02013R0283 — EN — 21.11.2022 — 002.002

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►B COMMISSION REGULATION (EU) No 283/2013 of 1 March 2013 setting out the data requirements for active substances, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market (Text with EEA relevance) (OJ L 093 3.4.2013, p. 1)

Amended by:





Corrected by:









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COMMISSION REGULATION (EU) No 283/2013

of 1 March 2013

setting out the data requirements for active substances, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market

(Text with EEA relevance)







Article 1

Data requirements for active substances

The data requirements for the active substance provided for in Article 8(1)(b) of Regulation (EC) No 1107/2009 shall be as set out in the Annex to this Regulation.

Article 2

Repeal

Regulation (EU) No 544/2011 is repealed.

References to the repealed Regulation shall be construed as references to this Regulation

Article 3

Transitional measures as regards procedures concerning active substances

With respect to active substances, Regulation (EU) No 544/2011 shall continue to apply as regards the following:

(a) procedures concerning the approval of an active substance or an amendment to the approval of such a substance pursuant to Article 13 of Regulation (EC) No 1107/2009 for which the dossiers provided for in Article 8(1) and (2) thereof have been submitted by 31 December 2013;

(b) procedures concerning the renewal of approval of an active substance pursuant to Article 20 of Regulation (EC) No 1107/2009 for which the supplementary dossiers referred to in Article 9 of Commission Regulation (EU) No 1141/2010 ( 1 ) have been submitted by 31 December 2013.

Article 4

Transitional measures as regards procedures concerning plant protection products

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1. In case of applications for authorisation, as referred to in Article 28 of Regulation (EC) No 1107/2009, which concern plant protection products containing one or more active substances for which the dossiers have been submitted in compliance with Article 3 or for which the approval has not been renewed in accordance with Article 14 of Regulation (EC) No 1107/2009 and in accordance with Commission Implementing Regulation (EU) No 844/2012 ( 2 ), Regulation (EU) No 544/2011 shall continue to apply to the submission of data concerning this(these) active substance(s).

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2. By way of derogation from paragraph 1, from 1 January 2014 applicants may choose to apply the data requirements, as set out in the Annex to this Regulation. This choice shall be made in writing when submitting the application and shall be irrevocable.

Article 5

Entry into force and date of application

1. This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union .

2. For procedures concerning the renewal of approval of active substances whose approval expires on 1 January 2016 or later, this Regulation shall apply as of entry into force.

As regards all other procedures, it shall apply from 1 January 2014.

This Regulation shall be binding in its entirety and directly applicable in all Member States.









ANNEX

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INTRODUCTION

Information to be submitted, its generation and its presentation

A dossier shall be submitted in accordance with Part A if the active substance is:

(a) a chemical substance (including both semiochemicals and extracts from biological material), or

(b) a metabolite produced by a micro-organism where: — the metabolite is purified from the micro-organism; or — the metabolite is not purified from a producing micro-organism which is no longer capable of replication or of transferring genetic material.

A dossier shall be submitted in accordance with Part B if the active substance is:

(a) a micro-organism, either as a single strain or as a qualitatively defined combination of strains as they occur naturally or by manufacture, or

(b) a micro-organism, either as a single strain or as a qualitatively defined combination of strains as they occur naturally or by manufacture, and one or more metabolites produced by the micro-organism that are claimed to be part of the plant protection action (i.e. when the application of the metabolite(s) purified from the micro-organism would not cause the claimed plant protection action).

1. For the purposes of this Annex, the following definitions apply:

(1) ‘efficacy’ means a measure concerning the overall effect of the application of a plant protection product on the agricultural system in which it is used (i.e. which includes positive effects of treatment in performing the desired plant protection activity and negative effects such as development of resistance, phytotoxicity or reduction of qualitative or quantitative yield);

(2) ‘relevant impurity’ means a chemical impurity that is of concern for human health, animal health or the environment;

(3) ‘effectiveness’ means the capacity of the plant protection product to produce a positive effect regarding the desired plant protection activity;

(4) ‘toxicity’ means the degree of injury or damage in an organism caused by a toxin or a toxic substance;

(5) ‘toxin’ means a substance that is produced within living cells or organisms and is able to injure or cause damage in a living organism.

The information submitted shall meet the requirements set out in points 1.1 to 1.14.

1.1. The information shall be sufficient to evaluate the foreseeable risks, whether immediate or delayed, which the active substance may entail for humans, including vulnerable groups, animals and the environment and contain at least the information and results of the studies referred to in this Annex.

1.2. Any information including any known data on potentially harmful effects of the active substance, its metabolites and impurities on human and animal health or on their potential presence in groundwater shall be included.

1.3. Any information including any known data on potentially unacceptable effects of the active substance, its metabolites and impurities on the environment, plants and plant products shall be included.

1.4. The information shall include all relevant data from the scientific peer reviewed open literature on the active substance, relevant metabolites, and where relevant breakdown or reaction products and plant protection products containing the active substance and dealing with side-effects on human and animal health, the environment and non-target species. A summary of that data shall be provided.

1.5. The information shall include a full and unbiased report of the studies conducted as well as a full description of them. Such information shall not be required, where a justification is provided showing that:

(a) it is not necessary owing to the nature of the plant protection product or its proposed uses, or it is not scientifically necessary; or

(b) it is technically not possible to supply.

1.6. The simultaneous use of the active substance as a biocidal product or in veterinary medicine shall be reported. If the applicant for the application for the approval of the active substance in the plant protection product is identical to the one responsible for the notification of the active substance as a biocidal product or as a veterinary medicine, a summary of all relevant data submitted for approval of the biocidal product or the veterinary medicine shall be submitted. Where relevant, that summary shall include toxicological reference values and MRL proposals, taking into account any possible cumulative exposure due to different uses of the same substance based on scientific methods accepted by the competent authorities of the Union, together with information on residues, toxicology data and use of the plant protection product. If the applicant for the application for the approval of the active substance in the plant protection product is not identical to the one responsible for the notification of the active substance as a biocidal product or in veterinary medicine, a summary of all available data shall be submitted.

1.7. Where relevant, the information shall be generated using test methods, which are included in the list referred to in Section 6.

In the absence of suitable internationally or nationally validated test guidelines, test protocol discussed with and accepted by the competent authorities of the Union shall be used. Any deviations from test guidelines shall be described and justified.

1.8. The information shall include a full description of the test methods used.

1.9. The information shall include a list of endpoints for the active substance, where relevant.

1.10. Where relevant, the information shall be generated in accordance with Directive 2010/63/EU of the European Parliament and of the Council ( 3 ).

1.11. The information on the active substance, taken together with the information concerning one or more plant protection products containing the active substance and together, if appropriate, with the information concerning safeners and synergists and other components of the plant protection product, shall be sufficient to:

(a) permit an assessment of the risks for humans, associated with handling and use of plant protection products containing the active substance;

(b) for chemical active substances: permit an assessment of the risks for human and animal health, arising from residues of the active substance and its relevant metabolites, impurities and, where relevant, breakdown and reaction products remaining in water, air, food and feed;

(c) for active substances that are micro-organisms: permit an assessment of the risks for human and animal health, arising from residues of the metabolites of concern in water, air, food and feed;

(d) for chemical active substances: predict the distribution, fate and behaviour in the environment of the active substance and metabolites, breakdown and reaction products where they are of toxicological, or environmental significance, as well as the time courses involved;

(e) permit an assessment of the impact on non-target species (flora and fauna), including the impact on their behaviour, which are likely to be exposed to the active substance, its relevant metabolites and, where relevant, breakdown and reaction products, where they are of toxicological, pathogenic or environmental significance. Impact can result from single, prolonged or repeated exposure and can be direct or, where relevant, indirect, reversible or irreversible;

(f) evaluate the impact on biodiversity and the ecosystem;

(g) identify non-target species and populations for which risks arise because of potential exposure;

(h) permit an evaluation of short and long-term risks for non-target species - populations, communities and processes;

(i) classify the chemical active substance as to hazard in accordance with Regulation (EC) No 1272/2008 of the European Parliament and of the Council ( 4 );

(j) specify the pictograms, the signal words and relevant hazard and precautionary statements for the protection of human and animal health, non-target species and the environment, which are to be used for labelling;

(k) establish, where relevant, an acceptable daily intake (ADI) level for humans;

(l) establish, where relevant, acceptable operator exposure levels (AOEL);

(m) establish, where relevant, an acute reference dose (ARfD) for humans;

(n) identify relevant first aid measures as well as appropriate diagnostic and therapeutic measures to be followed in the event of poisoning or infection in humans;

(o) for chemical active substances: establish the isomeric composition and the possible metabolic conversion of the isomers, where relevant;

(p) establish residues definitions appropriate for risk assessment, where relevant;

(q) establish residues definitions appropriate for monitoring and enforcement purposes, where relevant;

(r) permit a risk assessment of consumer exposure, including, where relevant, a cumulative risk assessment deriving from exposure to more than one active substance;

(s) permit an estimation of the exposure of operators, workers, residents and bystanders including, where relevant, the cumulative exposure to more than one active substance;

(t) establish, where relevant, maximum residue levels and concentration/dilution factors in accordance with Regulation (EC) No 396/2005 of the European Parliament and of the Council ( 5 );

(u) permit an evaluation to be made as to the nature and extent of the risks for humans, animals (species normally fed and kept by humans or food-producing animals) and of the risks for other non-target vertebrate species;

(v) identify measures necessary to mitigate the risks identified for human and animal health, the environment and/or non-target species;

(w) for chemical active substances: decide whether or not the active substance has to be considered as persistent organic pollutant (POP), persistent, bio accumulative and toxic (PBT) or very persistent and very bio accumulative (vPvB) in accordance with the criteria laid down in Annex II to Regulation (EC) No 1107/2009;

(x) decide whether or not the active substance is to be approved;

(y) for chemical active substances: decide whether or not the active substance has to be considered as a candidate for substitution in accordance with the criteria laid down in Annex II to Regulation (EC) No 1107/2009;

(z) decide whether or not the active substance has to be considered as a low-risk active substance in accordance with the criteria laid down in Annex II to Regulation (EC) No 1107/2009;

(aa) specify conditions or restrictions to be associated with any approval.

