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

• — 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 ([^E0013]), 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 exposure or incidents of intentional self-poisoning, and shall be reported if available.

5.9.1.   Medical surveillance on manufacturing plant personnel and monitoring studies

Reports of occupational health surveillance programs and of monitoring studies shall be submitted, supported with detailed information on the design of the programme, the number of exposed persons included in the programme, the nature of their exposure to the active substance, and their exposure to other potentially hazardous agents. Such reports shall, where feasible, include data relevant to the mechanism of action of the active substance. These reports shall, where available, include data from persons exposed in manufacturing plants, or during or after application of the active substance (for example from monitoring studies in operators, workers, residents, bystanders or victims of accidents). Available information on adverse health effects including allergenic responses in workers and others exposed to the active substance, shall be provided, and include where relevant details of any incident. The information provided shall, where available, include details of frequency, level and duration of exposure, symptoms observed and other relevant clinical information.

5.9.2.   Data collected on humans

Where available, reports from studies with humans, such as tests on toxicokinetics and metabolism, or tests on skin irritation or skin sensitisation, shall be submitted.

In general, the reference values shall be based on animal studies, but if appropriate scientifically valid and ethically generated human data are available and show that humans are more sensitive and lead to lower regulatory limit values, these data shall take precedence over animal data.

5.9.3.   Direct observations

Available reports from the open literature, relating to clinical cases and poisoning incidents, where they are from refereed journals or official reports, shall be submitted together with reports of any follow-up studies undertaken. Such reports shall, where available, contain complete descriptions of the nature, level and duration of exposure, as well as the clinical symptoms observed, first aid and therapeutic measures applied and measurements and observations made.

Where supported with the necessary level of detail, such documentation shall be used to confirm the validity of extrapolations from animal data to man and to identify unexpected adverse effects which are specific to humans.

5.9.4.   Epidemiological studies

Relevant epidemiological studies shall be submitted, where available.

5.9.5.   Diagnosis of poisoning (determination of active substance, metabolites), specific signs of poisoning, clinical tests

Where available, detailed description of the clinical signs and symptoms of poisoning, including the early signs and symptoms and full details of clinical tests useful for diagnostic purposes shall be provided including full details of the time courses involved relevant to the ingestion, dermal exposure or inhalation of varying amounts of the active substance.

5.9.6.   Proposed treatment: first aid measures, antidotes, medical treatment

First aid measures to be used in the event of poisoning (actual and suspected) and in the event of contamination of eyes shall be provided. Therapeutic regimes for use in the event of poisoning or contamination of eyes, including where available the use of antidotes, shall be described in full. Information based on practical experience, where it exists and is available, in other cases on theoretical grounds, as to the effectiveness of alternative treatment regimes, where relevant, shall be provided. Contraindications associated with particular regimes, particularly those relating to 'general medical problems' and conditions, shall be described.

5.9.7.   Expected effects of poisoning

Where known, the expected effects and the duration of these effects following poisoning shall be described. That description shall include the impact of:

• — the type, level and duration of exposure, or ingestion, and

• — varying time periods between exposure, or ingestion, and commencement of treatment.

SECTION 6

Residues in or on treated products, food and feed

6.1.   Storage stability of residues

Studies concerning storage stability of residues shall investigate the stability of residues in plants, plant products and products of animal origin during storage prior to analysis.

Circumstances in which required

Provided that samples are frozen within 24 hours after sampling and unless a compound is otherwise known to be volatile or labile, stability data shall not be required for samples extracted and analysed within 30 days from sampling (six months in the case of radio-labelled material).

The stability of extracts shall be investigated if extracts are not analysed immediately.

Test conditions

Studies with non-radio-labelled active substances shall be carried out with representative substrates. They may be either performed on samples from treated crops or animals with incurred residues or by fortification experiments. In the latter case, aliquots of prepared control samples shall be spiked with a known amount of chemical before storage under normal storage conditions.

The studies shall address stability of individual components of the residue definition relevant to risk assessment, which may require spiking different samples with different analytes. In case of different analytical targets (for example targeting either single compounds or a common moiety) more than one set of storage stability data may be needed.

The duration of the stability studies shall be suitable to address the length over which the samples or extracts have been stored in the corresponding studies.

