Member States shall take into consideration the relevant information provided for under point 4.2 of Part B of the Annex to Regulation (EU) No 283/2013 and under point 5.2 of Part B of the Annex to Regulation (EU) No 284/2013.

• 1.4.2.1.Density of the micro-organism

• Member States shall evaluate the methods proposed to identify and quantify the density of the micro-organism, where relevant, on and/or in crops, in foodstuffs and feeding stuffs, in animal and human body tissues and fluids, in relevant environmental compartment.

- 1.4.2.2.Residues of metabolites of concern

• Member States shall evaluate the analytical methods proposed to identify and quantify residues of metabolites of concern, where relevant, on and/or in crops, in foodstuffs and feeding stuffs, in animal and human body tissues and fluids, in relevant environmental compartment.

1.5.   Impact on human and animal health

Member States shall evaluate data on human and animal (i.e. species normally fed and kept by humans or food-producing animals) health submitted in accordance with Sections 5 and 6 of Part B of the Annex to Regulation (EU) No 283/2013 and Sections 7 and 8 of Part B of the Annex to Regulation (EU) No 284/2013.

The most important aspects that shall be assessed are:

• — infectivity and pathogenicity;

• — toxicity of metabolites of concern, safeners, synergists, and relevant impurities;

• — relevant antimicrobial activity of metabolites present in the plant protection product;

• — susceptibility to relevant antimicrobial agents to ensure the availability of sufficient treatment options in case of an opportunistic infection.

These aspects comprise a complex set of interactions between micro-organisms and the hosts, and need to be assessed in an integrated way and applying a weight of evidence approach.

An assessment of infectivity and pathogenicity is always necessary.

• 1.5.1.Effects on human or animal health arising from the plant protection product

• 1.5.1.1.Availability of sufficient treatment options against the micro-organism contained in the plant protection product shall be evaluated.

• 1.5.1.2.Member States shall evaluate infectivity and pathogenicity of the micro-organism and toxicity of metabolites of concern and relevant impurities. This evaluation shall take into consideration the following information:

• (a) the available information on infectivity and pathogenicity (e.g. based on biological properties, peer-reviewed literature, animal studies performed by the applicant) as provided for in Part B of the Annex to Regulation (EU) No 283/2013. For micro-organisms, infectivity and pathogenicity tests on animals may not always be suitable for extrapolation to humans due to differences between humans and test animals (e.g. immune system, microbiome). Micro-organisms might have a narrow host range, hence it cannot always be assumed that a micro-organism that does cause disease in the animals tested has the same result in humans, and vice-versa. Information available and provided by the applicant, as required in points 2.1, 2.3, 2.4, 2.6 and 5.1 of Part B of the Annex to Regulation (EU) No 283/2013, and/or retrieved from any other reliable sources (e.g. Qualified Presumption of Safety, peer-reviewed literature) may provide robust and reliable scientific indication on infectivity and pathogenicity of the micro-organism. Where an applicant provides a summary of information already available on infectivity and pathogenicity of the micro-organism, as described in point 5.2 of Part B of the Annex to Regulation (EU) No 283/2013, Member States shall assess such scientific evidence provided by the applicant using a weight of evidence approach, in order to evaluate whether the possible non-submission of certain studies required in points 5.3.1 and 5.4 of Part B of the Annex to Regulation (EU) No 283/2013 is justified. The evaluation shall take into consideration the following principles:
• — to avoid unnecessary animal testing, in a first instance infectivity and pathogenicity shall be assessed on the basis of existing information as provided for under point 5.2 of Part B of the Annex to Regulation (EU) No 283/2013;
• — infectivity and pathogenicity studies described in point 5.3.1 of Part B of the Annex to Regulation (EU) No 283/2013 may be necessary;
• — further specific studies may be required, as indicated in point 5.4 of Part B of the Annex to Regulation (EU) No 283/2013. For instance, if there are indications of infectivity, or any adverse effects, further testing shall be conducted, taking into account the exposure scenario and an observation period suitable for the micro-organisms, to allow observing a clearance in the host. The choice of appropriate timing of the observational period may be based on available information such as biological properties of the micro-organism or other relevant available information. The evaluation of available information and possible animal studies performed by the applicant, shall take into consideration the ability of the micro-organism to infect, persist or grow in the mammalian host, and its ability to cause effects or reactions in the host. Parameters that indicate the absence of ability to persist and multiply in the host, and the absence of ability to produce adverse effects in a host, include clearance from the body, if relevant. Replication temperatures may be different from mammalian body temperature, possibly indicating low likelihood of persistence and multiplication in the host. However, temperature adaptation may occur, and this parameter alone shall not be considered sufficient to conclude on persistence and multiplication of the micro-organism in the host. Evaluation based on relevant parameters of study results and available information shall lead to an assessment of the possible effects of occupational exposure.