1.12. Where relevant, tests shall be designed and data analysed using appropriate statistical methods. Details of the statistical analysis shall be reported transparently.

1.13. Exposure calculations shall refer to scientific methods accepted by the European Food Safety Authority, where available. Additional methods, when used, shall be justified.

1.14. For each section of this Annex, a summary of all data, information and evaluation made shall be submitted. This shall include a detailed and critical assessment in accordance with Article 4 of Regulation (EC) No 1107/2009.

2. The requirements set out in this Annex constitute the minimum set of data to be submitted. Member States may set out additional requirements at national level to address specific circumstances, specific exposure scenarios and specific patterns of use other than those taken into account for approval. The applicant shall pay careful attention to environmental, climatic and agronomic conditions when tests are set up subject to the approval by the Member State where the application has been submitted.

3. Good laboratory practice (GLP)

3.1. Tests and analyses shall be conducted in accordance with the principles laid down in Directive 2004/10/EC of the European Parliament and of the Council ( 6 ) where testing is done to obtain data on the properties or safety with respect to human or animal health or the environment.

3.2. By way of derogation from point 3.1:

(a) for active substances that are micro-organisms, tests and analyses done to obtain data on their properties and safety with respect to other aspects than human health may be conducted by official or officially recognised testing facilities or organisations which satisfy at least the requirements set out in points 3.2 and 3.3 of the Introduction of the Annex to Commission Regulation (EU) No 284/2013 ( 7 );

(b) for tests and analyses made to obtain data for minor crops required under points 6.3 and 6.5.2 of Part A: — the field phase may have been conducted by official or officially recognised testing facilities or organisations which satisfy the requirements as laid down in points 3.2 and 3.3 of the Introduction of the Annex to Regulation (EU) No 284/2013; — the analytical phase, if not realised in accordance with the principles of good laboratory practice (‘GLP principles’), shall be conducted by laboratories accredited for the relevant method in accordance with the European standard EN ISO/IEC 17025 ‘General requirements for the competence of testing and calibration laboratories’;

(c) studies conducted before the application of this Regulation, although not fully compliant with GLP principles or with current test methods, may be integrated into the assessment if carried out in accordance with scientifically validated test guidelines, thereby avoiding repeating animal tests, especially for carcinogenicity and reprotoxicity studies. This derogation from point 3.1 shall apply in particular to studies with vertebrate species.

4. Test material

4.1. A detailed description (specification) of the test material used shall be provided. Where tests are done using the active substance, the test material used shall comply with the specification that will be used in the manufacture of plant protection products to be authorised, except for radio-labelled chemicals or the purified chemical active substance.

4.2. Where studies are conducted using an active substance manufactured in the laboratory or in a pilot plant production system, the studies shall be repeated using the active substance as manufactured, unless the applicant shows that the test material used is essentially the same, for the purposes of toxicological, pathological, ecotoxicological, environmental and residue testing and assessment. In cases of uncertainty, bridging studies shall be submitted to serve as a basis for a decision as to the possible need for repetition of the studies.

4.3. Where studies are conducted using an active substance of different purity or which contains different impurities or different levels of impurities to the technical specification or where the active substance is a mixture of components, the significance of the differences shall be addressed either by data or scientific case. In cases of uncertainty, appropriate studies using the active substance as manufactured for commercial production shall be submitted to serve as a basis for a decision.

4.4. In the case of studies in which dosing extends over a certain period (for example, repeated dose studies), the same batch of active substance shall be used, if stability permits. Whenever a study implies the use of different doses, the relationship between dose and adverse effect shall be reported.

4.5. For chemical active substances, when tests are conducted using a purified chemical active substance (≥ 980 g/kg) of stated specification, the purity of such test material shall be as high as can be achieved using the best available technology and shall be reported. A justification shall be provided in cases where the degree of purity achieved is less than 980 g/kg. Such justification shall demonstrate that all technically feasible and reasonable possibilities for the production of the purified chemical active substance have been exhausted.

4.6. For chemical active substances, where radio-labelled test material of the chemical active substance is used, radio-labels shall be positioned at sites (one or more as necessary) to facilitate elucidation of metabolic and transformation pathways and to facilitate the investigation of the distribution of the active substance and of its metabolites, reaction and breakdown products.

5. Tests on vertebrate animals

5.1. Tests on vertebrate animals shall be undertaken only where no other validated methods are available. Alternative methods shall include in vitro methods or in silico methods. Reduction and refinement methods for in vivo testing shall also be encouraged to keep the number of animals used in testing to a minimum.

5.2. The principles of replacement, reduction and refinement of the use of vertebrate animals shall be taken into account in the design of the test methods, in particular when appropriate validated methods become available to replace, reduce or refine animal testing.

5.3. Study designs shall be carefully considered from ethical point of view, taking into account the scope for reduction, refinement and replacement of animal tests. For example, by including one or more additional dose groups or time points for blood sampling in one study, it may be possible to avoid the need for another study.

6. For purposes of information and of harmonisation the list of test methods and guidance documents relevant to the implementation of this Regulation shall be published in the Official Journal of the European Union. That list shall be regularly updated.