Detailed information with respect to the sample preparation and storage conditions (temperature and duration) of samples and extracts shall be submitted. Where the degradation during storage is significant (more than 30%) a change in the storage conditions or not storing the samples prior to analysis shall be considered. All studies where unsatisfactory storage conditions were used shall be repeated.

Storage stability data using sample extracts shall also be required unless samples are analysed within 24 hours of extraction.

Results shall be presented as absolute values in mg/kg and not adjusted by recovery, as well as percentage of nominal spike value.

6.2.   Metabolism, distribution and expression of residues

Data on metabolism representative for existing or intended good agricultural practices (GAPs) shall be provided, together with a schematic diagram of the metabolic pathways in plants and animals with a brief explanation of the distribution and chemical reactions involved. These studies shall be conducted with one or more radio-labelled forms of the active substance and, where relevant, stereoisomer forms of the active substance and its metabolites. For plant extracts, a different approach may be taken if adequately justified.

For plants, the objectives of these studies shall be:

• (a) to provide an estimate of total terminal residues in the relevant portion of crops at harvest following treatment as proposed;

• (b) to identify the major components of the total terminal residue;

• (c) to indicate the distribution of residues between relevant crops parts;

• (d) to quantify the major components of the residue and to show the efficiency of extraction procedures for these components;

• (e) to characterise and quantify conjugated and bound residues;

• (f) to indicate the components to be analysed for in residue quantification studies (crop residue studies).

For food producing animals, the objectives of these studies shall be:

• (a) to provide an estimate of total terminal residues in edible animal products;

• (b) to identify the major components of the total terminal residue in edible animal products;

• (c) to indicate the distribution of residues between relevant edible animal products;

• (d) to provide evidence whether or not a residue should be classified as fat soluble;

• (e) to quantify the total residue in certain animal products (milk or eggs) and excreta;

• (f) to quantify the major components of the residue and to show the efficiency of extraction procedures for these components;

• (g) to characterise and quantify conjugated and bound residues;

• (h) to indicate the components to be analysed for in residue quantification studies (livestock feeding studies);

• (i) to generate data from which a decision on the need for feeding studies on food producing animals can be made.

The results of the metabolism study conducted with poultry, normally laying hens, shall be extrapolated to all food producing poultry whereas the results of the metabolism study conducted with ruminants, normally lactating goats and, where necessary, with pigs, shall be extrapolated to all food producing mammals.

Metabolites not found in the ADME studies or that cannot be explained as intermediates, but identified in metabolism/transformation studies (plant, food producing animals, processing and rotational crops) shall be considered relevant for the consumer risk assessment, unless it can be demonstrated by scientific evidence (such as structure-activity relationship, toxicological bridging studies) that, also in view of their concentration, they cause no potential risks to the consumer.

6.2.1.   Plants

Circumstances in which required

Studies on plants shall be performed unless no part of the plants or plant products will be used as food or feed material or unless a ‘zero’ residue situation applies (such as bait applications).

Test conditions

The intended method of application (such as seed treatment, soil/foliar spraying, dipping, fogging) and the properties of the active substance (such as systemic properties or volatility) shall be taken into account when planning metabolism studies. Metabolism studies have to involve crops from different categories of crops in which plant protection products containing the active substance in question would be used. For this purpose crops shall be considered as falling into one of the following categories:

• (a) fruit (code F);

• (b) root crops (code R);

• (c) leafy crops (code L);

• (d) cereal/grass crops (code C/G);

• (e) pulses and oilseeds (code P/O);

• (f) miscellaneous.

The category ‘miscellaneous’ shall only be used on a case by case basis.

A metabolism study shall be submitted for each type of crop group for which use is proposed. In order to extrapolate results from metabolism studies with an active substance to all crop groups, metabolism studies on a minimum of three representative crops (from the different crop groups except ‘miscellaneous’) shall be conducted. If the results of these three studies indicate a comparable metabolic route (qualitatively and to a lesser extent quantitatively), then additional studies shall not be needed. If the results from the available studies from three of these categories indicate that the route of degradation is not similar in all three categories, studies from the remaining categories except ‘miscellaneous’ shall be provided.

If authorisation is sought for one crop group only, metabolism studies in one crop from that crop group shall be sufficient as long as the crop is truly representative of the crop group and the metabolic pathway is elucidated.