• (b) the available information on toxicity (e.g. based on biological properties, peer-reviewed literature, animal studies performed by the applicant) as described in points 2.8 and 5.5 of Part B of the Annex to Regulation (EU) No 283/2013, and Section 7 of Part B of the Annex to Regulation (EU) No 284/2013. Information available on toxicity, such as from published literature, medical information, Integrated Approach to Testing and Assessment (IATA), results of CLP calculation rules in accordance with Regulation (EC) No 1272/2008, or bridging data from similar plant protection products, may provide robust and reliable scientific indication on the toxicity of relevant chemical substances contained in the plant protection product, and be used for classification and labelling. Where an applicant provides information available on human and animal toxicity of (chemical substances present in) the plant protection product (including in vitro and ex vivo data), Member States shall assess such scientific evidence provided by the applicant using a weight of evidence approach, in order to evaluate whether the possible non-submission of certain studies required in points 7.3.1 to 7.3.6 of Part B of the Annex to Regulation (EU) No 284/2013 is justified. The evaluation shall take into consideration the following principles:
• — to avoid unnecessary animal testing, in a first instance toxicity shall be assessed on the basis of existing information as provided for in point 7.2 of Part B of the Annex to Regulation (EU) No 284/2013;
• — toxicity studies may be necessary;
• — further specific studies may be required taking into consideration the intended use, according to the provisions of points 2.8 and 5.5 of Part B of the Annex to Regulation (EU) No 283/2013, and of points 7.4 and 7.7 of Part B of the Annex to Regulation (EU) No 284/2013. The evaluation of available information and possible animal studies performed by the applicant, shall take into consideration the ability of metabolites of concern, safeners, synergists, and relevant impurities to cause adverse effects on humans or animals. Evaluation based on relevant parameters of the tests shall lead to an assessment of the possible effects of non-dietary exposure, taking into account the intensity and duration of exposure under the proposed conditions of use.

• (c) other relevant information provided for under Part B of the Annex to Regulation (EU) No 284/2013, such as:
• — composition of the plant protection product,
• — nature of the plant protection product,
• — size, design and type of packaging.

• 1.5.1.3.Member States shall evaluate the effects to human and animal health related to non-dietary exposure of operators, workers, bystanders and residents to the micro-organism which is contained in the plant protection product, and the components which may be toxicologically relevant (e.g. metabolites of concern, relevant impurities), and which are likely to occur under the proposed conditions of use (including, in particular, dose, application method and climatic conditions). Realistic data on exposure levels to the plant protection product shall be used. If such data is not available, a suitable, and if possible validated, calculation model for plant protection products containing a micro-organism shall be employed. This evaluation shall take into consideration the following aspects:

• (a) on the basis of the information referred to in point 1.5.1.2 the following overall end-points shall be established for single or repeated operator, worker, bystanders and residents exposure following the intended use, as regards:
• — observed or expected infectivity and pathogenicity of the micro-organism(s) in the plant protection product,
• — observed or expected adverse toxicological effects of the plant protection product due to metabolites of concern safeners, synergists, and/or relevant impurities.

• (b) the evaluation of the exposure of the operator shall be made for each type of application method and application equipment proposed for the use of the plant protection product as well as for the different types and sizes of packaging containers to be used, taking into account mixing, loading operations, application of the plant protection product and cleaning and routine maintenance of application equipment. Where relevant, other authorised uses of the plant protection product in the area of envisaged use, concerning the same active substance or which give rise to the same residues, shall also be taken into account.

• (c) the possibility of adverse effects in humans shall be assessed with regard to measured or estimated levels of human exposure as compared to the tested dose levels, as provided for under Section 7 of Part B of the Annex to Regulation (EU) No 284/2013. This risk assessment shall include consideration of e.g. mode of action, physical and chemical properties of the micro-organism and other components in the plant protection product, such as metabolites of concern, safeners, synergists and relevant impurities.