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PART A

CHEMICAL ACTIVE SUBSTANCES

TABLE OF CONTENTS SECTION 1. Identity of the active substance 1.1. Applicant 1.2. Producer 1.3. Common name proposed or ISO-accepted and synonyms 1.4. Chemical name (IUPAC and CA nomenclature) 1.5. Producer's development code numbers 1.6. CAS, EC and CIPAC numbers 1.7. Molecular and structural formula, molar mass 1.8. Method of manufacture (synthesis pathway) of the active substance 1.9. Specification of purity of the active substance in g/kg 1.10. Identity and content of additives (such as stabilisers) and impurities 1.10.1. Additives 1.10.2. Significant impurities 1.10.3. Relevant impurities 1.11. Analytical profile of batches SECTION 2. Physical and chemical properties of the active substance 2.1. Melting point and boiling point 2.2. Vapour pressure, volatility 2.3. Appearance (physical state, colour) 2.4. Spectra (UV/VIS, IR, NMR, MS), molar extinction at relevant wavelengths, optical purity 2.5. Solubility in water 2.6. Solubility in organic solvents 2.7. Partition coefficient n-octanol/water 2.8. Dissociation in water 2.9. Flammability and self-heating 2.10. Flash point 2.11. Explosive properties 2.12. Surface tension 2.13. Oxidising properties 2.14. Other studies SECTION 3. Further information on the active substance 3.1. Use of the active substance 3.2. Function 3.3. Effects on harmful organisms 3.4. Field of use envisaged 3.5. Harmful organisms controlled and crops or products protected or treated 3.6. Mode of action 3.7. Information on the occurrence or possible occurrence of the development of resistance and appropriate management strategies 3.8. Methods and precautions concerning handling, storage, transport or fire 3.9. Procedures for destruction or decontamination 3.10. Emergency measures in case of an accident SECTION 4. Analytical methods Introduction 4.1. Methods used for the generation of pre-approval data 4.1.1. Methods for the analysis of the active substance as manufactured 4.1.2. Methods for risk assessment 4.2. Methods for post-approval control and monitoring purposes SECTION 5. Toxicological and metabolism studies Introduction 5.1. Studies on absorption, distribution, metabolism and excretion in mammals 5.1.1. Absorption, distribution, metabolism and excretion after exposure by oral route 5.1.2. Absorption, distribution, metabolism and excretion after exposure by other routes 5.2. Acute toxicity 5.2.1. Oral 5.2.2. Dermal 5.2.3. Inhalation 5.2.4. Skin irritation 5.2.5. Eye irritation 5.2.6. Skin sensitisation 5.2.7. Phototoxicity 5.3. Short-term toxicity 5.3.1. Oral 28-day study 5.3.2. Oral 90-day study 5.3.3. Other routes 5.4. Genotoxicity testing 5.4.1. In vitro studies 5.4.2. In vivo studies in somatic cells 5.4.3. In vivo studies in germ cells 5.5. Long-term toxicity and carcinogenicity 5.6. Reproductive toxicity 5.6.1. Generational studies 5.6.2. Developmental toxicity studies 5.7. Neurotoxicity studies 5.7.1. Neurotoxicity studies in rodents 5.7.2. Delayed polyneuropathy studies 5.8. Other toxicological studies 5.8.1. Toxicity studies of metabolites 5.8.2. Supplementary studies on the active substance 5.8.3. Endocrine disrupting properties 5.9. Medical data 5.9.1. Medical surveillance on manufacturing plant personnel and monitoring studies 5.9.2. Data collected on humans 5.9.3. Direct observations 5.9.4. Epidemiological studies 5.9.5. Diagnosis of poisoning (determination of active substance, metabolites), specific signs of poisoning, clinical tests 5.9.6. Proposed treatment: first aid measures, antidotes, medical treatment 5.9.7. Expected effects of poisoning SECTION 6. Residues in or on treated products, food and feed 6.1. Storage stability of residues 6.2. Metabolism, distribution and expression of residues 6.2.1. Plants 6.2.2. Poultry 6.2.3. Lactating ruminants 6.2.4. Pigs 6.2.5. Fish 6.3. Magnitude of residue trials in plants 6.4. Feeding studies 6.4.1. Poultry 6.4.2. Ruminants 6.4.3. Pigs 6.4.4. Fish 6.5. Effects of processing 6.5.1. Nature of the residue 6.5.2. Distribution of the residue in inedible peel and pulp 6.5.3. Magnitude of residues in processed commodities 6.6. Residues in rotational crops 6.6.1. Metabolism in rotational crops 6.6.2. Magnitude of residues in rotational crops 6.7. Proposed residue definitions and maximum residue levels 6.7.1. Proposed residue definitions 6.7.2. Proposed maximum residue levels (MRLs) and justification of the acceptability of the levels proposed 6.7.3. Proposed maximum residue levels (MRLs) and justification of the acceptability of the levels proposed for imported products (import tolerance) 6.8. Proposed safety intervals 6.9. Estimation of the potential and actual exposure through diet and other sources 6.10. Other studies 6.10.1. Residue level in pollen and bee products SECTION 7. Fate and behaviour in the environment 7.1. Fate and behaviour in soil 7.1.1. Route of degradation in soil 7.1.1.1. Aerobic degradation 7.1.1.2. Anaerobic degradation 7.1.1.3. Soil photolysis 7.1.2. Rate of degradation in soil 7.1.2.1. Laboratory studies 7.1.2.1.1. Aerobic degradation of the active substance 7.1.2.1.2. Aerobic degradation of metabolites, breakdown and reaction products 7.1.2.1.3. Anaerobic degradation of the active substance 7.1.2.1.4. Anaerobic degradation of metabolites, breakdown and reaction products 7.1.2.2. Field studies 7.1.2.2.1. Soil dissipation studies 7.1.2.2.2. Soil accumulation studies 7.1.3. Adsorption and desorption in soil 7.1.3.1. Adsorption and desorption 7.1.3.1.1. Adsorption and desorption of the active substance 7.1.3.1.2. Adsorption and desorption of metabolites, breakdown and reaction products 7.1.3.2. Aged sorption 7.1.4. Mobility in soil 7.1.4.1. Column leaching studies 7.1.4.1.1. Column leaching of the active substance 7.1.4.1.2. Column leaching of metabolites, breakdown and reaction products 7.1.4.2. Lysimeter studies 7.1.4.3. Field leaching studies 7.2. Fate and behaviour in water and sediment 7.2.1. Route and rate of degradation in aquatic systems (chemical and photochemical degradation) 7.2.1.1. Hydrolytic degradation 7.2.1.2. Direct photochemical degradation 7.2.1.3. Indirect photochemical degradation 7.2.2. Route and rate of biological degradation in aquatic systems 7.2.2.1. ‘Ready biodegradability’ 7.2.2.2. Aerobic mineralisation in surface water 7.2.2.3. Water/sediment study 7.2.2.4. Irradiated water/sediment study 7.2.3. Degradation in the saturated zone 7.3. Fate and behaviour in air 7.3.1. Route and rate of degradation in air 7.3.2. Transport via air 7.3.3. Local and global effects 7.4. Definition of the residue 7.4.1. Definition of the residue for risk assessment 7.4.2. Definition of the residue for monitoring 7.5. Monitoring data SECTION 8. Ecotoxicological studies Introduction 8.1. Effects on birds and other terrestrial vertebrates 8.1.1. Effects on birds 8.1.1.1. Acute oral toxicity to birds 8.1.1.2. Short-term dietary toxicity to birds 8.1.1.3. Sub-chronic and reproductive toxicity to birds 8.1.2. Effects on terrestrial vertebrates other than birds 8.1.2.1. Acute oral toxicity to mammals 8.1.2.2. Long-term and reproductive toxicity to mammals 8.1.3. Active substance bioconcentration in prey of birds and mammals 8.1.4. Effects on terrestrial vertebrate wildlife (birds, mammals, reptiles and amphibians) 8.1.5. Endocrine disrupting properties 8.2. Effects on aquatic organisms 8.2.1. Acute toxicity to fish 8.2.2. Long-term and chronic toxicity to fish 8.2.2.1. Fish early life stage toxicity test 8.2.2.2. Fish full life cycle test 8.2.2.3. Bioconcentration in fish 8.2.3. Endocrine disrupting properties 8.2.4. Acute toxicity to aquatic invertebrates 8.2.4.1. Acute toxicity to Daphnia magna 8.2.4.2. Acute toxicity to an additional aquatic invertebrate species 8.2.5. Long-term and chronic toxicity to aquatic invertebrates 8.2.5.1. Reproductive and development toxicity to Daphnia magna 8.2.5.2. Reproductive and development toxicity to an additional aquatic invertebrate species 8.2.5.3. Development and emergence in Chironomus riparius 8.2.5.4. Sediment dwelling organisms 8.2.6. Effects on algal growth 8.2.6.1. Effects on growth of green algae 8.2.6.2. Effects on growth of an additional algal species 8.2.7. Effects on aquatic macrophytes 8.2.8. Further testing on aquatic organisms 8.3. Effect on arthropods 8.3.1. Effects on bees 8.3.1.1. Acute toxicity to bees 8.3.1.1.1. Acute oral toxicity 8.3.1.1.2. Acute contact toxicity 8.3.1.2. Chronic toxicity to bees 8.3.1.3. Effects on honeybee development and other honeybee life stages 8.3.1.4. Sub-lethal effects 8.3.2. Effects on non-target arthropods other than bees 8.3.2.1. Effects on Aphidius rhopalosiphi 8.3.2.2. Effects on Typhlodromus pyri 8.4. Effects on non-target soil meso- and macrofauna 8.4.1. Earthworm — sub-lethal effects 8.4.2. Effects on non-target soil meso- and macrofauna (other than earthworms) 8.4.2.1. Species level testing 8.5. Effects on soil nitrogen transformation 8.6. Effects on terrestrial non-target higher plants 8.6.1. Summary of screening data 8.6.2. Testing on non-target plants 8.7. Effects on other terrestrial organisms (flora and fauna) 8.8. Effects on biological methods for sewage treatment 8.9. Monitoring data SECTION 9. Literature data SECTION 10. Classification and labelling

SECTION 1

Identity of the active substance

The information provided shall be sufficient to precisely identify each active substance and define it in terms of its specification and nature.

1.1. Applicant

The name and address of the applicant shall be provided, as well as the name, position, telephone, e-mail address and telefax number of a contact point.

1.2. Producer

The name and address of the producer of the active substance shall be provided, as well as the name and address of each manufacturing plant in which the active substance is manufactured. A contact point (name, telephone, e-mail address and telefax number) shall be provided. Where following approval of the active substances, there are changes in the location or number of producers, the information required shall again be notified to the Commission, the Authority and the Member States.

1.3. Common name proposed or ISO-accepted, and synonyms

The International Organization for Standardization (ISO) common name, or proposed ISO common name and where relevant, other proposed or accepted common names (synonyms), including the name (title) of the nomenclature authority concerned, shall be provided.

1.4. Chemical name (IUPAC and CA nomenclature)

The chemical name as given in Part III of Annex VI to Regulation (EC) No 1272/2008, or, if not included in that Regulation, in accordance with both the International Union of Pure and Applied Chemistry (IUPAC) and Chemical Abstracts (CA) nomenclature, shall be provided, where applicable.

1.5. Producer's development code numbers

Code numbers used to identify the active substance, and where available, formulations containing the active substance, during development work, shall be reported. For each code number reported, the material to which it relates, the period for which it was used, and the Member States or other countries in which it was used and is being used, shall be stated.

1.6. CAS, EC and CIPAC numbers

Chemical Abstracts Service (CAS), European Commission (EC) and Collaborative International Pesticides Analytical Council (CIPAC) numbers, where they exist, shall be reported.

1.7. Molecular and structural formula, molar mass

The molecular formula, molar mass and structural formula of the active substance, and where relevant, the structural formula of each isomer present in the active substance, shall be provided.

For plant extracts, a different approach may be taken if adequately justified.

1.8. Method of manufacture (synthesis pathway) of the active substance

The method of manufacture, in terms of the identity (name, CAS number, structural formula) and purity of the starting materials and whether they are commercially available, the chemical pathways involved, and the identity of impurities present in the final product, shall be provided, for each manufacturing plant. Detailed information shall be given as to the origin of those impurities. Each impurity shall be categorised as resulting from side reactions, impurities in the starting material, remaining reaction intermediates or starting materials. Their toxicological, ecotoxicological and environmental relevance shall be addressed. This information shall also include impurities that are not detected but that could theoretically be formed. Generally process engineering information is not required.

Where the required information is provided for a pilot plant production system, that information shall again be provided once industrial scale production methods and procedures have stabilised. Where available, industrial scale data shall be provided before approval under Regulation (EC) No 1107/2009. Where data on industrial scale production are not available, a justification shall be provided.

1.9. Specification of purity of the active substance in g/kg

The minimum content in g/kg of pure active substance in the manufactured material used for production of plant protection products, shall be reported. A justification shall be provided for the minimum content proposed in the specification; this shall include a statistical analysis of the data on at least five representative batches, as referred to in point 1.11. Additional supporting data may be provided to further justify the technical specification.

Where the required information is provided for a pilot plant production system, that information shall again be provided once industrial scale production methods and procedures have stabilised. Where available, industrial scale data shall be provided before approval under Regulation (EC) No 1107/2009. Where data on industrial scale production are not available, a justification shall be provided.

If the active substance is manufactured as technical concentrate (TK), the minimum and maximum content of the pure active substance shall be given, along with its content in the theoretical dry weight material.

If the active substance is a mixture of isomers, the ratio or the ratio range of the content of isomers shall be provided. The relative biological activity of each isomer, both in terms of efficacy and toxicity, shall be reported.