The studies shall reflect the intended use pattern of the active ingredient such as foliar, soil/seed or post-harvest treatments. If, for instance, three studies have been conducted using foliar application and at a later date soil application (such as seed treatment, granular or soil drench) is proposed, then at least one additional study reflecting soil application shall be conducted. The applicant shall discuss with the national competent authorities the possible replacement of a foliar study with a post-harvest study.

An evaluation of the results from different studies shall be submitted on:

• (a) the site of uptake (for example via leaves or roots);

• (b) the formation of metabolites and breakdown products;

• (c) the distribution of residues between relevant parts of the crop at harvest (with particular emphasis on food and feed);

• (d) the metabolic pathways.

If studies show that the active substance or relevant metabolites or breakdown products are not taken up by the crop, a rationale shall be given.

6.2.2.   Poultry

Circumstances in which required

Metabolism studies on poultry shall be provided where the plant protection product is to be used in crops whose parts or products, also after processing, are fed to poultry and where the intake is expected to exceed 0,004 mg/kg bw/day ([^E0014]).

Test conditions

Studies shall be carried out in laying hens.

Dose rates shall be at least equivalent to the likely maximum daily exposure resulting from all intended uses.

If the identification of metabolites cannot be carried out with dose rates of 10 mg/kg feed (dry matter), higher doses may be used.

If no feeding studies are carried out, plateau levels in eggs shall be demonstrated in the metabolism study taking into account that plateau levels usually occur no later than 14 days from the beginning of dosing in laying poultry.

6.2.3.   Lactating ruminants

Circumstances in which required

Metabolism studies on lactating ruminants shall be provided where the plant protection product is to be used in crops whose parts or products, also after processing, are fed to ruminants and where the intake is expected to exceed 0,004 mg/kg bw/day.

Test conditions

Studies shall be carried out in lactating goats, where available, or in lactating cows as an alternative.

Dose rates shall at least be equivalent to the likely maximum daily exposure resulting from all intended uses.

If the identification of main metabolites cannot be carried out with dose rates of 10 mg/kg feed (dry matter), higher doses may be used.

If no feeding studies are carried out, plateau levels in milk shall be demonstrated in the metabolism study taking into account that plateau levels usually occur five to seven days after the beginning of dosing in lactating ruminants.

6.2.4.   Pigs

Circumstances in which required

Metabolism studies on pigs shall be provided where the plant protection product is used in crops whose parts or products, also after processing, are fed to pigs and where it becomes apparent that metabolic pathways differ significantly in the rat as compared to ruminants and where the intake is expected to exceed 0,004 mg/kg bw/day.

Test conditions

Studies shall be carried out in pigs.

Dose rates shall at least be equivalent to the likely maximum daily exposure resulting from all intended uses.

If the identification of metabolites cannot be carried out with dose rates of 10 mg/kg feed (dry matter), higher doses may be used.

The duration of this study shall be the same as for lactating ruminants.

6.2.5.   Fish

Circumstances in which required

Metabolism studies on fish may be required where the plant protection product is used in crops whose parts or products, also after processing, are fed to fish and where residues in feed may occur from the intended applications.

Results from studies provided for under point 8.2.2.3 may be used if it can be demonstrated with scientific evidence that the results of these studies may be assumed to be equivalent. Special consideration shall be given to the different routes of ingestion.

6.3.   Magnitude of residue trials in plants

The objectives of magnitude of residue trials in plants shall be the following:

• — to quantify the highest likely residue levels of all components of the different residue definitions in treated crops, at harvest or outloading from store, in accordance with the proposed GAP, and

• — to determine, where appropriate, the decline rate of plant protection product residues in plants.

Circumstances in which required

These studies shall always be performed where the plant protection product is to be applied to plants or plant products that are used as food or feed or where residues from soil or other substrates can be taken up by such plants except where extrapolation from adequate data on another crop is possible.

When planning residue trials, it shall be borne in mind that information on the residues in ripe or unripe crops may be of interest with respect to the risk assessment in other areas like ecotoxicology or worker safety.