• (d) other relevant information provided for under Part B of the Annex to Regulation (EU) No 284/2013, such as:
• — field of use and nature of the crop or target,
• — method of application including handling, mixing and loading of the plant protection product,
• — exposure reduction measures recommended,
• — protective clothing recommendations,
• — maximum application rate,
• — cleaning and routine maintenance of application equipment, , taking into account also seed treatment and good occupational practice,
• — recommendation to be followed after application, such as re-entry period and working duration,
• — minimum (spray) application volume stated on the label,
• — number and timing of applications, including intervals between applications,
• — re-entry periods, necessary waiting periods or other precautions to protect humans and animals,
• — dried residues of the plant protection products on plants and plant products after treatment, taking into account the capacity of the micro-organism to grow in situ, and the influence of factors such as temperature, UV light, pH and the presence of certain substances,
• — further information on exposure (e.g. operator/worker/bystander/resident exposure study, further activities whereby workers are exposed).

• 1.5.1.4.Member States shall evaluate information relating to the nature and characteristics of the packaging proposed, in particular the following aspects:

• (a) the type of packaging;

• (b) its dimensions and capacity;

• (c) the size of the opening;

• (d) the type of closure;

• (e) its strength, leak proofness and resistance to normal transport and handling;

• (f) its resistance to and compatibility with the contents.

• 1.5.1.5.Member States shall evaluate the nature and characteristics of the protective clothing and equipment proposed, in particular the following aspects:

• (a) obtainability and suitability;

• (b) effectiveness;

• (c) ease of wearing taking into account physical stress and climatic conditions;

• (d) resistance to and compatibility with the plant protection product.

• 1.5.1.6.Micro-organisms approved as active substances of plant protection product are not expected to be infective for humans. However, in order to ensure the availability of sufficient therapeutic measures in the event of opportunistic infections, Member States shall, where relevant based on biological properties of the micro-organism, evaluate the susceptibility of the micro-organism (except viruses) to antimicrobial agents.

• 1.5.2.Effects on human or animal health arising from residues of metabolites of concern

• The evaluation of consumer exposure to residues of metabolites, for which a hazard to human and animal health was identified, is based either on the applicant’s substantiated estimation or, in case where the substantiated estimation does not demonstrate an acceptable risk to consumers, on residue trials for metabolites of concern.

• In cases provided for in point 6.1 of Part B of the Annex to Regulation (EU) No 283/2013, also information on viable micro-organisms may be required and assessed with the information on residues of metabolites of concern.

• 1.5.2.1.Member States shall evaluate the potential residue levels of metabolites of concern for which a hazard was identified to human or animal health in points 2.8 and 5.5 of Part B of Annex to Regulation (EU) No 283/2013. This evaluation shall be performed for each proposed use and shall take into account the following information:

• — the intended use, including data on application and proposed pre-harvest intervals for envisaged uses or withholding periods or storage periods in the case of post-harvest uses;

• — analytical methods as provided for under point 5.2 of Part B of the Annex to Regulation (EU) No 284/2013;

• — the specific information on residues in/on treated plants, plant products, food and feed as provided for in Section 8 of Part B of the Annex to Regulation (EU) No 284/2013;

• — realistic possibilities for extrapolating data from one crop to another.

• Member States shall evaluate the potential exposure of consumers to metabolites of concern through diet using a suitable calculation model. This evaluation shall take into account, where relevant, other sources of the same metabolite of concern for which either maximum residue levels have been set in accordance with Regulation (EC) No 396/2005, or maximum tolerances have been set in accordance with Council Regulation (EEC) No 315/93 ([^E0014]) on contaminants in food.

• In cases where the estimation of residue levels does not demonstrate acceptable risk to consumers, Member States shall refine the evaluation, either based on data generated through residues trials, or on toxicity of metabolites of concern through determination of a toxicological endpoint, such as the acceptable daily intake (ADI), or, where appropriate, the Threshold of Toxicological Concern (TTC) value having regard to the specific information provided in accordance with point 6.2 of Part B of the Annex to Regulation (EU) No 283/2013.

• 1.5.2.2.Member States shall, where relevant, estimate the exposure of animals to residues of metabolites of concern, taking into account the residue levels estimated or measured in treated plants or plant products intended to be fed to animals.

• 1.5.2.3.Member States shall, where relevant, evaluate the residues of metabolites of concern estimated or measured in products of animal origin and their toxicity, taking into consideration the information provided for under points 2.8 and 5.5 and Section 6 of Part B of the Annex to Regulation (EU) No 283/2013.