For plant extracts, a different approach may be taken if adequately justified.

1.10. Identity and content of additives (such as stabilisers) and impurities

The minimum and maximum content in g/kg of each additive shall be provided.

The maximum content in g/kg of each further component other than additives shall also be provided.

If the active substance is manufactured as technical concentrate (TK), the maximum content of each impurity shall be given, along with their content in the theoretical dry weight material.

Isomers that are not part of the ISO common name are considered as impurities.

Where the information provided does not fully identify a component (for example condensates), detailed information on the composition shall be provided for each such component.

Where the required information is provided for a pilot plant production system, that information shall again be provided once industrial scale production methods and procedures have stabilised. Where available, industrial scale data shall be provided before approval under Regulation (EC) No 1107/2009. Where data on industrial scale production are not available, a justification shall be provided.

For plant extracts, a different approach may be taken if adequately justified.

1.10.1. Additives

The trade name of components added to the active substance, prior to manufacture of the plant protection product, to preserve stability and facilitate ease of handling, hereinafter ‘additives’, shall also be provided. The following information shall, where relevant, be provided for such additives:

(a) chemical name in accordance with IUPAC and CA nomenclature;

(b) ISO common name or proposed common name if available;

(c) CAS number, EC number;

(d) molecular and structural formula;

(e) molar mass;

(f) minimum and maximum content in g/kg; and

(g) function (for example stabiliser).

1.10.2. Significant impurities

Impurities present in quantities of 1 g/kg or more shall be considered as significant. For significant impurities the following information, where relevant, shall be provided:

(a) chemical name in accordance with IUPAC and CA nomenclature;

(b) ISO common name or proposed common name, if available;

(c) CAS number, EC number;

(d) molecular and structural formula;

(e) molar mass; and

(f) maximum content in g/kg.

Information on how the structural identity of the impurities was determined shall be given.

1.10.3. Relevant impurities

Impurities that are particularly undesirable because of their toxicological, ecotoxicological or environmental properties, shall be considered as relevant. For relevant impurities the following information, where relevant, shall be provided:

(a) chemical name in accordance with IUPAC and CA nomenclature;

(b) ISO common name or proposed common name if available;

(c) CAS number, EC number;

(d) molecular and structural formula;

(e) molar mass; and

(f) maximum content in g/kg.

Information on how the structural identity of the impurities was determined shall be reported.

1.11. Analytical profile of batches

At least five representative batches from recent and current industrial scale production of the active substance shall be analysed for content of pure active substance, impurities, additives and each further component other than additives, as appropriate. All of the representative batches shall be within the last five years of manufacture. Where data from the last five years of production are not available, a justification shall be provided. The analytical results reported shall include quantitative data, in terms of g/kg content, for all components present in quantities of 1 g/kg or more and typically should account for at least 980 g/kg of the material analysed. For plant extracts and semiochemicals (such as pheromones), justified exemptions can be made. The statistical basis for the content proposed in the technical specification shall be explained (for example: maximum level found in practice, average plus three standard deviations of levels found in practice, etc.). Supporting data may be provided to further justify the technical specification. The actual content of components which are particularly undesirable because of their toxicological, ecotoxicological or environmental properties shall be determined and reported even if present in quantities below 1 g/kg. Data reported shall include the results of the analysis of individual samples and a summary of that data, to show the minimum, maximum and mean content of each relevant component.

Where an active substance is produced in different plants the information set out in the first paragraph shall be provided for each of the plants separately.

In addition, where relevant, samples of the active substance produced at laboratory scale or in pilot production systems, shall be analysed, if such material was used in generating toxicological or ecotoxicological data. If this data is not available a justification shall be provided.

Where the information provided relates to a pilot plant production system, the information required shall again be provided once industrial scale production methods and procedures have stabilised. Where available, industrial scale data shall be provided before approval under Regulation (EC) No 1107/2009. Where data on industrial scale production are not available, a justification shall be provided.

SECTION 2

Physical and chemical properties of the active substance

2.1. Melting point and boiling point

The melting point or where appropriate the freezing or solidification point of purified active substance shall be determined and reported. Measurements shall be taken up to 360 °C.

The boiling point of purified active substance shall be determined and reported. Measurements shall be taken up to 360 °C.

Where melting point or boiling point cannot be determined because of decomposition or sublimation, the temperature at which decomposition or sublimation occurs shall be reported.

2.2. Vapour pressure, volatility

The vapour pressure of purified active substance at 20 °C or 25 °C shall be reported. Where vapour pressure is less than 10–5 Pa at 20 °C the vapour pressure at 20 °C or 25 °C shall be estimated by a vapour pressure curve with measurements at higher temperatures.

In the case of active substances which are solids or liquids, volatility (Henry’s law constant) of purified active substance shall be determined or calculated from its water solubility and vapour pressure and be reported (in Pa × m3 × mol–1).

2.3. Appearance (physical state, colour)

A description of both the colour, if any, and the physical state of both the active substance as manufactured and purified active substance, shall be provided.

2.4. Spectra (UV/VIS, IR, NMR, MS), molar extinction at relevant wavelengths, optical purity

The following spectra, including a table of signal characteristics needed for interpretation, shall be determined and reported: ultraviolet/visible (UV/VIS), infrared (IR), nuclear magnetic resonance (NMR) and mass spectra (MS) of purified active substance.

Molar extinction at relevant wavelengths shall be determined and reported (ε in L × mol–1 × cm–1). Relevant wavelengths include all maxima in the UV/visible absorption spectrum, as well as the wavelength range of 290-700 nm.

In the case of active substances which are resolved optical isomers, the optical purity shall be measured and reported.

Where necessary for the identification of the impurities considered to be of toxicological, ecotoxicological or environmental significance, the UV/visible absorption spectra, IR, NMR and MS spectra, shall be determined and reported.

2.5. Solubility in water

The water solubility of purified active substances under atmospheric pressure shall be determined and a value reported for 20 °C. These water solubility determinations shall be made in the neutral range (that is to say in distilled water in equilibrium with atmospheric carbon dioxide). If the pKa is between 2 and 12, water solubility shall also be determined in the acidic range (pH 4 to 5) and in the alkaline range (pH 9 to 10). Where the stability of the active substance in aqueous media is such that water solubility cannot be determined, a justification based on test data shall be provided.

2.6. Solubility in organic solvents

The solubility of the active substances as manufactured or purified active substance in the following organic solvents at 15 to 25 °C shall be determined and reported if less than 250 g/L; the temperature applied shall be specified. Results shall be reported as g/L.

(a) Aliphatic hydrocarbon: preferably heptane

(b) Aromatic hydrocarbon: preferably toluene

(c) Halogenated hydrocarbon: preferably dichloromethane

(d) Alcohol: preferably methanol or isopropyl alcohol

(e) Ketone: preferably acetone

(f) Ester: preferably ethyl acetate.

If for a particular active substance, one or more of those solvents is unsuitable (for example reacts with test material), alternative solvents may be used instead. In such cases, choices of solvents shall be justified in terms of their structure and polarity.

2.7. Partition coefficient n-octanol/water

The n-octanol/water partition coefficient (Kow or log Pow) of purified active substance and of all components of the residue definition for risk assessment shall be determined and reported for 20 °C or 25 °C. The effect of pH (4 to 10) shall be investigated when the active substance has a pKa value between 2 and 12.

2.8 Dissociation in water

Where dissociation in water occurs, the dissociation constants (pKa values) of the purified active substance shall be determined and reported for 20 °C. The identity of the dissociated species formed, based on theoretical considerations, shall be reported. If the active substance is a salt the pKa value of the non-dissociated form of the active substance shall be given.

2.9. Flammability and self-heating

The flammability and self-heating of active substances as manufactured shall be determined and reported. A theoretical estimation based on structure shall be accepted if it meets the criteria set out in Appendix 6 of the United Nations’ Recommendations on the Transport of Dangerous Goods Manual of Tests and Criteria ( 8 ). In justified cases, data for purified active substance may be used.

2.10. Flash point

The flash point of active substances as manufactured with a melting point below 40 °C shall be determined and reported. In justified cases, data for purified active substance may be used.

2.11. Explosive properties

The explosive properties of active substances as manufactured shall be determined and reported. A theoretical estimation based on structure shall be accepted if it meets the criteria set out in Appendix 6 of the United Nations ‘Recommendations on the Transport of Dangerous Goods, Manual of Tests and Criteria’. In justified cases, data for purified active substance may be used.

2.12. Surface tension

The surface tension of purified active substance shall be determined and reported.

2.13. Oxidising properties

The oxidising properties of active substances as manufactured, shall be determined and reported. A theoretical estimation based on structure shall be accepted if it meets the criteria set out in Appendix 6 of the United Nations ‘Recommendations on the Transport of Dangerous Goods Manual of Tests and Criteria’. In justified cases data for purified active substance may be used.

2.14. Other studies

Supplementary studies necessary for the classification of the active substance by hazard shall be carried out in accordance with Regulation (EC) No 1272/2008.

SECTION 3

Further information on the active substance

3.1. Use of the active substance

The information provided shall describe the intended purposes for which plant protection products containing the active substance are used, or are to be used and the dose and manner of their use or proposed use.

3.2. Function

The function shall be specified from among the following:

(a) acaricide;

(b) bactericide;

(c) fungicide;

(d) herbicide;

(e) insecticide;

(f) molluscicide;

(g) nematicide;

(h) plant growth regulator;

(i) repellent;

(j) rodenticide;

(k) semio-chemical;

(l) talpicide;

(m) viricide;

(n) other (shall be specified by the applicant).

3.3. Effects on harmful organisms

The nature of the effects on harmful organisms shall be stated:

(a) contact action;

(b) stomach action;

(c) inhalation action;

(d) fungitoxic action;

(e) fungistatic action;

(f) desiccant;

(g) reproduction inhibitor;

(h) other (shall be specified by the applicant).