Test conditions

Supervised residue trials shall correspond to the proposed critical GAP. The test conditions (such as maximum number of proposed applications, shortest interval between applications, maximum application rate and concentration, most critical safety intervals ([^E0015]) with regard to exposure) shall be defined to identify the highest residues which may reasonably arise and shall be representative of the realistic conditions at the critical GAP in which the active substance is to be used.

When establishing a supervised residue trial programme, factors such as main growing areas and the range of conditions, likely to be encountered in the main growing areas concerned shall be considered.

Differences in agricultural production methods (for example outdoor versus indoor uses), seasons of production and types of formulations shall be taken into account.

For the evaluation of residue behaviour and the setting of maximum residue levels (MRLs) according to Regulation (EC) No 396/2005, the Union shall be divided into two zones, a Northern European and a Southern European zone. For the purpose of use in greenhouses, as post-harvest treatment and for treatment of empty storage rooms, one residue zone shall apply.

The number of trials necessary is difficult to determine before the evaluation of their results. Assuming all other variables having an impact on the residue levels are comparable, the minimum number of trials shall vary for each residue zone between a minimum of 4 trials for a minor crop and a minimum of 8 trials for a major crop.

However, if the GAP is the same in both residue zones, 6 trials equally distributed in the representative growing zones are normally sufficient for a minor crop.

The number of studies to be performed may be reduced if residue trials show that the residue levels in plants or plant products are lower than the LOQ. The number of trials shall not be below the minimum of three per zone for minor crops and four per zone for major crops.

In cases were a ‘zero’ residue situation is predicted from representative plant metabolism studies, three trials shall be performed for commodities significant in diet. No trials shall be required for commodities insignificant in diet. A ‘zero’ residue situation shall be predicted where no detectable residues occur in studies with exaggerated application rates compared to the envisaged ones.

Provided that conditions are comparable and that trials are widely spread over different zones, it shall be sufficient to carry out trials over one growing season.

Part of the trials may be replaced by trials performed outside the Union, provided that they correspond to the critical GAP and that the production conditions (such as cultural practices, climatic conditions) are comparable.

Trials showing the residue behaviour in post-harvest treatments shall be carried out at different locations with different cultivars. A set of trials shall be carried out for each application method and storage condition, unless the worst case residue situation can be clearly identified.

Where a plant protection product has both a field use and an indoor use with the same GAP, a full data package shall be submitted for both situations, unless it is already accepted that one use is the critical GAP.

It shall be checked on a case-by-case basis, taking into account plant morphology and application conditions, whether extrapolation from the crop used for the metabolism study to other crops belonging to the same crop group is possible.

Where a significant part of the consumable commodity is present at the time of application, half of the supervised residue trials reported shall include data to show the effect of time on the level of residue present (residue decline studies), unless the consumable part is not exposed during application of the plant protection product under the proposed conditions of use. For crops harvested after blossom (such as fruits or fruiting vegetables) a significant part of the consumable crop is present from full blossom (BBCH 65) onwards. In case of most crops from which leafy parts are harvested (for example lettuce), this condition is satisfied if 6 true leaves, leaf pairs or whorls are unfolded (BBCH 16).

In case of an active substance for which an ARfD has been derived, the distribution of residues among single units may be investigated through variability studies. If a sufficient number of results is available, the default variability factor may be replaced by a specific factor derived from these studies.

6.4.   Feeding studies

The objective of feeding studies shall be to determine residues in products of animal origin which result from residues in feed.

The results from a feeding study conducted with laying hens shall be extrapolated to all food producing poultry. The results from a feeding study with lactating cows and, where necessary, with pigs shall be extrapolated to all food producing mammals.

Circumstances in which required

Feeding studies shall be provided where metabolism studies indicate that residues at levels of above 0,01 mg/kg may occur in edible animal tissue, milk, eggs or fish, taking into account the residue levels in potential feeding stuffs, obtained at the 1 × dose rate, calculated on the dry weight basis.

Feeding studies shall not be required where intake is below 0,004 mg/kg bw/day, except in cases where the residue, that is to say the active substance, its metabolites or breakdown products, as defined in the residue definition for risk assessment, tends to accumulate.

6.4.1.   Poultry

Poultry feeding studies shall be carried out in laying hens. For each treatment regime chosen a minimum of nine chickens should be treated.

In general, the feed shall be administered in three dosages (first dose = expected residue level). The animals shall be dosed for a minimum of 28 days or until plateau level is reached in eggs.