- 1.5.2.4.Member States shall, where relevant, estimate the potential exposure of consumers to metabolites of concern through diet via the products of animal origin mentioned in point 1.5.2.3, using a suitable calculation model. This evaluation shall take account, where relevant, of other sources of the same metabolite of concern for which either maximum residue levels had been set in accordance with Regulation (EC) No 396/2005 (in case of authorised uses of the micro-organism producing it in biocidal or veterinary products), or maximum tolerances have been set in accordance with Regulation (EEC) No 315/93, where relevant.

• 1.5.2.5.Member States shall assess data on density of micro-organisms on edible parts of treated crops, if those are provided to support the estimation of residues of metabolites of concern produced in-situ. Data on density of micro-organisms on edible parts of treated crops is required only in few circumstances, as provided for in point 6.1 of Part B of Annex to Regulation (EU) No 283/2013, since micro-organisms which are infective or pathogenic to humans or other vertebrate animals will not be eligible for approval, and non-pathogenic micro-organisms are not expected to cause adverse effects to consumers, apart from possible production of metabolites of concern to be assessed in accordance with the points 1.5.2.1 to 1.5.2.4. Absence of viable micro-organisms on edible parts excludes the risk of in-situ production of metabolites of concern.

1.6.   Environmental occurrence of the micro-organism, including fate and behaviour of metabolites of concern

Member States shall assess data on the environmental occurrence of the micro-organism, including fate and behaviour of metabolites of concern, submitted in accordance with Section 7 of Part B of the Annex to Regulation (EU) No 283/2013 and Section 9 of Part B of the Annex to Regulation (EU) No 284/2013.

The evaluation of the environmental occurrence of an active substance that is a micro-organism needs to take into account that micro-organisms may be already occurring in relevant European environments, have the ability to replicate and have the ability to become dormant allowing for the formation of seed banks of micro-organisms.

The evaluation of the environmental exposure to the relevant components of the plant protection product, i.e. the micro-organism and metabolites of concern, shall be considered in order to conduct risk assessments as regards:

• — non-target organisms (concerning the exposure to the micro-organism and to the metabolites of concern);

• — humans via the environment (concerning the exposure to the metabolites of concern).

The evaluation of environmental exposure shall be based either on a substantiated estimation or, in case where this substantiated estimation does not demonstrate an acceptable risk, on experimental data. This experimental data may include measurements concerning the population dynamics of the micro-organism in specific environmental compartments upon use of the plant protection product, and the fate and behaviour of metabolites of concern.

• 1.6.1.Environmental occurrence of the micro-organism

• Member States shall evaluate the possibility of exposure of soil and/or surface water to the micro-organism based on the intended use and the biological properties of the micro-organism. If the possibility of exposure cannot be excluded, Member States shall evaluate the estimated exposure of soil and/or surface water after the use of the plant protection product in accordance with the intended conditions of use.

• For non-target organisms for which a hazard is identified, for instance based on the calculation of the predicted environmental density as provided for under point 7.1.1 of Part B of the Annex to Regulation (EU) No 283/2013, Member States shall evaluate the estimation of the exposure of the relevant non-target organisms to the micro-organism. This estimation shall be performed for each intended use and shall take into account the following information:

• — the data on the proposed good agricultural practice, including data on application;

• — nature of the plant protection product;

• — analytical methods, as provided for under point 4.2 of Part B of the Annex to Regulation (EU) No 283/2013, and under point 5.2 of Part B of the Annex to Regulation (EU) No 284/2013;

• — the specific information on occurrence of the micro-organism, e.g. possible increase of microbial density in the relevant environmental compartment compared to the occurrence at the relevant highest taxonomic level in European environments, as provided for under point 7.1 of Part B of the Annex to Regulation (EU) No 283/2013, and, where relevant, Section 9 of Part B of the Annex to Regulation (EU) No 284/2013;

• — data extrapolated from one crop to another, if considered realistic by Member States;

• — in addition, for micro-organisms not occurring in the relevant European environments at the relevant highest taxonomic level, and which are known to be pathogenic either for plants or for other organisms, the exposure of non-target organisms through colonised host organisms shall be evaluated taking into account also the information on the population density of the micro-organism in host organisms, and the exposure of non-target organisms to colonised host organisms.