It shall be stated whether or not the active substance is translocated in plants and where relevant whether such translocation is apoplastic, symplastic or both.

3.4. Field of use envisaged

The fields of use, existing and proposed, for plant protection products containing the active substance shall be specified from among the following:

(a) field use, such as agriculture, horticulture, forestry and viticulture;

(b) protected crops;

(c) amenity;

(d) weed control on non-cultivated areas;

(e) home gardening;

(f) house plants;

(g) plant products storage practice;

(h) other (shall be specified by applicant).

3.5. Harmful organisms controlled and crops or products protected or treated

Details of existing use and the intended use in terms of crops, groups of crops, plants, or plant products treated and where relevant protected shall be provided.

Where relevant, details of harmful organisms against which protection is afforded shall be provided.

Where relevant, effects achieved, such as sprout suppression, retardation of ripening, reduction in stem length, enhanced fertilisation shall be reported.

3.6. Mode of action

To the extent that it has been elucidated, a statement shall be provided as to the mode of action of the active substance in terms, where relevant, of the biochemical and physiological mechanisms and biochemical pathways involved. Where available, the results of relevant experimental studies shall be reported.

Where it is known that to exert its intended effect, the active substance has to be converted to a metabolite or breakdown product following application or use of plant protection products containing it, the following information shall be provided for active metabolite or breakdown products:

(a) chemical name in accordance with IUPAC and CA nomenclature;

(b) ISO common name or proposed common name;

(c) CAS-number EC number;

(d) molecular and structural formula; and

(e) molar mass.

The information referred to in points (a) to (e) shall be cross referenced to and drawing on information provided under Sections 5 to 8, where relevant.

Available information relating to the formation of active metabolites and breakdown products shall be provided. Such information shall include:

— the processes, mechanisms and reactions involved,

— kinetic and other data concerning the rate of conversion and if known the rate limiting step,

— environmental and other factors effecting the rate and extent of conversion.

3.7. Information on the occurrence or possible occurrence of the development of resistance and appropriate management strategies

Where available, information on the occurrence or possible occurrence of the development of resistance or cross-resistance shall be provided.

Appropriate risk management strategies shall be addressed for national/regional areas.

3.8. Methods and precautions concerning handling, storage, transport or fire

A safety data sheet pursuant to Article 31 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council ( 9 ) shall be provided for all active substances.

The studies, data and information submitted, together with other relevant studies, data and information, shall both specify and justify the methods and precautions to be followed in the event of fire. The possible products of combustion in the event of fire shall be estimated, based on the chemical structure and the chemical and physical properties of the active substance.

3.9. Procedures for destruction or decontamination

In many cases the preferred or sole means to safely dispose of active substances, contaminated materials, or contaminated packaging is through controlled incineration in a licensed incinerator. Such incineration shall be carried out in accordance with the criteria set out in Council Directive 94/67/EC ( 10 ).

Other methods to dispose of the active substance, contaminated packaging and contaminated materials, where proposed, shall be fully described. Data shall be provided for such methods, to establish their effectiveness and safety.

3.10. Emergency measures in case of an accident

Procedures for the decontamination of water and soil in case of an accident shall be provided.

The studies, data and information submitted, together with other relevant studies, data and information, shall demonstrate the suitability of measures proposed for use in emergency situations.

SECTION 4

Analytical methods

Introduction

The provisions of this Section cover analytical methods used for the generation of pre-approval data and required for post-approval control and monitoring purposes.

Descriptions of methods shall be provided and include details of equipment, materials and conditions used.

On request, the following shall be provided:

(a) analytical standards of the purified active substance;

(b) samples of the active substance as manufactured;

(c) analytical standards of relevant metabolites and all other components included in all monitoring residue definitions;

(d) samples of reference substances for the relevant impurities.

Where possible, the standards referred to in points (a) and (c) shall be made commercially available and, on request, the distributing company shall be named.

4.1. Methods used for the generation of pre-approval data

4.1.1. Methods for the analysis of the active substance as manufactured

Methods shall be provided, with a full description, for the determination of:

(a) pure active substance in the active substance as manufactured and specified in the dossier submitted in support of approval under Regulation (EC) No 1107/2009;

(b) significant and relevant impurities and additives (such as stabilisers) in the active substance as manufactured.

The applicability of existing CIPAC methods shall be assessed and reported. In case of use of a CIPAC method, further validation data shall not be required, but example chromatograms shall be submitted, where available.

The specificity of the methods shall be determined and reported. In addition, the extent of interference by other substances present in the active substance as manufactured (such as impurities or additives), shall be determined.

The linearity of methods shall be determined and reported. The calibration range shall extend (by at least 20 %) beyond the highest and lowest nominal content of the analyte in relevant analytical solutions. Either duplicate determinations at three or more concentrations or single determinations at five or more concentrations shall be made. The equation of the calibration line and the correlation coefficient shall be reported and a typical calibration plot shall be submitted. In cases where a non-linear response is used, this shall be justified by the applicant.

The precision (repeatability) of the methods shall be determined and reported. A minimum of five replicate sample determinations shall be made and the mean, the relative standard deviation and the number of determinations shall be reported.

For the determination of the active substance content, an assessment of accuracy of the method shall be made by an assessment of the interference and precision.

As regards additives and significant and relevant impurities:

— the accuracy of the methods shall be determined on at least two representative samples at levels appropriate to the batch data and material specification. The mean and the relative standard deviation of the recoveries shall be reported,

— the experimental determination of the limit of quantification (LOQ) shall not be required. However, it shall be demonstrated that the methods are sufficiently precise to analyse significant impurities at levels appropriate to the material specification and relevant impurities at a concentration equivalent to at least 20 % less than the specification limit.

4.1.2. Methods for risk assessment

Methods shall be submitted, with a full description, for the determination of non-isotope-labelled residues in all areas of the dossier, as set out in detail in the following points:

(a) in soil, water, sediment, air and any additional matrices used in support of environmental fate studies;

(b) in soil, water and any additional matrices used in support of efficacy studies;

(c) in feed, body fluids and tissues, air and any additional matrices used in support of toxicology studies;

(d) in body fluids, air and any additional matrices used in support of operator, worker, resident and bystander exposure studies;

(e) in or on plants, plant products, processed food commodities, food of plant and animal origin, feed and any additional matrices used in support of residues studies;

(f) in soil, water, sediment, feed and any additional matrices used in support of ecotoxicology studies;

(g) in water, buffer solutions, organic solvents and any additional matrices used in the physical and chemical properties tests.

The specificity of the methods shall be determined and reported. Validated confirmatory methods shall be submitted if appropriate.

The linearity, recovery and precision (repeatability) of methods shall be determined and reported.

Data shall be generated at the LOQ and either the likely residue levels or ten times the LOQ. Where relevant, the LOQ shall be determined and reported for each analyte.

4.2. Methods for post-approval control and monitoring purposes

Methods, with a full description, shall be submitted for:

(a) the determination of all components included in the monitoring residue definition as submitted in accordance with the provisions of point 6.7.1 in order to enable Member States to determine compliance with established maximum residue levels (MRLs); they shall cover residues in or on food and feed of plant and animal origin;

(b) the determination of all components included for monitoring purposes in the residue definitions for soil and water as submitted in accordance with the provisions of point 7.4.2;

(c) the analysis in air of the active substance and relevant breakdown products formed during or after application, unless the applicant shows that exposure of operators, workers, residents or bystanders is negligible;

(d) the analysis in body fluids and tissues for active substances and relevant metabolites.

As far as practicable these methods shall employ the simplest approach, involve the minimum cost, and require commonly available equipment.

The specificity of the methods shall be determined and reported. It shall enable all components included in the monitoring residue definition to be determined. Validated confirmatory methods shall be submitted if appropriate.

The linearity, recovery and precision (repeatability) of methods shall be determined and reported.

Data shall be generated at the LOQ and either the likely residue levels or ten times the LOQ. The LOQ shall be determined and reported for each component included in the monitoring residue definition.

For residues in or on food and feed of plant and animal origin and residues in drinking water, the reproducibility of the method shall be determined by means of an independent laboratory validation (ILV) and reported.

SECTION 5

Toxicological and metabolism studies

Introduction

1. The relevance of generating toxicity data in animal models with dissimilar metabolic profiles to those found in humans shall be addressed, if such metabolic information is available, and taken into consideration for study design and risk assessment.

2. All potentially adverse effects found during toxicological investigations (including effects on organs/systems such as the immune system, the nervous system, or the endocrine system) shall be reported. Additional studies may be necessary to investigate the mechanisms underlying effects that could be critical to hazard identification or risk assessment.

All available biological data and information relevant to the assessment of the toxicological profile of the active substance tested, including modelling, shall be reported.

3. Where available, historical control data shall be provided routinely. The data submitted shall be for endpoints that could represent critical adverse effects, and shall be strain-specific and from the laboratory which carried out the index study. They shall cover a five-year period, centred as closely as possible on the date of the index study.

4. When preparing a study plan, available data on the test substance, such as its physico-chemical properties (such as volatility), purity, reactivity (such as rate of hydrolysis, electrophilicity) and structure-activity relationships of chemical analogues, shall be taken into account.

5. For all studies actual achieved dose in mg/kg body weight, as well as in other convenient units (such as mg/L inhalation, mg/cm2 dermal), shall be reported.

6. The analytical methods to be used in toxicity studies shall be specific for the entity to be measured and shall be adequately validated. The LOQ shall be adequate for the measurement of the range of concentration anticipated to occur in the generation of the toxicokinetic data.