6.4.2.   Ruminants

Ruminant feeding studies shall be carried out in lactating cows. For each treatment regime chosen, a minimum of three dairy cows shall be treated.

In general, the feed shall be administered in three dosages (first dose = expected residue level). The animals shall be dosed for a minimum of 28 days or until plateau level is reached in milk.

6.4.3.   Pigs

Where it appears from the metabolism studies that metabolic pathways differ significantly in pigs as compared to ruminants, a pig feeding study may be conducted. For each treatment regime chosen a minimum of three pigs shall be treated.

In general, the feed shall be administered in three dosages (first dose = expected residue level). The animals shall be dosed for at least the same time as ruminants.

6.4.4.   Fish

A fish feeding study may be required where residues at levels above 0,01 mg/kg may be reasonably expected in edible tissues, based on the findings of the fish metabolism study and the estimated maximum residues which might occur in fish feed. Particular attention should be laid on lipophilic substances with an intrinsic tendency for accumulation.

6.5.   Effects of processing

6.5.1.   Nature of the residue

The objective of studies on the nature of the residue shall be to establish whether or not breakdown or reaction products arise from residues in the raw agricultural commodity during processing, which may require a separate risk assessment.

Circumstances in which required

Studies on the nature of residues in processing shall be provided where residues in products of plant or animal origin subject to processing may occur at a level of or higher than 0,01 mg/kg (based on the residue definition for risk assessment for the raw commodity). No studies shall, however, be required in the following cases:

• — substances with a water solubility < 0,01 mg/L;

• — only simple physical operations, not involving a change in temperature of the commodity are carried out, such as washing, trimming or pressing; or

• — the distribution of residues between pulp and inedible peel is the only effect of processing.

Test conditions

Depending upon the expected level and chemical nature of the residue in the product of plant or animal origin, a set of representative hydrolysis situations simulating the relevant processing operations shall be investigated, where appropriate. Consideration shall also be given to the effects of processes other than hydrolysis and the potential for the formation of toxicologically significant breakdown products.

The studies shall be conducted with one or more radio-labelled forms of the relevant substance.

6.5.2.   Distribution of the residue in inedible peel and pulp

The objectives of studies concerning distribution of the residue in inedible peel and pulp shall be:

• — to determine the quantitative distribution of residues between inedible peel and pulp,

• — to estimate peeling factors, and

• — to allow a more realistic estimation of dietary intake of residues.

Circumstances in which required

These studies shall be provided for plant products where the peel is either inedible (such as melons, bananas) or is very rarely entirely eaten by consumers (such as citrus fruit).

Test conditions

These studies shall be performed as part of supervised residue trials, the number of results reported depending on the number of residue trials conducted. Special attention shall be paid to possible contamination of the pulp. Precautionary measures shall be taken in order to quantify a realistic highest residue level.

6.5.3.   Magnitude of residues in processed commodities

The main objectives of studies concerning magnitude of residues in processed commodities shall be:

• — to determine the quantitative distribution of residues in the various processed commodities used as food or feed,

• — to estimate processing factors, and

• — to allow a more realistic estimation of dietary intake of residues.

Circumstances in which required

The following points shall be taken into consideration when deciding whether it is necessary to carry out processing studies:

• (a) the dietary burden of a processed product in the human (such as apples) or animal diet (such as apple pomace);

• (b) the level of residue in the plant or plant product to be processed (normally ≥ 0,1 mg/kg);

• (c) the physical and chemical properties of the active substance and its relevant metabolites (such as fat-solubility in case of oil seed processing); and

• (d) the possibility that breakdown products of toxicological significance may occur after processing of the plant or plant product.

If the level of residues is less than 0,1 mg/kg, processing studies shall be carried out if the contribution of the commodity under consideration to the theoretical maximum daily intake (TMDI) is ≥ 10 % of the ADI or if the estimated daily intake is ≥ 10 % of the ARfD for any European consumer group diet.

Processing studies shall not be required if plants or plant products are exclusively used raw (unprocessed) for food and feed purposes.

In some cases, a simple calculation shall be sufficient to determine the processing factor such as concentration from dehydration or dilution factors, as long as the process under consideration is not expected to have an influence on the nature of residues.