• 1.6.2.Environmental fate and behaviour of the metabolites of concern

• In case a hazard has been identified for humans and/or non-target organisms due to a metabolite of concern, as provided for under points 2.8, 5.5 and 8.8 of Part B of the Annex to Regulation (EU) No 283/2013, and Sections 7 and 10 of Part B of the Annex to Regulation (EU) No 284/2013, Member States shall estimate the concentrations in the relevant environmental compartments that lead to exposure of humans and non-target organisms for which the hazard has been identified. This estimation shall be performed for each intended use and shall take into account the following information:

• — the data on the proposed good agricultural practice, including data on application;

• — nature of the plant protection product;

• — analytical methods, as provided for under point 4.2 of Part B of the Annex to Regulation (EU) No 283/2013, and under point 5.2 of Part B of the Annex to Regulation (EU) No 284/2013;

• — the specific information on environmental fate and behaviour of the metabolite of concern present in the plant protection product, as provided for under point 7.2 of Part B of the Annex to Regulation (EU) No 283/2013, and, if relevant, Section 9 of Part B of the Annex to Regulation (EU) No 284/2013;

- — if available and if submitted by the applicant to perform a qualitative exposure assessment as provided for under point 7.2.2 of Part B of the Annex to Regulation (EU) No 283/2013, on background level of the same metabolite of concern in the relevant environmental compartments;

• — realistic possibilities of extrapolating data from one crop to another.

1.7.   Effects on non-target organisms

Member States shall assess data on the risks to non-target organisms that the plant protection product may cause submitted in accordance with Section 8 Part B of the Annex to Regulation (EU) No 283/2013 and Section 10 Part B of the Annex to Regulation (EU) No 284/2013.

This assessment shall take into consideration the biology of the micro-organism, the exposure of non-target organisms under field condition according to the proposed conditions of use, and shall take into consideration possible increase of microbial density in the relevant environmental compartment compared to the occurrence of the micro-organism in European environments at the relevant highest taxonomic level.

To assess the possibility of exposure the following information shall be taken into consideration:

• (a) conditions of use;

• (b) information on fate and behaviour as provided in Section 9 of Part B of the Annex to Regulation (EU) No 284/2013.

Where an applicant does not perform certain studies required in Section 8 of Part B of the Annex to Regulation (EU) No 283/2013 and Section 10 of Part B of the Annex to Regulation (EU) No 284/2013, Member States shall assess if the scientific evidence provided by the applicant using a weight of evidence approach justifies the non-submission of these data.

• 1.7.1.Member States shall evaluate the risks to terrestrial vertebrates after the use of the plant protection product in accordance with the proposed conditions of use and taking into account the evaluation criteria provided for in point 1.6.

• (a) Member States shall evaluate the risks to terrestrial vertebrates due to the micro-organism and its potential to infect and multiply in the host, taking into account the following information on the micro-organism:
• — mode of action;
• — other biological properties;
• — studies on mammalian infectivity and pathogenicity;
• — studies on avian infectivity and pathogenicity;
• — other relevant information on terrestrial vertebrate infectivity and pathogenicity.

• (b) Member States shall evaluate the risk to terrestrial vertebrates due to toxic effects of the plant protection product in accordance with relevant provisions referred to in point 1.5.2.1 of Part A.

• 1.7.2.Member States shall evaluate the risks to aquatic organisms after the use of the plant protection product in accordance with the proposed conditions of use and taking into account the evaluation criteria provided for in point 1.6.

• (a) Member States shall evaluate the risks to aquatic organisms due to the micro-organism and its potential to infect and multiply the host, taking into account the following information on the micro-organism:
• — its mode of action;
• — other biological properties;
• — studies on infectivity and pathogenicity to aquatic organisms and/or other existing relevant information.

• (b) Member States shall evaluate the risk to aquatic organisms due to toxic effects of the plant protection product in accordance with relevant provisions referred to in point 1.5.2.2 of Part A.

• 1.7.3.Member States shall evaluate the risks to bees after the use of the plant protection product in accordance with the proposed conditions of use and taking into account the evaluation criteria provided for in point 1.6.

• (a) Member States shall evaluate the risks to bees due to the micro-organism and its potential to infect and multiply the host, taking into account the following information on the micro-organism:
• — its mode of action;
• — other biological properties;
• — studies on infectivity and pathogenicity to bees and/or other existing relevant information.