7. Where, as a result of metabolism or other processes in or on treated plants, in livestock, in soil, in ground water, open air, or as a result of processing of treated products, the terminal residue to which humans will be exposed contains a substance which is not the active substance itself and is not identified as a significant metabolite in mammals, toxicity studies shall, where technically possible, be carried out on that substance unless it can be demonstrated that human exposure to that substance does not constitute a relevant risk to health.

Toxicokinetic and metabolism studies relating to metabolites and breakdown products shall only be required if toxicity findings of the metabolite cannot be evaluated by the available results relating to the active substance.

8. The oral route shall always be used if it is practical. In cases where exposure of humans is mainly by the gas phase, it can be more appropriate to perform some of the studies via inhalation.

9. For dose selection, toxicokinetic data such as saturation of absorption measured by systemic availability of substance and/or metabolites shall be taken into consideration.

5.1. Studies on absorption, distribution, metabolism and excretion in mammals

Information on blood and tissues concentration of the active substance and relevant metabolites, for example around the time to reach the maximum plasma concentration (Tmax), shall be generated in short and long-term studies on relevant species to enhance the value of the toxicological data generated in terms of understanding the toxicity studies.

The main objective of the toxicokinetic data is to describe the systemic exposure achieved in animals and its relationship to the dose levels and the time course of the toxicity studies.

Other objectives are:

(a) to relate the achieved exposure in toxicity studies to toxicological findings and contribute to the assessment of the relevance of these findings to human health, with a particular regard to vulnerable groups;

(b) to support the design of a toxicity study (choice of species, treatment regimen, selection of dose levels) with respect to kinetics and metabolism;

(c) to provide information which, in relation to the findings of toxicity studies, contributes to the design of supplementary toxicity studies as outlined in point 5.8.2;

(d) to compare the metabolism of rats with the metabolism in livestock as outlined in point 6.2.4.

5.1.1. Absorption, distribution, metabolism and excretion after exposure by oral route

Limited data restricted to one in vivo test species (normally rat) may be all that is required as regards absorption, distribution, metabolism and excretion after exposure by oral route. These data can provide information useful in the design and interpretation of subsequent toxicity tests. However, it shall be remembered that information on interspecies differences is crucial in extrapolation of animal data to humans and information on metabolism following administration via other routes may be useful in human risk assessments.

It is not possible to specify detailed data requirements in all areas, since the exact requirements will depend upon the results obtained for each particular test substance.

The studies shall provide sufficient information about the kinetics of the active substance and its metabolites in relevant species after being exposed to the following:

(a) a single oral dose (low and high dose levels);

(b) an intravenous dose preferably or, if available, a single oral dose with assessment of biliary excretion (low dose level); and

(c) a repeated dose.

A key parameter is systemic bioavailability (F), obtained by comparison of the area under the curve (AUC) after oral and intravenous dosing.

When intravenous dosing is not feasible a justification shall be provided.

The design of the kinetic studies required shall include:

(a) an evaluation of the rate and extent of oral absorption including maximum plasma concentration (Cmax), AUC, Tmax and other appropriate parameters, such as bioavailability;

(b) the potential for bioaccumulation;

(c) plasma half-lives;

(d) the distribution in major organs and tissues;

(e) information on the distribution in blood cells;

(f) the chemical structure and the quantification of metabolites in biological fluids and tissues;

(g) the different metabolic pathways;

(h) the route and time course of excretion of active substance and metabolites;

(i) investigations whether and to what extent enterohepatic circulation takes place.

Comparative in vitro metabolism studies shall be performed on animal species to be used in pivotal studies and on human material (microsomes or intact cell systems) in order to determine the relevance of the toxicological animal data and to guide in the interpretation of findings and in further definition of the testing strategy.

An explanation shall be given or further tests shall be carried out where a metabolite is detected in vitro in human material and not in the tested animal species.

5.1.2. Absorption, distribution, metabolism and excretion after exposure by other routes

Data on absorption, distribution, metabolism and excretion (ADME) following exposure by the dermal route shall be provided where toxicity following dermal exposure is of concern compared to that following oral exposure. Before investigating ADME in vivo following dermal exposure, an in vitro dermal penetration study shall be conducted to assess the likely magnitude and rate of dermal bioavailability.

Absorption, distribution, metabolism and excretion after exposure by the dermal route shall be considered on the basis of the above information, unless the active substance causes skin irritation that would compromise the outcome of the study.

Dermal absorption estimation from data generated in these studies on the active substance shall be critically assessed for relevance to humans. Dermal absorption measurement of the plant protection product is specifically considered under point 7.3 of Part A of the Annex to Regulation (EU) No 284/2013.

For volatile active substances (vapour pressure > 10–2 Pascal) absorption, distribution, metabolism and excretion after exposure by inhalation may be useful in human risk assessments.

5.2. Acute toxicity

The studies, data and information to be provided and evaluated shall be sufficient to permit the identification of effects following a single exposure to the active substance, and in particular to establish, or indicate:

(a) the toxicity of the active substance;

(b) the time course and characteristics of the effects with full details of behavioural changes, clinical signs, where evident, and possible gross pathological findings at post-mortem;

(c) the possible need to consider establishing acute reference doses (such as ARfD, aAOEL ( 11 ));

(d) where possible mode of toxic action;

(e) the relative hazard associated with the different routes of exposure.

While the emphasis shall be on estimating the toxicity ranges involved, the information generated shall also permit the active substance to be classified in accordance with Regulation (EC) No 1272/2008. The information generated through acute toxicity testing is of particular value in assessing hazards likely to arise in accident situations.

5.2.1. Oral

Circumstances in which required

The acute oral toxicity of the active substance shall always be reported.

5.2.2. Dermal

Circumstances in which required

The acute dermal toxicity of the active substance shall be reported unless waiving is scientifically justified (for example where oral LD50 ( 12 ) is greater than 2 000 mg/kg). Both local and systemic effects shall be investigated.

Findings of severe skin irritation (Grade 4 erythema or oedema) in the dermal study shall be used instead of performing a specific irritation study.

5.2.3. Inhalation

Circumstances in which required

The acute inhalation toxicity of the active substance shall be reported where any of the following apply:

— the active substance has a vapour pressure > 1 × 10 –2 Pa at 20 °C;

— the active substance is a powder containing a significant proportion of particles of a diameter < 50 μm ( > 1 % on weight basis);

— the active substance is included in products that are powders or are applied by spraying.

The head/nose only exposure shall be used, unless whole body exposure can be justified.

5.2.4. Skin irritation

The results of the study shall provide information on the potential for skin irritancy of the active substance including, where relevant, the potential reversibility of the effects observed.

Before undertaking in vivo studies for corrosion/irritation of the active substance, a weight-of-evidence analysis shall be performed on the existing relevant data. Where insufficient data are available, they can be developed through application of sequential testing.

The testing strategy shall follow a tiered approach:

(1) the assessment of dermal corrosivity using a validated in vitro test method;

(2) the assessment of dermal irritation using a validated in vitro test method (such as human reconstituted skin models);

(3) an initial in vivo dermal irritation study using one animal, and where no adverse effects are noted;

(4) confirmatory testing using one or two additional animals.

Circumstances in which required

The skin irritancy study of the active substance shall always be provided. Where available, a dermal toxicity study shown not to produce irritation of the skin at the limit test dose level of 2 000 mg/kg body weight shall be used to waive the need for any dermal irritation studies.

5.2.5. Eye irritation

The results of the study shall provide the potential of eye irritancy of the active substance including, where relevant, the potential reversibility of the effects observed.

Before undertaking in vivo studies for eye corrosion/irritation of the active substance, a weight-of-evidence analysis shall be performed on the existing relevant data. Where available data are considered insufficient, further data may be developed through application of sequential testing.

The testing strategy shall follow a tiered approach:

(1) the use of an in vitro dermal irritation/corrosion test to predict eye irritation/corrosion;

(2) the performance of a validated or accepted in vitro eye irritation study to identify severe eye irritants/corrosives (such as Bovine Corneal Opacity and Permeability (BCOP) assay, Isolated Chicken Eye (ICE) assay, Isolated Rabbit Eye (IRE) assay, Hen's Egg Test - Chorio-Allantoic Membrane assay (HET-CAM)), and where negative results are obtained, the assessment of eye irritation using an in vitro test method for identification of non-irritants or irritants, and where not available;

(3) an initial in vivo eye irritation study using one animal, and where no adverse effects are noted;

(4) confirmatory testing using one or two additional animals.

Circumstances in which required

The eye irritancy of the active substance shall always be tested, except where it is likely that severe effects on the eyes may be produced based on criteria listed in the test methods.

5.2.6. Skin sensitisation

The study shall provide sufficient information to assess the potential of the active substance to provoke skin sensitisation reactions.

Circumstances in which required

The study shall always be carried out, except where the active substance is a known sensitiser. The local lymph node assay (LLNA) shall be used, including where appropriate the reduced variant of the assay. In case the LLNA cannot be conducted, a justification shall be provided and the Guinea Pig Maximisation Test shall be performed. Where a guinea pig assay (Maximisation or Buehler), meeting OECD guidelines and providing a clear result, is available, further testing shall not be carried out for animal welfare reasons.

Since an active substance identified as a skin sensitiser can potentially induce hypersensitivity reaction, potential respiratory sensitisation should be taken into account when appropriate tests are available or when there are indications of respiratory sensitisation effects.

5.2.7. Phototoxicity

The study shall provide information on the potential of certain active substances to induce cytotoxicity in combination with light, for example active substances that are phototoxic in vivo after systemic exposure and distribution to the skin, as well as active substances that act as photoirritants after dermal application. A positive result shall be taken into account when considering potential human exposure.