Industrial processing

If the properties of the active substance, the impurity or the metabolite, as appropriate, indicate that it might concentrate in a given processed fraction, then a processing study shall be necessary even in situations where the residue in the plant or plant product to be processed is lower than 0,1 mg/kg. In such cases, exaggerated application rates up to 5 × or shortened PHIs shall be applied where necessary to achieve a quantifiable residue in the plant or plant product to be processed. A processing study shall not be required if exaggerated application rates (up to 5 ×) fail to yield a quantifiable residue in the plant or plant product to be processed. Phytotoxicity shall be considered when contemplating exaggerated rate treatments.

Domestic processing

For domestic or home transformation processes and minor industrial ones, when no residues are found at or above 0,1 mg/kg in the raw agricultural commodity at recommended GAP from supervised field trials conducted at the maximum label rate and minimum PHI, no processing studies shall be required.

Test conditions

Processing studies shall represent domestic preparations (for example cooked vegetables) or commercial industrial processes (for example production of apple juice). Processing studies shall be carried out at least on a representative crop of a crop group, where use is envisaged. The choice of the crop and of the process shall be justified and explained.

The technology used in processing studies shall correspond as closely as possible to the actual conditions that are normally used. For each crop to be investigated two studies per process shall be carried out to determine concentration and dilution factors in processed commodities. If more than one processing method is in use, the one which is expected to give the highest residues in the processed product for human consumption shall be chosen. The results shall be extrapolated to all crops within a crop group undergoing the same process.

When the results (processing factor) of the two studies differ in the main processed products by more than 50 %, further studies shall be provided to derive a consistent processing factor.

Additional studies shall be carried out if, when using processing factors derived by extrapolation, the estimate of the dietary intake exceeds the ADI or ARfD. Those studies shall be carried out on major processes and commodities which contribute most to the ADI/ARfD exceedance.

6.6.   Residues in rotational crops

Studies concerning residues in rotational crops shall be performed to allow the determination of the nature and extent of potential residue accumulation in rotational crops from soil uptake and of the magnitude of residues in rotational crops under realistic field conditions.

Rotational crop studies shall not be required for uses of plant protection products in permanent crops (such as citrus and pome fruits crop group), semi-permanent crops (such as asparagus, pineapples) or fungi, where rotations on the same substrate are not part of the normal agricultural practices.

6.6.1.   Metabolism in rotational crops

The objectives of metabolism studies in rotational crops shall be:

• (a) to provide an estimate of the total terminal residues in the relevant portion of crops at harvest of rotational crops following treatment of the preceding crop as proposed;

• (b) to identify the major components of the total terminal residue;

• (c) to indicate the distribution of residues between relevant crop parts;

• (d) to quantify the major components of the residue;

• (e) to indicate additional components to be analysed for in residue quantification studies (field crop rotation studies);

• (f) to decide on restrictions in crop rotation; and

• (g) to decide on the necessity of field residue trials in rotational crops (limited field studies).

Circumstances in which required

Metabolism studies in rotational crops shall be provided if the parent compound or soil metabolites are persistent in soil or significant concentrations of metabolites in soil occur.

Rotational crop metabolism studies shall not be required if worst case conditions can be appropriately represented by other available studies in treated crops in accordance with point 6.2.1, where the plant protection product was applied directly to the soil (for example as a pre-planting or pre-emergence application).

Test conditions

Metabolism studies shall at least involve three crops from three different groups of crops: root and tuber vegetables, leafy vegetables and cereals. Data from further crop groups may be relevant for MRL setting. These crops shall be planted into soil treated at the recommended maximum total application rate for the preceding crops after an appropriate plant-back interval that mimics crop failure early in the vegetation of the crop, crop rotation in the same vegetation period or year and crop rotation in the next vegetation period or year.

6.6.2.   Magnitude of residues in rotational crops

The objectives of studies on residues in rotational crops shall be:

• (a) to permit an evaluation of the magnitude of residues in rotational crops;

• (b) to decide on restrictions in crop rotation;

• (c) to provide information for assessing the overall significance of the residues for dietary risk assessment; and

• (d) to decide on the necessity of MRLs for rotational crops.