• (b) Member States shall evaluate the risk to bees due to toxic effects of the plant protection product, in accordance with relevant provisions referred to in point 1.5.2.3 of Part A.

• 1.7.4.Member States shall evaluate the risks to non-target arthropods other than bees after the use of the plant protection product in accordance with the proposed conditions of use and taking into account the evaluation criteria provided for in point 1.6. Member States shall pay particular attention to the risks to beneficial organisms deliberately released for biocontrol purposes.

• (a) Member States shall evaluate the risks to arthropods other than bees due to the micro-organism and its potential to infect and multiply the host, taking into account the following information on the micro-organism:
• — its mode of action;
• — other biological properties;
• — studies on infectivity and pathogenicity to honeybees and other arthropods and/or other existing relevant information.

• (b) Member States shall evaluate the risk to arthropods other than bees due to toxic effects of the plant protection product in accordance with relevant provisions referred to in point 1.5.2.4 of Part A.

• 1.7.5.Member States shall evaluate the risks to non-target meso- and macro-organisms in soil after the use of the plant protection product in accordance with the proposed conditions of use and taking into account the evaluation criteria provided for in point 1.6.

• (a) Member States shall evaluate the risks to meso- and macroorganisms in soil due to the micro-organism and its potential to infect and multiply the host, taking into account the following information on the micro-organism:
• — its mode of action;
• — other biological properties;
• — studies on infectivity and pathogenicity to meso- and macro-organisms and/or other existing relevant information.

• (b) Member States shall evaluate the risk to meso- and macro-organisms in soil due to toxic effects of the plant protection product in accordance with relevant provisions referred to in point 1.5.2.5 of part A.

• 1.7.6.Member States shall evaluate the risks to non-target terrestrial plants after the use of the plant protection product in accordance with the proposed conditions of use and taking into account the evaluation criteria provided for in point 1.6.

- (a) Member States shall evaluate the risks to terrestrial plants due to the micro-organism and its potential to infect and multiply the host, taking into account the following information on the micro-organism:

• — its mode of action;
• — other biological properties;
• — studies on infectivity and pathogenicity to terrestrial plants;
• — relatedness to known plant-pathogens.

• (b) Member States shall evaluate the risk to terrestrial plants due to toxic effects of the plant protection product.

1.8.   Conclusions and proposals

Member States shall draw conclusions on the need for further information and/or testing and the need for measures to limit the risks arising. Member States shall justify proposals for the classification and labelling of plant protection products.

2. DECISION-MAKING

The following principles shall apply without prejudice to the general principles referred to in Section 3 of the general introduction.

2.1.   Identity

• 2.1.1.For each authorisation granted the Member States shall ensure that the active substance concerned has been approved in accordance with Regulation (EC) No 1107/2009.

• 2.1.2.For each authorisation granted the Member States shall set the specification as regards the composition of the plant protection product. The minimum and maximum content of the micro-organism that is the active substance contained in the plant protection product shall be defined. The content of metabolites of concern, relevant impurities, co-formulants, safeners and synergists in the plant protection product, and relevant contaminating micro-organisms derived from the production process shall to the extent possible be defined. Member States shall verify, based on the information provided in the dossier, that quality assurance on the manufacturing process allows levels of metabolites of concern, relevant impurities, and relevant contaminating micro-organisms to be controlled to an acceptable level.

• 2.1.3.No authorisation shall be granted unless the manufacturing processes of the MPCA as manufactured and the plant protection product ensure that the production of MPCA as manufactured and plant protection product is of consistent quality, as set out in the specification set out in point 2.1.2.

• 2.1.4.In accordance with Article 48 of Regulation (EC) No 1107/2009 and Directive 2001/18/EC of the European Parliament and of the Council ([^E0015]), where the micro-organism has been genetically modified no authorisation shall be granted unless:

• — the evaluation conducted in accordance with Directive 2001/18/EC as well as the relevant decision taken by the Member States has been provided by the applicant in the dossier, and

- — an authorisation is granted in accordance with Part C of Directive 2001/18/EC under which that organism can be released into the environment, or placed on the market in a plant protection product.

• 2.1.5.Member States shall ensure that adequate quality control measures are applied to ensure the identity of the micro-organism and of the other components of the plant protection product.