Circumstances in which required

The in vitro study shall be required where the active substance absorbs electromagnetic radiation in the range 290-700 nm and is liable to reach the eyes or light-exposed areas of skin, either by direct contact or through systemic distribution.

If the Ultraviolet/visible molar extinction/absorption coefficient of the active substance is less than 10 L × mol–1 × cm–1, no toxicity testing is required.

5.3. Short-term toxicity

Short-term toxicity studies shall be designed to provide information as to the amount of the active substance that can be tolerated without adverse effects under the conditions of the study and to elucidate health hazards occurring at higher dose levels. Such studies provide useful data on the risks for those handling and using plant protection products containing the active substance, among other possible exposed groups. In particular, short-term studies provide an essential insight into possible repeated actions of the active substance and the risks to humans who may be exposed. In addition short-term studies provide information useful in the design of chronic toxicity studies.

The studies, data and information to be provided and evaluated, shall be sufficient to permit the identification of effects following repeated exposure to the active substance, and in particular to further establish, or indicate:

(a) the relationship between dose and adverse effects;

(b) toxicity of the active substance including where possible the No Observed Adverse Effect Level (NOAEL);

(c) target organs, where relevant (including immune, nervous and endocrine systems);

(d) the time course and characteristics of adverse effects with full details of behavioural changes and possible pathological findings at post-mortem;

(e) specific adverse effects and pathological changes produced;

(f) where relevant the persistence and reversibility of certain adverse effects observed, following discontinuation of dosing;

(g) where possible, the mode of toxic action;

(h) the relative hazard associated with the different routes of exposure;

(i) relevant critical endpoints at appropriate time points for setting reference values, where necessary.

Toxicokinetic data (that is to say blood concentration) shall be included in short term studies. In order to avoid increased animal use, the data may be derived in range finding studies.

If nervous system, immune system or endocrine system are specific targets in short term studies at dose levels not producing marked toxicity, supplementary studies, including functional testing, shall be carried out (see point 5.8.2).

5.3.1. Oral 28-day study

Circumstances in which required

Where available, 28-day studies shall be reported.

5.3.2. Oral 90-day study

Circumstances in which required

The short-term oral toxicity of the active substance to rodents (90-day), usually the rat, a different rodent species shall be justified, and non rodents (90-day toxicity study in dogs), shall always be reported.

In the 90-day study, potential neurotoxic and immunotoxic effects, genotoxicity by way of micronuclei formation and effects potentially related to changes in the hormonal system shall be carefully addressed.

5.3.3. Other routes

Circumstances in which required

For human risk assessment additional dermal studies shall be considered on a case by case basis, unless the active substance is a severe irritant.

For volatile active substances (vapour pressure >10–2 Pascal) expert judgement (for example based on route-specific kinetic data) shall be required to decide whether the short term studies have to be performed by inhalation exposure.

5.4. Genotoxicity testing

The aim of genotoxicity testing shall be to:

— predict genotoxic potential,

— identify genotoxic carcinogens at an early stage,

— elucidate the mechanism of action of some carcinogens.

Appropriate dose levels, depending on the test requirements, shall be used in either in vitro or in vivo assays. A tiered approach shall be adopted, with selection of higher tier tests being dependent upon interpretation of results at each stage.

Special testing requirements in relation to photomutagenicity may be indicated by the structure of a molecule. If the Ultraviolet/visible molar extinction/absorption coefficient of the active substance and its major metabolites is less than 1 000 L × mol–1 × cm–1, photomutagenicity testing is not required.

5.4.1. In vitro studies

Circumstances in which required

The following in vitro mutagenicity tests shall be performed: bacterial assay for gene mutation, combined test for structural and numerical chromosome aberrations in mammalian cells and test for gene mutation in mammalian cells.

However, if gene mutation and clastogenicity/aneuploidy are detected in a battery of tests consisting of Ames and in vitro micronucleus (IVM), no further in vitro testing needs to be conducted.

If there are indications of micronucleus formation in an in vitro micronucleus assay further testing with appropriate staining procedures shall be conducted to clarify if there is an aneugenic or clastogenic response. Further investigation of the aneugenic response may be considered to determine whether there is sufficient evidence for a threshold mechanism and threshold concentration for the aneugenic response (particularly for non-disjunction).

Active substances which display highly bacteriostatic properties as demonstrated in a range finding test shall be tested in two different in vitro mammalian cell tests for gene mutation. Non performance of the Ames test shall be justified.

For active substances bearing structural alerts that have given negative results in the standard test battery, additional testing may be required if the standard tests have not been optimised for these alerts. The choice of additional study or study plan modifications depends on the chemical nature, the known reactivity and the metabolism data on the structurally alerting active substance.

5.4.2. In vivo studies in somatic cells

Circumstances in which required

If all the results of the in vitro studies are negative, at least one in vivo study shall be done with demonstration of exposure to the test tissue (such as cell toxicity or toxicokinetic data), unless valid in vivo micronucleus data are generated within a repeat dose study and the in vivo micronucleus test is the appropriate test to be conducted to address this information requirement.

A negative result in the first in vivo test in somatic cells shall provide sufficient reassurance for active substances that are negative in the three in vitro tests.

For active substances for which an equivocal or a positive test result is obtained in any in vitro test, the nature of additional testing needed shall be considered on a case-by-case basis taking into account all relevant information using the same endpoint as in the in vitro test.

If the in vitro mammalian chromosome aberration test or the in vitro micronucleus test is positive for clastogenicity, an in vivo test for clastogenicity using somatic cells such as metaphase analysis in rodent bone marrow or micronucleus test in rodents shall be conducted.

If the in vitro micronucleus test for numerical chromosome aberrations on mammalian cells is positive or the in vitro mammalian chromosome test is positive for numerical chromosome changes, an in vivo micronucleus test shall be conducted. In case of positive result in the in vivo micronucleus assay, appropriate staining procedure such as fluorescence in-situ hybridisation (FISH) shall be used to identify an aneugenic and/or clastogenic response.

If either of the in vitro gene mutation tests is positive, an in vivo test to investigate the induction of gene mutation shall be conducted, such as the Transgenic Rodent Somatic and Germ Cell Gene Mutation Assay.

When conducting in vivo genotoxicity studies, only relevant exposure routes and methods (such as admixture to diet, drinking water, skin application, inhalation and gavage) shall be used. There shall be convincing evidence that the relevant tissue will be reached by the chosen exposure route and application method. Other exposure techniques (such as intraperitoneal or subcutaneous injection) that are likely to result in abnormal kinetics, distribution and metabolism shall be justified.

Consideration shall be given to conducting an in vivo test as part of one of the short-term toxicity studies described under point 5.3.

5.4.3. In vivo studies in germ cells

Circumstances in which required

The necessity for conducting these tests shall be considered on a case by case basis, taking into account information regarding toxicokinetics, use and anticipated exposure.

For most of the active substances recognised as in vivo somatic cell mutagens no further genotoxicity testing shall be necessary since they will be considered to be potential genotoxic carcinogens and potential germ cell mutagens.

However, in some specific cases germ cells studies may be undertaken to demonstrate whether a somatic cell mutagen is or is not a germ cell mutagen.

The type of mutation produced in earlier studies namely gene, numerical chromosome or structural chromosome changes, shall be considered when selecting the appropriate assay.

A study for the presence of DNA adducts in gonad cells may also be considered.

5.5. Long-term toxicity and carcinogenicity

The results of the long-term studies conducted and reported, taken together with other relevant data and information on the active substance, shall be sufficient to permit the identification of effects, following repeated exposure to the active substance, and in particular shall be sufficient to:

— identify adverse effects resulting from long-term exposure to the active substance,

— identify target organs, where relevant,

— establish the dose-response relationship,

— establish the NOAEL and, if necessary, other appropriate reference points.

Correspondingly, the results of the carcinogenicity studies taken together with other relevant data and information on the active substance, shall be sufficient to permit the evaluation of hazards for humans, following repeated exposure to the active substance, and in particular shall be sufficient:

(a) to identify carcinogenic effects resulting from long-term exposure to the active substance;

(b) to establish the species, sex, and organ specificity of tumours induced;

(c) to establish the dose-response relationship;

(d) where possible, to identify the maximum dose eliciting no carcinogenic effect;

(e) where possible, to determine the mode of action and human relevance of any identified carcinogenic response.

Circumstances in which required

The long-term toxicity and carcinogenicity of all active substances shall be determined. If in exceptional circumstances it is claimed that such testing is unnecessary, that claim shall be fully justified.

Test conditions

A long-term oral toxicity study and a long-term carcinogenicity study (two years) of the active substance shall be conducted using rat as test species; where possible these studies shall be combined.

A second carcinogenicity study of the active substance shall be conducted using mouse as test species, unless it can be scientifically justified that this is not necessary. In such cases, scientifically validated alternative carcinogenicity models may be used instead of a second carcinogenicity study.

If comparative metabolism data indicate that either rat or mouse is an inappropriate model for human cancer risk assessment, an alternative species shall be considered.

Experimental data, including the elucidation of the possible mode of action involved and relevance to humans, shall be provided where the mode of action for carcinogenicity is considered to be non-genotoxic.

Where submitted, historical control data shall be from the same species and strain, maintained under similar conditions in the same laboratory and shall be from contemporaneous studies. Additional historical control data from other laboratories may be reported separately as supplementary information.

The information on historical control data provided shall include:

(a) identification of species and strain, name of the supplier, and specific colony identification, if the supplier has more than one geographical location;

(b) name of the laboratory and the dates when the study was performed;

(c) description of the general conditions under which animals were maintained, including the type or brand of diet and, where possible, the amount consumed;

(d) approximate age, in days, and weight of the control animals at the beginning of the study and at the time of killing or death;

(e) description of the control group mortality pattern observed during or at the end of the study, and other pertinent observations (such as diseases, infections);

(f) name of the laboratory and the examining scientists responsible for gathering and interpreting the pathological data from the study;

(g) a statement of the nature of the tumours that may have been combined to produce any of the incidence data.