Circumstances in which required

If the metabolism studies indicate that residues of the active substance or of relevant metabolites or breakdown products either from plant or soil metabolism may occur (> 0,01 mg/kg), limited field studies and, if necessary, field trials shall be carried out.

Studies shall not be required in the following cases:

• — no metabolism studies on rotational crops are to be performed, or

• — metabolism studies on rotational crops show that no residues of concern are to be expected in rotational crops.

Test conditions

A tiered approach shall be adopted to fulfil the above mentioned objectives. In the first tier, limited field studies at two sites in major growing areas shall be conducted. The plant protection product for which authorisation is sought or a very similar formulation shall be used.

No further studies shall be required where, based on the result from the first tier studies, no detectable residues (< 0,01 mg/kg) in rotational crops are to be expected or if in metabolism studies no residues requiring risk assessment are observed.

For the second tier, additional data shall be submitted to enable appropriate evaluation of dietary risks and establishment of MRLs. These studies shall cover the common crop rotation practice. They shall be performed taking into account the requirements under point 6.3. Trials shall be conducted as closely as possible to agricultural practice on representative crops from major crop groups. At least four trials per crop shall be conducted across the Union in one year. These trials shall be performed in the main production areas across the Union at the highest application rate for the preceding crops. If annual applications of persistent active substances result in higher plateau concentrations in soil than a single application, the plateau concentration shall be taken into account. The necessary residue trials data shall be set up in consultation with the national competent authorities in the Member States.

6.7.   Proposed residue definitions and maximum residue levels

6.7.1.   Proposed residue definitions

The following elements shall be considered when judging which compounds are to be included in the residue definition:

• — the toxicological significance of the compounds,

• — the amounts likely to be present, and

• — the analytical methods proposed for post-approval control and monitoring purposes.

Two different residue definitions may be needed: one for enforcement purposes, based on the marker concept, and one for risk assessment purposes, taking into account toxicologically relevant compounds.

Analytical work in residue trials and feeding studies shall cover all the components of the residue definition for risk assessment.

6.7.2.   Proposed maximum residue levels (MRLs) and justification of the acceptability of the levels proposed

A maximum residue level shall be provided for all products of plant and animal origin covered by Regulation (EC) No 396/2005. In all other cases of products of plant and animal origin used as food or feed and in case of tobacco and medical herbs, a guideline level, that is to say a level derived on the same principles used for MRL setting, shall be provided.

For processed products processing factors shall be provided, unless no processing studies are required.

Furthermore, supervised trials median residue (STMR) and highest residue (HR) values shall be derived and, in cases where processing factors are proposed, STMR-P and HR-P values.

In exceptional cases, when the conditions laid down in Article 16(1) to Regulation (EC) No 396/2005 are met, MRLs may be proposed on the basis of monitoring data. In such cases the proposal shall cover the 95^th percentile of the data population at the 95 % confidence level.

6.7.3.   Proposed maximum residue levels (MRLs) and justification of the acceptability of the levels proposed for imported products (import tolerance)

Point 6.7.2 shall apply to MRLs proposed for imported products (import tolerances).

6.8.   Proposed safety intervals

Safety intervals (that is to say pre-harvest intervals for envisaged uses, or withholding periods or storage periods, in the case of post-harvest uses) shall be set taking into account the pest to be controlled and the results from the residue trial data. These intervals shall last at least one day.

6.9.   Estimation of the potential and actual exposure through diet and other sources

When estimating the exposure it shall be born in mind that the risk assessment has to take into account the residue definition established for risk assessment.

Where relevant, the possible presence of pesticide residues arising from sources other than current plant protection uses of active substances (for example use of active substances resulting in common metabolites, use as biocide or veterinary drug), and their aggregate exposure shall be taken into account. In addition, the cumulative exposure to more than one active substance shall, where relevant, be considered.

6.10.   Other studies

6.10.1.   Residue level in pollen and bee products

The objective of these studies shall be to determine the residue in pollen and bee products for human consumption resulting from residues taken up by honeybees from crops at blossom.

The type and conditions of the studies to be performed shall be discussed with the national competent authorities.

SECTION 7

Fate and behaviour in the environment

7.1.   Fate and behaviour in soil

All relevant information on the type and the properties of the soil used in the studies, including pH, organic carbon content, particle size distribution and water holding capacity shall be reported.