2.2.   Biological and technical properties

• 2.2.1.No authorisation shall be granted for a plant protection product containing a micro-organism, if the micro-organism that is the active substance is a non-virulent variant of a plant pathogen virus, and the likelihood of regaining virulence and causing adverse effects in target and non-target plants through mutation, after application under the proposed conditions of use (including possible risk mitigation measures), is not negligible.

2.3.   Efficacy and absence of unacceptable effects on plants and plant products

• 2.3.1.Efficacy

• 2.3.1.1.No authorisation shall be granted where, on the basis of experience acquired or scientific evidence under normal agricultural, plant health and environmental (including climatic) conditions, the proposed uses include:

• — recommendations for the control of or protection against target organisms, or any other effects, which are not considered to cause adverse effects on crops, plants, or plant products; or,

• — effects which are not considered to be beneficial under those conditions.

• 2.3.1.2.No authorisation shall be granted when the proposed minimum dose, or a range of minimum doses, necessary to achieve sufficient efficacy against a target pest or any other relevant benefit across the proposed use, i.e. the minimum effective dose, is not justified based on available information or efficacy trials.

• 2.3.1.3.The level, consistency and duration of control or protection or other intended effects shall be at least higher than those observed in the untreated control, and if possible similar to a suitable reference product. Where relevant, yield response when the plant protection product is used, or reduction of loss in storage, shall be quantitatively and/or qualitatively at least higher than those observed for the untreated control, and if possible similar to a suitable reference product. The plant protection product shall be shown to give a defined benefit under the agricultural, plant health and environmental (including climatic) conditions in the area of proposed use.

• 2.3.1.4.Conclusions as to the efficacy of the plant protection product shall be valid for all areas and conditions in which it is to be authorised.

• 2.3.1.5.Where the proposed label includes recommendations or requirements for use of the plant protection product with other specified plant protection products and/or adjuvants in a tank mix, spray sequences, or employing other relevant types of applications, or any other recommendations (e.g. weather conditions, soil conditions, irrigation application), Member States shall not accept the recommendations or requirements unless they are justified, if applicable, by supporting information and comply with the principles referred to in points 2.3.1.1 to 2.3.1.4.

• 2.3.1.6.Where negative interactions are expected between the plant protection product containing the micro-organism(s) and other plant protection products, which the label requires to use in tank mix, spray sequences, or employing other relevant types of applications, or other common practices (e.g. conservation biological control), affecting the efficacy of one or the others, Member States shall set appropriate conditions in the authorisation of the plant protection product containing the micro-organism(s), and they shall ensure that a warning labelling phrase is indicating such negative interaction.

• 2.3.2.Absence of unacceptable effects on plants and plant products

• 2.3.2.1.There shall be no relevant phytotoxic or pathogenic effects on treated plants or plant products, except where the proposed label indicates appropriate limitations of use.

• 2.3.2.2.There shall be no reduction of yield at harvest below that which could be obtained without the use of the plant protection product, unless this reduction is compensated for by other advantages beside the plant protection action, such as an enhancement of the quality of the treated plants or plant products.

• 2.3.2.3.There shall be no unacceptable adverse effects on the quality of treated plants or plant products, except in the case of adverse effects on food and feed transformation processes (e.g. wine making, brewing, bread making, or silage productions as feed) where proposed label specifies that the plant protection product shall not be applied to crops to be used in transformation processes.

• 2.3.2.4.There shall be no unacceptable adverse effects on treated plants or plant products used for propagation or reproduction, such as effects on viability, germination, sprouting, rooting and establishment, except where proposed label specifies that the plant protection product shall not be applied to plants or plant products to be used for propagation or reproduction.

• 2.3.2.5.There shall be no unacceptable impact on succeeding crops, except where proposed label specifies that particular crops, which would be affected, shall not be grown following the treated crop.

• 2.3.2.6.There shall be no unacceptable impact on adjacent crops, except where proposed label specifies that the plant protection product should not be applied when particular sensitive adjacent crops are present.

- 2.3.2.7.Where the proposed label of the plant protection product includes recommendations or requirements for the use with other plant protection products and/or adjuvants as a tank mix, the same criteria referred to in points 2.3.2.1 to 2.3.2.6 apply in relation to the information supplied for the tank mix.

• 2.3.2.8.The proposed instructions for cleaning the application equipment shall be both practical and effective so that they can be applied with ease so as to ensure the removal of residual traces of the plant protection product which could subsequently cause damage.

2.4   Identification/detection and quantification methods