The historical control data shall be presented on a study by study basis giving absolute values plus percentage and relative or transformed values where these are helpful in the evaluation. If combined or summary data are submitted, these shall contain information on the range of values, the mean, median and, if applicable, standard deviation.

The doses tested, including the highest dose tested, shall be selected on the basis of the results of short-term testing and where available at the time of planning the studies concerned, on the basis of metabolism and toxicokinetic data. Dose selection should consider toxicokinetic data such as saturation of absorption measured by systemic availability of active substance and/or metabolites.

Doses, causing excessive toxicity shall not be considered relevant to evaluations to be made. Determination of blood concentration of the active substance (for example around Tmax) shall be considered in long-term studies.

In the collection of data and compilation of reports, incidence of benign and malignant tumours shall not be combined. Dissimilar, un-associated tumours, whether benign or malignant, occurring in the same organ, shall not be combined for reporting purposes.

In the interests of avoiding confusion, conventional histopathological terminology commonly used when the study is conducted such as that published by the International Agency for Research on Cancer shall be used in the nomenclature and reporting of tumours. The system used shall be identified.

Biological material selected for histopathological examination shall include material selected to provide further information on lesions identified during gross pathological examination. Where relevant to the elucidation of mechanism of action and available, special histological (staining) techniques, histochemical techniques and electron microscopic examinations, might be of value, and when conducted, shall be reported.

5.6. Reproductive toxicity

Possible effects on reproductive physiology and the development of progeny shall be investigated and reported concerning the following aspects:

— Impairment of male and female reproductive functions or capacity, for example from effects on oestrus cycle, sexual behaviour, any aspect of spermatogenesis or oogenesis, or hormonal activity or physiological response which would interfere with the capacity to fertilise, fertilisation itself or development of the fertilised ovum up to and including implantation.

— Harmful effects on the progeny, for example any effect interfering with normal development, both before and after birth. This includes morphological malformations such as anogenital distance, nipple retention, and functional disturbances (such as reproductive and neurological effects).

Effects accentuated over generations shall be reported.

The active substance and its relevant metabolites shall be measured in milk as a second tier investigation where relevant effects are observed in the offspring or are expected (for example from a range-finding study).

Potential neurotoxic, immunotoxic effects and effects potentially related to changes in the hormonal system shall be carefully addressed and reported.

Investigations shall take account of all available and relevant data, including the results of general toxicity studies if relevant parameters (such as semen analysis, oestrous cyclicity, reproductive organ histopathology) are included, as well as knowledge concerning structural analogues to the active substance.

While the standard reference point for treatment responses shall be concurrent control data, historical control data may be helpful in the interpretation of particular reproductive studies. Where submitted, historical control data shall be from the same species and strain, maintained under similar conditions in the same laboratory and shall be from contemporaneous studies.

The information on historical control data provided shall include:

(a) identification of species and strain, name of the supplier, and specific colony identification, if the supplier has more than one geographical location;

(b) name of the laboratory and the dates when the study was performed;

(c) description of the general conditions under which animals were maintained, including the type or brand of diet and, where possible, the amount consumed;

(d) approximate age, in days, and weight of the control animals at the beginning of the study and at the time of killing or death;

(e) description of the control group mortality pattern observed during or at the end of the study, and other pertinent observations (such as diseases, infections);

(f) name of the laboratory and the examining scientists responsible for gathering and interpreting the pathological data from the study.

The historical control data shall be presented on a study by study basis giving absolute values plus percentage and relative or transformed values where these are helpful in the evaluation. If combined or summary data are submitted, these shall contain information on the range of values, the mean, median and, if applicable, standard deviation.

In order to provide useful information in the design and interpretation of developmental toxicity studies, information on blood concentration of the active substance in parents and foetus/offspring may be included in higher tier studies and reported.

5.6.1. Generational studies

The generational studies reported, taken together with other relevant data and information on the active substance, shall be sufficient to permit the identification of effects for reproduction, following repeated exposure to the active substance, and in particular shall be sufficient:

(a) to identify direct and indirect effects on reproduction resulting from exposure to the active substance;

(b) to identify any non-reproductive adverse effects occurring at lower doses than in short-term and chronic toxicity testing;

(c) to establish the NOAELs for parental toxicity, reproductive outcome and pup development.

Circumstances in which required

A reproduction toxicity study in rats over at least two generations shall be reported.

The OECD extended one-generation reproductive toxicity study may be considered as an alternative approach to the multi-generation study.

Where necessary for a better interpretation of the effects on reproduction and as far as this information is not yet available, supplementary studies may be required to provide information on the affected gender and the possible mechanisms.

5.6.2. Developmental toxicity studies

The developmental toxicity studies reported, taken together with other relevant data and information on the active substance, shall be sufficient to permit the assessment of effects on embryonic and foetal development, following repeated exposure to the active substance, and in particular shall be sufficient:

(a) to identify direct and indirect effects on embryonic and foetal development resulting from exposure to the active substance;

(b) to identify any maternal toxicity;

(c) to establish the relationship between observed responses and dose in both dam and offspring;

(d) to establish NOAELs for maternal toxicity and pup development;

(e) to provide additional information on adverse effects in pregnant as compared with non-pregnant females;

(f) to provide additional information on any enhancement of general toxic effects of pregnant animals.

Circumstances in which required

Developmental toxicity studies shall always be carried out.

Test conditions

Developmental toxicity shall be determined for rat and rabbit by the oral route; the rat study shall not be conducted if developmental toxicity has been adequately assessed as part of an extended one-generation reproductive toxicity study.

Additional routes may be useful in human risk assessment. Malformations and variations shall be reported separately and combined in such a way that all relevant changes which are observed to occur in characteristic patterns in individual foetuses or those that can be considered to represent different grades of severity of the same type of change are reported in a concise manner.

Diagnostic criteria for malformations and variations shall be given in the report. The glossary of terminology under development by the International Federation of Teratology Societies shall be considered where possible.

When indicated by observations in other studies or the mode of action of the test substance, supplementary studies or information may be required to provide information on the postnatal manifestation of effects such as developmental neurotoxicity.

5.7. Neurotoxicity studies

5.7.1. Neurotoxicity studies in rodents

Neurotoxicity studies in rodents shall provide sufficient data to evaluate the potential neurotoxicity of the active substance (neurobehavioural and neuropathological effects) after single and repeated exposure.

Circumstances in which required

Such studies shall be performed for active substances with structures that are similar or related to those capable of inducing neurotoxicity, and for active substances which induce specific indications of potential neurotoxicity, neurological signs or neuropathological lesions in toxicity studies at dose levels not associated with marked general toxicity. Performance of such studies shall also be considered for substances with a neurotoxic mode of pesticidal action.

Consideration shall be given to including neurotoxicity investigations in routine toxicology studies.

5.7.2. Delayed polyneuropathy studies

Delayed polyneuropathy studies shall provide sufficient data to evaluate if the active substance may provoke delayed polyneuropathy after acute and repeated exposure. A repeated exposure study may be waived unless there are indications that the compound accumulates and significant inhibition of neuropathy target esterase or clinical/histopathological signs of delayed polyneuropathy occur at around the hen LD50 as determined in the single dose test.

Circumstances in which required

These studies shall be performed for active substances of similar or related structures to those capable of inducing delayed polyneuropathy such as organophosphorus compounds.

5.8. Other toxicological studies

5.8.1. Toxicity studies of metabolites

Supplementary studies, where they relate to substances other than the active substance, are not a routine requirement. Decisions as to the need for supplementary studies shall be made on a case by case basis.

Where as a result of metabolism or other processes, metabolites from plants or in animal products, soil, groundwater, open air differ from those in animals used for the toxicology studies or are detected in low proportions in animals, further testing shall be carried out on a case by case basis, taking into account the amount of metabolite and the chemical structure of the metabolite compared to the parent.

5.8.2. Supplementary studies on the active substance

Supplementary studies shall be carried out where they are necessary to further clarify observed effects taking into account the results of the available toxicological and metabolism studies and the most important exposure routes. Such studies may include:

(a) studies on absorption, distribution, excretion and metabolism, in a second species;

(b) studies on the immunotoxicological potential;

(c) a targeted single dose study to derive appropriate acute reference values (ARfD, aAOEL);

(d) studies on other routes of administration;

(e) studies on the carcinogenic potential;

(f) studies on mixture effects.

Studies required shall be designed on an individual basis, in the light of the particular parameters to be investigated and the objectives to be achieved.

5.8.3. Endocrine disrupting properties

If there is evidence that the active substance may have endocrine disrupting properties, additional information or specific studies shall be required:

— to elucidate the mode/mechanism of action,

— to provide sufficient evidence for relevant adverse effects.

Studies required shall be designed on an individual basis and taking into account Union or internationally agreed guidelines, in the light of the particular parameters to be investigated and the objectives to be achieved.

5.9. Medical data

Where available and without prejudice to Article 10 of Council Directive 98/24/EC ( 13 ), practical data and information relevant to the recognition of the symptoms of poisoning and on the effectiveness of first aid and therapeutic measures shall be submitted. Such data and information shall include reports of any studies investigating antidote pharmacology or safety pharmacology. Where relevant, the effectiveness of potential antagonists to poisoning shall be investigated and reported.

Data and information relevant to the effects of human exposure, where available, shall be used to confirm the validity of extrapolations made and conclusions reached with respect to target organs, dose-response relationships, and the reversibility of adverse effects. Such data may be generated following accidental, occupational e